Professional Documents
Culture Documents
Practical Algorithms in Pediatric Hematology and Oncology PDF
Practical Algorithms in Pediatric Hematology and Oncology PDF
Series Editor
Practical Algorithms in Pediatrics
Professor, Pediatric Endocrinology
Meyer Children’s Hospital
Haifa, Israel
Introduction
Algorithms are practical tools to The algorithms addressing hemato- As with any approach that attempts
help us address diagnostic and thera- logic disorders also concentrate on di- to simplify complex problems, there
peutic problems in a logical, efficient agnosis, but include issues of man- will always be exceptions. Each algo-
and cost-effective fashion. Practical agement of conditions such as sickle rithm must be used in the context of
Algorithms in Pediatric Hematology cell anemia, hemophilia and red blood the individual findings of each patient
and Oncology uses this approach to cell transfusions. under examination and in conjunction
assist the clinician caring for children The format is designed to provide with the current published literature.
with blood disorders and possible as much information as possible. The The clinician must always be aware
malignancies. The book is designed diagnostic algorithms sequentially that any individual patient’s presenta-
for the general practitioner and pedia- move to specific diagnoses, and when tion may be atypical enough, or con-
trician who are not exposed to these space allows, to therapy. To provide a founded by concomitant disorders or
problems on a daily basis as well as better sense of which diagnoses are complications, to render our aproach-
residents and trainees in Pediatrics more likely, very common diagnoses es invalid. In addition, advances in di-
and Pediatric Hematology and Oncol- causing each problem are noted in agnosis and management can render
ogy. bold text, the usually larger number current approaches obsolete.
In addressing oncologic problems, of common diagnoses in standard We hope you will find the book
our goal is to efficiently determine font and rare diagnoses in italics. No helpful in managing the children un-
whether children have malignant or algorithm can contain every possible der your care.
benign disorders, and to establish the diagnosis; many rare diagnoses are
specific diagnosis. Details of specific not included while others may be list-
therapeutic regimens for malignant ed in the algorithm but not the text. Richard H. Sills, MD
disorders are not addressed because Cross-references to other algorithms
they should be determined individual- make the book easier to use. An ap-
ly in consultation with a pediatric on- pendix of age-dependent normal val-
cologist. Algorithms also address the ues and a convenient list of all abbre- My thanks to all the students,
management of complications which viations used are also provided. residents, attending physicians and
may occur at the time of clinical pres- staff at Albany Medical College
3 who graciously took the time to
entation, such as superior vena cava
syndrome, febrile neutropenia, and tu- review and edit the algorithms, and
mor lysis syndrome as well as an ap- to Irene and Sara for their support
proach to recognizing the late effects and love.
of treatment. I dedicate this book to the memory
of my father, Sidney Sills.
Red Cell Disorders R.H. Sills · A. Deters Initial evaluation of anemia
햲 햲
Initial
X evaluation of anemia
4 WBC – Absolute neutrophil count – Platelets – Blood smear 햳
& WBC 7 WBC + 7 ANC 7 WBC +/or ANC 7 Platelets & Platelets 햴
± shift to left 햴 7 Platelets Nl WBC/ANC
Blood smear
DCT 햽
(see ‘Thrombocytosis’,
(see ‘Leukocytosis’, p 38) p 62)
Nl platelet
count
(see ‘Consumptive
MCV
coagulopathy’, p 68)
TEC 햶 Shwachman-Diamond Drug induced Acute bacterial Acute or Collagen vascular Evans syndrome 햾
syndrome 햷 infection 햹 chronic viral disorder 햻
illness 햺
Microcytic anemia
6 RBC indices
Blood smear
7 Fe intake or blood loss 햲 ± Family Hx of anemia or Chronic illness or + Target cells & Pb level Rare disorders
7 RBC, & RDW ± 7 MCHC thalassemia infection + Family Hx
Anisocytosis Mediterranean/Asian/African African/Asian
Mild ovalocytosis ancestry 햵 ancestry
± dimorphic population
Trial oral Fe 햳 & RBC, Nl or Hepatosplenomegaly Fe, TIBC, TS, ferritin Hb electrophoresis
minimal & RDW Hb <9 g/dl (1.4 mmol/l)
Hb >
_ 9 g/dl (1.4 mmol/l) Severe hypochromia
No hepatosplenomegaly Anisopoikilocytosis
Target cells Target cells
± basophilic stippling Normoblastemia
& Hb Hb fails to &
Continue Fe therapy 햴
햲 –– Iron deficiency anemia (IDA) is most
쏹 쏹 –– Hepatosplenomegaly, more severe
햶 쏹 –– There are several rare etiologies of
햺
common in infants and young children with anemia (typically Hb <9.0 g/dl, 1.4 mmol/l) and microcytosis. The hereditary sideroblastic
poor Fe intake (often cow’s milk intake of a more severe hypochromia are consistent anemias are a rare heterogenous group of
liter or more daily), but with malnutrition it is with -thalassemia major or -thalassemia disorders characterized by anemia, reticulo-
seen at any age. Blood loss should always be intermedia, but are not expected in either ␣- cytopenia and abnormal patterns of iron
considered, but is more likely in older children or -thalassemia trait. Hb levels can be as high deposition in marrow erythroblasts. Protein
and particularly in adolescent girls. An under- as 10.0 g/dl (1.51 mmol/l) in Hb H disease. calorie malnutrition usually causes normo-
lying bleeding disorder, such as von Wille- Normoblastemia, the presence of nucleated cytic/normochromic anemia but it can cause
brand disease, can cause excessive blood loss. erythrocytes in peripheral blood, is prominent microcytosis without IDA. There are a number
Typical findings of IDA are 7 RBC and & RDW. in severe forms of -thalassemia. However, of metabolic defects of Fe absorption and
Smear reveals hypochromia, microcytosis, and small numbers of normoblasts may be seen in metabolism, but they are very rare.
often ovalocytes. A dimorphic population severe anemia of any etiology.
(microcytic hypochromic cells mixed with
normocytic, normochromic cells) is commonly 쏹 –– The anemia of chronic disease can be
햷 Selected reading
present early in the disease or following the associated with any severe infection or
Chui DH, Wage JS: Hydrops fetalis caused
onset of Fe therapy. inflammatory disorder. It is usually normocytic,
by alpha thalassemia: An emerging health
but microcytosis occurs in 20–30% of patients.
care problem. Blood 1998;91:2213–2222.
쏹 –– The diagnosis of IDA is usually estab-
햳 Anemia is usually fairly mild with Hb levels
lished by a successful trial of oral Fe therapy. 2–3 g/dl (0.31–0.47 mmol/l) below expected Clark M, Royal J, Seeler R: Interaction of
Use ferrous sulfate in a dose of 2–3 mg/kg/day normals for age. The combinations of a low iron deficiency and lead and the hematolog-
of elemental Fe (10–15 mg/kg/day of ferrous serum iron and TIBC, with an elevated ferritin, ic findings in children with severe lead
sulfate) divided t.i.d.; doses of up to 6 mg/ are typical and help to differentiate it from IDA. poisoning. Pediatrics 1988;81:247–254.
kg/day of elemental Fe are used for severe
Glader BE, Look KA: Hematologic
Fe deficiency to increase the Hb to safer levels 쏹 –– Homozygous hemoglobin C or E disease,
햸
disorders in children from Southeast Asia.
more quickly. If there is no response in E-thalassemia and sickle thalassemia are asso-
Pediatr Clin N Am 1996;43:665–681.
2–3 weeks, see the algorithm for failure of ciated with 7 MCV and prominent numbers of
IDA to respond to Fe. The etiology of the Fe target erythrocytes. These are also seen in E Kwiatkowski JL, West TB, Heidary N,
deficiency is usually apparent and measure- trait, but without anemia. Rare unstable hemo- Smith-Whitely K: Severe iron deficiency in
ments of serum Fe (7), TIBC (&), TS (7), and globins may be associated with microcytic ane- young children. J Pediatr 1999;135:514–516.
ferritin (7) are not usually necessary. mia and the Hb electrophoresis may be nor-
Schwartz J, Landrigan PJ, Baker EL, et al:
mal; they are suspected with hemolysis of
Lead-induced anemia: Dose-response
쏹 –– Fe treatment is usually continued for at
햴 unidentified etiology. Hb stability studies can
relationships and evidence for a threshold.
least 3–4 months to correct the anemia and establish this diagnosis.
Am J Publ Hlth 1990;80;165–168.
rebuild Fe stores. Changes in diet (particularly
a decrease in cow’s milk intake) and manage- 쏹 –– Microcytic anemia in Pb poisoning is
햹
ment of blood loss, when appropriate, are more often due to concomitant IDA and not the
necessary to prevent recurrence. Pb poisoning itself; anemia is a late sign of
Pb poisoning. Basophilic stippling is often but
쏹 –– Mediterranean, Asian or African ancestry
햵 not consistently present.
is not universal, but is usually present. The
Mentzer index (MCV/RBC) may be helpful to
differentiate thalassemia minor. In IDA the
index is generally >13, whereas in thalassemia
7
trait it is usually <13.
Normocytic anemia
8 Evaluate clinical and laboratory evidence of blood loss 햲 Nl reticulocytes
Indirect bilirubin Nl indirect bilirubin
Reticulocyte count No blood loss
Blood smear
Nl Abnormal
7 Fe and TIBC
& ferritin
Reassess
Recent/ongoing Protein-calorie Anemia of Anemia of Anemia of Anemia of TEC 햺 IDA Early megaloblastic
hemorrhage malnutrition pregnancy 햵 infection renal disease chronic DBA anemia or combined
disease 햸 Acquired pure IDA + megaloblastic
RBC aplasia anemia
Macrocytic anemia
10 RBC indices
Blood smear
Macro-ovalocytosis No macro-ovalocytosis
PMN hypersegmentation No PMN hypersegmentation
Anemia Nl Hgb or
7 B12 level 7 folate Nl B12 and folate only mildly 7
Nl B12
Bone marrow
Megaloblastic anemia aspirate
not due to vitamin and biopsy
deficiency
Spurious
Pure RBC Hypocellular & MCV
Appropriate Drug No implicated
aplasia & Hgb F
drug Hx drugs
± congenital
anomalies
B12 deficiency Folate Drug-induced Rare Reticulo- Diamond- Fanconi Rare Cold agglutinins Drugs
deficiency megaloblastic disorders cytosis Blackfan anemia findings Hyperglycemia Congenital heart
anemia anemia
Leukocytosis disease
Down syndrome
Hypothyroidism
Liver disease
Identify cause Identify Consider if Evaluate for Corticosteroid Confirmed with Asplenia
R/O pernicious cause
drug can be hemolysis, Rx lymphocyte chromosomal
anemia Rx folate discontinued blood loss, analysis ± DNA studies
Rx B12 deficiency recovering aplasia
–– Megaloblastic anemia, most commonly due to B12 or
–– Megaloblastic anemias unrelated to vitamin deficien-
–– Spurious macrocytosis is most often due to cold agglu-
folate deficiency, is the result of impaired DNA synthesis. cies or drugs are rare and may be congenital (deficiency of tinins which cause RBCs clumped together to be counted as a
It is critical to differentiate the megaloblastic anemias from the transcobalamin II or intrinsic factor, other metabolic defects single cell; the same artifact decreases the RBC. Warming the
other etiologies of macrocytosis. Hypersegmented neutrophils or congenital dyserythropoietic anemia), or acquired (myelo- sample normalizes the MCV. This cold agglutinin effect often
(>
_ 5% of PMNs with 5 nuclear lobes and > _ 1% with 6 lobes) are dysplastic syndrome, alcoholism). BMA and BMB may be occurs in the absence of hemolysis or anemia. Extreme hy-
found in 98% of patients with megaloblastic hematopoiesis. necessary to exclude myelodysplastic syndrome. perglycemia and leukocytosis occasionally cause spurious
The combination of macro-ovalocytosis and neutrophil hy- macrocytosis.
persegmentation has a specificity of 96–98% and a positive –– Even without macro-ovalocytosis and hypersegmenta-
predictive value of 94% for either folate or B12 deficiency in tion, B12 (particularly important given its neurologic compli- –– A number of disorders, most associated with no or min-
studies in adults. In the absence of malnutrition, megaloblas- cations) and folate levels should be obtained if an obvious imal anemia, can alter RBC size. Normal neonates are often
tic anemia is uncommon in children; no cases of folate or B12 etiology for the macrocytosis is not identified. mistakenly identified as macrocytic because the normal MCV
deficiency were observed in 146 American children evaluated of a full-term neonate is 98–118 fl. Drugs can cause isolated
because of macrocytosis. –– Reticulocytes are approximately 20% larger than mature
macrocytosis, including those that usually cause obvious
RBCs so a substantially elevated reticulocyte count increases megaloblastic changes. Congenital heart disease (usually
–– Serum folate reflects recent intake while RBC folate
the overall MCV of an otherwise normocytic RBC population. cyanotic) and, independently, Down syndrome are also
reflects longer term intake and is a more reliable indicator of associated with macrocytosis; the mechanism by which this
folate deficiency. Serum B12 levels are usually diagnostic. –– Anemic children who have true macrocytic, non-
occurs is not well understood. Excessive membrane lipids
megaloblastic anemia usually have diminished or abnormal can cause macrocytosis, usually without anemia, in hypo-
–– B12 deficiency is most commonly caused by pernicious
erythropoiesis so both BMA and BMB are generally indicated. thyroidism, liver disease and after splenectomy. In these in-
anemia, but may also be due to ileal disease, malabsorption, stances, the RBCs have a larger surface area causing them to
vegan diet, and fish tapeworm. The most common etiology
–– Diamond-Blackfan anemia is congenital RBC aplasia,
spread more widely on blood smears, but this may not be as-
in infancy may be selective malabsorption of cobalamin which usually presents in the first 3 months of life. Most are sociated with an actual increase in measured volume (MCV).
(Imerslund-Gräsbeck disease). macrocytic especially if diagnosed after the first months of
life. Associated congenital malformations are common. Most
–– It is critical to exclude B12 deficiency in megaloblastic
patients require long-term corticosteroid therapy. TEC is not a Selected reading
patients because of its potential irreversible neurologic macrocytic process unless recovery is occurring with a reticu-
Bessman JD, Banks D: Spurious macrocytosis:
damage. Combined deficiency occurs, so even if folate levels locytosis.
A common clue to erythrocyte cold agglutinins.
are low B12 levels must be determined as well. Treatment of
Am J Clin Pathol 1980;74:797–800.
B12 deficiency with folate may correct the hematologic find- –– Fanconi anemia does not usually present with isolated
ings and the patient’s improvement can mask the progression anemia, but the macrocytosis often precedes other hemato- Holt JT, DeWandler MJ, Arvan DA: Spurious elevation
of neurologic disease. If the diagnosis is not certain, normal logic changes. Congenital anomalies are typical but are ab- of the electronically determined mean corpuscular
serum methylmalonic acid and total homocysteine levels sent in approximately 25% of patients. Marrow hypoplasia is volume and hematocrit caused by hyperglycemia.
effectively exclude B12 deficiency; a normal homocysteine usually noted, but hyperplasia with dyserythropoiesis (disor- Am J Clin Pathol 1982;77:561–567.
alone suggests that it is not folate deficiency. dered cell development) can be seen. Hb F is &. The most Lindenbaum J: Status of laboratory testing in the
utilized diagnostic finding is enhanced chromosomal break- diagnosis of megaloblastic anemia. Blood 1983;61:
–– Folate deficiency can be due to drugs (e.g. phenytoin,
ages in peripheral blood lymphocytes stimulated in culture. 624–627.
barbiturates, valproate, methotrexate, trimethoprim), mal- Other rare bone marrow failure syndromes, such as dyskera-
nutrition, malabsorption, diet of goat’s milk, alcoholism, and tosis congenita, should be considered if Fanconi anemia is McPhedran P, et al: Interpretation of electronically
increased cell turnover (hemolysis, pregnancy). excluded. determined macrocytosis. Ann Intern Med 1973;78:
677–783.
–– Drug-induced macrocytic anemias are the most com-
–– Other rare marrow disorders associated with macro-
Pappo AS, Fields BW, Buchanan GR: Etiology of red
mon etiology of macrocytosis in children in industrialized na- cytosis include myelodysplasia, dyserythropoiesis and side- blood cell macrocytosis during childhood: Impact of new
tions. The pathogenesis is not always clear, but it is likely due roblastic anemia. MDS is diagnosed on the basis of myelo- diseases and therapies. Pediatrics 1992;89:1063–1070.
to megaloblastic changes and/or marrow injury. The drugs dysplastic changes in the marrow; the finding of a clonal
11 most commonly involved are chemotherapeutic agents (e.g. chromosomal abnormality in a majority of patients is useful Rasmussen SA, Fernhoff PM, Scanlon KS:
6-mercaptopurine and hydroxyurea), but also anticonvulsants confirmation. Dyserythropoietic changes suggest the rare di- Vitamin B12 deficiency in children and adolescents.
(most often carbamazepine, valproic acid, phenytoin, pheno- agnosis of congenital dyserythropoietic anemia. Sideroblastic J Pediatr 2001;138:10–17.
barbital), zidovudine, immunosuppressive agents and sulfa anemias demonstrate a ring of iron staining which surrounds
drugs. the nucleus; some hereditary forms are associated with
macrocytosis.
햲
Pancytopenia
12 Red cell indices
Blood smear
Reticulocytes – indirect bilirubin
Clinical evidence + DCT Splenomegaly 햶 Chronic hemolysis Nl MCV 햺 MCV & MCV Macro-ovalocytosis 햿
of sepsis and/or ± spherocytes ± hemoglobinuria Hypersegmentation PMN
shock Liver disease
Portal hypertension
BMA/BMB 햹 BMA/BMB 햹
– +
Sepsis 햴 Autoimmune Hypersplenism PNH 햷 Leukemia Infection 햻 Aplastic Fanconi anemia 헀 B12 Folate MDS
pancytopenia 햵 Lymphoma anemia 햽 Dyskeratosis deficiency deficiency Other 헂
Neuroblastoma congenita
LCH
Antibiotics Probable Determine underlying etiology Osteopetrosis
Supportive care corticosteroids R/O portal hypertension Other solid tumors
R/O DIC
쏹 –– Pancytopenia consists of leukopenia, anemia and
햲 (nucleated erythrocytes), more immature neutrophils, tear- 쏹 –– Pancytopenia is common in children with mega-
햿
thrombocytopenia; if the WBC is normal, but the absolute drop-shaped RBCs, and giant platelets. This is usually due loblastic anemia. The simplest initial screen for megaloblas-
neutrophil count is decreased (neutropenia), the patient to malignant replacement but is also caused by benign tic anemia in the macrocytic patient is to review the periph-
should still be considered pancytopenic. More than 1/3 of conditions such as osteopetrosis, storage disease, infection, eral smear. Hypersegmented neutrophils (> _ 5% of PMNs
the children with acute lymphoblastic anemia have a nor- myeloproliferative disorders, severe hemolytic disease, with 5 lobes and > _ 1% with 6 lobes) are found in 98% of
mal WBC, but most are neutropenic. thalassemia major and hypoxia. Bone marrow examination patients with megaloblastic anemias. The combination of
should be performed. macro-ovalocytosis and hypersegmentation has a specifici-
쏹 –– Evidence for hemolysis: indirect hyperbilirubinemia,
햳 ty of 96–98% and the positive predictive value for either
reticulocytosis, abnormal smear (e.g., anisocytosis, RBC 쏹 –– When examining the bone marrow, an aspirate is
햹 folate or B12 deficiency is ~94% in adult studies.
fragmentation, spherocytosis, elliptocytosis), & RDW always done; in addition to more routine morphologic
(reflecting the variation in cell size with & numbers of studies, including special stains, samples for chromosomal 쏹 –– Fanconi anemia is an autosomal-recessive disorder
헀
larger reticulocytes and overall variation in cell size), and flow cytometric analysis should be obtained. Unless in which aplastic anemia develops later in the first decade.
7 haptoglobulin, hemoglobinuria (if the hemolysis is intra- a diagnosis of leukemia is strongly suspected, a bone The MCV is often >100 fl even before anemia develops.
vascular), and & LDH (also & in many malignancies). marrow biopsy should also be done to provide information Most patients have dysmorphic features which are present
concerning cellularity, myelofibrosis, infiltrative processes at birth. The hypersensitivity of chromosomes to diepoxy-
쏹 –– Sepsis can cause pancytopenia due to both
햴 and storage diseases. butane (DEB) establishes the diagnosis. Other rarer congen-
diminished production and/or increased destruction. ital aplastic anemias may be macrocytic, including dysker-
DIC should be considered in critically ill children. 쏹 –– Bone marrow examination should be strongly
햺 atosis congenita.
considered in these children. If the pancytopenia is mild
쏹 –– Concomitant AIHA, ITP and autoimmune neutropenia
햵 and consistent with a transient infection, marrow 헁 –– Serum B12 levels are generally reliable but assays of
쏹
occurs occasionally and the direct Coombs test is almost examination can be deferred. RBC folate are more accurate than serum levels.
always positive. It may occur in isolation or in association
with collagen vascular disorders, particularly SLE. 쏹 –– Many viral and bacterial illnesses cause pancyto-
햻 쏹 –– Megaloblastic anemias can occur in the absence
헂
penia, but the marrow is rarely aplastic and recovery of deficiencies of folate or B12 and include myelodysplasia,
쏹 –– Hypersplenism can result in mild-to-moderate (but
햶 usually coincides with resolution of the infection. Examples drug-induced changes (e.g. zidovudine, hydroxyurea),
rarely severe) pancytopenia from a combination of splenic include EBV, CMV, HIV, brucellosis, tuberculosis, Q fever, congenital dyserythropoietic anemia, and metabolic defects
sequestration and hemolytic anemia. Splenomegaly is and Legionaires disease. of folate or B12 metabolism (e.g. methylmalonic acidurias).
usually prominent and its etiology is evident. Chronic liver
disease and/or portal hypertension should be considered. 쏹 –– Aplastic anemia is idiopathic in approximately 3/4 of
햽
Disorders such as cavernous transformation of the patients. Most others are drug- (chloramphenicol, gold Selected reading
portal vein may present with only pancytopenia and/or compounds and non-steroidal anti-inflammatory agents
Alter BP, Young NS: The bone marrow failure
splenomegaly. most clearly implicated) or toxin-induced (most often
syndromes; in Nathan DG, Orkin SH (eds):
benzene), related to infection (most often hepatitis not
Hematology of Infancy and Childhood, ed 5.
쏹 –– Paroxysmal nocturnal hemoglobinuria is a rare
햷 usually associated with a specific type), constitutional
Philadelphia, Saunders, 1998, p 239.
acquired clonal disorder which typically presents with (Fanconi anemia, Shwachman-Diamond syndrome), and,
chronic hemolytic anemia. It can also cause varying very rarely, PNH. Altschuler S (ed): Pediatric Medicine, Emedicine, 2002
degrees of marrow aplasia so it should be considered in (available at http://www.emedicine.com) has several
the child with pancytopenia and a reticulocytosis. The 쏹 –– Rare findings include myelodysplasia or myelofibro-
햾 chapters on anemia useful as references.
traditional screening tests (sucrose hemolysis test and sis. Myelodysplasia is an acquired clonal disorder of the Schwartz CL, Cohen HT: Preleukemic syndromes
Ham test) should be replaced by specific flow cytometric bone marrow characterized by abnormal maturation of one and other syndromes predisposing to leukemia.
analysis for deficient CD55 or CD59. or more hematopoietic cell lines. Chromosomal analysis Pediatr Clin North Am 1988;35:653–871.
of BMA is abnormal in 50–80%. Myelofibrosis is diagnosed
쏹 –– Blasts in peripheral blood are consistent with
햸 by special staining of bone marrow biopsy specimens.
13
leukemia. Leukoerythroblastosis (myelophthisic anemia) It is very rare in children but when it occurs it is usually in
is less common in children and usually results from bone toddlers with trisomy 21 and represents a form of acute
marrow invasion. Anemia may be accompanied by several megakaryoblastic leukemia.
findings in peripheral blood, including erythroblasts
Anemia in the neonate
14 CBC Indirect bilirubin
RBC indices Blood smear
Reticulocytes Direct Coombs
Reticulocytes <2%
Nl indirect bilirubin
Reticulocytes usually >5–8% Direct Coombs +
Direct Coombs negative Reticulocytes >5–8%
& Indirect bilirubin
(see ‘Neonatal anemia
due to impaired RBC
production’, p 16)
& Indirect bilirubin ABO and Rh type infant and
Nl blood smear Abnormal smear mother
Nl bilirubin Specificity anti-RBC antibody
Sick infant
Evidence of Shock Nonspecific Specific smear Mother type O Infant Rh+ No ABO/Rh
infection Hypoxia blood smear abnormalities Baby A or B Mother Rh– incompatibility
Acidosis Anti-A or -B Ab + anti-Rh Ab Elute RBC
antibody
Iatrogenic G6PD testing
blood loss
– +
Blood loss Viral infections DIC Viral illness G6PD ABO disease
ABO Rh Minor blood
Bacterial infections Rare deficiency Hereditary spherocytosis disease disease group incom-
Fungal infections etiologies Hereditary elliptocytosis patibility
Protozoal infections Hereditary pyropoikilocytosis
Hereditary stomatocytosis
MAHA
Malaria
␣-Thalassemia trait Blood loss and Acute and Infection 햷 Neuroblastoma DBA 햹 Megaloblastic
Hb H disease 햳 resulting iron chronic disease 햶 Congenital leukemia Rare diagnoses anemia 햻
deficiency LCH
Osteopetrosis
(see ‘Thalassemia’, p 24)
햲 –– MCV normally varies with postnatal age
쏹 햸 –– Bone marrow replacement is uncommon
쏹
as well as gestational age. The lower limit of in the neonate. It is most often caused by Selected reading
normal in cord blood at term is 98, 95 in the neuroblastoma and congenital leukemia, but is Blanchette VS, Zipurskey A: Assessement of
first 3 days from capillary samples and 88 at also seen with Langerhans cell histiocytosis anemia in newborn infants. Clin Perinatol
1 week of age. (which is particularly severe in neonates) and 1984;11:489–510.
osteopetrosis. Aplastic anemia in the neonate
햳 –– ␣-Thalassemias manifest in the neonate
쏹 is very rare; most forms of hereditary aplastic Christensen RD: Hematologic Problems of
because both Hb A and F contain ␣ chains. anemia, such as Fancon’s anemia, present later the Neonate. Philadelphia, Saunders, 2000.
Note that hydrops fetalis (which will be clinical- in life. Gallagher PG, Ehrenkrenz RA: Nutritional
ly obvious) and Hb H disease are almost never anemias in infancy. Clin Perinatol 1995;22:
seen in people of African descent. 햹 –– With no evident etiology for more severe
쏹 671–692.
or persistent anemia, Diamond-Blackfan ane- Ohls RK, Hunter DD, Christensen RD:
쏹 –– Chronic blood loss, usually prenatal,
햴 mia (congenital hypoplastic anemia) should A randomized, placebo-controlled trial of
causes iron deficiency and associated micro- be considered. Bone marrow aspirate reveals recombinant erythropoietin as treatment for
cytosis. It is most often due to feto-maternal virtual absence of erythroid precursors. Other the anemia of bronchopulmonary dysplasia.
hemorrhage, twin-twin transfusions and pla- forms of hypoplastic anemia in neonates are J Pediatr 1993;123:996.
centae previa. The reticulocyte count is often rare and include drug-induced RBC aplasia,
decreased because iron deficiency inhibits Aase syndrome (associated with skeletal ano- Quirolo K, Foote D, Vichinsky EP: Changing
reticulocyte production. malies), Pearson’s syndrome (associated with outcome of homozygous alpha thalassemia:
hypoplastic sideroblastic anemia), and con- Cautious optimism. J Pediatr Hematol/Oncol
햵 –– Although iatrogenic and other types of
쏹 genital dyserythropoietic anemia. 2000;22:539–542.
blood loss are not disorders of impaired pro-
duction, they often exacerbate anemia primari- 햺 –– Ill neonates may have persistent anemia
쏹
ly due to impaired erythrocyte production. without a recognized etiology and a normal
Blood loss can also cause Fe deficiency ane- bone marrow. Most often these are ill neonates
mia. with multiple and persistent medical problems.
Red Cell Disorders R.H. Sills · A. Deters Neonatal anemia due to impaired RBC production
Red Cell Disorders A. Deters · A.E. Kulozik Hemolytic anemia
Hemolytic anemia
History 햲 Laboratory criteria 햴
18
CBC, & reticulocyte count, & indirect bilirubin,
Physical examination 햳 abnormal peripheral blood smear, ± & LDH, 7 haptoglobin
Coombs specificity 햶 Osmotic fragility test 햷 Hb analysis (see ‘Consumptive coagulopathy’, p 68) G6PD assay
Type and cross-match Family studies
Platelet count RIA/ELISA
ANA
PTT Positive Negative
Family study
Autoimmune Red cell enzyme panel
hemolytic anemia Flow cytometry for GPI-linked
surface proteins (PNH)
Primary Secondary Hereditary HbSS Malaria G6PD deficiency Other enzyme deficiencies
Warm reactive (IgG) Autoimmune disease spherocytosis HbSC Sepsis/infection Paroxysmal nocturnal
Cold reactive (IgM) Malignancy Hereditary HbST Hereditary hemoglobinuria
Paroxysmal Immunodeficiency elliptocytosis Other unstable pyropoikilocytosis 햺
cold reactive (IgG) Infection Hypersplenism Hb variants Hereditary
(i.e. mycoplasmal, viral) Coombs negative AIHA stomatocytosis
Drugs
쏹 –– Symptoms that suggest severe hemoly-
햲 쏹 –– Determine thermal amplitude (warm
햶 쏹 –– Obtain a quantitative Hb analysis (elec-
햸
sis include headache, dizziness, syncope, fever, [23°C] vs. cold [4/10°C]), antigen specificity of trophoresis) and, if necessary, DNA analysis.
chills, dark urine (see on ‘Hemoglobinuria’, the antibody and whether IgG, C3 or both are This should identify a hemoglobinopathy such
p 20) and abdominal/back pain. Possible pre- present on red cells. These tests differentiate as sickle cell anemia and its related diseases or
cipitating factors include infection, medica- warm-reactive (mostly IgG) from cold-reactive other unstable Hb variants such as Hb Köln
tions, and foods (e.g. fava beans in G6PD defi- autoantibodies (mostly IgM, the exception be- causing inclusion body anemia.
ciency). Past medical history should inquire ing paroxysmal cold hemoglobinuria). Know-
about jaundice as a neonate or later. A history ing the antigen specificity will help choosing a 쏹 –– Red cell fragmentation suggests a micro-
햹
of recurrent infections, arthritis, rash, mouth ul- safe blood product. Attempt to find compatible angiopathic hemolytic process. Consider DIC
cers or thyroid disease suggests autoimmune units of packed RBCs, but avoid transfusion if or HUS in the acutely ill child, among other
hemolysis. Family history should include an- possible. Most cases of autoimmune hemolytic diagnoses. (see ‘Consumptive coagulopathy’).
cestry (African, Mediterranean, or Arab ances- anemia in childhood are idiopathic or related History/physical examination may identify a
try suggests G6PD deficiency [mainly but not to infection, and are transient. Concomitant cardiac prosthesis as a cause of hemolysis.
exclusively in males] or sickle cell disease) and thrombocytopenia, neutropenia, prolonged
address anemia, jaundice, splenectomy or un- PTT, or positive ANA suggest underlying au- 쏹 –– A variety of abnormalities on peripheral
햺
explained gallstones (the latter especially in toimmune or other systemic disease, and in blood smear may lead to a diagnosis: malarial
the young). these patients the autoimmune hemolytic ane- parasites, the classic fish mouth stomatocytes
mia is much more likely to be chronic. of hereditary stomatocytosis, the irregular frag-
쏹 –– Clinical signs of anemia are dependent
햳 ments of pyropoikilocytosis, and findings of in-
on Hb and cardiovascular dynamics: pallor, 쏹 –– Spherocytes or elliptocytes occur in
햷 fection (toxic granulation, Döhle bodies, vac-
tachycardia, tachypnea, hypotension, or shock. many clinical settings. Hereditary spherocyto- uolization, visible bacteria).
Note fever as a sign for intravascular hemoly- sis and elliptocytosis are usually autosomal-
sis, acute infection or autoimmune disease. dominant and are common. Therefore, obtain 쏹 –– Obtain G6PD testing, noting that screen-
햻
Growth retardation suggests a longstanding blood smears from family members and look ing tests can produce false-negative results in
anemia or autoimmune disease. Splenomegaly for splenomegaly. In hereditary spherocytosis, milder variants during a reticulocytosis. If the
can be a cause or consequence of hemolytic parents are normal in 5–10% of cases so that G6PD testing is negative, consider red cell en-
anemia and petechiae or bruising are signs of these patients are considered to have new mu- zyme panel to look for other enzyme deficien-
coagulopathy or thrombocytopenia. tations. In about 20% of cases both parents are cies. A rare cause for hemolysis in childhood
clinically normal but have slight laboratory ab- may be paroxysmal nocturnal hemoglobinuria
쏹 –– CBC: A normal Hb does not exclude he-
햴 normalities that may suggest a carrier state as (PNH), a clonal abnormality of a hematopoietic
molysis. An increased reticulocyte count (ideal- in autosomal-recessive diseases. Enhanced os- stem cell, characterized by a membrane pro-
ly corrected for variation in RBC count) sug- motic fragility usually confirms the diagnosis tein defect that renders red blood cells suscep-
gests hemolysis, but a low or normal reticulo- of hereditary spherocytosis. Membrane protein tible to damage by serum complement. Diag-
cyte count occurs when a hypoplastic crisis studies are helpful in selected cases. Coombs nosis can be made by flow cytometry for GPI-
complicates hemolytic anemia. Microcytosis negative autoimmune hemolytic anemia can linked surface proteins (such as CD 55/59) on
can be a sign of hemoglobinopathy or coexis- also cause spherocytosis and a pathological erythrocytes and granulocytes.
tent iron deficiency. Other criteria for hemoly- osmotic fragility; use RIA/ELISA to look for anti-
sis include elevated indirect bilirubin, de- erythrocyte antibodies if there is reason to
creased haptoglobin, free hemoglobin suspect the diagnosis of AIHA. With hereditary Selected reading
(acute/severe hemolytic anemia), and in- elliptocytosis, the diagnosis is usually made
Berman S: Pediatric Decision Making, ed 2.
creased LDH (which is not very specific). simply by the presence of large numbers of
Philadelphia, Dekker, 1991.
elliptocytes on smear. The majority of patients
쏹 –– Perform both direct and indirect Coombs
햵 are asymptomatic. Beutler E, Luzzatto L: Hemolytic anemia.
19
tests. Direct Coombs test detects antibodies on Semin Hematol 1999;36(suppl 7):38–47.
the red cell surface, whereas indirect Coombs
Nathan and Oski’s Hematology of
test identifies anti-erythrocyte antibodies in
Infancy and Childhood, ed 5. Philadelphia,
serum. Coombs negative autoimmune he-
Saunders, 1998.
molytic anemia occurs, but is rare in children.
Hemoglobinuria
20 History 햲 Laboratory criteria 햴
U/A, CBC, blood smear and reticulocyte count R/O hematuria/
Free hemoglobin in plasma, 7 haptoglobin, & LDH myoglobinuria
Physical examination 햳
Blackwater fever Clostridium Paroxysmal cold G6PD deficiency Paroxysmal ABO incompatibility Hemolytic March
(rare complication of welchii hemoglobinuria 햷 nocturnal or other transfusion uremia hemoglobinuria 햹
malaria) septicemia hemoglobinuria 햸 mismatch syndrome
쏹 –– Note past medical and family history of
햲 쏹 –– Beware of renal failure as a complication
햶
Selected reading
hemolytic anemia, especially G6PD deficiency. of hemoglobinuria. The mechanism for acute
Ask about potential trigger such as drugs, food, renal failure in hemoglobinuria is not com- Massry and Glassock’s Textbook of
and recent travel (particularly to areas endemic pletely understood. The following could be in- Nephrology, ed 4. Baltimore,
for malaria). In cases with severe open trauma volved: (1) Intranephronal obstruction resulting Lippincott/Williams & Wilkins, 2001.
or burns, Clostridium welchii septicemia may from precipitation or polymerization of the
Nathan and Oski’s Hematology of Infancy
cause acute hemolysis. Prior transfusion fol- globin portion of Hb with acidic mucoproteins.
and Childhood, ed 5. Philadelphia,
lowed by abdominal pain and hemoglobinuria (2) Renal ischemia due to concomitant release
Saunders, 1998.
suggests a transfusion reaction. Consider he- of vasoconstrictive substances. (3) Direct
molytic uremic syndrome in an acutely ill child nephrotoxicity of breakdown products such Packman CH: Pathogenesis and
with a history of recent gastroenteritis. as ferrihemate resulting in tubular necrosis. management of paroxysmal nocturnal
As prophylactic measures use forced diuresis haemoglobinuria. Blood Rev 1998;12:1–11.
쏹 –– Look for clinical signs of anemia such as
햳 and alkalinization of urine to pH >7.0 using i.v.
Wynn RF, et al: Paroxysmal cold haemo-
pallor, tachycardia/tachypnea, hypotension or sodium bicarbonate. In prolonged oliguria/
globinuria of childhood: A review of the
shock. Note fever as a sign of intravascular he- anuria from acute renal failure, peritoneal or
management and unusual presenting
molysis or acute infection. hemodialysis may be needed.
features of six cases. Clin Lab Haematol
1998;20:373–375.
쏹 –– Hemoglobinuria occurs when the renal
햴 쏹 –– Paroxysmal cold hemoglobinuria (PCH)
햷
threshold for urinary excretion of Hb of approx- is a form of primary autoimmune hemolytic
imately 150 mg/dl (0.023 mmol/l) is exceeded. anemia characterized by cold reactive anti-ery-
Differentiate hematuria, and myoglobinuria throcyte autoantibodies of the IgG subtype
from hemoglobinuria: urine test strips for Hb (Donath-Landsteiner antibodies). This class of
will be positive for all three. In hematuria, the antibodies binds the polysaccharide P autoanti-
color of centrifuged urine is normally clear gen on RBC surfaces and fixes complement at
and microscopic examination of unspun urine 4°C. On warming to 37°C, the complement is
shows red blood cells. In myoglobinuria and activated and hemolysis induced. PCH should
hemoglobinuria, spun urine remains red. be considered if the patient has hemoglobin-
Myoglobinuria is excluded immunochemically. uria and C3 alone is present on the RBC. Chil-
Additionally, in hemoglobinuria free Hb can dren may develop PCH after a viral-like illness.
be measured and even visually observed in
plasma or serum. 쏹 –– A rare cause for hemolysis in childhood
햸
is paroxysmal nocturnal hemoglobinuria
쏹 –– If acute intravascular hemolysis is identi-
햵 (PNH), a clonal abnormality of the hematopoi-
fied, look for the underlying disease as dis- etic stem cell. It is characterized by a mem-
cussed under note 1 above (and see ‘Hemolytic brane protein that renders red blood cells sus-
anemia’, p 18). ceptible to damage by serum complement.
Classically, patients have intermittent episodes
of dark urine, most commonly in the morning.
7 MCV, 7 Fe, & TIBC Nl TS, Fe, TIBC 7 Fe, 7 TIBC & Pb & TS
7 TS, 7 ferritin, 7 RBC, & RDW, ± 7 MCHC
Ferritin ± 7 TS & Fe
& ferritin & TIBC
Hb electrophoresis
Dx of iron deficiency anemia
Normal Abnormal
Bone marrow
Ongoing blood loss?
aspirate
-Thalassemia Ringed
sideroblasts
No Yes Possible malabsorption No
Fe absorption test
+ –
Iron deficiency Poor compliance Malabsorptive syndrome Concurrent B12 or Concurrent S-thalassemia (␣ or ) Anemia of Pb Sideroblastic
anemia due Incorrect folate deficiency illness CC or EE disease infection or poisoning anemia
to blood loss medication/dose Defects of Hb E – -thalassemia inflammation
Fe metabolism Hb C – -thalassemia
E – trait
Red Cell Disorders R.H. Sills · A. Deters Presumed iron deficiency anemia which fails to
respond to oral iron
Red Cell Disorders A.E. Kulozik · A. Deters Thalassemia
Thalassemia
History 햲 Laboratory criteria: 햴
24
CBC: hypochromic microcytic anemia
Physical examination 햳 Target cells on blood smear
Clinical Intrauterine death 햶 Neonatal anemia 햷 Mild anemia or normal 햸 Severe anemia in Anemia beyond Mild, asymptomatic
Stillborn Signs of hemolysis late infancy 햹 infancy 햺 anemia
Hydrops fetalis
Hb analysis No HbA/HbF Hb Barts 20–30% Neonate: Hb Barts No or 777 HbA && HbF & HbA2
Hb Barts (4) 80–90% In later childhood, 5–10% or normal HbF 90% & HbA2 +/– & HbF
Hb Portland (22) HbH (4) 4–20% Childhood: normal 7 HbA
Genotype -globin gene: – –/– – -globin gene: –/– – -globin gene: –/–, -globin gene: 0/0 -globin gene: + /+ -globin gene:
/– –, or /– 0/ (dominant) heterozgote +– or
0/ + -globin gene triplication 0-mutation
0/0 + HPFH mutation or
-thalassemia
0/0 or 0/+ – + -Thalassemia trait
-Thalassemia major HbH disease -Thalassemia minor -Thalassemia major -Thalassemia intermedia -Thalassemia
minor
Therapy Prenatal transfusion 햻 Transfusion in Family studies and Regular transfusion 햻 No or irregular transfusion Family studies and
Regular transfusion hemolytic/aplastic counseling 햽 Iron elimination therapy ± Iron elimination therapy counseling 햽
Iron elimination therapy crisis ± splenectomy BMT ? Splenectomy
BMT Folic acid Family studies and Family studies and
Family studies and Family studies and counseling 햽 counseling 햽
counseling 햽 counseling 햽
쏹 –– Consider age of presentation: patients with -tha-
햲 In contrast to -thalassemia, 95% of the known molecular fancy and patients become dependent on transfusions. The
lassemia major are symptomatic in the fetal or neonatal pe- defects of -thalassemia are caused by deletions of DNA frequency of heterozygous -thalassemia also depends on
riod, whereas patients with -thalassemia usually develop (deletional -thalassemia). Deletion of 4 -globin genes is ethnic origin. In Mediterranean countries the gene frequen-
symptoms in late infancy when fetal hemoglobin decreases usually fatal leading to intrauterine death or a stillborn (Hb cy ranges from 2 to 20%.
and lack of HbA becomes apparent. Moderate to severe Barts hydrops fetalis syndrome). There also are non-dele-
anemia in toddlers might be due to -thalassemia interme- tional forms of -thalassemia due to point mutations. At 쏹 –– -Thalassemia intermedia is an ill-defined clinical
햺
dia. Ask for patients’ ethnic origin, as the thalassemias are birth, unexpected hemoglobins occur in the absence of form of -thalassemia which varies in severity from an
common in South East Asia, Mediterranean, Middle East chains; Hb Barts is absent during normal fetal develop- asymptomatic condition identified incidentally to relatively
and North/West Africa. Note positive family history espe- ment, and Hb Portland (2 chains and 2 chains) normally severe anemia requiring occasional transfusions. It results
cially for ‘iron deficiency’ that fails to respond to iron. The occurs only in early embryonic development. from a wide variety of distinct genotypes, including ho-
thalassemias are usually autosomal-recessive disorders. mozygosity for mild +-thalassemia, high persistent levels
쏹 –– HbH disease is a chronic hemolytic disorder. HbH is
햷 of fetal Hb, co-inheritance of -thalassemia, and rare domi-
쏹 –– Note signs of anemia (e.g. pallor, tachycardia, and
햳 found in small amounts as chain synthesis increases fol- nant forms of -thalassemia. These patients may develop
tachypnea) and extramedullary erythropoiesis (e.g. he- lowing birth. Clinical severity is dependent on genotype. extramedullary erythropoiesis. Age of diagnosis, usually in
patosplenomegaly). Patients with thalassemia major or tha- Classically, 3 of the 4 -globin genes are deleted (–/– –). the second year of life, is later than in -thalassemia major.
lassemia intermedia who are insufficiently transfused Clinically, this is usually mild (Hb range 7–12 g/dl [1.09–1.86
demonstrate typical bone deformities due to marrow hyper- mmol/l]). In contrast, compound heterozygosity for dele- 햻 –– Patients with - or -thalassemia major are regularly
쏹
plasia. tional -thalassemia and non-deletional -thalassemia in- transfusion dependent. For -thalassemia major, early pre-
volving the 2-globin gene (– –/T; T noting a non-deletion- natal diagnosis is essential to institute prenatal transfusion
쏹 –– Perform a CBC and a blood smear. Most forms of
햴 al mutated gene) causes more severe disease that might in- therapy to allow survival. In both - and -thalassemia ma-
thalassemia are associated with a hypochromic microcytic clude transfusion dependency. The frequency of -tha- jor, essential transfusions and increased iron resorption re-
anemia of varying severity. Target cells, anisocytosis and lassemias depends on ethnic origin. In people of African de- sult in secondary hemosiderosis leading to dilatative car-
poikilocytosis are seen in the peripheral blood smear. Ex- scent, homozygous +-thalassemia (–/–) is frequent diomyopathy, liver cirrhosis and extensive endocrine disor-
clude other causes of microcytic anemia such as iron defi- (1.9%), but since the thalassemic genes are almost always ders. Therefore, iron chelation therapy with parenterally ad-
ciency. See the algorithms on (1) microcytic anemia, and (2) paired with a normal gene on each chromosome, more se- ministered deferoxamine is important for increased life ex-
presumed iron deficiency anemia that fails to respond to vere disease (HbH disease and Hb Barts hydrops fetalis syn- pectancy. Deferriprone, which can be given orally, is used in
iron. drome which require – –/ conformation) is very rare. In patients who fail to comply with deferoxamine. Matched re-
Southeast Asia, all genetic variants are found. In Thailand, lated (unrelated) bone marrow transplantation is the only
쏹 –– Diagnosis can usually be made clinically in combi-
햵 10% of the population are heterozygous for +-thalassemia curative form of therapy.
nation with CBC and Hb analysis (Hb electrophoresis). In (– /) and 10% for 0-thalassemia (– –/). Because of
- and -thalassemia major, HbA is absent or severely de- these gene frequencies, 1% of the population suffer from 쏹 –– Family studies are important to identify couples at
햽
creased. In -thalassemia major and HbH disease, -globin HbH disease (– –/–) and Hb Barts hydrops fetalis syndrome risk for offspring with thalassemia major and to allow for
deficiency leads to decreased (or absent) HbF (22) and (– –/– –) occurs in 1:2,000 newborns. DNA analysis may be prenatal diagnosis when appropriate.
HbA formation (22). Excess - and -globin chains form required for diagnosis.
Hb Barts (4) and HbH (4), respectively. These - and -glo-
bin tetramers precipitate and thus cause hemolysis. In the 햸 –– -Thalassemia trait can result from the -cis (– –/),
쏹 Selected reading
neonate, -thalassemia minor can be identified by the pres- or trans (–/–) conformation. These children are asympto-
Lucarelli G et al: Bone marrow transplantation
ence of Hb Barts, but in later childhood Hb analysis is usu- matic but have a mild microcytic anemia. Mild elevations of
in thalassemia: The experience of Pesaro.
ally normal. In -thalassemia major, fetal hemoglobin is in- Hb Barts are noted in the neonate but soon after the hemo-
Ann NY Acad Sci 1998;850:270–275.
creased to >90%. In -thalassemia intermedia, fetal hemo- globin analysis is normal: HbH is not found. Individuals with
globin and HbA2 are also increased whereas HbA is moder- a single gene deletion (–/) are hematologically normal Nathan and Oski’s Hematology of Infancy and
ately decreased. In -thalassemia minor, HbA2 is character- but may have up to 1–2% Hb Barts in the neonatal period. Childhood, ed 5. Philadelphia, Saunders, 1998.
istically increased to 3.5–6%. HbF levels are variable and of-
25 쏹 –– -Thalassemia major is due to severe -globin defi-
햹
Olivieri NF: Medical progress: The (beta) thalassemias.
ten slightly increased.
N Engl J Med 1999;341:99–109.
ciency. The expression of the -globin gene is inactivated in
쏹 –– The gene for -globin on chromosome 16 is duplicat-
햶 the 0 form or expression is severely decreased in the + Steinberg MH, Forget BG, Higgs DR, Nagel RL: Disorders
ed so there are normally 4 -globin genes. -Thalassemia form so that there is no or minimal HbA formation. Patients of Hemoglobin. London, Cambridge University Press,
major occurs when all 4 -globin genes are deleted (– –/– –). usually become symptomatic when HbF levels fall in late in- 2001.
Hemoglobin phenotype 햳
Sickle cell
Sickle cell disease 햷 Unusual Transfused
disease 햶 phenotype
phenotype phenotype 햻 phenotype
Both parents
thalassemia
Reference minor (& HbA2)
laboratory
Both parents Parental Parental Parental Parental Parental
HbS donors HbF donor and microcytosis/ HbC donor and microcytosis/ HgbF donor
(e.g. HbAS) HbS donor elevated HbA2 HbS donor elevated HbA2
Parents
normal
Normal Trait HbSS HbS-HPFH HbS0 T HbSC HbS+ T -Thalassemia HPFH Extreme
phenotype phenotype 햴 HbS+ T 햹 major prematurity
Red Cell Disorders M.M. Heeney · R.E. Ware Newborn screening for hemoglobinopathies
Red Cell Disorders A.S. Al-Seraihy · R.E. Ware Sickle cell anemia with fever
All sickle cell disease patients Temperature >38.5°C 햵 Temperature <40°C 햵 Temperature >40°C 햵
with temperature <38.5°C 햵
Observation Admission
쏹 –– Fever is the only reliable indicator of potential infec-
햲 쏹 –– The WBC count tends to be higher among bacteremic
햷 쏹 –– High-risk patients: Parenteral antibiotics should be
햺
tion in patients with SCD. There are no rapidly available children in the first 2 years of life. Most studies show administered immediately after obtaining the blood count
laboratory tests on hand that can rule out all bacterial that the WBC count is not reliable for predicting sepsis in and the blood culture, but before taking the radiograph and
infections such as pneumococcal bacteremia. All febrile an individual child with SCD. However, among children waiting for the laboratory results. Lumbar puncture should
children with SCD must be evaluated for serious bacterial 24 months of age or younger who have the highest inci- be performed on toxic children and those with signs of
infection. For children with HbSS younger than 5 years of dence of sepsis, the presence of leukopenia or extreme meningitis. Nontoxic children with temperature below 40°C,
age, the risk of acquiring sepsis and meningitis is more leukocytosis with high fever are ominous signs. but with chest X-ray infiltrate, or with WBC >30 or <5 × 106/l
than 15% and mortality rate is 30–50%. Work-up and should be admitted and treated with parenteral antibiotics.
management depend on the clinical evaluation considering 쏹 –– Intermediate risk patients should receive a long-
햸 Antibiotic choice should be selected based on the ability to
age, specific hemoglobinopathy, and physical examination. acting antibiotic (e.g. ceftriaxone 50 mg/kg) immediately af- kill both Pneumococcus and H. influenzae and to penetrate
CBC with differential, reticulocyte count, and blood culture ter obtaining the blood culture. The presence of a focus of into the CSF. Toxic patients or patients suspected of having
must always be obtained. Chest X-ray should be included in infection (e.g. otitis) does not alter the urgency of giving meningitis should be treated with ceftriaxone (50–75 mg/kg)
the evaluation of young patients, those with any pulmonary parenteral antibiotics. Urine culture and chest X-ray should or cefotaxime (45 mg/kg/dose), and vancomycin (10–15
symptoms, and those with leukocytosis or with increased be done if clinically indicated. Patients should be observed mg/kg/dose for resistant organisms). If the patient is known
circulating immature neutrophils. Routine U/A and culture for several hours to ensure they are clinically stable. Only if or suspected to have allergy to cephalosporin, clindamycin
is mandatory for all infants, and older children with urinary the family is reliable can the patient be discharged home can be substituted. Documented sepsis should be treated
symptoms, but therapy should not be delayed while await- with specific plan for out-patient follow-up. Minimum fol- parenterally for a minimum of 1 week. Bacterial meningitis
ing urine collection. low-up includes phone contact the next day. Repeated should be treated for a minimum of 10 days or 1 week after
physical examination and a second dose of ceftriaxone may the CSF has been sterilized. Patients can be discharged
쏹 –– SCD patients with fever should be triaged rapidly and
햳 be advisable in some cases. Physicians should consider ad- from the hospital if afebrile for 24 h with 48 h negative cul-
evaluated immediately. After taking a brief history, focused mission if patient is less than 1 year, or has a previous his- tures, able to take oral fluids well, with resolution of any
physical examination should be done with emphasis on tory of bacteremia or sepsis, or becomes toxic, or receives respiratory symptoms and adequate oxygenation on room
vital signs, O2 saturation, degree of pallor, cardiopulmonary clindamycin as a substitute for ceftriaxone, or if there is any air, and no evidence of worsening of anemia (e.g. aplastic
status, evidence of systemic and localized infection, spleen concern about the follow-up. or sequestration crisis).
size (compared with baseline) and neurological examina-
tion. 쏹 –– Patients with chest X-ray infiltrate should have culture
햹
of blood, sputum and stool. Those with hypoxemia should Selected reading
쏹 –– HbSC is generally milder disease than HbSS. How-
햴 receive supplemental oxygen to keep pulse-oximetry above
Cole TB, Smith SJ, Buchanan GR: Hematological
ever, children under 5 years of age with HbSC have an 92%, and incentive spirometry to help prevent atelectasis.
alterations during acute infection in children with sickle
increased risk of bacteremia and fatal sepsis. In general, Blood transfusion should be given when oxygen carrying
cell disease. Pediatr Infec Dis J 1987; 6:454–457.
children with HbSC should be managed with the same de- capacity is needed, but not as a routine. Because of the
gree of caution with regard to infection as those with HbSS. overwhelming incidence of pneumococcal pneumonia, Lane PA, Rogers ZR, Woods GM, et al: Fatal
Children with HbS0 thalassemia are considered to be of patients should be treated with parenteral antibiotics pneumococcal septicemia in hemoglobin SC disease.
the same clinical severity as those with HbSS. However, (e.g. cefuroxime). Atypical pneumonia with Mycoplasma J Pediatr 1995;127:685–690.
those with HbS+ thalassemia have a milder course, and pneumoniae occurs commonly in SCD, and may lead to
Rogers ZR, Morrison RA, Vedro DA: Outpatient manage-
their risk of infection is much less than high-risk patients. acute chest syndrome. Macrolide therapy (erythromycin or
ment of febrile illness in infants and young children with
azithromycin) should be added to antibiotic coverage in
sickle cell anemia. J Pediatr 1990;117:736–739.
쏹 –– The height of initial fever is the most reliable indicator
햵 treating SCD patients with pneumonia. A positive stool
of septicemia. This is particularly true when the tempera- culture may be the only evidence for Salmonella pneumo- West TB, West DW, Oheme-Frempong K: The presenta-
ture is 40°C or greater, especially in children 24 months of nia. Patients with clinical findings that are highly suggestive tion, frequency, and outcome of bacteremia among
age or younger, but sepsis can occur with any degree of of septic arthritis or osteomyelitis should have needle children with sickle cell disease and fever. Pediatr Emerg
fever. Recent antipyretics may reduce the fever but will not aspiration and culture of the joint or bone. Antibiotic choice Care 1994;10:141–143.
change the risk of bacteremia. should include agents effective against Salmonella species
29 Wilimas JA, Flynn PM, Harris S, et al: A randomized
and Staphylococcus aureus. Abdominal ultrasonography,
study of outpatient treatment with ceftriaxone
쏹 –– Low-risk patients can be managed symptomatically
햶 liver function tests, amylase, and lipase should be
for selected febrile children with sickle cell disease.
like patients without sickle cell disease, but the higher considered for patients with RUQ, epigastric or severe
N Engl J Med 1993;329:472–479.
risk of acute chest syndrome, osteomyelitis and other abdominal pain to rule out cholelithiasis, cholecystitis,
complications must be considered. and pancreatitis.
Red Cell Disorders A.S. Al-Seraihy · R.E. Ware Sickle cell anemia with fever
Red Cell Disorders M.M. Heeney · R.E. Ware Management of painful vaso-occlusive episodes
in sickle cell disease
Painful episode
31
X
Red Cell Disorders M.M. Heeney · R.E. Ware Management of painful vaso-occlusive episodes
in sickle cell disease
Red Cell Disorders A.S. Al-Seraihy · R.E. Ware Evaluation and management of anemia in sickle cell disease
Anemia
Measurement of Hb concentration 햲
Enlarged spleen Enlarged liver No hepatosplenomegaly Normal spleen size Enlarged spleen size Normal spleen size
Low or normal BP Low or normal BP Low or normal BP Low reticulocytes <5% Reticulocytes present >5% High reticulocytes >15%
Reticulocytes >5% Reticulocytes >5% Very low reticulocytes <1%
Parvovirus serology (IgG, IgM)
Acute splenic Acute hepatic Transient aplastic crisis 햶 Sub-acute splenic Hemolytic crisis 햸
sequestration crisis 햴 sequestration crisis 햵 sequestration crisis 햷 Rule out concomitant
hemolytic conditions
G6PD deficiency
Spherocytosis
Drug exposure
Infection
Red Cell Disorders A.S. Al-Seraihy · R.E. Ware Evaluation and management of anemia in sickle cell disease
Red Cell Disorders A.E. Kulozik · A. Deters Polycythemia (erythrocytosis)
Polycythemia (erythrocytosis)
34 History 햲 Laboratory criteria 햳
CBC, HCT >upper end of
Physical examination reference range on 2 occasions
햲
Red cell transfusion
36
Red cell destruction Acute blood loss Red cell production failure
Observe for hypotension and CHF Religious objection to transfusion 햺 Transfusion reaction 헁 Immunocompetent
Monitor Hb closely
Reconsider transfusion if Hb 7 Irradiated PRBC 햹
? Autologous donation 헀 Leukodepletion if repeated Leukodepleted PRBC
? EPO transfusions likely CMV-safe PRBC
쏹 –– PRBC transfusions increase the oxygen-carrying ca-
햲 should have a full RBC phenotype and should receive PRBC 쏹 –– Irradiation of blood prevents transfusion-associated
햾
pacity in anemic patients. One unit of PRBC derived from a matched for C, D, E, and Kell antigens and any other specific GvHD caused by engraftment of donor lymphocytes. Irradi-
routine blood donation preserved in CPDA-1 anticoagulant = antigen for which they have preexisting antibodies. This ated blood is indicated for fetuses requiring intrauterine
250–300 ml RBCs, Hct = 75–80% and shelf life = 35 days. should also be done for patients with thalassemia major be- transfusions, some neonates and infants up to 4 months, ac-
Stored in additive preservatives, Hct = 52–60% and shelf life cause they may require life-long transfusions. HbSS patients quired or congenital immunodeficiency states, chemoradio-
= 42 days. 10 ml/kg of PRBC should raise the Hb by 2–3 g/dl should be transfused, if necessary, to bring their Hb to therapy, hematopoietic stem cell and solid organ transplant
(0.31–0.47 mmol/l). Leukoreduction of PRBC usually uses 10 g/dl for general anesthesia, but preferably not higher. recipients, and those receiving blood from HLA homozygous
special filters, preferably immediately after blood donation or haploidentical donors including blood relatives.
rather than before the actual transfusion. Washed PRBC are 쏹 –– Massive blood loss requires urgent management of
햸
mainly used to prevent recurrent allergic reactions. Frozen both hypovolemia and anemia. Rapidly infuse crystalloid/ 쏹 –– Bone marrow transplant candidates with aplastic ane-
햿
PRBC are used for storage of rare phenotypes or autologous colloid until PRBC are available. If hypotensive, group O Rh- mia should be transfused only when absolutely necessary to
units. Units of blood must be infused within 4 h of leaving negative uncrossmatched PRBC may be necessary until minimize transfusion-induced HLA alloimmunization which
the blood bank. With appropriate testing of units, the current group-specific or crossmatch-compatible PRBC are avail- complicates engraftment. Hb as low as 5–6 g/dl may be tol-
estimated risk of infection = 1:1,930,000 for HIV, <1:543,000 able; transfuse 10–20 ml/kg/h if necessary to maintain the erated well. If forced to transfuse, avoid family members
for hepatitis C and 1:138,700 for hepatitis B. Hb level and blood volume. Once stable, slow down to who may serve as transplant donors.
10–20 ml/kg/4 h as determined by clinical status and Hb.
쏹 –– In warm AIHA, IgG antibodies react at 37°C. RES block-
햳 Dilutional thrombocytopenia, coagulopathy and metabolic 쏹 –– The medical, ethical and legal issues of religious ob-
헀
ade with prednisone or equivalent, 2–10 mg/kg/day, is the complications may occur with massive transfusion (>75 ml/ jections to transfusions (e.g. Jehovah's Witnesses) are com-
first-line therapy. Transfuse if needed because of the risk of kg/24 h); monitor and correct ionized hypocalcemia due to plex. The effectiveness of blood substitutes remains un-
fatal anemia. The antibody usually reacts with Rh-like anti- citrate toxicity. Hypothermia from refrigerated blood can be proven. EPO increases hemoglobin but requires 2–3 weeks
gens present on RBCs so an incompatible crossmatch is avoided by using a blood warmer. for a noticeable effect.
common. Slowly infuse small volumes of the most compati-
ble units after pretreatment with steroids. 쏹 –– Sick or premature newborns frequently require trans-
햹 쏹 –– The incidence of transfusion reactions is allergic >
헁
fusions. The neonatal immune system typically does not re- febrile nonhemolytic > hemolytic > anaphylactic > septic. Al-
쏹 –– Cold AIHA is usually due to IgM antibodies reactive at
햴 spond to RBC antigen stimulation. If the initial ABO, Rh is lergic reactions cause pruritus, rash/urticaria and flushing at
0–30°C, fixing complement and causing hemolysis even af- compatible and antibody testing is negative, repeat cross- the infusion site and respond to briefly pausing the transfu-
ter the blood warms centrally to 37°C. When transfusing, matching and antibody screening is unnecessary prior to sion and giving antihistamines. Febrile/nonhemolytic reac-
use a servotemperature blood warmer to reduce hemolysis subsequent transfusions. The blood bank should divide a tions demonstrate fever elevated to >1°C ± rigors, headache,
of transfused cells. compatible unit into multiple small aliquots for infants re- malaise, and emesis; stop the transfusion, give antipyretics
quiring multiple small volume transfusions which should be and initiate a blood bank transfusion reaction workup. He-
쏹 –– If the cause of hemolysis is unknown, obtain RBC en-
햵 irradiated to prevent GvHD and be CMV safe, either prestor- molytic reactions are characterized by fever, chills, back
zyme, membrane and Hb analyses prior to transfusion so as age leukodepleted or CMV-negative. pain, Hburia, lowered BP, and DIC; stop the transfusion im-
not to mask the diagnosis once normal cells are transfused. mediately and support BP and renal function with fluids/di-
쏹 –– Recombinant erythropoietin (EPO) support is effective
햺 uretics/pressors as needed. Blood bank transfusion reaction
쏹 –– WBC depletion using third-generation prestorage
햶 in treating anemia associated with HIV, renal failure, and workup is critical. Septic contamination of blood and espe-
leukodepletion filters for blood and blood products is rec- prematurity. Routine use of EPO in pediatric oncology pa- cially platelets causes febrile reactions, which can be fatal.
ommended for immunocompromised children, infants who tients remains controversial.
have an immature immune system, and those expected to
receive multiple transfusions. The reduction in WBC con- 쏹 –– Severe but less acute anemia (e.g. TEC, Fe deficiency)
햻 Selected reading
tamination may decrease febrile reactions, exposure to HLA raises vascular volume and can cause CHF. Even if relatively
Lumadue JA, Ness PM: Current approaches to red cell
antigens, and risk of CMV transmission. Frozen, washed red stable, too rapid transfusion can precipitate CHF. Transfuse
transfusion. Semin Hematol 1996;33:277–289.
cells eliminate some WBC, but additional time for prepara- as slowly as 1 ml/kg/h (usually 4–5 ml/kg/4 h). To limit the
tion and loss of RBC volume limit use. number of donor exposures, request sterile splitting of Roodie PH, Turner ML, Williamson LM: Leucocyte
37 PRBC into small aliquots. depletion of blood components. Blood Rev
쏹 –– Patients of African descent have different rates of ex-
햷 2000;14:145–156.
pression of common RBC antigens. 30% may become al- 쏹 –– Myelosuppressive chemotherapy often requires PRBC
햽
Sandler SG, Sander DA: Transfusion reactions;
loimmunized from chronic RBC transfusions. Alloimmuniza- support that can prevent GvHD and CMV transmission. In
in Phatak PD (ed): Medicine., emedicine.com, 2001
tion may make it difficult or impossible to find compatible other chronic anemias the Hb may fall lower before PRBC
(http://www.emedicine.com)
PRBC. To decrease this risk by ~80%, children with SCD are indicated.
Red Cell Disorders C. Lawlor · N.L.C. Luban · J.C. Porter · R.H. Sills Red cell transfusion
White Cell Disorders L.A. Boxer Leukocytosis
Leukocytosis
Class of WBC that is elevated
38 Duration of leukocytosis
Degree of elevation 햲
7 & or normal 햷
Stress/trauma CML Chronic infection Down syndrome TB Recovering marrow Systemic lupus Hypersensitivity Infectious mono-
Exercise or inflammatory Asplenia syndromes Syphilis Hemolysis erythematosus reactions nucleosis
Infection disease Leukocyte adhesion Typhoid Hodgkin disease Juvenile rheumatoid Chronic sinusitis Pertussis
Hypoxia Corticosteroids deficiency Brucellosis Non-Hodgkin lymphoma arthritis Varicella Acute lymphoblastic
Hemorrhage Hemolysis Chronic idiopathic Neutropenias Langerhans cell JRA leukemia
Acute bacterial Chronic blood loss neutrophilia Post-splenectomy histiocytosis Ulcerative colitis Cytomegalovirus
infections Asplenia Familial myelo- Leukemias Ulcerative colitis Hemolysis Tuberculosis
Drugs Malignancies proliferative disease Regional enteritis CML Brucellosis
Hemolysis Myeloproliferative Hereditary neutrophilia Polyarteritis Hodgkin disease Thyrotoxicosis
Tissue infarction disease Myeloid metaplasia Addison disease
Diabetic ketoacidosis Thyrotoxicosis
Renal failure
Hepatic coma
햲 –– To evaluate the patient with leukocytosis, it is impor-
쏹 diabetic ketoacidosis, renal failure, hepatic coma, hemolytic 햹 –– The upper range of normal of monocyte counts is
쏹
tant to determine which class or classes of white blood cells anemia, and hemorrhage. The specific etiology of the 1,900 cells/µl in the neonate, as low as 900 at 1 year, and
are elevated. Next it is important to determine the duration leukocytosis is often evident and usually transient, so fur- then 1,300 through adolescence.
and extent of the leukocytosis. Each blood count should be ther evaluation is often unnecessary. If the leukocytosis per-
evaluated on the basis of the absolute number of cells/µl sists or increases in severity, evaluation may be indicated. 햺 –– Basophilia occurs when the basophil count exceeds
쏹
(e.g. the absolute eosinophil count) and not on the basis of 100–120 cells/µl. Basophilia is a nonspecific sign of a wide
the differential count percentage. A relatively high percent- 햶 –– In patients with a longer history in whom neutrophilia
쏹 variety of disorders and is usually of limited diagnostic im-
age of neutrophils may not be abnormal if the total WBC is is acquired, a different list of possibilities than for acute portance.
not high. All normal ranges remain at ± 2 SD of large popu- causes of neutrophilia needs to be considered and diagnos-
lation samplings. Consideration must be made of the age tic evaluation is indicated more often. Neutrophil produc- 햻 –– Normal lymphocyte count varies considerably with
쏹
of the patient because the leukocyte values change during tion rate can increase severalfold with chronic infections and age, from upper limits of normal of 7,300 cells/µl in neo-
childhood (see tables of normal values). Often the etiology in response to exogenously administered hematopoietic nates, to 11,500 at 6 months of age, to 6,500 at 10 years,
of the leukocytosis will be evident (e.g. acute infection, growth factors (G-CSF and GM-CSF). Chronic inflammation and 4,500 in adolescents and adults. Lymphocytosis is as-
drugs, trauma) and no specific evaluation associated with vasculitis, pleuritis, or pericarditis, Hodgkin sociated with many infections, particularly infectious mono-
is necessary. disease, and a variety of tumors including non-Hodgkin nucleosis, acute infection lymphocytosis and pertussis, as
lymphomas initiate chronic neutrophilia. Elevated neu- well as a variety of other disorders including the lympho-
햳 –– Once the specific cell type that is elevated is deter-
쏹 trophil counts can be the presenting sign of chronic myelo- cytic leukemias.
mined, the clinician must review the history and physical genous leukemia, but this is usually suspected on the basis
examination of the patient and focus on those features that of a profound shift to the left (with metamyelocytes, myelo-
can differentiate the specific diagnosis under consideration. cytes and promyelocytes constituting an average of 25% of Selected reading
the neutrophilic series) and a total WBC usually >100,000/µl.
Dinauer MC: The phagocyte system and disorders of
쏹 –– Neutrophilia refers to an alteration in the total num-
햴 In pursuing the differential diagnosis of chronic neutro-
granulopoiesis and granulocyte function; in Nathan DG,
ber of neutrophils in the blood that is in excess of about philia, the chemical stain of circulating white blood cell
Orkin SH (eds): Hematology of Infancy and Childhood,
7,500 cells/µl in adults. During the first few days of life, the leukocyte alkaline phosphatase is useful. The result is near
ed 5. Philadelphia, Saunders, 1998, chapt 22, pp 889–967.
upper limit of the normal neutrophil count ranges from zero in chronic myelogenous leukemia (CML) and is normal
7,000 to 13,000 cells/µl for neonates born prematurely and to elevated in reactive secondary neutrophilias. If the result Inoue S: Leukocytosis; in Jones GR (ed): Pediatric
at term, respectively. It then drops to as low as 4,300 at is low, bone marrow aspiration for cytogenetics to detect Medicine. emedicine 2002 (http://emedicine.com).
2 months of age, reaches 8,000 through most of childhood the chromosomal translocation t(9:22) should be performed
Stockman JA III, Ezekowitz RAB: Hematologic
and then reaches the adult upper limit of 7,500. Africans to confirm the diagnosis of CML.
manifestation of systemic diseases; in Nathan DG, Orkin
have somewhat lower neutrophil counts than Caucasians.
SH (eds): Hematology of Infancy and Childhood, ed 5.
Neutrophilia arises from a disturbance in the normal equi- 햷 –– If the leukocyte alkaline phosphatase result is normal
쏹
Philadelphia, Saunders, 1998, chapt 54, pp 1841–1892.
librium involving neutrophil bone marrow production, or elevated, specific measures to identify or rule out the
movement in and out of the marrow compartments into the causes of persistent reactive neutrophilia should be pur-
marginating (found along endothelial cells in small blood sued. Chronic infection or inflammatory states (such as
vessels) and circulating pools, and neutrophil destruction. autoimmune disorders or inflammatory bowel disease) do
this most commonly. Hemolysis and chronic blood loss can
햵 –– Acute neutrophilia occurs rapidly within minutes in
쏹 result in a mild-to-moderate leukocytosis (usually < 25,000
response to exercise or epinephrine-induced reactions. It is cells/µl).
caused by a shift of cells from the marginal to the circulat-
ing pool. Acute neutrophilia also occurs as a consequence 햸 –– Sustained moderate neutrophilia occurs with anatom-
쏹
of release of marrow cells from the storage pool. This ic or functional asplenia and arises from failure to remove
mechanism produces acute neutrophilia in response to in- circulating neutrophils by the spleen. Down syndrome and
flammation and infection. The neutrophilia arises following familial myeloproliferative disorders are also associated
39
an increase in TNF, IL-1 and a cascade of other cytokine with neutrophilia. Neutrophilia is associated with functional
growth factors. Glucocorticoids may also cause the release disorders of the neutrophil associated with impaired adhe-
of the neutrophils from the marrow reserve pool as well as sion or motility such as that found in patients with leuko-
slow the egress of neutrophils from the circulation into tis- cyte adhesion deficiency types I and II. There is an autoso-
sue. Acute neutrophilia is also seen in trauma, tissue infarc- mal-dominant form of hereditary neutrophilia as well as a
tion associated with sickle cell crisis and burns, hypoxia, form of chronic idiopathic neutrophilia.
Eosinophilia
40 History, physical examination: fever, allergies, atopy, wheezing, cough, ronchi,
Consider severity of eosinophilia 햲 crackles, recent travel, diarrhea, failure to thrive, environmental exposures,
medications, pets, gastrointestinal symptoms, symptoms/signs of systemic disease
Acute 햳 Chronic 햸
History of Stool for O+P× 3 Pulmonary Skin and Gastro- Rheumatologic Lymphadenop- Evidence of immune
asthma, disease 햹 subcutaneous intestinal disease 햻 athy ± hepato- deficiency or
eczema, disease disease 햺 splenomegaly post-transplant 햿
hay fever Abnormal CBC
and blood smear
+ O+P 햵 – O+P
Strongyloides
Ascariasis
Hookworm
Isospora belli
Dientamoeba fragilis
41
Neutropenia
History and physical examination, CBC
Chronic neutropenia
ANC <500 + fever
Discontinuing (see ‘Pancytopenia’, p 12) (see ‘Febrile Repeat CBC
neutropenia’, p 98)
drugs or toxic in 3–4 weeks
exposure & to evaluate
ANC recovery
Bone survey
± metabolic Abnormal
ANC 3×/ week No specific Bone marrow studies
× 6 weeks etiology and aspiration and
Cultures no serious cytogenetics
± serologic infections + +
studies for Cyclic pattern
infection ~ every 21 days
Drug-induced Bacterial Viral illness Cyclic Chronic benign Bone marrow Autoimmune Malnutrition Fanconi anemia HIV
Protozoal neutropenia neutropenia replacement neutropenia Folate and/or B12 Cartilage-hair Dysgamma-
Rickettsial MDS Isoimmune deficiency hypoplasia globulinemia
Severe fungal Kostmann neonatal Shwachman Dyskeratosis congenita Lymphoproliferative-
infections syndrome neutropenia syndrome Chediak-Higashi mediated neutropenia
Myelokathexis Metabolic disorders PNH
Avoid the drug Appropriate Supportive G-CSF often No Rx As per specific No Rx if no infections Treatment as per
if possible antimicrobial care unless helpful diagnosis G-CSF if on-going specific diagnosis
therapy a role for problems
Ensure neutropenia antiviral therapy
resolves
–– Leukopenia results from either neutropenia and/or leukopenia,
–– The overwhelmingly most common cause of transient neu-
–– Patients with a history of malabsorption from infancy should
but neutropenia is much more commonly an important clinical tropenia is viral infection. The neutropenia may persist for 3–8 days be evaluated for Shwachman syndrome; this includes skeletal films
problem. The risks of neutropenia are discussed in ‘Febrile neutro- during acute viremia. These patients do not generally require the (25% have metaphyseal dysplasia), a bone marrow (aspirate, biopsy
penia’ (p 98). Neutropenia is quantified using the absolute neu- intensive use of broad-spectrum antibiotics during febrile episodes and cytogenetics), and an evaluation of exocrine pancreatic func-
trophil count (ANC) = WBC × % (band + PMN). Although the lower unless there is evidence suggesting a more chronic and severe form tion. Severe malnutrition can cause neutropenia directly or via folate
limit of absolute neutrophil count is 1,500–1,800 at most ages, the of neutropenia that is not likely to resolve quickly. The most reason- and/or vitamin B12 deficiency (the latter two usually associated with
risk of serious infection increases when the ANC is <500. Acute neu- able approach in uncomplicated illnesses is simply to repeat the anemia or pancytopenia, macrocytosis, macro-ovalocytosis and hy-
tropenia is generally evaluated when the ANC is <1,000. The more CBC 3–4 weeks later when the neutropenia has usually recovered. persegmentation of neutrophils).
extensive evaluation of chronic neutropenia is usually undertaken Persistent neutropenia raises the question of hepatitis (A, B or C),
when the ANC is <500, in the absence of other clinical clues to a HIV, or an alternative, nonviral diagnosis such as autoimmune neu- –– Congenital neutropenias can be associated with specific physi-
specific etiology. The average ANC is 200–600 cells/µl lower in peo- tropenia. cal findings, bone abnormalities or metabolic diseases (e.g. hyper-
ple of African descent. glycinuria, methylmalonic aciduria, tyrosinemia).
–– Cyclic neutropenia is sporadic or inherited often in an autoso-
–– History and physical examination must consider whether the
mal-dominant fashion, and is characterized by regular, periodic (21 ± –– Neutropenia may accompany dysgammaglobulinemia as
neutropenia is acute or chronic, occurrence of unexpected infections 4 days) oscillations in the number of peripheral neutrophils from a well as hyper-IgM syndrome. A lymphoproliferative-mediated neu-
(cellulitis, abscess, stomatitis, pneumonia, perirectal infections, and peak usually <1,900 cells/µl to profound neutropenia. The nadir is tropenia may also be associated with circulating large granular
the frequency, symptom-free interval, response to treatment), failure often accompanied by fever, stomatitis and cervical adenitis. Most lymphocytes (i.e. suppressor T cells or NK cells). Paroxysmal noctur-
to thrive, drugs/toxins, family history of leukopenia or unusual infec- of these children have symptoms, usually cyclical, which prompt nal hemoglobinuria (PNH) is often accompanied by anemia and oc-
tions. Physical examination focuses on failure to thrive or recent further evaluation (including sequential neutrophil counts). These casionally neutropenia and thrombocytopenia. Diagnosis is
weight loss. Scarred tympanic membranes, postnasal drip or cervi- patients have mutations in the neutrophil elastase gene. G-CSF can established by the failure of expression of CD16 on circulating neu-
cal adenopathy suggest chronic respiratory infection. Recurrent be helpful in preventing infections. trophils.
cough, wheezing or chest deformity may indicate pulmonary dis-
ease. Lymphadenopathy, hepatosplenomegaly, pallor, wasting or –– No specific diagnosis is established in many children with
weight loss suggests a systemic disease. Gingivitis and aphthous ul- chronic granulocytopenia. There is often no history of complicating Selected reading
cers often accompany chronic neutropenia. Documentation of fevers infections in spite of fairly severe neutropenia. This was labeled as
Bernini JC: Diagnosis and management of chronic neutropenia
is important, but rectal temperatures should be avoided because of chronic benign granulocytopenia of childhood in young children,
during childhood. Pediatr Clin North Am 1996;43:773–792.
the risk of initiating perirectal cellulitis. Examine the entire CBC and but most are now believed to have autoimmune neutropenia. There
blood smear. remain many children and young adults who have chronic benign Boxer LA, Blackwood RA: Leukocyte disorders: Quantitative
neutropenia who are asymptomatic and no underlying diagnosis is and qualitative disorders of the neutrophil. Pediatr Rev 1996;
–– Drugs frequently cause neutropenia by immune, toxic, or hy-
ever established. Occasionally, these are familial. 17:19–28.
persensitivity reactions. While neutropenia is expected with chemo-
Dale DC, Person RE, Bolyard AA, et al: Mutations in the gene en-
therapy, drug-induced neutropenia usually involves an idiosyncratic –– Bone marrow replacement with leukemia, lymphoma or
coding neutrophil elastase in congenital and cyclic neutropenia.
reaction. This most commonly involves antimicrobials (penicillins metastatic solid tumors that infiltrate the bone marrow more often
Blood 2000;1996:2317–2322.
and sulfonamides), antirheumatics (gold, phenylbutazone, penicil- cause pancytopenia rather than isolated neutropenia. Bone marrow
lamine, ibuprofen), sedatives (barbiturates and benzodiazepines), biopsy is invaluable in assessing marrow cellularity, which is
phenothiazines, and antithyroid drugs. Toxic exposures are uncom- markedly diminished in aplastic anemia and myelofibrosis. Severe
mon. Very rarely the neutrophil fails to recover after discontinuation congenital neutropenia (Kostmann syndrome) is characterized by an
of the drug. arrest in myeloid maturation at the promyelocyte stage of the bone
marrow resulting in an ANC less than 200/µl; it is also often caused
–– Marked splenomegaly (usually at or below the umbilicus) can
by mutations in the neutrophil elastase gene. These patients suffer
cause hypersplenism with resulting neutropenia, usually accompa- from recurrent severe pyogenic infections, especially of the skin,
nied by moderate thrombocytopenia and anemia. Milder degrees of mouth, and rectum. Marrow cytogenetics is important for diagnos-
splenomegaly often accompany many of the illnesses which cause ing myelodysplasia. Myelokathexis can also be diagnosed by mar-
neutropenia. row findings. In general, neutropenia is caused rarely by intrinsic
defects in myeloid cells or their progenitors.
–– Bacterial sepsis frequently causes neutropenia, but also con-
sider that pre-existing severe neutropenia can result in a high risk of –– This most common cause of chronic neutropenia in infants is
43 bacterial or fungal sepsis. Empiric, broad-spectrum antibiotic thera- identified by the presence of antineutrophil antibody. Most patients
py may be indicated, particularly if the ANC is below 500 cells/µl. have a fairly benign clinical course with few if any infections. Isoim-
The CBC should be repeated 3–4 weeks later to ensure that the neu- mune neutropenia, analogous to Rh isoimmunization, occurs tran-
tropenia was a result of the infection and that it has resolved. If the siently in neonates and may last for several weeks.
neutropenia persists, further evaluation may be indicated.
7
7
Abbreviated O2– production glutathione hypogammaglobulinemia
anomaly 햷 Specific granule
&
7
7
Abnormal chemotaxis only complement
Partial albinism, abnormal granules
7
7
PMN actin deficiency deficiency
if normal, consider serial ANCs to mentemia syndromes 헂
7
7
7
45
White Cell Disorders L.A. Boxer The child with recurrent infection: leukocyte dysfunction
Reticuloendothelial Disorders P. Ancliff · I. Hann Lymphadenopathy. 1. Generalized lymphadenopathy
Lymphadenopathy . 1. Generalized lymphadenopathy
History: duration, fever, weight loss, night sweats – evidence of systemic
46 infection, inflammatory disease or neoplasia, sexual history, travel Respiratory difficulties, Possible superior vena cava
wheezing, facial syndrome
swelling, plethora or (see ‘Recognition and management
Examination: distribution (localized or generalized) , orthopnea of superior vena cava syndrome’, p 96)
size, consistency, tenderness, warmth, surrounding erythema
Localized adenopathy
(see ‘Lymphadenopathy.
Generalized adenopathy 2. Localized adenopathy’, p 48)
Flu-like symptoms, rhinitis, pharyngitis, CBC, blood smear, ESR, LDH, uric acid, renal and hepatic function, ± CXR Suggestive of collagen vascular
malaise, headache
disease or chronic inflammation
Fever expected but not specific Vasculitic rash, arthritis/arthralgia
Nodes relatively soft, often tender, non- Weight loss, night sweat, bone pain Symptoms often chronic
erythematous, rash, mild-to-moderate Painless, progressive node enlargement and/or supraclavicular adenopathy, Medication use
hepatosplenomegaly nodes firm/rubbery and fixed to skin/underlying tissues ± & ESR, abnormal renal function
Normal CBC or mild leukopenia, Abnormal CBC, smear, & uric acid, & LDH, abnormal CXR
± atypical lymphocytes, normal uric acid
ESR often normal if viral illness
High risk for malignancy Still consider malignancy if No Yes
Uric acid, Ca, P, K, BUN, CXR no other etiology apparent
Infection likely Lymph node biopsy and/or bone marrow
Consider EBV, CMV, varicella, aspirate or biopsy ± cultures Leukocyte assays Anti-ds-DNA antibodies
rubella, mumps, toxoplasmosis, (marrow studies first if CBC consistent for storage diseases and ACE
measles, chlamydia, HIV, TB, with bone marrow involvement) if very prominent Drug use
syphilis, fungal splenomegaly
Consider collagen vascular and
inflammatory disorders
(see ‘Management of – for malignancy + for malignancy & uric acid, P, K, BUN
biopsy tissue in
Positive
Lymph node biopsy Treat/observe as appropriate Chemotherapy ± radiation protocol for Therapy as per specific Therapy dependent on the
and/or bone marrow for the specific infection each specific malignancy or as per protocol storage disease specific diagnosis and the
aspirate ± biopsy or inflammatory disorder for the specific histiocytic disorder individual presentation
–– Lymph nodes are not generally palpable in the neo-
and physical examinations provide any concerns that this –– Malignant nodes are often fixed to the skin and/or
nate. During childhood, nodes are not considered enlarged may be more than a simple, transient viral illness, laborato- underlying tissues and the nodes are often large, firm or
unless at least 1 cm in diameter for cervical and axillary ry tests are essential. CBC, blood smear, ESR, LDH, uric rubbery and may be matted together. Supraclavicular ade-
nodes or 1.5 cm for inguinal nodes. Most children have acid, as well as renal and hepatic function studies, are rea- nopathy is very concerning and usually indicative of malig-
shotty adenopathy in the cervical, posterior auricular and sonable initial screening studies. EBV titers are done if the nancy or other serious pathology. It must be remembered
inguinal areas. Even using these standards, lymphadeno- clinical picture suggests infectious mononucleosis or if a that not all malignant infiltration presents with large lymph
pathy is still very common in children and is most often due substantial percentage of atypical lymphocytes are noted nodes. In particular, in acute lymphoblastic leukemia shotty
to routine, uncomplicated intercurrent infections. on blood smear. Clearly, normal blood cell counts and mild- lymphadenopathy can be a presenting feature – clues to
ly raised transaminases suggest a viral illness whereas this diagnosis will be obtained from the CBC. The lymph-
–– History should include travel (e.g. tuberculosis, histo-
depressed hemoglobin and platelet count with &7 WBC adenopathy of Hodgkin lymphoma may wax and wane
plasmosis), possible food contamination (brucella, myco- would suggest bone marrow infiltration. Examination of leading to apparent ‘responses’ to antibiotic therapy and
bacterium), pets (cats for cat scratch or toxoplasmosis), the blood film may yield further clues before proceeding to diagnostic delay. Note that tuberculous nodes can be firm,
medications, allergies, and sexual history (HIV, lympho- possible lymph node biopsy and/or bone marrow examina- matted and fixed to surrounding tissues, leading to diag-
granuloma venereum). Fever, drenching night sweats (clas- tion. LDH often increases in malignant disorders, but also nostic confusion.
sically necessitating changing of bedclothes) and weight does in hepatic disease and hemolysis. Elevated uric acid,
loss of >10% in the previous 6 months represent the ‘B’ P and BUN and lowered Ca are components of tumor lysis –– Although storage diseases cause adenopathy, mas-
symptoms classically associated with Hodgkin disease; syndrome and suggest a malignancy. A CXR should be done sive splenomegaly is usually much more obvious. Contem-
these are not specific for this disorder, but the latter two if there are any chest symptoms, adenopathy surrounding plation of such a diagnosis without splenomegaly should
particularly necessitate further evaluation. the thorax or concerns about malignancy; it may identify, prompt repeat abdominal examination with splenic palpa-
among others, mediastinal adenopathy due to malignancy, tion beginning in the left iliac fossa.
–– Generalized (>
_ 2 non-contiguous lymph node groups) mycobacterium or sarcoidosis. Mediastinal widening on
lymphadenopathy is indicative of systemic disease. Local- CXR is most likely due to malignancy (see ‘Assessment of a –– A number of drugs can result in lymphadenopathy
ized enlargement suggests a local cause in the area of mediastinal mass’, p 76). alone or as part of a systemic lupus erythematosus-like dis-
drainage. Concomitant splenomegaly suggests a systemic order, including phenytoin, isoniazid, hydralazine, dapsone,
disorder, but this occurs with generalized adenopathy due
–– ‘Flu-like’ symptoms without weight loss suggests a
procainamide and allopurinol.
to malignant or benign disorders. The evaluation of local- viral illness. Weight loss (especially >10%) infers a more
ized lymphadenopathy is continued in the next algorithm, serious diagnosis such as malignancy, tuberculosis, or HIV –– These symptoms suggest mediastinal adenopathy or
‘Lymphadenopathy. 2. Localized adenopathy’, p 48. infection. The clinical picture, a high WBC or shift to the left a mass causing superior vena cava syndrome, or a malig-
and an elevated ESR suggest bacterial infection. Consider nant effusion (see ‘Recognition and management of superi-
–– Tenderness, warmth, and erythema are usually due
TB exposure, high-risk sexual activity, substance abuse, and or vena cava syndrome’, p 96).
to bacterial infection. Fluctuance suggests secondary history of transfusions.
abscess development. These findings are usually localized.
–– No specific diagnosis is established in many children
Selected reading
–– One of the difficult decisions is which initial laborato-
who are presumed to have a viral illness. In such children,
Ghirardelli ML, Jemos V, Gobbi PG: Diagnostic
ry studies to perform. Although the vast majority of minor the possibility of an underlying malignancy should always
approach to lymph node enlargement. Haematologica
lymphadenopathy and flu-like symptoms in children are be kept in mind. If the adenopathy continues to increase
1999;84:242–247.
due to minor viral illness, these can be presenting features over a 2-week period or fails to resolve over a 6-week peri-
of leukemia and other malignancies. In a child whose od, or there are other changes (e.g. development of a more Grossman M, Shiramizu B: Evaluation of lymphadeno-
clinical picture is very typical of a viral illness and whose firm or matted consistency of the nodes, supraclavicular pathy in children. Curr Opin Pediatr 1994;6:68–76.
adenopathy is mild, it may be reasonable to simply follow adenopathy, weight loss, night sweats or respiratory dis-
Sills R, Jorgensen S: Lymphadenopathy. Emedicine
the child without laboratory studies. However, if the history tress), biopsy should then be done.
Pediatric Medicine 2002 (http://emedicine.com).
47
햲
Lymphadenopathy . 2. Localized adenopathy
History: recent fever, weight loss, night sweats, duration of symptoms, ‘B symptoms’, recent
48
injuries/wounds/infections/surgery/dental complications, pets, sexual history, recent travel 햲
Examination: involves a single set of nodes or contiguous sets of nodes – size, consistency,
warmth, erythema, tenderness, fluctuance, dental disease, rashes, wounds 햳
Localized
Scalp Cat-scratch disease 햵 Streptococcal Local infection of Malignancy 햺 Infections of ALL Non-Hodgkin Infections of
infections 햴 Eye infections tonsillitis 햶 teeth and mouth TB arm and axilla Hodgkin disease lymphoma leg/groin
Rubella Skin infections Upper respiratory Acute lymphadenitis Histoplasmosis Cat-scratch Non-Hodgkin Hodgkin disease Syphilis
Roseola Tularemia infection Hodgkin or non- Coccidioidomycosis disease 햵 lymphoma Mesenteric adenitis Lymphogranuloma
Malignancy Acute adenitis Hodgkin lymphoma Reactions to Neuroblastoma Other malignancies venereum
EBV Tuberculosis immunizations Tuberculosis Plague
Malignancy 햷 Malignancy Malignancy Fungal infection
Kawasaki disease 햸 Teratoma
Toxoplasmosis Thyroid cancer
Nonlymphoid Thymoma
masses 햹 Sarcoidosis 햻
Sinus histiocytosis Cystic fibrosis
Likely acute adenitis or related Suspected viral illness – observe for 2–6 weeks Suspicion of malignancy – CBC, blood smear, ? if this is a non-lymphoid mass
to bacterial infection renal/hepatic function, LDH, uric acid, Ca, P, CXR,
possible CT scan of involved region
Laboratory studies if ? about diagnosis, Radiologic studies – US,
Trial of antibiotics, surgical progressing adenopathy, new symptoms plain films, ? CT or MRI
drainage if suppurative or signs or failure to resolve in 6 weeks Early lymph nodes biopsy (and/or marrow aspirate/biopsy if CBC
evidence of marrow involvement); biopsy the largest, most
recently enlarging lymph node and not always the easiest one
Possible biopsy or excision
Failure to improve, symptoms or laboratory findings suggestive of malignancy depending on individual case
Splenomegaly
50 History and physical examination If any doubt that this is not a spleen,
do abdominal ultrasound
Suggestive of
non-hematological systemic
disease such as
SLE
Rheumatoid arthritis & Lymphocytes &, 7 or normal WBC Growth retardation African descent
Inflammatory bowel disease Atypical Neutropenia ‘Erlenmeyer’ flask ± Massive spleen
Celiac disease mononuclear cells Thrombocytopenia deformity of femur (infant)
Sarcoidosis Adenopathy ± Blasts in ? Cytopenias Hemolytic anemia
Langerhans cell histiocytosis peripheral blood Often massive Sickle cells on
splenomegaly blood smear
± CBC, ESR, Appropriate Bone marrow ± EBV, Malaria film Bone Lymph node 7 Leukocyte Hemoglobin electropheresis Abdominal US
LFTs which studies for aspirate with CMV, HIV Toxoplasmosis marrow biopsy or -glucosidase with Doppler
would be these diagnoses hemophago- serology titers aspirate bone marrow studies
normal if suspected cytosis Blood culture if abnormal Thrombophilia
blood counts screen
Normal Inflammatory Hemophago- Viral Malaria Leukemia Non-Hodgkin Gaucher disease Thalassemia Sickle cell Hemolytic Congestion
childhood or cytic lympho- infection Leishmaniasis lymphoma Other storage major disease
anemia Splenic cyst(s)
splenic autoimmune histiocytosis Toxoplasmosis Hodgkin disease diseases Hemoglobin H Hemangioma
tip disease Bacterial Langerhans cell disease
endocarditis histiocytosis
(see ‘Assessment of a child with suspected leukemia’, p 74) (see ‘Hemolytic anemia’, p 18)
–– Massive splenomegaly, defined as a spleen below the
–– Visceral leishmaniasis (Kala-Azar) is caused by proto-
carrier state of either ␣- or -thalassemia minor is not asso-
level of the umbilicus, has few causes in children – splenic zoan organisms belonging to the Leishmania donovani ciated with splenomegaly. The more severe forms of ␣-tha-
sequestration in sickle cell disease, thalassemia major, complex transmitted by various species of sand fly. Visceral lassemia (hemoglobin H disease and ␣-thalassemia major)
Gaucher disease and, occasionally, leukemia or portal hy- Leishmaniasis involves the liver, spleen, bone marrow and are associated with splenomegaly.
pertension. The causes of lesser degrees of splenomegaly lymph nodes, and can be acquired on a short vacation to an
are innumerable and require careful history and examina- affected area. Incubation is typically 1–3 months. Diagnosis
–– The spleen removes damaged red cells and thus is
tion before extensive laboratory investigation. A very firm is based upon identification of ‘L-D bodies’ in macrophages often palpable in the early years of life in a child with sickle
spleen is more consistent with non-infectious etiologies. in the bone marrow or specific serology. Relatively easily cell disease. However, by adulthood the spleen has been
Caution should be observed in assuming that a left upper treated in the immunocompetent host but can be much replaced by a fibrous nubbin secondary to multiple vaso-
quadrant abdominal mass is a spleen. Retroperitoneal tu- harder to eradicate in the immune suppressed. occlusive events – auto-splenectomy. Splenomegaly can
mors (neuroblastoma and Wilms tumor) can be mistaken persist into adulthood in patients with hemoglobin S-C dis-
for a spleen. Abdominal ultrasound can distinguish splenic –– Sixty percent of children with ALL present with fever.
ease and sickle cell -thalassemia. Splenic sequestration
from nonsplenic masses if in any doubt. Most have neutropenia, anemia and thrombocytopenia, crisis involves the sudden pooling of a large proportion of
and half of them have elevated WBCs. Those with low the blood volume in the spleen of infants with sickle cell
–– A soft, thin spleen tip can be palpated in 15% of
WBC counts may not have blasts in the peripheral blood. disease with consequent and often massive splenomegaly;
neonates, 10% of healthy children and 5% of adolescents Children with lymphadenopathy due to non-Hodgkin lym- it can be rapidly fatal if not recognized and treated prompt-
and is not indicative of any pathological process. Baseline phoma can also present with marrow involvement. The ly. Parents should be taught splenic palpation to allow for
investigations, particularly if there are other clinical con- distinction between these disorders is ill defined, with early recognition and treatment.
cerning issues, should include a CBC, ESR, and kidney and many using the arbitrary criteria of more than 25% of blasts
liver profiles; however, a soft spleen tip in an otherwise in the marrow as signifying leukemia and not lymphoma.
–– Jaundice in the absence of any overt liver disease
well child does not always necessitate further investigation. With marrow involvement it may be possible to diagnosis can be an early indicator of hemolysis. Pallor and anemia
Associated hepatomegaly can occur in most disorders the lymphoma using pathology and flow cytometry on are usually noted. The hyperbilirubinemia is unconjugated
causing splenomegaly, but would not be expected in the bone marrow, avoiding lymph node biopsy. (see ‘Hemolytic anemia’, p 18).
well child with a palpable spleen tip.
–– Gaucher disease is divided into 3 subtypes and is
–– Neonatal umbilical vein catheterization and conse-
–– A rare but important diagnosis as prompt treatment
due to deficiency of the enzyme -glucosidase (glucocere- quent thrombosis causing portal hypertension is becoming
can be life-saving. Hemophagocytic lymphohistiocytosis is brosidase). Large lipid-filled macrophages (Gaucher cells) a much more common cause of isolated splenomegaly in
divided into primary – an autosomal-recessive disease that accumulate in the bone marrow, spleen and liver. Type I the developed world. A detailed ultrasound examination
typically has a florid presentation in infancy, and secondary (& prevalence in Ashkenazi Jews) is the most common and with Doppler estimation of portal pressures and flow is nec-
– (sporadic) that occurs at an older age. The diagnosis is leads to splenomegaly which may be massive by adoles- essary to confirm the diagnosis. Pancytopenia can result
made by the combination of peripheral cytopenias, bone cence. Hypersplenism (pooling of cellular components of from ‘hypersplenism’. Splenomegaly secondary to cardiac
marrow hemophagocytosis, coagulopathy (with hypo- blood within the spleen) is common. Bony abnormalities are or liver failure is uncommon in children and would not nor-
fibrinogenemia predominating), & ferritin (may be &&&) caused by lipid accumulation in the bone marrow. The diag- mally provoke a hematology referral. Thrombophilia is be-
and & fasting triglycerides. The primary form requires nosis is now established based on leukocyte -glucosidase coming increasingly recognized as a cause of portal hyper-
bone marrow transplantation for cure. activity and no longer requires bone marrow examination. tension in children and certainly all children without a histo-
Types II and III are much rarer and are characterized by pro- ry of umbilical vein catheterization require a thrombophilia
–– Serologies are often not necessary in mild cases,
gressive neurological disease (absent in type I) and an ex- screen (see ‘Thrombophilia evaluation for a newborn infant
so clinical judgement should be used. HIV should be con- tremely fulminant course. Replacement recombinant enzyme with thrombosis’, p 70).
sidered with appropriate risk factors or chronicity. therapy (Cerezyme®) is now available and has produced ben-
efit in type I disease. Niemann-Pick type B, Hunters and Hur-
–– Hyper-reactive malarial splenomegaly syndrome, for-
lers disease are other rare causes of splenomegaly second- Selected reading
merly known as tropical splenomegaly, occurs widely ary to infiltration because of metabolic enzyme deficiency.
Hall GW, Hann IM: Investigating splenomegaly.
throughout Africa, India and SE Asia and is probably
51 Curr Paediatr 1998;8:220–224.
caused by an immune ‘over-reaction’ to chronic malaria in- –– Untreated -thalassemia major and intermedia can
fection. It is characterised by massive splenomegaly, weight lead to massive splenomegaly, secondary to extra-medullary Hoie W, Sills R: Splenomegaly. Emedicine Pediatric
loss, & anti-malaria antibody titres, & serum IgM and a hematopoiesis. Hypertransfusion (typically aiming to keep Medicine, 2002 (http://emedicine.com).
slow resolution with prolonged anti-malarial prophylaxis. the nadir Hb >10 g/dl) suppresses the extramedullary
Kumar M: Tropical splenomegaly. Emedicine Pediatric
hematopoiesis and may reduce the splenomegaly. The
Medicine, 2002 (http://emedicine.com).
Platelet count
Normal Decreased
Acute illness Corrects 1:1 mix of patient: normal plasma Does not correct
FVIII:C, VWF:RCo, – +
VWFAg
Normal
Abnormal PT + PTT
Oral anticoagulants
FIX, XI, XII Liver disease
Vitamin K deficiency
Mild DIC
FII, V, or X deficiency
Meningococcus ? Platelet dysfunction VWD FXI or XII deficiency VWD Only PT abnormal 1:1 mix corrects Lupus-like
Purpura fulminans Child Variant VWD Mild hemophilia A Mild hemophilia B Hemophilia A or B Early in oral anticogulant 7 fibrinogen anticoagulant
Varicella abuse Mild hemophilia or or carrier or carrier Severe FXI deficiency therapy Dysfibrinogenemia Heparin
Pneumococcus carrier of hemophilia Prekallikrein or FVII deficiency Does not correct (confirm with
Mild DIC FXIII or mild FXI high-molecular weight Abnormal PT, PTT, TT and Reptilase normal: & TT + normal
Protein C, S or deficiency kininogen deficiency thrombocytopenia Heparin reptilase time)
ATIII deficiency DIC Reptilase time &:
(see ‘Plalelet dysfunction’, p 60) Severe liver disease Fibrin split products
햲 –– Bleeding in a child can present as petechiae, purpura,
쏹 wound healing, but normal coagulation screen; a specific 햷 –– A prolonged PT is usually associated with a prolonged
쏹
epistaxis/mucosal bleeding, hematomas, gastrointestinal assay is required for this diagnosis. Vascular disorders PTT, most often due to oral anticoagulants, liver disease,
and genitourinary bleeding, excessive bleeding with proce- causing purpura include Henoch-Schönlein purpura, infec- and vitamin K deficiency, and rarely to isolated deficiencies
dures and surgery, as well as intracranial hemorrhage. Oth- tions, collagen vascular diseases, and collagen deficiencies of factors II, V or X. The TT will be normal with oral anti-
er children present with an incidental abnormal coagulation (Ehlers-Danlos syndrome and Marfan syndrome). coagulants and vitamin K deficiency, but may be abnormal
screen, often during presurgical screening, in the absence in liver disease because of hypofibrinogenemia and/or
of clinical bleeding. Consider a platelet or vascular disorder 햴 –– Normal platelet count and abnormal coagulation
쏹 elevated FSP. Rare isolated factor VII deficiency can cause
if the bleeding is mucosal in nature or a clotting factor defi- screen suggests a clotting factor deficiency or an anticoa- an isolated prolongation of the PT, but this is usually seen
ciency if it consists of deep-seated hematomas or gulant. Repeating the abnormal test with a mixture of 1 part at the beginning of oral anticoagulation therapy or vitamin
hemarthroses. Nosebleeds and menorrhagia are the most of patient plasma with 1 part normal plasma will normalize K deficiency; FVII, which is only measured by the PT, falls
common manifestations of von Willebrand disease (VWD). the test when a deficiency of a factor is present, but the much faster (half-life 3–6 h) than the other vitamin K- and
A family history of bleeding in only males suggests hemo- screening test will remain abnormal after mixing if an anti- hepatic-dependent factors. Prolongation of the PTT should
philia A or B. A palpable, purpuric rash with the typical low- coagulant is present. Lupus-like anticoagulants in children be noted within 24–48 h. An abnormal TT suggests heparin
er extremity predominance suggest the vasculitis of are frequent and transient postviral asymptomatic auto- effect or fibrinogen defects.
Henoch-Schönlein purpura. Less well localized rashes are immune reactions. Rarely, they cause thromboembolic dis-
often seen in viral illnesses, but an acutely ill child with a ease and even less often bleeding problems. Lupus-like
purpuric rash should be assumed to have me- anticoagulants usually prolong the PTT. In the rare child in Selected reading
ningococcemia or other bacterial septicemia until proven whom the anticoagulant results in acquired prothrombin
Brogan PA, Raffles A: The management of fever and
otherwise; although these children may develop DIC with deficiency, a bleeding tendency occurs and the PT is pro-
petechiae: Making sense of rash decisions. Arch Dis
low platelets and abnormal coagulation screen this often is longed. The presence of a lupus-like anticoagulant should
Child 2000;83:506–507.
not the case. A purpuric rash which becomes necrotic sug- be confirmed by other phospholipid correction studies, in-
gests purpura fulminans due to viral or bacterial infection, cluding the platelet neutralization test and the Russell Viper Cohen AJ, Kessler CM: Treatment of inherited coagula-
or a deficiency of a natural anticoagulant (protein C, S or venom test (RVVT). Heparin in the patient, or more often tion disorders. Am J Med 1995;99:675–682.
antithrombin). Organomegaly suggests an infiltrative simply contaminating the sample, is frequent in the hospi-
Leung AK, Chan KW: Evaluating the child with purpura.
process: either malignancy or a storage disease. tal setting.
Am Fam Physician 2001;64:419–428.
햳 –– A normal platelet count and normal coagulation
쏹 햵 –– If heparin is present in the patient (or simply the labo-
쏹 Saulsbury FT: Henoch-Schonlein purpura in children:
screen suggests several disorders. If there is an acute illness ratory sample), the TT will always be prolonged if the PTT Report of 100 patients and review of the literature
consider purpura fulminans or mild DIC with infection. If is (the PT may be but is less sensitive to heparin). The repti- (review). Medicine 1999;78:395–409.
the bleeding history is negative and the child is healthy lase (or Ancrod) time utilizes a snake enzyme which per-
Wells LC, Smith JC, Weston VC, Collier J, Rutter N:
consider the possibility of a bruising in a normal, active forms exactly like thrombin except that it is not inhibited by
The child with a non-blanching rash: How likely is
child, or the possibility of child abuse; the appearance of heparin. Therefore, a prolonged TT and a normal reptilase
meningococcal disease? Arch Dis Child 2001;85:218–222.
linear bruises or burns is strongly suspicious of abuse. If time confirm the presence of heparin. Prolongation of both
there is a past history of bleeding consider VWD and obtain the TT and reptilase times are consistent with a fibrinogen Werner EJ: von Willebrand disease in children and
factor VIII coagulant (FVIII:C), ristocetin co-factor which is defect or increased FSP. adolescents (review; 131 refs). Pediatr Clin North Am
the functional von Willebrand factor assay (VWF:RCo), and 1996; 43:683–707.
von Willebrand antigen (VWFAg) activities. FA100 closure 햶 –– If the coagulation screening test corrects with a 1:1
쏹
time, if available, may provide an indicator of VWD and mix of patient and normal plasma, there is a factor deficien-
other platelet dysfunctions that is more accurate than the cy. A markedly abnormal PTT with no history of bleeding
bleeding time (see ‘Platelet dysfunction’, p 60). Mild hemo- suggests factor XII deficiency. Mild abnormalities of the PTT
philia or a hemophiliac carrier may present with normal alone are most often due to vWD, given the 1% incidence of
coagulation studies and a positive history; the PTT may not this disorder in the general population, but can also be due
prolong until the factor level is <30% (normal ~50–150%) to mild factor deficiencies in mild hemophilia A or B or in
53
so mild deficiencies may be missed. Factor XIII deficiency carriers, or due to factor XI deficiency. Severe prolonga-
is a rare coagulation disorder that presents with umbilical tions of the PTT due to factor deficiencies are usually due to
stump hemorrhage, soft tissue hematomas and poor hemophilia, but consider DIC in acutely ill patients.
No
Normal
7
Yes No Medications RBC macroovalocytosis?
7 B12 or 7 RBC folate Signs of portal Eczema Hepatosplenomegaly ill appearing febrile illness
Immunizations
hypertension Recurrent infection Superior vena cava
Irradiation
Platelet >50,000 Small platelets syndrome
Toxins?
± pancytopenia Abdominal mass
B12 or folate deficiency
No
Yes
WBC enzyme assays Biopsy of lymph node, HIV assay Blood culture
Macrothrombocytes 햷 Ultrasonography mass or bone marrow ANA ? antibiotics
Drug-induced 햶 Thick smear Consider tumor lysis U/A
Yes No
Live immunization and superior vena cava Renal function
Irradiation syndromes
Toxins
Other No other Bone marrow
morphologic platelet
platelet change
changes
&/Nl megakaryocytes 7 megakaryocytes
Cyanotic heart disease Syndromes: ITP 햸 Leukemia 햹 Malaria 햺 Wiskott-Aldrich Lymphoma 햽: HIV 햾 Sepsis 햿
Fanconi anemia May-Hegglin Hereditary thrombocytopenia Aplastic anemia Gaucher disease syndrome 햻 Hodgkin Autoimmune or Varicella
Dyskeratosis congenita Hermansky- Bernard-Soulier Drug-induced Portal hypertension Non-Hodgkin connective tissue EBV
Trisomy 13 or 18 Pudlak Amegakaryocytic Hepatic Neuroblastoma disease CMV
Syndromes: Gray platelet thrombocytopenia schistosomiasis Leukemia HUS/TTP + other Malaria
Kasabach-Merritt Myelodysplasia Cavernous Myelodysplasia microangiopathies Dengue hemor-
TAR transformation of Prosthetic cardiac rhagic fever
Alport variants the portal vein valve HIV
ITP is a diagnosis of exclusion HUS
Response to therapy, Hantavirus
if needed (corticosteroids, Parvovirus
IVIg, anti-D antibody), Other viruses
confirms the diagnosis TTP
햲 –– For infants <3 months of age, see ‘Thrombocytopenia
쏹 햷 –– Macrothrombocytes are large platelets whose mean
쏹 햺 –– The most common etiologies of hypersplenism (and
쏹
in the well neonate’ (p 56). Assess bleeding manifestations platelet volume (MPV) exceed the normal 7–11 fl. Young the appropriate initial studies) include cavernous trans-
including bruising, petechiae, epistaxis, and menorrhagia, platelets resulting from rapid turnover are larger, but ab- formation of the portal vein, cirrhosis, and hepatic schisto-
as well as travel, immunizations, HIV risk factors, diet and normally large platelets unrelated to platelet age occur in somiasis (ultrasonography), malaria (thick smears) and
medications. Extensive petechiae and mucosal bleeding are several rare platelet disorders. Gaucher disease (leukocyte enzyme assay).
indicators of greater hemorrhagic risk. Look for congenital
malformations, joint or skin changes, adenopathy, and he- 햸 –– ITP is the most common childhood TP. The usual
쏹 햻 –– Wiskott-Aldrich syndrome is a rare X-linked recessive
쏹
patosplenomegaly. presentation is acute onset of petechiae and bruising in an immunodeficiency. Splenectomy can improve the TP, but is
otherwise well child, often related to a recent viral infection. often followed by overwhelming sepsis and death.
햳 –– Spurious thrombocytopenia (TP) is usually caused by
쏹 CBC shows isolated, marked TP and smear reveals giant
in vitro platelet clumping in anticoagulant and occurs in platelets. Although it is a diagnosis of exclusion, a well-ap- 햽 –– These malignancies may present primarily with
쏹
about 1/1,000 samples. Platelet clumps are noted on blood pearing child who abruptly develops profound TP with an lymphadenopathy or masses. Pancytopenia is more com-
smear. Spurious results also occur if platelets aggregate in otherwise normal CBC almost always has ITP. Bone marrow mon but isolated TP occurs.
the syringe before reaching the anticoagulant, especially studies are not necessary unless the diagnosis is in ques-
with difficulty obtaining the specimen. If suspected, obtain tion or possibly before starting corticosteroids, but would 햾 –– TP occurs in 5–10% of patients with HIV infection and
쏹
a new sample. show increased or normal megakaryocytes. Most children may be the presenting symptom. The TP may respond to
have acute, self-limited disease; 90% regain normal platelet antiviral therapy as well as steroids, IVIG, and splenectomy;
햴 –– It remains difficult to easily distinguish disorders of
쏹 counts within 9–12 months. The most serious complication the TP can remit spontaneously.
platelet destruction and production. Newer studies, such is intracranial hemorrhage (<<1%). Mild-to-moderate dis-
as reticulated platelets may be helpful, but are not widely ease usually requires no specific therapy. If necessary, treat- 햿 –– Septicemia can cause moderate TP in the absence
쏹
available. Bone marrow examination may still be difficult to ment options are: IVIG, Rho (D) immune globulin (only if the of DIC. Other infections, particularly viral, cause TP. During
interpret. Practically, it is more helpful to simply consider child is Rh+), corticosteroids, and splenectomy. The latter is acute Plasmodium falciparum attacks, the platelet count
whether the child appears ill or well. used only for life-threatening bleeding in acute ITP, but may can fall as low as 10,000–20,000/µl.
be used in severe chronic ITP. Platelets are administered on-
햵 –– Several disorders, mostly rare, are associated with
쏹 ly for life-threatening hemorrhage. Most children with 헀 –– Vitamin B12 or folate deficiency can present with TP,
쏹
congenital anomalies. Children with congenital cyanotic chronic ITP ultimately do recover. A minority of children but PMN hypersegmentation, RBC macroovalocytosis
heart disease may have moderate TP. Kasabach-Merritt syn- with chronic ITP have an underlying abnormality, such as or macrocytosis anemia are almost always present (see
drome is consumptive coagulopathy in a cavernous heman- SLE or HIV. The combination of ITP and autoimmune hemo- ‘Macrocytic anemia’, p 10). TP occurs in Fe deficiency when
gioma. Although the hemangioma is usually obvious, it lytic anemia (Evan syndrome) is a much more serious dis- the microcytic anemia is usually obvious.
may be hidden in the viscera. Hemangiomas can resolve order, and is identified by a positive direct Coombs test. ITP
spontaneously, but corticosteroids and interferon may has- often precedes AIHA by months or years. Treatment is often
ten involution. Radiation therapy is rarely used because of necessary. Selected reading
growth impairment and disfigurement. Compression or ex-
Beardsley DS, Nathan DG: Platelet abnormalities in
cision may be associated with uncontrollable hemorrhage. 햹 –– Bone marrow examination is indicated when no etiol-
쏹
infancy and childhood; in Nathan DG, Orkin SH (eds):
Fanconi anemia is a rare autosomal-recessive disorder usu- ogy is apparent. If ITP is likely, a marrow aspirate is often
Hematology of Infancy and Childhood, ed 5. Philadel-
ally associated with multiple physical anomalies. Mild-to- sufficient. If marrow involvement is suspected, a marrow
phia, Saunders, 1998, part 2, chapt 43, pp 1586–1630.
moderate TP or leukopenia as well as macrocytosis often biopsy should also be done. Infiltrative marrow disorders
precedes the eventual pancytopenia. TAR (thrombocytope- commonly present with lethargy, fever, infection, and bone Bussel JB: Autoimmune thrombocytopenic purpura.
nia and absent radii) is an autosomal-recessive syndrome pain; a leukocytosis with blast cells on smear or pancytope- Pediatr Clin North Am 1990;4:179–191.
with extremity deformity. Dyskeratosis congenita is a rare nia is usually present. Replacement of normal marrow with
Cheerva AC: Kasabach-Merritt syndrome; in Jones GR
disorder with multiple anomalies (e.g. nail dystrophy, skin blasts confirms the diagnosis, usually leukemia but occa-
(ed): Pediatric Medicine. Emedicine.com 2002
pigmentation, leukoplakia, eyes and teeth) in which TP or sionally a solid tumor. Marrow examination also identifies
(http://emedicine.com).
anemia precedes what ultimately becomes pancytopenia. bone marrow failure; aplastic anemia usually presents with
55
pancytopenia but may initially demonstrate only TP. Rarely, Meideiros D, Buchanan G: Current controversies in the
햶 –– Drug-induced TPs are most often due to quinine,
쏹 pure megakaryocytic hypoplasia, with isolated TP, occurs management of idiopathic thrombocytopenic purpura
quinidine, sulfa drugs, heparin and anticonvulsants. Attenu- due to congenital disease or drugs. Hereditary TP, usually during childhood. Pediatr Clin North Am 1996;43:
ated vaccines, particularly measles and varicella, can cause with autosomal-dominant inheritance, often presents with 757–772.
mild-to-moderate thrombocytopenia. normal-sized platelets and normal numbers of megakaryo-
cytes in the marrow.
Congenital anomalies History, examination, CBC, blood smear evaluation, maternal platelet count 햲 If there is no obvious etiology for the TP,
bacterial sepsis must be considered 헁
Maternal history positive Neonatal TP in siblings 햽 Nl CBC and smear Maternal history negative
Blood cultures,
prophylactic antibiotics
Mild TP
Maternal TP 햷 Maternal 햻 Platelets <20,000–30,000 햾 Platelet >20,000–30,000
No bleeding
drug use ± clinical bleeding No bleeding
7
Platelets <50,000
Preeclampsia 햹
7
IVIg <20,000
HELLP syndrome Transfuse maternal No or transient Persistent
DIC platelets & platelets & platelets
Hyperthyroidism
Viral illness
Transfuse washed, Count stable Abnormal platelet Abnormal Hb, WBC,
Platelet <50,000: irradiated maternal or increasing size ± other morpho- ANC, RBC indices or
IVIg platelets logic changes 헂 RBC fragments
? Corticosteroids IVIg 1 g/kg × 1–3
Random donor days
platelet transfu-
sions if bleeding
(which is unusual)
Platelet Ag Persistent 햿 No or only
and Ab studies & platelets transient
on parents 헀 posttransfusion & platelets
Early sepsis 헄
7
Blueberry muffin lesions Neonatal Placenta infarcts Drug-induced NAIT Neonatal Syndromes Bone marrow
congenital infection 햳 autoimmune Chorioangioma TP autoimmune Viral infection Large platelets infiltration 헃
Hemangiomas 햴
7
햲
Thrombocytopenia in the ill neonate
58 History, examination, CBC, blood smear evaluation 햳 Any etiology of thrombocytopenia (see 'Thrombocytopenia
that occurs in the well child in the well neonate', p 56)
Platelets 100,000–149,000/µl Platelets <100,000/µl If platelets <50,000 ? Cranial ultrasound to R/O intracranial hemorrhage resulting
from severe TP of any etiology
&
>150,000 No
further evaluation
Follow platelet count 햴
&
100,000–149,000
Continue to follow
PTT, PT, TT
Polycythemia 햵 Erythroblastosis Etiologies RDS 햹 Infection 햺 Perinatal Unknown NEC 햾 Metabolic Thrombosis 헀 Drug-induced
Cyanotic congenital fetalis 햶 Acute infection Pulmonary Viral asphyxia 햻 etiology 햽 defects 햿
heart disease Exchange Asphyxia hypertension Bacterial
transfusion RDS Meconium aspiration Fungal
Phototherapy Meconium aspiration Mechanical
Obstetrical complications ventilation Ongoing
Shock re-evaluation
Thrombosis if platelets
Severe hemolytic disease <50,000
of the newborn
Severe hepatic disease
TP usually mild enough not to Treat underlying disease Supportive care - Platelet transfusions to maintain count >20,000 in stable full-term neonates, Remove catheter Stop drug
require transfusion except in DIC Maintain platelets >50,000 with hemorrhage, surgery, or more extremely preterm infants 햸 when possible
due to erythroblastosis fetalis >50,000 with transfusions 햸 Observe for DIC 헀 LMWH
Maintain fibrinogen ?? Thrombolytic
>1.0 g/l and PT WNL with therapy 헁
FFP ± cyroprecipitate
쏹 –– Thrombocytopenia (TP) is much more common in the
햲 noted in the algorithm. Treatment of DIC depends on the 쏹 –– Neonates with no identified etiology usually have
햽
ill neonate. Any disorder that affects a well neonate can al- ability to diagnosis and treat the underlying cause. It is not platelet counts of 50,000–100,000 and are more often pre-
so affect an ill neonate (such as neonatal alloimmune TP), clear that hemostatic management alone improves the term. If the TP is severe, ongoing reevaluation is more likely
but many other disorders are only likely to cause TP in a prognosis. to reveal an etiology.
sick newborn. While 0.5–0.9% of all neonates have TP, it oc-
curs in ~25% of neonates admitted to tertiary neonatal in- 쏹 –– There is no scientific evidence in neonates for a pre-
햸 쏹 –– 80–90% of infants with necrotizing enterocolitis have
햾
tensive care units, and in 20% of these the platelet count is cise platelet number which necessitates platelet transfu- TP although most do not have DIC.
below 50,000. The pattern of TP in ill neonates is often con- sion. A common approach is to transfuse to maintain a
sistent; 75% have TP by day 2, the nadir is on day 4 and platelet count of 20,000 in all neonates in general, and a lev- 쏹 –– Several metabolic defects cause TP as well as lethar-
햿
86% are normal by day 10. The etiology of TP is not estab- el of 50,000 in neonates with other hemostatic compromise, gy, acidosis and failure to thrive, including isovaleric, propi-
lished in 60% of sick neonates. such as extreme prematurity, DIC, or hemostatic challenge, onic and methylmalonic acidemias as well as holocarboxy-
such as surgery. Random donor platelets which are ABO lase synthetase deficiency.
쏹 –– The normal platelet count in premature infants is in
햳 and Rh compatible are usually used, and it is reasonable to
the same general range as more mature infants, older chil- confirm a rise in platelet count an hour later (especially 쏹 –– Large thrombi consume platelets and can cause TP.
헀
dren and adults (150,000–400,000/µl). when the etiology of the TP is not clear and it is the first These are most commonly associated with central venous
transfusion given). Transfusion of 0.2 units of platelets/kg catheters and the renal veins, but can also involve the sagit-
쏹 –– The significance of platelet counts of 100,000–150,000
햴 of body weight should increase the platelet count tal sinus. A pulseless extremity due to arterial thrombosis
is unclear in this group; these babies are usually observed, 75,000–100,000; practically 10–15 ml/kg of standard platelet may initiate DIC.
but evaluated if the platelet count falls to <100,000. Depend- concentrates are given, and these transfused platelets
ing on the clinical status of the infant, the count can be re- should survive 3–5 days unless the TP is destructive in 쏹 –– The treatment of thrombosis is complex. If a catheter
헁
peated daily if acutely ill or every few days if stable. nature. If there is a question of survival of these platelets, is involved, it should be removed if possible. Low-molecu-
check a count at 1 and 4 h and then daily. Platelet trans- lar-weight heparin can be effective. The role of systemic
쏹 –– Polycythemia alone or in association with cyanotic
햵 fusions in the neonate are best irradiated (especially if from thrombolytic therapy remains unclear.
congenital heart disease causes TP. blood relatives), CMV safe and leukodepleted.
햲
Platelet dysfunction
Document sites, duration and amount of bleeding especially epistaxis, menorrhagia, mucosal bleeding,
60
history of systemic illness, medications, family history.
Examination documents bleeding and signs of systemic disease 햳
Normal upon
repeat testing VW multimer
Abnormal Normal assay
Platelet aggregation
Abnormal
studies 햶 Normal Abnormal
CBC and
blood smear Some very large platelets
+ abnormal ristocetin platelet
Abnormal
7
aggregation Bernard-Soulier
Large, pale, ghost-like platelets
7
gray platelet syndrome
Drug-induced Uremia MDS Intrinsic platelet X-linked thrombo- Wiskott-Aldrich Large platelet, PMN Dohle bodies ITP
Liver disease dysfunction cytopenia Other macro-
7
Underlying May-Hegglin anomaly
platelet dysfunction Glanzmann Amegakaryocytosis Other macrothrombocytopenias thrombocytopenias
7
Stop drug Manage BMA DDAVP Type I VWD Type 2A, 2B, 3, platelet-type Splenectomy may DDAVP may 7 bleeding Platelet dysfunction can
7 bleeding
7
if possible underlying BMB Rarely platelet DDAVP VWF replacement Platelet transfusions rarely be seen in ITP but 7
disease transfusion challenge Platelet transfusion for latter BMT needed platelets more important
쏹 –– Consider platelet dysfunction in patients with bleed-
햲 lation of guanidinosuccinic acid and nitric oxide, which in- while type 2B will be worsened by DDAVP therapy. Types
ing symptoms and normal platelet counts, PTT, PT and TT. hibit platelet aggregation. Dialysis removes these toxins 2B and 3 generally require replacement with human factor
They should also be considered in occasional patients with and improves platelet function. DDAVP can improve platelet VIII concentrates that also contain vWf. The rare platelet-
mild thrombocytopenia who have bleeding symptoms dis- function. type VWD requires platelet transfusion for treatment of
proportional in severity to the degree of thrombocytopenia. bleeding episodes.
Whether acquired or inherited, these disorders are usually 쏹 –– In the presence of platelet-type bleeding symptoms
햶
mild in severity and may not require any therapy. Bleeding and the absence of drugs, systemic disease or VWD, further 쏹 –– Small platelet size is associated with X-linked reces-
햸
is generally mucocutaneous in nature and not life threaten- testing for intrinsic platelet defects should be done. Bleed- sive Wiskott-Aldrich syndrome and a less severe variant
ing except in severe trauma, major surgery, the rare CNS ing times are too unreliable to be useful in most situations. X-linked thrombocytopenia. Wiskott-Aldrich is characterized
hemorrhage or a concomitant coagulation defect. Clinically PFA-100 analysis is a newer diagnostic test that is finding by immunodeficiency, eczema and thrombocytopenia.
significant platelet dysfunction very rarely presents in the more utility than bleeding times, but is not widely available. Small platelet size is also associated with poor marrow
newborn. Platelet aggregation studies can identify intrinsic platelet production as seen in congenital amegakaryocytosis; these
defects (as opposed to extrinsic defects like VWD where a patients exhibit varying degrees of thrombocytopenia.
쏹 –– Document the site and amount of bleeding and the
햳 plasma defect is not ‘intrinsic’ to the platelet). A heteroge-
duration of symptoms. Bleeding symptoms are most neous group of inherited defects in platelet secretion and 쏹 –– Large platelets are seen in Bernard-Soulier syndrome,
햹
often epistaxis, oral bleeding, bruising, and menorrhagia; signal transduction constitute the most common intrinsic with variable thrombocytopenia. Ristocetin-induced platelet
GI bleeding and CNS bleeding may occur, particularly in platelet dysfunction disorders. They are usually identified aggregation is abnormal. A defective glycoprotein Ib-IX-V
severe but rare disorders like Glanzmann thrombasthenia. by abnormal platelet aggregation in response to epineph- complex is responsible for impaired platelet adhesion to
Platelet dysfunction should not cause deep muscle hema- rine, collagen, ADP, or arachidonic acid. These disorders are vascular endothelium via the von Willebrand factor (vWf).
tomas or joint hemarthroses. Distinguish new onset from generally very mild and respond to DDAVP therapy. Other Large platelets can also be seen in other disorders. In gray
lifelong bleeding symptoms to discern whether the defect rare disorders, such as Glanzmann thrombasthenia, and platelet syndrome, the large platelets appear gray on smear
is likely acquired or hereditary. Review of systems should Bernard-Soulier, are much more severe and can cause life- and lack ␣-granules. May-Hegglin anomaly is characterized
consider renal, liver, and myeloproliferative disorders. threatening bleeding. Glanzmann thrombasthenia is asso- by large platelets, variable thrombocytopenia and Döhle
Family history should include gender of affected members, ciated with abnormal platelet aggregation to epinephrine, inclusion bodies in neutrophils. There are other rare macro-
site and duration of bleeding and therapies instituted. ADP and collagen (but is normal with ristocetin) and a de- thrombocytopenias that may have mild platelet dysfunction.
Medication history should identify any agents which can fect in the glycoprotein IIb-IIIa complex. These more severe In ITP platelets are large due to increased platelet turnover;
cause platelet dysfunction (e.g. NSAIDs, penicillins, cepha- disorders may require platelet transfusion. Platelet dysfunc- in addition to the thrombocytopenia, there may be some
losporins, antiplatelet agents). Physical examination should tion due to diminished storage pools in platelet granules is degree of platelet dysfunction due to the anti-platelet anti-
document sites of bleeding. Platelet disorders are not gen- associated with a distinct abnormality of ADP-induced ag- body.
erally associated with splenomegaly or lymphadenopathy gregation. These disorders tend to be milder and include
(except in the case of ITP and Wiskott-Aldrich syndrome). gray platelet, Hermansky-Pudlak, and Chediak-Higashi syn-
Eczema occurs in Wiskott-Aldrich. dromes. Selected reading
Buchanan G: Quantitative and qualitative platelet
쏹 –– Examination of the blood smear and a CBC are essen-
햴 쏹 –– Platelet counts and morphology are normal in VWD.
햷
disorders. Clin Lab Med 1999;19:71–86.
tial. Platelet size measured by automated cell counts as the Affecting approximately 1% of the population, VWD is the
mean platelet volume (MPV) is now more widely available. most common bleeding disorder and should be excluded Geil JD: Von Willebrand disease; in Johnston JM (ed):
Normal platelet size during childhood ranges from 7 to 11 fl. prior to further investigation in patients with bleeding Pediatric Medicine. Emedicine, 2002
Normal platelet counts are similar in children and adults symptoms, and normal platelet count and morphology. The (http://emedicine.com).
ranging from 150,000/mm3 to 400,000/mm3. PT, PTT and diagnosis can be made by the coagulation tests outlined.
Noris M, Remuzzi G: Uremic bleeding: Closing the
thrombin time (TT) should be normal unless von Willebrand There is considerable overlap of the normal range and the
circle after 30 years of controversies? Blood 1999;94:
disease (VWD) is prolonging the PTT (which it does not in range of factor levels in patients with VWD. Blood type, hor-
2569–2574.
most cases) or there is associated liver disease. mones, stress and other factors may affect the vWF levels.
Therefore, a single set of normal studies, particularly if the Nurden A: Inherited abnormalities of platelets. Thromb
61
쏹 –– Normal platelet counts and morphology occur with
햵 values are below the mean, do not exclude VWD; repeat as- Hemost 1999;82:468–480.
acquired defects such as medication-induced platelet dys- says, and even family studies, may be indicated to prove or
Storey R, Heptinstall S: Laboratory investigation of
function, uremia and liver disease. The platelet dysfunction exclude this diagnosis. If the screening tests suggest VWD,
platelet function. Clin Lab Haem 1999;21:317–329.
in uremia is complex but is likely related to serum accumu- then multimer analysis should be done to subtype the dis-
ease. Types 1 and 2A can generally be treated with DDAVP,
햲
Thrombocytosis
62 History, physical examination 햳 Smear reveals RBC or Spurious thrombocytosis
CBC, smear evaluation, WBC fragments 햿
reticulocyte count 햴
Acute febrile Chronic illness, RBC indices 햷 Persistent thrombocytosis WBC >100,000
illness usually afebrile Hypersegmented PMN Large, pale, hypogranular platelets && shift to left
± macroovalocytosis Splenomegaly or Polycythemia
Blood loss ± Thromboses and/or hemorrhage ± symptoms 햾
Stool for occult blood _ 13 g/dl 햽
Hb <
Rarely + family history
Acute Preterm infant Fe deficiency Lymphomas Exercise Sickle cell disease Trisomy 21 Essential thrombocytosis CML
infection Autoimmune and Hemorrhage Non-Hodgkin Surgery or other causes Platelet count often & Familial essential Polycythemia vera
Kawasaki connective tissue Rebound lymphoma Child birth functional asplenia in 1st year of life 햺 thrombocytosis M7-AML
syndrome 햶 disorders thrombocytopenia Hodgkin disease Epinephrine Post-splenectomy Transient myelopro-
Acute rheumatic Crohn disease Hemolysis Neuroblastoma Corticosteroids Congenital asplenia liferative disorder
fever Ulcerative colitis Megaloblastic anemia Hepatoblastoma Fracture M7-AML
Tuberculosis Vitamin E deficiency Other solid tumors Neonatal methadone
Chronic hepatitis withdrawal
Nephrotic syndrome Vincristine
Langerhans cell Vinblastine
histiocytosis
Chronic osteomyelitis
Celiac sprue
Congenital adrenal
hyperplasia
Caffey syndrome
Sarcoidosis
GvHD
햲 –– Thrombocytosis in children is almost always a reactive
쏹 햷 –– A variety of hematologic conditions cause thrombo-
쏹 tive conditions. The presence of large, hypogranular platelets
response secondary to an underlying process, most often in- cytosis; iron deficiency either at diagnosis or during therapy, is helpful but not diagnostic. Splenomegaly is usually pres-
fectious or inflammatory. Elaboration of cytokines such as in- hemorrhage, hemolysis and rebound from any thrombocy- ent, but is nonspecific. Complicating thromboses occur in ap-
terleukin-6 and C-reactive protein likely play a role in stimu- topenia (particularly common with chemotherapy). Thrombo- proximately one-quarter of patients, may be very serious (in-
lating platelet production. The severity of the thrombocytosis cytosis may persist in chronic conditions such as hemoglo- tracerebral, peripheral arterial, deep vein thromboses) and
parallels the disease activity of the underlying process, and binopathies. Megaloblastic anemia, usually presenting with their occurrence is a very strong indication of essential
is, in effect, an acute-phase reactant like the erythrocyte sedi- macrocytosis and macro-ovalocytosis, may have an associat- thrombocytosis. Hemorrhage also can occur. In most chil-
mentation rate. The thrombocytosis resolves when the under- ed thrombocytosis. With newer infant formulas, vitamin E de- dren, who are asymptomatic, it is persistence of the thrombo-
lying process does, and complicating thromboses probably ficiency is uncommon. cytosis (usually at least 600,000 and often > 1,000,000) over
do not occur. Therefore, therapy to reduce the platelet count months or years without any other etiology apparent which
or prevent thrombosis is not indicated in reactive thrombocy- 햸 –– The simple stress of exercise, surgery, childbirth, as
쏹 eventually leads to the diagnosis by exclusion. Therapies are
tosis. Thrombocytosis is no more specific in the neonate, but well as several drugs, all commonly cause thrombocytosis. available although children without thrombotic complications
mild thrombocytosis is very common in preterm infants. may not merit intervention. Families with an autosomal-dom-
햹 –– One-third of the circulating platelets are normally se-
쏹 inant form of the disease have been identified.
햳 –– History should focus on concurrent chronic disease, in-
쏹 questered within the spleen. Congenital or surgical asplenia
fection, complicating hemorrhage or thrombosis, anemia or shifts these platelets into the circulating pool, often causing a 햾 –– Chronic myelogenous leukemia and polycythemia
쏹
icterus, rash, lymphadenopathy, polyuria/polydipsia, relative thrombocytosis. Although surgical asplenia is usually vera are both myeloproliferative disorders associated with
diet, medications, prior surgery and trauma. Physical exami- obvious, congenital or functional asplenia may not be. How- thrombocytosis. In the former, a severe leukocytosis
nation should consider growth and development, rash, in- ell-Jolly bodies in red blood cells are a clue to underlying as- (averaging more than 300,000 cells/µl and almost always
flammation, lymphadenopathy, organomegaly, masses, con- plenia. The sickle hemoglobinopathies are the most common > 100,000 in children) and shift to the left (including meta-
junctivitis, and surgical scars. cause of functional asplenia. After splenectomy platelet myelocytes, myelocytes and promyelocytes in peripheral
counts > 1,000,000 are not uncommon and the thrombocyto- blood) readily identifies this disorder. Polycythemia vera is
햴 –– If a transient thrombocytosis due to a benign intercur-
쏹 sis may persist for years. extremely rare in children and when it occurs the poly-
rent infection is suspected, simply repeat the platelet count in cythemia is usually the predominant concern; plethora, weak-
3–4 weeks. If there is a serious concern, laboratory studies at 햺 –– In Down syndrome, thrombocytosis is very common by
쏹 ness, headache, hypertension and splenomegaly are usually
a minimum should include CBC, reticulocyte count, and pe- the second month of life and often persists in the first year noted. The M7 variant of AML rarely presents with thrombo-
ripheral smear. ESR, PPD, hepatic function studies, chest X- without other hematologic abnormalities. Less commonly, cytosis.
ray, bone X-rays, ANA, ASO, urinalysis, cultures, bone mar- neonates with Down syndrome have thrombocytosis as a
row aspirate and biopsy, as well as levels of vitamin B12 and E manifestation of the transient myeloproliferative disorder 햿 –– Red cell or white cell fragments, as found in microan-
쏹
and folic acid may be indicated depending on the clinical which occurs in these infants. Children with Down syndrome giopathic hemolytic anemia, hemoglobin H disease and
evaluation. If there is a likely underlying disorder, laboratory are at increased risk for acute megakaryoblastic leukemia (M7 leukemias , can be mistaken for platelets in automated cell
studies should investigate that diagnosis and not the throm- variant of AML), of which thrombocytosis is rarely a present- counters, which rely on cell size for identification. Peripheral
bocytosis. ing sign. smear review confirms this pseudothrombocytosis.
햲
Treatment of bleeding in children with hemophilia
64 Collaborate with Hemophilia Treatment Center 햳 Mild or moderate hemophilia 햻
Severe hemophilia
Life-threatening Non-life-threatening
Fails to Recurrent
improve bleeding
Obtain inhibitor level (always prior to elective surgery) If neurovascular
Infuse factor to 100% level with i.v. bolus dose compromise, Rx as
Initiate continuous infusion to maintain 80–100% level life-threatening bleed, Consider prophylaxis 50–100% dose Persistent or
or bolus therapy maintaining a trough level of >50% Obtain neurology + regimen for recurrent depending on recurrent bleeding
surgical consult 햷 hemarthroses 햸 severity 30–50% dose q.d. × 5
Antifibrinolytics No antifibrinolytics 햹
for 3–5 days 햹
Measure levels to ensure adequacy of Rx
Continuous or bolus therapy at minimum 50% level
until wound healing begins and then 7 to minimum Orthopedic evaluation Evaluate for Persistent, Persistent,
30% level for 7–14 days depending on type of bleeding Consider X-ray, US, MRI radio-isotopic or recurrent bleeding recurrent bleeding
surgical
synovectomy 햸
May need 30–50% level for physical therapy or 30–50% dose q.o.d. Redose to 100%
other procedures in healing phase up to 1 week Prednisone
May use prophylaxis for 6–12 weeks after CNS bleed Epistaxis: refer to 1–2 mg/kg/day ×
to prevent early recurrence otolaryngology 1–2 weeks
for possible nasal GU evaluation
packing or cautery
(for any child failing Rx, see ‘Evaluation of a child
with hemophilia who fails infusion therapy’, p 66)
햲 –– Hemophilia A (factor VIII deficiency) and B (factor IX
쏹 햴 –– CNS hemorrhage is the most serious complication
쏹 radiologically. Hemophilia specialists should be consulted
deficiency) affect all racial groups worldwide, with hemo- with prevalence and recurrence rates of ~10%. Symptoms to choose the regimen and when to institute it. Factor is
philia A responsible for ~85% of cases. Disease severity may be delayed for days after trauma and often no trauma usually infused 2–3 times weekly to prevent factor levels
is defined by the plasma level of deficient factor; severe is recognized. A suspected CNS bleed must be treated ur- <1%. Prophylaxis can drastically improve quality of life by
disease <1% (0.01 IU/ml), moderate 1–5%, and mild >5%, gently with factor prior to CNS imaging since function can markedly reducing bleeding, but it is very costly. Target
compared to Nl = 100%. Most patients have severe disease. rapidly deteriorate. Factor replacement must also precede joints may also benefit from surgical synovectomy or ra-
Primary treatment is factor replacement of either factor VIII lumbar puncture to prevent an epidural or subdural spinal dioisotopic synovectomy (using injection of the radioisotope
or factor IX using either monoclonal antibody purified fac- hematoma. [e.g., 32P] into the joint) to control synovial inflammation.
tor concentrates derived from human plasma or recombi- Hip hemorrhage can result in aseptic necrosis of the joint;
nant protein products. Viral screening of blood donors and 햵 –– Dental block anesthesia without prior factor replace-
쏹 both hip and shoulder hemarthroses are corrected to 100%
viral inactivation processes have made plasma-derived ment can result in dissecting hematomas, which can cause immediately and managed aggressively until resolution.
products much safer, but children should be treated with potentially fatal airway obstruction.
recombinant products whenever possible. If neither product 햹 –– Antifibrinolytics may be helpful for oral mucosal
쏹
is available, cryoprecipitate is a source of factor VIII and 햶 –– Surgery without factor replacement is extremely dan-
쏹 bleeding but are generally contraindicated in patients with
fresh-frozen plasma a source of factor IX, but both should gerous. Prophylaxis for surgery or Rx of any life-threaten- hematuria. For oral mucosal bleeding (i.e. dental extrac-
be avoided if at all possible because of the risk of viral ing bleeding requires monitoring factor levels frequently to tions), use ⑀-aminocaproic acid (75–100 mg/kg/dose every
transmission in these untreated plasma products. Factor assure safe levels are maintained. Continuous infusions of 6 h p.o. or i.v.) or tranexamic acid (10 mg/kg/dose i.v. or 25
dosage is measured in units which are equivalent to the factor are more effective, safe and cost effective in manag- mg/kg/ dose p.o.).
amount of factor in a milliliter of ‘normal’ plasma. To re- ing these serious complications (typical starting dose of fac-
place factor VIII with either monoclonal or recombinant fac- tor VIII = 50 U/kg followed by ~4 U/kg/h). Inhibitor develop- 햺 –– 10% of patients experience hematuria, which is
쏹
tor, 1 U/kg increases the plasma factor VIII level by 2%; if a ment is a critical complication (see ‘Evaluation of a child seldom of medical significance. Factor replacement is often
level of 100% is required, give 50 U/kg. In the algorithm with hemophilia who fails infusion therapy’, p 66). Inhibitor not helpful. Bed rest and hydration are first-line therapy,
treatment is defined as the percent level of factor desired to assays are performed prior to elective procedures, during but steroids are occasionally useful.
treat different hemorrhages. Except as noted, this is the life-threatening events and annually as part of routine care.
peak level from a single bolus of intravenous factor. For fac- Serious blood loss can accompany mucosal, GI, retroperi- 햻 –– Treatment of children with mild and moderate hemo-
쏹
tor IX, 1 U/kg of factor IX with monoclonal concentrates in- toneal, and large muscle (iliopsoas, quadriceps and ham- philia is very similar to that of severe disease but may be
creases the plasma level by 1% while the same dose of re- string) hemorrhage. Iliopsoas bleeds can present with up- modified. Life-threatening or serious (e.g. hemarthrosis)
combinant product produces a 0.4–0.8% increase. Because ward flexion of the thigh, lower quadrant tenderness, or bleeding are treated identically, but somewhat lower and
of this variability, recovery studies (factor levels before and paresthesias in the femoral nerve distribution. These major less frequent factor dosing may be adequate. In mild and
1
/4–1/2, 1, 2–4, 8–12 and 24 h after infusion, or at least a level muscle hemorrhages require 10–14 days of factor replace- occasionally moderate hemophilia A, i.v. or nasal DDAVP
1 h postinfusion) should be performed on patients with ment for full recovery and to prevent recurrence. increases factor VIII levels and in some situations obviates
hemophilia B to determine dosing. The Nl T1/2 of factors VIII the need for factor. DDAVP is ineffective in hemophilia B.
and IX are, respectively, ~12 and 24 h; the longer T1/2 of 햷 –– Compartment syndrome may result from bleeding
쏹
factor IX allows for less frequent dosing than factor VIII. into flexor muscle groups (e.g. forearm or calf). Impaired
Because infants and young children have a higher volume blood flow and peripheral nerve damage can be serious Selected reading
of distribution and clearance of factors, dose and frequency and deficits can be permanent. Factor replacement is impe-
Dimichele D, Neufeld EJ: Hemophilia: A new approach
may be higher in younger patients. After calculating the rative. Fasciotomy is rarely required.
to an old disease. Hematol/Oncol Clins N Am
dose, use the number of whole factor vials to bring you
1998;12:1315–1344. http://www.haemophilia-forum.org
closest to that dose; do not waste parts of a vial. Factor is 햸 –– Hemarthrosis is the most common debilitating com-
쏹
and http/www.hemophilia.org
very expensive (USD >$1/unit for recombinant and ~1/3 less plication of hemophilia and may occur without recognized
for plasma-derived factor concentrates). trauma. Joint hemorrhage causes synovial thickening and Manco-Johnson MJ, Nuss R, Geraghty S, et al:
friability, triggering chronic inflammation. This results in a A prophylactic program in the United States: Experience
햳 –– Rx should be provided in collaboration with a
쏹 ‘target joint’, prone to chronic arthritis, loss of mobility and and issues. Semin Hematol 1994;31(suppl 1):10–12.
65
comprehensive hemophilia treatment center because this recurrent hemorrhage. Prophylactic factor regimens are in-
approach leads to lower morbidity and mortality. If patients stituted, either following a small number of hemarthroses
cannot travel to centers, physician consultation with the (1–3 in a single joint), or following the development of a
center is critical. ‘target joint’ either clinically or via evidence of synovitis
Coagulation Disorders M.A. Leary · R.H. Sills · M.J. Manco-Johnson Treatment of bleeding in children with hemophilia
Coagulation Disorders M.J. Manco-Johnson Evaluation of a child with hemophilia who fails infusion therapy
Child with hemophilia who manifests bleeding events that have become more frequent,
more spontaneous or are unresponsive to standard therapy
Assess adherence to current treatment regimen, compliance with home Rx (product used, dosage, storage, and reconstitution),
concurrent medications/treatments/exercise/physical therapy, prior inhibitor, new medical problems 햲
Incorrect Factor VIII (or IX) inhibitor using Bethesda assay (BU) 햴
therapy
Poor
compliance
Inhibitor + 햵 Inhibitor – Determine factor recovery and T1/2 햹
Factor inhibitor
Low factor recovery (7T 1/2) Nl factor recovery and T 1/2
Adjust factor dosage 2nd bleeding disorder
Confirm Dx if not certain and frequency to reflect VWD
Rx of inhibitors is complex – Consult with specialist
based on Hx and records 햳 individual variation Drug-induced
Thrombocytopenia
Hepatitis/liver dysfunction
Other bleeding disorder
FVIII:C, VWF:RCo, VWFAg Treatment of acute bleeding 햶 Consider immune tolerance induction Continued frequent Hemarthroses only
FIX levels (ITI) for long-term management bleeding events Synovitis
Unrelated joint disease
Adjust Rx VIII + IX Nl Standard therapies >5 U: high titer inhibitor 햷 Initiate prophylaxis
Work with family Repeat complete bleeding Factor replacement to <10 BU: begin ITI immediately and titrate dose
evaluation overcome inhibitor >10 BU: begin ITI when titer is <10;
Recombinant FVIIa or if need is emergent, reduce titer with
Incorrect type of hemophilia or VWD
Activated PCCs plasmapheresis and begin ITI;
Educate family Non-standard therapies or begin ITI at >10 BU
Dx of hemophilia correct Porcine factor VIII
<5 BU: low titer inhibitor 햸
Inhibitor assay (hemophilia A only) Isolated hemarthroses Hemostatic evaluation
Possible plasmapheresis + May begin immune tolerance induction (ITI) US and/or MRI to CBC, PT, PTT, TT
factor replacement or treat with higher doses of factor VIII prn confirm synovitis FVIII:C, VWF:RCo, VWFAg
Monitor at least monthly Platelet function
Clinical evaluation to R/O
other joint disease
Initiate prophylaxis
The specific immune tolerance regimen should be chosen in consultation with a Consider radiosynovectomy
hemophilia specialist given the complex and rapidly changing nature of this therapy or surgical synovectomy
햲 –– Ensure that the treatment plan is correct. For home
쏹 햶 –– Management of acute bleeding in inhibitor patients
쏹 햹 –– If there is no inhibitor, determine recovery (R) and
쏹
therapy, assess if factor storage is appropriate to maintain is complex, extremely costly and produces inconsistent half-life (T1/2 ) of infused factor. Obtain baseline level, infuse
potency and observe family administering the factor. It may results. Simple factor replacement, often in high doses, may factor and measure factor levels at 1/4 – 1/2 , 1, 2–4, 8–12 and
be necessary to stop home therapy or provide more home overcome modest inhibitors. More severe inhibitors are 24 h. If R or T1/2 is reduced, that patient may require higher
supervision. Assess all medications, including NSAIDs, as usually treated with recombinant activated factor VII (rVIIa – or more frequent doses of factor; if bleeding persists, ongo-
a possible cause of treatment failure. usual dosage 90–120 µg/kg) or activated prothrombin com- ing prophylactic factor therapy may be indicated (titrating
plex concentrates (PCC, usual dosage 75–100 IU/kg) both of the dose to the T1/2 ) and a hemophilia specialist should be
햳 –– Ensure the diagnosis is hemophilia and the correct
쏹 which bypass the need for factors VIII or IX. Bleeding can consulted. If T1/2 is normal, joint bleeding may be due to
type. This is rarely a problem if the family is well known to be treated in many patients with porcine factor VIII. Plasma synovitis or other joint disease and not ongoing hemor-
the provider, but occurs with new families if decisions are exchange and high-dose factor replacement is also an op- rhage. This can be confirmed by ultrasound and, if neces-
based solely on history. Parents may confuse hemophilia A tion with serious bleeding. The very high cost of these sary, MRI. Recurrent hemarthroses ± synovitis are an
and B, VWD or another bleeding disorder, and rarely there products may limit their use in many areas. indication for prophylactic factor infusion and specialty con-
is no bleeding disorder (Munchausen syndrome by proxy). sultation. Either radio- or surgical synovectomy may be
If there is a question, FVIII:C, VWF:RCo, VWFAg and FIX as- 햷 –– High titer inhibitors are serious complications which
쏹 indicated. If there is no other joint disease, or the recurrent
says to distinguish hemophilia A, B and VWD. The factor do not increase the frequency of hemorrhage but greatly bleeding is not in the joint, consider again if the diagnosis
concentrates only contain the individual factor (e.g. factor complicate its treatment. High titer inhibitors can render or correct or if there is a concomitant second bleeding
VIII will not work in hemophilia B and even in VWD if the factor therapy ineffective. The long-term approach is to disorder. Given that VWD occurs in 1% of the population, it
concentrate contains FVIII:C but not VWF it may fail). institute immune tolerance induction (ITI) to suppress inhi- may be mistaken for hemophilia A or may be a concomitant
bitor production. It is very costly but in ~70–80% of patients disorder with either form of hemophilia; factor VIII studies
햴 –– Development of an anti-factor VIII inhibitor com-
쏹 the inhibitor can be eradicated over a period of months. in the patient and family should be performed. Check for
plicates factor replacement in 5–10% of all patients with A variety of regimens have been tried; most use > _ 100 U/kg/ disorders potentially associated with hemophilia, such as
hemophilia A, but > _ 20% of those with severe disease. The day of factor daily for weeks to years until the inhibitor dis- HIV-induced TP or hepatitis-induced coagulopathy, as well
incidence of anti-factor IX antibodies is lower in hemo- appears. Immunomodulatory therapy (low-dose cyclo- as the much less likely possibility of some other coinciden-
philia B at 3%. Inhibitors are IgG antibodies which develop phosphamide, IVIG, prednisone) has been added but is of- tal bleeding disorder.
after an average 10 days of exposure to factor replacement. ten avoided in children. Success is improved if ITI is begun
Inhibitors are documented and quantitated with the Bethes- early when the inhibitor is <10 BU. If the titer is >10 BU, it
da assay using timed incubations of normal and patient is not clear if it is better to start ITI immediately, wait until Selected reading
plasma; 1 Bethesda unit neutralizes 50% of the normal fac- the titer falls to <10 BU and then start, or if urgent bleeding
Briet E, Peters M: The incidence of inhibitors in
tor in the sample. If the assay is not readily available, an in- occurs to treat reduce the inhibitor titer with plasmaphere-
hemophilia A and the induction of immune tolerance.
hibitor is likely if the PTT of a mixture of both normal and sis and then begin ITI. Ongoing studies should soon define
Adv Exp Med Biol 2001;489:89–92.
patient plasma remains prolonged after 1–2 h of incubation the best approach. Factor IX antibodies are somewhat less
at 37°C. These findings must be confirmed with the Bethes- responsive (50%) with analogous regimens using factor IX, DiMichele D, Neufeld EJ: Hemophilia: A new approach
da assay as soon as possible. but anaphylactic reactions have been reported. Consulta- to an old disease. Hematol Oncol Clin North Am
tion with a hemophilia specialist is critical for the manage- 1998;12:1315–1344.
햵 –– Positive results should be confirmed. It is then critical
쏹 ment of all children with hemophilia and inhibitors.
Shapiro A: Inhibitor treatment – State of the art.
to determine if the patient is a low responder (1/4 of patients
Semin Hematol 2001;38(suppl 12):26–34.
who have 3–5 BU level titers and whose titers do not rise 햸 –– Low titer inhibitors can be transient ( /3 of patients),
쏹 1
with additional treatment) or a high responder (3/4 of pa- may persist but not increase over time, or may develop into
tients with >5 BU and an anamnestic response to additional high titer inhibitors. If the inhibitor is <5 BU ITI can be start-
factor therapy). ed, but it is reasonable to monitor the inhibitor and to treat
bleeding, if necessary, with higher doses of factor to over-
come the inhibitor; if the inhibitor is transient and resolves,
no therapy is necessary. If it becomes anamnestic or per-
67
sists at low titer, ITI is started.
Coagulation Disorders M.J. Manco-Johnson Evaluation of a child with hemophilia who fails infusion therapy
Coagulation Disorders A. Deters · A.E. Kulozik Consumptive coagulopathy
Consumptive coagulopathy
History 햲 Laboratory criteria: CBC, platelets, PT, PTT, D-dimer or FSP
68
Expected findings: 7 platelets, & PT, & PTT, & D-dimer or FSP
Physical examination 햳 ± microangiopathic hemolytic anemia and others 햴
Diagnosis: DIC
Identify the underlying etiology
Appropriate
antibiotic therapy Treat underlying disease 햺
Heparin ± antithrombin 햻 Fresh frozen plasma (or cryoprecipitate) ?New treatment approaches? 햾
Absolute contraindication to heparin Platelet transfusion Antithrombin alone
is active bleeding in closed spaces Activated protein C
Thrombophilia evaluation in
a newborn infant with thrombosis
70
Infants (<28 days old) with arterial or venous thrombosis, confirmed with Doppler ultrasound or appropriate imaging technique
Signs of stroke; altered level of consciousness, seizures, hemiparesis, or abnormal neurologic examinations
Known thrombophilia in either parent Multiple thromboses or Static thrombosis Preterm infant with
Purpura fulminans or DIC unprovoked thrombosis Maternal diabetes, cocaine use catheter-related thrombosis
Progressive or recurrent thrombosis Neonatal dehydration, poor feeding, vomiting,
Prior fetal/neonatal loss, PE diarrhea, placental abruption, demise of fetal twin
Thrombosis evaluation at diagnosis Thrombosis evaluation at diagnosis or at Thrombosis evaluation at age 6 months or expectant observation for recurrent thrombosis
Consider protein replacement and/or anticoagulation age 6 months and expectant observation
Expectant observation for recurrent thrombosis for recurrent thrombosis
Observe
Coagulation Disorders M.J. Manco-Johnson Thrombophilia evaluation in a newborn infant with thrombosis
Coagulation Disorders M.J. Manco-Johnson Thrombophilia evaluation in a child with thrombosis
Positive level I evaluation Perform level I evaluation (at time of thrombosis) 햵 Negative level I evaluation Normal studies and underlying
CBC, blood smear, liver and renal function, PT, PTT, predisposing medical condition or
ESR, C-reactive protein, FVIII:C provoking factor:
Lupus anticoagulant and anticardiolipin antibody 햶 Anticoagulation for 3 months or until
1–2 defects >2 defects Antithrombin (functional assay) 햷 the predisposing condition resolves
Treat 1–2 years Consider long-term (indefinite) Protein C (functional assay) 햸
after thrombotic event anticoagulation Protein S (free antigen)
and observe with Factor V Leiden PCR or functional APCR 햹
prophylactic heparin Prothrombin G20210A (PCR) Recurrent or Recurrent or
around high-risk events 햻 Homocysteine level 햺 progressive thrombosis progressive thrombosis
Sickle cell screen Positive family history
CBC and smear BUN, electrolytes P, Ca, urate Chest X-ray – Mandatory Coagulation screen
before anesthesia
Examine for anemia, Check for evidence of Mediastinal mass 햵 Check for evidence of DIC 햶
thrombocytopenia, 7& WBCs, tumor lysis syndrome 햴 (diagnosis possible from
neutropenia, presence of blasts pleural tap)
Bone marrow aspirate 햷 (see ‘Recognition and management of tumor lysis syndrome’, p 94) (see ‘Assessment of a mediastinal mass’, p 76)
and lumbar puncture 햸
L1/2 blasts 햽 L1/2 blasts 햾 L3 blasts 햿 Myeloid blasts 헀 Age <1 year 헁 && all stages myeloid development
CD10+, CD19+, TdT+ CD2+, CD7+ CD19+, SmIg+ MPO+, CD13+, CD33+ L1/2 blasts Ph1 chromosome +, LAP 77 헂
CD10–, CD19+, 7.1+
Common ALL T-cell ALL B-cell ALL AML Infant/null ALL CML
Standard ALL protocol B-ALL/NHL protocol AML protocol Infant ALL protocol CML Protocol
(with risk stratification) BMT
햲 –– Among children with ALL at the time of diagnosis, ap-
쏹 햸 –– If the diagnosis is clearly ALL on the blood film, then
쏹 Their immunophenotype is characterized by the presence
proximately 60% have fever, 50% have bleeding, and over it is usual to give the first intrathecal chemotherapy at this of immunoglobulin on the surface of the cell, signifying a
20% have bone pain or limp. The symptoms are similar in juncture (assuming the coagulation screen is normal or has more mature cell of origin than that of common ALL. The
children with AML although the proportion affected is been corrected according to institutional guidelines). How- risk of tumor lysis syndrome is very high.
somewhat less. ever, a clean tap must be obtained first as the presence of
CNS blasts at diagnosis may infer a worse prognosis. 헀 –– Myeloid blasts are typically larger and have more
쏹
햳 –– Bulky nontender nodes ± splenomegaly in an afebrile
쏹 cytoplasm. Often the presence of myeloperoxidase positive
child are highly suggestive of a malignant process. Supra- 햹 –– Most laboratories have large standard panels of anti-
쏹 granules or Auer rods confirms their lineage. However, it
clavicular adenopathy is especially concerning. bodies for flow cytometry that are performed in a designat- is not always possible to separate L2 ALL from AML and it
ed order (according to morphology); only the characteristic is on this occasion where cytochemistry and extensive im-
햴 –– Critical management steps are outlined in the
쏹 antigens have been shown here. Terminology assigns a CD munophenotyping become invaluable.
algorithm on ‘Recognition and management of tumor lysis (cluster differentiation) number to identify most antigens.
syndrome’ (p 94). Flow cytometry has become a very powerful tool and 헁 –– Infant ALL is characterized by the presence of 11q23
쏹
enables the leukemic subtype to be confirmed within a few chromosomal translocations and a much worse prognosis
햵 –– The differential diagnosis of a mediastinal mass is
쏹 hours of the bone marrow aspirate. The most specific than childhood ALL. The ‘7.1’ antibody recognizes a surface
discussed in the algorithm on this topic. The presence of an markers are noted in bolded text. antigen which is only expressed by cells carrying the 11q23
anterior mediastinal mass in a child with suspected leu- translocation. An accurate same-day diagnosis can thus be
kemia is almost always associated with the presence of a 햺 –– Cytochemistry has largely been replaced by flow cy-
쏹 achieved. This is important particularly for the child in the
T-cell ALL or non-Hodgkin lymphoma. Mediastinal masses tometry in the majority of laboratories, but can be useful in second year of life as there is increasing evidence that such
can be a medical emergency. General anesthetic and seda- difficult cases when it is hard to separate ALL from AML. children without 11q23 have a much better prognosis and
tion should be avoided as the muscle relaxation on the op- do not need the aggressive and dangerous infant chemo-
erating table allows the mass to fall posteriorly and com- 햻 –– Chromosomal translocations are the most significant
쏹 therapy.
press the trachea deep within the mediastinum beyond the prognostic factor in AML. In ALL, translocations are less fre-
reach of a standard endotracheal tube. Often such cases are quent and often of adverse prognostic significance (t(4;11), 헂 –– CML is usually easily diagnosed. WBC averages
쏹
associated with pleural and/or pericardial effusion; a simple t(9;22)). However, standard G-banding techniques do not 250,000 but few blasts are noted and platelets are & or nor-
aspirate of the effusion usually yields adequate cells to al- produce results for 14 days and can thus not be used in the mal. && blasts only occur with conversion from chronic to
low a diagnosis to be reached and often enough to set up initial assessment. The cytogenetics laboratory may also blast phase. Juvenile myelomonocytic leukemia (‘juvenile
cytogenetic cultures. However, it is still important to per- perform PCR to identify specific translocations and should CML’) is a rare but distinct entity, occurs at <2 years of age,
form a bone marrow aspirate to establish the degree of store DNA and RNA for future studies. is Ph1 chromosome negative and associated with elevated
infiltration as soon as possible and certainly within 3 days fetal hemoglobin.
of starting chemotherapy. Less than 20% blasts within the 햽 –– A homogeneous population of cells with a very high
쏹
bone marrow would generally be called T cell-non-Hodgkin nuclear/cytoplasmic ratio and the absence of prominent nu-
lymphoma, have a slightly better prognosis and less ag- cleoli typify L1 morphology. L2 cells have more pale blue Selected reading
gressive treatment. cytoplasm and nucleoli. Distinction between the two is not
Acute Leukaemias; in Voute PA, Kalifa C, Barret A (eds):
of prognostic significance, but they must be separated from
Cancer in Children, Clinical Management, ed 4. London,
햶 –– Most common with acute promyelocytic leukemia.
쏹 L3 blasts. L3 blasts signify a different disease, which needs
Oxford University Press, 1998.
Also found in monocytic leukemias and to a lesser extent in different treatment and responds poorly with standard ALL
any subtype of leukemia. A partial thromboplastin time therapy. Burnett AK: Treatment of acute myeloid leukaemia in
(PTT) and prothrombin time (PT) should be performed as a younger patients. Best Pract Res Clin Haematol
minimum coagulation screen. 햾 –– ‘Hand-mirror’ cells have been suggested to typify
쏹 2001;14:95–118.
T-cell morphology, in which the nucleus of the cell forms
Chessells JM: Pitfalls in the diagnosis of childhood
햷 –– Even if the diagnosis of leukemia is not obvious at
쏹 the glass and the cytoplasm the handle. However, objective
leukaemia. Br J Haematol 2001;114:506–511.
this stage, it is usual to aspirate sufficient marrow to allow analysis of large numbers of cases does not support this
75
all the investigations listed to be performed. Occasionally, view. Felix CA, Lange BJ, Chessells JM: Pediatric acute
the marrow can be fibrotic and insufficient marrow can lymphoblastic leukemia: Challenges and controversies
be obtained by aspiration alone; a trephine bone marrow 햿 –– L3 blasts are striking for their deep blue vacuolated
쏹 in 2000. Hematology (Am Soc Hematol Educ Program)
biopsy then becomes essential. cytoplasm. However, care still needs to be applied, as not 2000:285-302.
all cases are as obvious as those in hematological atlases.
Mediastinal mass
Large anterior mass
Nl CBC (see ‘Recognition and
management of superior vena
cava syndrome’, p 96)
Bone marrow aspirate ± biopsy Posterior mass
Anteromedial mass Chest CT
Leukemia or Lymphoma Benign tumor Thymoma Mature teratoma Immature Neuroblastoma Neurofibroma
lymphoma teratoma Neurofibrosarcoma
with marrow Schwannoma
involvement Lymphoma
NHL Hodgkin
Ganglioneuroma
Ewings sarcoma
Rhabdomyosarcoma
Bone marrow Benign masses
CT (abdomen/pelvis)
(see ‘Assessment of Gallium/PET
a child with suspected Bone scan
leukemia’, p 74)
Malignant Disorders M. Weyl Ben Arush · J.M. Pearce Assessment of a mediastinal mass
Malignant Disorders M. Weyl Ben Arush · J.M. Pearce Assessment of an abdominal mass
Hepatosplenomegaly Isolated mass with or without pain Cushingoid US/CT scan abdomen
Adenopathy Obstructive symptoms of GI or GU systems Feminization If no abdominal mass with
Virilization feminization/virilization, MRI/CT brain 헀
Pediatric endocrine evaluation
Intrahepatic mass Biliary tract and pancreatic Renal Adenopathy Adrenal Other Abdominal
mass present
AFP, HCG 햳 Renal disease Excision or biopsy Tumor lysis labs 햹 Urine VMA/HVA 햻 AFP
without tumor Bone marrow HCG
CSF
MRI + –
Hydronephrosis
Polycystic kidney
Dysplastic kidney Biopsy
Biopsy Biopsy Biopsy Biopsy Biopsy
Leukemia Metastatic disease 햴 Rhabdomyosarcoma Wilms tumor 햷 B cell/Burkitt 햺 Neuroblastoma 햾 Adrenal 햽 Sarcomas Adrenal tumor 헁
Viral illness Hepatoblastoma 햳 Other sarcomas Other renal tumors 햸 lymphoma Pheochromocytoma 햿 incidentaloma PNET Extragonadal germ
Hepatocellular carcinoma Pancreatic tumor 햶 Hodgkin disease Ganglioneuroma 햾 Teratoma cell tumor
Benign liver tumors 햵 Other adrenal
tumors 햿
Malignant Disorders M. Weyl Ben Arush · J.M. Pearce Assessment of an abdominal mass
Malignant Disorders M. Weyl Ben Arush · J.M. Pearce Assessment of a pelvic mass
Origin of mass
– + – +
Biopsy Biopsy or paracentesis
Pregnancy Ewing Hydro- Abscess Gonadal tumor Rhabdomyosarcoma Neuroblastoma
Burkitt non-Hodgkin
sarcoma metrocolpos Ovarian cyst Germ cell tumor Other sarcomas lymphoma
Primitive neuro- Ovarian carcinoma Non-germ cell tumor Primitive neuroectodermal tumor
ectodermal tumor Leiomyosarcoma Germ cell tumor
(see ‘Recognition and management
of tumor lysis syndrome’, p 94)
Bone marrows Surgery Surgical intervention Staging laparotomy Excision when possible Bone marrows Spinal tap
Chest CT ± antibiotics and chemotherapy if Chemotherapy ± Bone scan Bone marrows
Chemotherapy for malignant radiotherapy Chemotherapy Chemotherapy
malignancy
–– A bone scan can determine the extent of tumor in the
identified as an external protuberance. GCT occasionally –– Plain X-rays and ultrasound can demonstrate calcifi-
pelvic bones and other distant sites of osseous involvement. originate in the retroperitoneum. Non-GCT gonadal tumors cations in the case of benign gonadal tumors or neuroblas-
include sex cord-stromal tumors (granulosa and Sertoli toma. US is very useful in assessing ureteral obstruction
–– There are several options for obtaining tissue for his-
Leydig cell) or epithelial tumors. Ovarian carcinomas are which could require emergency urinary diversion to pre-
tologic diagnosis. US-guided biopsy (fine-needle aspirate extremely rare in childhood. serve renal function. Ovarian masses can be determined to
or needle-core biopsy), biopsy through rectoscopy or cysto- be cystic or solid and hydrometrocolpos can be identified.
scopy, laparoscopy or open biopsy through laparotomy. –– Rhabdomyosarcoma (RMS) arises from mesenchy-
If the tumor has associated ascites, a paracentesis may mal cells committed to developing into striate muscle. The –– Contrast-enhanced CT gives information on the pri-
yield diagnostic fluids (especially in GCT and lymphomas). histologic subtypes are correlated with the prognosis. mary tumor and intra-abdominal metastases. Spiral CT and
The approach is determined by the skill and experience of Botryoid and spindle-cell RMS are the rarest subtypes and MRI have the advantage of imaging the tumor in the coronal
the surgeon as well as the information needed (such as have the best prognosis. Alveolar RMS (high incidence of a and sagittal planes. MRI better defines spinal cord invasion.
whether there are peritoneal studs in a GCT which may t2;13 chromosomal translocation) is generally seen in the
require direct visualization by laparotomy). Fine-needle as- extremities in adolescents, and has the worst prognosis. –– Vaginal bleeding can be due to a botryoid rhabdomyo-
pirate may be performed in very sick children but in most Two-thirds of all RMS are embryonal which are more often sarcoma which presents as a grape-like cluster of clear
cases does not provide enough material to obtain all of the seen in the trunk of younger children and have an inter- tissue protruding from the vagina or cervix, which should
histologic and molecular genetic information required. mediate prognosis. About 25% of all RMS occur in the be excised or biopsied. Vaginal bleeding is also caused by
GU/retroperitoneal area and they can be very large masses feminization due to sex-hormone-secreting ovarian or adre-
–– Ewing sarcoma and primitive peripheral neuroecto-
before causing physical symptoms such as bladder obstruc- nal tumors.
dermal tumor (PNET) belong to the same family of neural- tion. Botryoid RMS typically presents as a grape-like cluster
derived tumors. PNET tends to be more differentiated and protruding from the cervix or vagina in very young girls. –– The predominant symptoms of malignant pelvic tu-
has a higher incidence of positive pathology markers such RMS are sensitive to both chemotherapy and radiation with mors are pain, palpable swelling/masses, fever, and signs
as neuron-specific enolase (NSE) and S100 which are indica- most successful treatment regimens incorporating both of obstruction of either GI or GU tract. Compression of
tors of more mature neural differentiation within the tumor. if the resection is not complete (for sarcomas other than nerve roots can lead to leg weakness and paresthesias.
rhabdomyosarcoma, see ‘Assessment of a soft tissue These symptoms may increase rapidly over a short period
–– ␣-Fetoprotein (AFP) levels are normally very high in
mass’, p 82). or remain constant for several months.
neonates and this may mask tumor-induced elevation of
AFP. The majority of germ cell tumors (GCT) in neonates
–– Neuroblastoma rarely originates in the pelvis but
are benign, requiring surgical excision only. Sacrococcygeal when it does it can extend into the neural foramina and Selected reading
tumors are more frequent in children under the age of three. compress the nerve roots (see ‘Assessment of an abdomi-
Cheville JC: Classification and pathology of testicular
Fifty percent of these are in neonates, primarily in girls. nal mass’, p 78).
germ cell and sex cord-stromal tumors. Urol Clin North
Am 1999;26:595–609.
–– Gonadal tumors are ovarian and testicular. The ma-
–– The pelvis/abdomen is the most frequent primary site
jority of gonadal tumors are germ cell in origin and one- (90%) of Burkitt (B cell) lymphoma. The most common pres- Groff DB: Pelvic neoplasms in children. J Surg Oncol
third of these GCT arise in the ovary; peak incidence is at 10 entation is a rapidly growing mass, often producing ascites. 2000;77:65–71.
years of age, and 70% are mature teratomas which require This leads to pain, abdominal swelling and intestinal ob-
Pappo AS, Shapiro DN, Crist W: Rhabdomyosarcoma:
surgical excision only. Ovarian tumors may not present un- struction, and can serve as a lead point for an intussuscep-
Biology and treatment. Pediatr Clin North Am 1997;44:
til they are very large and may present with torsion or rup- tion. Tumor lysis is very common and often life threatening.
953–972.
ture. The pattern of spread of malignant GCT is ascites and Diagnosis can be made from tumor biopsy, ascitic fluid
peritoneal implants followed by metastases to lung, lymph or involved bone marrow. The cells are clonal B cells with Pfeifer SM, Gosman GG: Evaluation of adnexal masses
nodes and liver. GCT occurring in extragonadal sites are surface immunoglobulin and there are characteristic trans- in adolescents. Pediatr Clin North Am 1999;46:573–592.
most frequently benign mature teratomas, but they may locations seen that are pathognomonic (t8;14, t8;22 or t2;8).
contain some malignant components requiring therapy; Chemotherapy is very effective.
therefore, careful pathologic study of the entire tumor is
81 –– Precocious puberty or virilization can result from
essential. The majority of malignant GCT involve extraem-
bryonal differentiation and secrete either AFP and/or HCG ovarian non-germ cell (stromal) tumors, less often from
(AFP in yolk sac tumor and HCG in choriocarcinoma). germ cell tumors, and rarely from extragonadal pelvic germ
Elevation of these markers in the serum is of great value cell tumors. Keep in mind that adrenal adenomas and car-
both in diagnosis and management. GCT can arise outside cinomas will cause similar symptoms. Pediatric endocrine
the gonad, most commonly as sacrococcygeal teratoma assessment is indicated.
Malignant Disorders M. Weyl Ben Arush · J.M. Pearce Assessment of a pelvic mass
Malignant Disorders M. Weyl Ben Arush · J.M. Pearce Assessment of a soft tissue mass
CBC, ultrasound 햴 Cystic lesions Solid lesion Urine for VMA, HVA
Blood and local cultures if feasible Ultrasound of abdomen
± CT/MRI ± CXR to look for
primary tumor site
Excision if indicated Biopsy, possible excision 햶
Malignant Disorders M. Weyl Ben Arush · J.M. Pearce Assessment of a soft tissue mass
Malignant Disorders M. Weyl Ben Arush · J.M. Pearce Assessment of bone lesions
Plain X-ray
Characteristic Leukemic lines 햹 Lytic lesion with Lytic lesion(s) without periosteal reaction
single lesions 햲 periosteal reaction 햿
Bone marrow
Biopsy Biopsy primary lesion
Benign lesions Leukemia Osteosarcoma 햺 Ewing Lymphoma 헂 Osteomyelitis Langerhans cell Neuroblastoma
Osteoid osteoma 햳 Neuroblastoma Chondrosarcoma 햻 sarcoma 햾 histiocytosis Other metastatic
Benign fibrous Fibrosarcoma 햽 disease
cortical defect 햴
Fibrous dysplasia 햵
Osteochondroma 햶
Endochondroma 햷
CT of lungs CT of lungs CT of lungs Culture Bone scan/skeletal survey
Aneurysmal
Bone Bone marrow Chest X-ray
bone cyst 햸
marrow Gallium/PET scan CBC, chemistries
(see ‘Assessment of
a child with suspected (see ‘Assessment of Focal disease Multifocal (see ‘Assessment of
leukemia’, a mediastinal mass’, an abdominal mass’, p 78)
p 74) p 76)
Malignant Disorders M. Weyl Ben Arush · J.M. Pearce Assessment of bone lesions
Malignant Disorders S. Bailey Initial management of a child with a newly diagnosed brain tumor
Pineal or suprasellar lesion or atypical 햶 (see ‘Brain tumors of the posterior fossa, (see ‘Brain tumors of the posterior fossa, see ‘Supratentorial brain tumors’, p 88) (see ‘Brain tumors of the posterior fossa,
brain stem and visual pathway’, p 90) brain stem and visual pathway’, p 90) brain stem and visual pathway’, p 90)
Perform serum ␣-fetoprotein and human chorionic gonadotrophin 햷 If cystic suprasellar lesion, consider craniopharyngioma 햸
Perform full endocrine screen: urine and serum
osmolality, growth hormone, IGF1, LH/FSH, T4/TSH
Elevated Normal
If ␣-fetoprotein >50 µg/l or chorionic gonadotrophin >50 IU/l, If markers not raised,
the diagnosis of secreting germ cell tumor can be made then proceed with biopsy
CSF markers and CSF staging to be performed via lumbar puncture
Treat on appropriate protocol Treat as appropriate Resection Other lesion: biopsy according to
Germinoma most likely, Possible postoperative radiotherapy type of lesion (e.g. hypothalamic
teratoma possible astrocytoma, pituitary tumor)
햲 –– Raised intracranial pressure headaches
쏹 햶 –– Given the close proximity or involvement
쏹
are typically present on waking. However, this of the hypothalamus/pituitary axis in supra- Selected reading
is not universally so. Vomiting may occur sellar lesions, a basic pre-operative endocrine
Freeman CR, Farmer JP, Montes J: Low
in isolation and an index of suspicion must be workup is essential to detect any gross
grade astrocytomas in children: Evolving
maintained. The headaches typically get endocrine disturbances. This should involve
management strategies. Int J Radiat Oncol
worse over time and last for longer each day. measures of both anterior and posterior
Biol Phys 1998;41: 979–987.
Papilledema is a relatively late sign. In pituitary function including growth hormone,
extremis the child will show signs of coning IGF1, LH/FSH, T4/TSH. Diabetes insipidus must Finlay JL: Chemotherapy for childhood
and become obtunded. A sixth nerve palsy be considered; it is commonly the presenting brain tumours: An appraisal for the
may be present. feature in germinomas. It is advisable to millennium. Child's Nerv Syst 1999;15:
involve a pediatric endocrinologist prior to 496–497.
햳 –– All unexplained focal seizures in children
쏹 surgery, as they may suggest more detailed
Heideman RL, Packer RJ, Albright LA,
require CNS imaging as do unexplained investigations prior to surgery in certain cases
Freeman CR, Rorke LB: Tumours of the
neurological signs. but will certainly be needed for long term
central nervous system; in Pizzo PA,
follow-up.
Poplack DG (eds): Principles and Practice of
햴 –– MRI with i.v. contrast is the preferred
쏹
Paediatric Oncology. Philadelphia,
imaging study and should be done if available 햷 –– Germ cell tumors are typically found in
쏹
Lippincott-Raven, 1997, pp 633–697.
readily. CT imaging is more widely and often the pineal or suprasellar region but may be
more rapidly available and if so should be found elsewhere. A high index of suspicion of Plowman PN, Pearson ADJ: Tumours of
done first. CT scanning should always be done these tumors must be maintained especially if the central nervous system; in Pinkerton CR,
with contrast when looking for brain tumors the lesion is not typical for any other type of Plowman PN (eds): Paediatric Oncology:
and is best read by a radiologist experienced in tumor. Secreting germ cell tumors will have Clinical Practice and Controversies, ed 2.
neuroradiology. CT scanning can occasionally raised serum markers (␣-fetoprotein and/or London, Chapman & Hall Medical, 1999,
miss a brain tumor so MRI should be per- human chorionic gonadotrophin, HCG) in both pp 320–356.
formed if the clinical level of suspicion is the serum and/or the CSF. A diagnosis can
strong. If the CT scan is positive, MRI scanning be made on raised markers and biopsy is not
of head and spine is mandatory before needed. These tumors respond well to a
definitive treatment is given. Postoperative combination of chemotherapy and radio-
imaging is very difficult to interpret especially therapy. Germinomas may have marginally
when looking for spinal disease since a lot raised markers but do not reach the 50 µg/l
of post-surgical debris may be present. level. These tumors respond very well to
radiotherapy.
햵 –– If a biopsy is performed it must be noted
쏹
that pathology of brain tumors can be very 햸 –– Craniopharyngiomas present at a median
쏹
difficult. The results should be seen initially or of 8 years of age. The majority of these tumors
reviewed by a neuropathologist with signifi- are cystic. These children may present with
cant experience of pediatric brain tumors prior raised ICP, visual changes, disorders in pitu-
to the institution of therapy beyond the initial itary function and sometimes mental abnor-
surgery. malities. Most centers use postoperative radio-
therapy.
87
Malignant Disorders S. Bailey Initial management of a child with a newly diagnosed brain tumor
Malignant Disorders S. Bailey Supratentorial brain tumors
Low-grade glioma 햳 High-grade glioma 햳 Other tumors 햴: Choroid plexus Choroid plexus
PNET, germ cell tumors carcinoma papilloma
not diagnosed on
markers, meningiomas
Watch and Adjuvant treatment Treat as per protocol Biopsy and treat Treat as per protocol Observation
wait strategy as per protocol as per tumor type
햲 –– Supratentorial tumors may present in a
쏹 햴 –– Other tumors such as PNET, germ cell
쏹
Selected reading
variety of ways; focal seizures, headaches and tumors and meningeal tumors are treated
neurological deficits are the most common. If a according to the current treatment recommen- Bailey S, Skinner R, Lucraft H, Perry R,
supratentorial tumor is not typical of any tumor dations for those tumors. Todd N, Pearson ADJ: Pineal tumours in the
type, then germ cell markers (␣-fetoprotein, North of England, 1968–1993. Arch Dis Child
human chorionic gonadotrophin) need to be 햵 –– Choroid plexus tumors are usually easily
쏹 1996;75:181–186.
done prior to biopsy/resection; positive germ recognizable on MRI scan. They are treated ini-
Heideman RL, Packer RJ, Albright LA,
cell markers allow the diagnosis of a secreting tially with surgery and if papillomatous then no
Freeman CR, Rorke LB: Tumours of the cen-
germ cell tumor to be established without further treatment is usually needed in the case
tral nervous system; in Pizzo PA, Poplack DG
biopsy. Chemotherapy and radiotherapy, the of complete resection. Choroid plexus carcino-
(eds): Principles and Practice of Paediatric
best initial therapy for secreting germ cell mas, however, need adjuvant treatment usually
Oncology. Philadelphia, Lippincott-Raven,
tumors, can then be started. with chemo- and radiotherapy.
1997, pp 633–697.
햳 –– Low-grade gliomas can be observed
쏹 Kleiheus P, Cavenee WK (eds): Tumours
with serial MRI scanning unless resection has of the Nervous System. Pathology and
not been possible. If unresectable, either Genetics. WHO Classification of Tumours.
chemotherapy or radiotherapy are very good New York, IARC Press, 2000.
treatment options. High-grade gliomas
Plowman PN, Pearson ADJ: Tumours of
(anaplastic astrocytomas and glioblastoma
the central nervous system; in Pinkerton CR,
multiforme) need adjuvant treatment with
Plowman PN (eds): Paediatric Oncology.
radiotherapy ± chemotherapy. Survival rates
Clinical Practice and Controversies, ed 2.
for these tumors are only in the region of 20%.
London, Chapman & Hall Medical, 1999,
pp 320–356.
Pollack IF, Boyett JM, Finlay JL: Chemo-
therapy for high grade gliomas of childhood.
Child’s Nerv Syst 1999;15:529–544.
89
Resectable
Attempt reasonable resection, if possible
Surgery
CSF diversion if necessary 햳
91
Malignant Disorders S.Bailey Brain tumors of the posterior fossa, brain stem and visual pathway
Malignant Disorders S. Bailey Initial management of a child with
a tumor involving or near the spinal cord
MRI of head
Dumbbell shaped tumor, Other tumor 햶
especially in younger child Osteosarcoma, Ewings, lymphoma,
Check for other signs of neuroblastoma 햵 and others including metastases
Send urine catecholamines Biopsy and decompression if necessary Tumor in dura or invading spinal cord from Intrinsic spinal
Biopsy Treatment as for primary tumor outside cord 햸 cord tumor
Consider drop metastases from cranial lesion
Surgical Radiotherapy Chemotherapy Treat according to tumor type Biopsy and treat accordingly 햹
laminectomy Myxopapillary ependymoma
Astrocytomas
Treatment as for
neuroblastoma
햲 –– Spinal cord tumors constitute 4% of
쏹 ment. For diagnosis, urine catecholamines
Selected reading
childhood tumors. A high index of suspicion (VMA, HVA) should be measured on a spot
must be maintained, as the onset of symptoms urine catecholamine/creatinine ratio; 24-hour Heideman RL, Packer RJ, Albright LA,
is often insidious. Back pain in children (espe- urine collections are not necessary and only Freeman CR, Rorke LB: Tumours of the cen-
cially younger children) is not a common com- serve to prolong the time needed to make a tral nervous system; in Pizzo PA, Poplack DG
plaint and should always be treated seriously. diagnosis. (eds): Principles and Practice of Paediatric
A careful neurological examination must al- Oncology. Philadelphia, Lippincott-Raven,
ways be performed. 햶 –– In older children and teenagers the most
쏹 1997, pp 633–697.
likely tumors to arise from outside the CNS are
Katzenstein HM, Kent PM, London WB,
쏹 –– CT scanning is not sufficient for imaging
햳 the bone tumors and in those cases laminecto-
Cohn SL: Treatment and outcome of 83
suspected spinal pathology and MRI scan is my and biopsy is probably the best initial treat-
children with intraspinal neuroblastoma:
mandatory. MRI scan must be performed even ment. Metastatic disease needs to be evaluated
The Pediatric Oncology Group Experience.
if there is only a suspicion of pathology as but surgery is usually best for symptomatic
J Clin Oncol 2001;19:1047–1055.
early detection may make treatment options control.
easier. The films need to be reviewed by an Kleiheus P, Cavenee WK (eds): Tumours
experienced neuroradiologist, as subtle abnor- 쏹 –– The decision whether to use laminecto-
햷 of the Nervous System. Pathology and
malities are easy to miss. Approximately 50% my, chemotherapy or radiotherapy is complex Genetics. WHO Classification of Tumours.
of children with acute spinal cord compression and requires discussion with an oncologist, New York, IARC Press, 2000.
will regain neurological function after treat- neurosurgeon and radiotherapist. The view
Nadkarni TD, Rekate HL: Pediatric intra-
ment. However, urgent treatment is required as generally held is that chemotherapy is the
medullary spinal cord tumours. Child’s Nerv
the longer the signs are present the less likely most appropriate treatment for neuroblastoma
Syst 1999;15:17–28.
the child is to recover. causing spinal cord compression (unless there
is complete paralysis). Once the compression Plowman PN, Pearson ADJ: Tumours of
쏹 –– Dexamethasone must be used with cau-
햴 is managed, a chemotherapy treatment proto- the central nervous system; in Pinkerton CR,
tion if a lymphoma is suspected. The adminis- col is then followed. Plowman PN (eds): Paediatric Oncology.
tration of dexamethasone in such patients may Clinical Practice and Controversies, ed 2.
result in tumor lysis and adequate hydration 햸 –– Intrinsic spinal tumors are usually meta-
쏹 London, Chapman & Hall Medical, 1999,
plus allopurinol/urate oxidase must first be stases from intracranial lesions (‘drop meta- pp 320–356.
commenced if a lymphoma is suspected. stases’) and in children medulloblastoma is
(See ‘Recognition and management of tumor the most likely cause. The treatment is usually
lysis syndrome’, p 94). in the form of a combination of radio- and
chemotherapy. Ependymomas and germ cell
햵 –– Tumors arising from outside the CNS
쏹 tumors are the other CNS tumors of childhood
are likely to be neuroblastomas in younger that are most likely to have drop metastases.
children. Lesions compressing the spinal cord If a germ cell tumor is suspected then serum
are classically dumbbell in shape. Treatment markers are mandatory before biopsy; if ele-
of cord compression can be either surgical or vated then biopsy is not necessary.
medical in the first instance. A laminectomy
and biopsy has the advantage of providing 햹 –– Tumors that are isolated in the spinal
쏹
tissue for histology and biology of the tumor cord are most likely to be myxopapillary
although radical surgery is not recommended. ependymomas which are relatively indolent
Radiotherapy and chemotherapy are also very tumors unlike their supratentorial counterparts
effective especially if there is not a total loss or astrocytomas (high or low grade). These
93
of function. Treatment for the neuroblastoma tumors are treated as per the current national
should follow the national guidelines for treat- protocols.
Start hydration and xanthine oxidase inhibitor such as allopurinol (100 mg/m2 3×/day – oral or i.v.)
or urate oxidase (uricozyme or rasburicase) (100 U/kg 1×/day i.v.)
_ 3 liters/m2/day) 햴
Hydration according to protocol (usually >
Fluid should contain only dextrose and NaCl but not potassium 햵
Rising potassium (level >6 mmol/l) Rising phosphate Signs of fluid overload (rising weight Rising uric acid; level >0.5 mmol/l
Kayexelate (1–2 g/kg/day p.o. 6 h or If level >3 mmol/l (9.3 mg/dl) contact and BP) or decrease in urine output (8.5 mg/dl) may need treatment
retention enema in 20% sorbitol) renal physician for hemodialysis/ Frusemide (furosemide) or mannitol 햺 Rising urea or creatinine associated
If ECG changes: salbutamol (albuterol), hemofiltration 햹 If continues to be problem consider with decrease in urine output
insulin/glucose, Ca gluconate There may be associated hypocalcemia hemodialysis/hemofiltration Frusemide (furosemide) or mannitol 햺
If no response possible hemodialysis/ Consider hemodialysis/hemofiltration
hemofiltration 햸
햲 –– Tumor lysis syndrome (TLS) is a life-
쏹 햵 –– Dialysis usually is only needed in the
쏹 햹 –– Hyperphosphatemia often occurs in as-
쏹
threatening emergency that may result in short term as kidney function usually returns to sociation with hypocalcemia. Unless necessary
death if not appropriately managed. It consists normal within a matter of days. Bicarbonate is calcium should not be given as it increases
of the triad of hyperkalemia, hyperuricemia not routinely used in hydration regimes for the chance of calcium phosphate deposition in
and hyperphosphatemia. TLS most commonly newly diagnosed hematological malignancies the kidneys. If it is necessary, give calcium glu-
complicates Burkitt lymphoma, acute lympho- as it may increase the chance of calcium phos- conate (0.5 ml/kg of 10% solution over 10 min).
blastic leukemia (particularly with high WBC phate deposition in the kidneys. However, it Aluminum hydroxide (50–150 mg/kg/day) may
and/or bulky disease such as hepatospleno- is practice in some units to use sodium bicar- be used to treat hyperphosphatemia if neces-
megaly or mediastinal mass), and occurs less bonate until the pH of the urine is 7.5 before sary. The calcium × phosphate ratio should not
commonly in non-lymphoblastic leukemias and chemotherapy (enhancing urate excretion), exceed 4.6 mmol/l. A renal physician should
very rarely in other solid tumors. and then to discontinue it. Calcium phosphate be contacted if the value rises above this level.
crystals are more likely to occur if the phos-
햳 –– Although tumor lysis usually occurs after
쏹 phate × calcium product exceeds 4.6 mmol/l. 햺 –– Rising uric acids rarely occur in isolation
쏹
instituting antineoplastic therapy, it may be to the degree that warrants treatment. If xan-
evident prior to treatment. This usually occurs 햶 –– A number of special circumstances may
쏹 thine oxidase inhibitors are not sufficient then
in Burkitt lymphoma and ALL with high WBC warrant earlier commencement of treatment. urate oxidase should be used instead.
or bulky disease. Elevated K, P, or uric acid lev- A mediastinal mass compromising airway pa-
els in these children require immediate treat- tency should be treated promptly. Children
ment to stabilize the child prior to commencing with a leukostasis syndrome should also have Suggested reading
therapy. early commencement of chemotherapy. The
Chast RC, Lui-Yin JA: Acute tumour lysis
leukostasis syndrome is due to aggregation of
syndrome. Br J Hosp Med 1993;49:488–492.
햴 –– Tumor lysis occurs most commonly with-
쏹 leukemic blasts in various organs, usually the
in 24 h of starting treatment although it can lungs or the brain and is more likely when the Coad NG, Mann JR: Metabolic problems
occur up to 5 days later. The likelihood of de- leukocyte count is greater than 100 × 109/l. in children with leukaemia and lymphoma;
veloping tumor lysis can be determined by a Children may present with progressive neuro- in Oakhill A (ed): The Supportive Care of
number of factors including tumor type, serum logical or respiratory signs. Leukostasis syn- the Child with Cancer. London, Butterworth,
uric acid level prior to the starting of xanthine drome is more common in patients with AML 1988, pp 76–87.
oxidase inhibitors or urate oxidase, very high than in patients with ALL. Fleming DR, Doukas MA: Acute tumour
lactate dehydrogenase levels (indicating tumor lysis in haematologic malignancies.
bulk) and abnormal electrolytes prior to start- 햷 –– Six-hourly fluid balances and weights
쏹 Leuk Lymphoma 1992;8:315–318.
ing treatment. Xanthine oxidase inhibitors at least 12-hourly are necessary to adequately
block the conversion of hypoxanthine to xan- assess fluid status of patient. The urine output Jones DP, Mahmoud H, Chesney RW:
thine and xanthine to uric acid. Urate oxidase should be maintained at a minimum of Tumour lysis syndrome: Pathogenesis and
converts uric acid to the more soluble allantoin 2 ml/kg/h and if necessary diuretics (frusemide management. Paediatr Nephrol 1995;9:
and is thought to be more effective than xan- or mannitol) should be used. Four-hourly 206–212.
thine oxidase inhibitors (but may not be uni- electrolytes should be measured for the first Lange B, O’Neill JA Jr, Goldwein JW,
versally available). If there is thought to be a 24 h if the child is at high risk of tumor lysis but Packer RJ, Ross AJ III: Oncologic emergen-
high chance of tumor lysis, a central line capa- less frequently in those at lower risk. cies; in Pizzo PA, Poplack DG (eds): Princi-
ble of supporting hemofiltration should be in- ples and Practice of Paediatric Oncology.
serted prior to starting treatment. 햸 –– If electrocardiographic changes of hyper-
쏹 Philadelphia, Lippincott-Raven, 1997, pp
kalemia occur then bicarbonate (0.5 mEq/kg as 1041–1043.
a bolus), calcium gluconate (0.5 ml/kg of 10%
Ribiero RC, Pui C-H: Acute complications;
solution over 10 min) and glucose and insulin
95 in Pui C-H (ed): Childhood Leukaemias.
(0.5 g/kg of 10% glucose i.v. with 0.3 units of
London, Cambridge University Press, 1999,
insulin per gram of glucose) should be given to
pp 443–449.
stabilize the cardiac membrane.
Silverman P, Distelhorst CW: Metabolic
emergencies in clinical oncology. Semin
Oncol 1989;16:504–515.
Malignant Disorders S. Bailey · R. Skinner Recognition and management of tumor lysis syndrome
Malignant Disorders S.R. Rheingold · A.T. Meadows Recognition and management of
superior vena cava syndrome
CXR 햳
Treatment with chemotherapy ± radiotherapy as per specific diagnosis Usually surgical resection depending upon anatomic involvement Appropriate antimicrobial therapy
햲 –– Superior vena cava (SVC) syndrome refers to signs
쏹 neuroblastoma. If the patient has an enlarged, suspicious, empirically for the most likely diagnosis based upon exam,
and symptoms resulting from compression, obstruction, or peripheral lymph node, biopsy can be performed using local laboratory and radiologic data, and response to therapy.
thrombosis of the SVC. The classic signs and symptoms in- anesthesia in an attempt to make the diagnosis. If an effu-
clude plethora, facial edema, jugular venous distension, and sion is present, thoracentesis or pericardiocentesis can offer 햿 –– Surgical resection is the only treatment for benign
쏹
respiratory symptoms such as dyspnea, orthopnea, cough, immediate relief from respiratory compromise or cardiac tumors, such as lipomas, goiter, bronchogenic cysts, and
stridor, or wheezing. Anxiety, confusion, lethargy, headache, tamponade, as well as provide diagnostic material. Send all hamartomas. Surgery may be inevitable for a malignant
vision changes, and syncope indicate CO2 retention and cen- tissue for morphologic exam, immunocytohistochemistry, tumor that does not respond to radiation or chemotherapy.
tral venous stasis. Dysphagia can occur due to esophageal and cytogenetics. Mediastinal biopsy should be reserved In this setting a pediatric anesthesiologist, cardiopulmonary
compression. The term superior mediastinal syndrome (of- only for those patients who have no evidence of respiratory bypass, and rigid bronchoscopy must be available.
ten used synonymously with SVC syndrome in children) in- compromise and less invasive means of diagnosis are unre-
cludes compression of the trachea. vealing. 헀 –– Infection is the second most common primary etiolo-
쏹
gy of SVC syndrome. Mediastinal granulomas or fibrosis
햳 –– The CXR often reveals a widened mediastinum or an
쏹 햹 –– Proceed with a diagnostic procedure if it can be per-
쏹 from tuberculosis, and fungi such as aspergillosis, histoplas-
anterior mediastinal mass, usually with a laterally deviated formed using only local anesthesia in a position that does mosis and actinomycoses cause compression of the SVC.
or compressed trachea. Pleural and pericardial effusions not compromise the child’s airway. Treatment consists of antibiotic or antifungal therapy in
may need to be tapped both for symptomatic relief and di- association with surgical debridement.
agnostic workup. Patients with mediastinal masses that are 햺 –– If establishing a diagnosis is too risky it is usually in
쏹
>45% of the transthoracic diameter on CXR are more likely the patients best interest to start empiric pre-biopsy therapy. 헁 –– In a child with no mediastinal mass or granulomas on
쏹
to be symptomatic than those with ratios <30%. In such instances, the clinical, laboratory and radiologic data CXR, an echocardiogram should be obtained emergently to
should support the likely diagnosis of a malignancy. Empiric look for a thrombosis of the SVC.
햴 –– Any child with a mediastinal mass should be closely
쏹 therapy usually includes i.v. methylprednisolone at 2 mg/kg
examined for signs or symptoms of respiratory compro- every 6 h concomitant with chemotherapy or radiation 헂 –– Patients are at increased risk for thrombosis if they
쏹
mise. If there are any respiratory symptoms the patient therapy. (see ‘Recognition and management of tumor lysis have a history of cardiac anomalies or cardiac surgery or if
should follow the high-risk pathway outlined even if there is syndrome’, p 94). they have a central line in place. If there are no contraindica-
no evidence of SVC syndrome. tions the central line should be left in place initially for infu-
햻 –– Although there are no established standards, there
쏹 sion of antithrombolytic therapy.
쏹 –– A CBC may reveal cytopenias or peripheral blasts. A
햵 has been an increasing trend to using emergent chemother-
tentative diagnosis may be made from peripheral blasts apy in lieu of radiation therapy for chemosensitive malig-
using morphology and immunocytochemistry. If left shifted, nancies such as leukemia and lymphomas. Cyclophos- Selected reading
the WBC may be indicative of an infectious etiology. phamide alone or in combination with vincristine and an an-
Bertsch H, Rudoler S, Needle NM, et al: Emergent/urgent
thracycline are effective cytotoxic agents for leukemia, non-
therapeutic irradiation in pediatric oncology:
햶 –– Uric acid, LDH and ESR should be elevated in lym-
쏹 Hodgkin lymphoma or Hodgkin disease. Emergent
Patterns of presentation, treatment, and outcome.
phomas. An AFP and HCG may be elevated in germ cell chemotherapy should not be used for neuroblastoma, sarco-
Med Pediatr Oncol 1998;30:101–105.
tumors. Urine VMA/HVA will be elevated in neuroblastoma. mas, or germ cell tumors due to their slower response.
Ingram L, Rivera G, Shapiro DDN: Superior vena cava
쏹 –– A patient in respiratory distress at presentation is high
햷 쏹 –– Radiation oncologists often use focused radiation por-
햽 syndrome associated with childhood malignancy:
risk. In a mildly symptomatic or an asymptomatic child, a tals to treat the tumor enveloping the trachea while attempt- Analysis of 24 cases. Med Pediatr Oncol 1990;18:476.
thorough airway evaluation is necessary before using seda- ing to leave viable tissue laterally that can be biopsied when
King DR, Patrick LE, Ginn-Pease ME, et al: Pulmonary
tives or general anesthesia. This includes pulmonary func- the patient is stable. The dose of radiation is generally
function is compromised in children with mediastinal
tion tests including a volume flow loop to assess pulmonary 100–200 cGy twice daily. Children must be monitored for
lymphoma. J Pediatr Surg 1997;32:294–300.
reserve and resilience and an echocardiogram to assess car- postradiation respiratory worsening due to tracheal edema.
diac function. When possible, a CT scan should be obtained. Neuman GC, Weingarten AE, Abramowitz RM, et al:
In a child with SVC syndrome, diagnosis should be attempt- 쏹 –– When the patient is stable, attempt to make the diag-
햾 The anesthetic management of the patient with an
97
ed by the least invasive means possible. Circulatory collapse nosis. With emergent therapy lymph nodes may become anterior mediastinal mass. Anesthesiology 1984;60:144.
or respiratory failure may occur in patients receiving seda- palpable, and thus biopsied in 24–48 h. The patient may tol-
Rheingold SR, Lange BJ: Oncologic emergencies;
tion or general anesthesia. erate a mediastinal biopsy under general anesthesia. In a
in Pizzo PA, Poplack DG (eds): Principles and Practice of
small percentage of cases no tissue or bone marrow will be
Pediatric Oncology, ed 4. Philadelphia, Lippincott/
햸 –– If the CBC is abnormal a bone marrow aspirate or
쏹 obtainable for diagnosis and the patient should be treated
Williams & Wilkins, 2002, pp 1177–1180.
biopsy may reveal leukemic blasts, lymphoma, or metastatic
Febrile neutropenia
98 0 hours Clinical examination and baseline investigations
Reculture
Discontinue vancomycin if used Review sensitivities Consider stopping antibiotics Continue minimum Stop antibiotics
except in tunnel infection of 7 days appropriate once afebrile (<
_ 37.5°C)
i.v. antibiotics; child for 48 h
should be well, afebrile Stop aminoglycoside
and have negative anyway at 96 h if
96 hours Reassess Fever settling cultures afebrile and antibiotics
continuing
negative. Single drug therapy with an anti- tive but nephrotoxic anti-fungal agent. Liposo-
pseudomonal penicillin or third generation mal preparations are now available and are as
cephalosporin is not as effective, whereas efficacious, less nephrotoxic, but much more
99
monotherapy with a carbapenem (imipenem, expensive. Most units begin with conventional
meropenem) may be as effective, but is usually amphotericin B and progress to the liposomal
reserved for second-line or specific therapy. preparation when a predetermined rise in crea-
Viridans streptococci bacteremia in the neu- tinine has occurred.
Pathologist contacted
Biopsy <3 mm Open biopsy or larger resection Intraoperative pathology Adequate tissue for diagnosis
Needle, core, endoscopic Consultation frozen section
Yes No
Focused limited
Consider culturing portion Formalin fixation Frozen tissue, –70°C Tissue culture medium
Obtain more Fixed tissue only
ancillary testing for microbiology (light microscopy) (molecular genetics) (cytogenetics) tissue if possible (light microscopy)
Formalin fixation Consider freezing or (immunohistochemistry) (tissue bank) (ploidy analysis) (postfixation in
(light microscopy) tissue culture (cooperative group (MYCN analysis) glutaraldehyde for
(immunohistochemistry) Fix remainder in formalin protocols) EM is possible)
(cytogenetics) (FISH)
(light microscopy)
(immunohistochemistry)
–– Prior consultation with the pathologist helps ensure
lymphomas, as diagnostic features may be obscured. Touch in alveolar RMS, Ewings/PNET, desmoplastic small round
that the contemplated procedure will be appropriate for imprints of the freshly cut lesional surface, stained with H&E cell tumor, and synovial sarcoma are best assayed via
making the diagnosis and that necessary ancillary studies and/or Wright-Giemsa are useful, and do not waste tissue. RT-PCR in snap-frozen tissue. Any remaining sample from
are performed. As some studies require prompt processing Although heavily calcified tissue cannot be cut frozen, many frozen section kept at –70°C can be used for RT-PCR, with as-
of fresh tissue, these biopsies are best performed during bone tumors have soft areas that can be cryosectioned. surance that lesional tissue is present. If possible, additional
normal working hours. If necessary to biopsy during off Frozen section can also determine which ancillary studies fresh tumor should be snap frozen in liquid nitrogen at
hours, arrangements to preserve tissue integrity are crucial. are most indicated. If additional tissue is available for per- –70°C. This tissue may be used for cooperative group proto-
manent sections, keep the frozen tissue at –70°C, making it cols, other molecular studies, research, and for RT-PCR.
–– With suspected malignancy, biopsy tissue should be
available for ancillary studies such as molecular genetics.
sent fresh (without fixative) without delay. Small biopsies –– Fresh tissue, in culture medium such as RPMI, is used
are placed on a moist, saline soaked sponge in a closed, –– Sterile microbial tissue cultures can be obtained in the
for conventional tissue cytogenetics. Characteristic chromo-
properly labeled container, and not immersed in fluid. Larg- operating room, or in pathology prior to specimen fixation. somal abnormalities occur in the Ewings/PNET family of
er specimens are also sent fresh. Once tissue is fixed, frozen Most inflammatory lesions are sent for routine bacterial, tumors, RMS, synovial sarcomas, lymphoma/leukemias,
section, culture, cytogenetic studies, and most molecular mycobacterial and fungal culture. Viral cultures may be use- retinoblastoma, Wilms tumor, and many rarer neoplasms.
studies are not possible. ful. Cytogenetics may also be useful in ‘reactive’ processes such
as inflammatory myofibroblastic tumors. Tumor cytogenet-
–– Tumor may be sampled via fine-needle aspiration, per-
–– Special fixatives provide superior nuclear detail to for-
ics is technically demanding, and variables such as tumor
cutaneous or fiberendoscopic needle (core) biopsy, wedge malin and are useful in evaluating lymphomas. B5, contain- cellularity, viability, and proliferative activity can affect tissue
biopsy, excisional biopsy, or larger resection. Fine-needle ing mercuric chloride, is widely used. growth in culture and the accrual of metaphase spreads.
aspiration samples are essentially limited to cytologic evalu- Optimization requires communication with and prompt sub-
ation, and will not be discussed further. Needle biopsies are –– Immunophenotyping using flow cytometry is critical in
mission of tissue to the cytogenetics laboratory. Fresh tissue
minimally invasive, but that is counterbalanced by the limit- evaluating non-Hodgkin lymphomas. Fresh tissue placed in in RPMI can be used for flow cytometry, ploidy analysis,
ed tissue available for potentially critical ancillary studies. tissue culture medium (e.g. RPMI) is processed without de- and is the preferred substrate for MYCN analysis in cases of
Wedge and excisional open biopsies, with intraoperative lay. During off hours, tissue in RPMI should be refrigerated. suspected NBL.
pathologic assessment of sampling adequacy, usually pro- The amount of tissue necessary is dependent upon the le-
vide sufficient tissue for both LM and ancillary studies. Ma- sion’s cellularity and cellular discohesiveness. In most pedi- –– Electron microscopy can be useful in tumor diagnosis.
jor resection without an established histologic diagnosis is atric lymphomas, a 5-mm3 piece is sufficient. Ultrastructural features can be diagnostic in many lesions
discouraged and amputation or limb resection never per- (e.g. LCH, NBL, and RMS). Very little tissue is needed as sev-
formed on the basis of frozen section. In certain situations –– The most important pathologic technique remains LM
eral 1-mm3 blocks are sufficient. The sample must be placed
such as suspected Wilms tumor, it is desirable to remove the examination of well-fixed tissue. With more available ancil- in chilled glutaraldehyde; since it does not penetrate tissue
organ primarily, as prior biopsy would increase tumor stage. lary tests, a tendency towards less invasive (and therefore well, small tissue sections are used. Tissue previously fixed
smaller) biopsies, and cooperative group requirements for in formalin before glutaraldehyde can be used, but inferior
–– The differential diagnosis determines how much of a
research, obtaining adequate tissue is critical. The fixative ultrastructural preservation is expected.
limited tissue sample is used for ancillary studies, given that for LM is most often 10% neutral-buffered formalin, which is
LM examination of properly fixed tissue is usually the most inexpensive, infiltrates tissue well, and is excellent for gen-
Selected reading
rewarding procedure. eral histologic purposes. Fortunately, most commercial im-
munohistochemical reagents work in formalin-fixed, paraf- Barr FG, Chatten J, D’Cruz CM, Wilson AE, Nauta LE,
–– The major indication for intraoperative pathology is
fin-embedded specimens. Immunohistochemistry is very Nycum LM, Biegel JA, Womer RB: Molecular assays for
immediate therapeutic need for diagnosis. This usually in- useful in evaluating pediatric malignancies, with standard- chromosomal translocations in the diagnosis of pediatric
volves frozen section. Other indications for frozen section in- ized antibodies available for many antigens found in many soft tissue sarcomas. JAMA 1995;273:553–557.
clude assessment of tissue adequacy for diagnosis, and as- tumors. In-situ hybridization procedures such as the EBER
stain for latent Epstein-Barr virus RNA also work well in Parham DM, Head DR, Dias P, Ashmun RA, Germain GS,
sessment of operative margins. As frozen section morpholo-
paraffin. DNA can also be extracted from paraffin blocks and Houghton PJ: Diagnostic and biologic techniques; in
gy is inferior to permanent sections and sampling is limited,
101 intraoperative diagnoses are preliminary, subject to perma- analyzed by PCR to determine lineage and clonality of lym- Parham DM (ed): Pediatric Neoplasia: Morphology and
phoid populations. Biology. Philadelphia, Lippincott-Raven, 1996, pp 13–32.
nent section review, and may only be sufficient to describe a
lesion’s general nature (e.g. reactive, inflammatory, benign, Triche TJ, Sorensen PHB: Molecular pathology of
malignant), without providing a specific diagnosis. Freezing –– Frozen tissue is valuable for research and diagnostics,
pediatric malignancies; in Pizzo PA, Poplack DG (eds):
can alter histology and is generally reserved for specimens especially for molecular assays for chromosomal transloca- Principles and Practice of Pediatric Oncology, ed 4.
>3 mm in size. Frozen section is discouraged in suspected tions in pediatric sarcomas. Specific gene fusions occurring Philadelphia, Lippincott-Raven, 2002, pp 161–204.
Atelectasis Viral Bacterial Fungal Pneumocystis Pulmonary Treatment- Malignancy 햺 Bronchiolitis Fibrosis Pulmonary ARDS 햽
infection 햶 infection 햷 infection 햸 carinii 햴 hemorrhage related toxicity 햹 obliterans edema
Physical Appropriate antimicrobial agents Trimethoprim- Supportive care Supportive care Chemotherapy Supportive care Supportive care
therapy Antiviral agents when appropriate 햶 sulfamethoxazole Maintain adequate Stop treatment causing Radiotherapy if ?? Corticosteroids
? Antibiotics Supportive care Pentamidine is platelets and pulmonary toxicity appropriate
alternative coagulation factors ? Corticosteroids
쏹 –– Pulmonary infiltrates in patients who are receiving
햲 쏹 –– The diagnosis of fungal or Pneumocystis pneumonia
햵 pneumonitis may occur within 2–3 months after lung irradi-
chemotherapy are most often due to infection, although may be obtained from bronchoalveolar lavage (BAL), al- ation, and may respond to steroids, but late radiation fibro-
other causes need to be considered. Patients with neutrope- though this technique is not very sensitive for other patho- sis is less likely to be steroid-responsive.
nia (ANC <500, or <1,000 and falling) are at the highest risk gens. Samples from BAL or biopsy should be sent for his-
of infection, in particular from bacteria or fungi. Some pa- tology, gram stain, culture (for bacterial, viral, and fungal 쏹 –– Tumors that commonly metastasize to the lungs in-
햺
tients with a normal ANC, especially those with leukemia, causes), and silver stain or indirect immunofluorescent anti- clude Wilms tumor, Ewing sarcoma, rhabdomyosarcoma,
lymphoma, or after BMT, may be immunocompromised for body testing for Pneumocystis. In patients who fail to im- and osteogenic sarcoma. Lymphoma, Langerhans cell histi-
as long as several months after the completion of therapy. prove with a combination of antibiotics and amphotericin B, ocytosis, and posttransplant lymphoproliferative disease
The pattern of infiltrate on the CXR may suggest a particu- a lung biopsy is more likely to provide a definitive diagno- may also present with pulmonary disease.
lar diagnosis, as a focal lesion is more likely to be bacterial, sis, especially if there are peripheral pulmonary lesions
while nodular lesions are more likely either fungi or metas- that are accessible by thoracoscopy. Thoracotomy carries 쏹 –– Patients with chronic graft-versus-host disease
햻
tases. However, most patients with CXR findings will have a higher morbidity, but may be necessary in the patient (GvHD) are at risk for numerous pulmonary complications,
diffuse infiltrates that are nonspecific. Moreover, many pa- whose lesions are less accessible. Sputum collection is both infectious and noninfectious. In the absence of infec-
tients with fever and neutropenia will have a normal CXR usually impossible and rarely helpful in the neutropenic tion, bronchiolitis obliterans due to GvHD and pulmonary
even in the presence of pulmonary disease, and a CT scan pediatric patient. fibrosis due to prior therapy are the most common causes
may be necessary to identify lung lesions; in neutropenic of pulmonary dysfunction and may be differentiated by
patients, however, CT may underestimate the extent of dis- 쏹 –– The most common viral causes of pneumonia are
햶 pulmonary function testing.
ease. The initial empiric antibiotic treatment for patients CMV, respiratory syncytial virus, influenza, and parainfluen-
with presumed pneumonia is the same as that for other pa- za. Herpes simplex, varicella zoster, human herpesvirus 6 쏹 –– Acute respiratory distress syndrome is often associat-
햽
tients with fever and neutropenia, but further evaluation of and adenovirus are other potential pathogens. CMV is espe- ed with bacterial or viral pneumonia, though a specific
a pulmonary process is indicated if respiratory signs and cially common after BMT. Specific antiviral therapy may be pathogen may not be identified.
symptoms, such as hypoxemia, tachypnea, cough, or dys- indicated for respiratory syncytial (ribavirin), CMV (ganci-
pnea, persist despite initial antibiotic therapy. clovir), and varicella zoster viruses (acyclovir or famci-
clovir). Selected reading
쏹 –– Multiple diagnoses may be present in an individual
햳
Collin BA, Ramphal R: Pneumonia in the compromised
patient; in particular, patients treated with broad-spectrum 쏹 –– The most common bacterial causes of pneumonia in
햷
host including cancer patients and transplant patients.
antibiotics for a presumed bacterial pneumonia are at risk the immunocompromised host are Streptococcus pneumo-
Infect Dis Clin N Am 1998;12:781–805.
for a secondary fungal infection. Patients at risk for CMV in- niae, Staphylococcus aureus, gram-negative bacillae (such
fection should have the serum CMV antigen level meas- as Klebsiella, Pseudomonas, Escherichia coli, Serratia, and Ewig S, Glasmacher A, Ulrich B, et al: Pulmonary
ured. In many cases, patients will improve without a specif- Enterobacter), and Mycoplasma. Streptococcus viridans in- infiltrates in neutropenic patients with acute leukemia
ic diagnosis or pathogen being identified. The initial empir- fections occur in some patients, particularly after high-dose during chemotherapy: Outcome and prognostic factors.
ic antibiotic regimen should treat both gram-positive and cytarabine or stem cell transplantation, and are commonly Chest 1998;114:444–451.
gram-negative bacteria, including Pseudomonas, and may associated with ARDS.
Heussel CP, Kauczor HU, Heussel GE, et al: Pneumonia
be tailored to the predominant organisms at the treating in-
in febrile neutropenic patients and in bone marrow
stitution and local patterns of antibiotic resistance. A 쏹 –– The most common causes of fungal infections in the
햸
and blood stem-cell transplant recipients: Use of high-
macrolide antibiotic may be necessary for mycoplasma lung are Aspergillus and, less frequently, Candida species.
resolution computed tomography. J Clin Oncol
pneumonia. Aspergillus is typically associated with a ‘halo sign’ on
1999;17:796–805.
high-resolution CT scan. Candida pneumonia usually re-
쏹 –– A new infiltrate or persistent fever while on broad-
햴 sults from hematogenous spread, and therefore fungal le- Murray PV, O’Brien MER, Padhani AR, et al: Use of first
spectrum antibiotics is most commonly due to a fungal in- sions are often seen in other organs. GM-CSF may be a line bronchoalveolar lavage in the immunosuppressed
fection. Fluconazole may be adequate therapy for most useful adjunct in the treatment of fungal infections. oncology patient. Bone Marrow Transplant 2001;27:
Candida infections, but it is not effective against Aspergillus 967–971.
and some Candida species. Pneumonia due to Pneumocys- 쏹 –– Pulmonary toxicity may result from a variety of
햹
103 Pagani JJ, Kangarloo H: Chest radiography in pediatric
tis carinii is rare because of the regular use of trimetho- chemotherapy agents, and may represent acute hypersensi-
allogeneic bone marrow transplantation. Cancer 1980;
prim-sulfamethoxazole as prophylaxis, but should be sus- tivity reactions (all-trans retinoic acid, procarbazine, vinca
46:1741–1745.
pected in the patient with fulminant respiratory failure and alkaloids, cytarabine) or pathology that develops over
alkalosis. weeks (bleomycin, methotrexate) to years after therapy (cy- Shenep JL, Flynn PM: Pulmonary fungal infections in
clophosphamide, BCNU, busulfan, methotrexate). Radiation immunocompromised children. Curr Opin Pediatr 1997;
9:213–218.
Patient underwent surgery 햳 Patient received chemotherapy 햸 Patient received radiation therapy 햾
Determine specific procedure Determine specific chemotherapy used Determine areas radiated
7
7
7
Corticosteroids (e.g. dexamethasone, prednisone) avascular
phylactic antibiotics, aggressive necrosis 햹 evaluate joint pain with X-ray/MRI sitting height – growth hormone is not effective
7
7
Anthracyclines (doxorubicin, daunomycin, idarubicin)
beginning 7 years after therapy clinical follow-up && risk breast Ca self
7
7
Pelvic orchiectomy/oophorectomy monitor echocardiogram/ECG every 3 years 햺
7
cardiotoxicity
monitor gonadal function 햵 examination monthly, regular physical examinations, mammogram
every 2 years >25 years of age 햿
7
7
Bleomycin/nitrosureas (carmustine/lomustine) pulmonary
concerning reproductive options
7
7
Nephrectomy monitor renal Cognition learning disability annual education assessment and intermittent
7
7
BUN, blood pressure and hemoglobin), Eye cataracts annual eye examination
7
protect from trauma Thyroid hypothyroidism annual T4
7
7
Thyroid cancer annual thyroid palpation
7
7
7
Amputation
7
Alkylating agents (mechlorethamine, melphalan, lomustine, Esophageal integrity monitor symptoms
7
77
7
procarbazine, cisplatin) gonadal dysfunction 햻 Growth growth hormone deficiency monitor growth
7
7
monitor
pubertal development, testicular and penile size, amenorrhea, Puberty precocious or delayed within 2 years
7
7
7
7
secondary leukemia 햽 echocardiogram/ECG
7
CBC annually
7
Pulmonary fibrosis PFT + CXR every 3 years if >15 Gy
7
Topoisomerase inhibitors (etoposide [VP-16] and teniposide Smoking cessation must be encouraged
7
[VM-26]) secondary leukemia 햽 Scoliosis screen annually (every 6 months prepuberty)
7
CBC annually
Abdominal/pelvic 헂
7
Malabsorption evaluate if symptoms
77
Gonadal function see note on alkylating agents
7
Malignant Disorders A.T. Meadows · W. Hobbie Monitoring for late effects in children with malignancies
R.H. Sills Useful normal laboratory values
Age Hb RBC HCT MCV WBC Neutrophils Lymphocytes Monocytes Eosinophils Basophils Platelets
g/dl × 1012/I fl × 109/I × 109/I × 109/I × 109/I × 109/I × 109/I × 109/I
Birth (term infants) 14.9–23.7 3.7–6.5 0.47–0.75 100–125 10.0–26.0 2.7–14.4 2.0–17.3 0.00–1.9 0.00–0.85 0.00–0.10 150–450
2 weeks 13.4–19.8 3.9–5.9 0.41–0.65 088–110 16.0–21.0 1.5–15.4 2.8–19.1 0.10–1.7 0.00–0.85 0.00–0.10 170–500
2 months 19.4–13.0 3.1–4.3 0.28–0.42 084–098 15.0–15.0 0.7–14.8 3.3–10.3 0.40–1.2 0.05–0.90 0.02–0.13 210–650
6 months 10.0–13.0 3.8–4.9 0.30–0.38 073–084 16.0–17.0 1.0–16.0 3.3–11.5 0.20–1.3 0.10–1.10 0.02–0.20 210–560
1 year 10.1–13.0 3.9–5.1 0.30–0.38 070–082 16.0–16.0 1.0–18.0 3.4–10.5 0.20–0.9 0.05–0.90 0.02–0.13 200–500
2–6 years 11.0–13.8 3.9–5.0 0.32–0.40 072–087 16.0–17.0 1.5–18.5 1.8–18.4 0.15–1.3 0.05–1.10 0.02–0.12 210–490
6–12 years 11.1–14.7 3.9–5.2 0.32–0.43 076–090 14.5–14.5 1.5–18.0 1.5–15.0 0.15–1.3 0.05–1.00 0.02–0.12 170–450
12–18 years
Female 12.1–15.1 4.1–5.1 0.35–0.44 077–094 14.5–13.0 1.5–16.0 1.5–14.5 0.15–1.3 0.05–0.80 0.02–0.12 180–430
Male 12.1–16.6 4.2–5.6 0.35–0.49 077–092 04.5–13.0 1.5–16.0 1.5–14.5 0.15–1.3 0.05–0.80 0.02–0.12 180–430
Compiled from various sources. Red cell values at birth derived from skin puncture blood; most other data from venous blood.
Reproduced with permission from Elsevier Science, from Hinchliffe RF: Reference values; in Lilleyman J, Hann I, Blanchette V (eds): Pediatric Hematology, ed 2. London,
Churchill Livingstone, 1999, p 2.
Reference values for coagulation tests and inhibitors of coagulation in the healthy full-term infant during the first 6 months of life and in adults
Tests Day 1 (n) Day 5 (n) Day 30 (n) Day 90 (n) Day 180 (n) Adult (n)
PT, s 13.0 ± 1.43 (61)1 12.4 ± 1.46 (77)1, 2 11.8 ± 1.25 (67)1, 2 11.9 ± 1.15 (62)1 12.3 ± 0.79 (47)1 12.4 ± 0.78 (29)
PTT, s 42.9 ± 5.80 (61) 42.6 ± 8.62 (76) 40.4 ± 7.42 (67) 37.1 ± 6.52 (62)1 35.5 ± 3.71 (47)1 33.5 ± 3.44 (29)
Fibrinogen, g/l 2.83 ± 0.58 (61)1 3.12 ± 0.75 (77)1 2.70 ± 0.54 (67)1 2.43 ± 0.68 (60)1, 2 2.51 ± 0.68 (47)1, 2 2.78 ± 0.61 (29)
FII, U/ml 0.48 ± 0.11 (61) 0.63 ± 0.15 (76) 0.68 ± 0.17 (67) 0.75 ± 0.15 (62) 0.88 ± 0.14 (47) 1.08 ± 0.19 (29)
FV, U/ml 0.72 ± 0.18 (61) 0.95 ± 0.25 (76) 0.98 ± 0.18 (67) 0.90 ± 0.21 (62) 0.91 ± 0.18 (47) 1.06 ± 0.22 (29)
FVII, U/ml 0.66 ± 0.19 (60) 0.89 ± 0.27 (75) 0.90 ± 0.24 (67) 0.91 ± 0.26 (62) 0.87 ± 0.20 (47) 1.05 ± 0.19 (29)
FVIII:C, U/ml 1.00 ± 0.39 (60)1, 2 0.88 ± 0.33 (75)1, 2 0.91 ± 0.33 (67)1, 2 0.79 ± 0.23 (62)1, 2 0.73 ± 0.18 (47)2 0.99 ± 0.25 (29)
VWFAg, U/ml 1.53 ± 0.67 (40)2 1.40 ± 0.57 (43)† 1.28 ± 0.59 (40)2 1.18 ± 0.44 (40)2 1.07 ± 0.45 (46)2 0.92 ± 0.33 (29)2
FIX, U/ml 0.53 ± 0.19 (59) 0.53 ± 0.19 (75) 0.51 ± 0.15 (67) 0.67 ± 0.23 (62) 0.86 ± 0.25 (47) 1.09 ± 0.27 (29)
FX, U/ml 0.40 ± 0.14 (60) 0.49 ± 0.15 (76) 0.59 ± 0.14 (67) 0.71 ± 0.18 (62) 0.78 ± 0.20 (47) 1.06 ± 0.23 (29)
FXI, U/ml 0.38 ± 0.14 (60) 0.55 ± 0.16 (74) 0.53 ± 0.13 (67) 0.69 ± 0.14 (62) 0.86 ± 0.24 (47) 0.97 ± 0.15 (29)
FXII, U/ml 0.53 ± 0.20 (60) 0.47 ± 0.18 (75) 0.49 ± 0.16 (67) 0.67 ± 0.21 (62) 0.77 ± 0.19 (47) 1.08 ± 0.28 (29)
FXIIIa, U/ml 0.79 ± 0.26 (44) 0.94 ± 0.25 (49)1 0.93 ± 0.27 (44)1 1.04 ± 0.34 (44)1 1.04 ± 0.29 (41)1 1.05 ± 0.25 (29)
FXIIIb, U/ml 0.76 ± 0.23 (44) 1.06 ± 0.37 (47)1 1.11 ± 0.36 (45)1 1.16 ± 0.34 (44)1 1.10 ± 0.30 (41)1 0.97 ± 0.20 (29)
Plasminogen CTA, U/ml 1.95 ± 0.35 (44) 2.17 ± 0.38 (60) 1.98 ± 0.36 (52) 2.48 ± 0.37 (44) 3.01 ± 0.40 (47) 3.36 ± 0.44 (29)
AT 0.63 ± 0.12 (58) 0.67 ± 0.13 (74) 0.78 ± 0.15 (66) 0.97 ± 0.12 (60)1 1.04 ± 0.10 (56)1 1.05 ± 0.13 (28)
HCII 0.43 ± 0.25 (56) 0.48 ± 0.24 (72) 0.47 ± 0.20 (58) 0.72 ± 0.37 (58) 1.20 ± 0.35 (55) 0.96 ± 0.15 (29)
Protein C 0.35 ± 0.09 (41) 0.42 ± 0.11 (44) 0.43 ± 0.11 (43) 0.54 ± 0.13 (44) 0.59 ± 0.11 (52) 0.96 ± 0.16 (28)
Protein S 0.36 ± 0.12 (40) 0.50 ± 0.14 (48) 0.63 ± 0.15 (41) 0.86 ± 0.16 (46)1 0.87 ± 0.16 (49)1 0.92 ± 0.16 (29)
NOTE: All factors except fibrinogen and plasminogen are expressed as units per milliliter where pooled plasma contains 1.0 U/ml. Plasminogen units are those recommended by
the Committee on Thrombolytic Agents (CTA). All values are expressed as mean ± 1 SD.
1
Values that do not differ statistically from the adult values.
2
These measurements are skewed because of a disproportionate number of high values. The lower limit that excludes the lower 2.5th percentile of the population has been given
in the respective figures. The lower limit for factor VIII was 0.50 U/ml at all time points for the infant.
Modified with permission from Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, Powers P: Development of the human coagulation system in the full-term
infant. Blood 1987;70:165–172.
107