2022 5.3b.

Diseases of the Blood (Part 2)

DR. MELANIE VICTORIA G. DAR | 04/21/2021
PEDIATRICS II

OUTLINE Pathology
I. Inherited Pancytopenias VI. Inherited Bleeding Disorders • Abnormal chromosome fragility
II. Acquired Pancytopenias VII. Acquired Bleeding Disorders • Inability of FA cells to remove oxygen-free radicals, resulting in
III. Hemostasis VIII. Platelet Disorders oxidative damage
IV. Clinical Approach to a IX. Disorders of the Blood Vessels • Shortened leukocyte telomere length, but increased telomere
Patient with Bleeding activity
V. Laboratory Assessment of − high proliferative rate of marrow progenitors leading to premature
Bleeding senescence
• Increased marrow cell apoptosis
• Diminished cellular interleukin-6 production and markedly
LEGEND heightened TNF-alpha generation
Remember Lecturer Book Previous Trans Presentation
HELLO Clinical Manifestation
• Most common anomaly:
− Hyperpigmentation of the trunk, neck, and intertriginous area
THE PANCYTOPENIAS − Café-au-lait spots
• there is a decrease of almost all of the blood elements either white
− Vitiligo
cells, red cells and platelet, or any combination of these
• Short stature
• Absence of radii and thumbs that are hypoplastic, supernumerary,
I. INHERITED PANCYTOPENIAS bifid, or absent
• Pancytopenia • Anomalies of the feet, congenital hip dislocation, leg abnormalities
− Reduction below normal values of all 3 peripheral blood • Males
lineages: − Underdeveloped penis
○ Leukocytes − Undescended, atrophic, or absence of testis
○ Platelets
− Hypospadias or phimosis
○ Erythrocytes
• Females: malformation of the vagina, uterus and ovary
− Requires microscopic examination of a BM biopsy specimen and
• Facies:
Bone Marrow Aspirate (BMA) to assess overall cellularity and
− Microcephaly
morphology
○ There are multiple causes of pancytopenia not only aplastic − Small eyes
anemia but even malignancy particularly leukemia − Epicanthal folds
− Abnormal shape, size or positioning of the ears
• Ectopic, pelvic, horseshoe-kidneys
3 GENERAL CATEGORIES
• Cardiovascular and Gl malformations
Hypocellular • 10% are cognitively delayed
• Inherited ("Constitutional") Marrow Failure Syndrome
• Acquired Aplastic Anemia Laboratory findings
• Hypoplastic variant of Myelodysplastic Syndrome (MDS)
• Thrombocytopenia
• Paroxysmal Nocturnal Hemoglobinuria (PNH) with Pancytopenia
• Granulocytopenia
• Macrocytic anemia
Cellular Marrow and MDS • Severe aplasia
• Primary BM disease such as Acute Leukemia and MDS • BM: Hypocellular and fatty
• Secondary to Systemic Disease
− Autoimmune Disorders (SLE) Complications
− Vitamin B or Folate Acid Deficiency
• Propensity for cancer
− Storage Disease
• Acute leukemia or MDS
− Overwhelming infection
− Sarcoidosis
− Hypersplenism
Diagnosis
• Considered in all children and young adults with unexplained
Bone Marrow Infiltration cytopenias
• Abnormal hematologic findings, physical anomalies
• Myelofibrosis
• Confirmatory: lymphocyte chromosomal breakage study with
• Osteopetrosis Diepoxybutane (DEB)
• Hemophagocytic Lymphohistiocytosis • Elevation of Alpha-fetoprotein (AFP)
• Metastatic Solid Tumors
Treatment
FANCONI ANEMIA
• Autosomal Recessive • Observation
• At presentation: • Endocrine evaluation
− Typical physical anomalies but normal hematologic findings • Blood counts q 1-3 months, BMA and biopsy
− Normal physical features but abnormal hematologic findings • HPV vaccination
− Physical anomalies and abnormal hematologic findings • Hematopoietic Stem Cell Transplant (HSCT): only curative therapy
• 75% of patients are 3-14 years of age at the time of diagnosis • Androgen therapy
• Gene therapy

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 2022 5.3b. Diseases of the Blood (Part 2)
DR. MELANIE VICTORIA G. DAR | 04/21/2021
PEDIATRICS II

SHWACHMAN-DIAMOND SYNDROME Laboratory findings:

• Autosomal recessive • Pancytopenia
• 2 essential diagnostic criteria: • Macrocytic RBC
− Exocrine pancreatic insufficiency • Elevated Hb F
− Variable hematologic cytopenias due to marrow failure • No abnormal chromosomal breakage

Clinical Manifestation: Diagnosis

• Symptoms of malabsorption from birth caused by pancreatic • History and PE
insufficiency
• 50% exhibit modest improvement in pancreatic enzyme secretion
as the age
Complications
• Anemia, neutropenia, thrombocytopenia • CA, MDS, Solid tumors
• Bacterial and fungal infection
• Short stature Treatment:
• Delayed bone maturation, metaphysical dysplasia, short or flared • Androgens, prednisone
ribs, thoracic dystrophy, bifid thumb
• GCSF
• Hepatomegaly
• HSCT: only curative treatment
• Dental abnormalities
• Neurocognitive problems
• Poor social skills
AMEGAKARYOCYTIC THROMBOCYTOPENIA
• Congenital Amegakaryocytic Thrombocytopenia (CAMT)
• Autosomal recessive
Laboratory Findings • Manifests in infancy as isolated thrombocytopenia due to reduction
• Fatty replacement of pancreatic tissue on CT scan or UTZ or absence of marrow megakaryocytes with initial preservation of
• 72-hour stool collection for fat malabsorption granulopoeitic and erythroid lineage
• Impaired pancreatic enzyme function • 1st year of life: Pancytopenia
• Neutropenia • Related to mutations in MPL gene
• Anemia, thrombocytopenia
• Pancytopenia Clinical Manifestations
• BM: Hypoplasia and fatty infiltration
• Petechial rashes, bruising, or bleeding at birth or in the 1st year of
• B cell defects: IgG subclasses
life
• Low T cell, NK cells
• 40% with physical anomalies
• Very very rare ○ Most common anomalies: neurologic and cardiac
○ Cerebellar and cerebral atrophy, developmental delay
Diagnosis ○ CHD: ASD, VSD, PDA, TOF, COA
• Definitive (90%): Mutational analysis for SBDS ○ Others:
 Abnormal hips or feet
 Kidney malformations
Complications
 Eye anomalies
• MDS and Leukemic transformation  Cleft or high-arched palate
 Microcephaly
Treatment  Abnormal facies
• Oral pancreatic enzyme replacement
• Supplemental fat-soluble vitamins Laboratory findings
• Long term plan to monitor Peripheral Blood (PB) counts − Thrombocytopenia
• Serial BMA, cytogenetics and marrow biopsy − Initially: normal hemoglobin and wbc count
• Daily GCSF − RBC: macrocytic
• Transfusions − Elevated Hb F, increased expression of i antigen
• HSCT: only curative option − BMA: normocellular with marked reduction or absence of
megakaryocytes
DYSKERATOSIS CONGENITA
• X-linked recessive inheritance, autosomal dominant or recessive Diagnosis
• Mucocutaneous abnormalities, BM failure, predisposition to cancer − BMA with biopsy
and MDS − Mutational analysis

Mucocutaneous triad: Therapy and prognosis

• Reticulate skin pigmentation of the upper body − Supportive management
• Mucosal leukoplakia − Nonsense MPL mutation: 100% mortality
• Nail dystrophy − Missense mutations: milder course
− HSCT: only curative treatment
Clinical Manifestation
• Skin pigmentation and nail changes II. ACQUIRED PANCYTOPENIAS
• Mucosal leukoplakia • Drugs, chemicals, toxins, infectious agents, radiation, immune
• Excessive ocular tearing disorder
• BM failure − Cause pancytopenia
• Malignancy ○ Direct destruction of hematopoietic progenitors
○ Disruption of marrow microenvironment
○ Immune-mediated suppression of marrow elements (SLE)

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DR. MELANIE VICTORIA G. DAR | 04/21/2021
PEDIATRICS II

• Majority of cases: idiopathic cause Prognosis

• Some viruses: Parvovirus B19
• Spontaneous recovery: rare
• Evaluation for PNH and Collagen vascular Disease
− When exposure to triggering factor has been removed
• Mortality rate: 50%
Pathology and Pathogenesis • Major cause of M/M: infection and bleeding
• Hallmark: Peripheral pancytopenia, coupled with hypoplastic or
aplastic BM III. HEMOSTASIS
• Severity of the clinical course is related to degree of • Process of how the body stops bleeding from a cut or injury
myelosuppression • Interplay between the vessel wall, platelets, coagulation factors and
− Severe Aplastic Anemia fibrinolysis
○ 2 or more cell lines are affected • Clot formation that closes the hole in the blood vessel
 ANC <500/mm3 • Repairing the opening in the blood vessel
 Platelet count <20,000/mm3 • Fixing the blood vessel so that it works like before the injury
 Reticulocyte count < 1% after correction for hematocrit
○ BM biopsy: moderately or severely hypocellular
− Moderate Aplastic Anemia Physiology
○ ANC 500-1,500/mm3 • As a result of injury to the blood vessel endothelium
○ Platelet count 20,000-100,00/mm3 − Vasoconstriction (vascular phase)
○ Reticulocyte count >1% − Platelet plug formation (primary hemostatic mechanism-platelet
phase)
Pathogenesis − Fibrin thrombus formation (initiation, amplification and
propagation phase)
• BM failure may be a consequence of
− Direct cytotoxic effect on HSC from a drug or chemical
− Cell-mediated or antibody-dependent cytotoxicity COMPONENTS
○ causing distraction of marrow environment ENDOTHELIUM
• Secretes substances that
Clinical Manifestations and Laboratory Results − Repel platelet (PGI2), adenosine diphosphate (ADP2) and nitric
• These would depend on the severity of the aplasia oxide
• Increased risks of cardiac failure, infection, fatigue − Initiate coagulation (collagen and fibronectin)
• CBC: Anemia, leukopenia, thrombocytopenia − Promote platelet adhesion (Von Willebrand Factor/VWF)
• Elevated serum cytokine − Fibrin dissolution (tissue plasminogen activator)
• PBS: Pancytopenia − Catalyze the inhibition of thrombin (heparin and thrombomodulin)
• Reticulocyte count <1% for severe and >1% for moderately severe − Inhibit the initiation of fibrin dissolution (Tissue Plasminogen
• Flow cytometry for PNH: CD55 and CD59 Activator/TPA)
• BMA and Biopsy
− to differentiate other causes of aplasia (aplastic anemia & PLATELETS
malignancy) • Interaction in coagulation are initiated by adhesion in areas of
vascular injury
Treatment • Provide surfaces for the assembly of coagulation factors
• Comprehensive supportive care • Aggregate and increase the mass of the hemostatic plug
− Blood transfusion • Mediated blood vessel constriction by releasing serotonin and
− Antibiotics in the presence of infections neutralize heparin
− Platelet transfusion for active bleeding
• Treat underlying marrow failure PLASMA COAGULATION FACTORS
− rule out all possible causes of aplasia • Produced in the liver
− if it is secondary to drugs or chemicals, removal of this will help in − Diseases in the liver will also cause problems with coagulation
the improvement of the marrow • FVIII also produced in the endothelial cells
− if because of infectious agent causing the aplasia then, treat the • II, VII, IX and X-vitamin K dependent clotting factors that require Vit K
more primary one Prothrombin, stable factor, Christmas factor,stuart factor
− If it is because of the autoimmune disorder then, treat the PRIMARY HEMOSTASIS
autoimmune disorder to correct the pancytopenia • Involves structure and functions
• Allogeneic BM transplant: 90% chances of survival of the blood vessels and
• Immunosuppression with Antithymocyte Globulin (ATG) and platelets and how they interact
Cyclosporine to form a temporary plug
− Response rate: 60-80% when damage occurs in the
− Median time response: 6 months circulatory vessels.
− explain this to the patient because some of them expect already • Damage to small blood
response immediately after treatment but some will present vessels and capillaries
bleeding or any form of infection even after treatment frequently occurs
− 25-30% relapse rate • Following damage, there is an
− <10%: increased risk of clonal BM disease (leukemia, MDS) immediate reflex that promotes
VASOCONSTRICTION thus
Complication diminishing blood loss
• Life-threatening bleeding
• Infection
− Bacterial
− Invasive mycoses

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DR. MELANIE VICTORIA G. DAR | 04/21/2021
PEDIATRICS II

1. Once there is vessel injury, blood vessel would cause constriction to

lessen the blood loss in that area.
2. The endothelial lining would expose collagen with the presence of
Von Willebrand factor would cause attraction of the platelets to cause
platelet adhesion to further stop the ongoing bleeding.
3. Platelet will release reaction particularly Adenosine Diphosphate
Thromboxane A2 Serotonin, and others to cause further constriction
and invite more platelets causing platelet aggregation to further stop
the bleeding.
4. Platelet aggregation will cause platelet clump and with the presence
of Thrombin will strengthen the platelet plug but remember this is just
primary hemostasis.
• Example: There is a defect on the secondary hemostasis, the
coagulation factors, this platelet plug will not be stable enough to
further stop the bleeding. It would just cause an initial stoppage of the
bleeding but further or as this goes by because of the defect of
secondary hemostasis, this platelet plug will be shed off and the
bleeding will continue
• For diseases under primary hemostasis, any abnormality of blood
vessel and the platelet plug will not cause the progression of the
primary hemostasis thus patient will present with bleeding

SECONDARY HEMOSTASIS
(FIBRIN THROMBUS FORMATION)
• Involves the structure and function of the soluble plasma proteins involved in the complex process of converting fibrinogen into insoluble fibrin
which is needed to strengthen the hemostatic plug
• Review: The complex coagulation cascade includes about 30 interacting
proteins. In case of a vessel cut or other injury, the tissue factor, (TF), gets
exposed to the blood stream. It binds the coagulation factor VII which leads
to activation of the coagulation cascade. When TF activates the coagulation,
it eventually results in an induction of the coagulation protein thrombin.
Thrombin has the ability to cleave fibrinogen which generates fibrin. The
main function for the coagulation cascade is to prevent big blood loss in case
of an injury. This is accomplished by forming stable haemostatic clots which
consists of a mesh of fibrin reinforcing the previously aggregated platelets.
• The coagulation cascade can be schematically separated into three areas:
− Intrinsic pathway which is activated by contact with surfaces
− Extrinsic pathway which is activated by vascular injury
− Common pathway which is initiated by the activation from the intrinsic
and/or extrinsic pathway.
• In case of damage to the vascular wall, TF is exposed and the extrinsic
pathway is initiated. Factor VII is a circulating coagulation factor which
forms a complex with tissue factor in presence of calcium. This complex
quickly converts the proenzyme factor X to the enzyme form factor Xa.
• The intrinsic pathway, also called the contact activation pathway, is the
other branch of the coagulation cascade. When circulating factor XII comes
in contact with and is bound to a negatively charged surface it spontaneously
activates, and the intrinsic pathway is thus activated. The activated factor
XII enzyme is then able to activate factor XI into the active enzyme factor
XIa. In presence of calcium, factor XIa converts factor IX to its active form,
factor IXa. Factor X can then be activated to factor Xa by factor IXa in the
presence of factor VIII, calcium and platelet phospholipids. The end of
both the extrinsic and the intrinsic pathway meet in the activation of factor X
to factor Xa and from here, the common pathway continues.
• Activated factor Xa and factor V acts as catalysts when prothrombin
(factor II) is converted to thrombin (factor IIa). This leads in turn to the
conversion of fibrinogen (factor I) to fibrin.
• Source: http://liu.diva-portal.org/smash/get/diva2:417791/FULLTEXT01.pdf
• Extrinsic pathway: once there is tissue damage, tissue factor is released causing conversion of Factor VII together with calcium to factor VIIA
− Factor VIIa is needed in the conversion of factor X to factor Xa with the help of calcium and phospholipids
− Factor Xa is now the start of common pathway
• Intrinsic pathway: together with contact with damage vessel, factor XII would be converted to Factor XIIa
− Factor XIIa convert factor XI to factor XIa with the aid of calcium
− Factor IXa will further convert or combine to common pathway to convert factor X to factor Xa with the help of calcium, factor VIII and platelet
phospholipid
• Common Pathway
− Factor Xa will further convert prothrombin to thrombin with the aid of calcium, factor V and platelet phospholipid
− Thrombin will help in the conversion of fibrinogen to fibrin together with factor Va and factor VIII
− Fibrin will lead to more stable clot particularly fibrin clot with the help of factor XIII and Factor XIIIa and fibrin
• Extrinsic pathway will be tested by Prothrombin Time and the intrinsic pathway will be the Activated Partial Thromboplastin Time

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 2022 5.3b. Diseases of the Blood (Part 2)
DR. MELANIE VICTORIA G. DAR | 04/21/2021
PEDIATRICS II

IV. CLINICAL APPROACH TO A PATIENT WITH BLEEDING • Purpura is bigger than petechia
• Ex: Patient came in with multiple bruises or swelling of the joints
• Detailed clinical history 80 to 90 % will be base in history
• Family history of bleeding is very important
• Differentiate between primary (platelet) and secondary hemostasis
(clotting factor deficiency)
• Screening tests

HISTORY
• Clinical manifestations
• Immediate history
• Sick child with fever, shock and mucocutaneous purpura >
Disseminated Intravascular Coagulation (DIC)
• Male toddler who has just started crawling with subcutaneous or
joint bleeding with a family history of bleeding → hemophilia
• Adolescent girl with severe menorrhagia with a family history of
bleeding → Von Willebrand Disease (VWD)
− Von Willebrand factor is very important in primary hemostasis
wherein platelets would adhere to this
PURPURA
• Well looking with petechiae → Immune Thrombocytopenic Purpura • Multiple red spots LARGER than petechiae which usually occurs
(ITP) from the fusion of several petechiae
• Bruising localized at buttocks, ankle, or feet associated with • Formed by the same causes as petechiae:
abdominal pain → Henoch Schonlein Purpura (HSP) − Thrombocytopenia
− Thrombocytopathia
SITE OF BLEEDING
• severity of bleeding (bruising after normal child play vs pathologic ECCHYMOSIS
bleeding) • commonly known as a "bruise"
• persistent bleeding from a single site is suggestive of a local cause • sometimes mistaken as a hematoma
(unilateral epistaxis due to excoriation of superficial vessels in the • defined as large area of blood under the skin due to simultaneous
Kiesselbach triangle) breaks of several blood vessels
− most common cause of epistaxis is trauma • particularly common in people with vascular or platelet disorders
• Mucous membrane bleeding (epistaxis, menorrhagia, bleeding from
gums) → primary hemostasis : platelet disorder or VWD
• Hereditary hemorrhagic telangiectasia- mucosal bleeding
− Nose, gums, menstruation
• Profuse bleeding into soft tissue or joint is suggestive of
coagulation factor deficiency (FVIII or FIX)
• Umbilical stump bleeding: FXIII deficiency but can also occur with
deficiency of prothrombin, factor X and fibrinogen

Mucous membrane bleeding

• epistaxis, excessive
menorrhagia, gum
bleeding
• is often the consequence of
a problem with primary
hemostasis namely,
platelet disorder (ITP),
congenital, or von
Willebrand disease
HEMATOMA
• Already has lumps or elevated
Profuse bleeding into soft tissues or joints • Can have the same size as
• is suggestive of ecchymoses or larger but the
deficiency of difference would be the
coagulation factors elevation and presence of
swelling
• Bleeding manifestation in which
blood has penetrated
subcutaneous tissue and
produced swelling as well as
discoloration
PETECHIAE • Common in people with
coagulation disorders
• Multiple red spots on the skin, each the size of the head of a pin
• Results from red blood cells leaving the small blood vessels at a
given point
• Observed in patients with:
 Thrombocytopenia - decrease number of platelets
 Thrombocytopathia - platelet function defects

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PEDIATRICS II

HEMARTHROSIS • Autosomal dominant pattern more consistent with VWD

• Most other clotting factor deficiencies are inherited in an autosomal
• More deep-seated
recessive manner. In this latter group, the FH is frequently negative for
• Hemorrhage into the bleeding although consanguinity may be noted
joint cavity
• Usually observed in
patients with severe
V. LABORATORY ASSESSMENT OF BLEEDING
coagulation disorders SAMPLE COLLECTION AND TECHNIQUE
such as hemophilia • Improper sample collection - most common reason for falsely
• Associated with severe elevated clotting times
disfigurement • Properly drawn blood sample is crucial
• For coagulation assays: draw by venipuncture not by prick
• Citrated tubes: one part anticoagulant to nine parts of whole blood
• Should be tested within 2 hours if maintained at room temp, 4 hours
if cold
• Positive bleeding history or who are actively hemorrhaging should have
a platelet count, PT, PTT Partial thromboplastin time prothrombin time
Differences in Clinical Manifestations • If the results are normal, thrombin time to evaluate fibrinogen function
and VWF testing should be considered
CLINICAL PRIMARY CLOTTING
CHARACTERISTICS HEMOSTATIC FACTOR • Individuals with abnormal screening test results, further specific factor
DEFECT DEFICIENCY work-up should be undertaken
Site of bleeding Skin, mucous Soft tissue, muscle, • In a patient with abnormal bleeding hx and a positive family history,
membranes joints normal screening tests should not preclude further lab evaluation
**deep-seated
BLEEDING TIME
Bleeding after minor Yes Not usually • assesses the function of platelets and their interaction with the
cuts **because the vascular wall
primary hemostasis • difficult laboratory test to standardize, each laboratory establishes its
is still functional but own normal range. (4-8 minutes)
not to the extent of • platelet counts < 100,000 are associated with prolonged BT
full stoppage • prolongation of bleeding time may suggest qualitative platelet defect
or vWD
Petechiae Present Absent
PROTHROMBIN TIME TEST
Ecchymosis Small, superficial Larger, deeper, • Screening test for the extrinsic pathway
palpable • Performed by adding tissue extract (i.e. FIII=tissue factor) and calcium
to the plasma
Hemarthrosis Rare Common • This initiates activation of FVII. And activated FVII activates FX, which
in the presence of FV will activate FII (prothrombin)
Bleeding after Immediate Delayed • Activated thrombin will convert fibrinogen to fibrin
trauma/surgery • If PROLONGED - cause could be deficiency or inhibition of factors VII,
X, V or II
• NV = 10 – 13 sec
AGE AT ONSET
• Early age at onset correlates with the severity of the bleeding disorder ACTIVATED PARTIAL THROMBOPLASTIN TIME TEST
and indicates congenital nature • screening test for factor deficiency of the intrinsic pathway which
• Development of bleeding later in childhood may indicate an acquired includes factors XII, XI, IX or VIII
problem or be suggestive of a milder congenital disease • performed by adding kaolin and phospholipid to the plasma.
− Kaolin activates factor XII and XI
PAST MEDICAL HISTORY − Phospholipid substitutes for platelets in the activation of factor
• Inquire about the past surgical procedures, serious injuries and VIII by factor IXa
fractures that provide hemostatic challenges • Activated factor IX, VIII and phospholipid and calcium then activate
• Bleeding outcome after invasive dentistry, transfusion requirement factor X and the remaining common pathway
may also be helpful
• History of surgical procedures or tooth extractions without abnormal THROMBIN TIME
bleeding is evidence against presence of congenital hemorrhage • measures the final step in the clotting cascade in which fibrinogen is
disorder converted to fibrin
• Detailed menstrual history should be obtained as menorrhagia is • normal thrombin time varies between laboratories but is usually 11 - 15
common symptom in VWD sec
• prolongation of thrombin time occurs with
FAMILY HISTORY − reduced fibrinogen levels (hypo- or afibrinogenemia)
• FH is helpful in formulating a differential diagnosis − Dysfunctional fibrinogen (dysfibrinogenemia)
• Inquire about any known bleeding problems in other family members − Substances that interfere in fibrin polymerization (heparin or FSP)
and whether a specific diagnosis has been made If FH is (+) for
bleeding, one should note the
○ type and severity of bleeding (joint bleed, epistaxis)
○ age at onset
○ relationship of affected family member or members to the
patient
• An X-linked recessive inheritance pattern suggests a diagnosis of
hemophilia A or B

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 2022 5.3b. Diseases of the Blood (Part 2)
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PEDIATRICS II

COAGULATION TESTS AND INTERPRETATION

• PTT – Partial Thromboplastin Time

• PT – Prothrombin Time
• TT – Thromboplastin Time

Common Laboratory Tests used to Determine Abnormalities in VI. INHERITED BLEEDING DISORDERS
Hemostasis and their Interpretations
FACTOR VIII AND FACTOR IX DEFICIENCY
Test Conclusion
(HEMOPHILIA A AND B )
Prolonged bleeding time and Vascular or platelet function • Most common severe inherited bleeding disorders
normal platelet count disease or VWD • Recognized as clinical entity since biblical times
• Term “hemophilia" ascribed to Schonlein in 1820
Prolonged BT and decreased ITP, platelet function defect
• Prolonged clotting time of hemophilic blood was first noted in 1893
platelets

Prolonged BT and abnormal VWD Pathophysiology

PTT
Prolonged PTT (Normal PT) Bleeding: factor 8 decrease
(hemophilia A or VWD), factor 9
decrease (hemophilia B), dec.
factor XI, Heparin
No Bleeding: Lupus like inhibitor,
decrease in factor XII,
prekallikrein, kininogen
• The genes for factor VIII and factor IX both reside on the X
chromosome
− as a result, hemophilia only occurs in males who have inherited the
abnormal gene, females are carriers
− although a family hx of hemophilia can be documented for most
patients, the frequency of de novo mutations has been estimated
to be as high as 30%

Prolonged PT (Normal PTT) Decreased factor VII

Prolonged PTT, PT Decreased factors II, V, X, I

Vitamin K deficiency
Warfarin therapy, DIC
Liver disease

Prolonged TT Decreased fibrinogen, DIC

Liver disease, Heparin

No abnormalities in routine Bleeding: Decreased Factor III

screening tests Mild coagulation defects that do
not give abnormal screening tests

BIOSYNTHESIS OF CLOTTING FACTORS

• All clotting factors (except factor VIII) are synthesized in the liver
• Factor VIII
− Endothelium (VWF) and megakaryocytes
− Hepatocytes
• Vitamin K: required for production of
− 4 clotting factors: II, VII, IX, X
− 2 anticoagulant proteins: Protein C and Protein S

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PEDIATRICS II

• Genetic defects that result in Laboratory Findings

hemophilia are heterogenous,
as deletions, insertions, etc • The partial thromboplastin time (PTT) is greatly prolonged
have all been described but • Platelet count, bleeding time, and prothrombin time are normal
the resultant clinical • Specific assay for factor 8 or 9 activity confirms diagnosis
manifestations of these
defects are similar Treatment
• Prompt and appropriate treatment of hemorrhage and prophylactic
therapy are the key to excellent care of patients with hemophilia
• The knowledge of:
− Half-life
− Volume distribution
− Appropriate replacement material
− Patient's inhibitory state are necessary to make an intelligent
decision for treatment of bleeding episodes
Demographics and Classification
• Occurs in 1 in 5000 males with no racial predilection Factor VIII Treatment Products
− Hemophilia A 80-85%
− Hemophilia B 10-15% • Recombinant Factor VIII Concentrate
• Severity of hemophilia classified on the basis of the patient's baseline − Factor VIII has been cloned, sequenced to produce recombinant
level of factor VIII or factor IX factor VIII
• The genes for both F8 and F9 are carried near the terminus of the − free from viral contamination
long arm of the X chromosome and are therefore X-linked traits • Plasma-Derived Factor VIII Concentrate
• The clinical severity depends on the level of factor 8 activity in the − intermediate purity concentrates are produced from large pools of
plasma: donor plasma by cryoprecipitate
− Severe - <1% (1 unit/dL) of normal activity
− Moderate – 1-5% (1-5 units/dL) activity Cryoprecipitate
− Mild - 5-25% (6-30 units/dL) activity • First widely used preparation of factor VIII was made 1965 by a method
• Degree of severity tends to be consistent within a given family of cryoprecipitation
• Each bag contains only 100 units of factor VIII and thus 10 - 20 donor
Relationship of Factor Levels to Severity of Clinical Manifestations of units are required for treatment of joint hemorrhage in an adult
Hemophilia A and B • There is increased risk of viral infection and inconvenient to
Type Percentage Type of hemorrhage administer.
factor 8/9 • NB: no longer a viable alternative except in areas of the world where
Severe <1 Spontaneous; hemarthroses and deep soft other forms of therapy are unavailable or in short supply
tissue hemorrhage
Moderate 1-5 Gross bleeding ff mild to moderate trauma; Desmopressin
some hemarthroses; seldom spontaneous
hemorrhage • Synthetic vasopressin analogue that increases plasma factor VIII
Mild 5-25 Severe hemorrhage only ff moderate to and VWF levels allowing successful treatment of bleeding episodes
severe trauma or surgery associated with dental and surgical procedures in patients with mild
/moderate hemophilia A and VWD
Incidence of Severity and Clinical Manifestations of Hemophilia • It is not effective in treatment of severe hemophilia A, severe VWD or
Severe any form of hemophilia B
Severity Severe Moderate Mild • Recommended IV dose is 0.3 ug/kg and is administered in 25-50 mL
Incidence of normal saline over 20 minutes
Hemophilia A 70% 15% 15%
Hemophilia B 50% 30% 20% Factor IX Treatment Products
Bleed • Plasma-Derived factor IX Concentrates
Manifestations • Recombinant factor IX Concentrates
Age of onset <1 уeaг 1-2 years 2 years - adult • Prothrombin Complex Concentrates
Neonatal hge • Fresh Frozen Plasma
Ff circumcision Common Common None
Intracranial Occasional Rare Rare Calculation of Dose
Muscle/Joint he Spontaneous Ff minor trauma Ff trauma
• Calculation of dose required to achieve a desired hemostatic level is
CNS hge High risk Moderate risk Rare
based on the formula by Abilgaard:
Postsurg he Common Common Rare • Dose of FVIII = u/dL (%) desired rise in plasma FVIII x (units, U) BW
Oral he Common Common Rare (kg) x 0.5
• Dose of FIX = u/dL (%) desired rise in plasma FIX x (units, U) BW (kg)
CLINICAL MANIFESTATIONS x 1.0

• Because factor 8 or 9 does not cross the placenta, bleeding may be

evident in the neonatal period.
• Hematomas after injections and bleeding from circumcision are
common
• As ambulation begins, excessive bruising occurs
• A minor traumatic laceration may bleed persistently for hours or days
• Hallmark of hemophilia - HEMARTHROSIS

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PEDIATRICS II

Treatment of Bleeding Disorders

Type of Hge Hemostatic factor level Hemophilia A Hemophilia B Comments/ adjuncts
Hemarthroses 30-50% Minimum F8 20-40 U/kg q12- 24h, treat F9 30-40 U/kg 24h as "RICE"
for further 2 days needed, treat for further 2
days
Muscle 40-50% min Iliopsoas 100% then 20-40 U/kg 2 12 24 as needed, 40-60 U/kg 224h as Calf/forearm bled can be
50-100% x 2-4 days iliopsoas bld at 50 U/kg needed, iliopsoas bld at 60- limb threatening
80 U/kg
Oral mucosa Initially 50%, then EACA at 25 U/kg 50 U/kg Antifibrinolytic therapy is
50mg/kg 26 x 7days important
Epistaxis Initially 30-40%, use of EACA 15-20 U/kg conc. only if 30-40 U/kgconc. only if Local measures: pressure,
50mg/kg q6h until healing occurs applying pressure for 15min, applying pressure for packing
packing with petrolatum gauze 15min, packing with
and antifibrinolytic therapy fails petrolatum gauze and
antifibrinolytic therapy fails
Hematuria Painless hematuria treated with F8 50 U/kg; if not resolved, 30- F9 80-100 U/kg; if not Evaluate for stones or UTI,
bed rest and vigorous hydration for 40 U/kg q day until resolved resolved then 30-40 U/kg q Prednisone 1-2 m/k/day x
48 hrs. Persistent=100% day until resolved 5-7 days may be helpful
CNS Initially 100%, then 50-100% x 14 50 U/kg, then 25 U/kg q 12 80-100 U/kg then 50 U/kg q Treat presumptively before
days 24h evaluating, hospitalize
Trauma or Initially 100% then 50% until 50 U/kg, then 25 U/kg q 12 100 U/kg, then 50 U/kg q Evaluate for inhibitor
surgery wound healing is complete 24h

VON WILLEBRAND DISEASE VII. ACQUIRED BLEEDING DISORDERS

• Most common hereditary bleeding disorder VITAMIN K DEFICIENCY
• Present in 1 - 2% of general population • Results from impaired production of the vitamin K-dependent clotting
• Inherited autosomally but generally more women are affected factors: II, VII, IX, and X
• Classified whether • Most often seen in conditions associated with the malabsorption of fat,
− Protein is quantitatively reduced but not absent (type 1) occasionally from malnutrition, patients on oral antibiotics
− Protein is qualitatively abnormal (type 2)
− Protein is absent (type 3) Causes of Vitamin K Deficiency
• In von Willebrand's disease there is either a quantitative or qualitative
abnormality on the von Willebrand portion of the F8 molecule such that • Malabsorption
effective bridging between the platelet and subendothelial collagen is • Malnutrition
not achieved. − In the elderly
• This is not a platelet disorder but an abnormality of the VW factor − In patients receiving oral antibiotics
that prevents platelets from fulfilling their role in the hemostatic process • Newborn
• VWF is important to bridge the platelet to the collagen • Anticoagulation with vitamin K antagonists

Clinical manifestations Lab

• Mucocutaneous hemorrhage • Prolonged PT (PTT may also be prolonged)
• Excessive bruising • A PT that corrects within 2 days after vitamin K treatment confirms the
• Epistaxis diagnosis
• Menorrhagia
• Postoperative hemorrhage after mucosal surgery Treatment
− Tonsillectomy • Vitamin K
− Wisdom tooth extraction • Routine administration of vitamin K to all newborn infants

Laboratory Findings LIVER DISEASE

• Historically pxs with VWD shows prolonged bleeding time and • Coagulopathy results mainly from
partial thromboplastin time however in type 1 VWD these lab − Failure of clotting factor production by the diseased liver
findings are normal (cannot completely rule out) − Reflects the release of an abnormal clotting factor
• Normal results on screening tests DO NOT PRECLUDE the diagnosis − Failure of the liver to clear certain coagulation-related proteins
of VWD from the blood
• No assay has demonstrated the ability to rule out VWD, thus if hx is
suggestive of a mucocutaneous bleeding disorder VWD test should be Treatment
done which includes:
1. Quantitative assay of VWF antigen • Vitamin K
2. Testing for VWF activity (ristocetin cofactor activity) • Replacement therapy in patients who are actively bleeding (FFP,
3. Test for plasma factor VIII activity Cryoprecipitate, Platelet concentrate)
4. Determination of VWF structure (multimers) • Cure of the underlying disease
5. Platelet count
Abnormality Explanation
Treatment Long prothrombin time Deficiency of vitamin K-dependent
clotting factors; presence of fibrin-
• Desmopressin split products
• Factor concentrates
− VWF concentrate Long partial thromboplastin Deficiency of factors II, V, IX,
− Factor VIII concentrate time prekallikrein; presence of fibrin-split
products

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PEDIATRICS II

Clinical Manifestations
Long thrombin time Presence of fibrin-split; abnormal
fibrinogen • Abrupt onset of bruising and bleeding in an otherwise healthy child
Long bleeding time Decreased platelets • (+) history of viral illness in weeks preceding the onset of bruising
• PETECHIAE and ECCHYMOSES are evident in most patients
Long fibrinogen Increased fibrinolysis • Epistaxis and oral mucosal bleeding seen in less than a third of
Increased fibrin-split products patients
Shortened euglobulin lysis • Hematuria, hematochezia less evident; menorrhagia are observed in
time adolescent girls
• Splenomegaly is rare as well as lymphadenopathy and pallor =
suggests other diagnosis (leukemia)
ACQUIRED ANTICOAGULANTS
• Peak age of diagnosis is 2 - 6 years
(CIRCULATING INHIBITORS) • Acute ITP may be diagnosed at any age but adolescent and infants
• Present as prolonged PTT not corrected by normal plasma are more likely to have chronic ITP
• Lupus anticoagulant, Fibrin-split products, Antibodies against • M=F
clotting factors (Anti factor VIII in hemophilia or spontaneous, Anti
factor V, Anti factor XIII during INH therapy for TB), Abnormal
Laboratory Findings
immunoglobulins in MM and related disease, Anticoagulant drugs
• Severe thrombocytopenia
VIII. PLATELET DISORDERS (platelet count < 20,000) is
common
THROMBOCYTOPENIA • Platelet size is normal or increased
• Normal platelet count is 150 - 450,000 reflective of increased platelet
• Lower than 150,000 turnover
• Causes include: • Leukocyte and red cell counts are
− decrease production on either a congenital or acquired basis usually normal, although anemia
− sequestration of platelet within enlarged spleen may be seen in 15% especially
− increased destruction of platelet on an immune or nonimmune with significant history of epistaxis,
basis hematuria, or GI bleeding
• Pathophysiological Classification of Thrombocytopenic States
− Increased platelet destruction
− Decreased platelet production
− Disorders of platelet distribution

IDIOPATHIC (IMMUNE) THROMBOCYTOPENIC PURPURA

• Characterized by accelerated destruction of antibody sensitized
platelets by phagocytic cells (spleen) • BONE MARROW
• Most common cause of acute onset thrombocytopenia in an otherwise aspirate reveals normal
well child or increased numbers of
megakaryocytes
• Annual incidence is 1:10,000 children
• Two major forms:
− ACUTE ITP = <6 months
− CHRONIC ITP = >6 months

Etiology
• One to four weeks after exposure to a common viral infection, an
autoantibody directed against the platelet surface develops
• After binding of the antibody to the platelet surface, circulating anti-
body coated platelets are recognized by the Fc receptor of the
splenic macrophages, ingested and destroyed
• Childhood acute ITP is usually benign, self-limited disorder that
requires minimal or no therapy in the majority of cases
• Indications for treatment vary among practitioners and are a source of
debate
• ASH indication for treatment includes:
1. PLT count <20,000 + significant mucosal bleed
2. PLT count < 10,000+ minor purpura
• At the heart of the treatment debate is a perceived risk for INTRA-
CEREBRAL HEMORRHAGE (ICH), a rare but potentially life-
threatening complication in children with ITP
• A review of 12 case series involving 1293 children places the incidence
of 0.9%, others say it is 0.1 and 0.5%
• Those at risk appear to have platelet counts < 20,000 and/or hx of
head trauma, aspirin use, etc

Treatment
• Observation Only
• ITP patients with minor purpura medical therapy may not be necessary
• Uniform consensus: platelets with platelet counts > 20,000 and only
minor purpura do not require therapy

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PEDIATRICS II

First-Line Medical Therapies for ITP IX. DISORDERS OF THE BLOOD VESSELS
• Glucocorticoids HENOCH-SCHONLEIN PURPURA
− MOA: • characterized by sudden development of a
Mechanism of action
○ Inhibition of both phagocytosis and antibody synthesis − Purpuric rash
○ Improved platelet production − Arthritis
○ Increased microvascular endothelial stability − Abdominal pain
− Dose: − Renal involvement
○ Oral - Prednisone 2 mg/k/day x 21 days • The characteristic rash, consisting of petechiae and often palpable
○ IV - Methylprednisolone 30 mg/k/d x 3 days purpura, usually involves the lower extremities and buttocks
• Intravenous Immunoglobulin • Pathologic lesions in the skin, intestines, and synovium are
− MOA: induce response by downregulating Fc-mediated leukocytoclastic angiitis, inflammatory damage to the endothelium of
phagocytosis of antibody coated platelets the capillaries mediated by WBCs and macrophages
− very expensive and time consuming to administer • Trigger is unknown
− Dose: 0,8 – 1.0 g/kg/day for 1 – 2 days induces rapid rise of platelet • In the kidney, the lesion is focal glomerulonephritis with deposition
count of immunoglobulin A
• Intravenous anti-D therapy • Renal involvement occurs in 25-50%
− MOA: RBC-antibody complexes bind to macrophage Fc • Results of coagulation studies as well as platelet count are normal. Lab
receptors and interfere with platelet destruction, thereby causing test results are not diagnostic
rise in platelet count
− may induce mild hemolytic anemia Treatment
− Dose: 50 - 75 ug/kg as a short IV infusion effect lasts for 1 to 5
• No specific therapy
weeks, less expensive than IVIG
• Symptomatic treatment is indicated for arthritis, rash, edema, fever
and malaise
SPLENECTOMY • Intestinal hge, obstruction, intussusception or perforation may be life-
• Reserved for 1 of 2 circumstances threatening and could be managed by early use of corticosteroids -
1. Older child (> 4 year) with severe ITP lasting > 1 year (chronic prednisone at 1-2 mg/kg/24hrs
ITP)
2. Also considered when life-threatening hemorrhage, (ICH)
complicates acute ITP and platelet count can't be rapidly corrected
with platelet transfusion and administration of IVIG and
corticosteroid
• Associated with lifelong risk of overwhelming postsplenectomy
infection caused by encapsulated organisms
• Before splenectomy, the child should receive
− Pneumococcal
− Meningococcal
− H. Influenza vaccination
• After splenectomy, patient should receive penicillin prophylaxis

Chronic ITP
• 20% of px with acute ITP will have persistent thrombocytopenia for >
6 months
• Re-evaluation should be in order especially for autoimmune disease
ex. SLE, chronic infection HIV and non-immune causes ex. 2B VWD
• Treatment is aimed at controlling symptoms and preventing serious
bleeding
• Splenectomy is successful in inducing complete remission in 64-
88%
• IVIG, anti-D, or rituximab also used to control bleed

HEMOLYTIC-UREMIC SYNDROME
• Acute disease of infancy and early childhood
• Follows an episode of AGE often triggered by E. Coli 0157:H7
• Shortly thereafter signs and symptoms of hemolytic anemia,
thrombocytopenia and acute renal failure ensue
• Sometimes neurologic symptoms are associated with these findings
(Thrombotic thrombocytopenic purpura) - adults
• Hemolytic anemia is characterized by abnormal RBCs presence of:
− helmet cells, spherocytes schistocytes, burr cells
• Thrombocytopenia despite normal numbers of megakaryocytes in the
marrow indicated excessive platelet destruction
• Evaluation of urine shows CHON, RBCs, casts
• Anuria and severe azotemia indicate grave renal damage

Treatment
• Involves institution of careful fluid management and prompt
appropriate dialysis
• Plasmapheresis is usually reserved for patients with HUS associated
with major neurological complications

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