CHAPTER

Benign white blood cell and

platelet disorders
5
Introduction
Automated hematology analyzer can rapidly analyze whole blood specimens for the complete blood
count (CBC). Results include red blood cell (RBC) count, white blood cell count (WBC), platelet
count, hemoglobin concentration, hematocrit, RBC indices, and a leukocyte differential. A less so-
phisticated automated hematology analyzer in a physician’s office setting may sometimes provide a
limited CBC, using older technology for whole blood analysis (for example, impedance technology),
which will generate only a three-part leukocyte differential. A three-part leukocyte differential will
provide values for neutrophils, lymphocytes, and all other white cells together. More modern hema-
tology analyzers are capable of analyzing all leukocytes using flow cytometry-based method, some in
combination with cytochemistry or fluorescences or conductivity to count all the different types
of WBC including neutrophils, lymphocytes, monocytes, basophils, and eosinophils (five-part dif-
ferential). Nucleated RBCs are also detected. Leukocytosis or elevated WBC count is a common
laboratory finding. Normal WBC differential also changes with age, and proper normal ranges must
be established. For example, a WBC count of 30 10 9/L (30,00/uL) is abnormal in an adult but
normal in a newborn within the first few days of life. Leukocytosis is also a feature of leukemias, and
thus distinguishing leukemias from other causes of leukocytosis is crucial. Examination of peripheral
blood smear along with review of CBC analysis is essential for such differentiation, and if necessary,
further analysis such as flow cytometry, molecular studies, and possible bone marrow examination
must be undertaken [1]. Similarly, platelet disorder such as thrombocytopenia or thrombocytosis
may be a benign condition or reflection of a serious condition such as severe thrombocytopenia
observed in patients with acute leukemias. In this chapter, benign WBC and platelet disorders are
reviewed.

Hereditary variation in white blood cell morphology

Various hereditary-mediated variations in WBC morphology have been described, which are mostly
clinically benign except for ChediakeHigashi syndrome. Pelger-Huet anomaly is a rare disorder
transmitted as autosomal dominant, where >75% of neutrophils are bilobed (neutrophils with hypo-
segmented nucleus). The characteristic morphology was described by Pelger in 1928, and in 1931,
Huet identified it as an inherited disorder. This is a benign condition due to inherited defect of terminal
neutrophil differentiation as a result of mutations in the lamin B receptor gene. Presence of occasional

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77
78 Chapter 5 Benign white blood cell and platelet disorders

bilobed neutrophils is also seen in myelodysplastic syndrome (MDS) and is referred to as pseudoe
Pelger-Huët cells. These have also been described in association with Filovirus infection.
Distinguishing benign form of Pelger-Huet anomaly from acquired or pseudoePelger-Huet anomaly is
important.
MayeHegglin anomaly, another rare disorder, is also transmitted as autosomal dominant and is
characterized by thrombocytopenia, giant platelets, and leukocyte defect causing the appearance of
very small rods (2e5 mm) in the cytoplasm (Dohle-like bodies). Actual Dohle bodies are seen with
reactive or toxic polymorphonuclear neutrophils (PMNs). Reactive or toxic PMNs also have promi-
nent azurophilic granules and vacuoles. These features are not seen in MayeHegglin anomaly.
MayeHegglin anomaly is a benign condition as most patients do not appear to have any significant
bleeding problem where treatment may be required.
Macrothrombocytopenia with neutrophilic inclusions (MYH9 disorders) is a group of disorders
characterized by mutations in the MYH9 gene. This gene encodes the nonmuscle myosin heavy chain
class IIA protein. These disorders are characterized by thrombocytopenia, large/giant platelet, and
Dohle-like bodies in neutrophils. This group of disorders includes MayeHegglin anomaly (autosomal
dominant), Sebastian syndrome, Fechtner syndrome (nephritis, ocular defects, and sensorineural
hearing loss), and Epstein syndrome.
ChediakeHigashi syndrome is a rare multisystemic disorder transmitted as autosomal recessive
characterized by hypopigmentation of the skin, eyes, and hair (silver hair), prolonged bleeding time,
easy bruisability, and immunodeficiency. The pathological feature of this rare disease is the presence
of massive lysosomal inclusion, which is formed through a combination of fusion, cytoplasmic injury
and phagocytosis, in WBC. This abnormal inclusion may be responsible for most of the impaired
leukocyte and other blood cell functions in these patients. In addition, dysfunction of natural killer cell
is also observed. Approximately 85% of affected individuals develop the accelerated phase of this
disease, a lymphoproliferative infiltration of bone marrow, and reticuloendothelial system mostly
during childhood [2]. This could be a potentially fatal condition if not treated. Hematopoietic stem cell
transplantation may be curative [3].
AldereReilly anomaly, a clinically benign rare condition, is transmitted as autosomal recessive and
is characterized by large azurophilic granules (partially degraded proteinecarbohydrate complexes
known as mucopolysaccharides) in neutrophils and others granulocytes, monocytes, and lymphocytes.
However, similar abnormalities are seen in mucopolysaccharidoses (MPS). MaroteauxeLamy
syndrome is when abnormal granulation of granulocytes and monocytes with lymphocyte occurs with
vacuolation, as seen in MPS VI.

Changes in white cell counts

Changes in white cell count can be observed in various conditions where values may be increased or
decreased. Leukocytosis is a common clinical observation where an increase in WBC count above two
standard deviation of the mean is observed (above 11,000 per microliter). Leukocytosis is mostly a
benign condition where elevated WBC reflects the normal response of bone marrow to infection, an
inflammatory process, or drugs. However, leukocytosis may also be due to bone marrow abnormality
related to leukemia or myeloproliferative disease. Widick and Winer summarized various causes of
leukocytosis [4]. In this chapter, various changes in WBC count due to benign conditions will be
discussed.
 Changes in white cell counts 79

Neutrophilia
Neutrophilia is the most common cause of leukocytosis. Various causes of neutrophilia are summa-
rized in Table 5.1. Most common cause is infection or inflammation, but there are congenital forms of
neutrophilia, and such conditions are rarely encountered. For example, leukocyte adhesion deficiency
is a rare autosomal recessive immunodeficiency disease characterized by severe recurrent bacterial
infection due to inability of neutrophils to adhere to endothelial cell walls and migrating to the site of
infection. Depending on the genetic effect, hematopoietic stem cell transplantation is often the only
cure [5].
Various morphological changes are observed in reactive neutrophilia. Such morphologic changes
seen in reactive neutrophils are summarized below:
• Dohle bodies (represent endoplasmic reticulum)
• Prominent 1st degree (azurophilic) granules in cytoplasm
• Vacuoles in cytoplasm
Significant neutrophilic leukocytosis may result in a picture resembling chronic myeloid leukemia
(CML), which is referred to as leukemoid reaction. Basophilia and eosinophilia are not significant.
The leukocyte alkaline phosphatase (LAP) score is high in such conditions. In contrast, the LAP score
in chronic myeloid leukemia (CML) is low. Another cause of low LAP, although unrelated, is
paroxysmal nocturnal hemoglobinuria.
To determine LAP score, PMNs are stained for alkaline phosphatase, and each neutrophil is given a
score from 0 to 4. One hundred cells are counted. The total score is the actual score.

Eosinophilia and monocytosis

Eosinophils are WBCs that participate in immunological and allergic events. Eosinophilia is usually
defined as eosinophil count greater than 500 cells per microliter (0.5  109/L). Parasitic infections are
often responsible for eosinophilia in pediatric patients. Infections such as scarlet fever, chorea, and
genitourinary infection may also cause eosinophilia. Skin rash, chronic inflammation such as rheu-
matoid arthritis and lupus erythematosus, and adrenal insufficiency such as Addison’s disease may also
cause eosinophilia. Pleural and pulmonary conditions such as Loffler’s syndrome may also cause
eosinophilia. Eosinophiliaemyalgia is a disorder associated with dietary supplement tryptophan.
Other causes of eosinophilia include malignancies affecting the immune system such as Hodgkin’s
lymphoma and non-Hodgkin’s lymphoma [6].

Table 5.1 Various causes of neutrophilia.

· Infection
· Inflammation
· Any form of stress
· Splenectomy, hyposplenism
· Drugs: corticosteroids
· Acute hemorrhage
· Hemolytic anemia
· Congenital forms (rare): leukocyte adhesion deficiency, chronic idiopathic neutrophilia, hereditary neutrophilia
80 Chapter 5 Benign white blood cell and platelet disorders

Hypereosinophilic syndrome is a rare and heterogenous group of hematological and systemic

disorder characterized by eosinophil count above 1.5  109/L (1,500 cells per microliter) lasting over
6 months in absence of other known cause of eosinophilia. This syndrome may cause end organ
damage, primarily heart, causing eosinophilic endomyocardial fibrosis. Patients with hyper-
eosinophilic syndrome do not typically have asthma [7].
Monocytes are WBCs that give rise to macrophages and dendritic cells in the immune
system. Causes of monocytosis include various infections (tuberculosis, brucellosis, typhoid,
typhus, Rocky Mountain spotted fever, malaria, etc.), chronic myelomonocytic leukemia, juvenile
myelomonocytic leukemia, Hodgkin lymphoma, acute myeloid leukemia (AML) M4/M5, and
autoimmune diseases.

Basophilia
Basophils are inflammatory mediators of substance such as histamine, and along with mast cells,
they have receptors for IgE. Basophilia is an uncommon situation. Causes include viral infections
(varicella, chicken pox), inflammatory conditions (ulcerative colitis), CML or myeloproliferative
disorder, myxoedema, and endocrinological causes (hypothyroidism, ovulation).

Neutropenia
Neutropenia is defined as an absolute neutrophil count that is more than two standard deviations below
the normal neutrophil count. Mild-to-moderate neutropenia may not predispose an individual to an
increased susceptibility to life-threatening infection, but patients with severe neutropenia (neutrophil
count <0.5  109/L) may be prone to severe even life-threatening infection. Severe neutropenia
accompanied by fever of recent onset is a medical emergency requiring immediate investigation and
treatment. Various causes of neutropenia (inherited and acquired) are summarized in Table 5.2.
Most often neutropenia in adults is due to acquired causes such as drug-induced or postinfection.
Felty’s syndrome is a well-characterized clinical abnormality consisting of rheumatoid arthritis,
splenomegaly, and severe neutropenia. The cause could be attributed to increased neutrophil
margination and inhibition of granulopoiesis mediated by antibodies to neutrophils or by T cells.

Table 5.2 Various causes of selective neutropenia.

Acquired · Drug induced (e.g., methimazole, sulfasalazine, trimethoprim/sulfamethoxazole, Bactrim)
Causes · Postinfectious
· Autoimmune disease (e.g., systemic lupus erythematosus)
· Paroxysmal nocturnal hemoglobinuria
· Felty’s syndrome (triad of rheumatoid arthritis, splenomegaly, and neutropenia)
· Splenomegaly
Inherited Forms · Ethnic familial neutropenia
· Cyclical neutropenia
· Kostmann syndrome
· ShwachmaneDiamond syndrome
 Changes in white cell counts 81

Neutropenia may also be inherited. Yemenite Jews and other population including Ethiopian Jews
and Bedouins have low neutrophil counts, and this condition is called ethnic benign neutropenia
because it is not associated with increased risk of infection. This condition may also be found in
populations around the world including Africans, Africans-Americans, and African-Caribbean [8].
Cyclical neutropenia is a rare disorder caused by a stem cell regulatory defect characterized by a
transient severe neutropenia occurring roughly every 21 days. The familial form seems to be inherited
in an autosomal dominant pattern.
ShwachmaneDiamond syndrome is transmitted as autosomal recessive and is characterized by
exocrine pancreatic deficiency and neutropenia, thrombocytopenia, short stature, and mental retar-
dation. This disorder may progress to MDS and AML.
Kostmann’s syndrome is a group of inherited diseases, causing a congenital form of neutropenia,
called severe congenital neutropenia (SCN). It was discovered in 1956 in a family in Sweden by the
physician Rolf Kostmann. This disorder was originally thought to be due to point mutations in gene
coding for granulocyte colonyestimulating factor (G-CSF). It has since been demonstrated that this
mutation is an acquired somatic mutation and may be associated with the development of
acute leukemia. The most common subtype, SCN1, is transmitted as autosomal dominant. Here, there
are mutations in the gene for neutrophil elastase (ELANE, previously called ELA2). The initial
recognized subtype, SCN3, is transmitted as autosomal recessive. Here, there are mutations in the
HAX1 gene. X-linked inheritance may also be seen in SCN due to mutations in the WAS gene.
Affected children develop frequent life-threatening infection due to severe neutropenia. There is
increased risk of acute leukemia.

Lymphocytosis and infectious mononucleosis

Lymphocytosis occurs most commonly after viral infections (e.g., cytomegalovirus, mumps, varicella,
influenza, rubella, etc.), lymphoid leukemias and lymphomas, and smoking. Lymphocytosis is rarely
observed in bacterial infection, an exception being Bordetella pertussis infection. With lymphocytosis,
reactive lymphocytes may be seen in the peripheral smear. Reactive lymphocytes are also referred to as
Downey cells. There are three types of Downey cells:
• Type I: small cells with minimum cytoplasm, indented nucleus/irregular nuclear membrane, and
condensed chromatin
• Type II: larger cells with abundant cytoplasm, the lymphocyte cytoplasm seem to hug the red
cells. This is the most common type of Downey cells.
• Type III: cells with large moderate basophilic cytoplasm and nucleus with coarse chromatin.
Nucleoli are apparent.
In infectious mononucleosis caused by EpsteineBarr virus, there is lymphocytosis with charac-
teristic large atypical lymphocyte in the blood. The virus infects B lymphocytes, and T lymphocytes
attack the virally infected B lymphocytes. Reactive lymphocytes are the T lymphocytes. Features of
infectious mononucleosis from the peripheral blood include
• white cells of 50% or more are mononuclear cells
• At least 10% of the lymphocytes exhibit reactive changes
• There is lymphocytic morphologic heterogeneity (this means different types of reactive
lymphocytes are seen)
82 Chapter 5 Benign white blood cell and platelet disorders

Lymphocytopenia
Lymphocytes consist of T lymphocytes, B lymphocytes, and natural killer cells. The term lympho-
cytopenia (lymphopenia) refers to less than 1000 lymphocytes per microliter of blood in adults or less
than 3000 lymphocytes per microliter of blood in children. Severe combined immunodeficiency is a
heterogenous disorder characterized by severe deficiency of T and B lymphocytes as well as natural
killer cells. The X-linked inherited form is most commonly characterized by the absence of T lym-
phocytes and natural killer cells but poorly functioning B cells. A deficiency of adenosine deaminase
underlies 30%e40% of autosomal recessive form of this inherited disorder. The different forms of
severe combined immunodeficiency are clinically indistinguishable and observed in early infancy
manifested by severe infection. Treatment includes correction of the defect by stem cell transplant or
enzyme replacement with adenosine deaminase. Lymphocytopenia may also be acquired, for example,
in patients with HIV infection [9].

Platelet disorders
Common platelet disorders include thrombocytopenia, thrombocytopathia, and thrombocytosis.
Bolton-Maggs et al. reviewed various inherited platelet disorders with guidelines for their management
[10]. Thrombocytopenia is often discovered incidentally during office visit of a patient when CBC is
ordered along with other tests. However, severe thrombocytopenia may be a reflection of a severe
disease. Similarly thrombocytosis is a common finding during a routine blood test and may represent a
benign condition. However, like severe thrombocytopenia, severe thrombocytosis may be a reflection of
a serious clinical condition requiring further investigation.
Normal platelet physiology and pathology leading to disorders of coagulation are discussed in
Chapter 15.

Thrombocytopenias
Thrombocytopenia is defined as platelet count below 150,000 per microliter of blood (150  109/L),
but patients even with a platelet count of 50,000 per microliter or more may be asymptomatic.
However, counts from 10,000 to 30,000 per microliter may be associated with bleeding, and espe-
cially patients with platelet count below 10,000 per microliter are very sensitive to spontaneous
bleeding.
Before discussing thrombocytopenia, it is important to mention pseudothrombocytopenia. This is
when the platelet count appears low but is not truly so. Causes of pseudothrombocytopenia are
• Platelet clumping (may occur when blood is collected in EDTA; blood needs to be recollected in
blue or green top)
• Platelet satellitism (when platelets adhere to neutrophils, again seen when blood is collected in
EDTA)
• Presence of numerous large platelets (platelets are falsely counted as red cells)
• Traumatic venipuncture (platelets are activated and cause them to aggregate)
True thrombocytopenia may be due to decreased platelet production (congenital or acquired),
increased destruction of platelets, increased platelet consumption, or sequestration. Various causes of
 Platelet disorders 83

Table 5.3 Various causes of thrombocytopenia.

Decreased Production · Bone marrow failure (aplastic anemia, paroxysmal nocturnal hemoglobinuria, etc.)
(any cause of bone · Bone marrow suppression due to medication, chemotherapy, or radiation therapy
marrow suppression/
· Infection (cytomegalovirus, HIV, parvovirus B19, hepatitis C, etc.)
failure)
· Myelodysplastic syndrome
· Neoplastic marrow infiltration
· Inherited forms are summarized in Table 5.4
Increased Platelet · Disseminated intravascular coagulation
Consumption · Thrombotic thrombocytopenic purpura
· Hemolytic uremic syndrome
Increased Platelet · Immune thrombocytopenic purpura
Destruction · Mechanical destruction, e.g., mechanical valves, extracorporeal bypass
Thrombocytopenias due
to Sequestration
· Sequestration in hemangiomas (KasabacheMerritt syndrome)

thrombocytopenias, except inherited forms, are given in Table 5.3. Inherited forms of thrombocyto-
penia are summarized in Table 5.4.
Congenital thrombocytopenia can be broadly divided into three groups namely cytopenia with
small platelets, cytopenia with normal platelets, and cytopenia with large platelets.
KasabacheMerritt syndrome is a rare locally aggressive vascular tumor characterized by a rapidly
enlarging vascular anomaly, consumption coagulopathy, thrombocytopenia, prolonged bleeding time,
hypofibrinogenemia, presence of D dimer, and fibrin split products with or without microangiopathic
hemolytic anemia. Prognosis is poor due to availability of few treatment options [11].

Table 5.4 Various types of congenital thrombocytopenia.

Congenital thrombocytopenia Congenital thrombocytopenia Congenital thrombocytopenia
with small platelets with normal-sized platelets with large platelets

· WiskotteAldrich syndrome
(WAS): X-linked recessive
related to mutation of WASP
gene
· X-linked thrombocytopenia:
isolated thrombocytopenia
related also to mutation of WASP
gene, but disease is milder than
· Thrombocytopenia with absent
radii (TAR syndrome)
· BernardeSoulier syndrome:
autosomal recessive
· Amegakaryocytic
thrombocytopenia due to
· MayeHegglin anomaly:
autosomal dominant
mutation of MPL gene · Sebastian syndrome: autosomal
· Fanconi’s anemia: autosomal dominant
recessive · Epstein
dominant
syndrome: autosomal

WAS · Fechtner syndrome: autosomal

· Inherited microthrombocytes: dominant
transmitted as autosomal
dominant with normal platelet
· Gray platelet syndrome:
autosomal recessive
function · DiGeorge and velocardiofacial
syndrome: autosomal dominant
84 Chapter 5 Benign white blood cell and platelet disorders

Congenital thrombocytopenia with small platelets could be related to WiskotteAldrich syndrome

(WAS), which is characterized by eczema, immunodeficiency, and thrombocytopenia. This disease is
transmitted as X-linked recessive due to inheritance of the WASP gene, located at Xp11 encoding
WAS protein (WASP). Platelets are dysfunctional. X-linked thrombocytopenia, a congenital disorder
characterized by isolated thrombocytopenia and small platelet but in general without other compli-
cations as seen in WAS, is a mild allelic variant also caused by mutation of WASP gene [12].
Inherited microthrombocytes is a disorder transmitted as autosomal dominant with normal platelet
function.
Congenital thrombocytopenia with normal-sized platelets can be related to thrombocytopenia with
absent radii (TAR syndrome), amegakaryocytic thrombocytopenia which is due to mutation of MPL gene
that encodes thrombopoietin receptor (thrombopoietin is required for maturation of megakaryoblasts
to megakaryocytes), or Fanconi’s anemia which is transmitted in autosomal recesssive pattern.
Congenital thrombocytopenia with large platelets can be related to BernardeSoulier syndrome,
which is transmitted as autosomal recessive pattern. In early phase of primary hemostasis, platelets
adhere to damaged vessel walls by binding via the platelet glycoprotein (GP)Ib-V-IX complex to von
Willebrand factor exposed on the subendothelium. In this disorder, the (GP)Ib-V-IX complex is
abnormal. Platelet aggregation studies show impaired aggregation to ristocetin. Some cases of
BernardeSoulier syndrome are due to defects of the GpIbbeta gene located on chromosome 22. This
gene may be affected in velocardiofacial syndrome or DiGeorge syndrome associated with deletion of
22q11.2. Mhawech et al. reviewed various inherited giant platelet disorders [13].
Congenital thrombocytopenia with large platelets can also be due to MayeHegglin anomaly,
another inherited disorder is transmitted in autosomal dominant pattern. This disorder is due to
defective myosin heavy chain 9 gene at 22q11. Neutrophils have Dohle-like bodies. Sebastian syn-
drome is transmitted as autosomal dominant pattern and is due to defective myosin heavy chain 9 gene
at 22q11. Epstein syndrome is transmitted as autosomal dominant pattern and is related to defective
myosin heavy chain 9 gene at 22q11. Patients have Alport’s-like syndrome with features of nephritis,
sensorineural deafness, and cataract. Fechtner syndrome is transmitted as autosomal dominant and
also due to defective myosin heavy chain 9 gene at 22q11. Patients have Alport’s-like syndrome with
features of nephritis, sensorineural deafness, cataract and Dohle-like bodies in neutrophils. Gray
platelet syndrome, a rare congenital autosomal recessive bleeding disorder, is due to hypogranular
platelets, which are dysfunctional. DiGeorge and velocardiofacial syndrome are transmitted as
autosomal dominant with loss of function of GP1BB gene at 22q11. In this disorder, cardiac, para-
thyroid, and thymus abnormalities may be observed.

Thrombocytosis
Thrombocytosis is defined as platelet count exceeding 450,000 per microliter (450  109/L).
This abnormality is termed as primary thrombocytosis if platelet increase is related to alterations
targeting the hematopoietic cells in the bone marrow. Examples of such states are essential throm-
bocythemia or thrombocytosis seen in other myeloproliferative disorders [14]. The disorder is
considered as secondary (also called reactive thrombocytosis) if platelet increase is due to external
cause such infection, inflammation, neoplasms, or iron deficiency. Secondary thrombocytosis can also
be due to redistribution such as observed postsplenectomy.
 Platelet disorders 85

There are several examples of primary thrombocytosis which are inherited disorders. Familial
thrombocytosis is transmitted in autosomal dominant pattern and is due to mutation in the thrombo-
poietin receptor gene (myeloproliferative leukemia virus oncogene MPL gene; first identified from the
murine myeloproliferative leukemia virus that was capable of immortalizing bone marrow
hematopoietic cells from different lineages). Several mutations of this gene causing thrombocytopenia
have been reported. Inherited primary thrombocytopenia may also due to mutation of the promoter of
thrombopoietin gene that encodes thrombopoietin. Thrombopoietin is the primary humoral regulator
of platelet production.

Thrombocytopathia
Thrombocytopathia is any of several hematological disorders characterized by dysfunctional platelets
(thrombocytes) which lead to prolonged bleeding time, defective clot formation, and a tendency for
hemorrhage. Thrombocytopathia may be congenital or acquired.
Congenital causes of thrombocytopathia include
• Disorders of platelet adhesion: von Willebrand disease (VWD), BernardeSoulier syndrome
• Disorders of platelet activation: storage pool disorders, ChediakeHigashi syndrome, and
HermanskyePudlak syndrome
• Disorders of platelet aggregation: Glanzmann’s syndrome
Acquired causes of thrombocytopathia include
• Drugs: Aspirin, NSAIDs (nonsteroidal antiinflammatory drugs)
• Uremia
• Acquired VWD
• Myeloproliferative diseases
• Antiplatelet antibodies

Key points
• PelgereHuet anomaly is transmitted as autosomal dominant pattern where >75% of neutrophils
are bilobed. Presence of occasional bilobed neutrophils is also seen in MDS and is referred to as
PseudoePelger-Huët cells.
• MayeHegglin anomaly is transmitted as autosomal dominant pattern and is characterized by
thrombocytopenia, giant platelets, prominent Dohle-like bodies.
• ChediakeHigashi syndrome is transmitted as autosomal recessive pattern and is characterized by
giant neutrophilic granules (due to fusion of lysosomes), defective chemotaxis and phagocytosis,
immunodeficiency, and oculocutaneous albinism.
• AldereReilly anomaly is transmitted as autosomal recessive pattern and is characterized by large
azurophilic granules in neutrophils and others granulocytes, monocytes, and lymphocytes; the
condition is clinically benign.
• Kostmann’s syndrome is an example of congenital neutropenia, which inherited as autosomal
recessive pattern due to point mutations in gene coding for G-CSF.
86 Chapter 5 Benign white blood cell and platelet disorders

• ShwachmaneDiamond syndrome is another example of congenital neutropenia, which is also

transmitted as autosomal recessive pattern. This disorder is characterized by exocrine pancreatic
deficiency and neutropenia, thrombocytopenia, short stature, and mental retardation; this may
progress to MDS and AML.
• Reactive lymphocytes are also referred to as Downey cells. There are three types of Downey
cells: Type I: small cells with minimum cytoplasm, indented nucleus/irregular nuclear
membrane, and condensed chromatin; Type II: larger cells with abundant cytoplasm; the
lymphocyte cytoplasm seem to hug the red cells. This is the most common type of Downey cells;
and Type III: cells with large moderate basophilic cytoplasm and nucleus with coarse chromatin.
Nucleoli are apparent.
• Features of infectious mononucleosis, from the peripheral blood; 50% or more of the white cells
are mononuclear cells; at least 10% of the lymphocytes exhibit reactive changes, and there is
lymphocytic morphologic heterogeneity (this means different types of reactive lymphocytes are
seen)
• WiskotteAldrich syndrome is characterized by eczema, immunodeficiency, and
thrombocytopenia. This disorder is transmitted as X-linked recessive due to inheritance of the
WASP gene, located at Xp11. Platelets are dysfunctional.
• BernardeSoulier syndrome is transmitted as autosomal recessive. The GpIb/IX/V complex is
abnormal. Platelet aggregation studies show impaired aggregation to ristocetin. Some cases of
BernardeSoulier syndrome are due to defects of the GpIbbeta gene located on chromosome 22.
This gene may be affected in velocardiofacial syndrome or DiGeorge syndrome associated with
deletion of 22q11.2
• Causes of thrombocytopenia with giant platelets and associated with defective myosin heavy
chain 9 gene at 22q11 are BernardeSoulier syndrome, May Hegglin anomaly, Sebastian
syndrome, Epstein syndrome, and Fechtner syndrome.

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