Miscellaneous Causes of Thrombocytopenia

Archana M. Agarwal

George M. Rodgers

This chapter summarizes miscellaneous forms of congenital and acquired thrombocytopenia (Table 49.1), including thrombocytopenia attributable to deficient platelet production, associated with abnormal platelet pooling in the spleen, and resulting from dilution with massive transfusions.

CONGENITAL THROMBOCYTOPENIA

Hereditary thrombocytopenias have been well documented and may be inherited as an autosomal dominant trait, an autosomal recessive trait, or an X-linked recessive trait. Bleeding can be mild, and in some instances the affected family members are virtually asymptomatic, being identified only through incidental platelet counts or family studies after the identification of the propositus. It is important to recognize these mild forms of familial thrombocytopenia because, although they may resemble autoimmune thrombocytopenic purpura, patients do not respond to steroid treatment or intravenous immunoglobulin, and this therapy may be harmful. These disorders can be classified according to platelet size (Table 49.2).

Autosomal Recessive Thrombocytopenias

Congenital Amegakaryocytic Thrombocytopenia

The presence of severe thrombocytopenia, absence of megakaryocytes in the bone marrow, and absence of any physical anomaly in an infant characterize congenital amegakaryocytic thrombocytopenia (CAMT).¹ Because of the recessive nature of the disease, family history is usually negative, with both parents having normal platelet counts and function. Patients with CAMT have markedly elevated serum levels of thrombopoietin (TPO)² and mutations in the c–mpl gene. Multiple mutations in the c–mpl gene have been reported, including deletions, nonsense mutations, and missense mutations. Many of the patients studied are compound heterozygotes with one mutation inherited from each parent.³, ⁴, ⁵ Because patients with CAMT develop progressive bone marrow aplasia during the course of the disease, it is likely that Mpl signaling is essential for the production of mature megakaryocytes as well as maintenance of the hematopoietic stem cell population.⁶

Further subgrouping of CAMT patients into two groups has been proposed based on their clinical course: Group CAMT I, with a more severe type of thrombocytopenia with constantly low platelet counts and an early onset of pancytopenia; and group CAMT II, which is characterized by a transient increase in platelet counts during the first year of life and a later or no development of pancytopenia.⁴ The type of mpl mutation determines the clinical course of CAMT; a total loss of the TPO receptor due to homozygous nonsense mutations, deletions, and frameshift mutations causes the more severe form of disease found in CAMT I patients. In contrast, the transient increase in platelet counts and the later development of pancytopenia in patients with homozygous or compound heterozygous missense mutations are the result of a residual function of the TPO receptor.⁷ Hematopoietic stem cell transplant is the only curative treatment for these patients, and matched sibling transplants have been successful.

Thrombocytopenia with Absent Radius Syndrome

The thrombocytopenia with absent radius (TAR) syndrome is a congenital malformation syndrome characterized by bilateral absence of the radii but with thumbs present, hypomegakaryocytic thrombocytopenia, and a number of additional features including skeletal and cardiac anomalies.⁸, ⁹ Among the skeletal anomalies, bilateral absence of the radii may be accompanied by ulnar or humeral anomalies, and the most severe cases exhibit phocomelia. Lower limb involvement is variable and includes dislocation of the patella and/or of the hips, absent tibiofibular joint, and lower limb phocomelia. Among the cardiac anomalies, tetralogy of Fallot and atrial septal defects are common.¹⁰, ¹¹ Studies have noted a high incidence (62%) of cow’s milk intolerance, which presents as persistent diarrhea and failure to thrive.
An episode of thrombocytopenia may be precipitated by introduction of cow’s milk and relieved by its exclusion from the diet.¹²

TABLE 49.1 MISCELLANEOUS CAUSES OF THROMBOCYTOPENIA

Congenital Thrombocytopenia
Autosomal recessive thrombocytopenias
	Congenital amegakaryocytic thrombocytopenia Thrombocytopenia with absent radius (TAR) syndrome Bernard-Soulier syndrome
Autosomal dominant thrombocytopenias
	MYH9-related disorder
		May-Hegglin anomaly Sebastian anomaly Fechtner anomaly Epstein anomaly
	Familial platelet disorder with predisposition to acute myelogenous leukemia Mediterranean macrothrombocytopenia Paris-Trousseau syndrome (in association with deletion of FLI1 gene) Autosomal dominant thrombocytopenia with linkage to human chromosome 10 (THC2) Gray platelet syndrome Amegakaryocytic thrombocytopenia with radial-ulnar synostosis (ATRUS) syndrome Variant von Willebrand disease (type 2b and platelet-type) (see Chapter 53)
X-linked thrombocytopenia
	X-linked microthrombocytopenia (WAS gene mutation) X-linked macrothrombocytopenia with dyserythropoiesis (GATA-1 mutation)
Others
	22q11 deletion syndrome (DiGeorge Syndrome)
Acquired Thrombocytopenia
Thrombocytopenia caused by deficient platelet production
	Acquired pure amegakaryocytic thrombocytopenic purpura Chemical and physical agents that produce generalized bone marrow suppression
		Drugs that selectively suppress the megakaryocyte Drugs that cause ineffective thrombopoiesis
Thrombocytopenia caused by abnormal platelet pooling Thrombocytopenia caused by hypothermia Thrombocytopenia associated with infections
	Thrombocytopenia associated with viral infections Thrombocytopenia associated with bacterial and protozoal infections
Thrombocytopenia after massive blood transfusions

TABLE 49.2 CLASSIFICATION OF INHERITED THROMBOCYTOPENIA BY PLATELET SIZE (MPV)

Low MPV	Normal MPV	Increased MPV
Wiskott-Aldrich syndrome	ATRUS syndrome	MYH9-related disorders
	Thrombocytopenia with absent radius syndrome	Mediterranean macrothrombocytopenia
	Congenital amegakaryocytic thrombocytopenia	Bernard-Soulier syndrome
	Familial platelet disorder with predisposition to AML	GATA-1 mutation
	THC2	Gray platelet syndrome
	X-linked thrombocytopenia with GATA-1 mutation	Paris-Trousseau syndrome
		vWD type 2B
		Platelet type vWD
		22q11 deletion syndrome
GATA-1 mutation platelets may have normal or increased MPV. AML, acute myelocytic leukemia; ATRUS, amegakaryocytic thrombocytopenia with radial-ulnar synostosis; MPV, mean platelet volume; THC2, autosomal dominant thrombocytopenia with incomplete megakaryocyte differentiation and linkage to chromosome 10; vWD, von Willebrand disorder. Adapted from Drachman JG, Inherited thrombocytopenia: when a low platelet count does not mean ITP. Blood 2004;103:390-398; Lambert MP. What to do when you suspect an inherited platelet disorder. Hematology Am Soc Hematol Educ Program 2011; 2011: 377-383.

These patients have elevated serum TPO levels and normal c–mpl and HOX genes. However, they have a profound defect in megakaryocyte differentiation and platelet production and no response of megakaryocytes to TPO.¹³, ¹⁴, ¹⁵ There may be a slight increase in platelet count in response to recombinant human erythropoietin.¹⁶ Although specific microdeletion of chromosome 1q21.1 has been reported in the majority of individuals with TAR syndrome, it is not the disease-causing mutation.¹⁷ Compound inheritance of a rare null mutation in exon-junction complex subunit RBM8A has been found to be the cause of TAR syndrome. RBM8A controls the production of the protein Y14, and its low level is responsible for the cause of low platelets.¹⁸

Diagnosis is rarely difficult because of obvious morphologic abnormalities in association with thrombocytopenia. Prenatal diagnosis has been described by ultrasonographic detection of morphologic abnormalities and detection of low fetal platelet counts.¹⁹, ²⁰, ²¹ Congenital rubella and some variants of Fanconi syndrome should be excluded. Platelet counts gradually increase during the first 2 years of life. The degree of thrombocytopenia is usually greatest at the time of birth; platelet transfusions are frequently required and are effective. Thrombocytopenia becomes less severe during the first year of life, and most affected individuals with TAR do not require platelet transfusions after infancy.¹⁰, ²²

Bernard-Soulier Syndrome

Bernard-Soulier syndrome is an autosomal recessive bleeding disorder associated with deficiency of platelet membrane proteins GPIb, GPIX, and GPV. This results in abnormal platelet interaction with ligands of these receptor proteins, which include thrombin, von Willebrand factor (vWF), P-selectin, and leukocyte integrin α_Mβ₂, in addition to causing thrombocytopenia. This topic is described in more detail in Chapter 52.

Autosomal Dominant Thrombocytopenia

A number of families have been described who have autosomal dominant inheritance of isolated mild thrombocytopenia characterized by normal platelet survival and a normal number of bone marrow megakaryocytes, a constellation of findings that suggests ineffective thrombopoiesis.²³, ²⁴, ²⁵ Thrombocytopenia (platelet counts between 20,000 and 100,000/µl) or a history of increased bruisability is apparent early in life, and examination of the peripheral blood smear demonstrates platelet macrocytosis (mean platelet volume >10 µm³). Splenic size is always normal. Platelet aggregation abnormalities have been described in some families, but platelet membrane glycoproteins (GPs) have been normal when studied.²⁴

MYH9-related Disorders

A group of autosomal dominant macrothrombocytopenias caused by mutations in the MYH9 gene with variable penetrance and expression has been defined.²⁶, ²⁷, ²⁸, ²⁹ These include May-Hegglin anomaly, Sebastian syndrome, Epstein syndrome, and Fechtner syndrome. These disorders are defined by the presence of mutations involving the MYH9 gene located at chromosome 22q12.3-13.1 and include single nucleotide changes, in-frame deletions or duplications, and frameshift and nonsense mutations.³⁰ The MYH9 gene encodes nonmuscle myosin heavy chain IIA (NMMHC-IIA).³¹ NMMHC-IIA is part of the nonmuscle myosin IIA hexamer that is a component of the contractile cytoskeleton in megakaryocytes, platelets, and other tissues. Thrombocytopenia is usually mild and derives from complex defects of megakaryocyte maturation and platelet formation. More specifically, these mutations likely affect the platelet release from the mature megakaryocytes.³⁰ All of these MYH9 gene mutation-related disorders have macrothrombocytopenia, leukocyte inclusion bodies (Döhle body-like inclusions) and can have various combinations of hereditary nephritis, deafness, and cataracts (Table 49.3). Sometimes, the inclusions are rarely appreciated on conventional May-Grunwald-Giemsa staining, especially in patients with mutations at codon 702 because of their low RNA content. These cases can be diagnosed by the use of immunofluorescence assays.³² Thrombocytopenia is generally mild to moderate. Peripheral blood smears reveal enlarged platelets with frequent giant platelets.

Clinically, patients have a mild platelet-type bleeding disorder. May-Hegglin anomaly and Sebastian syndrome both have macrothrombocytopenia and granulocyte inclusions, but ultrastructural analysis of the Döhle-like inclusions demonstrates diagnostic differences between these two syndromes, and both types of inclusions can also be distinguished from Döhle bodies seen in acute infection. Patients with Fechtner syndrome and Epstein syndrome have hearing disability and nephritis. In Fechtner syndrome, cataracts are also present.³³ These two disorders result from allelic mutations at amino acid 702, which cause conformational changes to the myosin head.³¹, ³⁴, ³⁵, ³⁶ Diagnosis is suggested by detection of macrothrombocytopenia and the presence of one or more of the above-mentioned clinical features. Döhle-like inclusion bodies within neutrophils on May-Grünwald-Giemsa-stained peripheral blood are highly suggestive of an MYH9-related disorder. Abnormal staining of neutrophil inclusions with anti-NMMHC-IIA may offer greater sensitivity. Definitive diagnosis requires the demonstration of a causative mutation within the MYH9 gene.³¹ Treatment options for bleeding include platelet transfusion, allogeneic stem cell transplantation, or use of a thrombopoietic drug (eltrombopag).³⁷

Platelet-type von Willebrand disease is another autosomal dominant disorder associated with hereditary thrombocytopenia, characterized by abnormal binding of large vWF multimers to platelets. This intrinsic platelet defect results in mild thrombocytopenia, increased ristocetin-induced platelet aggregation, and a selective
loss of high-molecular-weight vWF multimers from the plasma. This disorder resembles type 2b von Willebrand disease (see Chapter 53).

TABLE 49.3 SYNDROMES CAUSED BY MYH9 GENE DEFECTS

Syndrome	Macrothrombocytopenia	Döhle-like Bodies	Nephritis	Deafness	Cataracts
May-Hegglin	Yes	Yes	No	No	No
Sebastian	Yes	Yes	No	No	No
Fechtner	Yes	Yes	Yes	Yes	Yes
Epstein	Yes	Yes	Yes	Yes	No

Familial Platelet Disorder with Predisposition to Acute Myelogenous Leukemia

Familial platelet disorder with predisposition to acute myelogenous leukemia (FPD/AML) is an autosomal dominant disorder characterized by moderate thrombocytopenia, a defect in platelet function, and predisposition to develop myeloid malignancy.³⁸ The defect in platelet function is manifested by prolonged bleeding times and abnormal platelet aggregation. Expansion of megakaryocyte progenitors in the bone marrow or peripheral blood cells reveals diminished megakaryocyte colony formation. Bone marrow from affected patients shows decreased megakaryopoiesis. Linkage analysis of several pedigrees affected by FPD/AML has led to identification of germline heterozygous mutations in the hematopoietic transcription factor AML1, also known as RUNX1 and CBFA2. These mutations include missense, frameshift, and nonsense mutations and a large intragenic deletion.³⁹, ⁴⁰ CBFA2 is a transcription factor that trans-activates the expression of a spectrum of genes required for normal development of hematopoietic cells. Mutation of CBFA2 has been implicated in the pathogenesis of human leukemias resulting from somatically acquired chromosomal translocations.⁴¹ Normal megakaryopoiesis requires TPO binding to the Mpl receptor. In FPD/AML, CBFA2 mutation leads to diminished Mpl receptor expression, resulting in impaired TPO signaling leading to thrombocytopenia. Consequently, serum TPO levels are usually elevated in these patients.⁴²

Mediterranean Macrothrombocytopenia

A relatively common and mild form of macrothrombocytopenia has been described in a group of 145 apparently healthy subjects from Italy and the Balkan peninsula. Because this abnormality was not detected in control subjects from northern Europe, the condition was named Mediterranean macrothrombocytopenia.⁴³ Linkage analysis localized the gene mutation to the short arm of chromosome 17, in an interval containing the GPIba gene. GPIbα, together with other proteins, constitutes the plasma vWF receptor, which is altered in Bernard-Soulier syndrome. Sequencing of the gene identified a mutation of GPIbα (Ala156Val) shared by 10 of 12 pedigrees studied.⁴⁴ These data demonstrate that for most families with Mediterranean thrombocytopenia, the genotype and phenotype are equivalent to that of a carrier of Bernard-Soulier syndrome. Clinically, patients have a mild bleeding diathesis, usually diagnosed after incidental discovery of thrombocytopenia. Peripheral blood shows platelets that are larger than normal.

Paris-Trousseau Syndrome (in Association with Deletion of the FLI1 Gene)

Paris-Trousseau syndrome (PTS) is an inherited disorder characterized by several congenital anomalies including dysmegakaryopoiesis with two morphologically distinct populations of megakaryocytes and giant α-granules in a low percentage of platelets. These features occur in association with deletion of the long arm of chromosome 11 at 11q23.3 (which includes the FLI1 gene), a region that is also deleted in Jacobsen syndrome (a variant form of PTS). Clinical features include a combination of mild to moderate psychomotor retardation, trigonocephaly, facial dysmorphism, cardiac defects, and thrombocytopenia.⁴⁵, ⁴⁶ Hematologic history, biologic data, ultrastructural, and molecular investigations were reported from a case series of 10 patients.⁴⁷ Thrombocytopenia is chronic, with mild clinical bleeding. Peripheral blood smears and electron microscopy show abnormal platelets with giant granules. Bone marrow findings consist of dysmegakaryopoiesis with many micromegakaryocytes. Abnormal α-granules are not seen in the bone marrow and cultured megakaryocytes. Platelets have a normal lifespan in the circulation. The number of megakaryocytes in the bone marrow is increased, accompanied by impaired maturation. Together these findings suggest that platelet release is substantially impaired. PTS occurs as a result of hemizygous loss of the FLI1 transcription factor gene, which has been shown to be critical for megakaryocyte differentiation and release of platelets. FLI1 shows monoallelic expression during a brief window in megakaryocyte differentiation. This monoallelic expression explains the dominant inheritance pattern of PTS despite the presence of one normal FLI1 allele.⁴⁸, ⁴⁹

Autosomal Dominant Thrombocytopenia with Incomplete Megakaryocyte Differentiation and Linkage to Chromosome 10

The genetic defect for this autosomal dominant thrombocytopenia has been mapped to a region on the short arm of chromosome 10 (10p11-12).⁵⁰ This disorder is characterized by moderate thrombocytopenia, abnormal platelet size, and incomplete differentiation of megakaryocytes. Clinical features consist of mild to moderate bruising but absence of major bleeding even with minor surgery and childbirth, suggesting that the residual platelets have normal hemostatic function. However, platelets are deficient in GPIa and α-granule content. Morphologically, the platelets appear normal. Bone marrow examination reveals impaired megakaryocyte maturation and small megakaryocytes. Colony assay on bone marrow and peripheral blood cells reveal expanded progenitors across all hematopoietic lineages, and tremendously increased expansion of immature megakaryocytes (CFU-Mk). Serum TPO level is only moderately elevated and is usually lower than expected for the degree of thrombocytopenia.⁵¹

Recently, mutations in ANKRD26 were identified in the original patients and in several additional families around the world; these mutations accounted for 10% of patients in an inherited thrombocytopenia database.⁵² The term “thrombocytopenia 2” (THC2) has been applied to this disorder.

Gray Platelet Syndrome

The gray platelet syndrome for which both autosomal recessive and autosomal dominant inheritance have been described is characterized by macrothrombocytopenia with bleeding tendency, myelofibrosis, and classical abnormal platelet morphology.⁵³ The α-granules are absent or greatly reduced, giving the platelets a gray color on Wright-Giemsa stain. The α-granules are the principal storage site for hemostatic proteins such as fibrinogen, vWF, thrombospondin, and factor V and for growth factors such as platelet-derived growth factor and transforming growth factor-β.⁵⁴ One result of absence of α-granules is a continued leakage of growth factors and cytokines into the marrow, causing myelofibrosis.

Amegakaryocytic Thrombocytopenia with Radial-Ulnar Synostosis Syndrome in Association with HOXA11 Mutation

Homeobox genes encode regulatory proteins that are critical to bone morphogenesis as well as hematopoietic differentiation and proliferation.⁵⁵ This defect is the first reported germline HOX gene mutation associated with a human nonneoplastic hematologic disorder, and only the third HOX gene implicated in a human disorder.⁵⁶ HOXA11 is suggested to be endogenously expressed in very early hematopoietic precursor cells and involved in regulation of megakaryocytic differentiation.⁵⁷ Clinical features consist of CAMT, aplastic anemia, proximal radial-ulnar synostosis, clinodactyly, syndactyly, hip dysplasia, and sensorineural hearing loss.⁵⁸ Platelet transfusions are effective as initial symptomatic management. The only definitive treatment is hematopoietic stem cell transplantation.⁵⁹

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