Inherited Thrombocytopenias

Paquita Nurden

Alan T. Nurden

Bleeding syndromes arising from an inherited defect of platelet production are an important group of rare diseases with a variety of causes.¹^,²^,³^,⁴ Some, such as the Bernard-Soulier syndrome (BSS) and Wiskott-Aldrich syndrome (WAS), associate alow circulating platelet count with a deficiency of a known functional protein. In others, platelet dysfunction has not been shown and bleeding arises from the inability of megakaryocytes (MKs) to produce platelets in sufficient numbers to ensure hemostasis. In some, there may be associated illnesses such as an increased risk for leukemia or β-thalassemia; sometimes, developmental changes result in profound skeletal defects. Haploinsufficiency of transcription factors can lead to decreased expression of multiple platelet proteins. In many cases, a low platelet count is accompanied by changes in platelet morphology with macrothrombocytopenias and enlarged or even giant platelets in variable numbers. Gene defects have been described for the major inherited thrombocytopenias and their characterization is providing basic knowledge of how MKs develop from the pluripotent hematopoietic stem cell (HSC) under the influence of thrombopoietin (TPO). Notwithstanding, the molecular basis for many moderate congenitally low platelet counts, often of mild clinical significance, remains to be elucidated. Our review deals with the biology, genetics, and clinical management of inherited thrombocytopenias. The fundamental aspects of megakaryocytopoiesis are dealt with in Chapter 23. Most important in this group of patients is the need to ensure correct diagnosis and to avoid inappropriate therapy such as steroid treatment and splenectomy. Where possible, a phenotypic approach has been taken to classifying the disorders (Table 63.1).

GIANT PLATELET SYNDROMES AFFECTING THE GPIb/VON WILLEBRAND FACTOR AXIS

In this group of disorders, the circulating platelet count is low and is accompanied by the presence of variable numbers of large platelets. Quantitative or qualitative defects of the GPIb-IX-V complex also result in defects of the platelet-vessel wall interaction (see Chapter 65); they also result in profound changes in megakaryocytopoiesis in the bone marrow.

BSS: First reported in 1948, BSS associates macrothrombocytopenia with decreased platelet adhesion to subendotheliumcausedby an absence (or nonfunctioning) of GPIbα³^,⁴^,⁵ A simple diagnostic test is that the giant platelets fail to agglutinate with ristocetin, an antibiotic that promotes the binding of von Willebrand factor (vWF) to GPIbα. The products of four separate genes (GPIBA, GPIBB, GP9, and GP5) assemble in a 2:2:2:1 ratio within maturing MK to form the GPIb-IX-V complex, stabilized through cytoplasmic

domains linked to the membrane cytoskeleton via filamin A (FlnA).⁶ Generally inherited as an autosomal recessive trait, mutations within GPIBA, GPIBB, and GP9 interfere with the biosynthesis, maturation, and/or trafficking of the complex through the endoplasmic reticulum and Golgi apparatus of MKs.⁷^,⁸ Recent data suggest that bleeding results from the loss of high shear- and vWFdependent platelet-to-platelet interactions in thrombus formation, as well as a defective platelet adhesion and the low platelet count.⁹ The additional absence of GPIbαdependent binding of P-selectin, TSP1, factor VIIa, factor XI, factor XII, aMβ2, high molecular weight kininogen, and thrombin may also contribute to the phenotype (see Chapter 26A). Early reports of an increased phosphatidylserine (PS) exposure but decreased prothrombin consumption and a decreased platelet survival in BSS remain largely unexplained. Nonetheless, BSS platelets of all sizes readily expose PS and undergo apoptotic-like changes on platelet activation.¹⁰

Early studies showed that mature MKs isolated from the bone marrow of BSS patients had major changes in morphology with an altered organization of internal membranes, many vacuoles, and a disparate localization of α-granules.¹¹ Such changes lead to decreased platelet production with the formation of large round platelets having distinctive morphologic abnormalities (FIGURE 63.1). The macrothrombocytopenia in BSS is usually moderate but can be severe in some patients and lead to extensive, occasionally life-threatening, mucocutaneous bleeding. In rare variant forms, platelets express decreased to normal amounts of nonfunctional GPIbα. Mutations resulting in variant BSS have included three missense mutations in GPIbα: R41H, L73F, and A156V (so-called Bolzano mutation).¹²^,¹³^,¹⁴ While the first two were heterozygous with autosomal dominant pattern of inheritance, the Bolzano variant was homozygous with autosomal recessive inheritance. Hemizygous mutations in GPIBB can also cause BSS when associated with the DiGeorge/velocardiofacial syndrome, a developmental disorder characterized by a hemizygous microdeletion at 22q11, the site of localization of GPIBB.¹⁵

Mice lacking GPIbα or GPIbβ have allowed evaluation of megakaryocytopoiesis in BSS and have confirmed aberrant membrane development early during MK maturation leading to a reduced demarcation membrane system (DMS), impaired proplatelet formation, and aberrant microtubule coil assembly.¹⁶^,¹⁷^,¹⁸ Studies of platelet production in situ revealed large platelets being released from unusually short, broad, proplatelets protruding into vascular sinuses.¹⁷

GPIbβ—/— MKs differentiated in vitro showed fewer proplatelet extensions with thicker shafts, fewer branches, and an increased diameter of terminal coiled elements that were enriched in tubulin fibers.¹⁸ Significantly, the macrothrombocytopenia was much less severe in a novel murine model where platelets were engineered to express a GP1393;bα subunit in which the extracytoplasmic sequence was replaced by that of the α-subunit of the human interleukin-4 receptor; despite improvement in platelet production a severe bleeding phenotype persisted.¹⁹^,²⁰ This suggests a role for the GP1393;bα cytoplasmic tail in signaling essential for normal MK maturation. Significantly, no correlations have yet been seen in BSS between phenotype (and bleeding severity) and genotype.²¹
Mediterranean Macrothrombocytopenia. In Mediterranean countries, patients manifesting a moderately low platelet count (70,000 to 150,000/µL), increased mean platelet volume, autosomal dominant inheritance with mild mucocutaneous or no bleeding, normal platelet function, and normal MK numbers are frequently observed. Linkage analysis and mutation screening of 12 Italian families identified a heterozygous A156 substitution in GPIbα in six with GPIb-IX levels comparable to those of BSS heterozygotes.²² It is noteworthy that A156V is the same mutation as that causing the Bolzano variant of BSS (see above). Balduini et al.²³ cultured MKs from six patients and showed that proplatelet formation was much reduced compared to controls. Again, proplatelet tips were enlarged and α-tubulin distribution abnormal. Because the GPIbα mutation is heterozygous and occurs in the context of the wild-type protein, it must be exerting an as yet unexplained dominant negative effect, especially since obligate heterozygotes for classic BSS are largely asymptomatic.
Platelet-type von Willebrand disease (platelet-type vWD). Platelet-type vWD is characterized by a gain of function phenotype with spontaneous binding of plasma vWF to platelets and increased platelet agglutination by low amounts of ristocetin in the presence of normal plasma. Platelet size can be increased in platelet-type vWD and there can be moderate thrombocytopenia. Selected heterozygous GPIbα substitutions with autosomal dominant inheritance cause platelet-type vWD, namely, G233V/S and M239V substitutions in the N-terminal domain; a 27-bp deletion in the macrogly copeptide-coding region of GPIBA implies that long-range conformational changes can also give rise to platelet-type vWD.⁴^,²⁴^,²⁵ Mechanistically, the GPIbα mutations promote and stabilize platelet adhesion to vWF at low shear by enhancing formation and increasing longevity of the tether bond.²⁶ Interestingly, a knock-in mouse model with the G233V mutation not only had a phenotype mimicking the human disorder, but also showed increased bone mass.²⁷ In the same model, spontaneous binding of vWF blocked the capacity of platelets to bind fibrinogen when stimulated.²⁸ This probably contributes to the bleeding caused by an inhibited GPIbα although enhanced ADAMTS13 cleavage of the more stable plateletbound vWF multimers may moderate the condition.²⁹
vWD2B. Enlarged platelets with size heterogeneity (FIGURE 63.1) and thrombocytopenia can also occur in vWD, type 2B (vWD2B) where mutated plasma vWF spontaneously binds to a normal GPIbα.³⁰ As with platelet-type vWD, inheritance is autosomal dominant. In one such family with an R1308P vWF substitution, platelets showed signs of apoptosis and culture of CD34+ cells from the peripheral blood resulted in an increased surface expression of the mutant vWF on mature MKs that caused interactions between proplatelets.³¹ This study was extended to nine patients with a total of seven different gain-offunction mutations and abnormal platelets typical of those seen in the circulation were produced ex vivo in MK cultures.³² Circulating platelet clumps in rare patients with vWD2B prompted comparison with the previously described phenotype of the Montreal platelet syndrome (MPS); this was resolved when patients of the founder MPS kindred were shown to have the common vWF V1316M mutation.³³ Among the described characteristics of MPS were platelet calpain deficiency (probably due to autodegradation) and a reduced thrombin-induced aggregation; both findings are a consequence of the spontaneous binding of large vWF multimers to GPIbα. Significantly, lineage-specific mouse knock-in models of vWD2B show that abnormal plasma vWF (with a vWD2B mutation) can broadly reproduce the human vWD2B phenotype, emphasize its hemostatic variability, and suggest a possible role for ADAMTS13-dependent modulation of disease severity.³⁴^,³⁵

Table 63.1 Inherited thrombocytopenias classified by gene mutation and associated phenotype

Syndrome	Gene Mutation	Chromosomal Location/Inheritance	Associated Phenotype
BSS	GPIBA, GPIBB, GP9	17,22, and 3 Autosomal recessive	Deficient GPIb-IX-V, giant platelets, vWF-dependent adhesion defect
Platelet-type vWD	GPIBA	17p13.2 Autosomal dominant	Blocked GPIbα(vWF), platelet anisotropy
vWD2B (some families)	vWD	12p13.3 Autosomal dominant	Enlarged platelets, sometimes platelet agglutinates, blocked GPIbα
Mediterranean macrothrombocytopeni.	GPIBA, possibly others	17p13.2 Autosomal dominant	Mild disorder, enlarged platelets
GT-like	ITGB3, ITGA2B	17q21.31/32 Autosomal dominant or recessive	Platelet anisotropy, defective platelet aggregation
MYH9-related thrombocytopenia, May-Hegglin anomaly, Fechtner, Epstein & Sebastian syndromes	MYH9	22q11.21 Autosomal dominant	Giant platelets, various combinations of neutrophil inclusions, sensorineural hearing loss, nephritis, cataracts
β1-tubulin-related thrombocytopenia	TUBB1	20q13.32 Autosomal dominant	Altered organization of β1-tubulin into microtubules, enlarged platelets
FlnA-related thrombocytopenia	FLNA	Xq28 Autosomal dominant	PNHs and other defects, platelet anisotropy
DiGeorge/velocardiofacial syndrome	Hemizygous microdeletion including GPIBB	22q11 Autosomal dominant	Facial dysmorphology, cardiac and other defects of development
WAS	WAS	Xp11.23	Immunodeficiency, eczema, lymphoma, small platelets, defective platelet and lymphocyte function
XLT	WAS	Xp11.23	Small platelets, no immune problems
GPS	NBEAL2	3p21.1-3p22.1 (3p21) Autosomal dominant (rare) or recessive	Myelofibrosis, enlarged platelets (no α-granules), platelet dysfunction
Familial platelet disorder/acute myelogenous leukemia	RUNX1 (CBFA2, AML1)	21q22.12	Autosomal dominant Myelodysplasia, acute myeloid leukemia, platelet dysfunction
Chromosome 10/thrombocytopenia 2	MASTL, ANKRD26	10p12.1 (both)	Autosomal dominant Bleeding syndrome only
CAMT	MPL	1p34.2 Autosomal recessiv	Low MK content in marrow, early development of pancytopenia (in most cases), elevated TPO
Thrombocytopenia with radio-ulnar synostosis	HOXA11	7p15.2 Autosomal dominant or recessive	Fused radius, incomplete range of motion, sometimes other defects
TAR	RBM8A null allele + lowfrequency regulatory SNP	1q21.1 Autosomal recessive	Shortened/absent radii bilaterally, cardiopathy
Paris-Trousseau syndrome	Hemizygous microdeletion includingFLI1	11q23/24 Autosomal dominant (or isolated)	Psychomotor retardation, facial anomalies (Jacobsen syndrome), enlarged platelets with abnormal granules
GATA-1-related thrombocytopenia with dyserythropoiesis	GATA-1	Xp11.23 X-linked	Dyserythropoiesis ± anemia, thalassemia in some patients Platelet dysfunction, enlarged platelets with few α-granules

FIGURE 63.1 Composite illustration showing some of the striking ultrastructural characteristics of platelets in selected inherited thrombocytopenias. In the upper panels are shown the typical large round platelets of a patient with the BSS as seen by electron microscopy. Note the heterogeneous distribution of α-granules but the absence of large MC. Adjacent are platelets from a vWD2B patient showing size heterogeneity. An enlarged α-granule is highlighted. The middle panels first show electron microscope images of large round platelets from a patient with MYH9-related disease (May-Hegglin anomaly); note the large abnormal platelets with abundant MC. Also shown are a cytochemically stained Döhle-like inclusion and NMMHC-IIA immunoprecipitates detected by immunofluorescence in leukocytes from the same patient. In the lower panel is first shown platelet anisotropy in a patient with amegakaryocytic thrombocytopenia with predisposition to leukemia (AML-1). Platelets are immature and proplatelet fragments are present. Finally two platelets from a patient with the GPS are shown. These platelets are totally lacking α-granules. Bars = 1 µm

PLATELET ANISOCYTOSIS AND THE αIIbβ3 INTEGRIN

Glanzmann thrombasthenia (GT), the principal disorder of platelet aggregation, is caused by quantitative and/or qualitative defi-ciencies of the integrin αIIbβ3 coded by the ITGA2B and ITGB3 genes located at 17q21-23.²^,³ Although platelet count, volume, and morphology are normal in classic GT, several reports have inferred a role for αIIbβ3 in megakaryocytopoiesis because isolated point mutations in either of the ITGA2B and ITGB3 genes combine an altered platelet production with selective deficiencies in platelet function.^36a^,^36b^,³⁷^,³⁸^,³⁹^,⁴⁰ This was brought to light by the discovery of R995Q/W mutations in αIIb and D723H in β3 that resulted in platelet anisotropy and thrombocytopenia.³⁷^,³⁸^,³⁹ R995 and D723, each located in the αIIbβ3 cytosolic tail, are thought to interact and aid in maintaining the integrin in its bent inactive conformation. Mutations weakening or abolishing this interaction increase the activation state of αIIbβ3 potentially changing the ability of MKs to interact with their environment and/or interfering with intracellular signaling pathways. Another mutation affecting platelet production is a heterozygous L718P substitution in the membrane-proximal extracellular domain of β3.41 Finally, a genome-wide search in a large Italian family with an autosomal dominant trait combining thrombocytopenia, large platelets, defective platelet function, and moderate/severe mucocutaneous bleeding mapped the affected gene to chromosome 17q.⁴² A novel heterozygous mutation (c.2134 + 1G>C) in the donor splice site of intron 13 of ITGB3 resulted in an in-frame 120-bp deletion and loss of amino acids 647 to 686 within the extracellular membrane-proximal region of β.3

‘MYH9-RELATED SYNDROMES

May-Hegglin anomaly and the Fechtner, Sebastian, and Epstein syndromes constitute a group of disorders with autosomal dominant inheritance and macrothrombocytopenia; they are now generally referred to as MYH9-related disorders (Table 63.1).¹^,²^,³^,⁴^,⁴³^,⁴⁴ Enlarged or giant platelets are a common feature (FIGURE 63.1).
Döhle-like inclusions in neutrophils, eosinophils, and some monocytes are diagnostic characteristics (FIGURE 63.1).⁴⁵ Thrombocytopenia is generally mild but can be severe; bleeding is infrequent and rarely life threatening. Other manifestations of these disorders include the progressive development of nephritis, sensorineural hearing loss, and cataracts. The Sebastian platelet syndrome associates macrothrombocytopenia with neutrophilic inclusions that differ in morphology from those in May Hegglin anomaly.⁴⁶ The Fechtner syndrome adds hearing loss, nephritis, and cataracts while in the Epstein syndrome only hearing loss and glomerulonephritis are present (Table 63.1).⁴⁷^,⁴⁸

These syndromes result from heterozygous mutations in the MYH9 gene encoding the nonmuscle myosin heavy chain IIA (NMMHC-IIA).⁴⁹^,⁵⁰^,⁵¹ Class II myosins are hexameric proteins composed of two heavy chains and two pairs of light chains. A globular head binds to actin and ATP, has ATPase activity, and is required for motor activity. The C-terminal α-helical domain features a coiled-coil and a rod-like tail that allows the molecules to polymerize into bipolar filaments. NMMHC-IIA is found in platelets, monocytes, and granulocytes while its tissue distribution includes kidney, eye, and cochlea.⁵² Immunofluorescence microscopy is now a diagnostic test with the mutated protein visualized in distinctive patches in granulocytes and platelets (FIGURE 63.1).⁵³ A wide range of heterozygous mutations havebeen identified, including substitutions, deletions or small insertions, frameshifts, and stop codons; these mutations mainly cluster in 9 of the 40 exons that encode the protein. The result is haploinsufficiency and/or a functionally defective protein.⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷^,⁵⁸^,⁵⁹ The mutations may have a dominant effect, for example, on filament assembly; in this way they influence morphology of Döhle bodies and the nature of immunofluorescence staining (data reviewed in ref⁴⁴). It is noteworthy that the same mutation can give rise to a variety of phenotypes; for example, a common D1424N substitution in the rod domain first described in May-Hegglin anomaly is also found in patients with various combinations of hearing loss, nephritis, and cataracts (data reviewed in ref⁵⁷). In 20 families with the E1841K substitution, 15 had May-Hegglin anomaly and five Fechtner syndrome; in contrast, in families with R702C or R702H substitutions all developed the severe Fechtner or Epstein syndrome.⁴⁸^,⁵⁷ In a large family with Fechtner syndrome, only 5 out of 10 affected members showed renal lesions at the time of study.⁴⁹ Also, sequence analysis MYH9 in a family with nonsyndromic hereditary deafness showed that a R705H substitution cosegregated with the hearing loss phenotype, but giant platelets were not present.⁶⁰ Such findings suggest that the disease is not truly monogenic. Myosin molecules expressing mutations in the head domain had only 4% and 25% of the maximal ATPase activity and failed to translocate actin filaments in an in vitro motility assay.⁵⁴ MYH9 mutations can affect myosin filament assembly or stability as well as function. De novo mutations maybe the cause in sporadic cases.

Studies on MKs from patients in culture suggest that NMMHC-IIA negatively regulates megakaryocytopoiesis. In normal MKs, myosin light chain (MLC) kinase and Rhoassociated kinase ensure the phosphorylation of MLC. Inhibition of this phosphorylation, possibly through the influence of stromal cell-derived factor-1, promotes proplatelet formation.⁶¹ Perturbation of NMMHC-IIA levels and distribution in MYH9-related diseases potentially affects MK maturation, mobility, and the extent and timing of proplatelet production. MK-restricted MYH9 inactivation in mice resulted in macrothrombocytopenia but conserved platelet aggregation and secretion as in the human disease. Nonetheless, bleeding times were prolonged, platelet shape change modest, and clot retraction defective; the latter linked to a defective αIIbβ3-outside-in signaling, a finding associated with an impaired thrombus formation under flow.⁶² Mature MKs from these mice showed severe morphologic abnormalities with a poorly developed DMS and the absence of the peripheral zone that normally contains myosin filaments.⁶³ The MKs were unable to form stress fibers on adhesion to collagen. The number of cells extending proplatelets in culture was increased and the proplatelet tips were larger. The authors speculated that platelet release was premature, and that the decreased DMS contributed to a poor platelet production. Pecci et al.⁶⁴ supported premature release by showing that MKs cultured from MYH9-related disease patients lose the physiologic suppression of proplatelet formation exerted by type I collagen, an important extracellular matrix component and adhesive substrate for MKs as they migrate from the osteoblastic niche to the marrow vessels. These authors also showed a decreased branching of proplatelets and a lower number of proplatelet tips.

The basis for the phenotypic variability in MYH9-related diseases remains unclear and other genetic and/or environmental factors may intervene. A proposed explanation is that additional II-B and II-C myosin isoforms can compensate, at least in part, for the malfunction of defective MYH9 A isoform when they are expressed in the same tissues.⁵³ Another gene, FBLN1, encoding fibulin-1, an extracellular matrix protein, has been proposed as a disease modifier.⁶⁵ Amino acid substitutions in the Ca²⁺-ATPase-containing head domain appear more often to be associated with deafness and renal disease while those affecting the rod domain, and possibly myosin-IIA assembly, more frequently only have hematologic consequences.⁵⁷^,⁶⁶ But there are many exceptions. Missense mutations in the APOL1 gene are highly associated with focal segmental glomerulosclerosis and end stage kidney disease risk previously attributed to MYH9 SNPs in western African patients.⁶⁷ APOL1 is a neighboring gene to MYH9 on chromosome 22. Such haplotypes should be studied in MYH9-related disease patients where renal disease develops often during adolescence.

The presence of functionally normal giant platelets has been speculated to compensate for the thrombocytopenia in MYH9 disorder in reducing bleeding risk and to also account for the risk of myocardial infarction in May-Hegglin anomaly patients.⁶⁸ Nevertheless because of the risk of hemorrhage, Pecci et al.⁶⁹ assessed the administration of eltrombopag, a new generation TPO mimetic.⁷⁰ Eltrombopag was able to increase platelet counts in MYH9-related disease and reduce bleeding over a 3-week test period. However, many patients with these disorders are asymptomatic and diagnosis may await adulthood or the occurrence of trauma-related bleeding. Often it is confused with immune thrombocytopenic purpura (ITP). Platelet transfusions are often given as a precaution prior to surgery, TPO mimetics may offer an alternative.

OTHER FAMILIAL THROMBOCYTOPENIAS WITH DEFECTS OF CYTOSKELETAL PROTEINS AND AN ALTERED PLATELET SIZE

Mutations of other genes encoding cytoskeletal proteins have resulted in the production of platelets in decreased numbers and of altered size.

Mutation of the β1-tubulin gene (TUBB1). Microtubule assembly and function are key elements of proplatelet formation from MKs, trafficking granules and other organelles to the proplatelet tips where platelets are released by budding, and maintenance of the platelet discoid shape.⁷¹^,⁷² Freson et al.⁷³ found a heterozygous Q43P polymorphism in a highly conserved residue of β1-tubulin in 24.2% of 33 unrelated families with inherited macrothrombocytopenia of unknown cause. Electron microscopy showed enlarged spherocytic platelets with a disturbed marginal microtubule band and organelle-free zones. Decreased platelet reactivity to physiologic agonists was also noted. However the same mutation was also seen in approximately 10% of normal subjects. Kunishima et al.⁷⁴ studied a Japanese patient with the heterozygous Q43P mutation but found that it did not cause macrothrombocytopenia. Instead, these authors found a second heterozygous R318W mutation predicted to disrupt side chain interactions near the α and β intradimer interface of β1 -tubulin. The authors found that R318W, but not Q43P, led to a 50% reduction in platelet β1-tubulin content. Cultured MKs from the patient showed morphologic changes consistent with a disturbed platelet production; the R318W β-tubulin was localized in punctate structures suggesting that it was forming aggregates. This unstable protein may be essential for the phenotype; while β1-tubulin (-/-) mice are thrombocytopenic and their platelets lose their discoid shape, heterozygotes do not show macrothrombocytopenia.⁷⁵
Mutations in the filamin A gene (FLNA). Heterozygous mutations in the FLNA gene encoding the cytoskeletal protein FlnA are associated with a series of rare X-linked autosomal dominant diseases, the major feature being periventricular nodular heterotopia (PNH).⁷⁶ FlnA is the attachment site for GP1393;bα in the platelet cytoskeleton, helping to maintain thrombus stability at high shear.⁷⁷ Bleeding is an important feature for a cohort of patients with FLNA mutations as is thrombocytopenia and platelet anisotropy.⁷⁸ This was shown to be due to a defective megakaryocytopoiesis, a finding confirmed from studies on a conditional mouse model where FlnA null platelets also showed signaling defects and a reduced shear-dependent platelet accumulation on collagen.⁷⁹ Mice whose platelets possessed intermediate amounts of FlnA also showed macrothrombocytopenia.

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