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Chapter 125 Molecular Basis of Platelet Function 1883

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shifts; genotype does not necessarily correlate with phenotype. Rare RUNX1 (also called AML1 or CBFA2) that encodes the alpha subunit
mutations result in macrothrombocytopenia (see section on Inherited of the core-binding factor transcription complex. This complex
Thrombocytopenias). regulates expression of genes involved in stem cell proliferation
Defects in the gene for kindlin-3 (FERMT3) or CalDAG-GEFI versus differentiation in hematopoiesis. The loss of this regulation
(RASGRP2) have been reported that prevent activation of αIIbβ3, predisposes to the development of myelodysplastic syndrome and
with subsequent absence of platelet aggregation. Deficiency in AML in approximately 40% of individuals with germ-line RUNX1
kindlin-3 is the basis for leukocyte deficiency-III syndrome, a severe mutations. In some pedigrees, the thrombocytopenia is accompa-
disorder that encompasses defective integrin β2 function in leuko- nied by abnormalities of granule structure or defects in granule
cytes and associated susceptibility to infections and poor wound secretion. 89
healing, as well as severe bleeding.
Paris-Trousseau Thrombocytopenia and Jacobsen
Syndrome
Inherited Thrombocytopenias Paris-Trousseau thrombocytopenia and Jacobsen syndrome are disor-
ders caused by deletions in chromosome 11q23-ter, the severity of
Inherited thrombocytopenias vary significantly in their severity, the syndrome, which includes cardiac and facial defects, depending
platelet morphology, and presence or absence of associated platelet on the size of the deletion. The loss of one copy of the transcription
dysfunction. There are approximately 20 human gene defects known factor gene FLI1 results in macrothrombocytopenia, and platelets
to be associated with inherited thrombocytopenias. In terms of with abnormal α granules and internal membrane structure (see
molecular mechanism, these can best be understood in the context Chapter 124). 89
of megakaryocyte differentiation, maturation, proplatelet formation,
and platelet release (Fig. 125.6; see also Chapter 124). 85,86 GATA-1–Related Thrombocytopenias
These are X-linked diseases associated with anemia, indicating this
transcription factor’s involvement in both megakaryocytic and ery-
Abnormalities of Megakaryocyte Differentiation throid maturation (see Chapter 124). Mutations in GATA-1 that
interfere with binding to its cofactor FOG1 result in dyserythropoi-
Defects in megakaryocyte maturation result in deficiency or absence etic anemia with thrombocytopenia and defects in α granule
of bone marrow megakaryocytes. Known defects include: maturation. 69
Congenital Amegakaryocytic Thrombocytopenia (CAMT) ANKRD26-Related Thrombocytopenia
This is an autosomal recessive disease caused by mutations in MPL, This is the result of point mutations in the 5′-UTR of ANKRD26,
the gene for the thrombopoietin (TPO) receptor. Binding of TPO leading to gene overexpression, dysmegakaryopoiesis, and an increased
to its receptor activates multiple signaling pathways including JAK2/ risk of myeloid malignancies. Some affected individuals also have
STAT, Ras/MAPK, and PI3K. TPO is essential for commitment and evidence of dysregulation of erythroid and myeloid maturation. 90
differentiation in megakaryocytes but also in the erythroid and
granulocytes lineages, as patients with CAMT, although thrombocy- Gray Platelet Syndrome
topenic at birth, develop trilineage bone marrow hypoplasia in the Gray platelet syndrome (GPS) is the result of homozygous mutations
first few years of life. 87 in NBEAL2, a regulator of membrane dynamics and vesicle traffick-
ing, affecting α granule development. The disorder is characterized by
Thrombocytopenia with Absent Radii (TAR) macrothrombocytopenia, absent platelet α granules, splenomegaly,
−/−
This is an autosomal recessive disorder characterized by absent radii and progressive bone marrow fibrosis. 42–44 The Nbeal2 mouse also
91
and isolated thrombocytopenia, also present at birth. In contrast to shows evidence of abnormal megakaryocyte maturation. Recently,
CAMT, platelet counts improve with age and other cell lines are mutations in GFI1B, encoding a transcription factor involved in
unaffected. The cause is a compound inheritance of a low-frequency megakaryopoeisis and erythropoiesis, have been identified in
single-nucleotide polymorphism and a rare null allele in RBM8A, a association a phenotype similar to GPS. Affected individuals have
gene encoding the exon-junction complex subunit member Y14. This macrothrombocytopenia and α granule deficiency, and some have
complex is involved in RNA processing and nuclear export. It is still erythrocyte abnormalities. 92
unknown how this defect affects megakaryocyte maturation, although
it may affect TPO signaling through its receptor. 88
Abnormalities of Proplatelet Formation and
Amegakaryocytic Thrombocytopenia with Radio-Ulnar Platelet Release
Synostosis (ATRUS)
This is the result of heterozygous defects in HOXA11, a member of The central role of platelet cytoskeletal components and their interac-
the HOX gene family of transcription factors involved in embryonic tion with surface membrane receptors in proplatelet formation
development. These patients have thrombocytopenia from birth that and platelet production have been clarified by the identification of
does not improve with time, associated with fusion of the proximal inherited defects in these molecules that are associated with
radius and ulna. 87 thrombocytopenias.
MYH9-Related Disease
Abnormalities of Megakaryocyte Maturation Previously referred to as the May-Hegglin, Sebastian, and Fechtner
syndromes and Epstein anomaly, MYH9-related disease is the result
Defects in differentiation are associated with mutations in specific of autosomal dominant mutations in MYH9, the gene that encodes
transcription factors. Some of these mutations are associated with an NMMHC-IIA. NMM is involved in the generation of energy-driven
increased risk of myeloid malignancies and some are associated with skeletal forces involved in cytokinesis, cell motility, and shape change.
additional functional platelet defects. They are characterized by Affected individuals have macrothrombocytopenia from birth, the
immature or dysplastic bone marrow megakaryocytes. result of branching defects in proplatelets. Branching increases the
number of free proplatelet ends and the number of platelets released.
Familial Platelet Disorder With Predisposition to Acute There also appear to be defects in the timing of platelet release. Some
Myeloid Leukemia MYH9 mutations are also associated with leukocyte inclusions and
Familial platelet disorder with predisposition to acute myeloid the development of progressive renal dysfunction, sensorineural
leukemia (FPD/AML) is the result of heterozygous mutations in hearing loss, and cataracts. 39