Page 2119 - Hematology_ Basic Principles and Practice ( PDFDrive )

1882 Part XII Hemostasis and Thrombosis

in vitro evidence of dense and α granule secretion defects with normal
Abnormalities of Platelet Adhesion granule cargo are observed in some forms of familial hemophagocytic
lymphohistiocytosis (FHL). Mutations for genes encoding SNARE
GPIb–IX–V 73 proteins or their regulators have been identified: Munc13-4
79
In Bernard-Soulier syndrome (BSS), mutations in GP1BA, GP1BB, (UNC13D) in FHL3, and Munc18b/syntaxin binding protein 2
or GP9 result in defective platelet surface expression of GPIb–IX–V, (STXBP2) in FHL5. 80
and thus a decreased ability of platelets to adhere to subendothelial
VWF, as well as a decreased in vitro response of platelets to thrombin α Granules
and ristocetin. Missense, nonsense, and frameshift alterations have The classic α granule deficiency, gray platelet syndrome, is discussed
been described 69,74 ; correlation of genotype with the moderate to in the section Inherited Thrombocytopenias. Platelet α granules are
severe bleeding phenotype in BSS is not apparent. The macrothrom- also absent in the multisystem disorder arthrogryposis-renal
bocytopenia that occurs in BSS is discussed in the section Inherited dysfunction-cholestasis syndrome, which is lethal within the first year
Thrombocytopenias. of life. Here, the gene defect is in VPS33B, which encodes a Sec1/
75
The autosomal dominant platelet-type VWD is the result of Munc18 interacting protein considered to be involved in intracellular
gain-of-function mutations in the VWF binding site on GPIbα. vesicular trafficking, or in VIPAS39 (VPS16B), which encodes
Enhanced binding of plasma VWF to GPIbα leads to platelet agglu- VPS33B-interacting protein. While α granules are present in platelets
tination and a bleeding phenotype. In vitro, enhanced agglutination from patients with the autosomal dominant Quebec platelet disorder,
to low-dose ristocetin is observed. Platelet-type VWD is clinically their contents are proteolytically degraded by plasmin generated by
indistinguishable, but genetically distinguishable, from type 2B urokinase-type plasminogen activator (u-PA), abnormally expressed
VWD, caused by gain-of-function mutations in the GPIbα binding due to tandem duplication of PLAU, the u-PA gene. Inappropriate
site of VWF. fibrinolysis after platelet secretion results in symptoms of delayed
bleeding after surgery or trauma; in vitro platelet responses to epi-
Collagen Receptors nephrine are decreased.
There is wide variability in the platelet surface expression levels of
GPVI and α2β1 that is determined by specific haplotypes in GP6 Signaling Pathways
and ITGA2, respectively. While absence of α2β1 expression has not Patients have been identified with apparent congenital disorders in
been observed, there are several reports of patients with a mild bleed- a variety of signaling pathways involving G proteins (G q , G s , G i ),
2+
ing phenotype associated with GP6 mutations, leading to deficiencies cPLA 2 , and PLC, PKC-θ, Ca mobilization, TxA 2 formation
in GPVI expression and decreased in vitro response of platelets to (including COX-1 and thromboxane synthase deficiencies), and
69
collagen. Acquired GPVI deficiency can also occur, with ectodomain granule secretion. However, for the most part, the underlying genetic
shedding (i.e., cleavage) of the receptor from the platelet surface in defects in these patients, who experience mild-to-moderate bleeding,
response to autoantibodies. remain unknown. An insertion mutation in the extra-large Gα s gene
(GNASXL) has been associated with Gα s hyperfunction in platelets
and a bleeding phenotype, neurological problems, and mild skeletal
Abnormalities of Platelet Activation abnormalities. Mutations in PLA2G4A encoding cPLA2 and in
TBXAS1 encoding thromboxane synthase (Ghosal syndrome) have
Soluble Agonist Receptors been described. Gain-of-function mutations in STIM1 resulting in a
Rare patients have been described with defects in the gene for the CRAC channelopathy have been shown in the autosomal dominant
ADP receptor P2Y12 (P2RY12) or in the gene for the TxA 2 TPα Stormorken syndrome, which is characterized by a mild bleeding
2+
receptor (TBXA2R). (There are no reports of patients with a defi- diathesis, thrombocytopenia, and, in resting platelets, elevated [Ca ] i
81
ciency in the P2Y1 ADP receptor.) The defects mimic the effects of and surface PS exposure. The York platelet syndrome, characterized
antiplatelet drugs: for P2RY12, clopidogrel, prasugrel, and ticagrelor by thrombocytopenia, ultrastructural abnormalities in platelet organ-
2+
that block P2Y12; and for TBXA2R, aspirin, which blocks TxA 2 elles, and deficiency of Ca storage in dense granules, has also
formation. As such, decreased platelet responses in vitro to ADP and recently been reported to be a CRAC channelopathy due to gain-of-
the stable thromboxane mimetic U46619, respectively, are observed function mutations in STIM1.
in these patients, who have a mild bleeding diathesis. There has been
a recent first description of an inherited defect in F2RL3, the gene PS Exposure
for the PAR4 thrombin receptor, which is associated with decreased Scott syndrome, in which there is a defect in PS exposure and
expression levels of PAR4 and decreased in vitro platelet responses to thus, platelet procoagulant activity, is associated with mutations
thrombin. 76 in TMEM16F (ANO6); TMEM16F (anoctamin 6) is essential for
2+
82
Ca -dependent PS exposure, but its specific role is not yet clarified.
Cytoskeletal Defects Decreased thrombin generation results in a moderate-to-severe bleed-
These are discussed later in the section on Inherited Thrombo- ing phenotype; in vitro platelet aggregation responses are not affected.
cytopenias.
Dense Granules 77 Abnormalities of Platelet Aggregation
Hermansky-Pudlak syndrome is characterized by oculocutaneous
78
albinism and platelet-dense granule deficiency. The distinct HPS αIIbβ3 83
subtypes arise from defects in nine genes, HPS1, AP3B1 (HPS2), and One of the best characterized platelet function disorders, Glanzmann
HPS3-9, the HPS protein products of which interact in BLOCs that thrombasthenia (GT), results from quantitative or qualitative defects
41
are involved in dense granule biogenesis. Some subtypes are also of the fibrinogen/VWF receptor αIIbβ3, and thus the inability of
associated with pulmonary fibrosis and granulomatous colitis. Patients platelets to aggregate. The bleeding phenotype ranges from mild to
with Chediak-Higashi syndrome have severe immunological defects life-threatening hemorrhage, and in vitro there are absent aggrega-
in addition to oculocutaneous albinism and dense granule deficiency; tion responses to all agonists, while ristocetin-induced agglutination
they have mutations in the LYST gene, the product of which is a is intact. Type I GT is defined as <5% surface-expressed αIIbβ3;
vesicular transport protein. These syndromic dense granule deficien- type II, as 5%–25%; and variant, as normal expression levels of a
cies are associated with mild-to-moderate bleeding; in vitro secretion αIIbβ3 complex that is nonfunctional. Approximately 200 muta-
responses as measured by lumiaggregometry are reduced. tions have been described in the ITGA2B and ITGB3 genes, most
Normal numbers of granules with decreased secretion responses commonly missense and nonsense mutations, and those involving
are indicative of defective granule secretion processes. For example, splice mutations and small deletions and insertions with frame