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2058 Part XII: Hemostasis and Thrombosis Chapter 120: Hereditary Qualitative Platelet Disorders 2059

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481
at the level of PLC-β , 2 479,480 Gαq, and PKC-θ were identified in mutations in the PLA coding region, leading to S111P and R485H sub-
2
these eight patients. In another study, eight patients were described stitutions. Another report documents twins with a history of gastro-
who had decreased initial rates and extents of platelet aggregation intestinal ulcers, associated with similarly impaired platelet function
494
in response to ADP, epinephrine, and the TXA mimetic U44069 ; associated with a homozygous D575H mutation in PLA (PLA2G4A).
476
2
2
subsequent studies in one patient demonstrated impaired phosphat- These patients had mildly decreased plasma factor XI as well.
idylinositol hydrolysis, phosphatidic acid formation, and pleckstrin
phosphorylation. 482,483 Cyclooxygenase (Prostaglandin H Synthase-1) Deficiency
2
In two related patients described with PLC-β deficiency, platelet Deficient platelet cyclooxygenase (prostaglandin H synthase-1) activ-
2
2
aggregation and secretion were impaired in association with impaired ity leading to impaired platelet function and a mild bleeding disorder
IP and DAG formation, calcium mobilization, and pleckstrin phospho- has been identified in a number of patients. 495–502 Platelets from such
3
rylation following activation with ADP, collagen, platelet-activating fac- patients cannot make thromboxane from arachidonic acid but can make
tor, or thrombin, indicating a defect in PLC activation. These patients it from cyclic endoperoxides (prostaglandin G and prostaglandin H ).
479
2
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had a mild bleeding disorder. Human platelets contain at least seven While some patients have had decreased platelet cyclooxygenase pro-
PLC isozymes and a selective decrease was observed in only the PLC-β tein, others have had evidence of a dysfunctional molecule. 501,502
2
480
isozyme. The decreased platelet PLC-β protein levels were associ-
2
ated with a normal gene coding sequence but with diminished PLC-β Thromboxane Synthase Deficiency
2
mRNA levels in platelets, but not neutrophils, suggesting a hemato- Presumed platelet thromboxane synthase deficiencies have been iden-
484
poietic lineage-specific defect in PLC-β gene regulation. Defects in tified in two families based on the failure of cyclic endoperoxides to be
2
phosphatidylinositol metabolism and protein phosphorylation have converted into TXA . 503,504
2
been described in other such patients, although the primary protein
abnormalities were not defined. 482,483,485–488
ABNORMALITIES OF PLATELET
DEFECTS IN PROTEIN PHOSPHORYLATION: COAGULANT ACTIVITY (SCOTT
PROTEIN KINASE C-Θ DEFICIENCY SYNDROME)
PKC isozymes, a family of serine- and threonine-specific protein
kinases, phosphorylate a wide array of proteins involved in signal DEFINITION AND HISTORY
transduction. PKC enzymes regulate several aspects of platelet func- Activated platelets play an essential role in providing the membrane
tion, including activation of integrin α β receptors, platelet aggrega- surface on which specific blood coagulation reactions occur leading
IIb 3
tion and secretion, and platelet production (Chap. 112). Deficiency of to thrombin generation. 505,506 Patients whose platelets fail to facilitate
a human platelet PKC isozyme (PKC-θ) has been described in a patient thrombin generation are defined as having defects in platelet coagulant
with lifelong mucocutaneous bleeding manifestations, mild throm- activity (PCA) (Chap. 112). Only a few patients have been described
bocytopenia, and markedly abnormal platelet aggregation (including with isolated defects in PCA and normal aggregation and secretion
primary wave) and dense granule secretion in response to multiple ago- responses. 505,507–513 Defects in PCA may also be secondary to abnormal-
nists. 481,489 Agonist-induced phosphorylation of pleckstrin and myosin ities in platelet aggregation, such as in patients with SPD and throm-
light chain were diminished in the patient’s platelets. This subject was basthenia. Patients with isolated abnormalities in PCA are referred to
505
subsequently shown to have a heterozygous mutation in a transcription as having the Scott syndrome after the first patient described in 1979 by
factor, RUNX1 (also termed core-binding factor A2, CBFA2, or AML1), Weiss and colleagues 505,507–510
which has been linked to a familial platelet function defect, associated
with thrombocytopenia and predisposition to acute leukemia 481,490 (see
“Transcription Factor Mutations and Associated Platelet Dysfunction” ETIOLOGY AND PATHOGENESIS
below). Platelet expression of myosin light chain (MYL9) was also The main functional abnormality in the Scott syndrome is the impaired
decreased in this patient. 491 ability of activated platelets to promote coagulation reactions; a sec-
ond abnormality in these patients is a defect in release of microvesicles
DEFECTS IN ARACHIDONIC ACID METABOLISM on cell activation. 514,515 In resting platelets, membrane phospholipids
AND THROMBOXANE PRODUCTION are asymmetrically distributed, with the aminophospholipids phos-
phatidylserine (PS) and phosphatidylethanolamine (PE) concen-
Defects in Arachidonic Acid Release from Phospholipids trated in the inner membrane leaflet, and phosphatidylcholine (PC)
Release of free arachidonic acid from phospholipids, mediated by cyto- and sphingomyelin concentrated in the outer leaflet. Cell activation
solic PLA , is the initial and rate-limiting step in thromboxane synthe- induces phospholipid translocation, with PS moving to the outer leaf-
2
sis upon platelet activation. Several patients have been described with let. This process is regulated by several proteins that are descriptively
abnormalities in the release of arachidonic acid. 469,485,492–494 In general, identified by their functions. They include a “flippase” (i.e., an amino-
their platelets aggregated normally in response to arachidonic acid phospholipid translocase identified as a P4 adenosine triphosphatase
but not to ADP, epinephrine, and/or collagen. In one of these patients [ATPase]), which promotes inward transport of lipids; a “floppase” that
this defect was related to an upstream abnormality in Gαq (see “Gαq regulates outward phospholipid transport (encoded by gene ABCC1);
Deficiency” above). Another patient had the HPS with δ-SPD and and one or more “scramblase” that promotes bidirectional move-
468
abnormal PLA activity. An inherited deficiency in cytosolic PLA ment of lipids between the two layers. Surface expression of PS is
492
506
2
2
has been reported in a patient with recurrent small intestinal ulcer- essential for platelets to accelerate coagulation reactions, in particu-
ation, markedly decreased eicosanoid synthesis (including in throm- lar, activation of the tenase complex leading to the activation of factor X
boxane, 12-hydroxyeicosatetraenoic acid [12-HETE], and leukotriene B ) to Xa and of the prothrombinase complex that converts prothrombin to
4
and impaired aggregation with ADP and collagen but normal with thrombin (Chaps. 113 and 114). Scott syndrome platelets have a defect
493
arachidonic acid. This patient had two heterozygous single-base-pair in PS translocation resulting in decreased binding of factors Va-Xa
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