Page 2082 - Williams Hematology ( PDFDrive )

2056 Part XII: Hemostasis and Thrombosis Chapter 120: Hereditary Qualitative Platelet Disorders 2057

and endosomal trafficking of the receptor leading to its decreased sur- the same polymorphism, but only those individuals inheriting it from
face expression. 462 their father had inducible Gαs hyperfunction and increased platelet
A defect in the P2X purinergic receptor has been described in Gαs protein.
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463
a 6-year-old patient with bleeding manifestations. The patient had Platelet Gαs deficiency has also been described in a patient with
isolated impairment of ADP-induced platelet aggregation and was pseudohypoparathyroidism Ib in association with disturbed imprinting
heterozygous for a deletion of a single leucine in a stretch of four and altered methylation in the GNAS1 gene cluster that encompasses
leucine residues 351–354 in the second transmembrane domain of P2X . the four GNAS1 splice variants, including the Gαs subunit. The Gαs
472
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The mutant protein apparently caused a dominant negative effect on coding sequence was normal. As expected from the deficiency in Gαs
P2X -mediated calcium channel activity. protein, there was decreased platelet cAMP formation upon activation
1
of receptors linked to Gαs. The authors did not indicate whether the
Epinephrine Receptor Defects patient had a bleeding diathesis.
Abnormalities of α-adrenergic receptors or α-adrenergic–specific sig-
nal transduction have been described in several patients, 464–466 but the Gαi1 Deficiency
relationship to bleeding manifestations remains unclear, particularly Platelet Gαi1 deficiency has been reported in association with a bleeding
because responses to epinephrine are blunted even in some otherwise disorder and abnormalities in integrin α β activation, platelet aggre-
IIb 3
normal individuals. Responses to epinephrine are blunted in the QPD. 437 gation, and dense granule secretion upon activation with one or more
473
agonists. In keeping with the known function of Gαi in inhibiting the
activation of adenylyl cyclase and the subsequent increases in cAMP
Platelet-Activating Factor Receptor Defect levels, the patient’s platelets failed to inhibit forskolin-stimulated cAMP
A defect in the platelet-activating factor receptor or platelet-activating levels on activation. Platelet Gαi1 protein was decreased by 75 percent,
factor-specific signal transduction has been reported. 467 whereas other members of the Gαi family (Gαi2, Gαi3, Gαiz) and Gαq
were normal. Although a large subset of patients has been considered as
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GUANOSINE TRIPHOSPHATE-BINDING having a defect in Gi signaling, this is based on abnormal responses
PROTEIN DEFECTS on platelet aggregation and secretion studies to ADP and epinephrine,
and direct evidence at the molecular level to support this conclusion has
GTP-binding proteins are a heterotrimeric class of proteins (consist- not been provided.
ing of α, β, and γ subunits) that link surface receptors and intracellular
enzymes (Chap. 112). Abnormalities involving Gαq, Gαi , and Gαs pro- CalDAG-GEFI Deficiency
1
teins have been described. Three siblings from first cousin parents and severe mucocutaneous bleed-
ing manifestations, had prolonged bleeding times and reduced platelet
Gαq Deficiency aggregation in response to ADP or epinephrine, and to low doses, but not
475
Gαq plays a major role in mediating platelet responses to activation high doses, of a thrombin receptor–activating peptide and collagen.
of G-protein–coupled receptors. One patient has been described with Clot retraction was normal. Whole-exome analysis revealed a homozy-
a selective platelet Gαq deficiency in association with a mild bleeding gous G248W mutation in RAS guanyl-releasing protein-2 (RASGRP2),
disorder, abnormal platelet aggregation and secretion in response to the gene for the protein calcium- and diacylglycerol (DAG)-regulated
a number of agonists, and diminished GTPase activity (a reflection of guanine exchange factor-1 (CalDAG-GEFI), affecting the CDC25 cata-
Gα-subunit dysfunction) in response to platelet activation. 468,469 The lytic domain critical for interacting with GTPases. The platelets demon-
downstream events from Gαq, including Ca mobilization, release of strated decreased Rap1 activation and fibrinogen binding and abnormal
2+
arachidonic acid from phospholipids, and activation of integrin α β adhesion and spreading on immobilized fibrinogen and collagen. These
IIb 3
receptors, were impaired. The Gαq coding sequence in this patient was results support a model of platelet activation in which CalDAG-GEFI
normal, but Gαq mRNA levels were decreased in platelets, suggesting stimulates GTP loading of Rap1 and Rac1 in response to an increase in
a potential defect in transcriptional regulation of the gene. This abnor- intracellular Ca and the activated Rap1 leads to integrin α β activa-
2+
IIb 3
mality appeared to be selective for platelets as the patient’s neutrophils tion and the activated Rac1 enhances platelet spreading. The heterozy-
had normal Gαq protein. 470 gotes were asymptomatic but their platelets had a defective spreading. 475
Gαs Hyperfunction and Genetic Variation in Extra Large Gαs PHOSPHOLIPASE C–β DEFICIENCY AND
Two unrelated families have been described with inducible hyper- 2
471
activity of Gαs. These patients had a bleeding diathesis, prolonged DEFECTS IN PHOSPHOLIPASE C ACTIVATION
bleeding times, variable mental retardation, and mild skeletal malfor- Several investigators have described patients with relatively mild
mations. Platelet aggregation responses to physiologic agonists were bleeding diatheses and impaired platelet aggregation and dense gran-
normal, but the platelets showed increased sensitivity to inhibition ule secretion, despite normal granule stores and the ability to synthe-
by agents (PGE , prostacyclin [PGI ]) that elevate cAMP. Platelet Gαs, size TXA . 445,446,476–478 An early event after stimulating several platelet
2
1
2
which when activated increases platelet cAMP levels and inhibits plate- G-protein–coupled receptors is activation of PLC-β, leading to for-
let aggregation and secretion, was increased in these patients. The Gαs mation of the intracellular mediators IP and DAG (Chap. 112); the
3
2+
gene (GNAS1) has multiple alternative promoters and isoforms as a former mediates Ca mobilization and the latter for PKC-induced
result of alternative splicing, including extralarge Gαs (XLαs). XLαs is protein phosphorylation. Defects in one or more of these responses
imprinted and thus normally only expressed from the paternal allele. has been documented in several patients. In one study of eight
A heterozygous 36-bp insertion and a 2-bp substitution were identified patients with abnormal platelet aggregation and secretion in response
2+
in exon 1 of the paternal XLαs gene in these patients. Because XLαs is to several different receptor-mediated agonists, Ca mobilization
not activated by the usual platelet Gαs-coupled receptors, the mecha- and/or pleckstrin phosphorylation was abnormal in seven patients,
nisms leading to increased cAMP levels and enhanced expression of suggesting that the impaired secretion and aggregation resulted from
Gαs protein is unclear. Of note, 2.2 percent of control subjects also had upstream abnormalities in early signaling events. Specific defects
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