Page 1901 - Williams Hematology ( PDFDrive )

1876 Part XII: Hemostasis and Thrombosis Chapter 112: Platelet Morphology, Biochemistry, and Function 1877

in response to ADP and that patients with abnormalities in Gαq have a Thromboxane A and Other Arachidonic Acid Metabolites:
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bleeding disorder and abnormal platelet function (Chap. 121). 1415 Acti- Thromboxane Prostanoid Receptor
vation of PLCβ and subsequent phosphoinositide hydrolysis has been The metabolism of arachidonic acid (AA) to TXA is a fundamental
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linked to both shape change and platelet activation. pathway contributing to agonist-induced platelet activation and aggre-
P2X , the third purine nucleotide receptor on platelets is P2X a gation. Many agonists stimulate the release of AA from phosphatidyl-
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member of the P2X family of ligand-gated ion channels rather than a choline (PC) and PE in the plasma membrane. 1444 Most AA is released
G-protein–coupled receptor. 1416 This receptor is predicted to span the by the action of PLA , but some is also released by the concerted actions
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plasma membrane twice and is largely extracellular. 1417 While P2X of PLC and DAG kinase, followed by PLA and perhaps by the action of
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has been described as both an ATP and an ADP receptor, the bulk of PLC followed by the action of DAG lipase. PLA is a cytosolic enzyme,
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current evidence suggests that it is an ATP receptor that is antagonized with multiple isoforms in platelets. 1445 PLA acts on the C2 position of
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by ADP. 1418,1419 Because ATP antagonizes the P2Y receptor, the over- triacylglycerols such as PC and PE to form free AA and the resulting
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all contribution of P2X , which is stimulated by ATP, to platelet acti- lysophospholipid. PLA also converts phosphatidic acid into lysophos-
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vation, is not clear. Nonetheless, ATP is released from platelets upon phatidic acid, which is also a platelet agonist. Some PLA isozymes are
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stimulation with agonists such as collagen 1420 and ATP binding to P2X activated by the rise in intracellular platelet Ca that occurs during
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causes a rapid Ca influx. 1421 However, Ca influx induced by stimula- agonist-stimulated activation, whereas other isozymes are activated in
tion of this receptor alone appears to be insufficient to induce platelet a Ca -independent manner. Studies in mice 1446 and in a patient with
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shape change or aggregation. 1405 It does, however, synergize with the recurrent small intestinal ulcers and platelet dysfunction 1447 have identi-
P2Y platelet ADP receptors. 1421 This synergy is likely caused by the spe- fied cytosolic PLA α as the principal PL responsible for the liberation of
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cific downstream signaling events evoked by ATP stimulation of this the AA that is essential for eicosanoid biosynthesis in platelets. Ligand
receptor, which include Ca influx and MAPK activation. 1420 Support binding to integrin α β activates cytosolic PLA α, perhaps through
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for a biologically important role for this receptor comes from data in one or more intermediary proteins. 1448 2
both mice with targeted deletions of P2X , which have impaired in vivo AA is subsequently metabolized by cyclooxygenase (COX) to
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thrombus formation, 1422 and mice that overexpress P2X , which have a generate PGs and TX and by LOX to generate leukotrienes (LTs) and
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prothrombotic phenotype. 1423 A variant of P2X P(2X1del), which lacks hydroxyeicosatetraenoic acids (HPETEs). The main COX in platelets,
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17 amino acids, has been described in megakaryocyte-like cell lines, 1424 COX-1, metabolizes AA to PGG , which is subsequently converted to
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but its functional role is uncertain. 1418,1419 PGH 1449,1450 TX synthase next converts PGH to TXA , which is spon-
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Several antiplatelet agents inhibit ADP-induced platelet activation. taneously and rapidly converted to the inactive metabolite, TXB . 1451
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Thus, metabolites of ticlopidine, clopidogrel, and prasugrel inhibit the TXA and its precursor, PGH , can both stimulate platelet TX recep-
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P2Y receptor 1425 (Chap. 134), whereas soluble CD39 catabolizes ADP tors to induce platelet aggregation. 1451–1453 An inducible COX (COX-2) is
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and ATP. 1426 present in many cells involved in mediating the inflammatory response
and megakaryocytes, but only trace amounts are present in normal
Epinephrine: α2A Adrenergic Receptors platelets. 1454,1455 COX inhibitors such as aspirin inhibit platelet function
When added to platelet-rich plasma, epinephrine uniquely-initiates by inhibiting COX-1 and decreasing TXA production. 1451 It has been
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a first phase of aggregation without first inducing shape-change; after hypothesized that some patients whose platelets are resistant to aspirin
a plateau period, a second wave of aggregation occurs. The ability of inhibition may have increased amounts of COX-2, which is not as read-
epinephrine to synergize with other agonists, such as ADP, is well doc- ily inhibited by aspirin as COX-1. 1452 Selective COX-2 inhibitor drugs
umented, but there is controversy as to whether epinephrine, in the are associated with increased risk of thrombosis and this is ascribed to
absence of released ADP or TXA , is sufficient to initiate platelet aggre- their inhibition of endothelial cell prostacyclin production without the
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gation. 1427–1429 Epinephrine can cause an elevation in intracellular Ca , compensatory inhibition of TXA production via COX-1. 1456
even in aspirin-treated platelets, 1427 possibly by opening an external TXA is a potent platelet agonist that exerts its effects via inter-
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channel or causing release of calcium from membrane sources 1428,1429 ; action with specific members of the thromboxane prostanoid receptor
it does not appear to mobilize intracellular Ca or generate measur- (TP) family of G-protein–coupled receptors. There are two TP isoforms
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able amounts of IP . Analysis of the purified epinephrine receptor and in human platelets (TPα and TPβ), which arise from alternative splic-
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its nucleotide sequence identified it as a seven-transmembrane, G- ing of exon 3 of the TP gene; TPβ, but not TPα, undergoes agonist-
protein–coupled, α2A adrenergic receptor of Mr 64,000. 1430,1431 It cou- induced internalization. 1457 Although both TPα and TPβ mRNA can be
ples to Gαi family members, primarily Gαz, to inhibit adenylyl cyclase detected in platelet lysates, it appears that TPα is the dominant form. 1458
and thus prevent formation of cAMP. 1432 The reduction in cAMP caused The TXA receptor has been localized to the platelet plasma membrane
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by epinephrine is probably not sufficient, however, to initiate platelet and on sodium dodecylsulfate (SDS)-polyacrylamide gel electrophore-
aggregation, and it is likely that other effectors are required for plate- sis it migrates as a broad band of Mr 55,000 to 57,000, 1459,1460 the range
let activation. 1433–1436 Platelets from a patient with a chronic bleeding a result of variability in glycosylation. 1458 Pharmacologic studies suggest
disorder contained reduced amounts of Gαi1 and displayed impaired the existence of two distinct TXA receptor subtypes based on differ-
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epinephrine-induced aggregation, suggesting that Gαi1 may also con- ing affinities for agonist ligands. The low-affinity binding sites may
tribute to epinephrine-mediated responses. 1437 Polymorphisms of the mediate platelet aggregation and granule secretion, whereas the high-
α2A adrenergic receptor have been associated with enhanced platelet affinity sites seem to be associated with platelet shape change. 1461 Stud-
reactivity and signaling. 1438,1439 ies of TP-deficient mice demonstrate that this gene locus is responsible
The physiologic and pathologic significance of epinephrine-induced for most, if not all, the biologic effects attributed to TXA 2. 1462 Bleeding
platelet activation remain unclear, but there is a possibility that sympa- times in these mice are prolonged, confirming the importance of this
thetic stimulation may contribute to enhanced platelet activation. 1440 pathway in normal hemostasis. Platelet aggregation to collagen, but not
In particular, in animal models, infusion of epinephrine can enhance ADP, is delayed, demonstrating the importance of TXA production to
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platelet thrombus formation and can overcome the inhibition produced the collagen response in platelets. TXA pathways activate Gαq, 1415,1463
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by aspirin. 1441,1442 Increased sympathetic tone may thus account for the Gα12 and Gα13, 1464,1465 Gα11, 1466 and Gαi2. 1467,1468 Activation of Gαq is
resistance to antiplatelet agents during acute coronary syndromes. 1443 essential for aggregation and secretion whereas the Gα12/13-pathways
Kaushansky_chapter 112_p1829-1914.indd 1876 17/09/15 3:30 pm