Page 1904 - Williams Hematology ( PDFDrive )

1878 Part XII: Hemostasis and Thrombosis Chapter 112: Platelet Morphology, Biochemistry, and Function 1879

thrombospondin, fibronectin, and α -antiplasmin. These serotonylated physically and functionally to the large G-protein, GαI, 1582 which is of
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proteins then associate to a subpopulation of activated platelets termed note because all known large G-proteins couple to receptors with seven
“coated” platelets, perhaps via interactions with fibrinogen or throm- rather than five transmembrane spanning regions. Further downstream
bospondin. 1550,1551 Tissue transglutaminase in platelets can also catalyze signaling probably involves the activation of tyrosine kinases, including
the addition of serotonin to the small G-proteins Rab4 and RhoA in a Syk, Lyn, and Fak, as well as PLCγ2. 1583 Studies of mice with targeted
reaction that renders them constitutively active and promotes α-granule deletions of CD47 indicate that it may block the inhibitory effects of NO
secretion. 1552 on platelets, 1584 which may contribute to its role in stimulating platelet
The serotonin transporter (SERT), which takes up and releases adhesion to activated endothelium under low shear rates. 1585
serotonin, contributes to platelet stores of serotonin. Expression of How other TSP binding sites on platelets contribute to the over-
SERT is required for normal ADP- and thrombin-mediated aggrega- all response induced by TSP is not clear. CD36 copurifies with several
tion of mouse platelets. 1553 Furthermore, SERT activity is enhanced by tyrosine kinases, including Fyn, Lyn, and Yes. 1315 However, whether TSP
ligand binding to integrin α β . Case reports have suggested an asso- binding to CD36 activates these kinases and whether they then contrib-
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ciation between the use of a serotonin reuptake inhibitor and bleeding ute to the observed platelet response is unknown.
abnormalities. 1554 Reports conflict as to whether these antidepressants TSP also functions as a reductase for VWF; in α granules it appears
may protect from MI or reduce the complications of acute thrombosis. to reduce VWF multimer size. 1586,1587 In contrast, TSP also binds to the
In mice, platelet release of serotonin is essential for liver regeneration A3 domain of plasma VWF, where it competes for ADAMTS-13 bind-
following partial hepatectomy. 1555 ing, thus slowing the rate of VWF cleavage, thus favoring large mul-
timers. 1587 TSP also makes a small, but significant, contribution to the
Vasopressin: V -Type Receptor conversion of latent TGF-β released from platelets to active TGF-β . 1 478
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Vasopressin interacts with platelets to induce shape change, aggrega-
tion, and dense granule release. 1556 These events follow an induced rise Collagen: GPVI and Integrin α β
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in intracellular calcium and PLC activation. 1557 The platelet binding site Upon vascular injury, collagens in the subendothelium become exposed
is classified pharmacologically as a V -type receptor, 1558 and radiola- to flowing blood and promote both platelet attachment and activation,
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beled vasopressin binds with a K of 1 to 10 nM. 1559 Unlike the case thereby contributing to normal hemostasis. Collagen is also one of the
D
with V receptors that activate adenylate cyclase, the V receptors appear most thrombogenic substances in atherosclerotic plaques, and upon
1
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to activate PLC, 1560 perhaps via coupling through Gαq11. 1561 There are plaque rupture it is believed to contribute to platelet aggregation and
fewer than 100 binding sites for vasopressin per platelet, 1562 and there is thrombus formation, leading to ischemic damage (Fig. 112–17). 1588 The
controversy as to whether physiologic concentrations of vasopressin are types of collagen present in the subendothelium include: I, III, IV, V,
sufficiently high to activate platelets directly 1563,1564 ; even if vasopressin VI, VIII, and XIII, 1589 the most abundant being types I and III (greater
does not directly activate platelets, it may be able to enhance platelet than 95 percent). Under conditions that mimic physiologic blood flow,
activation induced by other agonists. Vasopressin V receptor antago- platelets adhere tightly to collagen types I, III, and IV, weakly to types
1a
nists inhibit vasopressin-induced platelet aggregation. 1565,1566 VI, VII, and VIII, and not at all to type V. However, under static condi-
tions, platelets can adhere to types I to VIII. 1335 Collagens are normally
Angiotensin II: AT1-Type Receptor acid insoluble fibers, but can form spiral microfibrils when subjected to
Platelets express angiotensin II (AngII) AT1-type receptors. 1567 AngII proteolysis. Differences in the nature of the collagen surface influence
treatment of platelet-rich plasma results in shape change but not plate- its recognition by platelets. 1590
let aggregation. 1568,1569 Infusion of AngII into normal volunteers results Collagen-induced platelet activation probably involves multiple
in platelet activation as assessed by plasma β-thromboglobulin levels receptors, most notably GPVI and integrin α β , with indirect activa-
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and platelet surface expression of P-selectin and fibrinogen binding tion of PAR-1 via activation of MMP-1. 1390 GPVI is a Mr 62,000 gly-
sites. 1570 Certain AT1 receptor antagonists, such as losartan and irbe- coprotein from the immunoglobulin superfamily 1591–1594 that functions
sartan, competitively inhibit TXA receptors on platelets. 1569,1571,1572 AT1 in concert with the FcRγ-chain, with the latter initiating intracellular
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receptor antagonists stimulate NO release from isolated platelets. 1573 In signaling. 804,1167,1168,1595–1598 Other collagen receptors on platelets include
hypertensive rats treated with losartan, platelet function appears to be CD36 1309 and a Mr 65,000 protein termed GP65. 1599 The I (inserted)
attenuated, 1574 but data in humans on the effects of administering AT1 domain in the α subunit of integrin α β is homologous to a number of
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receptor antagonists are inconsistent. 1575–1578 collagen-binding domains in other proteins and mediates adhesion of
the receptor to collagen. Integrin α β recognizes spiral microfibrils, but
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Thrombospondin: Integrin-Associated Protein (Cd47) not the acid insoluble form of collagen in which the monomers assume
Thrombospondin (TSP), a large disulfide-bonded trimer (subunit Mr a banded pattern. 1590 The potential interrelation of all of the collagen
160,000), is both a platelet α-granule protein and an extracellular matrix receptors is unknown, but GPVI appears to be responsible for platelet
protein present in the subendothelium. TSP is rapidly released from interactions with insoluble collagens and GPVI and α β work in con-
2 1
platelets upon thrombin stimulation. In addition to its role as an adhe- cert to recognize collagen spiral microfibrils, perhaps by assembling
sive protein, TSP also functions as an agonist to stimulate integrin α β - intracellular proteins into complexes. 964,1600,1601
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mediated platelet aggregation. 386,1579 Multiple potential TSP receptors GPVI exists as both monomer and dimer in a stable physical com-
are present on platelets, including CD36, integrins α β and α β , and plex with the dimeric FcRγ-chain; FcRγ-chain is absent from GPVI-
V 3
IIb 3
integrin-associated protein (termed CD47). Of these receptors, CD47 deficient platelets. 1168,1171,1180 The tertiary structure of GPVI revealed
is most strongly implicated as the major signaling receptor in response a dimeric structure with parallel orientation of the collagen binding
to TSP. CD47 was first discovered as a protein that copurifies with inte- domains, separated by a distance (5.5 nm) that matches the orientation
386
grins, including integrins α β , α β 1580 and α β . 1581 The sequence of of the collagen triple helix. 1596 Molecular docking studies suggested that
IIb 3
V 3
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CD47 indicates that it has a single immunoglobulin-like extracellular collagen interacts with a shallow groove on the surface. The addition of
domain, five membrane spanning regions, and a short cytoplasmic either collagen or an antibody that can crosslink GPVI induces tyrosine
tail. 391,1579,1580 CD47 probably generates signals independent of integrins phosphorylation of the FcRγ-chain. 1180 The kinases contributing to this
and affects integrin function via downstream effects. CD47 couples event are probably Fyn and/or Lyn. 1041,1104,1602 Tyrosine phosphorylation

Kaushansky_chapter 112_p1829-1914.indd 1879 17/09/15 3:30 pm