Page 1903 - Williams Hematology ( PDFDrive )

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

Tachykinins: Substance P and Endokinins A and B LPA. 1519 Mild oxidation of LDL generates LPA, and the LPA component
The tachykinin neurotransmitter substance P induces platelet aggrega- of oxidized LDL in the lipid-rich thrombogenic core of atherosclerotic
tion and the release reaction at micromolar concentrations and enhances lesions exposed during plaque rupture may be an important platelet
aggregation induced by other agonists at lower concentrations. 1506 activator. 1520
Platelets express two seven-transmembrane G-coupled–receptors for In human platelets, LPA elicits shape change, 1521 platelet-
substance P (NK and NK ) and NK has been implicated in mediat- monocyte aggregate formation, 1522 and fibronectin-matrix assembly 1523 ;
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ing the response to substance P. 1507 In addition, an amidated peptide it also potentiates ADP-induced platelet aggregation. LPA signaling
from the C-terminus of the related tachykinins, endokinins A and B pathways couple by activation of the small G-protein Rho, 1521 Src kinase
(GKASQFFGLM-NH ), initiates platelet aggregation. Substance P has activity, and calcium entry, 1524 with little activation of Gq-dependent
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also been identified in platelets and platelets secrete substance P when pathways. 1525 Some of the platelet responses to LPA in whole blood
activated. are attenuated by P2Y and P2Y receptor antagonists, suggesting that
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released ADP may play an important role in mediating aspects of the
response to LPA. 1524 The platelet receptor(s) responsible for LPA signal-
Chemokines: Chemokine Receptors CCR1, CCR3, CCR4, ing are not known.
CXCR1, CXCR4 S1P is a weaker activator of platelets than LPA and requires high
Based on monoclonal antibody binding and/or mRNA expression concentrations (>10 μM) to induce platelet aggregation, 1526 raising the
studies, platelets and/or megakaryocytes have been reported to express possibility that a contaminant or a S1P-derived metabolite may account
the seven-transmembrane G-protein–coupled chemokine receptors for its biologic activity. 1527 S1P elicits platelet shape change, 1528 acti-
CCR1, CCR3, CCR4, CXCR1, and CXCR4 (reviewed in Refs. 762 and vates protein kinases, and stimulates fibronectin matrix assembly. 1523
1508). These receptors may play a role in megakaryopoiesis and plate- Paradoxically, S1P has also been reported to inhibit thrombin- and
let production. In addition, a number of chemokines, in particular PF4 epinephrine-induced platelet aggregation. 1529
(CXCL4), CXCL12, CCL13, and CCL22, have been variably found to be
able to either augment platelet activation and aggregation induced by
other agonists, or to actually fully initiate platelet adhesion, activation, Serotonin
and aggregation. Because high concentrations of the chemokines rela- Platelets serve as the major serotonin (5-hydroxytryptophan [5HT])
tive to plasma concentrations are required to demonstrate these effects, storage site in the circulation because they have the capacity to take
it is unclear what role these receptors play in platelet physiology, but it is it up actively and store it in dense granules. The release of serotonin
possible that local chemokine levels are higher in areas of inflammation. from dense granules during platelet activation may amplify platelet
aggregation and granule release. Serotonergic receptors, which are
seven-transmembrane G-protein–coupled receptors, exist in seven main
Lipid Mediators (Platelet-Activating Factor, Lysophosphat- subfamilies termed 5HT to 5HT . 1530 The receptor that mediates sero-
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idic Acid, and Sphingosphine-1-Phosphate) tonin’s effects on platelet function is of the 5HT subtype and is identi-
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PAF (a mixture of 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocho- cal to the 5HT receptor present in the brain frontal cortex. 1531–1534 The
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line and 1-O-octadecyl-2-acetyl-sn-glycero-3-phosphocholine 1509 ) is a 5HT receptor-blocking compound ketanserin antagonizes serotonin’s
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phospholipid ether produced by platelets, leukocytes, and other cells. stimulatory effects on platelets and neurons. 1535 Two naturally occurring
PAF is a potent platelet agonist and mediator of inflammation. Cellu- amino acid substitutions have been identified in the receptor. 1536 Plate-
lar responses to PAF are mediated by a specific seven-transmembrane lets from patients heterozygous for the H452Y polymorphism have a
G-protein–coupled receptor. 1510,1511 PAF induces G-protein–dependent blunted calcium response when stimulated with serotonin compared to
inhibition of adenylyl cyclase and activation of PLC, 1512 which cause platelets from patients homozygous for H452. 1536 Silent polymorphisms
phosphoinositide turnover, leading to the activation of PKC and an in the 5HT gene (T102C in exon 1 and –1438A/G in the promoter
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increase in intracellular Ca . PAF also indirectly activates PLA , region) have been correlated with nonfatal acute MIs and enhanced
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which causes release of AA from the platelet membrane. 1513 All of these 5HT receptor-mediated small platelet aggregate formation. 1537 Many
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effects contribute to the overall platelet response to PAF. PAF is catabo- studies have been performed correlating platelet serotonin transporter
lized by PAF acetylhydrolase and this enzyme may play an important activity and 5HT receptors with a number of neuropsychiatric dis-
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role in inflammation and atherosclerosis. 1514 orders. 1538–1542 There is some concern, however, about the correlation
LDLs activate human platelets, and oxidized LDLs are more potent between 5HT receptors on platelets and those in the brain. 1543 Hyper-
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platelet activators. One active component in oxidized LDLs is oxidized responsive 5HT receptors have been implicated in the association
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phosphatidylcholine (oxPC ), which increases with diet-induced between depression and increased risk of cardiovascular events. 1544
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hyperlipidemia. oxPC signals through CD36 1325 via phosphorylation Addition of serotonin in micromolar concentrations to plate-
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of the MAPKs p38 and c-Jun N-terminal kinase. 1323 Platelet activation lets in vitro causes elevation of intracellular calcium, PLC activation,
by oxidized LDLs in the absence of hyperlipidemia may also require SR protein phosphorylation, and mild aggregation. 1545,1546 In whole blood,
A. 1324 Increases in levels of oxPC with hyperlipidemia may provide an serotonin does not itself cause platelet aggregation, but it does enhance
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explanation for observations that atherogenic mice have a prothrom- aggregation induced by ADP and thrombin. 1547 Serotonin released from
botic phenotype as indicated in vivo by decreased tail-bleed time and platelets can cause vasoconstriction of blood vessels that have suffered
propensity to thrombosis in response to either ferric chloride or pho- endothelial damage, 1548 further promoting thrombus formation. Inhi-
tochemical injury, and in vitro by increased platelet aggregation. 1325,1515 bition of serotonin’s action has a favorable effect in animal models of
Activated platelets likely contribute to lysophosphatidic acid (LPA) thrombosis and vascular damage, but it is not clear whether the benefit
generation in blood 1516 via lysophospholipase D (lysoPLD)-catalyzed derives from effects on platelet aggregation or vasoconstriction. 1549 Mice
hydrolysis of a lysophosphatidyl choline (LPC). 1517 Autotaxin, initially deficient in serotonin have prolonged bleeding times, suggesting a phys-
identified as a tumor-cell derived motility factor, appears to be respon- iologic role for serotonin in hemostasis. 1550
sible for the majority of lysoPLD activity in serum; it is also responsible A role for serotonin in linking procoagulant proteins to activated
for the formation of LPA from LPC 1518 and release of autotaxin from platelets has been described. Serotonin can attach via a transglutaminase-
platelets may promote tumor cell metastasis through the generation of dependent reaction to multiple substrates, including fibrinogen, VWF,

Kaushansky_chapter 112_p1829-1914.indd 1878 17/09/15 3:30 pm