Page 1870 - Williams Hematology ( PDFDrive )

1844 Part XII: Hemostasis and Thrombosis Chapter 112: Platelet Morphology, Biochemistry, and Function 1845

for fibroblasts. β-thromboglobulin-F NAP2 (CXCL7) binds to CXCR2 only the approximately 5 percent of PAI-1 complexed with vitronec-
340
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and is chemotactic for granulocytes and activates them to undergo tin in platelet α granules is active. Mice deficient in vitronectin have
endocytosis. 339,340,366 Platelet α granules also contain additional chemok- been reported to be protected from, or have a predisposition to develop,
ines that can variably activate leukocytes and platelets. 339 thrombosis, depending on the method of inducing thrombosis. 376–378
The biochemistry of the adhesive glycoproteins contained in α Thrombospondin-1 is unique among the adhesive glycoproteins
granules and others variably present in plasma and extracellular matrix in blood in that it is present almost exclusively inside the platelet. 379–381
is described in Table 112–2 and in other chapters (e.g., Chaps. 113 and It constitutes approximately 20 percent of the released platelet proteins.
125 for fibrinogen and Chap.126 for VWF). Their relative concentra- Thrombospondin-1 is synthesized by megakaryocytes, cultured endo-
tions in α granules varies significantly. Their localization in platelet α thelial cells, and other cultured cells. 382,383 Although integrin α β , GPIb/
IIb 3
granules allows them to achieve high local concentrations when released IX, integrin α β , proteoglycans, integrin-associated protein (CD47 or
V 3
from platelets at the site of vascular injury. IAP), and CD36 (GPIV) have all been implicated as receptors for throm-
Multimerin comprises a family of disulfide-linked homomultim- bospondin, 384–390 CD47 appears to be most important in initiating plate-
ers, ranging in molecular weight from 450,000 to many millions. The let activation by thrombospondin (see “Signaling Pathways in Platelet
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Mr 450,000 multimer is thought to be a trimer of a single subunit of Activation and Aggregation” below). 386,387,391 The phosphorylation state of
either Mr 167,000 or Mr 155,000 that is synthesized in megakary- CD36 (GPIV) may affect its ability to bind thrombospondin. Throm-
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385
ocytes and endothelial cells and stored in the electron-lucent region of bospondin contains an RGD (RGD) sequence, which may contribute to
α granules in platelets and dense-core granules in endothelial cells. It its binding to platelets, but other regions are probably also involved. 381,392
370
colocalizes with VWF in platelets, but not endothelial cells. Although The conformation of thrombospondin varies with the calcium concen-
multimerin’s multimeric structure is similar to that of VWF, the deduced tration of the surrounding environment. Thrombospondin can interact
368
amino acid sequence of its subunit is not homologous to that of VWF. with many other adhesive glycoproteins, including fibronectin and fibrin-
395
The prepromultimerin subunit contains 1228 amino acids. It undergoes ogen, 210,393,394 and it is a component of the extracellular matrix. Throm-
396
glycosylation and proteolysis during synthesis. It is composed of a num- bospondin appears to stabilize platelet aggregates that are formed ; it
ber of domains, including an aminoterminal region that includes an may also act as a negative regulator of angiogenesis, modulate fibrinoly-
RGD sequence, coiled coil sequences, epidermal growth factor (EGF)- sis, and contribute to activation of latent transforming growth factor
like domains, and a carboxyterminal globular head similar to that found (TGF)-β released from platelets (see below in this section). 397,398
1
in the complement protein C1q. Multimerin binds both factor V and Platelets contribute approximately 20 percent of the factor V pres-
factor Va, and all of the biologically active factor V in platelets is bound ent in whole blood, with nearly all of it in α granules. 399–401 Human
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to multimerin. With thrombin activation of platelets, factor V sep- platelet factor V appears to be taken up from plasma rather than being
arates from multimerin, and the higher molecular weight multimerin synthesized in megakaryocytes, which is in stark contrast to the sit-
multimers bind to platelets. Multimerin does not circulate in plasma at uation in mice. When stored in α granules, factor V associates with
an appreciable concentration, but it may act as an adhesive extracellular multimerin. 402,403 Platelet-derived factor V appears to undergo unique
matrix protein. posttranslational modifications and proteolytic activation, resulting
Fibrinogen is concentrated in α granules as judged by the ratio of in resistance to protein C-catalyzed inactivation. 404–406 Evidence from
platelet-to-plasma fibrinogen. Megakaryocytes do not appear to synthe- patients with inhibitors and deficiencies of plasma and platelet factor V
size fibrinogen; instead, it is taken up from plasma by a process that indicate that platelet-derived factor V has an important role in hemo-
371
involves the α β receptor. Because fibrinogen molecules that con- stasis. 399,407,408 Platelets undergo microvesiculation when activated, and
IIb 3
tain altered sequences in the γ chain are not stored in α granules, even the microvesicles, which are rich in factor V, are potent promoters of
when the molecules are heterodimeric (i.e., contain one normal and one coagulation. 409
abnormal γ chain), it is possible that uptake requires simultaneous bind- Protein S (Chap. 114), plasminogen activator-1 (Chap. 135), and
ing of a single fibrinogen molecule to two different α β receptors via α -plasmin inhibitor (Chap. 135) are also contained in α granules and
IIb 3
2
the γ-chain carboxyterminal sequence (see α β in the section “Platelet can be released from platelets. Similarly, tissue factor pathway inhibitor
IIb 3
Membrane Glycoproteins” below and Chap. 121). 371,372 (TFPI; Chap. 114), α -protease inhibitor, and C-1 inhibitor (Chap. 114)
1
The VWF stored in platelet α granules appears to contribute to have also been identified in α granules.
hemostasis because in certain pathologic states it correlates better with Gas6 is a 75-kDa vitamin K-dependent protein that contains γ-
bleeding symptoms than does plasma VWF concentration (Chap. 126). carboxyglutamic acids and is similar in structure to protein S. 410,411 Gas6
VWF is synthesized in megakaryocytes and endothelial cells. The mul- was originally isolated as a growth arrest-specific gene from quiescent
timeric structure of platelet VWF is thought to reflect endothelial VWF fibroblasts, but subsequently was found to enhance platelet aggrega-
412
more nearly than plasma VWF, as higher Mr multimers are present. tion and secretion in response to several agonists. Mice deficient in
Fibronectin is present in α granules, but no clear role in platelet Gas6 have abnormalities in platelet aggregation and are protected from
412
function under normal conditions has been identified for this adhesive experimental thrombosis. Gas6 is present in α granules and secreted
protein. Paradoxically, in murine models fibronectin has been reported with platelet activation. Platelets also express Mer, a tyrosine kinase
to both support platelet thrombus formation and inhibit platelet aggre- receptor for Gas6, and mice deficient in Mer demonstrate both abnor-
gation and thrombus formation 41,373 ; the former effect may be mediated malities in platelet aggregation and protection from thrombosis, but not
by insoluble fibronectin fibrils whereas the latter may be mediated by to the same extent as mice deficient in Gas6. 413,414 Other Gas6 receptors
soluble fibronectin. 374 in the same family as Mer also appear to contribute to platelet thrombus
Vitronectin, which gets its name from its propensity to bind to stability. 413–417
glass, also binds to PAI-1, the urokinase receptor (uPAR), collagen, and Platelet-derived growth factor (PDGF) is a disulfide-linked
heparin; it also forms ternary complexes with serine proteases and ser- dimeric molecule of approximately Mr 30,000 that is mitogenic for
pins in the coagulation and complement systems. It is present in plate- smooth muscle cells. Platelet α granules contain a mixture of the
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375
lets at levels that suggest it is concentrated, but it does not appear to be homodimer PDGF-BB (30 percent) and the heterodimer PDGF-AB
synthesized in megakaryocytes. The binding of PAI-1 with vitronectin (70 percent); the different forms appear to have different functional
419
stabilizes PAI-1 in its active conformation, and it has been proposed that activities. PDGF may play a role in normal cell proliferation, as well

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