Page 1873 - Williams Hematology ( PDFDrive )

1848 Part XII: Hemostasis and Thrombosis Chapter 112: Platelet Morphology, Biochemistry, and Function 1849

as in the development of atherosclerosis, tumor growth, wound repair, Platelet α granules contain a high concentration of TGF-β , an
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and fibroproliferative responses. 420–422 After it was discovered in platelets Mr 25,000 homodimeric protein that promotes the growth of certain
and termed PDGF, other tissues were found to produce the same factor; cells and inhibits the growth of others. 466–469 For example, TGF-β can
thus, despite its name, PDGF is not exclusively derived from platelets. increase thrombopoietin production by marrow stromal cells. In turn,
sis
PDGF is structurally related to the transforming protein p28 of simian thrombopoietin induces both increased megakaryocyte production
425
sarcoma virus, 423,424 and its receptor is in the tyrosine kinase family. and megakaryocyte expression of TGF-β receptors. The interaction of
Recombinant human PDGF-BB (becaplermin) is approved as adjunc- TGF-β with these receptors then results in inhibition of megakaryocyte
tive therapy to improve healing of foot ulcerations in diabetics. 426 maturation. TGF-β also induces synthesis of extracellular matrix pro-
470
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Platelets contain high concentrations of VEGF, an important stim- teins, PAI-1, and metalloproteinases. It has been implicated in wound
ulator of angiogenesis, and can release VEGF after stimulation in vitro healing, malignancy, and tissue fibrosis. In addition, TGF-β has been
471
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and during the hemostatic response to a bleeding time wound. 427–429 reported to enhance platelet aggregation through a nontranscriptional
472
Megakaryocytes express mRNA of the three VEGF isoforms (121, 165, effect. Migration of endothelial cells is inhibited by TGF-β , but it acts
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430
and 189 amino acids), and by immunoblot VEGF protein bands of as a chemoattractant for monocytes and fibroblasts. TGF-β exists in
apparent molecular weights 34,000 and 44,000 are identifiable in plate- three isoforms (TGF-β , TGF-β , and TGF-β ), but platelets contain only
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lets. Platelets and megakaryocytes also express the gene transcript for TGF-β . TGF-β released from platelets can stimulate smooth muscle
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the VEGF receptor termed KDR. Another endothelial growth fac- cells to express and release VEGF, thus perhaps supporting reendotheli-
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tor structurally related to VEGF, VEGF-C, has also been identified in alization after vascular injury. 473
platelets. Platelet levels of VEGF have been reported to be increased TGF-β released from platelets is inactive (latent) because it
433
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in malignancies, and so elevated levels of platelet VEGF may be a can- is complexed with the remaining portion of its precursor protein
cer biomarker. 434,435 Platelet VEGF has also been postulated to play (latency-associated peptide [LAP]). LAP, in turn, is covalently cou-
474
in role in tumor growth and proliferative retinopathy in sickle cell pled to another protein, the latent TGF-β–binding protein-1 (LTBP-1),
436
disease. 437,438 which localizes the complex to the extracellular matrix. Activation
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EGF has also been identified in platelets, but the kinetics of its of latent TGF-β is a complex process that is thought to involve a con-
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release upon thrombin or collagen stimulation differs from that of other formational change in LAP that results in altering its ability to shield
475
granule proteins. 439 the active site in TGF-β . Activation of latent TGF-β can be achieved
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Platelets contain the highest levels of all peripheral tissues of by several different mechanisms, including acidification; proteolysis by
amyloid precursor protein (APP), which contains the sequence for plasmin, a furin-like enzyme, or other enzymes; traction produced by
the self-aggregating 40- to 43-amino-acid-residue peptide, Aβ, that LTBP-1 binding to extracellular matrix and LAP interaction with integ-
has been strongly implicated in the pathogenesis of Alzheimer dis- rin α β or α β ; interaction with thrombospondin-1 or a small peptide
V 8
V 6
ease. 440,441 The isoforms containing the Kunitz protease inhibitor domain derived from thrombospondin-1; or exposure to stirring or shear. 475–479
(APP 770 and APP 751) predominate in platelets. Although synthesized The interaction of LAP with integrin receptors via its RGD sequence
as a membrane protein, platelet APP is cleaved by α-, β-, and γ-secretase probably plays a dominant role as mice with a mutation in this sequence
480
activities, producing all of the fragments produced by neurons, as well have a phenotype like that of TGF-β null mice. The ability of throm-
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as the soluble sAPPα, sAPPβ, and Aβ peptides, and the correspond- bospondin-1 to activate TGF-β is of special interest because both TGF-
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ing remaining C-terminal membrane-associated fragments. 440,442,443 β and thrombospondin-1 are present in α granules. However, data from
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444
Calpain, which is present in platelets, can also cleave platelet APP. mice suggest a minor role for platelet thrombospondin in either TGF-β
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Approximately 90 percent of platelet APP is soluble and stored in α packaging or activation. 481–483 Only a very small percentage of the TGF-
granules, but full-length APP surface expression is increased threefold β released from platelets with thrombin stimulation becomes activated,
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445
by thrombin stimulation. Platelets are the major source of plasma but this amount is sufficient to activate synthesis of PAI-1. 479,481,482,484
sAPPs and Aβ. 443,446 APPs released by platelets are potent inhibitors Based on animals models, TGF-β released from platelets has been
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of factor XIa and IXa, 448,449 and also can inhibit platelet aggregation implicated in promoting tumor metastases and cardiac fibrosis in
447
induced by ADP or epinephrine. In contrast, Aβ appears to enhance response to constriction of the aorta or aortic valve stenosis. 485–487 Active
ADP-induced platelet aggregation and support platelet adhesion. It is TGF-β can bind to three different cell surface proteins, a proteoglycan
possible, but not certain, that plasma Aβ contributes to brain Aβ in (β-glycan), and two serine/threonine kinases. 471,485–488
Alzheimer disease. Patients with Alzheimer disease have been Platelets may also release proteins that affect the uptake of oxidized
441
reported to display altered platelet APP metabolism. 450–455 low-density lipoproteins by macrophages, furnishing another potential
Factor XIII is present in the cytoplasm of platelets; it differs from link between platelet activation and atherosclerosis. 489
plasma factor XIII in having only the “a” subunits (Chap. 113). 456–459
Platelet factor XIII accounts for approximately 50 percent of total blood Exosomes
factor XIII, 456,457 and platelet factor XIII may contribute to the plasma In addition to the contents of α granules, activated platelets release both
460
pool. Upon platelet activation, factor XIII redistributes to the plate- microparticles (see “Platelet Coagulant Activity” below), which are
let periphery where it associates with the cytoskeleton and crosslinks derived from the plasma membrane, and exosomes, which are internal
filamin and vinculin. It may also crosslink thymosin β to fibrin after membrane MVBs. Exosomes are smaller than microparticles (40 to
461
490
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thrombin stimulation and, in concert with calpain, decrease integ- 100 nm vs. 100 to 1000 nm), enriched in CD63 and tetraspanins (see
462
rin α β adhesive function in thrombus formation on collagen. section “Platelet Membrane Glycoproteins” below), and relatively defi-
463
IIb 3
Transglutaminase-mediated conjugation of serotonin to α-granule pro- cient in membrane proteins such as GPIb/IX and platelet-endothelial
teins after platelet stimulation with collagen and thrombin results in the cell adhesion molecule (PECAM)-1. Unlike microparticles, exosomes
generation of a subpopulation of platelets that are coated with fibrino- are not highly procoagulant as judged by their inability to bind proth-
gen, thrombospondin, factor V, VWF, and fibronectin, either directly rombin or factor X, or to present negatively charged phospholipids on
through ligand-receptor interactions or through interactions between their surface. They may, however, contain NAD(P)H oxidase activity,
the serotonin conjugates and platelet surface fibrinogen or thrombo- which has the potential to generate reactive oxygen species that contrib-
spondin (COAT platelets). 464,465 ute to endothelial cell apoptosis in sepsis. 491
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