Page 1897 - Williams Hematology ( PDFDrive )

1872 Part XII: Hemostasis and Thrombosis Chapter 112: Platelet Morphology, Biochemistry, and Function 1873

domain, post synaptic density protein (PSD95), Drosophila disk large to agonists via signal transduction mediated in part by Src kinases and a
tumor suppressor (Dlg1), and zonula occludens-1 protein (zo-1)]. A MAPK. 1323–1325 The variability in platelet CD36 expression may account
total of eight ephrins have been identified that serve as cell-surface lig- for the variability in platelet hyperreactivity in response to elevated lev-
ands for the Eph kinases. In general, Eph A kinases recognize ephrins els of oxidized LDL. 1326 CD36 can also mediate microparticle binding
that contain a GPI anchor (ephrin A family), while Eph B kinases bind to platelets, which augments platelet-mediated thrombosis in model
to ligands with a transmembrane domain (ephrin B family). The Eph systems. 1327 Thus, CD36 has been reported to contribute to athero-
receptors and the ephrins appear to signal bidirectionally at sites of genesis, diabetes, the metabolic syndrome, angiogenesis, and inflam-
cell-to-cell contact. Platelets contain Eph kinases EphA4 and EphB1, mation. 1328–1331 CD36 also interacts with the S100 calcium-modulated
and their ligand ephrin B1, as well as EphB2. 276,1293 Messenger RNA for protein family member myeloid-related protein (MRP)-14 (also known
ephrinA3 has also been detected in platelets, but confirmation of the as S100A9), which can be released from activated neutrophils and plate-
presence of ephrinA3 protein in platelets is lacking. Forced clustering lets. It has been proposed as a platelet receptor for thrombospondin 1332
of either Eph kinases or ephrins in platelets promotes cytoskeletal reor- and collagen, 1333,1334 but the functional significance of these interactions
ganization, adhesion, granule secretion, and Rap1b activation in con- remains unclear because individuals who lack CD36 on an inherited
cert with other platelet stimuli. 1293,1294 Eph kinase–ephrin interactions basis (Nak -negative) do not have a bleeding disorder 1335 (Chap. 121).
a
may stabilize platelet aggregates and thrombus formation after platelet– CD36 may play a role in the thrombospondin-mediated interaction
platelet contact has occurred. 276,1295 reported between platelets and sickle erythrocytes, 1336 apoptosis, innate
immunity, and in the binding of Plasmodium falciparum-infected ery-
Thrombopoietin Receptor (c-mpl, CD110) throcytes to endothelial cells and monocytes. 1310,1314
The thrombopoietin receptor (c-mpl; Mr 80 to 85,000) is expressed at
low levels on platelets (approximately 25 to 224 per platelet) and binds Scavenger Receptor-BI (SCARB1; CLA-I)
thrombopoietin with high affinity. (K approximately 0.50 nM). 1296–1299 The class B SR-BI (CLA-I) is related to CD36 and is expressed on plate-
D
Steady-state plasma levels of thrombopoietin are maintained, in part, lets, endothelial cells, and hepatocytes. 1313 It transports the cholesteryl
by platelets and megakaryocytes, which bind thrombopoietin via the esters from high-density lipoprotein (HDL) cholesterol and facilitates
thrombopoietin receptor and then internalize and degrade the growth bidirectional flux of free cholesterol between cells and lipoproteins.
factor. Additional mechanisms for regulation of thrombopoietin levels Oxidized, but not unoxidized, HDL can inhibit platelet aggregation via
have been described (Chap. 111). Although its major function is to stim- binding to SR-BI. 1337 SR-BI has many other lipid ligands, however, and it
ulate megakaryocyte growth and maturation (Chap. 111), thrombopoi- is uncertain how these interact under physiologic conditions. A number
etin also is able to sensitize platelets to activation by agonists. 1300–1305 of mutations are associated with elevated HDL levels. 1338 A heterozygous
Mutations of the receptor have been associated with inherited throm- missense mutation has been associated with increased platelet unester-
bocytopenia (Chap. 117) and myeloproliferative neoplasms (Chaps. 83 ified cholesterol and both increased and decreased platelet function. 1338
to 85). 1306,1307 It can also contribute to hematopoiesis through effects on Mouse studies indicate that disrupting the SR in nonhematopoietic
hematopoietic stem cells and other progenitors. tissues can affect platelet function via alterations in plasma lipids and
alterations in the platelet SR can protect against hyperactivity induced
by increased platelet cholesterol content. 1326
SCAVENGER RECEPTORS
CD36 (GPIV)
CD36 (GPIV) is a Mr 88,000 glycoprotein that is highly, but variably, MISCELLANEOUS
expressed on platelets (approximately 20,000 copies per platelet). 1308–1313 CD40 Ligand (CD40L, CD154) and CD40
The nucleotide sequence of CD36 (GPIV) cDNA encodes a protein of CD40 ligand (CD40L, CD154) is a trimeric transmembrane protein
471 residues with a predicted Mr of 53,000 and 10 potential N-linked (Mr 33,000) of the tumor-necrosis family that localizes to α granules
glycosylation sites, 1314 accounting for the difference between predicted in resting platelets and rapidly appears on the surface of platelets upon
and experimentally determined Mr. It is unusual in having two putative activation. Within minutes to hours of platelet activation, an Mr 18,000
transmembrane domains and two short cytoplasmic tails. The cytoplas- fragment of CD40L is released from the platelet surface, perhaps medi-
mic regions may associate with intracellular tyrosine kinases of the Src ated in part by matrix metalloproteinase (MMP-2) bound to integrin
family and undergo phosphorylation. 1315 Antibodies to CD36 (GPIV) α β . 1339 This soluble form of CD40L circulates as a trimer. The bulk
IIb 3
have been reported to produce neonatal alloimmune thrombocytopenia of soluble CD40L in plasma is derived from activated platelets and,
(Chap. 117). 1316 Biochemical data suggest that it may form dimers and hence, can serve as a marker for platelet activation in vivo. Elevated
multimers. 1317 Increased platelet surface expression of CD36 (GPIV) has levels of soluble CD40L are observed in acute coronary syndromes, fol-
been described in patients with myeloproliferative neoplasms. 1318 CD36 lowing percutaneous coronary intervention, in the setting of coronary
(GPIV) is also expressed on phagocytic cells (with the exception of artery bypass surgery, and in peripheral vascular disease 1340 (reviewed
neutrophils), fat and muscle cells, cardiac myocytes, and microvascular in Refs. 1341 and 1342). Soluble CD40L activates neutrophil integrin
endothelial cells. The phosphorylation status of the extracellular region α β , enhances neutrophil adhesion, and induces the neutrophil oxida-
M 2
of the protein may control its ligand-binding properties, 1319 offering a tive burst. 1343 Moreover, elevated levels of soluble CD40L are associated
potential explanation for some of the variable results obtained under with recurrent cardiovascular events in the setting of acute coronary
different conditions. 1308,1319,1320 syndromes 1340,1344 and restenosis following percutaneous coronary inter-
CD36 (GPIV) plays an important role in long-chain fatty acid vention. 1345 CD40L and, to a lesser extent, its counterreceptor CD40
transport in the heart, fat, and muscle, and may contribute to athero- have been implicated in the progression of atherosclerosis in animal
sclerosis and insulin sensitivity. 1321,1322 Oxidized low-density lipopro- models. 1346,1347
teins (LDL), which can be produced by the effects of endothelial cell The extracellular portion of CD40L binds to CD40, a Mr 48,000
or platelet nitric oxide (NO) on LDL, bind to CD36 and, perhaps in transmembrane receptor. Approximately 600 to 1000 copies of CD40
concert with scavenger receptor (SR)-A, can increase platelet reactivity are present on both resting and activated platelets, 1348 and while CD40L

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