Page 1896 - Williams Hematology ( PDFDrive )

1870 Part XII: Hemostasis and Thrombosis Chapter 112: Platelet Morphology, Biochemistry, and Function 1871

lymph node stromal cells, and the choroid plexus epithelium that can It appears on the surface membrane when platelets are activated, mak-
aggregate platelets. 1247–1250 Its receptor on platelets is CLEC-2, a C-type ing it a useful marker for platelet activation. 310,1224 CD63 colocalizes
lectin-like receptor selectively expressed on megakaryocytes and plate- with integrin α β and CD9 on the surface of activated platelets in a
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lets (approximately 2,000 copies per platelet) that binds podoplanin process that appears to require CD63 palmitoylation. 1263 CD63 is mark-
and the snake venom platelet-activating protein rhodocytin. 1251–1253 The edly reduced or absent from the dense bodies of patients with Herman-
cytoplasmic tail of CLEC-2 contains an atypical ITAM (hemITAM) sky-Pudlak syndrome, 1277 who have oculocutaneous albinism and a
with a single YITL sequence that can be tyrosine phosphorylated by Src defect in platelet dense bodies (Chap. 121). The amino acid sequence of
kinases when platelets are activated. Because CLEC-2 exists as a dimer, CD63 has been deduced from complementary DNA (cDNA) cloning. 1278
it can supply two ITAMS and lead to activation of Syk and, ultimately,
PLCγ . 1254 This signaling system is similar to that of GPVI in combi- CD151 (Also Termed GP27, MER2, RAPH, SFA1, PETA-3, and
2
nation with the FcRγ-chain. Activation of CLEC-2 leads to proteolytic TSPAN24)
cleavage of GPVI and FcγRIIa. 1255 In experimental tumor models, inhib- CD151, a glycoprotein of Mr 27,000 is present on platelets, endothelial
iting the podoplanin/CLEC-2 system reduces metastases. 1256 CLEC-2 cells, and many other cells. 1279–1281 Antibodies to CD151, like those to
interaction with podoplanin on lymphatic endothelial cells, followed by CD9, can initiate platelet aggregation by binding to both CD151 and
platelet activation and CLEC-2-podoplanin clustering, is required for FcγRIIA. 1280 The role of CD151in platelet physiology remains to be
the separation of blood and lymph vessels during development. 1257–1259 firmly established but it may participate with FcγRIIA as a signal trans-
CLEC-2 also plays a role in lymph node development and mainte- duction complex. 1280 CD151 appears to functionally associate with inte-
nance. 1260 HIV-1 can also bind to CLEC-2. grin α β and, in mice, loss of CD151 impairs platelet aggregation, clot
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retraction, 1282 and thrombus formation. 1283
TETRASPANINS TSSC6 (PHMX, PHEMX FLJ17158, FLJ97586, MGC22455,
Tetraspanins are a family of four-transmembrane-domain-containing TSPAN32)
proteins that have conserved Cys residues that form crucial disulfide TSSC6 is a 340-amino-acid tetraspanin that is expressed in marrow,
bonds. The extracellular and intracellular loops in these proteins con- spleen, thymus, and several hematopoietic cell types. It is present in
898
tain many motifs that mediate interactions with other proteins. 1261 platelets and has been reported to interact with integrin α β . Mice
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While the specific function(s) of tetraspanins is not yet clear, these deficient in TSSC6 display a slightly prolonged bleeding time and a
proteins are able to associate with several membrane proteins and have significantly increased rebleeding. 1265 Platelets lacking TSSC6 show
been reported to modulate integrin function, perhaps in part by orga- impaired aggregation and clot retraction.
nizing membrane and intercellular signaling molecules in cholesterol-
associated microdomains distinct from lipid rafts. 1262 CD9, CD63, and
CD151 have juxtamembrane Cys residues that can be palmitoylated and GLYCOSYLPHOSPHATIDYLINOSITOL-
this modification may contribute to assembly of complexes with other ANCHORED PROTEINS (CD55, CD59, CD109,
proteins and localization to lipid microdomains. 1263 Studies in mice PRION PROTEIN)
implicate CD151 and TSSC6 in outside-in signaling of integrin α β . 1264
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Oligomers of tetraspanins are known to facilitate the formation of larger At least five separate platelet proteins are attached to the membrane
complexes of membrane proteins that could serve as scaffolds for sev- through a GPI link. These include proteins involved in complement
eral platelet signaling events. 1265 CD9 is the most abundant platelet regulation (CD55, decay accelerating factor, and CD59, membrane
1284
tetraspanin (approximately 40,000 molecules per platelet), followed by inhibitor of reactive lysis) ; CD109, a Mr 170,000 protein present
CD151, Tspan9, and CD63. 1266 The levels of TSSC6 are not known. on platelets, endothelial cells, hematopoietic cells, and fibroblasts that
carries both ABO oligosaccharides and an alloantigen (HPA-15, Gov)
involved in neonatal isoimmune thrombocytopenia 1285,1286 ; and a Mr
CD9 (5H9; BA2; P24; GIG2; MIC3; MRP-1; BTCC-1; DRAP-27; 500,000 protein of unknown identity. Patients with paroxysmal noc-
TSPAN29) turnal hemoglobinuria (PNH) have abnormalities in the GPI anchor
CD9 is a 228-amino-acid tetraspanin that is present on platelets, endo- and thus variably lack all of the GPI-linked proteins. The diagnosis of
thelial cells, smooth muscle cells, cultured fibroblasts, some lympho- PNH can be established by assessing platelet expression of these pro-
blasts, eosinophils, basophils, and other cells. 1267–1269 It colocalizes with teins. 897,1287,1288 Patients with PNH have been reported to have platelet
integrin α β on the inner surface of α granules in resting platelets and function abnormalities, 1287 raising the possibility that one or more of
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on pseudopods of activated platelets. 1270 Binding of monoclonal anti- these proteins has a role in platelet function, but no specific plate-
bodies specific for CD9 to platelets results in platelet aggregation by let function roles have yet been assigned to the proteins. Of particu-
triggering phosphatidylinositol metabolism via a mechanism that also lar interest is the presence of the normal prion protein, which is a Mr
requires binding to the platelet FcγRIIA receptor. 1271–1273 The platelet 27,000 to 30,000 GPI-linked protein that is both upregulated and shed
activation induced by the binding of such antibodies requires exter- from the platelet surface with platelet activation. 1289–1292 In fact, platelets
nal calcium and results in an association between CD9 and integrin contain the majority of the prion protein present in normal blood.
α β . 1274 CD9 has been proposed to play a role in microparticle release
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from platelets. 1275 Studies in mice lacking CD9 suggest that CD9 is a
negative regulator of integrin α β signaling, as the mice have enhanced TYROSINE KINASE RECEPTORS
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platelet aggregation, fibrinogen binding, and thrombus formation. 1276 Eph Kinases and Ephrin Ligands
Eph kinase receptors comprise the largest family of cell surface-
CD63 (Also Termed Granulophysin and LAMP-3) associated tyrosine kinases with 14 members identified in mammals. Eph
CD63 (Mr 53,000) appears to be present in both lysosomal and dense kinases have a conserved structure consisting of an N-terminal extra-
granule membranes in platelets. 310,1263,1277 CD63 is also present in cellular ephrin-binding domain, two fibronectin type II repeats, and
Weibel-Palade bodies in endothelial cells, the lysosomal membranes intracellular kinase, sterile α motif (SAM), and PDZ binding domains
of a variety of other cells, as well as the membranes of melanosomes. [defined by the first three proteins to display this protein–protein

Kaushansky_chapter 112_p1829-1914.indd 1871 17/09/15 3:29 pm