Page 1895 - Williams Hematology ( PDFDrive )

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

FcγRIIA expression on platelets shows considerable variation P-selectin has a modular structure in which the aminoterminal
among individuals (approximately 600 to 1500 molecules per plate- region has a calcium-dependent lectin domain that binds carbohydrates.
let), and this variation correlates with FcγRIIA-mediated function. 1188 Adjacent to the lectin domain is an EGF domain, followed by nine
This variation in receptor density may explain individual differences repeats that are homologous to complement regulatory proteins (“sushi”
in immune-mediated disorders such as heparin-induced thrombocy- domains), a transmembrane domain, and a cytoplasmic domain. 759,1220
topenia with thrombosis. 1198 An H131R polymorphism within FcγRIIA The cytoplasmic domain contains Ser, Thr, Tyr, and His residues that can
affects the binding of different IgG subclasses. 1199,1200 The H131R poly- be phosphorylated. In addition, a Cys residue becomes acylated with
morphism may also have clinical significance because the R131 allele is stearic or palmitic acid. Alternatively spliced forms of P-selectin may
associated with increased binding of activation-dependent antibodies be produced in which sushi domains are omitted. The selectin family
to platelets. 1201 A variety of associations have been identified between also includes E-selectin (ELAM-1; CD62E), which is expressed on the
the H131ER polymorphism and different aspects of heparin-induced surface of activated endothelial cells, and L-selectin (LAM-1; CD62L),
thrombocytopenia and immune thrombocytopenia, but the data differ which is expressed on the surface of myeloid and lymphoid cells. 1225
from study to study and no consensus has yet emerged. 1202–1207 Soluble P-selectin is present in plasma from humans and mice.
Alternative splicing generates a soluble form of human P-selectin that
Intercellular Adhesion Molecule-2 (CD102) lacks the transmembrane domain. 1226 In mice, at least a portion of solu-
ICAM-2, a member of the immunoglobulin family of receptors, is an ble P-selectin is derived from proteolytic cleavage of surface P-selectin
endothelial cell ligand for the β -integrin α β (LFA-1) on lymphocytes by an unidentified protease. 1227
2
L 2
and myeloid cells. 1208 Approximately 2600 ICAM-2 molecules are pres- Recognition of ligand by P-selectin requires specific carbohydrate
ent on platelets, distributed on the membrane surface and open cana- and protein structures. Fucose and sialic acid are important carbohydrate
licular system. 1208 Platelet ICAM-2 may contribute to platelet-leukocyte components, with sialyl-3-fucosyl-N-acetyllactosamine (SLe ; CD15S) a
x
interactions (see “Platelet–Leukocyte Interactions” below). preferred ligand structure. 756,1228–1230 Myeloid and tumor cell sulfatides
may also act as ligands for P-selectin. 1231,1232 PSGL-1, a mucin-like trans-
FcεRI membrane glycoprotein homodimer (Mr 220,000) expressed on neu-
Platelets express the high affinity IgE receptor FcεRI and appear to par- trophils, monocytes, lymphocytes, and to a small extent on platelets, is
ticipate in both defense against parasitic diseases, including malaria, an important ligand for P-selectin. 1138,1233–1235 Both sulfation of tyrosine
and allergic phenomena. 799,1209–1211 residues contained in an anionic region and branched fucosylation of
O-linked carbohydrates are required for optimal binding to P-selectin.
Junctional Adhesion Molecule-A (A Also Termed F11) P-selectin can mediate the attachment of neutrophils and mono-
JAM-A was identified on platelets by the ability of a monoclonal anti- cytes to platelets and endothelial cells. Thus, neutrophils and monocytes
body directed against the receptor to initiate platelet activation via may be recruited to sites of vascular injury where platelets deposit and
crosslinking to FcγRIIA. 1212–1216 It is phosphorylated during platelet become activated (see “Platelet–Leukocyte Interactions” below). Platelet
activation and loss of JAM-A in a mouse model results in a prothrom- P-selectin can also recruit procoagulant monocyte-derived micropar-
botic phenotype. 1217 JAM-A appears to inhibit outside-in signaling via ticles containing both PSGL-1 and tissue factor to growing thrombi
integrin α β by recruiting Csk, which, in turn, phosphorylates Src at in vivo. 1236 Binding of P-selectin to PSGL-1 on monocytes can trigger
IIb 3
Y529. 1217,1218 It is also able to interact with the integrin α β receptor on tissue factor synthesis 1237 and infusing a P-selectin chimeric molecule
L 1
leukocytes, and in endothelial cells it participates in tight junction for- into mice results in the generation of procoagulant microparticles.
781
mation and leukocyte recruitment and transmigration. 920 In a reciprocal fashion, P-selectin engagement of PSGL-1 may lead to
Junctional Adhesion Molecule-C platelet activation. 1238 Soluble P-selectin may also promote a prothrom-
The JAM-C transmembrane protein has an Mr of 43,000 and 279 amino botic state in humans by increasing tissue factor–expressing micropar-
acids. It contains two C2-type immunoglobulin domains in its extracel- ticles in plasma. Indeed, the risk of future cardiovascular events is
lular domain and three potential tyrosine phosphorylation sites in its elevated in apparently healthy women with the highest levels of soluble
1239
cytoplasmic domain. 767,920 JAM-C is expressed on platelets but not gran- P-selectin.
ulocytes, monocytes, lymphocytes, or erythrocytes. It shares 32 percent In intact blood vessels, the rapid on and off rates of the interactions
homology with JAM-A. Based on monoclonal antibody binding studies, between PSGL-1 on neutrophils and P-selectin on endothelial cells
platelets contain approximately 1600 copies of JAM-C. Platelet JAM-C allows leukocytes to roll on the endothelium, the first step in leuko-
1240
acts as a counterreceptor for leukocyte integrins α β and α β and con- cyte transmigration (Chap. 66). The rapid upregulation of P-selectin
M 2
X 2
tributes to platelet–leukocyte interactions under some conditions. Its after endothelial cell activation allows for a quick response. Platelets
767
precise role in platelet physiology is uncertain, but it has been impli- have been reported to roll on activated endothelium, and this appears
cated in binding CD34 stem cells. 1219 to result from an interaction between endothelial P-selectin and per-
haps either platelet GPIbα 1093,1137 or platelet PSGL-1. 1138,1241 Upon their
corelease from endothelial Weibel-Palade bodies, P-selectin may tether
LECTIN-CONTAINING RECEPTORS ultralarge VWF to the surface of activated endothelium, and thereby
P-Selectin (Also Termed GMP140, PADGEM, and CD62P) promote platelet GPIbα-mediated platelet rolling. 1242
P-selectin, which has a Mr of 140,000, is a glycoprotein present in Genetic and pharmacologic targeting of P-selectin or PSGL-1 in
α-granule membranes in resting platelets that joins the plasma mem- experimental animal models suggests that these receptors may modulate
brane when platelets are activated. 759,1220–1222 Approximately 13,000 P- thrombolysis, sickle cell vasoocclusion, restenosis, deep venous throm-
selectin molecules are detected by antibodies on the surface of activated bosis, cerebral ischemia and infarction, atherosclerosis, metastasis, and
platelets. The expression of P-selectin on circulating platelets has, there- thrombotic glomerulonephritis (reviewed in Refs. 1243 to 1246).
fore, been used as an indicator of their in vivo activation. 1223,1224 It is also
present in the Weibel-Palade body membranes of endothelial cells; as C-Type Lectin-Like Receptor-2
in platelets, it joins the plasma membrane when endothelial cells are Podoplanin is a sialoglycoprotein present on a variety of tumor cells,
activated. 759,1222 lymphatic endothelial cells, kidney podocytes, lung epithelial cells,

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