Page 1894 - Williams Hematology ( PDFDrive )

1868 Part XII: Hemostasis and Thrombosis Chapter 112: Platelet Morphology, Biochemistry, and Function 1869

that under certain circumstances PECAM-1 might be a costimulatory thrombosis in some but not all experimental models. GPVI and FcRγ-
agonist, working in concert with platelet integrin α β . 1161 Moreover, chain appear to play important roles in ferric chloride-mediated arte-
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mice lacking PECAM-1 can undergo normal inside-out activation rial thrombosis in mice, but not in laser-induced thrombosis, perhaps
of integrin α β , but have a partial defect in integrin α β -mediated because the former, but not the latter, injury elicits collagen exposure
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outside-in signaling. 1162 PECAM-1 crosslinking may also lead to GPIb along the damaged vessel. Inherited and acquired defects in human
internalization, resulting in decreased platelet adhesion. 1163 platelet GPVI have been reported (Chap. 121) and the associated bleed-
In endothelial cells, PECAM-1 is localized to the contact areas ing disorders have been variably described as mild to severe. 1172–1176 Two
between endothelial cells, in the lateral border recycling compartment, alternatively spliced forms and several polymorphisms have been iden-
where it is involved in controlling stimulus-specific transmigration of tified for GPVI and variably linked to alterations in platelet function or
leukocytes. 1155,1164 It appears to be capable of both homotypic and het- risk of thrombotic disease. 1177,1178
erotypic interactions, with the latter mediated by CD177 on neutrophils
(and perhaps glycosaminoglycans, integrin α β , or CD38) interact-
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ing with the fifth or sixth PECAM-1 immunoglobulin domain. 1155,1165 Fc Receptor γ-Chain
PECAM-1 engagement triggers signaling and leukocyte integrin The FcRγ-chain 1179 exists as a homodimer of Mr 20,000 that physically
receptor activation that facilitates transmigration, with activation of and functionally associates with GPVI 1180 and GPIb/IX. 1102 In mouse
the laminin receptor, integrin α β , of particular importance. Endothe- platelets, the absence of FcRγ-chain results in lack of surface expres-
6 1
lial PECAM-1 is also important in maintaining vascular integrity and sion of GPVI. The FcRγ-chain, along with FcγRIIA, are the only known
endothelial and leukocyte PECAM-1 mediate both proinflammatory platelet proteins with ITAMs. 1104 Phosphorylation of the ITAM domain
and antiinflammatory phenomena in model systems. 1155 serves to recruit proteins with Src homology 2 (SH2) domains, which
are essential for collagen-mediated signaling through the GPVI/FcRγ-
Triggering Receptors Expressed on Myeloid Cells–Like chain pathway. 1041,1104,1181 The FcRγ-chain may also contribute to GPIb/
1035,1102,1105
Transcript-1 IX-mediated intracellular signaling after VWF binding.
Triggering receptors expressed on myeloid cells (TREM)-like transcript-1
(TLT-1) is a receptor whose external domain is homologous to those in Fcγ Receptor IIA (FcγRIIA, Also Termed CD32)
the family termed TREM. Like those receptors, it contains a single V-set The FcγRIIA is a low affinity immunoglobulin receptor of Mr 40,000
804
immunoglobulin domain, but its cytoplasmic domain is much longer, is that is widely distributed on hematopoietic cells. Three different
palmitoylated and carries a canonical ITIM capable of becoming phos- mRNA transcripts (A, B, and C) make similar FcγRIIA molecules 1182 and
phorylated and binding the Src homology-containing protein, tyrosine these are preferentially expressed on different cells. FcγRIIA contains an
phosphate-1 (SHP-1). 627,1166 The phosphatase can then dephosphorylate ITAM domain and thus may be important for signaling by its associated
signaling molecules, leading to inhibition of platelet activation. PECAM-1 proteins, including GPIb and select integrins, as well as through direct
has a similar ability to bind SHP-1. TLT appears to be restricted in expres- stimulation by immune complexes. Crosslinking of FcγRIIA initiates
sion to platelets and megakaryocytes. It is primarily in α-granule mem- tyrosine phosphorylation, PI metabolism, activation of PLCγ , calcium
2
branes in resting platelets and joins the plasma membrane when platelets signaling, and cytoskeletal rearrangements. 960,961 FcγRIIA appears to be
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are activated. in close proximity to the GPIb/IX/V complex in lipid rafts, and signal
transduction that accompanies VWF binding to GPIb may be mediated
GPVI at least in part through FcγRIIA. 885,971 FcγRIIA is also be important in
GPVI is a Mr 62,000 transmembrane glycoprotein of 316 amino mediating integrin α β outside-in signaling, including effects on plate-
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acids. 18,804,1167,1168 It belongs to the immunoglobulin superfamily, let spreading, clot retraction, and thrombus formation. 1183,1184 Platelet
and is the major platelet signaling receptor for collagen. It may also 12(S)-lipoxygenase (LOX) is required for platelet activation mediated
mediate platelet interactions with monocytes by binding the ligand by FcγRIIA. 1185
EMMPRIN. 1169 GPVI on the platelet surface exists in a complex with The FcγRIIA on platelets may bind immune complexes generated
Fc receptor (FcR) γ-chain. Because the latter is a dimer, two GPVI mol- in certain diseases, and by engaging these complexes the platelets may
ecules associate with one FcR γ-chain, forming a high-affinity com- become sensitized to other stimuli. 1186–1188 It may also provide a second
plex. 1168 The GPVI extracellular region contains two immunoglobulin binding site for antibodies that bind to platelets via their antibody-
C2-like domains and its transmembrane domain contains an Arg resi- binding site (see “CD9” below). This second interaction can potentially
due that is essential for association with the FcRγ-chain. The 51-amino- lead to bridging between platelets, with the antibody binding to an anti-
acid cytoplasmic domain contains a proline-rich sequence that binds gen on one platelet and an FcγRIIA receptor on another platelet. 1189 It is
SH3 (Src homology 3) domains of Src family tyrosine kinases. GPVI also possible that antibodies can bind to both an antigen and an FcγRIIA
signals through the FcRγ-chain, which contains an ITAM. An unpaired on a single platelet. These interactions can lead to platelet activation
thiol in the cytoplasmic tail of GPVI can undergo oxidation, resulting through engagement of FcγRIIA, followed by crosslinking of FcγRIIA
in homodimer formation, 1170 required for high-affinity interactions with receptors, which can lead to tyrosine phosphorylation, PI metabolism,
collagen peptides and GPVI-mediated signaling. 1171,1172 Resting platelets activation of PLCγ , calcium signaling, and cytoskeletal rearrange-
2
have approximately 29 percent of their GPVI molecules in dimers and ments. 1190,1191 This type of interaction appears to play an important role
interactions with CRPs or thrombin activation increase the percentage in heparin-induced thrombocytopenia (Chap. 117). FcγRIIA under-
of GPVI in dimers. 1171 When GPVI binds collagen, the ITAM domain of goes proteolysis when platelets are activated and FcγRIIA proteolysis
the FcRγ-chain becomes phosphorylated by the Src kinases Fyn and/or has been proposed as an assay for heparin-induced thrombocytope-
Lyn, resulting in the formation of large complex of signal-transducing nia. 1192,1193 Cooperation between FcγRIIA and C1q receptor has been
proteins (for a discussion of the role of GPVI as a receptor for collagen, reported. 1194 A variety of viruses and bacteria can interact with, and acti-
see “Signaling Pathways in Platelets” below.). 1041,1104 GPVI is required for vate platelets and this is variably mediated by FcγRIIA, with or without
stable platelet thrombus formation on collagen surfaces in vitro. Mice immunoglobulin. 795,1195,1196 FcγRIIA may also contribute to cancer cell
lacking GPVI have a relatively mild phenotype and are protected from activation in platelets. 1197

Kaushansky_chapter 112_p1829-1914.indd 1869 17/09/15 3:29 pm