Page 1898 - Williams Hematology ( PDFDrive )

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

has been reported to initiate platelet activation via binding to CD40, 1349 immune complexes, and when crosslinked by aggregated C1q, it can
the functional significance of CD40–CD40L interactions in platelet initiate platelet activation, aggregation, secretion, and expression of
physiology remains to be determined. CD40L also contains a KGD platelet coagulant activity. 1365,1366 Thus, the binding of C1q monomers
sequence (RGD in mice) that has been implicated in binding to integ- to platelets inhibits collagen-induced platelet aggregation but has lit-
rin α β . In mice, CD40L–α β interactions appear to stabilize throm- tle effect on platelet adhesion to collagen. 1367 C1q multimers support
IIb 3
IIb 3
bus growth, 1348 perhaps by activating receptor mediated signaling. 1350 platelet adhesion and can induce aggregation via activation of integrin
Additionally, integrin α β antagonists block the release of soluble α β . 1368 C1q can also augment platelet aggregation induced by aggre-
IIb 3
IIb 3
CD40L from activated platelets. Both platelet-associated and soluble gated IgG. 1194 The gC1qR may self-associate to form a doughnut-shaped
CD40L may stimulate leukocytes to release proinflammatory cytok- ternary complex. 1369 In addition to binding C1q, this receptor can bind
ines; CD40L may also inhibit endothelial cell migration after vascular S. aureus protein A on endothelial cells, where it functions as a receptor
injury. 1351 The inhibitory effects of CD40L on reendothelialization may for high-molecular-weight kininogen. 1363 It may, therefore, participate
partially explain why elevated levels of soluble CD40L are associated in contact activation.
with higher rates of clinical restenosis. 1345 Finally, platelet CD40L may
modulate adaptive immunity by serving as a costimulatory signal for GMP-33 (Thrombospondin N-Terminal Fragment)
antigen presenting cells. 1352,1353 A Mr 33,000 α-granule membrane protein was initially identified as
an activation-dependent protein that joins the plasma membrane
Fas Ligand, LIGHT and TRAIL when platelets undergo the release reaction. Approximately 4000 anti-
Fas ligand (FasL), LIGHT (also termed TNF superfamily member body molecules directed against GMP-33 bind to resting platelets, and
14), and TNF-related apoptosis-inducing ligand (TRAIL), along with 19,000 bind to activated platelets. 1370 Subsequent studies identified this
CD40L, belong to the TNF family of cytokines. 1354 With activation, plate- antigen as a membrane-associated fragment from the N-terminal of
lets express FasL, LIGHT, and TRAIL on their surface and release solu- thrombospondin. 1371
ble forms of these receptors, 1354–1356 analogous to activation-dependent Leukosialin, Sialophorin (CD43)
CD40L platelet expression and release. The receptor Fas (Apo-1, CD95), Leukosialin, a glycoprotein of Mr 90,000, may act as a ligand for ICAM-
is expressed on a wide variety of normal and malignant cells. Engage- 1. 1372 It is expressed on myeloid and some lymphoid cells. Abnormalities in
ment of Fas by FasL initiates signaling that results in apoptosis, and this leukosialin have been described in Wiskott-Aldrich syndrome (Chap. 121).
process is important in embryonic development, cellular hemostasis,
and immune regulation. 1354 The surface-expressed FasL on platelets is Toll-Like Receptors 1, 2, 4, 6, 9
biologically active and can initiate apoptosis. The soluble form of FasL Toll-like receptors (TLRs) are involved in innate immunity by virtue of
may act as an inhibitor of apoptosis induced by surface-expressed their ability to sense products of protozoa, fungi, viruses, and bacteria,
FasL. 1354 Similarly, platelet-derived LIGHT is biologically active and can including endotoxin (lipopolysaccharide [LPS]), and then activate intra-
initiate inflammatory responses in monocytes and endothelial cells. 1356 cellular signaling pathways to initiate the inflammatory response. 1373
TLRs 1, 2, 4, 6, and 9 have been identified in platelets. 1373,1374 Activation of
Lysosome-Associated Membrane Proteins 1 and 2 (CD107a, TLR-1 and TLR-2 can lead to platelet activation via a GPVI-like mecha-
CD107b) nism with TLR-4 through the nuclear factor (NF)-κB pathway. 1375 All of
LAMP-1 and LAMP-2 are lysosome-associated membrane proteins that the components of the LPS signaling complex, including relatively high
are approximately 30 percent homologous and constitute approximately levels of TLR-4 1376 and CD14, MD2, and MyD88, have been identified
50 percent of lysosomal membrane proteins. 1357 They are integral mem- in platelets. LPS binding to platelets stimulates secretion and potentiates
brane glycoproteins of Mr 110,000 and 120,000, respectively, that are agonist-activation by signaling thru the TLR-4 complex. 1377 LPS binding
contained within lysosomal membranes. 1358 When platelets undergo the to platelet TLR-4 causes release of CD40L 1378 and modulates the release
release reaction, they join the plasma membrane. Each protein has two of cytokines by platelets. 1379,1380 In experimental animal models, TLR-4
extracellular disulfide-bonded loops containing 36 to 38 amino acids. may mediate LPS-induced microvascular thrombosis and thrombocy-
The loops are separated by a region rich in Pro and Ser that shares topenia. 1376,1381 TLR-4–null mice have prolonged times to vasoocclusion
homology with the hinge region of IgA. There are multiple N-linked after vascular injury, but endothelial TLR-4 rather than platelet TLR-4
glycosylation sites on each glycoprotein and they contain more than 60 seems to be more important in supporting platelet thrombus forma-
percent carbohydrate. Among the carbohydrate residues are polylac- tion. 1382 The interactions of LPS, produced by toxigenic E. coli, with
x
tosaminoglycans that may possess sialylated Lewis structures, which platelet TLR-4 has been proposed to contribute to the pathophysiology
are thought to interact with selectins. LAMP-1 and LAMP-2 play roles of hemolytic uremic syndrome. 1378 Ligand binding to platelet TLR-4 also
in control of lysosome fusion in autophagosomes and phagosomes. 1357 promotes platelet–neutrophil interactions, neutrophil activation, and
along with TLR-2, the formation of NETs, which capture and seques-
C1q Receptors ter bacteria from the circulation. 792,1383 Activation of TLR-9 with protein
Platelets have several receptors for C1q, a Mr 460,000 glycoprotein com- adducts leads to Src-dependent platelet activation. 1374
posed of six globular domains attached to a short collagen-like triple
helix. 1359–1361 One is for the collagen-like domain (cC1qR, Mr 60,000 Peroxisome Proliferator-Activated Receptors
to 67,000 nonreduced and 72,000 to 75,000 reduced), and another is Peroxisome proliferator-activated receptors (PPARs) belong to a
for the globular domain (gC1qR, Mr 28,000 to 33,000). 1362,1363 A third nuclear hormone receptor family of ligand-activated transcription fac-
receptor of Mr 126,000 enhances phagocytosis. 1364 C1q circulates with tors. 1384 PPARγ is one of the three PPAR family members and is widely
C1r and C1s as a calcium-dependent complex, but interaction with expressed in white adipose tissue, macrophages, B and T lymphocytes,
immune complexes leads ultimately to dissociation of the complex smooth muscle cells, fibroblasts, and endothelial cells. It has been impli-
and release of free C1q, with its collagen-like domain exposed. cC1qR cated in metabolism, insulin responsiveness, adipocyte differentiation,
has sequence homology to calreticulin and can modulate platelet- immune function, and inflammation. The thiazolidinedione class of
collagen interactions at low collagen concentrations. It may also localize insulin-sensitizing drugs used to treat type 2 diabetic patients act by

Kaushansky_chapter 112_p1829-1914.indd 1873 17/09/15 3:29 pm