Page 1881 - Williams Hematology ( PDFDrive )

1856 Part XII: Hemostasis and Thrombosis Chapter 112: Platelet Morphology, Biochemistry, and Function 1857

adherent platelets. In addition to PSGL-1, leukocyte CD24 may also bind to a model in which platelet P-selectin recruits tissue factor-contain-
P-selectin. The transient P-selectin–mediated interactions are stabilized ing leukocyte microparticles to platelet-rich thrombi. Neutrophil-
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by subsequent contacts mediated, in large part, by activation of leuko- derived microparticles express active integrin α β , which can interact
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cyte β integrins. Platelet surface-immobilized and released chemokines with platelets by binding to GPIbα. This, in turn, can initiate platelet P-
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promote firm leukocyte adhesion and arrest by acting through G- selectin expression, which will enhance the interactions with neutrophil
protein–coupled receptors to activate leukocyte β integrins. Platelets microparticles containing the counterreceptor PSGL-1. In mice,
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can synthesize and release PAF, which can activate leukocyte α β . increases in soluble P-selectin levels promote a procoagulant state asso-
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CCL5 and the CXC chemokines ENA-78 and GRO-α, released by acti- ciated with elevated levels of leukocyte-derived microparticles, and
vated platelets, can also activate leukocytes. The chemokine neutrophil- a P-selectin–immunoglobulin chimeric molecule can increase levels of
activating peptide-2 (NAP-2) can be produced by the action of leukocyte leukocyte-derived microparticles in vitro and normalize the bleeding
cathepsin G on β-thromboglobulin secreted by platelets. 762,763 Activated time in hemophilia A mice. 781
α β on leukocytes can interact with platelet GPIbα as well as with Several clinical observations support a potential role for platelet–
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platelet-bound fibrinogen via a region(s) on the γ chain (amino acids leukocyte interactions in vascular disease, including the presence of
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190 to 202, and 377 to 395). Thrombospondin may serve as a bridg- circulating platelet–leukocyte aggregates in patients with unstable
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ing molecule between CD36 (GPIV) receptors, which are expressed on angina and after coronary artery angioplasty ; in the latter situation,
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both platelets and mononuclear cells. Platelets also have intercellular the presence of such aggregates appears to confer a worse prognosis
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adhesion molecule (ICAM)-2 on their surface, which is a ligand for the for ischemic vascular complications. Circulating platelet–leukocyte
leukocyte integrin receptor α β ; although this ligand-receptor interac- aggregates are perhaps the most sensitive indicator of systemic plate-
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tion appears to have only a minor role in platelet–leukocyte adhesion, let activation, reflecting the expression of P-selectin on the surface of
it may be more important in leukocyte tethering. Platelet junctional platelets. Analysis of polymorphisms of PSGL-1 involving variable
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adhesion molecule (JAM)3 has also been suggested as a counterrecep- numbers of tandem repeats indicates that the longer PSGL-1 molecules
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tor for leukocyte α β . The immunoreceptor tyrosine-based activa- are better able to form platelet–leukocyte aggregates; in some, but not
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tion motif (ITAM)-associated receptors GPVI and C-type lectin-like all, studies, the longer molecules were associated with increased risk
receptor-2 (CLEC-2) also promote platelet–leukocyte interactions dur- of some forms of thrombotic vascular disease. 785–790 The S100 calcium-
ing inflammation via their respective counterreceptors matrix metallo- modulated protein family member MRP-14 (also known as S100A9),
proteinase inducer (EMMPRIN) on neutrophils and macrophages and which is abundant in neutrophils and released by activated platelets,
podoplanin on inflammatory macrophages. promotes platelet thrombus, at least in part through CD36. 791
Transcellular metabolism of eicosanoids can result in production Platelets can contribute to both innate and adaptive immunity
of unique products (Fig. 112–10) and leukocytes can modify platelet in several ways. Bacterial endotoxin binding to toll-like receptors can
activation. In a complementary fashion, the intimate relationship activate platelets (see “Toll-Like Receptors 1,2,4,6,9 ”), enhance platelet–
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between leukocytes and platelets allows the latter to contribute to the neutrophil interactions, and promote bacterial trapping by stimulating
inflammatory response, including the release of chemokines that can the production of neutrophil extracellular traps (NETs) composed of
activate leukocytes; PDGF can affect fibroblast and smooth muscle cells; DNA, histones, and enzymes that degrade pathogens. 792–794 The produc-
TGF-β both stimulates and inhibits cellular growth; and PF4 primes tion of NETs confers resistance to a variety of pathogens, including Gram-
1
neutrophils and has antiangiogenic activity. Platelets synthesize the positive (Staphylococcus aureus, Streptococcus pneumoniae, and Group
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cytokine IL-1β, an important mediator of the inflammatory response. A streptococci) and Gram-negative (Salmonella typhimurium, Shigella
Platelets contain FcγIIA receptors that can localize IgG and immune flexneri, and Escherichia coli) bacteria. A number of Gram-positive
complexes, resulting in complement activation. Platelets express CD40L bacteria can activate and aggregate platelets and the platelet immune
on their surface after activation, and this molecule can interact with receptor RcγRIIA, integrin α β , Src, and Syk, along with PF4, ADP,
IIb 3
CD40, a member of the tumor necrosis factor (TNF) receptor family, and TXA all play a role in the process. Platelets release mitochondria,
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on leukocytes and endothelial cells, leading to their activation and their which are related to bacteria in composition, when activated either in
elaboration of a number of proinflammatory molecules 770–772 (see “CD40 microparticles or free into plasma, where they associate with neutrophils
Ligand (CD40L, CD154) and CD40”). Platelet CD40L also promotes and the platelet enzyme PLA2 IIA, which hydrolyzes mitochondrial and
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procoagulant activity in endothelial cells. Finally, platelet–leukocyte bacterial membranes, releasing a variety of proinflammatory molecules,
interactions can promote the generation of reactive oxygen species, but including mitochondrial DNA, arachidonic acid, and lysophospholipids
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platelets can also generate signals to stop their production. 774 that are themselves capable of initiating NET formation. Release of
Platelet–leukocyte interactions may be important in the initiation platelet mitochondria during storage for transfusion has been suggested
of coagulation and fibrin formation through a P-selectin–dependent as being a contributor to platelet-associated nonhemolytic transfusion
pathway. In fact, platelet–leukocyte aggregates facilitate thrombin gen- reactions. 796
eration to a greater extent than either platelets or leukocytes alone. 775,776 Thrombocytopenia is often present in association with bloodborne
Coincubation of platelets and leukocytes generates tissue factor activity, bacterial infections (sepsis) and the severity of the thrombocytopenia
in part, through P-selectin–PSGL-1 interactions. The induction of tis- mirrors the severity of the infection and prognosis. Platelet factor V
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sue factor activity involves both de novo protein synthesis and exposure contributes to resistance to Group A streptococcal infection by pro-
(“deencryption”) of latent tissue factor. The latter may occur by P- moting thrombin generation and fibrin deposition, which may help to
selectin–mediated production of tissue factor containing microparti- wall off the bacteria. Platelets also influence the function of lympho-
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cles from leukocytes. Real-time imaging of platelet thrombus forma- cytes. They enhance cytolytic T-cell proliferation and antibody pro-
tion in vivo indicates that tissue factor accumulates in growing thrombi duction by B cells. Platelets can inhibit the responses of helper T-cells,
before leukocytes become associated with the thrombus. The accumu- and via release of TGF-β , increase regulatory T (Treg) cells. Finally,
1
lation of tissue factor and fibrin formation in thrombi depend on both platelets can bind to malarial-infected erythrocytes and both suppress
platelet P-selectin and PSGL-1. These observations, coupled with the the growth of the parasites and destroy the intraerythrocytic malarial
finding of bloodborne tissue factor antigen in the circulation, has led parasites. 799
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Kaushansky_chapter 112_p1829-1914.indd 1856 17/09/15 3:28 pm