Page 1880 - Williams Hematology ( PDFDrive )

1854 Part XII: Hemostasis and Thrombosis Chapter 112: Platelet Morphology, Biochemistry, and Function 1855

PLATELETS AND THROMBOLYSIS The effects of fibrinolytic agents on platelets are similarly complex.
For example, there is considerable evidence that fibrinolytic agents
The interactions between platelets and the fibrinolytic system are com- can activate platelets soon after administration, 703–709 via either a direct
714
plex; Table 112–3 contains a partial listing of reported findings. 680–684 effect of plasmin, 710–713 perhaps acting on PAR-4 or an indirect effect
Both profibrinolytic 398,685–692 and antifibrinolytic 693–701 effects of platelets through the paradoxical generation of thrombin. 683,715–718 Interpretation
have been described, and so it is difficult to predict the net effect. Since of the latter studies are complicated by the ability of tissue plasminogen
platelet-rich thrombi are known to resist thrombolysis in animal models, activator to release fibrinopeptides from fibrinogen, one of the biomark-
the antifibrinolytic effects of platelets appear to predominate in vivo. 702 ers used to assess thrombin activation. 719
Stimulation of platelets by thrombolytic agents may prolong the
time required for reperfusion of thrombosed blood vessels and may
TABLE 112–3. Platelets and Thrombolysis contribute to reocclusion after successful reperfusion. 680,720 In animal
Profibrinolytic effects of platelets models and in humans, potent antiplatelet agents can, in fact, speed
Tissue plasminogen activator (t-PA) and single-chain urokinase- reperfusion, abolish reocclusion, and diminish the size of myocardial
type t-PA identified on or in platelets. infarcts. 721–723 In human studies, the benefits of combining integrin α β
IIb 3
antagonists with fibrinolytic agents in enhancing coronary thromboly-
Unactivated platelets bind plasminogen, and binding is enhanced sis have been counterbalanced by an increase in major hemorrhage.
724
by thrombin.
Combining a potent integrin α β antagonist with a reduced dose of
IIb 3
Thrombospondin, a plasminogen-binding protein, is expressed a fibrinolytic agent in acute ST-elevation MI when patients are rapidly
on the surface of platelets after activation. treated with percutaneous coronary intervention has demonstrated evi-
Activation of plasminogen by t-PA is enhanced by platelets. dence for more rapid reperfusion, but clinical benefit has been variable
and bleeding has been increased. 725,726 In experimental models of stroke,
Clot lysis is enhanced by platelets in some model systems.
paradoxically, early treatment with integrin α β antagonists reduces
IIb 3
Antifibrinolytic effects of platelets the hemorrhage associated with thrombolytic therapy, perhaps by pre-
Plasminogen activator inhibitor-1 and α -antiplasmin are present venting platelet aggregation in the microcirculation and the release of
2
in platelet granules. agents that can damage the vasculature and diminish its integrity. 727–729
In human studies, however, a potent integrin α β antagonist given
Platelets contain protease nexin-1, a serpin that inhibits plasmino- 730,731 IIb 3
gen activators and plasmin. alone did not improve clinical outcomes.
With prolonged use of thrombolytic agents, inhibition of plate-
Platelets contain factor XIII, which can crosslink fibrin, making let function can occur via a variety of mechanisms. 102,707,708,732–744 These
it resist fibrinolysis, and can crosslink α -antiplasmin to fibrin, effects may contribute to some of the hemorrhagic phenomena observed
2
enhancing its antifibrinolytic effects.
with this therapy. One proposed mechanism is that the thrombolytic
Platelets contain tissue factor pathway inhibitor-2, which inhibits agents make platelets refractory to further stimulation by agonists.
tissue plasminogen activator.
Platelet α β can bind plasma factor XIIIa directly or indirectly,
IIb 3
localizing it to the site of thrombus formation.
Platelets facilitate clot retraction, which diminishes the efficiency PLATELETS IN INFLAMMATION
of fibrinolysis. AND INFECTION
Platelet-activating effects of thrombolytic agents
Leukocytes can bind to activated platelets and in model systems
Streptokinase and t-PA activate platelets in vivo and in vitro. transmigrate through a platelet monolayer (reviewed in Ref. 745; see
Plasmin, at high doses, can aggregate platelets. Fig. 112–9). Animal models and studies of human tissue demonstrate
Thrombolytic agents may paradoxically generate the potent that within hours after vascular injury, leukocytes become enmeshed in
platelet agonist thrombin or release it from thrombi. platelet thrombi and/or transiently form a monolayer on top of adher-
ent or aggregated platelets. 746,747 These interactions may be important
Thrombolytic agents may blunt the prostacyclin increase that at sites of vascular injury or inflammation where leukocytes have been
accompanies acute thrombosis.
shown to deposit on adherent and aggregated platelets. Platelet recruit-
Platelet-inhibiting effects of thrombolytic agents ment of leukocytes has been associated with a number of systemic and
Plasmin, at low doses, can inhibit platelet activation and inflammatory processes in animal models, including the development
748
aggregation. of intimal hyperplasia after vascular injury, ischemia–reperfusion
injury, alloimmunity-mediated transplant rejection, obesity, and
749
750
Platelets can be disaggregated by t-PA by selective lysis of 751
platelet-bound fibrinogen. acute lung injury. By depositing chemokines such as CCL5 (also
termed RANTES [regulated upon activation, normal T-cell expressed
Plasmin can cause redistribution and/or cleavage of platelet and secreted]) on activated endothelium 752,753 or by direct interactions
glycoprotein Ib.
with leukocytes, platelets may also enhance leukocyte recruitment
754
Inhibition of platelet aggregation by the depletion of plasma to inflamed or atherosclerotic endothelium and thereby promote the
fibrinogen, if severe, and generation of fibrin (ogen) degradation development and progression of atherosclerosis.
products. Many mechanisms of platelet–leukocyte interactions have been
Proteolysis of plasma von Willebrand factor. defined, but the initial interaction appears to be mediated primarily by
the interaction between P-selectin (CD62P) expressed on the surface of
Prolongation of the bleeding time.
activated platelets and PSGL-1 on the surface of neutrophils and mono-
Adapted with permission from Fozzard HA, et al: The Heart and cytes. 755–761 P-selectin–PSGL-1 interactions are characterized by rapid
Cardiovascular System. New York, NY: Raven Press; 1991. on-and-off rates that promote tethering and rolling of leukocytes along

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