Heparin immobilization substantially reduces the thrombogenicity of small-diameter ePTFE in a newly developed human ex vivo model. In this study, we provide evidence that the mechanism of action of the heparin bonding is due not only to anticoagulant but also to antiplatelet effects. Heparin bonding may be an important improvement of ePTFE, resulting in better patency rates for vascular reconstructions.
Several lines of evidence suggest that recombinant factor VIIa (rFVIIa) is able to activate factor X on an activated platelet, in a tissue factor-independent manner. We hypothesized that, besides the anionic surface, a receptor on the activated platelet surface is involved in this process. Here, we showed that, in an ELISA setup, a purified extracellular fragment of GPIb␣ bound to immobilized rFVIIa. Surface plasmon resonance established a affinity constant (K d ) of approximately 20 nM for this interaction. In addition, CHO cells transfected with the GPIb-IX-V complex could adhere to immobilized rFVIIa, whereas wild-type CHO cells could not. Furthermore, platelets stimulated with a combination of collagen and thrombin adhered to immobilized rFVIIa under static conditions. Platelet adhesion was inhibited by treatment with O-sialoglycoprotein endopeptidase, which specifically cleaves GPIb␣ from the platelet surface. In addition, rFVIIamediated thrombin generation on the activated platelet surface was inhibited by cleaving GPIb␣ from its surface. In summary, 3 lines of evidence showed that rFVIIa interacts with the GPIb-IX-V complex, and this interaction enhanced tissue factor-independent thrombin generation mediated by rFVIIa on the activated platelet surface. The rFVIIa-GPIb␣ interaction could contribute to cessation of bleeding after administration of rFVIIa to patients with bleeding disorders. (Blood. 2008; 112:3227-3233) IntroductionRecombinant factor VIIa (rFVIIa) was originally developed for the treatment of hemophilia A and B, which have developed inhibitory antibodies against factor VIII and IX as a result of treatment with FVIII or FIX concentrates. 1 Nowadays, it has also been registered for use in patients with factor VII deficiency, acquired hemophilia, and inhibitor-complicated Glanzmann's thrombasthenia. Its mechanism of action is thought to involve the local enhancement of thrombin generation at the site of vessel wall damage. Enhancement of thrombin generation will result in enhanced fibrin formation as well as changes in fibrin structure that will result in a clot that is better protected against fibrinolysis. 2 Improved clot stability is also achieved through increased activation of thrombinactivatable fibrinolysis inhibitor (TAFI). 3 Finally, enhanced thrombin generation results in an acceleration of platelet activation, which will facilitate induction of hemostasis in 2 ways. First, platelet activation directly contributes to formation of the hemostatic plug. Second, activation of platelets results in an increase in thrombin generation, as platelet activation will expose procoagulant phospholipids on the platelet surface.It has been suggested that enhancement of thrombin generation by rFVIIa is solely dependent on the presence of tissue factor (TF). 4,5 However, different independent experiments have shown that the effect of rFVIIa can proceed via TF-dependent 3,6 as well as TF-independent 7-9 pathways, and it has been postulated that both mechanisms are operative in vivo. 10 Although the mech...
Summary. Objectives: Staphylococcal superantigen-like 5 (SSL5) is an exoprotein secreted by Staphylococcus aureus that has been shown to inhibit neutrophil rolling over activated endothelial cells via a direct interaction with P-selectin glycoprotein ligand 1 (PSGL-1). Methods and Results: When purified recombinant SSL5 was added to washed platelets in an aggregometry set-up, complete and irreversible aggregation was observed. Proteolysis of the extracellular part of GPIba or the addition of dRGDW abrogated platelet aggregation. When a mixture of isolated platelets and red cells was perfused over immobilized SSL5 at a shear rate of 300 s )1, stable platelet aggregates were observed, and platelet deposition was substantially reduced after proteolysis of GPIb or after addition of dRGDW. SSL5 was shown to interact with glycocalicin, a soluble GPIba fragment, and binding of SSL5 to platelets resulted in GPIb-mediated signal transduction as evidenced by translocation of 14-3-3f. In addition, SSL5 was shown to interact with endothelial cell matrix (ECM) and this interaction enhanced aggregation of platelets from whole blood to this ECM. Conclusions: SSL5 activates and aggregates platelets in a GPIba-dependent manner, which could be important in colonization of the vascular bed and evasion of the immune system by S. aureus.
Platelets play a key role in hemostasis and thrombosis. The formation of a platelet plug is accompanied by the generation of thrombin, which results in the generation of fibrin required for stabilization of the platelet plug. Platelet plug formation and coagulation are closely linked processes. Thrombin is a potent platelet activator, which proceeds through proteolysis of the protease activated receptors (PARs). Furthermore, thrombin binds glycoprotein Ib(alpha), which amplifies platelet activation by accelerating PAR-1 activation, and possibly also by direct signaling events through glycoprotein Ib(alpha). Moreover, thrombin's specificity towards other substrates changes after binding glycoprotein Ib(alpha). Fibrinogen and fibrin, the end product of the coagulation cascade, are also involved in platelet aggregation. Both fibrinogen and fibrin bind the integrin alpha(IIb)beta(3), and another fibrin receptor involved in platelet aggregation has been postulated. This review will discuss the role of thrombin and fibrin(ogen) in platelet functioning, and will highlight pathways at the crossroad of coagulation and platelet functioning, which are potential targets for antithrombotic therapy.
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