Maureane Hoffman

..We believe that even in the presence of the FIXa/FVIIIa complex, rFVIIa may be able to enhance both FXa and FIXa levels on the surface of activated platelets, thus increasing the production of thrombin...

..This cell-based model suggests that the "intrinsic" and "extrinsic" pathways are in fact not redundant systems, but operate in parallel on different cell surfaces...

..Generation of the right amount of thrombin during the coagulation process not only may be essential for effective hemostasis but also may set the stage for effective wound healing...

..Thus, perivascular TF expression is down-regulated during wound healing. This may prevent thrombosis of neovessels during angiogenesis but renders hemophiliacs vulnerable to hemorrhage during healing...

..However, direct evidence is still lacking that these modifications contribute to the increased atherothrombotic risk associated with hyperhomocysteinemia and diabetes...

..Thus, there are still unanswered questions in fully understanding the mechanism of hemostatic action of recombinant FVIIa...

..NN1731 has a conformation similar to TF-bound FVIIa, even in the absence of TF. This results in much greater intrinsic proteolytic activity, but similar activity in the presence of TF...

..Our findings suggest that an acquired dysfibrinogenemia could play a role in the increased risk of atherothrombotic disease in mildly hyperhomocysteinemic human subjects...

..We hypothesize that the modification of lysine by Hcys thiolactone might occur in vivo, lead to abnormal resistance of clots to lysis, and thereby contribute to the prothrombotic state associated with homocysteinemia...

..Our findings have significant implications for treatment of patients with hemophilia, and also highlight the importance of rapidly establishing hemostasis following trauma or surgery...

..These data suggest that trials of LILT as an adjunct to the usual hemostatic therapies in hemophilia are warranted...

..CONCLUSION: FVIIa should be effective in enhancing hemostasis in hypothermic patients. However, because the activity of FVIIa is so dramatically affected by pH, its efficacy may be reduced in acidotic patients...

..From the studies reported here, we conclude that in vivo, despite the important role of the protein C system in regulating thrombosis, activated protein C does not serve as a primary regulator of platelet-dependent thrombin generation...

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..Based on their review of the literature, the authors suggest that in a hemodynamically stable patient population there is a range of mildly prolonged INR values for which FFP transfusion is not beneficial, and is potentially harmful...

..Our data suggest that the ability to inhibit platelet surface IIa generation correlates with the therapeutic level of heparins and confirms similarities between the anticoagulant properties of M118 and UFH...

..The observed down-regulation of TF expression may serve to prevent thrombosis of developing neovessels and contribute to the well-recognized tendency of granulation tissue to bleed readily and profusely...

..This combination of exosite 1 and exosite 2 inhibitors may provide a particularly effective antithrombotic approach...

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..These articles discuss the causes of posttraumatic microvascular bleeding and the potential treatment options for controlling catastrophic hemorrhage in combat areas...

..Our understanding of how specific cellular features control the processes of hemostasis and thrombosis is developing rapidly. This review discusses some aspects of the cellular control of coagulation...

..These findings support the notion that HCII could function as an extravascular thrombin inhibitor and might play a role in the regulation of wound healing...

..This molecule exhibits greater potency than FVIIa in biochemical assays, in vitro and animal models, and in early phase clinical trials...

..The goal of such treatment would be to avoid a feedback cycle in which bleeding tends to lead to further bleeding. Once initiated, this cycle may be difficult to control...

..The literature in this are remains somewhat sparse, but suggests that modulation of TF expression plays a role in modulating the host response to injury...

..The difference in metabolism of homocysteine may protect the juvenile rabbits from the damaging effects of homocysteine. Future studies are planned to elucidate the mechanism of this adaptive response...

..The formation of clots that are abnormally resistant to fibrinolysis could directly contribute to the increased risk of thrombosis in hyperhomocysteinemia...

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..Our data suggest that in a cellular system high-dose FVIIa acts primarily by enhancing the rate of thrombin generation on platelet surfaces and not by overcoming inhibition by zymogen FVII of TF-dependent activation of FX...

..Furthermore, these results suggest that increasing plasma prothrombin concentration prior to rFVIIa administration may offer advantages over the use of rFVIIa alone in the treatment of haemophilic bleeding...

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..Individual differences in platelet thrombin generation might be accounted for by differences in platelet-binding proteins...

..We hypothesize that this alteration in fibrin clot structure is an important determinant of the risk of thrombosis...

..We have attempted to reconcile the various proposed mechanisms of action of rFVIIa with its apparent efficacy in such diverse clinical settings...

..However, at temperatures below 33 degrees C, both reduced platelet function and enzyme activity likely contribute to the coagulopathy...

..Finally, those situations in which rFVIIa therapy may not be safe, such as disseminated intravascular coagulation (DIC) and sepsis, will also be discussed...

..Convulxin-induced increases in thrombin generation are regulated by the proportion of platelets with increased coagulation factor binding...

..We have also shown that activated protein C does not inactivate Va on the platelet surface but rather on endothelial cell surfaces...

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