Dougald M Monroe

..In addition, heparin does not enhance the inhibition of factor Xa by mouse TFPIbeta although it does accelerate factor Xa inhibition by TFPI...

..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...

..We speculate that this platelet-localized thrombin generation may, in part, account for the clinical efficacy of high-dose FVIIa...

..This article reviews current knowledge on the function and regulation of TF and its role in a range of biological processes, including hemostasis, thrombosis and inflammation...

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

..However, the platelet surface may be able to process only a limited amount of FXa, accounting for the observation that some models of non-hemophilic coagulopathy show a plateau in the effect of rFVIIa...

..This may suggest a mechanism to account for the efficacy of factor VIIa in reducing blood loss in some settings of dilutional coagulopathy...

..Finally, enhanced thrombin generation on platelets would mean that fewer platelets are required for hemostasis...

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..The current data suggests that ongoing coagulation function needs to be maintained to support a normal wound healing process...

..This allows the coagulation system to be more easily tipped into a state favoring either hemorrhage or thrombosis...

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

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

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

..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...

..Several questions pertaining to the use of factor VIIa require further investigation, including the mechanism of action; the optimal dose; definitive indications; ultimate safety; and laboratory tests for monitoring therapy...

..To determine factors regulating human aortic smooth muscle cells (HASMC) supported tissue factor-induced thrombin generation...

..Thrombin then activates platelets, which serve as the physiologically important surface for large-scale thrombin generation...

..These results suggest that BAX499 may be a useful addition to the armamentarium of bypassing agents to control bleeding in hemophilic patients with inhibitors...

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

..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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..Finally, recombinant factor VIIa has been used off-label as a hemostatic agent in some surgical situations associated with excessive bleeding that is not responsive to conventional therapy...

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

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

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

..Thus, normalizing haemostasis, until the process of angiogenesis has resolved, may be required to prevent re-bleeding and additional tissue damage...

..Idling' or ongoing low-level activity of the tissue factor (TF) pathway is a postulated mechanism by which the coagulation process can become active without a lag period at sites of injury...

..quot;Antiphospholipid" antibodies against the phospholipid-binding protein beta-2-glycoprotein-1 enhance thrombin generation in this model system, primarily by enhancing procoagulant reactions on tissue factor-bearing cells...

..Activation of FIX and FX on platelet surfaces in thrombocytopenia would result in more thrombin generation per platelet, possibly leading to formation of a stable fibrin network even in the absence of an optimal initial platelet plug...

..This cell based model explains some aspects of hemostasis that a protein-centric model does not...

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..Cloning and expression of the mouse TFPI gene will offer useful information and material for coagulation studies performed in a mouse model system...

..Recently, Rezaie showed that calcium further enhanced the heparin-catalyzed AT inhibition of FXa by promoting 'ternary complex' formation, and these results showed a role for the gamma-carboxyl-glutamate (Gla)-domain of FXa...

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..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...

..Classically, it is thought that the vast majority of thrombin is generated on the surface of platelets, however, thrombotic events occur in patients despite treatment with potent antiplatelet agents...

..Our results suggest that the first EGF-like domain is required for binding to tissue factor and that the F.VII zymogen lacks activity and requires activation for expression of biologic activity...

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

..Further, our data suggest that the mutation results in a molecule that interacts with components of the extrinsic pathway to give a prolonged ox brain prothrombin time...

..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...

..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...

..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...

..It also highlights how host factors that are not part of the coagulation process per se can influence the effectiveness of coagulation...

..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...