Anticoagulation beyond direct thrombin and factor Xa inhibitors: indications for targeting the intrinsic pathway?

Abstract

SummaryAntithrombotic drugs like vitamin K antagonists and heparin have been the gold standard for the treatment and prevention of thromboembolic disease for many years. Unfortunately, there are several disadvantages of these antithrombotic drugs: they are accompanied by serious bleeding problems, it is necessary to monitor the therapeutic window, and there are various interactions with food and other drugs. This has led to the development of new oral anticoagulants, specifically inhibiting either thrombin or factor Xa. In terms of effectiveness, these drugs are comparable to the currently available anticoagulants; however, they are still associated with issues such as bleeding, reversal of the drug and complicated laboratory monitoring. Vitamin K antagonists, heparin, direct thrombin and factor Xa inhibitors have in common that they target key proteins of the haemostatic system. In an attempt to overcome these difficulties we investigated whether the intrinsic coagulation factors (VIII, IX, XI, XII, prekallikrein and high-molecular-weight kininogen) are superior targets for anticoagulation. We analysed epidemiological data concerning thrombosis and bleeding in patients deficient in one of the intrinsic pathway proteins. Furthermore, we discuss several thrombotic models in intrinsic coagulation factor-deficient animals. The combined results suggest that intrinsic coagulation factors could be suitable targets for anticoagulant drugs.

Factor XI Regulates Pathological Thrombus Formation on Acutely Ruptured Atherosclerotic Plaques

“…This indicates that there is a discrepancy between mice and humans about factor XI levels and bleeding. 21 Because of the half-life of factor XI (≈48 hours), it takes 2 to 3 days before an antithrombotic effect is observed in mice and men. In humans, because of multiple factors, it will probably take 1 to 3 weeks before antithrombotic protection can be achieved.…”

Ecotin: Exploring a feasible antithrombotic profile

“…Nevertheless, this blockage has no relevance in the thrombosis models used in our study, since it impairs the thrombus formation preventing the activation of fibrinolytic pathway. The literature indicates that inhibition of these molecules can be efficient and safer since they do not promote bleeding, suggesting that ecotins could have a safer profile because they can also inhibit factors from the intrinsic cascade [49].…”

Coagulation Factor XII –A Key Pro-Inflammatory and Pro-Coagulant Protein

“…Over the years, the number of drugs for prevention and treatment of thrombosis is very limited, and all these drugs are correlated with severe, sometimes lethal bleedings, since all these drugs target the key proteins (e.g. FX, thrombin) of the coagulation cascade [30]. On the contrary, FXII is not only specific to pathological thrombosis, but also regulates excess inflammatory response, providing a new target for prevention and treatment of ischemic stroke.…”