Tissue factor pathway inhibitor for cardiovascular disorders

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Abstract
The tissue factor (TF) pathway of coagulation plays a decisive role for normal haemostasis as well as in the pathophysiology of various diseases. As endogenous inhibitor of TF-mediated coagulation, the Kunitz-type proteinase inhibitor tissue factor pathway inhibitor (TFPI) is an important factor in the regulation of haemostasis and the control of clotting activation. TFPI exerts its biological effects by the binding of Factor Xa (FXa) forming a TFPI/FXa complex which then, in a second step, binds to and effectively inhibits the TF/Factor VIIa (FVIIa) complex. Due to its mechanism of action TFPI causes strong anticoagulant and antithrombotic effects under experimental conditions. Furthermore, the inhibitor was shown to be a potent antiproliferative agent both in vitro and in vivo. Based on the pathogenetic role of TF and the TF/FVIIa complex and on the effectiveness of TFPI demonstrated in preclinical studies it is assumed that TFPI might become an important drug for various clinical indications, especially for the management of acute coronary syndromes such as unstable angina and myocardial infarction. The enhanced procoagulant activity in patients with ischaemic heart diseases as documented e.g., by increased plasma levels of TF, requires an effective inhibition of clotting activation either by physiologic mechanisms or by exogenous substances. To increase circulating plasma concentrations of free TFPI, recombinant TFPI could be administered in high doses either locally or systemically, or high amounts of TFPI could be released from vascular pools by interaction with other drugs such as heparin or low molecular weight heparin derivatives. Despite the limited data on the use of TFPI in specific clinical indications, it can be concluded that TFPI and similar compounds represent a new class of drugs with a remarkable developmental potential.