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Newsletter
Tifacogin, Recombinant Tissue Factor Pathway InhibitorKW Tim Park, MD
The central role of tissue factor (TF) in the coagulation cascade is increasingly recognized.1 When the vascular endothelium is damaged by, e.g., mechanical trauma (angioplasty, surgical incision) or disease states (sickle cell disease), the subendothelial constituents such as smooth muscle cells and fibroblasts are exposed to the blood stream and express TF, a member of the type II cytokine family of glycoproteins. TF then complexes with the circulating factor VII (FVII). The TF/FVIIa complex initiates the coagulation cascade by cleaving the proenzyme FX to FXa. FXa complexes with FVa to form the "prothrombinase" complex, which converts prothrombin to thrombin or FIIa. FIIa then (a) cleaves fibrinogen to generate insoluble fibrin as well as fibrinopeptides A and B and (b) helps activate platelets by cleaving platelet protease-activated receptor-1.2 The TF/VIIa complex propagates and maintains the coagulation reactions by catalyzing generation of FIXa, which complexes with FVIIIa to form the "intrinsic tenase" complex that promotes FX activation. FIIa further augments propagation of coagulation by generating FXIa, which then activates FIXa. In the augmentation phase, not only the TF from the subendothelial constituents, but also circulating TF may participate. Because of its central role in coagulation, TF is being implicated in the pathogenesis of such disease states as atherosclerosis, coronary artery disease, and sepsis. Toschi et al.3 have shown that TF is not only expressed in human atherosclerotic lesions, but also that TF expression is correlated with the lipid content of the atherosclerotic plaques and with the platelet deposition in the plaques. Studying coronary atherectomy specimens, Marmur et al.4 found that immunologically detectable TF antigen was present in 43 of 50 lesions (86%). Whereas thrombus was present in 19 of the 43 lesions with detectable TF, no thrombus was evident in the other 7 lesions. Furthermore, atheroma plaques from patients with unstable angina or myocardial infarction demonstrate significantly higher TF acitivity than plaques from patients with stable angina.5 Likewise, in human and animal models of sepsis, TF levels are significantly elevated. Inflammatory mediators of sepsis such as lipopolysaccharide, interleukin-1, and tumor necrosis factor increase TF expression from vascular endothelial cells.6-8 And in animal models, anti-TF antibody can attenuate the coagulopathy (DIC) of sepsis.9,10 TF pathway inhibitor-1 (TFPI-1) is the principal endogenous inhibitor of the TF pathway.11 It is produced by vascular endothelial cells as well as mesangial cells, smooth muscle cells, monocytes, fibroblasts, and cardiomyocytes. It is a serine protease inhibitor with three domains (K1, K2, K3). The K2 domain binds FXa and inhibits it directly. Once TFPI-1 is bound to FXa, it is able to bind and inhibit TF/FVIIa complex via its K1 domain, preventing further generation of FXa and FIXa. The K3 domain contains heparin-binding sites and exogenous administration of heparin will release TFPI-1 from the endothelial cells. TFPI blocks both the initiation and the propagation/amplification of coagulation cascade. Because of the potential central role of TF in the pathogenesis of coronary artery disease and sepsis, the efficacy of recombinant TFPI-1 (rTFPI-1) has been investigated. In animal models of sepsis, rTFPI-1 produced reduction in coagulation activation and interleukin-6 levels and prolongation of survival.12-15 In phase I and II studies in humans, rTFPI-1 was well-tolerated without significant increase in bleeding complications and showed a trend toward up to a 20% reduction in 28-day all-cause mortality.16,17 However, in a subsequent phase III OPTIMIST trial, the initial enthusiasm for the drug has not borne out.18,19 Whereas the interim analysis of the first 722 patients in the study showed a reduction in 28-day mortality from 38.9% to 29.1%, at the completion of the study with 1,754 patients with severe sepsis and a high INR (3 1.2), there was no significant difference in mortality between rTFPI-1 and control (34.2% v. 33.9%). A confounding factor was that many patients in the study received concomitant heparin for other reasons and patients in the placebo group who received heparin had a much lower mortality than those who did not (29.8% v. 42.7%). In addition, in a parallel cohort of 201 patients with low INR (< 1.2), rTFPI-1 did show a trend to mortality reduction (12% v. 23%). While rTFPI-1 may turn out to have a role in treatment of sepsis, especially at its early stages, its precise role is uncertain at present. The mechanism of restenosis after coronary angioplasty includes thrombosis and neointimal proliferation as well as acute elastic recoil and long-term constrictive vessel wall remodeling. Angioplasty is associated with an enhanced local expression of TF and blocking TF has been theorized to reduce restenosis after angioplasty.20 Indeed, in animal models of balloon-induced injury to an artery, TFPI has been shown to reduce accumulation of platelets and fibrin (ogen) deposition, decrease angiographic restenosis, and attenuate neointimal hyperplasia.21-23 However, whether TFPI may be efficacious in reducing restenosis after percutaneous coronary intervention in humans or may be effective in treating acute coronary syndromes in humans remain to be investigated. References:
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