Role of PAI-1 and TAFI in the mediation of fibrinolytic deficit in cancer patients

Abstract

9727 Background: Cancer associated thrombosis is known to have a multi-factorial pathogenesis involving up regulation of coagulation factors, down regulation of inhibitors and endothelial dysfunction. More recently, cancer patients have been shown to exhibit fibrinolytic deficit with impaired clot lysis. This has been mostly attributed to an increase in the circulating levels of plasminogen activator inhibitor 1 (PAI-1). Thrombin activatable fibrinolytic inhibitor (TAFI) has recently been identified as an additional mediator of fibrinolytic deficit that transforms fibrin to a plamsin resistant variant. Methods: To decipher the role of TAFI in this process, plasma samples obtained from 170 cancer patients with symptomatic thrombosis were analyzed for PAI-1, TAFI functional (F) and TAFI immunologic (I). An ELISA method was used for PAI-1 (Stago, Stamford, CT) and TAFI-I (American Diagnostic, Greenwich, CT), while a functional method was used for TAFI-F (Pentapharm, Ltd., Basel Switerland) Results: Baseline samples exhibited a marked increase in PAI-1 levels (140 ± 21) compared to normal (94 ± 14). The TAFI-I levels ranged from 56 –183 %NHP (123 ± 28 %NHP) which was higher than normal (85.1 ± 14 %NHP; n= 82). Interestingly, TAFI measured by functional levels were disproportionately lower (85 ± 26 %NHP) suggesting the consumption of this protease in cancer patients. In contrast to the TAFI I/F ratio approximately 1 for normal individuals, this ratio for cancer patients was 1.6 ± 0.1 (5.6 –0.7). When the PAI-1 levels were compared with F and I TAFI levels, no correlation was evident. This suggests independent regulation of these two proteins in cancer. The increased PAI-1 and TAFI-I levels were independent of the fibrinogen levels. Conclusions: The results clearly suggest that thrombotic complications in cancer patients may be partly due to the fibrinolytic deficit, which is modulated by an up regulation of both PAI-1 and TAFI. Furthermore, the two regulators of fibrinolysis mediate their effects independently. Since the TAFI-I levels are disproportionately high, this enzyme may complex with endogenous proteins modulating its functionality. No significant financial relationships to disclose.