Thrombophilia and direct thrombin inhibitor lepirudin clinical and monitoring aspects

Thrombophilia (TF) predisposes both to venous and arterial thrombosis at a young age. TF may also impact the thrombosis or stenosis of hemodialysis (HD) vascular access in patients with end-stage renal disease (ESRD). When involved in severe thrombosis TF may associate with inappropriate response to anticoagulation. Lepirudin, a potent direct thrombin inhibitor (DTI), indicated for heparin-induced thrombocytopenia-related thrombosis, could offer a treatment alternative in TF. Monitoring of narrow-ranged lepirudin demands new insights also in laboratory. The above issues constitute the targets in this thesis. We evaluated the prevalence of TF in patients with ESRD and its impact upon thrombosis- or stenosis-free survival of the vascular access. Altogether 237 ESRD patients were prospectively screened for TF and thrombogenic risk factors prior to HD access surgery in 2002-2004 (mean follow-up of 3.6 years). TF was evident in 43 (18%) of the ESRD patients, more often in males (23 vs. 9%, p=0.009). Known gene mutations of FV Leiden and FII G20210A occurred in 4%. Vascular access sufficiently matured in 226 (95%). The 1-year thrombosis- and stenosis-free access survival was 72%. Female gender (hazards ratio, HR, 2.5; 95% CI 1.6-3.9) and TF (HR 1.9, 95% CI 1.1-3.3) were independent risk factors for the shortened thrombosis- and stenosis-free survival. Additionally, TF or thrombogenic background was found in relatively young patients having severe thrombosis either in hepatic veins (Budd-Chiari syndrome, BCS, one patient) or inoperable critical limb ischemia (CLI, six patients). Lepirudin was evaluated in an off-label setting in the severe thrombosis after inefficacious traditional anticoagulation without other treatment options except severe invasive procedures, such as lower extremity amputation. Lepirudin treatments were repeatedly monitored clinically and with laboratory assessments (e.g. activated partial thromboplastin time, APTT). Our preliminary studies with lepirudin in thrombotic calamities appeared safe, and no bleeds occurred. An effective DTI lepirudin calmed thrombosis as all patients gradually recovered. Only one limb amputation was performed 3 years later during the follow-up (mean 4 years). Furthermore, we aimed to overcome the limitations of APTT and confounding effects of warfarin (INR of 1.5-3.9) and lupus anticoagulant (LA). Lepirudin responses were assessed in vitro by five specific laboratory methods. Ecarin chromogenic assay (ECA) or anti-Factor IIa (anti-FIIa) correlated precisely (r=0.99) with each other and with spiked lepirudin in all plasma pools: normal, warfarin, and LA-containing plasma. In contrast, in the presence of warfarin and LA both APTT and prothrombinase-induced clotting time (PiCT®) were limited by non-linear and imprecise dose responses. As a global coagulation test APTT is useful in parallel to the precise chromogenic methods ECA or Anti-FIIa in challenging clinical situations. Lepirudin treatment requires multidisciplinary approach to ensure appropriate patient selection, interpretation of laboratory monitoring, and treatment safety. TF seemed to be associated with complicated thrombotic events, in venous (BCS), arterial (CLI), and vascular access systems. TF screening should be aimed to patients with repeated access complications or prior unprovoked thromboembolic events. Lepirudin inhibits free and clot-bound thrombin which heparin fails to inhibit. Lepirudin seems to offer a potent and safe option for treatment of severe thrombosis. Multi-centered randomized trials are necessary to assess the possible management of complicated thrombotic events with DTIs like lepirudin and seek prevention options against access complications.