Thrombin Inhibitors and Anti-Factor Xa Agents in the Treatment of Arterial Occlusion

Abstract

Cardiovascular disease is the leading cause for mortality and morbidity in the western world. Arterial thrombosis has multiple origins and may present with different clinical presentations such as acute coronary syndromes, stroke, and peripheral embolization. Furthermore, thrombotic complications may occur during percutaneous interventions. The underlying causes range from atherosclerosis with plaque rupture or erosion, embolization, stasis and hypercoagulable states. Thrombotic complications lead to activation of the intrinsic coagulation system and to platelet aggregation. Despite the development of effective platelet inhibitors, there is still the need for an optimal anticoagulation regimen. While unfractionated heparin is the most commonly used antithrombotic agent, which has major inherent limitations. Direct thrombin inhibitors and anti factor Xa agents are agents which may overcome the limitation of unfractionated heparin. The potential advantages of these new compounds are discussed on the basis of available clinical data in patients with coronary artery disease.

Occurrence of Post-Acute Recanalization and Collateral Formation in Patients with Cerebral Venous and Sinus Thrombosis. A Serial Venographic Study

“…Similarly, the contribution of anticoagulation in promoting post-acute recanalization independent of preventing progression or recurrence remains unclear. In arterial occlusion events, direct thrombin inhibitors promote recanalization by enhancing the action of intrinsic thrombolytics (endogenous tissue plasminogen activator), by increasing permeability within fibrin network and by preventing re-occlusion and hence shifting the balance in favor of continued recanalization [22,23]. Low molecular weight heparins by preferentially inhibiting the positive feedback triggered by thrombin (anti-Xa activity), and unfractionated heparin by inhibiting thrombin activity (anti-IIa activity), interrupt thrombin-dependent mechanisms of re-occlusion [24,25].…”

Coagulation Factor Xa Modulates Airway Remodeling in a Murine Model of Asthma

“…Although FPX is less effective than fluticasone, which is one of the most efficient drugs for treating asthma, FPX ameliorated the airway remodeling process. FPX is a synthetic antithrombin-III (AT-III) binding pentasaccharide and shows a therapeutic advantage in preventing thromboembolism (19). The mechanism by which FPX inhibits FXa is by enhancing the reactivity of AT-III to FXa.…”

Recent Research Developments in the Direct Inhibition of Coagulation Proteinases – Inhibitors of the Initiation Phase

“…Direct inhibition does not require an intermediary protein to mediate the anticoagulant effect. Rather it involves the direct binding of an inhibitor to a procoagulant proteinase, e.g., thrombin or factor Xa, to generate the anticoagulation effect [55][56][57]. Hirudin, bivalirudin and argatroban (Fig.…”

“…Recent studies suggest that direct inhibitors that use a basic group as a P1-arginine mimic Fondaparinux for recognizing the enzyme appear to have another side effect -the degranulation of mast cells leading to histamine release [68,69]. Finally, trials with ximelagatran, and other direct inhibitors, e.g., dabigatran, DX9065a and razaxaban, show the persistence of bleeding risk [56,57,[60][61][62][63][64]. Thus, major challenges with direct inhibitors include establishing an enzyme affinity that is not associated with excessive bleeding, avoiding liver toxicity, eliminating histamine release, achieving oral bioavailability and maintaining sufficient duration of action.…”