An Update on Safe Anticoagulation

Abstract

Blood coagulation is essential to maintain the integrity of a closed circulatory system (hemostasis), but also contributes to thromboembolic occlusion of vessels (thrombosis). Thrombosis may cause deep vein thrombosis, pulmonary embolism, myocardial infarction, peripheral artery disease, and ischemic stroke, collectively the most common causes of death and disability in the developed world. Treatment for the prevention of thromboembolic diseases using anticoagulants such as heparin, coumarins, thrombin inhibitors, or antiplatelet drugs increase the risk of bleeding and are associated with an increase in potentially life-threatening hemorrhage, partially offsetting the benefits of reduced coagulation. Thus, drug development aiming at novel targets is needed to provide efficient and safe anticoagulation. Within the last decade, experimental and preclinical data have shown that some coagulation mechanisms principally differ in thrombosis and hemostasis. The plasma contact system protein factors XII and XI, high-molecular-weight kininogen, and plasma kallikrein specifically contribute to thrombosis, however, have minor, if any, role in hemostatic coagulation mechanisms. Inherited deficiency in contact system proteins is not associated with increased bleeding in humans and animal models. Therefore, targeting contact system proteins provides the exciting opportunity to interfere specifically with thromboembolic diseases without increasing the bleeding risk. Recent studies that investigated pharmacologic inhibition of contact system proteins have shown that this approach provides efficient and safe thrombo-protection that in contrast to classical anticoagulants is not associated with increased bleeding risk. This review summarizes therapeutic and conceptual developments for selective interference with pathological thrombus formation, while sparing physiologic hemostasis, that enables safe anticoagulation treatment.

Factor XI Inhibition With Heparin Reduces Clot Formation in Simulated Pediatric Extracorporeal Membrane Oxygenation

“…Indeed, patients with congenital FXII or FXI deficiency generally do not have an increase in spontaneous clinical bleeding episodes. 9…”

“…To reduce device-related thrombosis without increasing bleeding, inhibitors of the contact activation pathway have been advanced in preclinical and early-phase clinical trials. 9 ECMO-induced activation of the coagulation cascade can be initiated by activation of FXII on the surfaces of vascular devices. 10 FXIIa then activates FXI, initiating a cascade of several events to propagate thrombin generation and clot formation.…”

Preoperative diagnosis and management of inherited bleeding disorders in female adolescents and adults

“… 2 , 55 – 57 , 59 – 63 The available anticoagulation drugs are used to reduce the risk of thrombosis but result in a concomitantly increased risk of bleeding ( Table 4 ). 61 , 62 Although perioperative management of patients who are receiving antiplatelet therapy is a common clinical occurrence, there are minimal high-quality studies to direct, continue or interrupt antiplatelet therapy, as well as concerning the role of bridging therapy. 63 …”

“… CI = confidence interval; NS = nonsignificant; RR = relative risk. * Adapted from Mailer and colleagues 61 and Alkhalil and colleagues. 62 …”

Recent advances in factor XII structure and function

“…Furthermore, FXIIa is a poor FXI activator in the absence of a surface. Although FXI activation by FXIIa does not appear to be required for haemostasis [3], it promotes pathologic clot formation (thrombosis) in clinical settings in which blood comes into contact with nonbiological materials that induce contact activation such as renal dialysis membranes, cardiopulmonary bypass circuits, extracorporeal membrane oxygenators and central venous catheters [5,26,27].…”