apixaban and Thrombosis

Many populations suffer from thrombotic disorders such as stroke, myocardial infarction, unstable angina and thromboembolic disease. Thrombus is one of the major threatening factors to human health and the prevalence of cardio-cerebrovascular diseases induced by thrombus is growing worldwide, even some persons got rare and severe blood clots after receiving the AstraZeneca COVID vaccine unexpectedly. In terms of mechanism of thrombosis, antithrombotic drugs have been divided into three categories including anticoagulants, platelet inhibitors and fibrinolytics. Nowadays, a large number of new compounds possessing antithrombotic activities are emerging in an effort to remove the inevitable drawbacks of previously approved drugs such as the high risk of bleeding, a slow onset of action and a narrow therapeutic window. In this review, we describe the causes and mechanisms of thrombus formation firstly, and then summarize these reported active compounds as potential antithrombotic candidates based on their respective mechanism, hoping to promote the development of more effective bioactive molecules for treating thrombotic disorders.

Topics: Fibrinolytic Agents; Humans; Molecular Structure; Thrombosis

Topics: Administration, Oral; Animals; Anticoagulants; Biological Availability; Clinical Trials as Topic; Drug Design; Drug Evaluation, Preclinical; Factor Xa Inhibitors; Hemostasis; Humans; Models, Molecular; Protein Conformation; Structure-Activity Relationship; Thrombosis

Apixaban is an oral, direct and highly selective factor Xa (FXa) inhibitor in late-stage clinical development for the prevention and treatment of thromboembolic diseases.. We evaluated the in vitro properties of apixaban and its in vivo activities in rabbit models of thrombosis and hemostasis.. Studies were conducted in arteriovenous-shunt thrombosis (AVST), venous thrombosis (VT), electrically mediated carotid arterial thrombosis (ECAT) and cuticle bleeding time (BT) models.. In vitro, apixaban is potent and selective, with a K(i) of 0.08 nm for human FXa. It exhibited species difference in FXa inhibition [FXa K(i) (nm): 0.16, rabbit; 1.3, rat; 1.7, dog] and anticoagulation [EC(2x) (microm, concentration required to double the prothrombin time): 3.6, human; 2.3, rabbit; 7.9, rat; 6.7, dog]. Apixaban at 10 microm did not alter human and rabbit platelet aggregation to ADP, gamma-thrombin, and collagen. In vivo, the values for antithrombotic ED(50) (dose that reduced thrombus weight or increased blood flow by 50% of the control) in AVST, VT and ECAT and the values for BT ED(3x) (dose that increased BT by 3-fold) were 0.27 +/- 0.03, 0.11 +/- 0.03, 0.07 +/- 0.02 and > 3 mg kg(-1) h(-1) i.v. for apixaban, 0.05 +/- 0.01, 0.05 +/- 0.01, 0.27 +/- 0.08 and > 3 mg kg(-1) h(-1) i.v. for the indirect FXa inhibitor fondaparinux, and 0.53 +/- 0.04, 0.27 +/- 0.01, 0.08 +/- 0.01 and 0.70 +/- 0.07 mg kg(-1) day(-1) p.o. for the oral anticoagulant warfarin, respectively.. In summary, apixaban was effective in the prevention of experimental thrombosis at doses that preserve hemostasis in rabbits.

Topics: Animals; Carotid Artery Thrombosis; Disease Models, Animal; Dogs; Factor Xa Inhibitors; Hemostasis; Humans; Platelet Aggregation; Pyrazoles; Pyridones; Rabbits; Rats; Thrombosis; Venous Thrombosis

Introduction of the phenyl piperidinone and phenyl pyridinone P4 moieties in the anthranilamide scaffold led to potent, selective, and orally bioavailable inhibitors of factor Xa. Anthranilamide 28 displayed comparable efficacy to apixaban in the rabbit arteriovenous-shunt (AV) thrombosis model.

Topics: Administration, Oral; Animals; Antithrombin III; Arteriovenous Shunt, Surgical; Binding Sites; Biological Availability; Models, Animal; ortho-Aminobenzoates; Piperidines; Pyridones; Rabbits; Serine Proteinase Inhibitors; Structure-Activity Relationship; Thrombosis