Abstract
A common deficiency of the anticoagulants used so far thrombin inhibitors, factor Xa inhibitors or anti-vitamins K is an increased risk of clinically significant bleeding. This varies between 1 and 3% per year across drug groups, across indications.
It is therefore not surprising that efforts are being made to reduce the risk of bleeding while maintaining antithrombotic effect. In recent years, there have been significant advances in the field of inhibitors of the intrinsic coagulation cascade.
This strategy is promising as the most common indications for anticoagulants include activation of haemostasis by contact (e.g. induced by polyphosphates on the surface of activated platelets or by contact with an artificial surface) or reparative-inflammatory processes (in particular, by filaments of extracellularly released deoxyribonucleic acid [DNA] from neutrophil leukocytes [neutrophil extracellular trap, NET] or by a number of cytokines). A prerequisite for activation of this intrinsic pathway of coagulation is blood stagnation allowing an effective local concentration of the enzymes of the coagulation cascade to be achieved.
The two most common indications for anticoagulation therapy, atrial fibrillation or thromboembolic disease, correspond to these conditions. Preservation of an active extrinsic pathway of coagulation then allows effective haemostasis in the presence of vascular wall damage.
To inhibit this intrinsic pathway of coagulation, a number of factor XI/XIa inhibitors based on classical small molecule drugs (e.g. asundexian, milvexian), monoclonal antibodies (e.g. abelacimab, osocimab) or oligonucleotides inhibiting factor XI synthesis (e.g. fesomersen) are in advanced clinical trials. Clinical trials are underway for the prophylaxis of thromboembolic disease, for the prevention of thromboembolic events in atrial fibrillation or for the indication of secondary prevention after myocardial infarction or stroke.