The use of direct oral anticoagulants (DOACs) – thrombin inhibitors and factor Xa inhibitors – for the prevention and treatment of thromboembolic events has increased significantly in the last 20 years. This is due to their efficiency similar to that of vitamin K antagonists, administration in fixed doses without the need to monitor coagulation tests, and the lower risk of bleeding(1). From a pharmacokinetic standpoint, the half-time of these drugs in patients with normal renal function is relatively short (5 to 14 hours)(1). Therefore, the anticoagulant activity of DOACs disappears in most cases within 24 hours, and reversal agents are rarely required(1). Even though the relative risk of major bleeding is approximately 40% lower when using DOACs compared to vitamin K antagonists, the absolute risk of bleeding remains significantly increased compared with non-anticoagulated individuals (1.5–3.0/100 person-years in DOAC groups compared to 0.31/100 person-years in general population)(2),(3). A new category of anticoagulant drugs with promising results, that is undergoing evaluation in phase 3 clinical trials is represented by factor XI inhibitors (antisense oligonucleotide – fesomersen, monoclonal antibodies – abelacimab, osocimab, xisomab, small molecules – asundexian, milvexian)(4).
The severity of the bleeding guides the therapy of hemorrhagic complications in patients receiving DOACs. For minor bleeding, such as epistaxis or hemorrhoidal bleeding, local hemostatic treatments, and the postponement of one or two DOAC doses can be employed(1). In patients with non-life-threatening moderate-to-severe bleeding, such as non-severe gastrointestinal bleeding, extensive hematuria, or persistent epistaxis, it is necessary to temporarily suspend the treatment with DOAC, and to administer red cell transfusion, tranexamic acid, or endoscopic therapy(1). In addition to these measures, patients with severe, life-threatening hemorrhage can be treated with reversal agents(1). Also, these agents can be considered in patients who require an urgent surgical intervention or a surgical intervention with a high risk of bleeding(1). Reversal can be achieved with non-specific (prothrombin complex concentrates, activated prothrombin complex concentrates or recombinant activated factor VII) or specific agents that bind to DOACs (idarucizumab, andexanet alfa)(1). A meta-analysis that followed 34 studies reported the hemostatic efficiency of using prothrombin complex concentrate in 80% of patients with bleeding complications secondary to DOAC(5). Also, 4% of these patients developed thromboembolic complications, and 17% died(5).
Ciraparantag and zymogen-like factor Xa variants are a category of reversal agents under development(1). Ciraparantag was initially developed to counteract the anticoagulant effect of low-molecular-weight and unfractionated heparin(1). However, it was observed that this agent binds to dabigatran and factor Xa inhibitors, shortening the whole blood clotting time through a dose-dependent effect(1). A variant of zymogen-like factor Xa is VMX-C0011. Once activated, this mutant factor Xa converts prothrombin to thrombin and is blocked by antithrombin but not by apixaban, rivaroxaban, or edoxaban, as is the case with wild-type factor Xa(1).
Regarding factor XI inhibitors, they seem to be a potential class of anticoagulant drugs associated with a lower risk of bleeding compared to currently available agents(1). In cases of major hemorrhagic complications, tranexamic acid, recombinant factor VIIa, or activated prothrombin complex concentrates can be used(1). The ongoing studies may revolutionize anticoagulant treatment by approving factor XI inhibitors in current practice.
Address for correspondence:
Camelia C. DIACONU