Time to Divorce Bleeding From Thrombosis

Volume 7, Issue 2

Thromboembolic disorders are estimated to cause 1 in 4 deaths worldwide, and anticoagulation therapy is a cornerstone for the prevention and treatment of thrombosis. Hemostasis and thrombosis are believed to be so intricately linked that any strategies that reduce thrombosis will have an inevitable impact on hemostasis. Consequently, bleeding is viewed as an unavoidable side effect of anticoagulant therapy.

This unfortunate association is likely due to the mechanism of action for most blood thinners, which work on common pathway factors like thrombin and Xa. However, emerging evidence suggests that factor XI (FXI) is important for thrombosis but has a minor role in hemostasis.

In this week’s issue of Talking Therapeutics, we explore the science behind a novel anticoagulant therapy, and present some emerging clinical trial data.

Talking Point: Factor XI May Be the Missing Link

FXI plays a relatively limited role in hemostasis. During hemostasis, FXI is thought to be converted to FXIa by thrombin, and this process consolidates coagulation through activation of FXI. FXI appears to be most important with injury to the oropharynx and urinary tract, and bleeding in patients with congenital FXI deficiency is relatively mild compared with that in hemophilia A or hemophilia B, which are deficiencies of factors VIII and IX, respectively.

Thrombosis, though, is a different story. Epidemiological data and studies in animals support the importance of FXI in thrombosis. FXI-deficient individuals have reduced incidences of venous thromboembolism (VTE) and ischemic stroke compared with the general population, whereas those with high FXI levels carry more than twice the risk of VTE. Furthermore, thrombosis in response to injury is attenuated in mice deficient in FXI, and FXI knockdown or inhibition reduces thrombosis in a variety of animal models.

Taken together, these data suggest that FXIa appears to be more important for thrombosis than for hemostasis.

Talking Point: Early Clinical Data Shows Promise

Abelacimab is a monoclonal antibody that binds to FXI and locks it in the zymogen (inactive precursor) conformation. A recently published open-label, parallel-group trial observed 412 patients who were undergoing total knee arthroplasty. They were randomly assigned to receive one of three regimens of abelacimab (30 mg, 75 mg, or 150 mg) administered postoperatively in a single intravenous dose, or to receive 40 mg of enoxaparin administered subcutaneously once daily.

Venous thromboembolism occurred in 13 of 102 patients (13%) in the 30-mg abelacimab group, 5 of 99 patients (5%) in the 75-mg abelacimab group, and 4 of 98 patients (4%) in the 150-mg abelacimab group, as compared with 22 of 101 patients (22%) in the enoxaparin group. The 30-mg abelacimab regimen was noninferior to enoxaparin, and the 75-mg and 150-mg abelacimab regimens were superior to enoxaparin (P<0.001).

Additionally, the findings showed that bleeding occurred in 2% of the 30-mg cohort and 2% of the 75-mg cohort. Of note, none of the patients in the 150-mg abelacimab cohort reported bleeding. Further, there was no bleeding reported among the patients in the enoxaparin group.

The FOXTROT trial showed similar findings with another XI inhibitor osocimab.

Taken together, these two trials demonstrate the promise of FXI inhibition as a means to finally decouple bleeding from thrombosis.

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