Experimental data suggest that targeting factor XI, a key component of the intrinsic pathway, attenuates thrombosis without affecting haemostasis. Although its role in thrombosis in humans is unknown, there is evidence that patients with congenital factor XI deficiency have a reduced risk of venous thromboembolism. Factor XI levels can be lowered with FXI-ASO, a second-generation antisense oligonucleotide that specifically reduces human factor XI messenger RNA expression in the liver. In the current study, treatment with FXI-ASO was initiated 36 days before surgery (day 1 of study). Patients received 3 subcutaneous doses during the first week (days 1, 3, and 5) followed by four once-weekly doses on days 8, 15, 22, and 29. On day 36, the day of surgery, patients received a dose 6 hours postoperatively. A final dose was given on day 39. Enoxaparin 40 mg once daily was initiated the evening before or 6 to 8 hours after surgery, according to the investigator’s preference, and was to be continued for at least 8 days postoperatively.
According to an accompanying editorial, inhibiting thrombosis without inducing bleeding is the holy grail of anticoagulant therapy and there are currently no commercially available anticoagulants that achieve this goal. It notes that this study does not prove that reduction of factor XI levels inhibits thrombosis without affecting bleeding, since the incidence of clinically relevant bleeding is relatively low after knee arthroplasty, even when patients are receiving anticoagulants; and although the incidence of bleeding was increased in the enoxaparin group as compared with 300mg group, the difference was not significant. In addition, the incidence of clinically relevant bleeding seen with the 200mg and 300mg doses of FXI-ASO was within the range previously observed after prophylaxis with 40mg enoxaparin in patients undergoing knee arthroplasty. Furthermore, FXI-ASO was associated with a high incidence of adverse events at the injection site; and at 70 days after the initiation of treatment, factor XI levels remained reduced by approximately 60% without evidence of recovery. The authors believe that issues of convenience and questions regarding reversibility might limit the use of FXI-ASO for prophylaxis of venous thrombosis in patients undergoing surgery. They conclude these data do not make a compelling case for the clinical use of the FXI-ASO over anticoagulants currently used for prophylaxis in patients undergoing knee arthroplasty. A larger study will be required to evaluate whether targeting factor XI spares haemostasis.