New Targets for Antithrombotic Medications: Seeking to Decouple Thrombosis from Hemostasis

Arterial and venous thromboses are leading causes of morbidity and mortality worldwide. Numerous antithrombotic agents are currently available with antiplatelet, thrombolytic/fibrinolytic, and anticoagulant activity. However, all the currently available antithrombotic agents carry a risk of bleeding that often prevents their use. This unfavorable risk-benefit profile is particularly challenging for patients with cancer-associated venous thromboembolism, patients with atrial fibrillation at a high risk of bleeding, and for patients with end-stage renal disease. Patients with ischemic stroke and acute coronary syndromes have not yet found a favorable risk-benefit profile with anticoagulant therapy to help reduce the residual thromboembolic risk that remains after antiplatelet and lipid therapy. Two emerging classes of antithrombotic agents, factor XI/XIa inhibitors and glycoprotein VI inhibitors, have shown promise in their ability to prevent pathologic thrombosis without increasing the risk of hemostatic-related bleeding in phase 2 studies. Among the factor XI/XIa inhibitors of coagulation, a parenterally administered monoclonal antibody (abelacimab) and two orally administered small molecule inhibitors (asundexian, milvexian) are collectively being studied in patients with atrial fibrillation, cancer-associated venous thromboembolism, acute coronary syndrome, and ischemic stroke. One parenterally administered glycoprotein VI antiplatelet agent (glenzocimab) is currently being studied in patients with ischemic stroke. If shown to be efficacious and safe in ongoing phase 3 studies, both classes of emerging antithrombotic agents have the potential to greatly improve outcomes for patients with challenging thrombotic conditions.