Therapeutic Strategies Combining Antiplatelet With Anticoagulant Actions: Heparin Proteoglycan Mimetic APAC as a Model.

Abstract

Current antithrombotic therapies (combining aspirin, P2Y₁₂ inhibitors, and anticoagulants) target both platelet and coagulation pathways to reduce ischemic events in high-risk cardiovascular patients. Despite efficacy, these regimens are limited by increased bleeding risk, as evidenced by multiple clinical trials. Suboptimal pharmacodynamics and nonindividualized treatment approaches complicate the therapeutic success. Pediatric cardiac conditions and severe thrombophilia underlying arterial and immune thrombosis pose special challenges. The dual actions aim at addressing these gaps by especially attenuating arterial platelet-rich thrombi and safety concerns. We highlight the need for improved antithrombotic strategies across diverse patient populations. To potentially overcome the limitations, we present antiplatelet and anticoagulant (APAC), a heparin proteoglycan mimetic integrating APAC effects. APAC, administered locally or intravenously, targets VWF (von Willebrand Factor) and thrombin, effectively inhibiting platelet-fibrin deposition, under high shear rate flow conditions over surfaces of collagen and TF (tissue factor). Preclinical models show that APAC reduces atherosclerotic and stenotic lesions, inflammation, and ischemia-reperfusion injury without bleeding propensity. These findings position APAC as a promising candidate for safe, translational dual antithrombotic. Early clinical trials demonstrated the safety of APAC under both systemic and local administration. A phase 2 clinical study in peripheral arterial disease is underway, and another is planned for arteriovenous fistula patency for renal patients.