A Novel Platelet-Inspired Nanotechnology to Restore Hemostasis in Patients on Antiplatelet Agents

/Abstract Antiplatelet therapy with P2Y12 inhibitors (clopidogrel, ticagrelor etc.) is widely used to prevent thrombotic events in patients with cardiovascular disease. However, these agents significantly increase the risk of bleeding complications, impacting over 1.4 million lives annually in the United States. The lack of specific reversal agents often leads to delayed surgical interventions and significant complications, including increased transfusions, in- hospital complications, higher mortality, and prolonged hospital stays. Bleeding management is particularly problematic in patients with traumatic brain injury (TBI), with 10-31% of TBI patients taking P2Y12 inhibitors prior to admission. TBI patients on P2Y12 inhibitors have a significantly increased risk of intracranial hemorrhage and mortality, with a 50-60% increased risk of severe bleeding and a 6-8-fold increased 30-day mortality when reversal of antiplatelet therapy is not possible. Current hemostatic agents, such as prothrombin complex concentrates, fibrinogen concentrates, and recombinant activated factor VII, are ineffective in rescuing hemostasis in the presence of P2Y12 inhibitors, leaving platelet transfusions as the only standard of care. However, platelet transfusions have significant limitations, including limited efficacy, donor dependence, short shelf-life, immune responses, and refractoriness. There is a critical unmet need for a readily available, donor- independent therapeutic that can effectively restore hemostatic function in TBI patients on P2Y12 inhibitors. We hypothesize that SynthoPlate (SP), a platelet-inspired synthetic hemostatic nanoparticle, can restore hemostasis in TBI patients on P2Y12 inhibitors by enhancing platelet adhesion and aggregation at the injury site, thereby reducing hemorrhage and mortality. Our preliminary data demonstrate SP's efficacy in improving clot formation under P2Y12 inhibition in vitro, reducing bleeding by 80%, and enhancing survival in preclinical models of P2Y12 inhibitor-induced hemorrhage. Aim 1 will establish SP's dose-response relationship in clinically relevant rat models of P2Y12 inhibitor-induced bleeding, including TBI, examining blood loss, hemodynamics, platelet function, hemostatic output and neurological outcomes. Aim 2 will determine SP's safety profile, pharmacokinetics, and any drug-drug interactions in the presence of P2Y12 inhibitors, identifying the therapeutic window and informing clinical dosing strategies. Aim 3 will develop a comprehensive clinical development plan, defining the regulatory pathway, and Phase 1 trial design for the target TBI population. This work will deliver a robust preclinical efficacy, safety, and pharmacokinetic package, and a strategic clinical roadmap to advance SP to IND filing and clinical evaluation in this vulnerable TBI population with a substantial unmet need. By reducing intracranial hemorrhage and mortality, SP has the potential to transform management of TBI in the setting of P2Y12 inhibitors and significantly improve patient outcomes. Establishing proof-of-concept in TBI will enable future expansion to other indications where P2Y12 inhibitor-associated bleeding is a major concern. Project Number: 1R44HL180258-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Ujjal Didar Singh Sekhon | Institution: HAIMA THERAPEUTICS, LLC, CLEVELAND, OH | Award Amount: $944,676 | Activity Code: R44 | Study Section: Special Emphasis Panel[ZRG1 IVBH-V (11)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R44HL18025801