Defective platelet PAR1 signaling is associated with perioperative bleeding and impaired host defense

Introduction Thrombin activates human platelets through cleavage of protease-activated receptor 1 (PAR1), leading to signaling via intracellular G proteins (e.g., Gαq, Gα12/13) and β-arrestin [ 1 ]. Platelet PAR1 contributes to innate immunity by promoting the release of antimicrobial factors and facilitating immune cell functions [ 2 ] [ 3 ]. Method Platelet function was assessed by light transmittance aggregometry (LTA), lumiaggregometry, flow cytometry, and platelet function analyzer (PFA). Results A 26-year-old homeless male from Romania presented with septic shock due to fungal and bacterial pneumonia with pleural empyema. The clinical course was complicated by compartment syndrome due to necrotizing fasciitis requiring thigh amputation, septic cardiomyopathy, acute kidney injury, multiple non-healing decubiti with adjacent osteomyelitis, and persistent intrapulmonary abscesses. Following placement of chest tubes, eight thoracotomies became necessary because of recurrent bleeding into the pleural space. The patient cumulatively received 77 units of packed red blood cells, 11 units of fresh frozen plasma, and one platelet concentrate. He had previously undergone no other invasive or surgical procedures and did not report a personal or family history of bleeding. After three months of hospitalization and near complete recovery, the patient agreed on being transferred back to his family in Romania. Initial work-up revealed normal platelet counts and global coagulation tests (PT/INR, aPTT). Normal PFA closure times with collagen/epinephrine and collagen/ADP and elevated von Willebrand factor levels with normal activity-to-antigen ratio ruled out (acquired) von Willebrand disease. Routine LTA using platelet-rich plasma revealed normal maximal platelet aggregation with 1 µg/mL collagen, 5 µM ADP, 1.2 mg/mL ristocetin, 1 mM arachidonic acid, and 10 µM epinephrine. In contrast, maximal platelet aggregation induced by 20 µM TRAP-6 (SFLLRN) was repeatedly decreased to