Procoagulant Platelets as a Compensatory Mechanism and Their Impact on Bleeding Severity in Hemophilia A

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Introduction: Hemophilia A is a congenital bleeding disorder caused by a deficiency or dysfunction of coagulation factor VIII (FVIII), leading to varying degrees of bleeding severity. Recent research suggests that procoagulant platelets may play a compensatory role in modulating bleeding tendencies in patients with bleeding of unknown cause. Procoagulant platelets, characterized by CD62P and Annexin V expression, may enhance plasmatic coagulation, potentially reducing bleeding episodes in hemophilia A. Aim: Investigation of the relationship between procoagulant platelet activity and clinical bleeding severity in hemophilia A and evaluate whether this activity could serve as a novel therapeutic target. Method: In thisstudy, we examined the potential of platelets to develop a procoagulant phenotype in 13 hemophilia A and 6 carriers. Clinical bleeding scores were assessed using the ISTH-BAT, and correlations between platelet procoagulant activity and bleeding severity were evaluated. Blood samples were collected and analyzed for platelet activation markers (CD62P, Annexin V), and calcium kinetics using flow cytometry (FC) in flow cytometer. Platelet aggregation was measured by light transmission aggregometry and thrombin generation on platelet surface.Additionally, clot retraction assays were performed to compare the contractile properties of platelets between hemophilia A and healthy donors (HC), aiming to assess platelet function independently of FVIII levels. Results : Patients had a mean ISTH-BAT of 10 (range 3-16). The hemophilia A carriers had a bleeding score of 11 (0-34). Procoagulant platelet formation was significantly higher in hemophilia A patients and carriers compared to HC (CD62P+/PS+[%] mean±SEM: 61.11±3.37 vs. 35.53±3.27; p<0.0001). A strong negative correlation was observed between the proportion of procoagulant platelets and clinical bleeding scores (p=0.0085), indicating that increased procoagulant platelet activity is associated with a lower bleeding tendency. Upon stimulation, hemophilia A patients demonstrated prolonged and enhanced calcium fluxes compared to HC, suggesting a priming of platelets for turning procoagulant. Interestingly, no significant correlation was found between FVIII activity and procoagulant platelet formation (p=0.5713), indicating that platelet-driven thrombin generation may operate independently of FVIII levels. Furthermore, clot retraction assays revealed comparable clot retraction between hemophilia A patients and HC (69.82%±3.20 vs. 65.54%±1.79 p=0.2927), suggesting preserved platelet contractile function in these patients despite FVIII deficiency. Conclusion: Procoagulant platelets may serve as a compensatory mechanism in hemophilia A, independent of FVIII levels. Integrating procoagulant platelet assessment into clinical practice could improve the prediction of bleeding risk and provide a basis for personalized treatment strategies, ultimately enhancing patient outcomes. Publication History Article published online: 13 February 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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