The Impact of non-factor VIII therapy in haemophilia A on procoagulant platelets

Introduction: Hemophilia A is an inherited bleeding disorder with functional deficiency of coagulation factor VIII. The treatment has improved over the last decades and depends on the severity of haemophilia A. But the factor activity in patients with hemophilia A does not always correlate with the bleeding tendency. Platelets promote coagulation by turning procoagulant through exposure of PS and by binding of prothrombinase complex on their surface. Recently we were able to show that a procoagulant phenotype correlates negatively with the ISTH-BAT score. The non-factor therapy concizumab, an anti-tissue factor pathway inhibitor, increases thrombin generation in plasma by inhibiting FXa binding to TFPI, and blocking of TFPI inhibition of TF–FVIIa. However, its significance for thrombin generation on platelets, particularly in the procoagulant state, remains unclear and requires further investigation.

Aim: The effect of concizumab on the platelets and assess its potential implications for patients with increased procoagulant activity.

Method: Citrated blood samples from 8 hemophilia A patients and healthy donors were collected. Demographic data, clinical treatment and bleeding history from ISTH-BAT bleeding scores were collected. PLTs phenotyping from platelet-rich plasma (PRP) were measured using flow cytometry (FC), procoagulant PLTs were induced by buffer and thrombin/convulxin (CVX). Concizumab (1000ng/mL) was added. Thrombin generation in PRP and platelet poor plasma (PPP) was assessed following platelet activation with buffer, TRAP-6, convulxin, or their combination and measured in a calibrated automated thrombogram (CAT). Healthy donors (HC) served as controls.

Results: We observed that adding concizumab did not significantly change the percentage of procoagulant platelets in either healthy controls (p=0.0952) or patients with hemophilia A (p=0.2447). However, patients with hemophilia A demonstrated a significantly greater capacity to enhance thrombin generation on platelets in a procoagulant state compared to healthy controls (mean of difference 846±165 [nM*min] vs. 174±52 [nM*min]). Most importantly, patients with hemophilia A achieved a fully normalized thrombin generation under procoagulant conditions with concizumab, reaching levels comparable to those of healthy controls (1481±109 [nM*min] vs. 1616±231 [nM*min]; p=0.7308).

Conclusion: Under procoagulant conditions, concizumab effectively normalizes thrombin generation on procoagulant platelets in hemophilia A patients, bringing it to levels comparable to healthy controls. This may significantly reduce bleeding risk. However, due to the associated increase in procoagulant activity, careful monitoring of thrombotic risks, especially in patients with cardiovascular conditions, is necessary.

 

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Conflict of Interest:

The authors have no conflict of interests related to this work. K.A. received honoraria to the Medical University Hospital of Tübingen for lectures from CSL Behring, Sobi, Meet the expert, Expanda, Werfen and research grants to the Medical University Hospital of Tübingen from Octapharma and Bayer.

Publication History

Article published online:
13 February 2025