Comparing thrombin generation in patients with hemophilia A and patients on vitamin K antagonists

Abstract

Essentials It is unknown if hemophilia patients with atrial fibrillation need anticoagulation. Endogenous thrombin potentials (ETP) in hemophilia patients and patients on coumarins were compared. Severe hemophilia patients had comparable ETP to therapeutic international normalized ratio (INR). In non-severe hemophilia, 33% had higher ETP than therapeutic INR and may need anticoagulation. Click to hear Dr Negrier's perspective on global assays for assessing coagulation SUMMARY: Background It is unknown whether patients with hemophilia A with atrial fibrillation require treatment with vitamin K antagonists (VKAs) to the same extent as the normal population. Objective To compare hemostatic potential in hemophilia patients and patients on VKAs using thrombin generation (TG). Methods In this cross-sectional study, TG, initiated with 1pM tissue factor, was measured in 133 patients with severe (FVIII < 1%, n = 15) and non-severe (FVIII 1-50%, n = 118) hemophilia A, 97 patients on a VKA with an international normalized ratio (INR) ≥ 1.5 and healthy controls. Endogenous thrombin potential (ETP) (nm*min) was compared according to FVIII level (< 1%, 1-19% and 20-50%) with healthy controls and patients with sub-therapeutic INR (1.5-1.9) and therapeutic INR (≥ 2.0). Medians and interquartile ranges (IQRs) were calculated. Results Compared with healthy controls (898 [IQR 803-1004]), both hemophilia patients and patients on VKAs had lower median ETPs at 304 (196-449) and 176 (100-250), respectively. ETP was quite similar in severe hemophilia patients (185 [116-307]) and patients with a therapeutic INR (156 [90-225]). Compared with patients with therapeutic INR, ETP in patients with FVIII 1-19% and patients with FVIII 20-50% was higher at 296 (203-430) and 397 (219-632), respectively. All patients with therapeutic INR had an ETP < 400. Considering this threshold, 93% of severe hemophilia patients, 70% of patients with FVIII 1-19% and 52% of patients with FVIII 20-50% had an ETP < 400. Conclusion In severe hemophilia patients, TG was comparable to that in patients with a therapeutic INR. In one-third of non-severe hemophilia patients, TG was higher. These results suggest that anticoagulation therapy should be considered in a substantial proportion of non-severe hemophilia patients.

New concepts for anticoagulant therapy in persons with hemophilia

“…Finally, it has been demonstrated that the ETP in patients with severe and moderate hemophilia is equal to that of patients on VKAs, whereas mild hemophilia patients are in between controls and VKAs. 16,17 This is in line with our suggestion to withhold anticoagulants in severe hemophilia without prophylaxis but we tend to use them in the very mild cases. As there is considerable heterogeneity within mild hemophilia patients, individualized thrombin generation guided therapy might be the future.…”

Management of cardiovascular disease in aging persons with haemophilia

“…In the same study, 5 patients with mild haemophilia were analysed, showing more thrombin generation potential than anticoagulated patients but not in the same extend as normal controls. These results were reproduced in a larger study of 133 PWH and 907 patients on VKA (16). These data support the cautiousness of anticoagulant therapy in patient s with severe and moderate haemophilia, but also reflect the ability of thrombin generation in a substantial part of patients with mild haemophilia.…”

The antithrombotic and haemostatic effects of LASSBio-752: a synthetic, orally active compound in an arterial and venous thrombosis model in rats

“…This effect could be related to the metabolism of the compound. Although an enlargement of the clotting time of almost 50% was observed, this does not indicate an effective anticoagulation as it should be in the range of 100–200% enlargement . In fact there is no correlation between the time course of the observed antithrombosis in both arterial and venous model and the effect on clotting ex vivo .…”

“…Notably, at the antithrombotic concentration used, LASSBio‐752 did not cause significant bleeding, measured by tail snip, compared with UFH, which was used as the positive control. These findings indicate that LASSBio‐752, in comparison with rivaroxaban, is an effective and safe antithrombotic agent that can be further developed for clinical use in the prevention and treatment of thrombosis or other pathologies associated with deregulated coagulation.…”