Heparin supplement counteracts the prohemostatic effect of prothrombin complex concentrate and factor IX concentrate: An in vitro evaluation

• FIX concentrate and PCC can contain anticoagulant heparin supplement
• During FIX concentrate and PCC infusions, levels of co-administered heparin may be within the heparin therapeutic window
• Heparin supplement has a major impact on the laboratory assessment of anticoagulation reversal by PT, aPTT, CAT and TEG
• Heparin supplement enhances the anticoagulant effect of rivaroxaban
• An anticoagulant effect of heparin supplement should be considered when treating emergency bleeds with high doses of factor concentrate

IntroductionCoagulation factor concentrates like factor IX (FIX) and prothrombin complex concentrate (PCC) can contain anticoagulant substances that may hamper their procoagulant effectiveness in the treatment of hemophilia B or reversal of oral anticoagulation, as well as the laboratory assessment thereof. The aim of the present study was to evaluate the influence of anticoagulant heparin supplement on the prohemostatic potential of different PCCs and FIX concentrates.Materials and methodsProhemostatic potential was evaluated in vitro employing PT/aPTT, thrombography (TGA) and thromboelastography (TEG) with FIX deficient plasma, vitamin K antagonist (VKA)-anticoagulated plasma and plasma anticoagulated with rivaroxaban.ResultsMost PCCs contained heparin, while heparin was detected in 1 out of 4 examined FIX concentrates. All heparin-containing clotting factor concentrates showed severely hampered prohemostatic effects when therapeutic doses were added to anticoagulated plasmas. Upon heparin removal, comparable prohemostatic effects were observed. Of importance is the notion that the anticoagulant effect of heparin was enhanced by rivaroxaban, resulting in a 7 fold increased PT sensitivity towards heparin in the presence of 500 μg/L rivaroxaban.ConclusionsCompositional differences between clotting factor concentrates should be taken into account. Therapeutic levels of heparin may be co-infused when treating emergency bleeds with high prohemostatic drug doses, particularly those recommended in the reversal of non-VKA anticoagulants such as rivaroxaban by PCC. Given the relative short half-life of heparin compared to vitamin K-dependent clotting factors, an anticoagulant heparin effect shortly after concentrate infusion should be considered clinically and while interpreting laboratory coagulation parameters.