title: Heparin supplement counteracts the prohemostatic effect of prothrombin complex concentrate and factor IX concentrate: An in vitro evaluation.
abstract: BACKGROUND
  Coagulation 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.
  
  
  METHODS
  Prohemostatic 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.
  
  
  RESULTS
  Most 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 500μg/L rivaroxaban.
  
  
  CONCLUSIONS
  Compositional 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.
authors.affiliation: Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands. Electronic address: h.brinkman@sanquin.nl.
authors.forename: Herm Jan M
authors.initials: HJ
authors.lastname: Brinkman
authors.affiliation: Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands.
authors.forename: Sanne
authors.initials: S
authors.lastname: Patiwael
authors.affiliation: Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands.
authors.forename: Shrijana
authors.initials: S
authors.lastname: Tripathi
authors.affiliation: Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands; Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Meijers
mesh_terms: D000925:Anticoagulants / Q000032:analysis / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D001779:Blood Coagulation Factors / Q000032:analysis / Q000494:pharmacology*; D001780:Blood Coagulation Tests; D003029:Coagulants / Q000032:analysis / Q000494:pharmacology*; D004338:Drug Combinations; D005164:Factor IX / Q000032:analysis / Q000494:pharmacology*; D002836:Hemophilia B / Q000188:drug therapy; D006493:Heparin / Q000032:analysis / Q000494:pharmacology*; D006801:Humans
chemical_list: D000925:Anticoagulants; D001779:Blood Coagulation Factors; D003029:Coagulants; D004338:Drug Combinations; C025667:prothrombin complex concentrates; D005164:Factor IX; D006493:Heparin
keywords: Blood products; Hemophilia B; Oral anticoagulants; Rivaroxaban; Vitamin K-dependent factors