title: Tranexamic acid as adjunct therapy to bypassing agents in haemophilia A patients with inhibitors.
abstract: Haemophilia patients with inhibitors require bypassing agents (BPA) like activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa) to control bleeds. Adjunct tranexamic acid (TXA) may improve haemostasis. The objective of this study was to investigate safety and haemostatic effect of TXA given in combination with BPA. Healthy volunteers (N = 5) and haemophilia inhibitor patients (N = 6) were enrolled in a prospective case crossover design. Controls were treated with TXA 20 mg kg(-1) orally (O.R.) Patients were treated with aPCC 75 IU kg(-1) intravenous (I.V.) on day 1 followed by TXA 20 mg kg(-1) O.R. combined with aPCC 75 IU kg(-1) I.V. on day 2. A 14-day washout occurred before crossover to rFVIIa 90 μg kg(-1) I.V. ±TXA. Safety evaluation and blood sampling processes were performed at baseline, 15, 30, 60, 120, 180 and 240 min post treatment. Primary outcome was maximum clot firmness (MCF) evaluated by whole blood thromboelastometry using a TF + tissue plasminogen activator-based assay. Healthy controls showed a 20-fold increase in MCF following TXA. Adjunct TXA to aPCC or rFVIIa induced a significant increase in MCF (P < 0.0001) reaching levels indistinguishable from healthy controls treated with TXA (P > 0.05). Infusion of aPCC or rFVIIa alone induced only 3-10 fold increase in MCF from baseline, with a decline in MCF starting after 60-120 min. TXA did not increase the endogenous thrombin potential. No clinical or laboratory signs of thromboembolic events, disseminated intravascular coagulation, or hypercoagulability were observed. Combination of aPCC or rFVIIa with TXA normalizes clot stability in haemophilia patients with inhibitor as compared to healthy controls. No clinical or laboratory adverse events were observed.
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Haematology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: H T T
authors.initials: HT
authors.lastname: Tran
authors.forename: B
authors.initials: B
authors.lastname: Sørensen
authors.forename: C J
authors.initials: CJ
authors.lastname: Rea
authors.forename: S
authors.initials: S
authors.lastname: Bjørnsen
authors.forename: T
authors.initials: T
authors.lastname: Ueland
authors.forename: A H
authors.initials: AH
authors.lastname: Pripp
authors.forename: G E
authors.initials: GE
authors.lastname: Tjønnfjord
authors.forename: P A
authors.initials: PA
authors.lastname: Holme
mesh_terms: D000328:Adult; D000933:Antifibrinolytic Agents / Q000627:therapeutic use*; D019774:Blood Coagulation Factor Inhibitors / Q000097:blood; D001779:Blood Coagulation Factors / Q000627:therapeutic use*; D018592:Cross-Over Studies; D006467:Hemophilia A / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013916:Thrombelastography; D014148:Tranexamic Acid / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000933:Antifibrinolytic Agents; D019774:Blood Coagulation Factor Inhibitors; D001779:Blood Coagulation Factors; C025667:prothrombin complex concentrates; D014148:Tranexamic Acid
keywords: activated prothrombin complex concentrates; haemophilia; inhibitors; recombinant activated FVII; tranexamic acid