title: Coagulation Factor Concentrates Fail to Restore Alterations in Fibrin Formation Caused by Rivaroxaban or Dabigatran in Studies With Flowing Blood From Treated Healthy Volunteers.
abstract: We evaluated the hemostatic alterations in blood from healthy individuals treated for 5 days with direct oral anticoagulants (DOACs) rivaroxaban (20 mg/d) or dabigatran (150 mg/12 h) in a single-blind clinical trial with crossover assignment (NCT01478282). We assessed the potential of prothrombin complex concentrates, activated prothrombin complex concentrates, or recombinant activated factor VII, when added ex vivo, to reverse the alterations caused by these DOACs. Blood was drawn at maximum plasma concentration after the last dose of each DOAC, and modifications in coagulation biomarkers were evaluated using a series of tests performed under steady conditions including routine coagulation, thrombin generation, and thromboelastometry assays. Additional studies in standardized flow devices were applied to evaluate alterations on platelet deposition and fibrin formation on damaged vascular surfaces exposed to flowing blood. Both DOACs caused important modifications of all coagulation biomarkers and significantly reduced fibrin formation in flow studies. Alterations in biomarkers observed in steady laboratory tests were normalized and occasionally overcompensated by procoagulant strategies. In contrast, reductions in fibrin formation observed in studies with flowing blood were improved, although never completely restored to baseline levels. Effects of dabigatran in flow studies appeared more resistant to reversal strategies than those of rivaroxaban. Inconsistencies between results of coagulation studies in steady or flowing assays not only raise concerns about the adequacy of the earlier tests to predict the restoration of the coagulopathy induced by DOACs but also suggest limitations of nonspecific procoagulant strategies to control severe coagulopathy in patients inadvertently overexposed these agents.
authors.affiliation: Service of Hemotherapy-Hemostasis, Hospital Clinic, CDB, IDIBAPS, Barcelona, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Arellano-Rodrigo
authors.affiliation: Service of Hemotherapy-Hemostasis, Hospital Clinic, CDB, IDIBAPS, Barcelona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Lopez-Vilchez
authors.affiliation: Service of Hemotherapy-Hemostasis, Hospital Clinic, CDB, IDIBAPS, Barcelona, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Galan
authors.affiliation: Service of Hemotherapy-Hemostasis, Hospital Clinic, CDB, IDIBAPS, Barcelona, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Molina
authors.affiliation: Service of Hemotherapy-Hemostasis, Hospital Clinic, CDB, IDIBAPS, Barcelona, Spain.
authors.forename: Joan Carles
authors.initials: JC
authors.lastname: Reverter
authors.affiliation: Clinical Pharmacology, Hospital Clinic, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Carné
authors.affiliation: Internal Medicine, Hospital Clinic, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Villalta
authors.affiliation: Service of Hemotherapy-Hemostasis, Hospital Clinic, CDB, IDIBAPS, Barcelona, Spain.
authors.forename: Dolors
authors.initials: D
authors.lastname: Tassies
authors.affiliation: Service of Hemotherapy-Hemostasis, Hospital Clinic, CDB, IDIBAPS, Barcelona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Lozano
authors.affiliation: Service of Hemotherapy-Hemostasis, Hospital Clinic, CDB, IDIBAPS, Barcelona, Spain.
authors.forename: Maribel
authors.initials: M
authors.lastname: Díaz-Ricart
authors.affiliation: Service of Hemotherapy-Hemostasis, Hospital Clinic, CDB, IDIBAPS, Barcelona, Spain. Electronic address: gescolar@clinic.ub.es.
authors.forename: Gines
authors.initials: G
authors.lastname: Escolar
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000009:adverse effects*; D001777:Blood Coagulation / Q000187:drug effects; D001779:Blood Coagulation Factors / Q000627:therapeutic use*; D000069604:Dabigatran / Q000009:adverse effects*; D005260:Female; D005337:Fibrin / Q000378:metabolism*; D064368:Healthy Volunteers; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D000069552:Rivaroxaban / Q000009:adverse effects*; D016037:Single-Blind Method; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D001779:Blood Coagulation Factors; C025667:prothrombin complex concentrates; D005337:Fibrin; D000069552:Rivaroxaban; D000069604:Dabigatran
keywords: Activated prothrombin complex concentrates; Dabigatran; Direct oral anticoagulants; Prothrombin complex concentrates; Reversal; Rivaroxaban; rFVIIa