title: The effect of tissue factor concentration on calibrated automated thrombography in the presence of inhibitor bypass agents.
abstract: Thrombin generation has been suggested as a method to monitor treatment with factor eight inhibitor bypassing activity (FEIBA) or recombinant FVIIa (rFVIIa). The sensitivity of the assay for individual coagulation factors is dependent on the tissue factor (TF) concentration. An inverse relation between the rFVIIa concentration needed to shorten the clotting time and TF concentration has been shown but the data on thrombin generation are inconsistent. Information on TF concentration in measurements with FEIBA is limited. We studied the influence of TF concentration (1 and 5 pM) on thrombin generation through spiking experiments with rFVIIa and/or FEIBA in the plasma of severe haemophilia A patients and after four and three treatment episodes, respectively, using the calibrated automated thrombin generation assay (CAT) in platelet poor plasma. Spiking with FEIBA showed a linear relation with the endogenous thrombin potential (ETP)/peak at 1 pM but substrate depletion at 5 pM. Spiking with rFVIIa showed a near linear dose-response relation with the ETP/peak at 1 pm but only a shortening of the initiation phase at 5 pM. Similar effects were present in post-treatment samples. FEIBA acted synergistically with rFVIIa. This suggest a role for CAT in monitoring inhibitor bypass treatment but low TF concentrations are required to avoid substrate depletion with FEIBA and to demonstrate the effect of rFVIIa.
authors.affiliation: Sheffield Haemophilia and Thrombosis Centre, Royal Hallamshire Hospital, Sheffield, UK. joost.vanveen@ukgateway.net
authors.forename: J J
authors.initials: JJ
authors.lastname: van Veen
authors.forename: A
authors.initials: A
authors.lastname: Gatt
authors.forename: A E
authors.initials: AE
authors.lastname: Bowyer
authors.forename: P C
authors.initials: PC
authors.lastname: Cooper
authors.forename: S
authors.initials: S
authors.lastname: Kitchen
authors.forename: M
authors.initials: M
authors.lastname: Makris
mesh_terms: D001779:Blood Coagulation Factors / Q000032:analysis / Q000627:therapeutic use*; D001780:Blood Coagulation Tests / Q000592:standards*; D016903:Drug Monitoring; D015942:Factor VIIa / Q000627:therapeutic use*; D006467:Hemophilia A / Q000097:blood* / Q000188:drug therapy; D006801:Humans; D011994:Recombinant Proteins / Q000097:blood / Q000627:therapeutic use; D013917:Thrombin / Q000032:analysis*; D013925:Thromboplastin / Q000737:chemistry*
chemical_list: D001779:Blood Coagulation Factors; D011994:Recombinant Proteins; D013925:Thromboplastin; C103587:recombinant FVIIa; C065655:anti-inhibitor coagulant complex; D015942:Factor VIIa; D013917:Thrombin