title: Monitoring bypassing agent therapy - a prospective crossover study comparing thromboelastometry and thrombin generation assay.
abstract: The aim of this study was to evaluate the capability of thromboelastometry (ROTEM) and thrombin generation assay (TGA) to monitor the treatment response of bypassing agent (BPA) therapy and to study whether one method is superior to another. In a prospective crossover study haemophilia A patients with high titre inhibitors were included to receive a dose of 75 U kg(-1) activated prothrombin complex concentrates (aPCC) intravenously. Blood sampling was performed at baseline, 15, 30 min, 1, 2, 3 and 4 h post-infusion for TGA and ROTEM analysis. After a washout period of 14 days the subjects received recombinant FVIIa (rFVIIa) at a dose of 90 μg kg(-1) and similar blood sampling was performed. Healthy subjects were used as controls. Six haemophilia A patients with inhibitors were included. We found that TGA parameters endogenous thrombin potential (ETP) and peak thrombin increased 2-3 folds from baseline 15-30 min after infusion. ROTEM parameters MaxVel and maximum clot firmness increased to a level comparable to that of healthy controls. An individual difference in response was observed for different parameters among participants. ETP and peak thrombin were almost two-fold greater following aPCC infusion compared to rFVIIa, whereas ROTEM parameters showed no difference in response between the two products. The study showed that ROTEM and TGA have a great potential to evaluate the effect of BPA in haemophilia patients with inhibitors. TGA seemed to be more sensitive than ROTEM in reflecting the difference in treatment response between aPCC and rFVIIa. Additional prospective clinical studies are needed to clarify which assay and what parameters are clinically predictive.
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway.|Department of Haematology, Oslo University Hospital, Oslo, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: H T T
authors.initials: HTT
authors.lastname: Tran
authors.affiliation: Alnylam, San Francisco, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Sørensen
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Bjørnsen
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway.|Department of Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway.
authors.forename: A H
authors.initials: AH
authors.lastname: Pripp
authors.affiliation: Department of Haematology, Oslo University Hospital, Oslo, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: G E
authors.initials: GE
authors.lastname: Tjønnfjord
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway.|Department of Haematology, Oslo University Hospital, Oslo, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: P
authors.initials: P
authors.lastname: Andre Holme
mesh_terms: D000328:Adult; D001780:Blood Coagulation Tests; D016022:Case-Control Studies; D018592:Cross-Over Studies; D005169:Factor VIII / Q000276:immunology; D006467:Hemophilia A / Q000097:blood* / Q000276:immunology; D006801:Humans; D007518:Isoantibodies / Q000276:immunology; D008297:Male; D008875:Middle Aged; D013916:Thrombelastography; D013917:Thrombin / Q000096:biosynthesis*; D055815:Young Adult
chemical_list: D007518:Isoantibodies; D005169:Factor VIII; D013917:Thrombin
keywords: ROTEM; TGA; aPCC; haemophilia A; inhibitors; rFVIIa