von Willebrand Factor and Factor VIII Clearance in Perioperative Hemophilia A PatientsFunding This study is part of the research program of the international multicenter OPTI-CLOT consortium (Patient tailOred PharmacokineTIc-guided dosing of CLOTting factor concentrate and DDAVP in bleeding disorders), which aims to implement PK-guided dosing of clotting factor replacement therapy by initiating studies that emphasize the impact of PK-guided dosing, by constructing prophylactic and on-demand dosing population PK models, and by evaluating cost-effectiveness of a PK-guided approach. This specific project was funded by an investigator-initiated research grant from the Dutch Research Institute NWO-ZonMW with co-financing by Baxter. A complete list of OPTI-CLOT research program members is available in the [Supplementary Material] (available in the online version).
13. März 2020
13. April 2020
01. Juni 2020 (online)
Background von Willebrand factor (VWF) is crucial for optimal dosing of factor VIII (FVIII) concentrate in hemophilia A patients as it protects FVIII from premature clearance. To date, it is unknown how VWF behaves and what its impact is on FVIII clearance in the perioperative setting.
Aim To investigate VWF kinetics (VWF antigen [VWF:Ag]), VWF glycoprotein Ib binding (VWF:GPIbM), and VWF propeptide (VWFpp) in severe and moderate perioperative hemophilia A patients included in the randomized controlled perioperative OPTI-CLOT trial.
Methods Linear mixed effects modeling was applied to analyze VWF kinetics. One-way and two-way analyses of variance were used to investigate perioperative VWFpp/VWF:Ag ratios and associations with surgical bleeding.
Results Fifty-nine patients with median age of 48.8 years (interquartile range: 34.8–60.0) were included. VWF:Ag and VWF:GPIbM increased significantly postoperatively. Blood type non-O or medium risk surgery were associated with higher VWF:Ag and VWF:GPIbM levels compared with blood type O and low risk surgery. VWFpp/VWF:Ag was significantly higher immediately after surgery than 32 to 57 hours after surgery (p < 0.001). Lowest VWF:Ag quartile (0.43–0.92 IU/mL) was associated with an increase of FVIII concentrate clearance of 26 mL/h (95% confidence interval: 2–50 mL/h) compared with highest VWF antigen quartile (1.70–3.84 IU/mL). VWF levels were not associated with perioperative bleeding F(4,227) = 0.54, p = 0.710.
Conclusion VWF:Ag and VWF:GPIbM levels increase postoperatively, most significantly in patients with blood type non-O or medium risk surgery. Lower VWF antigen levels did not lead to clinically relevant higher FVIII clearance. VWF:Ag or VWF:GPIbM levels were not associated with perioperative hemorrhage.
Keywordshemophilia A - von Willebrand factor - surgery - factor VIII - linear mixed effect modeling - postsurgical bleeding
M.C., I.M., and H.C.A.M.H. were responsible for protocol design and study implementation. I.M. enrolled patients, performed blood sampling for PK analysis, collected data, performed statistical analyses, and is main author of the manuscript together with M.C. L.B. performed population pharmacokinetic calculations. R.S., B.L., L.H., F.M., K.F., F.L., and K.M. monitored patient inclusion. M.C., R.M., J.E., F.L., K.F., K.M., and M.d.M. gave critical guidance during the project. M.C. and R.M. supervised the study. All authors substantially contributed to the writing and critically revised the manuscript, with approval of the final draft.
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