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 March 2020
13 April 2020
01 June 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.
- 1 Srivastava A, Brewer AK, Mauser-Bunschoten EP. , et al; Treatment Guidelines Working Group on Behalf of The World Federation Of Hemophilia. Guidelines for the management of hemophilia. Haemophilia 2013; 19 (01) e1-e47
- 2 Hazendonk HC, Lock J, Mathôt RA. , et al. Perioperative treatment of hemophilia A patients: blood group O patients are at risk of bleeding complications. J Thromb Haemost 2016; 14 (03) 468-478
- 3 Leebeek FWG, Mauser-Bunschoten EP. Richtlijn diagnostiek en behandeling van hemofilie en aanverwante hemostase stoornissen. Utrecht: Van Zuiden Communications BV; 2009
- 4 Pipe SW, Montgomery RR, Pratt KP, Lenting PJ, Lillicrap D. Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A. Blood 2016; 128 (16) 2007-2016
- 5 Fijnvandraat K, Peters M, ten Cate JW. Inter-individual variation in half-life of infused recombinant factor VIII is related to pre-infusion von Willebrand factor antigen levels. Br J Haematol 1995; 91 (02) 474-476
- 6 Kahlon A, Grabell J, Tuttle A. , et al. Quantification of perioperative changes in von Willebrand factor and factor VIII during elective orthopaedic surgery in normal individuals. Haemophilia 2013; 19 (05) 758-764
- 7 Hazendonk HC, van Moort I, Fijnvandraat K. , et al. The “OPTI-CLOT” trial. A randomised controlled trial on periOperative PharmacokineTIc-guided dosing of CLOTting factor concentrate in haemophilia A. Thromb Haemost 2015; 114 (03) 639-644
- 8 Koshy M, Weiner SJ, Miller ST. , et al; Cooperative Study of Sickle Cell Diseases. Surgery and anesthesia in sickle cell disease. Blood 1995; 86 (10) 3676-3684
- 9 Schulman S, Angerås U, Bergqvist D, Eriksson B, Lassen MR, Fisher W. ; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb Haemost 2010; 8 (01) 202-204
- 10 Sanders YV, Groeneveld D, Meijer K. , et al; WiN study group. von Willebrand factor propeptide and the phenotypic classification of von Willebrand disease. Blood 2015; 125 (19) 3006-3013
- 11 Hazendonk H, Fijnvandraat K, Lock J. , et al; “OPTI-CLOT” study group. A population pharmacokinetic model for perioperative dosing of factor VIII in hemophilia A patients. Haematologica 2016; 101 (10) 1159-1169
- 12 Jonsson EN, Karlsson MO. Xpose--an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed 1999; 58 (01) 51-64
- 13 van Loon JE, Sonneveld MA, Praet SF, de Maat MP, Leebeek FW. Performance related factors are the main determinants of the von Willebrand factor response to exhaustive physical exercise. PLoS One 2014; 9 (03) e91687
- 14 Claus RA, Bockmeyer CL, Sossdorf M, Lösche W, Hilberg T. Physical stress as a model to study variations in ADAMTS-13 activity, von Willebrand factor level and platelet activation. J Thromb Haemost 2006; 4 (04) 902-905
- 15 Borchiellini A, Fijnvandraat K, ten Cate JW. , et al. Quantitative analysis of von Willebrand factor propeptide release in vivo: effect of experimental endotoxemia and administration of 1-deamino-8-D-arginine vasopressin in humans. Blood 1996; 88 (08) 2951-2958
- 16 Sporn LA, Marder VJ, Wagner DD. Inducible secretion of large, biologically potent von Willebrand factor multimers. Cell 1986; 46 (02) 185-190
- 17 Castaman G, Tosetto A, Eikenboom JC, Rodeghiero F. Blood group significantly influences von Willebrand factor increase and half-life after desmopressin in von Willebrand disease Vicenza. J Thromb Haemost 2010; 8 (09) 2078-2080
- 18 Sanders YV, Giezenaar MA, Laros-van Gorkom BA. , et al; WiN study group. von Willebrand disease and aging: an evolving phenotype. J Thromb Haemost 2014; 12 (07) 1066-1075
- 19 Atiq F, Fijnvandraat K, van Galen KPM. , et al; WiN study group. BMI is an important determinant of VWF and FVIII levels and bleeding phenotype in patients with von Willebrand disease. Am J Hematol 2019; 94 (08) E201-E205
- 20 Loomans JI, Stokhuijzen E, Peters M, Fijnvandraat K. Administration of DDAVP did not improve the pharmacokinetics of FVIII concentrate in a clinically significant manner. J Clin Transl Res 2018; 3 (Suppl. 02) 351-357