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. 2017 Dec;37(Suppl 1):S15–S25. doi: 10.5482/HAMO-17-04-0018

The role of ultralarge multimers in recombinant human von Willebrand factor – a review of physico-and biochemical studies and findings in in vivo models and in humans with von Willebrand disease

Zur Funktion der großen Multimere in rekombinantem humanem von Willebrand Faktor – Ein Review physiko-und biochemischer Studien und von Ergebnissen aus Tiermodellen und klinischen Studien in Patienten mit von Willebrand Syndrom

Peter L Turecek 1,Korrespondenzadresse, Michael Spannagl 2, Thorsten Kragh 2, Guenter Allmaier 3, Marietta Turecek 1, Gerald Schrenk 1, Herbert Gritsch 1, Ortrun Obermann-Slupetzky 1, Bruce M Ewenstein 4, Leonard A Valentino 5
PMCID: PMC13557004  PMID: 29582921

Summary

Ultralarge multimers (ULM) of VWF are considered to be the most active with respect to binding to platelets and to subendothelial structures and therefore are of critical importance for the function of VWF in stabilizing the primary hemostatic plug. In contrast to plasma-derived FVIII-VWF concentrates, human rVWF obtained from mammalian cell culture retains the full-spectrum of intact multimers, including ULM, as physiologically formed in the Golgi apparatus and stored in platelet α-granules and endothelial cell Weibel–Palade bodies. In the course of physico and biochemical, functional and animal studies, rVWF exhibited superiority in structure and function compared to pdVWF. These effects seemed to correlate with the multimer size and therefore might be attributed to the presence of ULM in rVWF preparations. The pharmacokinetic (PK), safety and efficacy characteristics seen in preclinical studies were further demonstrated in clinical trials.

Keywords: Recombinant von Willebrand Factor, von Willebrand Disease, multimers, hemostasis

Ultralarge multimers (ULM) of VWF are considered to be the most active with respect to binding to platelets and to subendothelial structures and therefore are of critical importance for the function of VWF in stabilizing the primary hemostatic plug. In contrast to plasma-derived FVIII-VWF concentrates, human rVWF obtained from mammalian cell culture retains the full-spectrum of intact multimers, including ULM, as physiologically formed in the Golgi apparatus and stored in platelet α-granules and endothelial cell Weibel–Palade bodies. In the course of physico and biochemical, functional and animal studies, rVWF exhibited superiority in structure and function compared to pdVWF. These effects seemed to correlate with the multimer size and therefore might be attributed to the presence of ULM in rVWF preparations. The pharmacokinetic (PK), safety and efficacy characteristics seen in preclinical studies were further demonstrated in clinical trials.

Footnotes

Conflict of interest P.L. Turecek, M. Turecek, H. Gritsch, O. Obermann-Slupetzky, and G. Schrenk are full-time employees of Baxalta Innovations GmbH, Vienna, Austria

M. Spannagl, and T. Kragh performed the work as investigator initiated research without funding and have therefore no conflict of interest to report.

G. Allmaier initiated and supervised the work as part of a project funded by Baxalta Innovations GmbH, Vienna, Austria

B.M. Ewenstein is a full-time employee of Shire, Cambridge, MA, USA

L. Valentino is a full-time employee of Shire, Chicago, IL, USA

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