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

Peter L Turecek; Michael Spannagl; Thorsten Kragh; Guenter Allmaier; Marietta Turecek; Gerald Schrenk; Herbert Gritsch; Ortrun Obermann-Slupetzky; Bruce M Ewenstein; Leonard A Valentino

doi:10.5482/HAMO-17-04-0018

Hämostaseologie, Table of Contents

Hamostaseologie 2017; 37(S 01): S15-S25
DOI: 10.5482/HAMO-17-04-0018

Original Article

Schattauer GmbH

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

Authors

Peter L Turecek

¹Baxalta Innovations GmbH, Vienna, Austria, now part of Shire
Michael Spannagl

²Department of Transfusion Medicine and Hemostasis, University Hospital Munich, Munich, Germany
Thorsten Kragh

²Department of Transfusion Medicine and Hemostasis, University Hospital Munich, Munich, Germany
Guenter Allmaier

³Institute of Chemical Technologies and Analytics, Vienna University of Technology, Vienna, Austria
Marietta Turecek

¹Baxalta Innovations GmbH, Vienna, Austria, now part of Shire
Gerald Schrenk

¹Baxalta Innovations GmbH, Vienna, Austria, now part of Shire
Herbert Gritsch

¹Baxalta Innovations GmbH, Vienna, Austria, now part of Shire
Ortrun Obermann-Slupetzky

¹Baxalta Innovations GmbH, Vienna, Austria, now part of Shire
Bruce M Ewenstein

⁴Shire, Cambridge, MA, USA
Leonard A Valentino

⁵Shire and Rush University, Chicago, IL, USA

Abstract

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.

Zusammenfassung

Den hochmolekularen Multimeren des VWF wird die höchste Aktivität zugeschrieben, an Thrombozyten und subendotheliale Strukturen zu binden und sind daher von kritischer Relevanz für die hämostatischen Funktionen von VWF bei der Stabilisierung des Thrombus. Im Gegensatz zu allen FVIII/VWF-haltigen Konzentraten, die aus Plasma gewonnen werden, behält humaner rVWF, der aus Säugetierzellkulturen gewonnen wird, ein intaktes Multimerspektrum, welches physiologisch im Golgi Apparat gebildet und in den α-Granula der Thrombozyten und in Weibel-Palade-Körperchen der Endothelzellen gespeichert wird. Im Rahmen physiko-und biochemischer, funktioneller und tierexperimenteller Studien wurde festgestellt, dass rVWF bessere Eigenschaften in Struktur und Funktion als plasmatischer VWF besitzt. Diese Eigenschaften korrelieren möglicherweise mit der Größe der Multimere und könnten daher durch die hochmolekularen Multimere in rVWF hervorgerufen werden. In den klinischen Studien, die mit rVWF im Vergleich zu einem plasmatischen FVIII-VWF-Konzentrat durchgeführt wurden, konnten die für rVWF anderen pharmakologischen und pharmakokinetischen Eigenschaften als für pdVWF bestätigt werden.

Keywords

Recombinant von Willebrand Factor - von Willebrand Disease - multimers - hemostasis

Schlüsselwörter

Rekombinanter von Willebrand Faktor - von Willebrand Syndrom - Multimere - Hämostase

Full Text

References

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