Redistribution and Hemostatic Action of Recombinant Activated Factor VII Associated with Platelets

Research output: Contribution to journalArticle

Abstract

Clinical evidence accumulated from hemophilic patients during prophylaxis with recombinant activated factor VII (rFVIIa) suggests that the duration of the hemostatic action of rFVIIa exceeds its predicted plasma half-life. Mechanisms involved in this outcome have not been elucidated. We have investigated in vitro the redistribution of rFVIIa in platelets from healthy donors, patients with FVII deficiency, and one patient with Bernard-Soulier syndrome. Platelet-rich plasma was exposed to rFVIla (3 to 60 mu g/mL). Flow cytometry, inununocytochemistry, and coagulation tests were applied to detect and quantify rFVila. The hemostatic effect of rFV1Ia associated to platelets was evaluated using perfusion models. Our studies revealed a dose-dependent association of rFVIla to the platelet cytoplasm with redistribution into the open canalicular system, and a granules. Mechanisms implicated in the internalization are multiple, involve GPIb and GPIV, and require phospholipids and cytoskeletal assembly. After platelet activation with thrombin, platelets exposed rFVIla on their membrane. Perfusion studies revealed that the presence of 30% of platelets containing FVIIa improved platelet aggregate formation and enhanced fibrin generation (P < 0.01 versus control). Our results indicate that, at therapeutic concentrations, rFVIIa can be internalized into platelets, where it is protected from physiological clearance mechanisms and can still promote hemostatic activity. Redistribution of rFVIIa into platelets may explain the prolonged prophylactic effectiveness of rFYlla in hemophilia. (AmJ Pathol 2011, 178:2938-294% DOI: 10.1016/j.ajpath.2011.02.026)

Details

Authors
  • Irene Lopez-Vilchez
  • Ulla Hedner
  • Carmen Altisent
  • Maribel Diaz-Ricart
  • Gines Escolar
  • Ana M. Galan
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology
Original languageEnglish
Pages (from-to)2938-2948
JournalAmerican Journal of Pathology
Volume178
Issue number6
Publication statusPublished - 2011
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Emergency medicine/Medicine/Surgery (013240200)