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

Lopez-Vilchez, Irene; Hedner, Ulla LU ; Altisent, Carmen; Diaz-Ricart, Maribel; Escolar, Gines and Galan, Ana M. (2011) In American Journal of Pathology 178(6). p.2938-2948
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... (More)
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) (Less)
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published
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in
American Journal of Pathology
volume
178
issue
6
pages
2938 - 2948
publisher
American Society for Investigative Pathology
external identifiers
  • wos:000298306900048
  • scopus:79959404217
ISSN
1525-2191
DOI
10.1016/j.ajpath.2011.02.026
language
English
LU publication?
yes
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ae945fc7-ed5e-401a-b136-3b2a1ff4b987 (old id 2333563)
date added to LUP
2012-02-01 07:39:31
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2017-08-06 03:04:21
@article{ae945fc7-ed5e-401a-b136-3b2a1ff4b987,
  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 &lt; 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)},
  author       = {Lopez-Vilchez, Irene and Hedner, Ulla and Altisent, Carmen and Diaz-Ricart, Maribel and Escolar, Gines and Galan, Ana M.},
  issn         = {1525-2191},
  language     = {eng},
  number       = {6},
  pages        = {2938--2948},
  publisher    = {American Society for Investigative Pathology},
  series       = {American Journal of Pathology},
  title        = {Redistribution and Hemostatic Action of Recombinant Activated Factor VII Associated with Platelets},
  url          = {http://dx.doi.org/10.1016/j.ajpath.2011.02.026},
  volume       = {178},
  year         = {2011},
}