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

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Redistribution and Hemostatic Action of Recombinant Activated Factor VII Associated with Platelets. / Lopez-Vilchez, Irene; Hedner, Ulla; Altisent, Carmen; Diaz-Ricart, Maribel; Escolar, Gines; Galan, Ana M.

In: American Journal of Pathology, Vol. 178, No. 6, 2011, p. 2938-2948.

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Harvard

Lopez-Vilchez, I, Hedner, U, Altisent, C, Diaz-Ricart, M, Escolar, G & Galan, AM 2011, 'Redistribution and Hemostatic Action of Recombinant Activated Factor VII Associated with Platelets', American Journal of Pathology, vol. 178, no. 6, pp. 2938-2948. https://doi.org/10.1016/j.ajpath.2011.02.026

APA

Lopez-Vilchez, I., Hedner, U., Altisent, C., Diaz-Ricart, M., Escolar, G., & Galan, A. M. (2011). Redistribution and Hemostatic Action of Recombinant Activated Factor VII Associated with Platelets. American Journal of Pathology, 178(6), 2938-2948. https://doi.org/10.1016/j.ajpath.2011.02.026

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Author

Lopez-Vilchez, Irene ; Hedner, Ulla ; Altisent, Carmen ; Diaz-Ricart, Maribel ; Escolar, Gines ; Galan, Ana M. / Redistribution and Hemostatic Action of Recombinant Activated Factor VII Associated with Platelets. In: American Journal of Pathology. 2011 ; Vol. 178, No. 6. pp. 2938-2948.

RIS

TY - JOUR

T1 - Redistribution and Hemostatic Action of Recombinant Activated Factor VII Associated with Platelets

AU - Lopez-Vilchez, Irene

AU - Hedner, Ulla

AU - Altisent, Carmen

AU - Diaz-Ricart, Maribel

AU - Escolar, Gines

AU - Galan, Ana M.

N1 - 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)

PY - 2011

Y1 - 2011

N2 - 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)

AB - 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)

U2 - 10.1016/j.ajpath.2011.02.026

DO - 10.1016/j.ajpath.2011.02.026

M3 - Article

VL - 178

SP - 2938

EP - 2948

JO - American Journal of Pathology

T2 - American Journal of Pathology

JF - American Journal of Pathology

SN - 1525-2191

IS - 6

ER -