Increased local procoagulant action: a mechanism contributing to the favorable hemostatic effect of recombinant FVIIa in PLT disorders

Galán, Ana M.; Tonda, Raúl; Pino, Marcos; Reverter, Joan Carles; Ordinas, Antonio; Escolar, Ginés

doi:10.1046/j.1537-2995.2003.00427.x

Cited by 54 publications

(48 citation statements)

References 54 publications

(98 reference statements)

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“…Using low-molecular-weight heparin-anticoagulated blood, which is commonly used to study fibrin deposition under flow conditions, 33 endogenous factor VII is partially activated by factor XIIa generated by the contact system, which is not blocked by low-molecular-weight heparin (T.L., unpublished observations, January 2001), resulting in an underestimation of the effect of exogenous added rFVIIa. However, Galan et al 34 recently reported improvement of both platelet deposition and fibrin formation under flow conditions using low-molecularweight heparin-anticoagulated blood from patients with GT, which corresponds to the hypothesized mechanism of action put forward in our current study.…”

Section: Discussionsupporting

confidence: 84%

Recombinant factor VIIa enhances deposition of platelets with congenital or acquired αIIbβ3 deficiency to endothelial cell matrix and collagen under conditions of flow via tissue factor–independent thrombin generation

Lisman

Moschatsis

Adelmeijer

et al. 2003

Blood

106

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A novel approach to treat bleeding episodes in patients with Glanzmann thrombasthenia (GT) and perhaps also in patients receiving ␣ IIb ␤ 3 inhibitors is the administration of recombinant factor VIIa (rFVIIa). The mechanism of action of rFVIIa in these patients is, however, still unclear. We studied the effect of rFVIIamediated thrombin formation on adhesion of ␣ IIb ␤ 3 -deficient platelets under flow conditions. Adhesion of ␣ IIb ␤ 3 -deficient platelets to the extracellular matrix (ECM) of stimulated human umbilical vein endothelial cells or to collagen type III was studied using a model system with washed platelets and red cells. When ␣ IIb ␤ 3 -deficient platelets were perfused over the surface at arterial shear rate for 5 minutes, a low surface coverage was observed (GT platelets, mean ؎ SEM, 37.5% ؎ 5.0%; normal platelets preincubated with an RGD-containing peptide, 7.4% ؎ 2.1%). When rFVIIa, together with factors X and II, was added to the perfusate, platelet deposition significantly increased (GT platelets, mean ؎ SEM, 67.0% ؎ 4.3%; normal platelets preincubated with an RGD-containing peptide, 48.2% ؎ 2.9%). The same effect was observed when normal platelets were pretreated with the commercially available anti-␣ IIb ␤ 3 drugs abciximab, eptifibatide, or tirofiban. It was shown that tissue factor-independent thrombin generation (presumably induced by binding of rFVIIa to adhered platelets) was responsible for the increase in platelet deposition. In conclusion, defective adhesion of ␣ IIb ␤ 3 -deficient platelets to ECM can be restored by tissue factor-independent rFVIIa-mediated thrombin formation. The enhanced generation of platelet procoagulant surface facilitates fibrin formation, so that lack of platelet aggregate formation might be compensated

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Section: Discussionsupporting

confidence: 84%

Recombinant factor VIIa enhances deposition of platelets with congenital or acquired αIIbβ3 deficiency to endothelial cell matrix and collagen under conditions of flow via tissue factor–independent thrombin generation

Lisman

Moschatsis

Adelmeijer

et al. 2003

Blood

106

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“…Previous studies have demonstrated that the presence of exogenously added rFVIIa in blood from patients with different coagulopathies or thrombopathies improved fibrin generation at sites of vascular damage, but did not improve platelet aggregate formation. 7,9,35,44 The thrombin generated in the previous situations influences the formation of a fibrin net and improves its structure and stability, which is not achieved at lower doses of rFVIIa. 45 Notably, in our studies using blood samples from patients with FVII deficiency, addition of platelets containing rFVIIa promoted the formation of larger platelet aggregates, but did not result in an increased fibrin deposition.…”

Section: Discussionmentioning

confidence: 99%

“…Although the most recognized mechanism of the hemostatic action of FVIIa is the binding to TF present in damaged vessels. 9,35 It is also possible that platelets at the site of injury could incorporate some TF from the injured site and further bind FVIIa, improving hemostasis. Other authors have proposed that high doses of rFVIIa could also exert hemostatic action on the activated platelet membrane.…”

Section: Discussionmentioning

confidence: 99%

“…5,6 Tissue factor (TF) exposed at sites of vascular damage would help to localize the hemostatic response, favoring fibrin generation and platelet recruitment in more stable thrombi. [7][8][9] Pharmacokinetic studies performed on rFVIIa by different groups have established a half-life of 2.7 hours in adults and 1.3 hours in children. 10 -12 Clinical experience from exploratory phase II trials, however, suggests that the hemostatic action of rFVIIa exceeds its predicted plasma half-life in patients subjected to prophylaxis.…”

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confidence: 99%

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

López-Vílchez

Hedner

Altisent

et al. 2011

The American Journal of Pathology

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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 rFVIIa (3 to 60 g/mL). Flow cytometry, immunocytochemistry, and coagulation tests were applied to detect and quantify rFVIIa. The hemostatic effect of rFVIIa associated to platelets was evaluated using perfusion models. Our studies revealed a dose-dependent association of rFVIIa to the platelet cytoplasm with redistribution into the open canalicular system, and ␣ 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 rFVIIa 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 rFVIIa in hemophilia.

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“…Vessels were cleaned, everted, cut into segments and maintained in PBS. 25 Perfusions studies were performed at a shear rate of 600/s for 10 min. Before it entered the flow chamber, citrate-anticoagulated blood was mixed with 6 mmol/L CaCl2.…”

Section: Perfusion Studiesmentioning

confidence: 99%

Reversal of Rivaroxaban-Induced Alterations on Hemostasis by Different Coagulation Factor Concentrates

Escolar

Arellano‐Rodrigo

López-Vílchez

et al. 2015

Circ J

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Increased local procoagulant action: a mechanism contributing to the favorable hemostatic effect of recombinant FVIIa in PLT disorders

Abstract: Our data indicate that rFVIIa promotes a procoagulant activity at sites of vascular damage. This mechanism could explain the beneficial hemostatic effect of rFVIIa in patients with thrombocytopenia or with Glanzmann's thrombasthenia.

Cited by 54 publications

References 54 publications

Recombinant factor VIIa enhances deposition of platelets with congenital or acquired αIIbβ3 deficiency to endothelial cell matrix and collagen under conditions of flow via tissue factor–independent thrombin generation

Recombinant factor VIIa enhances deposition of platelets with congenital or acquired αIIbβ3 deficiency to endothelial cell matrix and collagen under conditions of flow via tissue factor–independent thrombin generation

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

Reversal of Rivaroxaban-Induced Alterations on Hemostasis by Different Coagulation Factor Concentrates

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