Effect of recombinant human FVIIA on warfarin-induced bleeding in rats

Diness, V.; Lund-Hansen, T; Hedner, Ulla

doi:10.1016/0049-3848(90)90116-t

Cited by 45 publications

(28 citation statements)

References 9 publications

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“…The effect of rFVIIa on aPTT may be the result of activation of FX in the presence of calcium and phospholipid, in the absence of TF, 33 and the effect of rFVIIa on PT may indicate that the residual level of FX after warfarin treatment was sufficient for hemostasis to occur. 43 Nevertheless, none of the groups showed a complete return to baseline levels in their clotting assays. This was not unexpected, because the multiple coagulation factor deficiencies in the warfarin-treated subjects were only partially compensated for by infusion of rFVIIa.…”

Section: Discussionmentioning

confidence: 99%

Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects

Skolnick

Mathews

Khutoryansky

et al. 2010

Blood

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The use of warfarin has a well-known bleeding risk. Recombinant activated factor VII (rFVIIa) is a non-plasma-derived, rapid-acting, and rapidly infused potential treatment. This randomized, singlecenter, placebo-controlled, double-blinded, dose-escalation, exploratory phase 1 trial assessed safety and effects of rFVIIa in reversing warfarin-induced changes in bleeding and coagulation parameters, using a punch biopsy-induced bleeding model in healthy subjects. The effects of warfarin (experiment 1) and rFVIIa (5-80 g/kg; experiment 2) were evaluated.Outcomes were bleeding duration, blood loss, coagulation parameters, and safety. Warfarin treatment significantly increased bleeding duration and blood loss from pretreatment (experiment 1, 12 subjects). However, these parameters after rFVIIa treatment were not significantly different from placebo (experiment 2, 85 subjects). Mean activated partial thromboplastin time, prothrombin time, and international normalized ratio were reduced from warfarin-elevated levels. rFVIIa (80 g/kg) significantly reversed warfarin effects on all thromboelastography parameters, compared with placebo (P < .05), and returned the thrombin generation speed to baseline. There were no thromboembolic or serious adverse events. In this exploratory trial, the reversal of warfarin effects was observed in the thromboelastography, thrombin generation, and clotting assays. However, this reversal did not translate to improvements in the bleeding model parameters evaluated in the punch biopsy model. Trial registration is exempt (phase 1). (Blood. 2010;116(5):693-701)

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Section: Discussionmentioning

confidence: 99%

Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects

Skolnick

Mathews

Khutoryansky

et al. 2010

Blood

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“…In the case of laboratory rats, Wistar rats had similar coagulation times to the warfarin-sensitive rats we used in the present study [32]. Indeed, it has been reported that after the administration of warfarin to Wistar rats, the PT and APTT measurements were both prolonged [33]. In the case of Sprague-Dawley rats, the PT was reported to be 14.5±1.4 sec while warfarin-resistant rats with the Tyr139Phe VKORC1 mutation had a PT of 15.5±1.4 sec.…”

Section: Discussionmentioning

confidence: 89%

The genetic mechanisms of warfarin resistance in Rattus rattus found in the wild in Japan

Tanaka

Kawai

Ikenaka

et al. 2012

Pesticide Biochemistry and Physiology

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Warfarin is commonly used worldwide as a rodenticide. It inhibits blood coagulation by inhibiting vitamin K 2,3-epoxide reductase (VKOR) activity leading to hemorrhage. However, it has been reported that repeated or long-term treatment with warfarin results in resistance emerging in wild rodents. Such resistance may explain why it is difficult to control rodents in many regions in Japan.In this report, we studied mutations in the VKOR gene (including the VKOR complex subunit 1 (VKORC1)), while also analyzing VKOR and clotting factor activity in black rats (Rattus rattus) in order to understand better the mechanism of warfarin resistance in this species.We sequenced the VKORC1 gene from 275 rats living in the wild in Japan. We found several types of novel base substitutions, some of which conferred warfarin resistance.There was no difference in coagulation times between warfarin-sensitive and resistant rats measured under physiological conditions. However, after warfarin administration, no effect was noted in warfarin-resistant rats, although a prolonged coagulation time was noted in warfarin-sensitive rats.We also determined the kinetic differences in hepatic microsomal VKOR-dependent activity between warfarin-resistant and sensitive rats. Warfarin-resistant rats showed 2-3-fold lower V max /K m values than did sensitive rats. In addition, we report that resistant rats found in the Tokyo area had a VKOR activity which was poorly inhibited by warfarin.Finally, we conclude that reduced VKOR activity and warfarin resistance in the Japanese black rat might be due to mutations in the VKORC1 gene. However, further study is needed to clarify how such rats can maintain adequate vitamin K-dependent clotting factor levels, while simultaneously exhibiting low VKOR activity and warfarin resistance.

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“…[33][34][35][36] We therefore administered enoxaparin to normal mice to determine whether sTF-annV would affect an in vivo measure of thrombin generation. Mice were injected subcutaneously with enoxaparin sodium (20 mg/kg), a drug known to inhibit thrombin generation, 31 and the bleeding time was measured 2 hours later.…”

Section: Effect Of Stf-annv On Mouse Tail-bleeding Timesmentioning

confidence: 99%

A soluble tissue factor-annexin V chimeric protein has both procoagulant and anticoagulant properties

Huang

Ding

Vaught

et al. 2006

Blood

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Tissue factor (TF) initiates blood coagulation, but its expression in the vascular space requires a finite period of time. We hypothesized that targeting exogenous tissue factor to sites of vascular injury could lead to accelerated hemostasis. Since phosphatidylserine (PS) is exposed on activated cells at sites of vascular injury, we cloned the cDNA for a chimeric protein consisting of the extracellular domain of TF (called soluble TF or sTF) and annexin V, a human PS-binding protein.Both the sTF and annexin V domains had ligand-binding activities consistent with their native counterparts, and the chimera accelerated factor X activation by factor VIIa. The chimera exhibited biphasic effects upon blood coagulation. At low concentrations it accelerated blood coagulation, while at higher concentrations it acted as an anticoagulant. The chimera accelerated coagulation in the presence of either unfractionated or lowmolecular-weight heparins more potently than factor VIIa and shortened the bleeding time of mice treated with enoxaparin. The sTF-annexin V chimera is a targeted procoagulant protein that may be useful in accelerating thrombin generation where PS is exposed to the vasculature, such as may occur at sites of vascular injury or within the vasculature of tumors. (Blood. 2006;107:980-986)

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Effect of recombinant human FVIIA on warfarin-induced bleeding in rats

Cited by 45 publications

References 9 publications

Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects

Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects

The genetic mechanisms of warfarin resistance in Rattus rattus found in the wild in Japan

A soluble tissue factor-annexin V chimeric protein has both procoagulant and anticoagulant properties

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