Active site-inactivated factor VIIa prevents thrombosis without increased surgical bleeding: Topical and intravenous administration in a rat model of deep arterial injury

Söderström, Torsten; Hedner, Ulla; Arnljots, Björn

doi:10.1067/mva.2001.112808

Cited by 21 publications

(15 citation statements)

References 39 publications

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“…Our present observation that administration of FVIIa AI promotes the procoagulant effect in hemophilia mouse model should not be misconstrued as conflicting with earlier observations that showed FVIIa AI acts as an antithrombotic agent in thrombosis model systems. 27–29 In thrombosis model systems, circulating blood is exposed to TF in blood vessel wall following injury/insult, and the resultant TF-FVIIa complexes activate factor X that lead to excessive thrombin generation and intravascular thrombosis. FVIIa AI , which binds TF with very high affinity, 15 could effectively block TF-FVIIa complex formation and thus inhibits TF-dependent thrombus formation.…”

Section: Discussionmentioning

confidence: 99%

Factor VIIa interaction with EPCR modulates the hemostatic effect of rFVIIa in hemophilia therapy: mode of its action

et al. 2017

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Recent studies established that clotting factor VIIa (FVIIa) binds endothelial cell protein C receptor (EPCR). It has been speculated that FVIIa interaction with EPCR might augment the hemostatic effect of rFVIIa in therapeutic conditions. The present study is carried out to investigate the mechanism by which FVIIa interaction with EPCR contributes to the hemostatic effect of rFVIIa in hemophilia therapy. Active-site inhibited FVIIa, which is capable of binding to EPCR but has no ability to activate factor X, reduced the concentration of rFVIIa required to correct the bleeding following the saphenous vein injury in mouse hemophilia model systems. Higher doses of rFVIIa were required to restore hemostasis in EPCR overexpressing hemophilia mice compared to hemophilia mice expressing normal levels of EPCR. Administration of FVIII antibody induced only mild hemophilic bleeding in EPCR-deficient mice, which was corrected completely with a low dose of rFVIIa. Administration of therapeutic concentrations of rFVIIa increased plasma protein C levels in EPCR overexpressing mice, indicating the displacement of protein C from EPCR by rFVIIa. EPCR levels did not significantly alter the bioavailability of rFVIIa in plasma. Overall, our data indicate that EPCR levels influence the hemostatic effect of rFVIIa in treating hemophilia. Our present findings suggest that FVIIa displacement of anticoagulant protein C from EPCR that results in down-regulation of activated protein C generation and not the direct effect of EPCR-FVIIa on FX activation is the mechanism by which FVIIa interaction with EPCR contributes to the hemostatic effect of rFVIIa in hemophilia therapy.

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Section: Discussionmentioning

confidence: 99%

Factor VIIa interaction with EPCR modulates the hemostatic effect of rFVIIa in hemophilia therapy: mode of its action

et al. 2017

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“…34 FVIIai has been shown to have a potent antithrombotic effect in 2 animal models of arterial thrombosis. 35,36 In summary, our data suggest that autoantibody-induced monocyte TF expression may be an important mechanism of hypercoagulability in patients with APS and, therefore, a potential target of therapy. Pharmacologic agents that block monocyte TF activity, such as dilazep, are a novel therapeutic approach in APS and worthy of further study.…”

Section: Discussionmentioning

confidence: 99%

Characterization of monocyte tissue factor activity induced by IgG antiphospholipid antibodies and inhibition by dilazep

Zhou

Wolberg

Roubey

2004

Blood

142

107

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Increasing evidence suggests that autoantibodies directly contribute to hypercoagulability in the antiphospholipid syndrome (APS). One proposed mechanism is the antibody-induced expression of tissue factor (TF) by blood monocytes. Dilazep, an antiplatelet agent, is an adenosine uptake inhibitor known to block induction of monocyte TF expression by bacterial lipopolysaccharide. In the current study we characterized the effects of immunoglobulin G (IgG) from patients with APS on monocyte TF activity and investigated whether dilazep is capable of blocking this effect. IgG from 13 of 16 patients with APS significantly increased monocyte TF activity, whereas normal IgG had no effect. Time-course experiments demonstrated that APS IgG-induced monocyte TF mRNA levels were maximal at 2 hours and TF activity on the cell surface was maximal at 6 hours. Dilazep inhibited antibody-induced monocyte TF activity in a dose-dependent fashion but had no effect on TF mRNA expression. The effect of dilazep was blocked by theophylline, a nonspecific adenosine receptor antagonist. In conclusion, IgG from certain patients with APS induce monocyte TF activity. Dilazep inhibits the increased expression of monocyte TF activity at a posttranscriptional level, probably by way of its effect as an adenosine uptake inhibitor. Pharmacologic agents that block monocyte TF activity may be a novel therapeutic approach in APS. IntroductionIt is widely hypothesized that autoantibodies directly contribute to hypercoagulability in patients with the antiphospholipid syndrome (APS), and numerous pathophysiologic mechanisms have been proposed. Once such mechanism is the antibody-induced expression of tissue factor (TF; CD142) on monocytes or vascular endothelial cells, or both. 1 TF is an integral membrane protein constitutively expressed in many cell types outside of the vasculature, but it is not normally expressed on cells that are in contact with flowing blood. It is a specific and high-affinity receptor for factor VII/VIIa and functions as a cofactor for factor VIIa enzymatic activity. Exposure of active TF to blood triggers physiologic blood coagulation and thrombosis in a wide variety of thrombotic diseases. 2 Blood monocytes do not constitutively express functional TF; however, they are capable of TF synthesis and expression when stimulated with lipopolysaccharide (LPS) or certain inflammatory cytokines. 3 Expression of TF on monocytes has been implicated as a mechanism of thrombosis in several conditions, including sepsis, 4 atherosclerosis, 5 the use of oral contraceptives, 6 cancer, 7 and hyperhomocysteinemia. 8 There is growing evidence that certain types of antiphospholipid antibodies, particularly those directed against ␤ 2 -glycoprotein I (␤2GPI), stimulate monocyte tissue factor expression in patients with APS. 9,10 Current treatment for the prevention of recurrent thrombosis in patients with APS is a high level of anticoagulation with warfarin. The identification of specific mechanisms of hypercoagulability in APS may allow for more spec...

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“…Unlike FXa/FIIa inhibition or warfarin treatment that often accompanies bleeding episodes in clincical practice, such upstream downregulation specifically targets the inducible extrinsic hypercoagulation while leaving the intrinsic 'constitutive' coagulation of haemostatic function intact. A minimal or no bleeding episode has been reported in the upstream regulation by TF/ FVIIa inhibitors (PHA-927F, 280 FFR-rFVIIa 281 or Pyrid 282 ) in recent experimental trials and animal studies. Effective anti-inflammation could also be expected, resulting from the broad limitation of the generation of proinflammatory signals along the enhanced coagulation cascade.…”

Section: Remarksmentioning

confidence: 97%

Tissue factor upregulation drives a thrombosis–inflammation circuit in relation to cardiovascular complications

Chu

2006

Cell Biochem. Funct.

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The extrinsic coagulation is recognized as an 'inducible' signalling cascade resulting from tissue factor (TF) upregulation by exposure to clotting zymogen FVII upon inflammation or tissue injury. Following the substantial initiation, an array of proteolytic activation generates mediating signals (active serine proteases: FVIIa, FXa and FIIa) that lead to hypercoagulation with fibrin overproduction manifesting thrombosis. In addition, TF upregulation plays a central role in driving a thrombosis-inflammation circuit. Coagulant mediators (FVIIa, FXa and FIIa) and endproduct (fibrin) are proinflammatory, eliciting tissue necrosis factor, interleukins, adhesion molecules and many other intracellular signals in different cell types. Such resulting inflammation could ensure 'fibrin' thrombosis via feedback upregulation of TF. Alternatively, the resulting inflammation triggers platelet/leukocyte/polymononuclear cell activation thus contributing to 'cellular' thrombosis. TF is very vulnerable to upregulation resulting in hypercoagulability and subsequent thrombosis and inflammation, either of which presents cardiovascular risks. The prevention and intervention of TF hypercoagulability are of importance in cardioprotection. Blockade of inflammation reception and its intracellular signalling prevents TF expression from upregulation. Natural (activated protein C, tissue factor pathway inhibitor, or antithrombin III) or pharmacological anticoagulants readily offset the extrinsic hypercoagulation mainly through FVIIa, FXa or FIIa inhibition. Therefore, anticoagulants turn off the thrombosis-inflammation circuit, offering not only antithrombotic but anti-inflammatory significance in the prevention of cardiovascular complications.

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Active site-inactivated factor VIIa prevents thrombosis without increased surgical bleeding: Topical and intravenous administration in a rat model of deep arterial injury

Cited by 21 publications

References 39 publications

Factor VIIa interaction with EPCR modulates the hemostatic effect of rFVIIa in hemophilia therapy: mode of its action

Factor VIIa interaction with EPCR modulates the hemostatic effect of rFVIIa in hemophilia therapy: mode of its action

Characterization of monocyte tissue factor activity induced by IgG antiphospholipid antibodies and inhibition by dilazep

Tissue factor upregulation drives a thrombosis–inflammation circuit in relation to cardiovascular complications

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