Reduction of r-hirudin induced bleeding in pigs by the administration of von Willebrand factor

Dickneite, Gerhard; Friesen, Heinz-Jürgen; Kumpe, G.; Reers, Martin

doi:10.3109/09537109609023590

Cited by 7 publications

(4 citation statements)

References 35 publications

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“…In our studies with recombinant FVIII, which is definitely devoid of vWF, improvement of rH induced bleeding was only marginal, correlating with the absence of increase in vWF plasma levels. On the other hand, we could show in a preceding paper (21), that a purified vWF preparation was equally efficacious in preventing bleeding as Haemate. We therefore conclude, that vWF, but not FVIII is the predominantly active principle to correct the excess bleeding.…”

Section: Discussionmentioning

confidence: 90%

“…rH and THC concentration in pig plasma were determined by ELISA as described in a previous paper (21).…”

Section: Rh Plasma Levels and Thrombin-hirudin-complex (Thc)mentioning

confidence: 99%

“…In a preceding paper (21) we have shown that von Willebrand factor (vWF) containing concentrates were able to suppress the rH induced skin bleeding time (SBT) in the pig while rH was continuously infused. vWF, a multimeric glycoprotein mediates the adhesion of platelets to the subendothelium and thus initializes primary hemostasis.…”

Section: Introductionmentioning

confidence: 99%

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Development of an Anti-Bleeding Agent for Recombinant Hirudin Induced Skin Bleeding in the Pig

Dickneite¹,

Nicolay²,

Friesen³

et al. 1998

Thromb Haemost

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SummaryRecombinant hirudin (rH) is a highly specific thrombin inhibitor which is under clinical investigation for various thrombotic disorders. However, one of its potential risks during clinical use might be hemorrhage, especially when combined with other agents interfering with the coagulation system like antiplatelet or fibrinolytic agents. In this experimental study we investigated whether Haemate, a von Willebrand Factor (vWF) and factor VIII containing product, could correct rH/aspirin induced bleeding in an experimental pig study. Skin bleeding time was evaluated in three open, placebo-controlled, randomized studies following comparable designs. A total of 62 animals were given a short-term infusion of aspirin (20 mg/kg) followed by a three-hour infusion of a high or low dose (0.3 or 0.5 mg/kg/h) of rH. At cessation of rH infusion, animals were allocated to treatment with either Haemate (30 FVIII U/kg) or the recombinant factor VIII, Helixate, which is devoid of vWF. The skin bleeding time (SBT, given as times of baseline) as measured four hours after the start of the rH infusion was defined as the prospective endpoint.In study 1 (low dose rH + Haemate) 4 h SBT was 2.18 (placebo) and 1.61 (Haemate, p = 0.0111). In study No. 2 (high dose rH + Haemate) SBT was 2.58 in placebo and 1.73 in Haemate (p = 0.0001). No significant difference between placebo and treatment were detected in study No. 3 (low dose rH + Helixate). Haemate but not Helixate significantly decreased bleeding time as compared to placebo at termination of the study (7 hours) which was defined as the secondary endpoint. No effect on either aPTT nor rH plasma levels were observed with any of the study drugs. It was concluded that Haemate decreases excess bleeding induced by rH/aspirin treatment without altering rH’s anticoagulant effect.

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Section: Discussionmentioning

confidence: 90%

“…rH and THC concentration in pig plasma were determined by ELISA as described in a previous paper (21).…”

Section: Rh Plasma Levels and Thrombin-hirudin-complex (Thc)mentioning

confidence: 99%

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Development of an Anti-Bleeding Agent for Recombinant Hirudin Induced Skin Bleeding in the Pig

Dickneite¹,

Nicolay²,

Friesen³

et al. 1998

Thromb Haemost

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“…Hemofiltration with cellulose-acetate filters with a cut-off point above 50,000 Da may be an option to eliminate hirudin, 24,28 but data have been primarily generated in animal models and no prospective data in humans are available. Pharmacologic measures suggested for reversal of hirudin overdosage are injection of desmopressin acetate (DDAVP), factor VII, 29,30,31 and of vonWillebrand factor (vWF) 32 or a factor VIII concentrate containing vWF. 33 Irami et al 34 described a case in which reversal of hirudin induced bleeding diathesis was achieved by administering prothrombin complex concentrate, as had been suggested based on animal models.…”

Section: Reversal Of Hirudinmentioning

confidence: 99%

Treatment of Heparin-Induced Thrombocytopenia

Greinacher¹

1999

Thromb Haemost

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IntroductionUnfractionated heparin (UFH) and low molecular weight heparin (LMWH) are the most widely used anticoagulants when parenteral anticoagulation with a short half-life is required. Both can be administered subcutaneously and intravenously, and both have been shown to be effective in a variety of clinical settings.1 UFH has several limitations. One is its poor bioavailability after subcutaneous injection and the marked variability in its anticoagulant response in patients with an acute thromboembolic complication.2,3 Another major issue associated with UFH is the induction of heparin-induced thrombocytopenia (HIT). Both limitations are closely linked,4 as the underlying cause is the high density of negative charges on the heparin molecule and its molecular weight. Both are responsible for the binding of heparin to plasma proteins other than antithrombin (AT), such as platelet factor 4 (PF4) and to several cell types. This leads to heparin-platelet interaction, the formation of HIT antigen (i.e., PF4/heparin complexes), and inhibition of the anticoagulant effect of heparin (aPTT-nonresponder).

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Treatment of porcine sepsis with high-dose antithrombin III reduces tissue edema and effusion but does not increase risk for bleeding

Dickneite

Kroez²

2001

Blood Coagulation and Fibrinolysis

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We evaluated the effectiveness of antithrombin III (AT III) infusions designed to achieve supraphysiologic plasma levels of this serine protease inhibitor in preventing vascular permeability and disseminated intravascular coagulation in a pig model of sepsis. In addition, we determined whether high AT III doses were associated with increased bleeding risk. Sepsis was induced in 18 pigs by injection of lipopolysaccharide (LPS) (0.25 microg/kg per h for 3 h). At 90 min after the start of LPS infusion, pigs were randomized (n = 6 per group) to receive either human serum albumin as a placebo, AT III 120/5 (120 U/kg, 30-min bolus + 5 U/kg per h for 240 min), or AT III 250/10 (250 U/kg + 10 U/kg per h). Three additional animals served as negative controls (no LPS, no AT III). Treatment with AT III significantly reduced the amount of effluents in body cavities and fibrin monomers. AT III did not significantly increase bleeding risk as determined by organ hemorrhage. An additional assessment of AT III's bleeding risk [skin bleeding time (SBT)] was carried out in 35 nonseptic pigs treated with either AT III alone (120/5 or 250/10) or in the combination with heparin. Heparin administration alone produced a dose-dependent increase in SBT, but AT III alone did not. Addition of AT III 120/5 to heparin did not induce a further increase in bleeding time over heparin alone. These results indicate that administration of AT III in doses designed to achieve very high plasma concentrations significantly ameliorates symptoms of sepsis-induced vascular leakage and disseminated intravascular coagulation without increasing bleeding risk.

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Reduction of r-hirudin induced bleeding in pigs by the administration of von Willebrand factor

Cited by 7 publications

References 35 publications

Development of an Anti-Bleeding Agent for Recombinant Hirudin Induced Skin Bleeding in the Pig

Development of an Anti-Bleeding Agent for Recombinant Hirudin Induced Skin Bleeding in the Pig

Treatment of Heparin-Induced Thrombocytopenia

Treatment of porcine sepsis with high-dose antithrombin III reduces tissue edema and effusion but does not increase risk for bleeding

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