Reduction of r-hirudin induced bleeding in pigs by the administration of von Willebrand factor.
Journal - Platelets (England )
To prevent r-hirudin induced excess bleeding an animal model was established in pigs for the investigation of an anti-bleeding strategy. We used the Simplate® device to monitor skin bleeding time (SBT) at the inner site of the ear. r-Hirudin infused in a dose of 0.3 mag per h induced a prominent increase of SBT. The aim of our studies was to reverse r-hirudin induced bleeding by enhancing platelet adhesion to the endothelium via the administration of von Willebrand Factor (vWF). Pigs were treated with vWF containing solutions (Haemate® and a vWF-concentrate) at 3h after the start of the r-hirudin infusion. Both compounds suppressed SBT 1h after administration and significantly prevented bleeding until the termination of the experiment. SBT values (given in times of baseline) in the placebo group were 3.32 ± 0.9, 1.51 ± 0.14 in the Haemate® and 1.85 ± 0.42 in the vWF concentrate group (P = 0.008 or 0.032, in a two-sided Kruskall-Wallis-test). Coagulation parameters (aPTT, PT) were unaltered by the treatment, as were the r-hirudin plasma levels suggesting that vWF is not an antidote in its strict sense. It is concluded that vWF reverses bleeding without altering the anticoagulant effect of r-hirudin. Addition of 20 mg/kg per h aspirin resulted in a further increase of SBT. Aspirin, moreover, suppressed platelet aggregation but did not alter platelet counts. In a further study, bleeding induced by r-hirudin and aspirin was antagonized by Haemate® (66 Ukg i.v. bolus + 187 Ukg per h for 2 h infusion) and a significant reduction of bleeding time occurred.
Influence of antithrombin III on coagulation and inflammation in porcine septic shock.
Journal - Arteriosclerosis, thrombosis, and vascular biology (UNITED STATES )
The physiological inhibitor of thrombin, antithrombin III (ATIII, Kybernin P) was investigated for its antiinflammatory and anticoagulant effects in a pig model of septic shock. Pigs were infused with a dose of 0.25 microgram. kg-1. h-1 of lipopolysaccharide (LPS) over a period of 3 hours. Animals developed systemic inflammation, disseminated intravascular coagulation (DIC), organ failure and cardiovascular abnormalities, namely pulmonary hypertension and systemic hypotension. Twenty septic pigs were allocated to 2 study groups, treated either with ATIII (n=10) or placebo (n=10). ATIII was administered as a 250-U/kg IV bolus infusion for 30 minutes (-60 to -30 minutes) followed by a single IV bolus of 125 U/kg (t=0) and a second 30-minute infusion of 250 U/kg (120 to 150 minutes). ATIII significantly prevented the development of a DIC; the increase in fibrin monomers (placebo, 11.4+/-9.1 reciprocal titers, at 6 hours) was completely overcome by ATIII (P<0. 05). ATIII significantly prevented the increase in thromboxane (TXB2) levels, which were 809+/-287 pg/mL in the placebo and 420+/-174 pg/mL in the verum group after 6 hours (P<0.02). On the other hand, ATIII had no influence on TNF levels. In a lethal study with an increased dose of LPS (0.5 microgram. kg-1. h-1). A significant reduction in mortality was observed in the ATIII group (0 of 7) compared with the placebo group (4 of 6) (P<0.05, chi2 test) a significant reduction of pulmonary hypertension (placebo, 42.0+/-11. 1 mm Hg; ATIII, 23.6+/-7.5 mm Hg, P<0.05), but no effect on systemic hypotension, was noted in the ATIII group. It was thus concluded that modulation of the procoagulatory state by substitution of ATIII results in a late beneficial antiinflammatory effect in this model of septic shock.
|ISSN : ||1079-5642|
|Mesh Heading : ||Animals Antithrombin III Blood Coagulation Disseminated Intravascular Coagulation Inflammation Male Shock, Septic Swine Thromboxane B2 analysis prevention & control blood blood|
|Mesh Heading Relevant : ||therapeutic use drug effects drug therapy drug therapy|
Development of an anti-bleeding agent for recombinant hirudin induced skin bleeding in the pig.
Journal - Thrombosis and haemostasis (GERMANY )
Recombinant 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.
|ISSN : ||0340-6245|
|Mesh Heading : ||Animals Aspirin Bleeding Time Factor VIII Hemorrhage Hirudins Infusions, Intravenous Male Platelet Aggregation Inhibitors Protein Engineering Recombinant Proteins Skin Swine von Willebrand Factor pharmacology chemically induced adverse effects pharmacology|
|Mesh Heading Relevant : ||pharmacology drug therapy adverse effects pharmacology blood supply|