| 1. |
- Holst, J., et al.
(författare)
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Antithrombotic effect of recombinant truncated tissue factor pathway inhibitor (TFPI1-161) in experimental venous thrombosis : A comparison with low molecular weight heparin
- 1994
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 71:2, s. 214-219
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Tidskriftsartikel (refereegranskat)abstract
- The aim was to investigate whether a truncated recombinant Tissue Factor Pathway Inhibitor (TFPI1-161) which lacked the third Kunitz-type domain and the basic c-terminal region, had an antithrombotic effect comparable to LMWH in a randomised double-dummy study. The experimental thrombosis was induced in jugular veins, in a total of 40 rabbits by a combination of destruction of the endothelium and restricted blood flow. Group 1: placebo, gr 2- LMWH 60 anti-FXa IU/kg, gr 3-5: 0.1, 1.0 and 10.0 mg/kg TFPI1-161. TFPI1-161 reduced the thrombus weights in all treated groups, significantly in doses of 1.0 and 10.0 mg/kg compared to placebo. The frequency of thrombosis and occlusive thrombosis were also significantly reduced in those doses. The antithrombotic properties of TFPI1-161 (1.0-10.0 mg/ kg) measured as thrombus weight, frequency of thrombosis and frequency of occlusive thrombosis was equivalent to the antithrombotic properties of LMWH. In the anti-FXa, APTT and PT-assays TFPI1-161 displayed a dose dependent increase of activity. Recombinant-TFPI1-161 did not influence the anti-FIIa-assay. No haemorrhagic side effects were noted.
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| 2. |
- Holst, J., et al.
(författare)
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Protamine neutralization of intravenous and subcutaneous low-molecular-weight heparin (tinzaparin, Logiparin(TM)). An experimental investigation in healthy volunteers
- 1994
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Ingår i: Blood Coagulation and Fibrinolysis. - 0957-5235. ; 5:5, s. 795-803
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to investigate whether tinzaparin sodium (a low-molecular-weight heparin (LMWH)) was fully and permanently neutralized in vivo in man by protamine sulphate (PS) after intravenous (i.v.) or subcutaneous (s.c.) injection. Fifty healthy adults equally divided in five age- and sex-matched groups were included. The groups received 50 IU unfractionated heparin (UH)/kg body weight (b.w.) i.v., 50 anti-factor Xa (anti-Xa) IU tinzaparin/kg b.w. i.v., 75 anti-Xa IU tinzaparin/kg b.w. s.c., 175 anti-Xa IU tinzaparin/kg b.w. s.c., or 1 ml of saline s.c. PS was given as a 10 min infusion in a dose of 1 mg/100 IU of heparin in the four first groups while 0.5 mg PS/kg b.w. was given in the placebo group. In the i.v. groups PS was administered 45 min after the heparin injection, and in the s.c. groups 180 min post-heparin injection. In the UH group PS fully and permanently neutralized all three activities. In the i.v. tinzaparin group PS reversed 80% of the anti-Xa activity, while the anti-IIa and aPTT activities were fully reversed. A slight, but statistically significant, increase in anti-Xa and anti-Ila activities were seen following i.v. tinzaparin. In the s.c. groups 60-65% of the observed peak anti-Xa activity was neutralized, anti-IIa was almost completely reversed, and aPTT returned nearly to baseline values. A gradual return of the anti-Xa activity (65-75%), anti-IIa activity (55%) and aPTT activity (35-45%) was seen in the s.c. groups 3 h after reversal compared with the observed peak values. A continuous absorption of tinzaparin from the s.c. depot is presumably the cause of the returned activity. PS caused an 8-27% transient drop in the platelet count in all groups. This study confirms that the anti-Xa activity following i.v. and s.c. administration of tinzaparin (a LMWH) is only partially neutralizable by protamine. This is not due to insufficient dosages of the antidote, as an excess of protamine could be demonstrated ex vivo immediately after the protamine infusion. The present results suggest that protamine neutralization of tinzaparin given s.c. should be obtained with intermittent injections or continuous infusion.
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| 3. |
- Matthiasson, S E, et al.
(författare)
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Effect of low molecular weight heparin, dextran and their combinations on experimental venous thrombosis in rabbits
- 1994
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 71:3, s. 363-365
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Tidskriftsartikel (refereegranskat)abstract
- An experimental model based on the combination of endothelial damage and flow reduction was used to induce jugular vein thrombosis in rabbits. The effect on thrombosis of a low molecular weight heparin (LMWH [Fragmin]), dextran 70, placebo and their combination was studied in a double-blind fashion with actual doses used in clinical thromboprophylaxis. Saline and polygeline were used as placebo in the control group. Four groups with 120 isolated vein segments in 60 animals were studied for presence of thrombus formation, occlusive thrombi and thrombus weights. Dextran reduced the thrombus weights (p = 0.048) and the formation of occlusive thrombi (p = 0.01), but not the formation of thrombi when compared with the placebo control group. Similarly, LMWH reduced the thrombus weights (p = 0.046), the formation of thrombi (p = 0.007) and occlusive thrombi (p = 0.0001). Compared with the LMWH group the group treated with the combination of LMWH and dextran was found to reduce the frequency of occlusive thrombi (p = 0.03) and numerically, but not significantly, further reduce the overall frequency of thrombosis (p = 0.18) and thrombus weights (p = 0.11). The results are consistent with an augmentation of the antithrombotic effect of LMWH by dextran 70. The need for further evaluation of the combined efficacy of LMWH and dextran is apparent from this study.
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| 4. |
- Matthiasson, S E, et al.
(författare)
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Study of the interaction of dextran and enoxaparin on haemostasis in humans
- 1994
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 72:5, s. 722-727
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Tidskriftsartikel (refereegranskat)abstract
- The effect on haemostatic variables by dextran 70, enoxaparin and their combinations, given in doses of 500 ml i.v. and 40 mg s.c. respectively, was studied in a randomised cross-over fashion in twelve healthy male volunteers. Antifactor-IIa activity, antifactor-Xa activity, APTT, factor VIII, vWF, bleeding time and blood counts were analysed over a 24-h period. Dextran alone did not affect antifactor-IIa activity and antifactor-Xa activity. No difference in antifactor-IIa and antifactor-Xa activity was found for Amax, tmax, AUC0-8 h and AUC0-24 h in the groups treated with enoxaparin or the combination of enoxaparin and dextran. Only minor changes in APTT were observed without statistical significance between the treatment groups. Factor VIII did not change significantly in the three treatment groups. However, vWF was significantly reduced in the dextran and the dextran/enoxaparin group (p = 0.046 and 0.01 respectively) but no difference was found between the two groups. Bleeding time was not significantly increased four hours after administration of the test substances and no difference was found between the individual treatment groups. Our findings indicate that dextran can be combined with enoxaparin, when used in thromboprophylactic doses, without increased risk for bleeding.
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