Desmin 370, a Low Molecular Weight Dermatan Sulfate, Reduces the Weight of Preformed Thrombi in Rats Made Afibrinogenemic by Ancrod

1995 ◽  
Vol 73 (02) ◽  
pp. 287-290 ◽  
Author(s):  
Miriam Barbanti ◽  
Fiorella Calanni ◽  
Egidio Marchi ◽  
Nicola Semeraro ◽  
Mario Colucci
Keyword(s):  
Molecular Weight ◽  
Direct Evidence ◽  
Dermatan Sulfate ◽  
Thrombus Formation ◽  
Vena Cava ◽  
Experimental Period ◽  
Venous Stasis ◽  
Low Molecular Weight ◽  
Time Interval ◽  
Thrombosis Model

SummaryDesmin 370 (D370), a low molecular weight dermatan sulfate, has been shown to induce a marked reduction of the weight of preformed venous thrombi in rats and rabbits by mechanisms that appeared largely independent of inhibition of thrombus accretion. In order to provide further support for such a mechanism, we exploited the defibrinating capacity of ancrod to obtain a thrombosis model characterized by the lack of thrombus growth and thus sensitive only to agents promoting thrombus lysis. Thrombus formation in anesthetized rats was induced by vena cava ligature. Injection of ancrod (5 U/kg) 5 h after induction of venous stasis caused a more than 95% reduction in plasma fibrinogen and prevented thrombus accretion as indicated by the lack of thrombus weight increase during the 3h experimental period (12.2 ° 0.6 vs 14.5 ° 1 as compared to 12.6 ° 0.6 vs 19.6 ° 0.8, p <0.01, in control rats) and by the almost complete (>90%) inhibition of125I- fibrin(ogen) binding to thrombi. Moreover, when ancrod was given 1 h before vena cava ligature, no thrombi were formed within 2 h whereas at the same time interval visible thrombi were present in all control rats. Administration of D370 (10 mg/kg) to thrombus bearing rats, 1 h after induction of afibrinogenemia, resulted in a significant reduction in thrombus weight (43% after 2h, p <0.01) which was only slightly lower than that recorded in normofibrinogenemic rats (54%). Enhancement of plasma fibrinolytic activity by ancrod had no influence on thrombus lysis and was not at all affected by administration of D370. These data provide additional and more direct evidence that D370 may promote thrombus lysis independently of inhibition of thrombus accretion.

EXPERIMENTAL THROMBUS FORMATION AND HAEMOSTASIS OF DIFFERENT LOW MOLECULAR WEIGHT HEPARINS AND DOSAGES

1987 ◽  
Author(s):  
R A Zimmerman ◽  
C T Rieger ◽  
K Hübner ◽  
C W Harenber ◽  
W Kübler
Keyword(s):  
Molecular Weight ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Bleeding Complications ◽  
Maximum Effect ◽  
Low Molecular Weight ◽  
Antithrombotic Effect ◽  
Low Molecular Weight Heparins ◽  
Antithrombotic Activity ◽  
Thrombosis Model

Low molecular weight heparin induces a higher anti factor Xa (a-Xa) and a lower antithrombin activity in plasma in comparison to conventional heparin. From this constellation a more pronounced antithrombotic effect and a minor incidence of bleeding Complications has been suggested.Therefore the antithrombotic activity of heparins was studied in a standardized experimental thrombosis model in rabbits. Three low molecular weight heparins with a mean molecular weight of 4.200 (heparin I),4.000 (heparin II),4.600 Dalton (heparin III) and standard heparin were tested at different dosages in 120 experiments. In the first series the dose of 60 anti Xa units (a-Xa U) given initially and 60 a-Xa U/kg/h induced a reduction of the thrombus size by 40 % (heparin I),37 % (heparin II) and 53 % (heparin III) and a prolongation of the aPTT to 45 (heparin I),66 (heparin II) and 79 sec (heparin III). The a-Xa activity was minor than 0.1 U/ml. In the second series heparins were given to aim at an a-Xa activity of 0.2-0.3 U/ml. Thereby the thrombus formation could be reduced by 84 % (heparin I), 62 % (heparin II) and 39 % (heparin III). aPTT and a-Xa activity were measured at 65.5 sec and 0.22 a-Xa U/ml (heparin I),67.3 sec and 0.3 a-Xa U/ml (heparin II) and 67.5 and 0.31 a-Xa U/ml (heparin III),respectively. In the third series the increase of the a-Xa activity to more than 0.3 U/ml showed no further reduction of the thrombus formation by heparin I, while heparins II and III already at this level reachedthe antithrombotic activity of heparin I.Our data on three different low molecular weight heparins demonstrate that already a heparin level ranging at a minimal a-Xa activity induces a clear and statistically significant antithrombotic effect. A higher heparin dosage with higher a-Xa activity increases the antithrombitic effect. At a level of 0.2-0.3 a-Xa U/ml an obvious and maximum effect could be reached, but the further elevation of the a-Xa activity produced no further antithrombotic action.

Therapeutic Effect of a Low Molecular Weight Dermatan Sulphate (Desmin 370) in Rat Venous Thrombosis - Evidence for an Anticoagulant-Independent Mechanism

1993 ◽  
Vol 69 (02) ◽  
pp. 147-151 ◽  
Author(s):  
M Barbanti ◽  
F Calanni ◽  
M R Milani ◽  
E Marchi ◽  
N Semeraro ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Venous Thrombosis ◽  
Thrombus Formation ◽  
Venous Stasis ◽  
Low Molecular Weight ◽  
Dermatan Sulphate ◽  
Pharmacologic Agent ◽  
Independent Mechanism ◽  
Dose Dependent

SummaryWe evaluated the capacity of a low molecular weight dermatan sulphate (D370) to prevent thrombus formation and to induce a reduction of a stabilized thrombus in a rat venous thrombosis model. Injection of D370, 10 min before induction of venous stasis (prevention model), prevented thrombus formation in a dose-dependent way (ED50: 2.3 mg/kg). When given to rats 6 h after induction of venous stasis (therapeutic model), D370 caused a time- and dose-dependent reduction in thrombus size (60% to 70% reduction 2 h after injection of 10 mg/kg). At comparable antithrombotic dosages (i.e. minimum dose giving complete inhibition of thrombus formation), heparin (0.5 mg/kg) only caused 40% reduction of a preformed thrombus while hirudin (1 mg/kg) was virtually ineffective (less than 10% reduction in weight). All three compounds inhibited 125I-fibrin(ogen) deposition on 6-h aged thrombi by more than 85%, suggesting that D370 and, to a lesser extent, heparin reduce thrombus size via mechanisms other than inhibition of thrombus accretion. The involvement of a fibrinolysis-mediated mechanism in the D370-induced effect is suggested by the following. EACA (1 g/kg), when given to thrombus-bearing control animals, did not influence thrombus weight. However, when administered before D370 treatment, it prevented the expected reduction in thrombus weight by more than 80%, without influencing the effect of D370 on 125I-fibrin(ogen) accumulation onto preexisting thrombi. D370 injection caused neither an enhancement of fibrinolytic activity nor a reduction of PAI in plasma. In vitro, D370 (200 μg/ml) was unable to potentiate the spontaneous or PA-induced lysis of 125I-fibrinogen labelled blood, plasma, or purified fibrin clots. It is suggested that prevention of thrombus formation by D370 is related mainly to inhibition of blood coagulation, whereas reduction of the weight of aged thrombi is primarily due to an anticoagulant-independent mechanism, most probably involving local enhancement of the fibrinolytic process. D370 may represent an alternative pharmacologic agent both in the prevention and in the therapy of venous thrombosis.

TREATMENT OF EXPERIMENTAL VENOUS STASIS MODEL IN RATS BY HEPARIN AND A VERY LOW MOLECULAR WEIGHT HEPARIN FRAGMENT. RELATIONSHIP TO PLASMATIC HEPARIN ACTIVITY

1987 ◽  
Author(s):  
C Doutremepuich ◽  
O de Sèze ◽  
T Castrioto ◽  
F Peirera ◽  
F Doutremepuich ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
Vena Cava ◽  
Heparin Therapy ◽  
Statistical Correlation ◽  
Correlation Factor ◽  
Venous Stasis ◽  
Low Molecular Weight ◽  
Standard Curve ◽  
Method R

In this work we investigated the possible relationship between plasmatic activity and antithrombotic activity of a Low Molecular Weight Heparin Fragment (CY222, Choay-Paris) compared with Heparin (Hep). A randomized administration of both test drugs was carried out on 198 rats receiving 4 different dosages (4,2,1 or 0.5 mg/Kg b.w.) or a placebo solution (normal saline). A ligature of the inferior vena cava was performed on rats at T = OH and test drugs were administered subcutaneously at T - 2H. Blood and thrombus samples were taken at T = 6H. For all the tests the Heparin level was computed from a standard curve made up of known amounts of the 3 rd STANDARD HEPARIN (W.H.O.).The statistical study between plasmatic and antithrombotic activities was conducted in 2 steps: 1°) search for linear statistical correlation (correlation factor R, independence test T)For Hep: Thrombin Clotting Time: R = −0.26, T = 0.38, p<0.01; APTT: R = −0.28, T = −2.56, p<0.01; Anti-Xa (chromogenic method CBS 31.39):R = 0.48, T = −4.70, p<0.01; Anti-Xa (Hepaclot, Stago):R = −0.35 T = −3.24, p<0.01; Anti-Xa (Heptest, Haemachem, INC): R = −0.36, T = −3.21, p<0.01; Anti-IIa (chromogenic method CBS 34.47): R = −0.32, T = -2.84, pCO.Ol; For CY222: Anti-Xa (chromogenic method): R = −0.23, T = −1.80, p=0.07; Anti-IIa (chromogenic method): R = −0.26, T = −2.07, p<0.05; 2°) a multivariate regression between thrombus weight (mg) and the plasmatic activity of both the test drugs: For Hep Anti-Xa (chromogenic method): F = 14.56 For CY222 Anti-IIa (chromogenic method): F = 14.40 and Anti-Xa (chromogenic method): F = 5.96.In conclusion, we observe a statistical correlation between Anti-IIa activity and thrombus regression. These parameters may use in human Low Molecular Weight Heparin therapy.

Antithrombotic Effect of Two Low Molecular Weight Thrombin Inhibitors and a Low-Molecular Weight Heparin in a Caval Vein Thrombosis Model in the Rat

1997 ◽  
Vol 78 (05) ◽  
pp. 1404-1407 ◽  
Author(s):  
B I Eriksson ◽  
S Carlsson ◽  
M Halvarsson ◽  
B Risberg ◽  
C Mattsson
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
Clinical Situation ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Low Molecular Weight ◽  
Surgical Trauma ◽  
Antithrombotic Effect ◽  
Caval Vein ◽  
Thrombosis Model

SummaryA sensitive thrombosis model with a high reproducibility was developed in the rat, utilizing stasis of the caval vein and a standardized surgical trauma as the only thrombogenic stimuli. Since no procoagulant substances were used, the results of the present study might be relevant in a clinical situation. The antithrombotic effect of two recently synthesized low-molecular-weight thrombin inhibitors have been compared to dalteparin, (Fragmin) a low-molecular-weight heparin fragment. Each compound was studied at 8 different doses with 10 rats in each group. On a gravimetric basis, the thrombin inhibitor melagatran was twice as potent as dalteparin (ED50 16 and 33 µ/kg per h, respectively). The second thrombin inhibitor, inogatran, had an intermediate effect, with an ED50 of 24 µLg/kg per h. No differences in antithrombotic effect were, however, found when the compounds were compared at anticoagulant equivalent doses (same APTT prolongation). A 50% reduction in the mean thrombus weight was obtained when APTT was prolonged to 1.2 to 1.3 times the pretreatment value.

Neutralization of a Low Molecular Weight Heparin (LHN-1) and Conventional Heparin by Protamine Sulfate in Rats

1986 ◽  
Vol 56 (03) ◽  
pp. 318-322 ◽  
Author(s):  
V Diness ◽  
P B Østergaard
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
Thrombus Formation ◽  
Experimental Models ◽  
Protamine Sulfate ◽  
Low Molecular Weight ◽  
Antithrombotic Effect ◽  
Higher Doses

SummaryThe neutralization of a low molecular weight heparin (LHN-1) and conventional heparin (CH) by protamine sulfate has been studied in vitro and in vivo. In vitro, the APTT activity of CH was completely neutralized in parallel with the anti-Xa activity. The APTT activity of LHN-1 was almost completely neutralized in a way similar to the APTT activity of CH, whereas the anti-Xa activity of LHN-1 was only partially neutralized.In vivo, CH 3 mg/kg and LHN-1 7.2 mg/kg was given intravenously in rats. The APTT and anti-Xa activities, after neutralization by protamine sulfate in vivo, were similar to the results in vitro. In CH treated rats no haemorrhagic effect in the rat tail bleeding test and no antithrombotic effect in the rat stasis model was found at a protamine sulfate to heparin ratio of about 1, which neutralized APTT and anti-Xa activities. In LHN-1 treated rats the haemorrhagic effect was neutralized when APTT was close to normal whereas higher doses of protamine sulfate were required for neutralization of the antithrombotic effect. This probably reflects the fact that in most experimental models higher doses of heparin are needed to induce bleeding than to prevent thrombus formation. Our results demonstrate that even if complete neutralization of APTT and anti-Xa activities were not seen in LHN-1 treated rats, the in vivo effects of LHN-1 could be neutralized as efficiently as those of conventional heparin. The large fall in blood pressure caused by high doses of protamine sulfate alone was prevented by the prior injection of LHN-1.

THROMBOLYSIS ENHANCING ACTIVITY OF A LOW MOLECULAR WEIGHT DERMATAN SULFATE (DESMIN 370) IN EXPERIMENTAL PULMONARY EMBOLISM IN RATS

1997 ◽  
Vol 87 (5) ◽  
pp. 441-446 ◽  
Author(s):  
Mario Colucci ◽  
Leonardo Sardella ◽  
Miriam Barbanti ◽  
Fiorella Calanni ◽  
Nicola Semeraro
Keyword(s):  
Molecular Weight ◽  
Pulmonary Embolism ◽  
Dermatan Sulfate ◽  
Low Molecular Weight

Interaction between Histidine-Rich Glycoprotein and Platelet Factor 4 with Dermatan Sulfate and Low-Molecular-Weight Dermatan Sulfate

Angiology ◽  
1992 ◽  
Vol 43 (1) ◽  
pp. 59-62 ◽  
Author(s):  
Giuseppe Cella ◽  
Giuseppe Boeri ◽  
Graziella Saggiorato ◽  
Rossella Paolini ◽  
Guido Luzzatto ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Dermatan Sulfate ◽  
Platelet Factor 4 ◽  
Low Molecular Weight ◽  
Platelet Factor

scholarly journals Efficacy, Safety, and Timing of Anticoagulant Thromboprophylaxis for the Prevention of Venous Thromboembolism in Patients With Acute Spinal Cord Injury: A Systematic Review

2017 ◽  
Vol 7 (3_suppl) ◽  
pp. 138S-150S ◽  
Author(s):  
Paul M. Arnold ◽  
James S. Harrop ◽  
Geno Merli ◽  
Lindsay G. Tetreault ◽  
Brian K. Kwon ◽  
...  
Keyword(s):  
Systematic Review ◽  
Molecular Weight ◽  
Lower Risk ◽  
Low Molecular Weight Heparin ◽  
Inferior Vena Cava Filter ◽  
Inferior Vena ◽  
Vena Cava ◽  
Low Molecular Weight ◽  
Mechanical Prophylaxis ◽  
Cord Injury

Study Design: Systematic review. Objectives: The objective of this study was to answer 5 key questions: What is the comparative effectiveness and safety of (1a) anticoagulant thromboprophylaxis compared to no prophylaxis, placebo, or another anticoagulant strategy for preventing deep vein thrombosis (DVT) and pulmonary embolism (PE) after acute spinal cord injury (SCI)? (1b) Mechanical prophylaxis strategies alone or in combination with other strategies for preventing DVT and PE after acute SCI? (1c) Prophylactic inferior vena cava filter insertion alone or in combination with other strategies for preventing DVT and PE after acute SCI? (2) What is the optimal timing to initiate and/or discontinue anticoagulant, mechanical, and/or prophylactic inferior vena cava filter following acute SCI? (3) What is the cost-effectiveness of these treatment options? Methods: A systematic literature search was conducted to identify studies published through February 28, 2015. We sought randomized controlled trials evaluating efficacy and safety of antithrombotic strategies. Strength of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Results: Nine studies satisfied inclusion criteria. We found a trend toward lower risk of DVT in patients treated with enoxaparin. There were no significant differences in rates of DVT, PE, bleeding, and mortality between patients treated with different types of low-molecular-weight heparin or between low-molecular-weight heparin and unfractionated heparin. Combined anticoagulant and mechanical prophylaxis initiated within 72 hours of SCI resulted in lower risk of DVT than treatment commenced after 72 hours of injury. Conclusion: Prophylactic treatments can be used to lower the risk of venous thromboembolic events in patients with acute SCI, without significant increase in risk of bleeding and mortality and should be initiated within 72 hours.

INFLUENCE OF THE SULFATION PATTERN ON CERTAIN BIOLOGICAL PROPERTIES OF GALACTOSAMINOGLYCANS

1987 ◽  
Author(s):  
B Casu ◽  
L Marchese ◽  
A Naggi ◽  
G Torri ◽  
J Fareed ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Dermatan Sulfate ◽  
Anticoagulant Activity ◽  
Chlorosulfonic Acid ◽  
Biological Properties ◽  
Sulfated Polysaccharides ◽  
Low Molecular Weight ◽  
Antithrombotic Activity

In order to investigate the influence of charge distribution and chain length on the biological properties of sulfated polysaccharides, additional sulfate groups were introduced into the galactosaminoglycans, chondriotin sulfate and dermatan sulfate. Using a flexible method (with sulfuric acid and chlorosulfonic acid) for concurrent sulfation and controlled depolymerization, numerous products were obtained and characterized by chemical, enzymatic and nuclear magnetic resonance spectroscopic methods. The biologic actions of these products were profiled in both in vitro and in vivo assays for antithrombotic activity. Despite a weaker in vitro anticoagulant activity, low molecular weight over sulfated galactosaminoglycans produced significant dose-dependent antithrombotic actions in animal models which were similar to the actions observed with oversulfated low molecular weight heparins. These results suggest that a significant antithrombotic activity can be elicited through non-specific interactions of polysulfates with cellular and plasma components, and that clusters of sulfate groups such as the 4-6 disulfate group on D-galactosaminoglycan residues may be important for these interactions. Furthermore, these results, also suggest that supersulfation of glycosaminogly-cans results in products with biologic activity distinct from the native material.

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