Anticoagulant and antithrombotic effects of heparin and low molecular weight heparin fragments in rabbits

Holmer, E.; Mattsson, Christer; Nilsson, Solveig

doi:10.1016/0049-3848(82)90089-5

Cited by 215 publications

(106 citation statements)

References 17 publications

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“…A simple, but rather crude, way is to visually inspect the thrombus as in the classical Wessler stasis thrombosis model [119], which was frequently used during the early development of LMWH [120,121]. In short, the model first involves a segment of the jugular vein being isolated in situ before the test compound is injected intravenously.…”

Section: Fibrin-rich Thrombus Modelsmentioning

confidence: 99%

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Björkman

Abrahamsson

Nerme

et al. 2005

Thrombosis Research

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The physiologically most important activator of intravascular fibrinolysis is tissue-type plasminogen activator (t-PA) released from endothelial cells. In man, sympathomimetic drugs increase the systemic concentration of t-PA. It is therefore of interest to investigate whether cardiac sympathetic activation can induce a local t-PA release, which could counteract intra-coronary clot formation.Thrombolytic therapy with recombinant t-PA (rt-PA) is effective in acute myocardial infarction, but the treatment is limited by a fairly slow reperfusion rate and frequent early reocclusions. A potential mechanism behind early reocclusions might be that active thrombin is released from the thrombus during thrombolytic therapy. Thrombin has recently been shown to activate procarboxypeptidase U, which in its active form (CPU) down-regulates endogenous fibrinolysis. Therefore, one way of improving thrombolytic efficacy may be to combine rt-PA with a lowmolecular weight direct thrombin inhibitor, which theoretically could have a pro-fibrinolytic effect, either by inhibition of fibrin-bound thrombin and/or by inhibition of CPU activation. An alternative way may be direct inhibition of CPU.In a porcine model, experimental activation of cardiac sympathetic nerves by electrical stimulation at 1 and 8 Hz induced 5-and 20-fold increase in the release of both total and active t-PA together with frequency-dependent increases in heart rate, blood pressure, and coronary blood flow. The t-PA release was independent of the heart rate and coronary flow response, but local infusion of isoprenaline suggested that part of the t-PA response was mediated by stimulation of β-adrenergic receptors. Next, we studied the combined effect of rt-PA and thrombin inhibitors (melagatran, hirudin and heparin) in a canine model of copper coil-induced coronary thrombosis. The profibrinolytic effect of rt-PA, either measured as patency rate or time-to-patency, was significantly enhanced with the low-molecular weight direct thrombin inhibitor melagatran, but to a lesser degree by hirudin and heparin. In the same model it was shown that active CPU is produced locally in the coronary vascular bed during both thrombus formation and clot lysis. Inhibition of thrombin attenuated CPU formation and improved patency. A similar effect was obtained with a direct inhibitor of CPU.In conclusion, the coronary t-PA response to sympathetic stimulation may constitute a thromboprotective defence mechanism to counteract its prothrombotic effects on the systemic level. Furthermore, direct thrombin and/or CPU inhibition may be potential targets for prevention of thrombus formation via facilitation of the endogenous fibrinolytic system.

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Section: Fibrin-rich Thrombus Modelsmentioning

confidence: 99%

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Björkman

Abrahamsson

Nerme

et al. 2005

Thrombosis Research

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“…Anti-Xa assays were performed 4 hours after the start of the treatment, 4 hours after any dose adjustment, and furthermore, daily at 9:00 AM and 4:00 PM. The dose was adjusted to give anti-Xa levels between 0.4 and 0.9 unit/ml in the low-risk group and between 0.3 and 0.6 unit/ml in the highrisk group.…”

Section: Methodsmentioning

confidence: 99%

“…[2][3][4][5][6] Clinical studies in humans have shown that low molecular weight heparins are effective in preventing postoperative venous thromboembolism.7-9 These studies, however, have not clarified whether or not these preparations also prevent extension and embolization of thrombi in patients with overt thrombosis. Furthermore, it still has to be established in humans whether or not low molecular weight heparins produce less bleeding for equivalent antithrombotic efficacy.…”

Section: Treatment Of Acute Venous Thromboembolism With Low Molecularmentioning

confidence: 99%

Treatment of acute venous thromboembolism with low molecular weight heparin (Fragmin). Results of a double-blind randomized study.

Albada¹,

Nieuwenhuis²,

Sixma³

1989

Circulation

161

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We performed a prospective, randomized, double-blind trial in 194 unselected patients to determine the safety and efficacy of low molecular weight heparin (Fragmin) compared with standard heparin as the initial treatment of acute venous thromboembolism. Ninety-eight patients received continuous intravenous heparin, and 96 patients received Fragmin for 5-10 days. Doses were adjusted to maintain anti-Xa levels between 0.3 and 0.6 unit/ml for patients with a high risk for a bleeding complication and between 0.4 and 0.9 unit/ml for patients with a low risk for bleeding. Treatment was stopped when a therapeutic level of anticoagulation (International Normalized Ratio >3.5) was reached with coumarins. Thirteen patients in the heparin group and 10 patients in the Fragmin group had a major bleeding complication. The incidence of major and minor bleeding complications combined decreased from 48.9% to 38.5% (95% confidence interval for the dilference, -3.5% to +24.2%), corresponding with a relative bleeding risk reduction of 21.2%. There were no significant differences in efficacy as defined by new high-probability defects on repeat ventilation-perfusion scintigraphy of the lung in 80 patients: six of 46 patients in the heparin group and 3 of 34 patients in the Fragmin group had new defects (95% confidence interval for the difference, -9.4% to + 17.8%). We conclude that low molecular weight heparin (Fragmin) given in adjusted, continuous, and intravenous doses is safe and effective as initial treatment of acute venous thromboembolism compared with heparin. There is a trend in risk reduction for bleeding in favor of low molecular weight heparin, a trend, however, that is smaller than expected compared with animal studies. (Circulation 1989;80:935-940) H eparin is used in relatively large doses in the management of thromboembolic disease with the aim of preventing extension and embolization of venous thrombi. The treatment, however, is associated with an appreciable risk of hemorrhage. This has prompted research to improve the benefit to risk ratio of the drug.Heparin acts as an anticoagulant by accelerating the complex formation between antithrombin III and various activated clotting factors, among which factor Xa and thrombin are the most important. Fractionation of the polydisperse heparin according to molecular size has led to the development of low molecular weight heparin preparations with an increased anti-Xa to antithrombin ratio.1 These low molecular weight heparins have been shown to

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“…Heparin molecules with less than 18 saccharide residues cannot bind to AT 111 and thrombin simultaneously, and therefore low molecular weight heparins cannot catalyze the inhibition of thrombin.14. 19 The primary anticoagulant effect of heparin is through the suppression of thrombin-dependent amplification of the coagulation cascade, and the inhibition of thrombin-mediated conversion of fibrinogen to fibrinI7 (Fig 1). Prothrombinase complex, composed of factor Xa, factor Va, calcium, and phospholipid, is the physiological activator of prothrombin to thrombin."…”

mentioning

confidence: 99%

Heparin: A Review of its Pharmacology and Therapeutic Use in Horses

Moore

Hinchcliff

1994

Veterinary Internal Medicne

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Heparin is used clinically in horses to treat hemostatic abnormalities associated with severe gastrointestinal disease, septicemia, and endotoxemia. The primary anticoagulant effect of heparin is through the suppression of thrombin-dependent amplification of the coagulation cascade, and inhibition of thrombin-mediated conversion of fibrinogen to fibrin. Heparin may be of benefit in preventing the complications associated with hypercoagulable states such as jugular vein thrombosis, laminitis, and organ failure. Heparin may also be beneficial in the prevention of intraabdominal adhesions after gastrointestinal surgery, and in amelioration of hernodynamic abnormalities associated with endotoxic shock. Because a sequential rise in serum unique compound with anticoagulant activity was ac-A cidentally discovered in 19 16 by McClean, a medical student, while he was attempting to identify a procoagulant in the liver.' The substance was named heparin because of its abundance in hepatic tissue.' In 1939, Brinkhous discovered that a plasma cofactor was necessary for the anticoagulant activity of h e~a r i n .~ Abildgaard named the cofactor antithrombin 111 (AT 111), and the specific mechanism of action of this cofactor was elucidated shortly thereafter. [4][5][6] Heparin is composed of a family of straight-chain, highly sulfated, anionic polysaccharides, specifically glycosaminoglycuronan sulfate esters, with molecular weights varying from 4,000 to 40,000 d.7-9 The structural unit of this complex molecule is a two hexose sugar that, in 8 to 15 repeating disaccharide subunits, forms a polymer of differing length^.^.' The structure of heparin is markedly heterogenous and varies with respect to the sequence and ratio of the different hexose units, the extent and type of sulfation, and the extent of N-a~etylation.~ The heterogeneity of heparin is not an artifact of preparation, but occurs because of the randomness of the biosynthetic process. lo Endogenous heparin is produced within mast cells of the lung, liver, and intestine.' ' Commercially-available heparin is derived from the mast cells of porcine intestinal mucosa and bovine lung."A small and distinct fraction of the heparin molecule is responsible for its anticoagulant effect. l 3 The active site of the heparin molecule contains a unique glucosamine unit with a specific pentasaccharide ~equence.'~.'~ This distinct fraction of the heparin molecule binds to AT 111, an endog-

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Anticoagulant and antithrombotic effects of heparin and low molecular weight heparin fragments in rabbits

Cited by 215 publications

References 17 publications

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Treatment of acute venous thromboembolism with low molecular weight heparin (Fragmin). Results of a double-blind randomized study.

Heparin: A Review of its Pharmacology and Therapeutic Use in Horses

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