Defining the heparin-binding domain of antithrombin

Wu, Yi; Sheffield, WP; Blajchman, MA

doi:10.1097/00001721-199402000-00012

Cited by 26 publications

(11 citation statements)

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“…22 Heparin is a heterogenous mixture of glycosaminoglycans of varying molecular weight (mean, 15,000 days; range, 3000 -30,000 days), only one-third of which possess the high-affinity binding site for AT-the "essential pentasaccharide" sequence. 25 Therefore, smaller heparin molecules are able to catalyze the inactivation of factor Xa, while larger molecules (consisting of at least 18 saccharide units) to effect the binding of both AT and thrombin are required to inactivate thrombin. Inactivation of factor Xa requires only the binding of AT by heparin, but thrombin inactivation requires the formation of a ternary complex between heparin, AT, and thrombin.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

The Use and Limitations of Unfractionated Heparin

Krishnaswamy¹,

Lincoff²,

Cannon³

2010

Critical Pathways in Cardiology: A Journal of Evidence-Based Medicine

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Despite the development of newer anticoagulants, unfractionated heparin remains an indispensible agent in the treatment of thrombotic disorders. Heparin exerts its major effect via antithrombin, converting antithrombin to a more efficient inhibitor of circulating thrombin (factor IIa), factor Xa, factor IXa, factor XIIa, and kallikrein. However, due to the multiple anticoagulant mechanisms of heparin, differential molecular weight-based clearance, issues of heparin resistance, and patient-specific characteristics (age, weight, gender, and tobacco), attaining therapeutic anticoagulation is complicated. As a result, a minority of patients in major clinical trials achieve an activated partial thromboplastin time within the target window in an appropriate time-frame despite the use of weight-based titration nomograms. The resultant under- or over-therapeutic anticoagulation is associated with increased risks of ischemic and bleeding complications, suggesting the importance of maintaining heparin anticoagulation within a relatively narrow therapeutic range. In this review we discuss the mechanisms of heparin action, clinical ramifications of incorrect dosing in major trials, and attempts to improve the achievement of therapeutic anticoagulation.

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Section: Mechanism Of Actionmentioning

confidence: 99%

The Use and Limitations of Unfractionated Heparin

Krishnaswamy¹,

Lincoff²,

Cannon³

2010

Critical Pathways in Cardiology: A Journal of Evidence-Based Medicine

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“…In arterial indications it is used as thromboprophylaxis in patients with unstable angina and non-Q-wave infarction and treatment of ACS and in combination with thrombo-lytics. The pentasaccharide structure in heparin [102], which is responsible for binding of antithrombin, has recently been synthesised on an industrial scale and launched as fondaparinux (Arixtra ® ) for the same indications as LMWAs [103].…”

Section: Anticoagulantsmentioning

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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“…Heparin is derived from porcine intestinal mucosa and is a structurally heterogeneous molecule with highly variable pharmacokinetics. The high-affinity pentasaccharide sequence required for the heparin-antithrombin complex is present in only one-third of heparin molecules 14, 15 . Additional heparin-thrombin binding, however, can occur electrostatically due to heparin’s strong anionic properties.…”

Section: Introductionmentioning

confidence: 99%

The immobilization of a direct thrombin inhibitor to a polyurethane as a nonthrombogenic surface coating for extracorporeal circulation

Brisbois

Handa

et al. 2016

J. Mater. Chem. B

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A biomaterial with both antithrombin and antiplatelet properties is the ideal surface for use in extracorporeal circulation (ECC) as it targets both fibrin generation and platelet adhesion. A hemocompatible surface coating avoids the need for systemic anticoagulation by providing a local anticoagulant effect at the polymer-blood interface. Previous work has demonstrated the potential use of argatroban, a direct thrombin inhibitor, as a nonthrombogenic material for extracorporeal devices. The work reported here focuses on the characterization of argatroban linked to a polyurethane-silicone polymer, CarboSil®. Chemical immobilization, the amount of argatroban, incubation times, and saturation point were evaluated to achieve maximal antithrombin activity at the polymer surface. Cross-linked polymer coatings reacted with 10 and 30 µmole of argatroban were prepared and tested. These coatings resulted in argatroban activity levels of 0.131 µM and 0.446 µM, respectively. After refining the cross-linking process, argatroban activity increased by approximately 3.6 fold. Maintenance of activity and leaching from the polymer surface were also evaluated. Using the refined process for linking argatroban to polymer, the resulting polymer was applied as a surface coating to the inner lumen of poly(vinyl chloride) ECC circuit tubing and its antithrombin effect evaluated using a 4 h rabbit ECC model. Following 4 h of blood exposure, the argatroban circuit demonstrated significantly less thrombus formation compared to the control CarboSil® coating with a 4.1 cm2 thrombus average area for the control coating compared to 1.2 cm2 for the argatroban coating (n=4). There was no significant change in thrombin time from baseline in plasma from animals in which the argatroban coated circuit was used, with a thrombin time of 16.2 s at t=0 and 14.5 s after 4 h. These results demonstrate the potential efficacy of immobilized argatroban as a hemocompatible biomaterial for extracorporeal life support devices.

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Defining the heparin-binding domain of antithrombin

Cited by 26 publications

References 0 publications

The Use and Limitations of Unfractionated Heparin

The Use and Limitations of Unfractionated Heparin

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

The immobilization of a direct thrombin inhibitor to a polyurethane as a nonthrombogenic surface coating for extracorporeal circulation

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