An Antithrombin-Heparin Complex Increases the Anticoagulant Activity of Fibrin Clots

Smith, Lesley; Mewhort-Buist, Tracy Anne; Berry, Leslie R.; Chan, Anthony

doi:10.1155/2008/639829

Cited by 3 publications

(1 citation statement)

References 9 publications

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“…To overcome some of the limitations of UFH, our laboratory has developed a covalent complex of antithrombin and heparin (ATH) with high anticoagulant activity (25). Numerous in vitro and in vivo investigations involving ATH have led to results showing potential clinical advantages of ATH over UFH (25)(26)(27)(28)(29)(30). More specifically, we have demonstrated that ATH inhibits FXa within a prothrombinase on an artificial phospholipid surface much better than AT+UFH (24).…”

Section: Introductionmentioning

confidence: 99%

Covalently linking heparin to antithrombin enhances prothrombinase inhibition on activated platelets

Stevic¹,

Chan²,

Chander³

et al. 2013

Thromb Haemost

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Factor (F)Xa within the prothrombinase complex is protected from inhibition by unfractionated heparin (UFH), enoxaparin and fondaparinux. We have developed a covalent antithrombin-heparin complex (ATH) with enhanced anticoagulant activity. We have also demonstrated that ATH is superior at inhibiting coagulation factors when assembled on artificial surfaces. The objective of the present study is to determine the ability of ATH vs AT+UFH to inhibit FXa within the prothrombinase complex when the enzyme complex is assembled on the more native platelet system. Discontinuous inhibition assays were performed to determine final k2-values for inhibition of FXa, FXa within the platelet-prothrombinase, or FXa within prothrombinase devoid of various components. Thrombin generation and plasma clotting was also assayed in the presence of resting/activated platelets ± inhibitors. Protection of FXa was not observed for ATH, whereas a moderate 60% protection was observed for AT+UFH. ATH inhibited platelet-prothrombinase ~4-fold faster than AT+UFH. Relative to intact prothrombinase, ratesfor FXa inhibition by AT+UFH in prothrombinase complexes devoid of either prothrombin (II)/activated platelets/FVa were higher. However, inhibition by AT+UFH of prothrombinase devoid of FII yielded slightly lower rates compared to free FXa inhibition. Thrombin generation and plasma clotting was enhanced with activated platelets, while inhibition was better by ATH compared to AT+UFH, thus suggesting an overall enhanced anticoagulant activity of ATH against platelet-bound prothrombinase complexes.

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Section: Introductionmentioning

confidence: 99%

Covalently linking heparin to antithrombin enhances prothrombinase inhibition on activated platelets

Stevic¹,

Chan²,

Chander³

et al. 2013

Thromb Haemost

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Antithrombin-heparin covalent complex reduces microemboli during cardiopulmonary bypass in a pig model

Klement

Berry

Liao

et al. 2010

Blood

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Transcranial Doppler-detected high-intensity transient signals (HITS) during cardiopulmonary bypass (CPB) surgery have been associated with postoperative neurocognitive dysfunction, suggesting microemboli in the brain could be a contributing factor. HITS occur despite administration of unfractionated heparin (UFH). This study was done to determine whether antithrombin-heparin covalent complex (ATH), a more potent anticoagulant than heparin, can reduce HITS during CPB. In a pig CPB model, ATH, UFH, or UFH ؉ antithrombin (AT) was intravenously administered to female Yorkshire pigs after sternotomy. Twenty minutes later, hypothermic CPB was initiated and continued for 1.25 hours, then normothermia was re-established for 45 minutes. Protamine sulfate was given to neutralize the anticoagulants, and pigs were allowed to recover. HITS were monitored using an arterial flow probe placed over the carotid artery. Compared with UFH (300 or 1000 U/kg), ATH reduced the number of HITS during CPB in a dose-dependent manner. AT (3 mg/kg) ؉ UFH (300 U/kg) resulted in an intermediate HITS rate between UFH and ATH (2 mg/kg in terms of AT). Examination of brain sections for emboli formation confirmed that, similar to HITS, number of thrombi decreased in direct proportion to ATH dosage. These results support the hypotheses that the majority of HITS represent thromboemboli and that ATH reduces emboli formation during CPB. IntroductionMany important advances in cardiac surgery were made in past decades including procedures such as cardiopulmonary bypass (CPB), coronary artery bypass grafting, and cardiac repair or replacement surgery. 1,2 There is some evidence of adverse neurological effects associated with cardiac surgery, particularly with CPB. Neurocognitive dysfunction is a common complication of cardiac surgery. [3][4][5][6] The etiology of neurocognitive dysfunction is controversial, but there is evidence suggesting that microemboli may be a contributing factor. Some studies have been performed using transcranial Doppler ultrasound to detect microemboli as high-intensity transient signals (HITS) during cardiac surgery. 7,8 In these studies, HITS were associated with neurocognitive deficits, especially with respect to memory loss. Of the possible sources of microemboli, including air, thrombi, and fat from cellular or particulate matter promoted by the bypass pump, thromboemboli are thought to be an important contributor to the neurocognitive dysfunction that occurs after CPB. 9,10 Currently, unfractionated heparin (UFH) is the standard agent used for anticoagulation during CPB. Although UFH provides sufficient anticoagulation to prevent clotting within the bypass circuit, clinical application of UFH is limited by its pharmacokinetic and biophysical properties. UFH has a short, dose-dependent intravenous half-life and an unpredictable anticoagulant effect, mainly due to variable nonspecific plasma and cell surface protein binding. 11,12 UFH is also unable to inactivate surface-bound coagulation factors, such as fibrin-bound thro...

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Review on Patents for Potent Anticoagulant Antithrombin-Heparin Covalent Complexes that Control Thrombosis In Vivo

Berry¹,

Chan²

2008

BIOMENG

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An Antithrombin-Heparin Complex Increases the Anticoagulant Activity of Fibrin Clots

Cited by 3 publications

References 9 publications

Covalently linking heparin to antithrombin enhances prothrombinase inhibition on activated platelets

Covalently linking heparin to antithrombin enhances prothrombinase inhibition on activated platelets

Antithrombin-heparin covalent complex reduces microemboli during cardiopulmonary bypass in a pig model

Review on Patents for Potent Anticoagulant Antithrombin-Heparin Covalent Complexes that Control Thrombosis In Vivo

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