Heparin: Mechanism of Action, Pharmacokinetics, Dosing Considerations, Monitoring, Efficacy, and Safety

Hirsh, Jack; Raschke, Robert; Warkentin, Theodore E.; Dalen, James E.; Deykin, Daniel; Poller, L.

doi:10.1378/chest.108.4_supplement.258s

Cited by 370 publications

(101 citation statements)

References 225 publications

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“…It acts by enhancing the ability of antithrombin (AT) to inactivate thrombin and factor Xa, enzymes that promote coagulation. 5 Therefore, heparin is the drug of choice when a rapid anticoagulant effect is required (e.g., during surgical procedures, particularly to prevent thrombosis in devices used in extracorporeal therapy such as dialysers and oxygentators). It also has many other therapeutic applications, for example, in unstable angina and acute myocardial infarction.…”

Section: Introductionmentioning

confidence: 99%

pH-Sensitive Genipin-Cross-Linked Chitosan Microspheres For Heparin Removal

et al. 2008

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Chitosan hydrogel microspheres were obtained by cross-linking chitosan in its inverse emulsion using genipin as cross-linker. The genipin-cross-linked chitosan microspheres (ChGp) swell significantly in water at pH values below 6.5 and shrink to a smaller extent at pH values above 6.5. ChGp microspheres bind heparin in water. The kinetics of heparin binding was found to be pH dependent and was faster and more efficient at a lower pH. That can be also controlled by the weight of ChGp microspheres used. Rate and efficiency of heparin adsorption at pH 7.4, which is typical of blood, could be increased by quaternization of ChGp microspheres using glycidyltrimethylammonium chloride (GTMAC). The polymeric material obtained thus can be potentially useful for heparin removal in biomedical applications.

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Section: Introductionmentioning

confidence: 99%

pH-Sensitive Genipin-Cross-Linked Chitosan Microspheres For Heparin Removal

et al. 2008

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“…The anticoagulant functions of heparin include inhibition of thrombin, coagulation factors Xa, IXa, XIa, and XIIa as well as inhibition of platelet function (1)(2)(3). Antithrombin III (AT III) 1 and heparin cofactor II (HC II) are major regulators of heparin but some anticoagulant functions of heparin are independent of both cofactors (1,4,5).…”

Section: Introductionmentioning

confidence: 99%

Anticoagulant synergism of heparin and activated protein C in vitro. Role of a novel anticoagulant mechanism of heparin, enhancement of inactivation of factor V by activated protein C.

et al. 1997

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Interactions between standard heparin and the physiological anticoagulant plasma protein, activated protein C (APC) were studied. The ability of heparin to prolong the activated partial thromboplastin time and the factor Xaone-stage clotting time of normal plasma was markedly enhanced by addition of purified APC to the assays. Experiments using purified clotting factors showed that heparin enhanced by fourfold the phospholipid-dependent inactivation of factor V by APC. In contrast to factor V, there was no effect of heparin on inactivation of thrombin-activated factor Va by APC. Based on SDS-PAGE analysis, heparin enhanced the rate of proteolysis of factor V but not factor Va by APC. Coagulation assays using immunodepleted plasmas showed that the enhancement of heparin action by APC was independent of antithrombin III, heparin cofactor II, and protein S. Experiments using purified proteins showed that heparin did not inhibit factor V activation by thrombin. In summary, heparin and APC showed significant anticoagulant synergy in plasma due to three mechanisms that simultaneously decreased thrombin generation by the prothrombinase complex. These mechanisms include: first, heparin enhancement of antithrombin III-dependent inhibition of factor V activation by thrombin; second, the inactivation of membrane-bound FVa by APC; and third, the proteolytic inactivation of membrane-bound factor V by APC, which is enhanced by heparin. (

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“…It has also been observed in blood flow over vascular prostheses (2) and in artificial internal organs, such as prosthetic heart valves (3). The thrombi are composed predominantly of platelets, and they can develop even in the presence of systemic anticoagulants such as heparin (4).…”

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confidence: 99%

Blood flow velocity effects and role of activation delay time on growth and form of platelet thrombi

Pivkin

Richardson

Karniadakis

2006

Proc. Natl. Acad. Sci. U.S.A.

144

120

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Mural thrombi are composed dominantly of platelets and develop under a blood flow. Portions can break off and are carried in the blood flow as emboli. Thrombus growth rates are affected by the velocity of the blood flow, but they do not simply increase with it, they exhibit a maximum, with subsequent decrease. Whereas this variation indicates an interaction of biochemical and physical processes, studies have concentrated widely on understanding only the biochemical processes. Here we show results of simulation of thrombus formation in 3D flows by accounting for the movements of individual platelets. Each platelet follows prescribed rules for interactions while the local flow around the thrombus continuously adjusts to the growing structure of the thrombus, also when embolization occurs. With an activation delay time assigned to each platelet we demonstrate the dependence of thrombus growth rate on blood velocity as found experimentally by Begent and Born [Begent N, Born GV (1970) Nature 227:926 -930]. With activated platelets having mutual tensile action sustainable up to a prescribed distance we achieve thrombus growth faster than with shorter maximum distances that make a thrombus less porous; when the prescribed maximum distance is large enough the thrombus shape is not like a ''hill'' but like a ''carpet.'' We find that thrombus growth rate is enhanced by modest pulsatility but less so when pulsations are amplified in part because of more embolization.direct numerical simulations ͉ platelet aggregation ͉ in vivo comparison ͉ stochastic modeling A cute thrombogenesis in a flowing bloodstream can occur on damaged tissues in normal circulation (1). It has also been observed in blood flow over vascular prostheses (2) and in artificial internal organs, such as prosthetic heart valves (3). The thrombi are composed predominantly of platelets, and they can develop even in the presence of systemic anticoagulants such as heparin (4).Blood flow velocity effects were investigated systematically in vivo by Begent and Born (1), who obtained quantitative data on thrombus growth rates for a range of blood flow rates. Their study remains the clearest time-resolved in vivo study of the effect of blood flow rates on thrombus formation. Richardson (5) subsequently proposed that Begent and Born's observations were consistent with a shear-flow aggregation process (6, 7) in which an activation delay time of the platelets is allowed for, a delay time between each platelet's close encounter with the thrombus and its development of ability to adhere to the thrombus, and which was estimated then to be the order of 0.1-0.2 s. A predicted consequence of this finding was that the height-to-length ratio for thrombi would be lower in blood flows, where a significant fraction of the activated platelets escaped the primary thrombus before their activation delay time had elapsed; this was demonstrated later by Born and Richardson (8). More recent experiments by Petrishchev and Mikhailova (9) in vivo and van Gestel et al. (10) in vitro produc...

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Heparin: Mechanism of Action, Pharmacokinetics, Dosing Considerations, Monitoring, Efficacy, and Safety

Cited by 370 publications

References 225 publications

pH-Sensitive Genipin-Cross-Linked Chitosan Microspheres For Heparin Removal

pH-Sensitive Genipin-Cross-Linked Chitosan Microspheres For Heparin Removal

Anticoagulant synergism of heparin and activated protein C in vitro. Role of a novel anticoagulant mechanism of heparin, enhancement of inactivation of factor V by activated protein C.

Blood flow velocity effects and role of activation delay time on growth and form of platelet thrombi

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