Heterogeneity in the composition of commercial heparins: Comparison of anticoagulant activities and biochemical compositions of anionic density-fractionated heparins

Hurst, Robert E.; Settine, Juanita M.; Poon, Man chiu; Lurie, A.

doi:10.1016/0049-3848(82)90245-6

Cited by 9 publications

(4 citation statements)

References 18 publications

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“…Hog mucosal heparin (176 U. S. Pharmacopeia, units per milligram; Diosynth BV, Holland) was fractionated by two-phase partition (10,12) to obtain heparin fractions, previously characterized in detail (9)(10)(11)(12), that vary systematically in linear charge density, Z. The highly purified and more homogeneous fractions have similar molecular-weight distributions, with an average molecular weight of 15,000, and contain no detectable dermatan sulfate or other contaminating glycosaminoglycans.…”

Section: Methodsmentioning

confidence: 99%

“…A short sequence of defined structure (2) is necessary for AT-heparin binding and, hence, activity with AT (3,4). Because additional properties such as molecular weight (5,6), thrombin affinity (6)(7)(8), and charge density (9)(10)(11)(12), can also markedly affect the activity of a heparin, the molecule must have multiple functional domains (6,7).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Structure-activity relationships of heparin. Independence of heparin charge density and antithrombin-binding domains in thrombin inhibition by antithrombin and heparin cofactor II.

Hurst¹,

Poon²,

Griffith³

1983

J. Clin. Invest.

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A B S T R A C T To better understand how heparin structure affects its activity the relationships between the functional domains for inhibitor binding and charge density were investigated to determine how these domains affect heparin-mediated thrombin inhibition by two different heparin-dependent protease inhibitors, antithrombin (AT) and heparin cofactor II (HC II). A series of heparins, fractionated systematically by charge density, was further fractionated on antithrombin agarose to isolate more homogeneous subfractions that were either inactive or highly active with respect to thrombin inhibition by AT. With AT, the activities of the AT-active subfractions increased sharply with heparin charge density, while those with little or no affinity for AT were virtually inactive. In contrast, with HC II inhibitor, the activities of the heparins depended only upon their charge densities and were independent of AT affinity. At any given charge density, the heparin before fractionation by AT affinity and the fractions that were highly active and inactive with AT were all equally active with HC II. The two inhibitors also differed in their reactivity with heparan sulfate and dermatan sulfate. A charge-density effect with the subfractions having similar high affinity for AT demonstrates that charge density rep-

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structure-activity relationships of heparin. Independence of heparin charge density and antithrombin-binding domains in thrombin inhibition by antithrombin and heparin cofactor II.

Hurst¹,

Poon²,

Griffith³

1983

J. Clin. Invest.

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“…Aufgrund der verschiedenen Herstellungsweisen werden eine unterschiedliche Zusammensetzung kommerziell erhältlicher Heparine und differierende gerinnungshemmende Effekte angenommen (71,72). Es zeigen sich Unterschiede bezüglich der anionischen Ladungsdichte zwischen Heparin, das aus Rinderlungen und dem, das aus Schweinedarm gewonnen wird (58). In vitro weist Heparin des Rindes eine geringere gerinnungshemmende Aktivität auf als das aus der Darmmukosa des Schweines (80)…”

Section: Discussionunclassified

Heparine, Thrombin- und Faktor-Xa-Inhibitoren

Harenberg¹,

Fenyvesi²

2004

Hamostaseologie

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ZusammenfassungDirekte Antikoagulanzien hemmen Serinproteinasen des Gerinnungssystems entweder indirekt über Antithrombin oder Heparin-Kofaktor II oder binden direkt an die einzelnen Serinproteasen. Heparin, niedermolekulare Heparine, Fondaparinux und Idraparinux potenzieren nach Bindung an Antithrombin die Inhibierung einzelner Gerinnungsfaktoren. Hirudin, Argatroban und Melagatran hemmen unabhängig von Antithrombin direkt und reversibel Thrombin. Zum Nachweis des antikoagulanten Effektes stehen globale und spezifische Gerinnungsmethoden zur Verfügung. Neue Antikoagulanzien, insbesondere orale Faktor-Xa- und orale Thrombininhibitoren, sowie Antikörper gegen aktivierten Faktor VII, gentechnologisch hergestellter Tissue-Faktor Pathway-Inhibitor und andere Proteine werden als Antikoagulanzien oder als Substanzen mit nicht antikoagulanten Wirkungen (wie aktiviertes Protein C bei Sepsis) entwickelt. Neue Methoden werden zur Verbesserung der Diagnostik und Therapie thromboembolischer Erkrankungen entwickelt.

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“…Figure 1 diagrammatically illustrates the heterogeneity of the commercially available heparin preparations as determined by the isoelectric focusing technique. 13 ' 21 ' 35 ' 38 ' 45 Each of the individual components exhibits distinct chemical and biologic activities. The so-called therapeutic anticoagulant action of heparin in fact represents a cumulative action of all of these components.…”

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confidence: 99%

Heparin, Its Fractions, Fragments and Derivatives Some Newer Perspectives

Fareed¹

1985

Semin Thromb Hemost

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A brief attempt has been made to provide an overview of the field of heparinology. As stated, in coming years one should witness significant developments in this area. It is, however, important to caution that the newer products derived from heparin may not behave like heparin, and one must consider their individual molecular and biochemical interactions. The available limited data on heparin may or may not be applicable to the newer heparin fractions or derivatives. Independent preclinical and clinical trials are needed to investigate the pharmacology and therapeutic actions of newer heparin derivatives.

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Heterogeneity in the composition of commercial heparins: Comparison of anticoagulant activities and biochemical compositions of anionic density-fractionated heparins

Cited by 9 publications

References 18 publications

Structure-activity relationships of heparin. Independence of heparin charge density and antithrombin-binding domains in thrombin inhibition by antithrombin and heparin cofactor II.

Structure-activity relationships of heparin. Independence of heparin charge density and antithrombin-binding domains in thrombin inhibition by antithrombin and heparin cofactor II.

Heparine, Thrombin- und Faktor-Xa-Inhibitoren

Heparin, Its Fractions, Fragments and Derivatives Some Newer Perspectives

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