Effect of Heparin, Hirudin, and a Synthetic Thrombin Inhibitor on Antithrombin III in Thrombin-Induced Disseminated Intravascular Coagulation in Rats

Hauptmann, J.; Brüggener, E; Markwardt, Fritz

doi:10.1159/000215764

Cited by 16 publications

(15 citation statements)

References 27 publications

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“…Furthermore, it must be considered that thrombin complexed with hirudin does not react with plasma antithrombin 111 (32,97) (Fig. 4).…”

Section: Influence On the Coagulation Systemmentioning

confidence: 99%

Hirudin: The Promising Antithrombotic

Markwardt

1992

Cardiovascular Drug Reviews

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It has long been known that medicinal leeches (Hirudo medicinalis) contain a substance with anticoagulant properties. In early studies, aqueous extracts and dry preparations from leeches containing minute amounts of the active substance were used to prevent blood from clotting. Only after the development of protein chemistry and the elucidation of the biochemistry of blood coagulation was the anticoagulant agent, hirudin, isolated and its chemical nature and mode of action clarified.The historical background of hirudin isolation as well as the individual steps of its biochemical and pharmacological characterization have been described in several reviews (36,68,70,72,74,79). BIOCHEMISTRYHirudin is extracted from the homogenized heads of medicinal leeches and enriched by precipitation procedures followed by ion-exchange chromatography and gel filtration (2,65,98,137). Affinity chromatography on matrix-bound thrombin can be used to obtain highly purified hirudin preparations (139,140). The pure anticoagulant agent obtained is a carboxyhydrate-free single chain miniprotein containing 65 amino acids with a molecular weight of about 7 kDa. The amino acid composition is characterized by a remarkably high content of acidic amino acids at the C-terminal, the absence of arginine, methionine, and tryptophan, and the presence of a sulfated tyrosine residue and three intramolecular disulfide bridges (62,65,70).Considerable progress in the isolation, purification, and analysis of hirudin has shown the medicinal leech generates several variants of the miniprotein in trace amounts. The isoinhibitor forms share 85-90% amino acid sequence homology. Their main structural elements, which include N-terminal hydrophobic amino acids, followed by a core region linked by three disulfide bridges and the unique clustering of acidic amino acid residues in the C-terminal portion remain constant (4,17,18,113). The N-terminal amino acids Val-Val can be replaced by Ile-Thr (Fig. 1).

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“…Furthermore, it must be considered that thrombin complexed with hirudin does not react with plasma antithrombin 111 (32,97) (Fig. 4).…”

Section: Influence On the Coagulation Systemmentioning

confidence: 99%

Hirudin: The Promising Antithrombotic

Markwardt

1992

Cardiovascular Drug Reviews

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“…However, controlled trials are complicated by the etiologic diversity and diagnostic difficulties of DIC. 30 Furthermore, thrombin inhibitors are not bound or inactivated by platelet factors or other proteins acting as antiheparin substances. They have no influence on platelet function and no direct or immune-mediated platelet-activating activity.…”

Section: Thrombin Inhibitors and Heparin-a Comparisonmentioning

confidence: 99%

Development of Direct Thrombin Inhibitors in Comparison with Glycosaminoglycans

Markwardt¹

2001

Semin Thromb Hemost

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The progress in molecular biology has stimulated interest in the structure and function of thrombin. It has improved the understanding of its central role in thrombogenesis and has clarified the molecular events of inhibitor binding. This development has resulted in the production of recombinant hirudins and the design of hirudin analogues. It has also allowed the molecular design of synthetic antithrombins and encouraged the development of these products for clinical use. All pharmacological aspects speak in favor of the use of the direct thrombin inhibitors as antithrombotic agents, especially in the potential indications in which thrombin plays a crucial role in the pathogenesis. If their apparent advantages in comparison to glycosaminoglycans can be shown effectively, the direct thrombin inhibitors may become the drug of choice for certain indications.

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“…So, antithrombin III is protected from consumption, as may occur during heparin therapy. 135 Moreover, low molecular weight synthetic thrombin inhibitors are able to block thrombin bound to a thrombus, where it is inaccessible to inhibition by antithrombin III. 133 Synthetic thrombin inhibitors may become valuable alternatives to heparin in clinical situations when anticoagulation is necessary and heparin cannot be recommended, as in case of heparin-induced thrombocytopenia in patients on hemodialysis.…”

Section: Advantages and Shortcomingsmentioning

confidence: 99%