Hirudin in Disseminated Intravascular Coagulation

Nowak, G; Markwardt, Fritz

doi:10.1159/000216276

Cited by 20 publications

(18 citation statements)

References 7 publications

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“…We have confirmed the antithrombotic action of hirudin against the diffuse activa tion of the clotting system in animal experi ments [71 ]. When hirudin was given, the pre viously induced changes in the clotting sys tem which are typical of consumption coagu lopathy were less pronounced and the num ber of fibrin deposits in the organs investi gated was significantly reduced.…”

Section: Diffuse Microthrombosissupporting

confidence: 73%

Past, Present and Future of Hirudin

Markwardt

1991

Pathophysiol Haemos Thromb

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The naturally occurring anticoagulant from medicinal leeches, hirudin, which we isolated and biochemically analyzed 30 years ago as a miniprotein with specific anti-thrombin activity, has afterwards been employed for scientific and diagnostic purposes in hematology. Pure hirudin proved to be an antithrombotic agent of high quality that displays an antithrombotic action dependent upon its blood level. After intravenous injection, it is distributed in the extracellular space and is almost completely eliminated through the kidneys by glomerular filtration in a biologically active form. The efficacy of hirudin in preventing venous and arterial thrombosis and disseminated intravascular coagulation was demonstrated in various animal models. Clinical pharmacological studies corroborated the specific pharmacodynamic and pharmacokinetic properties of hirudin found in animal experiments. Genetic engineering led to the availability of sufficient quantities of recombinant hirudin (r-hirudin) for clinical purposes. Pharmacologic profiling of r-hirudin showed that both its pharmacokinetic and pharmacodynamic characteristics are very similar to those of native hirudin. Clinical pharmacological studies with r-hirudin revealed that, at single therapeutically relevant doses, r-hirudin is a well-tolerated and potent anticoagulant without any detectable side effects and allergic reactions. Further preclinical studies of r-hirudin should concentrate on identifying possible indications for use, on the development of r-hirudin preparations and derivatives, and on the development of antidotes for hirudin.

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Section: Diffuse Microthrombosissupporting

confidence: 73%

Past, Present and Future of Hirudin

Markwardt

1991

Pathophysiol Haemos Thromb

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“…44 and 82). The antithrombotic effect was affirmed by the prevention of the development of clotting thrombi experimentally induced in the jugular vein (19,24,55,106,126) and was also demonstrated in arterial thrombosis, especially in coronary thrombosis (14,43,49,73) induced by vessel wall lesions and in extracorporeal circulation (11,75), The action of hirudin in DIC was repeatedly demonstrated in animal experiments (24,38,104,117). The dose and plasma concentration of rH required for antithrombotic action depend on the type and strength of the thrombogenic stimulus.…”

Section: Antithrombotic Effectsmentioning

confidence: 94%

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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“…Recombinant hirudin, a single polypep tide chain composed of 65 amino acids, is a specific thrombin inhibitor with a Kj value of 20 fM [7], The compound is now available as a genetically engineered product. The effect of recombinant hirudin has been studied in ani mal models of deep venous thrombosis [8], anticoagulation during cardiopulmonary by pass surgery [9] and treatment of dissemi nated intravascular coagulation (DIC) [10], The first study with natural hirudin in chronic DIC patients was published by Markwardt's group in 1988 [11] showing a normalization of clotting parameters. Meanwhile recombi nant hirudin is under clinical evaluation for acute myocardial infarction, deep venous thrombosis after hip surgery [ 12] and percuta neous transluminal coronarv angioplasty [13].…”

Section: Introductionmentioning

confidence: 99%

Influence of Recombinant Hirudin on Tissue-Factor-Induced Activation of Coagulation in Rabbits

Kouz

Czech²,

Nicolay³

et al. 1996

Pathophysiol Haemos Thromb

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Uncontrolled activation of the tissue-factor (TF)-dependent extrinsic pathway of coagulation can lead to severe impairment of the hemostatic balance. As thrombin plays the central role in the initiation of clotting, we used the highly specific thrombin inhibitor recombinant hirudin to prevent TF-induced coagulation activation in a rabbit model. Infusion of 0.5 μg·kg^–1 •h^–1 TF in rabbits for 7 h led to a decrease in fibrinogen and platelets, to an increase in fibrin monomers and to a prolongation of TT, aPTT and PT. Recombinant hirudin was administered in doses of 0.5, 1 and 2 mg·kg^–1 body weight (intravenous bolus), the protocol included a pre-TF (recombinant hirudin given at t = 0) and a post-TF study group (recombinant hirudin given at t = 2 h after the start of the TF infusion). Fibrinogen plasma levels, platelet counts and recombinant hirudin plasma levels were measured at baseline (t = 0) at 0.5, 1, 2, 3, 4, 5, 6 and 7 h; the deceleration rate of fibrinogen and platelets per hour was calculated for the control and the recombinant-hirudin-treated groups. The deceleration rate for fibrinogen in the TF group was -0.227 g·1^-1 •h^–1 and was reduced by recombinant hirudin to -0.119, -0.116 and -0.095 g·1^-1·h^–1 for 0.5, 1 or 2 mg·kg^-1, respectively (significant differences to control group, Jonck-heere-Terpstra test). The inhibitor similarly prevented the decrease of platelets dose-dependently. Recombinant hirudin was cleared from plasma with a terminal half-life of about 100 min; however, even after its clearance from plasma, recombinant hirudin significantly prevented the fibrinogen and platelet drop. Recombinant hirudin was effective when given in the pre-TF as well as in the post-TF phase.

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Hirudin in Disseminated Intravascular Coagulation

Cited by 20 publications

References 7 publications

Past, Present and Future of Hirudin

Past, Present and Future of Hirudin

Hirudin: The Promising Antithrombotic

Influence of Recombinant Hirudin on Tissue-Factor-Induced Activation of Coagulation in Rabbits

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