The development of hirudin as an antithrombotic drug

Markwardt, Fritz

doi:10.1016/0049-3848(94)90032-9

Cited by 247 publications

(126 citation statements)

References 83 publications

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“…Thrombin-activated platelets provide an appropriate surface for the assembly of coagulation complexes involved in the amplification of the clotting cascade (7). Several established thrombin inhibitors are available, including unfractionated heparin (8) and hirudin (9). These drugs, however, are limited in terms of their efficacy and safety because of a narrow therapeutic window and poor penetration into the thrombus (10).…”

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confidence: 99%

Inhibition of Thrombin Abrogates the Instant Blood-Mediated Inflammatory Reaction Triggered by Isolated Human Islets

et al. 2002

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A thrombotic/inflammatory reaction is elicited when isolated islets of Langerhans come in contact with ABO-compatible blood. The detrimental effects of this instant blood-mediated inflammatory reaction (IBMIR) provide a reasonable explanation for the observation that an unexpectedly high number of islets, from several donors, are needed to produce normoglycemia in transplant patients with type 1 diabetes. In this study, the hypothesis that a specific thrombin inhibitor, Melagatran, could reduce IBMIR in an in vitro model in which human islets are exposed to ABO-compatible blood was tested. The administration of Melagatran abrogated IBMIR dose-dependently. Islets exposed to blood, in the absence or presence of 0.4 mol/l Melagatran, exhibited a loss of integrity and were found to be trapped in macroscopic clots containing platelets and CD11b؉ leukocytes. At concentrations from 1 to 10 mol/l, Melagatran inhibited both coagulation and complement activation. Also, platelet and leukocyte activation and consumption were decreased. Islet morphology was maintained with almost no platelets adhering to the surface, and infiltration by CD11b ؉ leukocytes was considerably reduced. In conclusion, Melagatran significantly reduced IBMIR in this model system. This protective effect indicates that thrombin plays a pivotal role in IBMIR and suggests that thrombin inhibition can improve the outcome of clinical islet transplantation.

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confidence: 99%

Inhibition of Thrombin Abrogates the Instant Blood-Mediated Inflammatory Reaction Triggered by Isolated Human Islets

et al. 2002

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“…Some examples of direct thrombin inhibitors include hirudin, hirulog (or bivalirudin), and agratroban (7)(8)(9). Hirudin is a 65-amino acid protein isolated from the salivary gland of the medicinal leech, Hirudo medicinalis (7,8,10). It has a globular N-terminal domain and an acidic C-terminal tail.…”

mentioning

confidence: 99%

Variegin, a Novel Fast and Tight Binding Thrombin Inhibitor from the Tropical Bont Tick

Koh

Kazimírová

Trimnell

et al. 2007

Journal of Biological Chemistry

102

101

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Tick saliva contains potent antihemostatic molecules that help ticks obtain their enormous blood meal during prolonged feeding. We isolated thrombin inhibitors present in the salivary gland extract from partially fed female Amblyomma variegatum, the tropical bont tick, and characterized the most potent, variegin, one of the smallest (32 residues) thrombin inhibitors found in nature. Full-length variegin and two truncated variants were chemically synthesized. Despite its small size and flexible structure, variegin binds thrombin with strong affinity (K i ϳ 10.4 pM) and high specificity. Results using the truncated variants indicated that the seven residues at the N terminus affected the binding kinetics; when removed, the binding characteristics changed from fast to slow. Further, the thrombin active site binding moiety of variegin is in the region of residues 8 -14, and the exosite-I binding moiety is within residues 15-32. Our results show that variegin is structurally and functionally similar to the rationally designed thrombin inhibitor, hirulog. However, compared with hirulog, variegin is a more potent inhibitor, and its inhibitory activity is largely retained after cleavage by thrombin.Blood coagulation is part of the physiological response to vascular injury, in which circulating zymogens of serine proteases are sequentially activated by limited proteolysis leading to the formation of a fibrin clot. Within this network of reactions, thrombin plays a central role in maintaining the integrity of hemostasis. Thrombin interacts with most of the zymogens and their cofactors, playing multiple procoagulant and anticoagulant roles in blood coagulation (1, 2). As a procoagulant protease, the first traces of thrombin generated in the initiation phase activate factor V (FV) 2 and factor VIII (FVIII) to provide positive feedback leading to the thrombin burst. Thrombin can also activate factor XI, triggering the intrinsic pathway. Thrombin cleaves fibrinogen to fibrin, forming insoluble clots. Fibrin polymers are further strengthened and stabilized through covalent cross-linking driven by thrombin-activated factor XIII. Thrombin also contributes to the generation of a platelet plug, possibly through two mechanisms: (a) it activates platelets by interacting with protease-activated receptors and glycoprotein V, and (b) it prevents destabilization of the platelet plug, by inactivating ADAMTS13, a disintegrin and metalloprotease with a thrombospondin type 1 motif, that cleaves von Willebrand factor. As an anticoagulant protease, thrombin activates protein C in the presence of the cofactor thrombomodulin.

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“…These studies were performed using an in vitro recirculation model with constant filtrate flow according to the requirements of Euronorm 1283 for determination of SC (12). Regarding pharmacology of hirudin, a distribution volume of 0.16 to 0.28 L/kg body wt and only slight protein binding have been reported (3,5). Given its molecular weight of approximately 7 kD, these data should favor its elimination by hemofiltration via high-flux hemodialyzer membranes with a cutoff Ͼ40 kD.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to heparin, (r-)hirudin does not require co-factors and inhibits also clot-bound thrombin (2). Furthermore, endogenous inhibitors do not exist (3), and an antidote is not available.…”

mentioning

confidence: 99%

Hemofiltration of Recombinant Hirudin by Different Hemodialyzer Membranes

Benz

Nauck

Böhler

et al. 2007

Clinical Journal of the American Society of Nephrology

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Recombinant hirudin (lepirudin) is a potent direct thrombin inhibitor that is used particularly for treatment of immunemediated heparin-induced thrombocytopenia. Because hirudin is almost exclusively eliminated by the kidneys, its half-life is markedly prolonged in patients with severe renal insufficiency. Therefore, these patients are at risk for bleeding, particularly because no antidote is available. To use hirudin safely in patients who are on renal replacement therapy, knowledge of hirudin-sieving characteristics of different hemodialyzers is required. Data on this issue are sparse and in part contradictory. Eight different conventional low-flux and high-flux hemodialyzers were tested in an in vitro circuit with ultrafiltrate reinfusion. In each experiment, lepirudin concentration was repetitively measured during 3 h in the prefilter, the postfilter, and the filtration line using a chromogenic assay. On the basis of these data, sieving coefficients were calculated. All high-flux hemodialyzers tested allowed filtration of hirudin yet with marked differences in steady-state sieving (sieving coefficients in whole blood: polysulfone

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The development of hirudin as an antithrombotic drug

Cited by 247 publications

References 83 publications

Inhibition of Thrombin Abrogates the Instant Blood-Mediated Inflammatory Reaction Triggered by Isolated Human Islets

Inhibition of Thrombin Abrogates the Instant Blood-Mediated Inflammatory Reaction Triggered by Isolated Human Islets

Variegin, a Novel Fast and Tight Binding Thrombin Inhibitor from the Tropical Bont Tick

Hemofiltration of Recombinant Hirudin by Different Hemodialyzer Membranes

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