Summary
Hirudin is the most potent natural inhibitor of thrombin known to date. It is gaining popularity as an anticoagulant now that recombinant and synthesized forms are available. It is a monospecific and co-factor-independent thrombin inhibitor with otherwise inert pharmacological properties. Being a surprisingly weak immunogen, its administration has exhibited no side effects, particularly on platelets. Bleeding complications are not to be expected at therapeutic doses. Effective anticoagulatory doses can be easily predicted and laboratory control is no problem. Application of hirudin or derivatives thereof may be indicated for: prophylaxis and treatment of postoperative venous thrombosis and diffuse microthrombosis; prevention of arterial thrombosis, especially in cardiac surgery; enhancement of fibrinolytic therapy and/or angioplasty to prevent reocclusion; extracorporeal circulation; and plastic surgery. Hirudin may be a particularly useful alternative anticoagulatory agent in patients sensitized to heparin or in patients with hereditary or acquired antithrombin III deficiency. However, whether hirudin is really an effective therapeutic tool and whether it can replace heparin in certain clinical indications can be judged only after extended clinical experience has been accumulated.
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References
Agnelli G, Pascucci C, Cosmi B, Nenci GG (1990) The comparative effects of recombinant hirudin (CGP 39393) and standard heparin on thrombus growth in rabbits. Thromb Haemost 63: 204–207
Bichler J, Fichtl B, Siebeck M, Fritz H (1988) Pharmacokinetics and pharmacodynamics of hirudin in man after single subcutaneous and intravenous bolus administration. Drug Res 38: 704–710
Bichler J, Siebeck M, Spannagl M, Fritz H, Schramm W, Recombinant hirudin: effects of single and repeated subcutaneous administrations of different doses in healthy volunteers. Drug Res., submitted
Bichler J, Gemmerli R, Fritz H (1991) Studies for revealing a possible sensitization to hirudin after repeated intravenous injections in baboons. Thromb Res 61: 39–51
Bichler J, Siebeck M, Maschler R, Pelzer H, Fritz H (1991) Determination of hirudin-thrombin complex in plasma with an enzyme-linked immunosorbent assay. Blood Coagulation Fibrinolysis 2: 129–133
Bizios R, Lai L, Fenton II JW, Sonder SA, Malik AB (1985) Thrombin-induced aggregation of lymphocytes: non-enzymic induction by an hirudin blocked thrombin exosite. Thromb Res 38: 424–429
Bourdon P, Maraganore JM (1989) Effects of BG8865 on thrombin-catalyzed protein-C activation in vitro. Thromb Haemost 62: 534
Braun PJ (1990) Binding properties of hirudin determined by gel filtration and gel electrophoresis. Thromb Res 59: 657–662
Brüggener E, Walsmann P, Markwardt F (1989) Neutralization of hirudin anticoagulant action by DIP-thrombin. Pharmazie 44: 648–649
Bucha E, Markwardt F, Nowak G (1990) Hirudin in haemodialysis. Thromb Res 60: 445–455
Chang JY (1983) The functional domain of hirudin, a thrombin-specific inhibitor. FEBS Lett 164: 307–313
Dennis S, Wallace A, Hofsteenge J, Stone SR (1990) Use of fragments of hirudin to investigate thrombin-hirudin interaction. Eur J Biochem 188: 61–66
Dodt J, Seemüller U, Maschler R, Fritz H (1985) The complete covalent structure of hirudin. Biol Chem Hoppe Seyler 366: 379–385
Dukes GE, Sanders SW, Russo J, Swenson E, Burnakis TG, Saffle JR, Warde GD (1984) Transaminase elevations in patients receiving bovine or porcine heparin. Ann Intern Med 100: 646–650
Freund M, Cazenave JP, Courtney M, Degryse E, Roitsch C, Bernt A, Delebassee D, Defreyn G, Maffrand JP (1990) Inhibition by recombinant hirudins of experimental venous thrombosis and disseminated intravascular coagulation induced by tissue factor in rats. Thromb Haemost 63: 187–192
Friedberg RC, Hagen PO, Pizzo SV (1988) The role of endothelium in factor Xa regulation: the effect of plasma proteinase inhibitors and hirudin. Blood 71: 1321–1328
Gallus AS (1989) Overview of the management of thrombotic disorders. Semin Thromb Hemost 15: 99–110
Gemmerli R (1987) Untersuchungen zur perkutanen Absorption und zur renalen Elimination des Blutegelwirkstoffes Hirudin bei Tier (Schwein, Pavian) und Mensch. Thesis, Munich University
Glusa E, Markwardt F (1990) Platelet functions in recombinant hirudin-anticoagulated blood. Haemostasis 20: 112–118
Grütter MG, Priestle JP, Rahuel J, Grossenbacher H, Bode W, Hofsteenge J, Stone SR (1990) Crystal structure of the thrombin-hirudin complex: a novel mode of serine protease inhibition. EMBO J 9: 2361–2365
Hauptmann J, Brüggener E, Markwardt F (1987) Effect of heparin, hirudin, and a synthetic thrombin inhibitor on antithrombin III in thrombin-induced disseminated intravascular coagulation in rats. Haemostasis 17: 321–328
Heras M, Chesebro JH, Penny WJ, Bailey KR, Badimon L, Fuster V (1989) Effects of thrombin inhibition on the development of acute platelet-thrombus deposition during angioplasty in pigs. Circulation 79: 657–665
Heras M, Chesebro JH, Webster MWI, Mruk JS, Grill DE, Penny WJ, Bowie EJW, Badimon L, Fuster V (1990) Hirudin, heparin, and placebo during deep arterial injury in the pig. Circulation 82: 1476–1484
Hoffmann H, Siebeck M, Spannagl M, Weis M, Geiger R, Jochum M, Fritz H (1990) Effect of recombinant hirudin, a specific inhibitor of thrombin, on endotoxin-induced intravascular coagulation and acute lung injury in pigs. Am Rev Respir Dis 142: 782–788
Hofsteenge J, Taguchi H, Stone SR (1986) Effect of thrombomodulin on the kinetics of the interaction of thrombin with substrates and inhibitors. Biochem J 237: 243–251
Hubbard T, Bacher P, Walenga JM, Fareed J, Galal H (1991) Use of recombinant hirudin to increase the patency rate of microanastomosis in a rabbit model. Blood Coagulation Fibrinolysis 2: 101–103
Ibbotson SH, Grant PJ, Kerry R, Findlay VS, Prentice CRM (1991) The influence of infusions of 1-desamino-8-D-arginine vasopressin (DDVAP) in vivo on the anticoagulant effect of recombinant hirudin (CGP 39393) in vitro. Thromb Haemost 65: 64–66
Ito R, Phaneauf MD, LoGerfo FW (1991) Thrombin inhibition by covalently bound hirudin. Blood Coagulation Fibrinolysis 2: 77–81
Jakubowski JA, Maraganore JM (1990) Inhibition of coagulation and thrombin-induced platelet activities by a synthetic dodecapeptide modeled on the carboxy-terminus of hirudin. Blood 75: 399–406
Kaiser B, Simon A, Markwardt F (1990) Antithrombotic effects of recombinant hirudin in experimental angioplasty and intravascular thrombolysis. Thromb Haemost 63: 44–47
Klöcking HP, Güttner J, Fink E, Markwardt F (1990) Studies in toxicity of recombinant hirudin. Blut 60: 129
Konno S, Fenton II JW, Villanueva GB (1988) Analysis of the secondary structure of hirudin and the mechanism of its interaction with thrombin. Arch Biochem Biophys 267: 158–166
Krstenansky JL, Broersma RJ, Owen TJ, Payne MH, Yates MT, Mao SJT (1990) Development of MDL 28,050, a small stable antithrombin agent based on a functional domain of the leech protein, hirudin. Thromb Haemost 63: 208–214
Krstenansky JL, Mao SJT (1987) Antithrombin properties of C-terminus of hirudin using synthetic unsulfated Nα-acetylhirudin 45–65. FEBS Lett 211: 10–16
Lindhout T, Blezer R, Hemker C (1990) The anticoagulant mechanism of action of recombinant hirudin (CGP 39393) in plasma. Thromb Haemost 64: 464–468
Mao SJT, Yates MT, Owen TJ, Krstenansky JL (1988) Interaction of hirudin with thrombin: identification of a minimal binding domain of hirudin that inhibits clotting activity. Biochemistry 27: 8170–8173
Maraganore JM, Chao B, Joseph ML, Jablonski J, Ramachandran KL (1989) Anticoagulant activity of synthetic hirudin peptides. J Biol Chem 264: 8692–8698
Maraganore JM, Bourdon P, Jablonski J, Ramachandran KL, Fenton JW II (1990) Design and characterization of hirulogs: a novel class of bivalent peptide inhibitors of thrombin. Biochemistry 29: 7095–7101
Markwardt F (1955) Untersuchungen über Hirudin. Naturwissenschaften 42: 537–538
Markwardt F (1956) Die antagonistische Wirkung des Hirudins gegen Thrombin in vivo. Naturwissenschaften 43: 111
Markwardt F (1985) Pharmacology of hirudin. Biomed Biochim Acta 44: 1007–1014
Markwardt F (1989) Development of hirudin as an antithrombotic agent. Sem Thromb Hemostas 15: 269–282
Markwardt F, Hauptmann J, Nowak G, Kleßen C, Walsmann P (1982) Pharmacological studies on the antithrombin action of hirudin in experimental animals. Thromb Haemost 47: 226–229
Markwardt F, Nowak G, Stürzebecher J, Grießbach U, Walsmann P, Vogel G (1984) Pharmacokinetics and anticoagulant effect of hirudin in man. Thromb Haemost 52: 160–163
Markwardt F, Nowak G, Stürzebecher J, Vogel G (1988) Clinicopharmacological studies with recombinant hirudin. Thromb Res 52: 393–400
Markwardt F, Fink G, Kaiser B, Klöcking HP, Nowak G, Richter M, Stürzebecher J (1988) Pharmacological survey of recombinant hirudin. Pharmazie 43: 202–207
Meyer BH, Luus HG, Müller FO, Badenhorst PN, Röthig HJ (1990) The pharmacology of recombinant hirudin, a new anticoagulant. S Afr Med J 78: 268–270
Minar E, Zazgornik J (1985) Local hirudin application — an aid in preventing occlusion of an arteriovenous fistula in dialysis patients? Klin Wochenschr 63: 190–191
Mruk JS, Chesebro JH, Webster MWJ, Heras M, Grill DE, Fuster V (1990) Hirudin markedly enhances thrombolysis with r-tPA. Circulation 83: (Abstract no. 0553)
Moncada R, Farred D, Hoppenstadt D, Walenga JM, Fareed J (1990) Comparative studies on the procoagulant actions of intravascular radiocontrast agents and their pharmacological modulation. Blut 60: 123
Naski MC, Fenton II JW, Maraganore JM, Olson ST, Shafer JA (1990) The COOH-terminal domain of hirudin. J Biol Chem 265: 13484–13489
Nowak G, Markwardt F (1980) Influence of hirudin on endotoxin-induced disseminated intravascular coagulation (DIC) in weaned pigs. Exp Pathol 18: 438–443
Prescott SM, Seeger AR, Zimmerman GA, Mc Intyre TM, Maraganore JM (1990) Hirudin-based peptides block the inflammatory effects of thrombin on endothelial cells. J Biol Chem 265: 9614–9616
Richter M, Walsmann P, Markwardt F (1989) Plasma level of dextran-r-hirudin. Pharmazie 44: 73
Rydel TJ, Ravichandran KG, Tulinsky A, Bode W, Huber R, Roitsch C, Fenton II JW (1990) The structure of a complex of recombinant hirudin and human α-thrombin. Science 249: 277–280
Scharf M, Engels J, Tripier D (1989) Primary structures of new “iso-hirudins”. FEBS Lett 255: 105–110
Shifman MA, Pizzo SV (1982) The in vivo metabolism of antithrombin III and antithrombin III complexes. J Biol Chem 257: 3243–3248
Spannagl M, Bichler J, Birg A, Lill H, Schramm W (1991) Chromogenic substrate assay for determination of hirudin in plasma. Blood Coagulation Fibrinolysis 2: 121–127
Spinner S, Stöffler G, Fink E (1986) Quantitative enzyme-linked immunosorbent assay (ELISA) for hirudin. J Immunol Methods 87: 79–83
Stone SR, Hofsteenge J (1986) Kinetics of the inhibition of thrombin by hirudin. Biochemistry 25: 4622–4628
Talbot MD, Ambler J, Butler KD, Findlay VS, Mitchell KA, Peters RF, Tweed MF, Wallis RB (1989) Recombinant desulphatohirudin (CGP 39393) anticoagulant and antithrombotic properties in vivo. Thromb Haemost 61: 77–80
Tsiang M, Lentz SR, Dittman WA, Wen D, Scarpati EM, Sadler JE (1990) Equilibrium binding of thrombin to recombinant human thrombomodulin: effect of hirudin, fibrinogen, factor Va, and peptide analogs. Biochemistry 29: 10602–10612
Verstraete M, Hoet B, Tornai I, Stockmans P, Arnout J (1989) Hirudin, a specific thrombin inhibitor: pharmacokinetics and hemostatic effects in man. Circulation 80: [Suppl 4] (Abstract no. 1673)
Vogel G (1990) Erste klinische Erfahrungen mit Hirudin. In: 6. Kongreß der Gesellschaft für Thrombose- und Hämostase-forschung. Kiel, 21.–24. Februar 1990, Hauptvorträge — ausgewählte freie Vorträge. Schattauer, Stuttgart — New York 1990, p 186
Wallace A, Dennis S, Hofsteenge J, Stone SR (1989) Contribution of the N-terminal region of hirudin to its interaction with thrombin. Biochemistry 28: 10079–10084
Wallis RB (1988) Hirudins and the role of thrombin: lessions from leeches. TIPS 9: 425–427
Walsmann P (1988) Über den Einsatz des spezifischen Thrombininhibitors Hirudin für diagnostische und biochemische Untersuchungen. Pharmazie 43: 737–744
Walsmann P, Maksimenko AV, Abramova V (1989) Hirudin binding to soluble dextran. Pharmazie 44: 72–73
Weitz JI, Hudoba M, Maraganore JM, Hirsh J (1990) Clotbound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 86: 385–391
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Bichler, J., Fritz, H. Hirudin, a new therapeutic tool?. Ann Hematol 63, 67–76 (1991). https://doi.org/10.1007/BF01707275
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DOI: https://doi.org/10.1007/BF01707275