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Semin Thromb Hemost 2002; 28(5): 405-414
DOI: 10.1055/s-2002-35292
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Hirudin As Alternative Anticoagulant- A Historical Review

Fritz Markwardt
  • Professor of Pharmacology, International Institute of Thrombosis and Vascular Diseases, Frankfurt/M, Germany
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Publication History

Publication Date:
06 November 2002 (online)

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ABSTRACT

Advances in separation techniques and biotechnology have contributed to the development of anticoagulant agents from hematophagous animals. The most potent known natural thrombin inhibitor from blood-sucking leeches (Hirudo medicinalis), hirudin has served as a standard for designing the natural coagulation inhibitors as an anticoagulant drug. The search for the development of hirudin from leech extract to genetically engineered products as an alternative anticoagulant has been resumed. The pharmacological profiling of the isolated thrombin inhibitor has shown that native hirudin is an antithrombotic agent of high quality. However, its clinical use has remained limited, because the substance has not been available in adequate amounts. The progress in molecular biology has stimulated the interest in the structure and function of hirudin. This development resulted in the production of recombinant hirudins (r-hirudins) through gene technology. The biological properties of hirudin combined with the ready availability of recombinant forms make the specific thrombin inhibitor well-suited for use as an antithrombotic drug. Its use should lead to a decisive progress in the management of thromboembolic diseases of both arterial and venous origin. Clinical trials, especially in diseases in which thrombin plays a crucial role, are in progress.

KEYWORDS

Hirudin - leeches - thrombin inhibitor - antithrombotic drug - pharmacology - history

REFERENCES

  • 1 Markwardt F. Coagulation inhibitors from blood sucking animals-a new line of developing antithrombotic drugs.  Pharmazie . 1996;  49 313-316
    PubMedGoogle Scholar
  • 2 Markwardt F. Antithrombotic agents from hematophagous animals.  Clin Appl Thromb Hemost . 1996;  2 75-82
    PubMedGoogle Scholar
  • 3 Haycraft J B. Über die Einwirkung eines Sekretes des officiellen Blutegels auf die Gerinnbarkeit des Bluts.  Naunyn Schmiedebergs Arch Exp Pathol Pharmacol . 1894;  18 209-217
    PubMedGoogle Scholar
  • 4 Franz F. Über den die Blutgerinnung aufhebenden Bestandteil des medizinischen Blutegels.  Naunyn Schmiedebergs Arch Exp Pathol Pharmacol . 1903;  49 342-357
    PubMedGoogle Scholar
  • 5 Jacoby Y. Über Hirudin.  Dtsch Med Wochenschr . 1904;  30 786-787
    PubMedGoogle Scholar
  • 6 Markwardt F. Untersuchungen über Hirudin.  Naturwissenschaften . 1955;  42 537-538
    PubMedGoogle Scholar
  • 7 Markwardt F. Die antagonistische Wirkung des Hirudins gegen Thrombin in vivo.  Naturwissenschaften . 1956;  43 111-112
    PubMedGoogle Scholar
  • 8 Markwardt F. Untersuchungen über den Mechanismus der blutgerinnungshemmenden Wirkung des Hirudins.  Naunyn Schmiedebergs Arch Exp Pathol Pharmacol . 1956;  229 389-399
    PubMedGoogle Scholar
  • 9 Markwardt F. Die Isolierung und chemische Charakterisierung des Hirudins.  Hoppe Seylers Z Physiol Chem . 1957;  308 147-156
    PubMedGoogle Scholar
  • 10 Jutiz M, Charbonnel-Berault A, Marinoli G. Purification de l'hirudine.  Bull Soc Chim Biol . 1963;  45 55-67
    PubMedGoogle Scholar
  • 11 Markwardt F, Schäfer G, Töpfer H, Walsmann P. Die Isolierung des Hirudins aus medizinischen Blutegeln.  Pharmazie . 1967;  22 239-241
    PubMedGoogle Scholar
  • 12 Markwardt F, Walsmann P. Reindarstellung und Analyse des Thrombin-Inhibitors Hirudin.  Hoppe Seylers Z Physiol Chem . 1967;  348 1381-1386
    PubMedGoogle Scholar
  • 13 Markwardt F. Hirudin as an inhibitor of thrombin. In: Colowick SP, Kaplan NO, eds. Methods in Enzymology Vol. XIX. Proteolytic Enzymes. New York: Academic Press 1970: 924-932
    Google Scholar
  • 14 Bagdy D, Barabas E, Graf L. Large scale preparation of hirudin.  Thromb Res . 1973;  2 229-232
    CrossrefPubMedGoogle Scholar
  • 15 Walsmann P, Markwardt F. On the isolation of the thrombin inhibitor hirudin.  Thromb Res . 1985;  40 563-570
    CrossrefPubMedGoogle Scholar
  • 16 Walsmann P. Isolation and characterization of hirudin from Hirudo medicinalis Semin Thromb Hemost .  1991;  17 83-87
    PubMedGoogle Scholar
  • 17 Petersen T E, Roberts H R, Sotrup-Jensen L, Magnusson S. Primary structure of hirudin, a thrombin-specific inhibitor. In: Peeters H, ed. Protides of the Biologic Fluids Oxford, UK: Pergamon Press 1976: 145-149
    Google Scholar
  • 18 Dodt J, Müller H P, Seemüller U, Chang J Y. The complete amino acid sequence of hirudin, a thrombin specific inhibitor.  FEBS Lett . 1984;  65 180-183
    PubMedGoogle Scholar
  • 19 Dodt J, Macheleit W, Seemüller U, Machler R, Fritz H. Isolation and characterization of hirudin isoinhibitors and sequence analysis of hirudin PA.  Biol Chem Hoppe Seyler . 1986;  367 803-811
    PubMedGoogle Scholar
  • 20 Kono S, Fenton II W J, Villanueva G B. Analysis of the secondary structure of hirudin and the mechanism of its interaction with thrombin.  Arch Biochem Biophys . 1988;  267 158-166
    CrossrefPubMedGoogle Scholar
  • 21 Rydel T J, Rachchandran K Q, Tulinsky A. The structure of a complex of recombinant hirudin and human alpha-thrombin.  Science . 1990;  49 277-280
    PubMedGoogle Scholar
  • 22 Markwardt F. Biochemistry and pharmacology of hirudin. In: Pirkle H, Markland FS Jr, eds. Hemostasis and Animal Venoms New York: Dekker 1988: 255-269
    Google Scholar
  • 23 Markwardt F. Development of hirudin as an antithrombotic agent.  Semin Thromb Hemost . 1989;  15 269-282
    PubMedGoogle Scholar
  • 24 Markwardt F. Die quantitative Bestimmung des Prothrombins durch Titration mit Hirudin.  Naunyn Schmiedebergs Arch Exp Pathol Pharmacol . 1958;  232 487-498
    PubMedGoogle Scholar
  • 25 Schmutzler R, Markwardt F. Der Hirudintest, eine Mikromethode zur Kontrolle des Prothrombinspiegels bei der Antikoagulantientherapie.  Klin Wochenschr . 1962;  40 796-798
    CrossrefPubMedGoogle Scholar
  • 26 Markwardt F, Stürzebecher J, Walsmann P. The hirudin standard.  Thromb Res . 1990;  59 395-400
    CrossrefPubMedGoogle Scholar
  • 27 Markwardt F. Versuche zur pharmakologischen Charakterisierung des Hirudins.  Naunyn Schmiedebergs Arch Exp Pathol Pharmacol . 1958;  234 516-529
    PubMedGoogle Scholar
  • 28 Markwardt F, Walsmann P. Die Reaktion zwischen Hirudin und Thrombin.  Hoppe Seylers Z Physiol Chem . 1958;  312 85-98
    PubMedGoogle Scholar
  • 29 Markwardt F, Hauptmann J, Nowak G, Klessen C, Walsmann P. Pharmacological studies on the antithrombotic action of hirudin in experimental animals.  Thromb Haemost . 1982;  47 226-229
    PubMedGoogle Scholar
  • 30 Markwardt F, Nowak G, Stürzebecher J. Pharmacokinetics and anticoagulant effect of hirudin in man.  Thromb Haemost . 1984;  52 160-163
    PubMedGoogle Scholar
  • 31 Markwardt F. Pharmacology of hirudin: one hundred years after the first report of the anticoagulant agent.  Biomed Biochim Acta . 1985;  44 1007-1013
    PubMedGoogle Scholar
  • 32 Markwardt F. Hirudin and derivatives as anticoagulant agents.  Thromb Haemost . 1991;  66 141-152
    PubMedGoogle Scholar
  • 33 Markwardt F, Nowak G, Stürzebecher U, Walsmann P. Studies on the pharmacokinetics of hirudin.  Biomed Biochim Acta . 1987;  46 237-244
    PubMedGoogle Scholar
  • 34 Richter M, Walsmann P, Markwardt F. Plasma level of dextran-r-hirudin.  Pharmazie . 1989;  44 73-74
    PubMedGoogle Scholar
  • 35 Markwardt F, Richter M, Walsmann P, Riesener G, Paintz M. Preparation of dextran-bound recombinant hirudin and its pharmacokinetic behavior.  Biomed Biochim Acta . 1990;  49 1103-1108
    PubMedGoogle Scholar
  • 36 Markwardt F. The comeback of hirudin as an antithrombotic agent.  Semin Thromb Hemost . 1991;  17 79-82
    PubMedGoogle Scholar
  • 37 Vogel G, Markwardt F. Preliminary clinical reports on the antithrombotic action of hirudin.  Thromb Res . 1987;  7(Suppl) 42-43
    PubMedGoogle Scholar
  • 38 Markwardt F. Past, present and future of hirudin.  Haemostasis . 1991;  21(Suppl 1) 11-26
    PubMedGoogle Scholar
  • 39 Harvey R P, Degryse E, Stefani L. Cloning and expression of cDNA coding for the anticoagulant hirudin from the blood sucking leech, Hirudo medicinalis.  Proc Nat Acad Sci USA . 1986;  83 1084-1088
    PubMedGoogle Scholar
  • 40 Bergmann C, Dodt J, Köhler S, Fink E, Gassen H G. Chemical synthesis and expression of a gene coding for hirudin, the thrombin-specific inhibitor from the leech Hirudo medicinalis.  Biol Chem Hoppe Seyler . 1986;  367 731-740
    CrossrefPubMedGoogle Scholar
  • 41 Märki W E, Grossenbacher H, Grüttner M G. Recombinant hirudin: genetic engineering and structure analysis.  Semin Thromb Hemost . 1991;  17 88-93
    PubMedGoogle Scholar
  • 42 Johnson P H, Sze P, Winant R, Payne P W, Lazur J B. Biochemistry and genetic engineering of hirudin.  Semin Thromb Hemost . 1989;  15 302-315
    PubMedGoogle Scholar
  • 43 Markwardt F. Le genie genetique conduit au retour de l'hirudine comme anticoagulant.  Sang Thrombos Vaisseaux . 1991;  3 519-522
    PubMedGoogle Scholar
  • 44 Markwardt F, Fink E, Kaiser B. Pharmacological survey of recombinant hirudin.  Pharmazie . 1988;  43 202-207
    PubMedGoogle Scholar
  • 45 Markwardt F, Nowak G, Stürzebecher J. Clinico-pharmacological studies with recombinant hirudin.  Thromb Res . 1988;  52 393-400
    CrossrefPubMedGoogle Scholar
  • 46 Markwardt F, Kaiser B, Nowak G. Studies on antithrombotic effects of recombinant hirudin.  Thromb Res . 1989;  54 377-388
    CrossrefPubMedGoogle Scholar
  • 47 Markwardt F, Novak G, Stürzebecher J. Clinical pharmacology of recombinant hirudin.  Haemostasis . 1991;  21(Suppl 1) 133-136
    PubMedGoogle Scholar
  • 48 Markwardt F. Hirudin and derivatives as anticoagulant agents.  Thromb Haemost . 1991;  66 141-152
    PubMedGoogle Scholar
  • 49 Stürzebecher J. Methods for determination of hirudin.  Semin Thromb Hemost . 1991;  17 99-102
    PubMedGoogle Scholar
  • 50 Walenga J M, Hoppensteadt D, Koza M, Pifarre R, Fareed J. Comparative studies on various assays for the laboratory evaluation of r-hirudin.  Semin Thromb Hemost . 1991;  17 103-112
    PubMedGoogle Scholar
  • 51 Nowak G, Bucha E. Quantitative determination of hirudin in blood and body fluids.  Semin Thromb Hemost . 1996;  22 197-202
    Article in Thieme ConnectPubMedGoogle Scholar
  • 52 Henschen A, Markwardt F, Walsmann P. Identification by HPLC analysis of the unaltered forms of hirudin and desulfated hirudin after kidney passage (Abst).  Thromb Res . 1987;  7(Suppl) 37
    PubMedGoogle Scholar
  • 53 Nowak G. Pharmacokinetics of hirudin.  Semin Thromb Hemost . 1991;  17 145-149
    PubMedGoogle Scholar
  • 54 Nowak G, Bucha E, Gööck T, Thieler H, Markwardt F. Pharmacology of r-hirudin in renal impairment.  Thromb Res . 1992;  66 707-715
    CrossrefPubMedGoogle Scholar
  • 55 Eschenfelder V. Pharmacologic considerations in the development of hirudin and its derivatives for cardiovascular indications. In: Pifarre R, ed. New Anticoagulants for the Cardiovascular Patient Philadelphia, PA: Hanley and Belfus 1997: 161-174
    Google Scholar
  • 56 Kaiser B, Markwardt F. Antithrombotic and haemorrhagic effects of synthetic and naturally occurring thrombin inhibitors.  Thromb Res . 1986;  43 613-620
    CrossrefPubMedGoogle Scholar
  • 57 Brüggener E, Walsmann P, Markwardt F. Neutralization of hirudin anticoagulant action by DIP-thrombin.  Pharmazie . 1989;  44 648-649
    PubMedGoogle Scholar
  • 58 Fareed J, Walenga J M, Hoppensteadt D, Iyver L, Pifarre R. Neutralization of recombinant hirudin. Some practical considerations.  Semin Thromb Hemost . 1991;  17 137-144
    PubMedGoogle Scholar
  • 59 Markwardt F, Kaiser B, Richter M. Haemostyptic effects of batroxobin with regard to hirudin treatment.  Thromb Res . 1992;  68 475-482
    CrossrefPubMedGoogle Scholar
  • 60 Markwardt F. Development of direct thrombin inhibitors in comparison to glycosaminoglycans.  Semin Thromb Hemost . 2001;  27 523-530
    Article in Thieme ConnectPubMedGoogle Scholar
  • 61 Markwardt F. The development of hirudin as an anticoagulant agent.  Current Cardiovascular Patents . 1991;  1 981-995
    PubMedGoogle Scholar
  • 62 Markwardt F. Hirudin: the promising antithrombotic.  Cardiovascular Drug Reviews . 1992;  10 211-232
    PubMedGoogle Scholar
  • 63 Markwardt F. The development of hirudin as an antithrombotic drug. In: Pifarre R, ed. New Anticoagulants for the Cardiovascular Patient Philadelphia, PA: Hanley and Belfus 1997: 145-160
    Google Scholar
  • 64 Hauptmann J, Markwardt F. Pharmacologic aspects of the development of selective synthetic thrombin inhibitors as anticoagulants.  Semin Thromb Hemost . 1992;  18 200-217
    PubMedGoogle Scholar
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