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Thromb Haemost 1995; 73(03): 478-483
DOI: 10.1055/s-0038-1653800
Original Articles
Fibrinolysis
Schattauer GmbH Stuttgart

Vampire Bat Salivary Plasminogen Activator Evokes Minimal Bleeding Relative to Tissue-Type Plasminogen Activator as Assessed by a Rabbit Cuticle Bleeding Time Model

Michael J Mellott
1   The Department of Pharmacology, West Point, PA, USA
,
Denise R Ramjit
1   The Department of Pharmacology, West Point, PA, USA
,
Inez I Stabilito
1   The Department of Pharmacology, West Point, PA, USA
,
Timothy R Hare
2   The Department of Biological Chemistry, Merck Research Laboratories, West Point, PA, USA
,
Edith T Senderak
3   The Department of Biometrics Research, Merck Research Laboratories, West Point, PA, USA
,
Joseph J Lynch Jr
1   The Department of Pharmacology, West Point, PA, USA
,
Stephen J Gardell
2   The Department of Biological Chemistry, Merck Research Laboratories, West Point, PA, USA
› Institutsangaben
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Publikationsverlauf

Received 18. Juli 1994

Accepted after revision 15. November 1994

Publikationsdatum:
09. Juli 2018 (online)

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Summary

Cuticle bleeding time (CBT) measurements in anesthetized rabbits were performed to assess the potential bleeding risks which may accompany the administration of tissue-type plasminogen activator (tPA) or vampire bat salivary plasminogen activator (BatPA). The dose of BatPA or tPA used in this study, 42 nmol/kg, was previously shown to be efficacious using a rabbit femoral artery thrombosis model (Gardell et al, Circulation 84:244, 1991). CBT was determined by severing the apex of the nail cuticle and monitoring the time to cessation of blood flow. CBT was minimally elevated (1.6-fold, p<NS) following bolus intravenous administration of BatPA; in contrast, bolus intravenous administration of tPA dramatically elevated CBT (6.2-fold, p<0.05). Rabbits treated with tPA, but not BatPA, displayed profound activation of systemic plasminogen and consequent degradation of Factor VIII and fibrinogen. Elevations in CBT after the administration of tPA were reversed by the replenishment of plasma Factor VIII activity to 40% of control, but were unaffected by complete replenishment of plasma fibrinogen. The results of this study suggest that the administration of BatPA, at a dose that promotes thrombolysis, may evoke a minimal bleeding risk, relative to an equi-efficacious dose of tPA. In addition, the tPA-provoked proteolytic consumption of Factor VIII may be a key contributor to the heightened bleeding risk.

 

  • References

  • 1 Collen D. Coronary thrombolysis streptokinase or recombinant tissue-type plasminogen activator. Ann Int Med 1990; 112: 529-538
    CrossrefPubMedGoogle Scholar
  • 2 Sherry S, Marder VJ. Streptokinase and recombinant tissue plasminogen activator (rt-PA) are equally effective in treating acute myocardial infarction. Ann Int Med 1991; 114: 417-423
    CrossrefPubMedGoogle Scholar
  • 3 Tiefenbrunn AJ, Sobel BE. Thrombolysis and myocardial infarction. Fibrinolysis 1991; 5: 1-15
    PubMedGoogle Scholar
  • 4 Topol EJ. Which thrombolytic agent should one choose. Prog Cardiovasc Dis 1991; 34: 165-178
    CrossrefPubMedGoogle Scholar
  • 5 Fennerty AG, Levine MN, Hirsh J. Hemmorrhagic complications of thrombolytic therapy in the treatment of myocardial infarction and venous thromboembolism. Chest 1989; 95: 88S-97S
    CrossrefPubMedGoogle Scholar
  • 6 Sane DC, Califf RM, Topol EJ, Stump DC, Mark DB, Greenberg CS. Bleeding during thrombolytic therapy for acute myocardial infarction: mechanisms and management. Ann Int Med 1989; 111: 1010-1022
    CrossrefPubMedGoogle Scholar
  • 7 Califf RM, Fortin DF, Tenaglia AN, Sane DC. Clinical risks of thrombolytic therapy. Am J Cardiol 1992; 69: 12A-20A
    PubMedGoogle Scholar
  • 8 Gardell SJ, Duong LT, Diehl RE, York JD, Hare TR, Register RB, Jacobs JW, Dixon RA, Friedman PA. Isolation, characterization, and cDNA cloning of a vampire bat salivary plasminogen activator. J Biol Chem 1989; 264: 17947-17952
    PubMedGoogle Scholar
  • 9 Bergum PW, Gardell SJ. Vampire bat salivary PA exhibits a strict and fastidious requirement for polymeric fibrin as its cofactor, unlike human tissue- type P A. A kinetic analysis J Biol Chem 1992; 267: 17726-17731
    PubMedGoogle Scholar
  • 10 Pennica D, Holmes WE, Kohr WJ, Harkins RN, Vehar GA, Ward CA, Bennett WF, Yelverton E, Seeburg PH, Heyneker HL, Goeddel DV, Collen D. Cloning and expression of human tissue-type plasminogen activator cDNA in E. coli. Nature 1983; 301: 214-221
    CrossrefPubMedGoogle Scholar
  • 11 Gardell SJ, Ramjit DR, Stabilito II, Fujita T, Lynch JJ, Cuca GC, Jain D, Wang S, Tung J, Mark GE, Shebuski RJ. Effective thrombolysis without marked plasminemia following bolus intravenous administration of a vampire bat salivary plasminogen activator in rabbits. Circulation 1991; 84: 244-253
    CrossrefPubMedGoogle Scholar
  • 12 Mellott MJ, Stabilito II, Holahan MA, Cuca GC, Wang S, Li P, Barrett JS, Lynch JJ, Gardell SJ. Vampire bat salivary plasminogen activator promotes rapid and sustained reperfusion without concomitant systemic plasminogen activation in a canine model of arterial thrombosis. Arterioscler Thromb 1992; 12: 212-221
    CrossrefPubMedGoogle Scholar
  • 13 Gimple LW, Gold HK, Leinbach RC, Coller BS, Werner W, Yasuda T, Johns JA, Ziskind AA, Finkelstein D, Collen D. Correlation between template bleeding times and spontaneous bleeding during treatment of acute myocardial infarction with recombinant tissue-type PA. Circulation 1989; 80: 581-588
    CrossrefPubMedGoogle Scholar
  • 14 Vaughan DE, Declerck PJ, De Mol M, Collen D. Recombinant PA inhibitor-1 reverses the bleeding tendency associated with the combined administration of tissue-type plasminogen activator and aspirin in rabbits. J Clin Invest 1989; 84: 586-591
    CrossrefPubMedGoogle Scholar
  • 15 Johnstone MT, Andrews T, Ware JA, Rudd MA, George D, Weinstein M, Loscalzo J. Bleeding time prolongation with streptokinase and its reduction with 1-desamino-8-D-arginine vasopressin. Circulation 1990; 82: 2142-2151
    CrossrefPubMedGoogle Scholar
  • 16 Garabedian HD, Gold HK, Leinbach RC, Svizzero TA, Finkelstein DM, Guerrero JL, Collen D. Bleeding time prolongation and bleeding during infusion of recombinant tissue-type plasminogen activator in dogs: potentiation by aspirin and reversal with aprotinin. J Am Coll Cardiol 1991; 17: 1213-1222
    CrossrefPubMedGoogle Scholar
  • 17 Bernardi MM, Califf RM, Kleiman N, Ellis SG, Topol EJ. For the TAMI Study Group, The Cleveland Clinic Foundation. Prolonged bleeding times do not predict hemorrhagic events in patients receiving the 7E3 glycoprotein IIB/IIIA platelet antibody Circulation 1992; 86: 1-260
    CrossrefPubMedGoogle Scholar
  • 18 Giles AR, Tinlin S, Greenwood R. A canine model of hemophilic (factor VIII:C deficiency) bleeding. Blood 1982; 60: 727-730
    PubMedGoogle Scholar
  • 19 Gardell SJ, Friedman PA. Vampire bat salivary plasminogen activator. Methods Enzymol 1993; 223: 233-249
    PubMedGoogle Scholar
  • 20 Jakobsen E, Kierulf P. A modified Beta-alanine precipitation procedure to prepare fibrinogen free of antithrombin-III and plasminogen. Thromb Res 1973; 3: 145-159
    CrossrefPubMedGoogle Scholar
  • 21 Clauss A. Gerinnungsphysiologische schnellmethode zur bestimmung des fibrinogens. Acta Haematol (Basel) 1957; 17: 237-240
    CrossrefPubMedGoogle Scholar
  • 22 Collen D, Lijnen HR. The Fibrinolytic System in Man: An Overview. In: Thrombolysis: Biological and Therapeutic Properties of New Thrombolytic Agents. Collen D, Lijnen HR, Verstraete M. eds. Churchill Livingstone; Edinburg: 1985. pp 1-18
    Google Scholar
  • 23 Marder VJ, Shulman NR, Carroll WR. Physicochemical and immunological characterization. J Biol Chem 1969; 244: 2111-2119
    PubMedGoogle Scholar
  • 24 Omar MN, Mann KG. Inactivation of factor Va by plasmin. J Biol Chem 1987; 262: 9750-9755
    PubMedGoogle Scholar
  • 25 McKee PA, Anderson JC, Switzer ME. Molecular structural studies of human factor VIII. Ann NY Acad Sei 1975; 240: 8-33
    CrossrefPubMedGoogle Scholar
  • 26 Hamilton KK, Fretto LJ, Grierson DS, McKee PA. Effects of plasmin on von Willebrand factor multimers. Degradation in vitro and stimulation of release in vivo J Clin Invest 1985; 76: 261-270
    CrossrefPubMedGoogle Scholar
  • 27 Adelman B, Michelson AD, Loscalzo J, Greenberg J, Handin RI. Plasmin effect on platelet glycoprotein IB-von Willebrand factor interactions. Blood 1985; 65: 32-40
    PubMedGoogle Scholar
  • 28 Pasche B, Collins L, Ouimet H, Francis S, Loscalzo J. Modulation of platelet function by plasmin and fibrin(ogen) degradation products during thrombolysis. Blood 1991; 78: 142 a
    PubMedGoogle Scholar
  • 29 Rabbani LE, Devine P, Rudd MA, George D, Johnstone MT, Samsel R, Michel T, Loscalzo J. Plasminogen activation alters in vitro endothelial cell integrity. Blood 1991; 78: 209
    PubMedGoogle Scholar
  • 30 Rudd MA, Johnstone MT, Rabbani LE, George D, Ware JA, Loscalzo J. Thrombolytic therapy causes an increase in vascular permeability that is reversed by l-deamino-8-d-vasopressin. Circulation 1991; 84: 2568-2573
    CrossrefPubMedGoogle Scholar
  • 31 Peuhkurinen KJ, Risteli L, Melkko JT, Linnaluoto M, Jounela A, Risteli J. Thrombolytic therapy with streptokinase stimulates collagen breakdown. Circulation 1991; 83: 1969-1975
    CrossrefPubMedGoogle Scholar
  • 32 Gardell SJ, Hare TR, Bergum PW, Cuca GC, O'Neill-Palladino L, Zavodny SM. Vampire bat salivary plasminogen activator is quiescent in human plasma in the absence of fibrin unlike human tissue plasminogen activator. Blood 1990; 76: 2560-2564
    PubMedGoogle Scholar
  • 33 Hare TR, Gardell SJ. Vampire bat salivary plasminogen activator promotes robust lysis of plasma clots in a plasma milieu without causing fluid phase plasminogen activation. Thromb Haemost 1992; 68: 165-169
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 34 Bergqvist D, Arfors K-E. Influence of fibrinolysis and coagulation on haemostatic plug formation. An experimental study in rabbits Thromb Res 1974; 4: 345-360
    CrossrefPubMedGoogle Scholar
  • 35 Rao A, Pratt C, Berke A, Jaffe A, Ockene I, Schreiber T, Bell W, Knatternd G, Robertson T, Terrin M. Thrombolysis in myocardial infarction (TIMI) trial-Phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988; 11: 1-11
    CrossrefPubMedGoogle Scholar
  • 36 Vander VeldenP, Giles AR. A detailed morphological evaluation of the evolution of the haemostatic plug in normal, factor VII and factor VIII deficient dogs. Br J Haematol 1988; 70: 345-355
    CrossrefPubMedGoogle Scholar
  • 37 Sixma JJ, Wester J. The hemostatic plug. Semin Hematol 1977; 14: 265-299
    PubMedGoogle Scholar
  • 38 Topol EJ, Bell WR, Weisfeldt ML. Coronary thrombolysis with recombinant tissue-type plasminogen activator. Ann Int Med 1985; 103: 837-843
    CrossrefPubMedGoogle Scholar
  • 39 Kasper W, Erbel R, Meinertz T, Drexler M, Ruckel A, Pop T, Prellwitz W, Meyer J. Intracoronary thrombolysis with an acylated streptokinase-plasminogen activator (BRL 26921) in patients with acute myocardial infarction. J Am Coll Cardiol 1984; 4: 357-363
    CrossrefPubMedGoogle Scholar
  • 40 Neuhaus K-L, Feuerer W, Jeep-Tebbe S, Niederer W, Vogt A, Tebbe U. Improved thrombolysis with a modified dose regimen of recombinant tissue-type plasminogen activator. J Am Coll Cardiol 1989; 14: 1566-1569
    CrossrefPubMedGoogle Scholar
  • 41 Smalling RW, Schumacher R, Morris D, Harder K, Fuentes F, Valentine RP, Battey Jr LL, Merhige M, Pitts DE, Lieberman HA, Nishikawa A, Adyanthaya A, Hopkins A. Improved infarct-related arterial patency after high-dose, weight-adjusted, rapid infusion of tissue-type plasminogen activator in myocardial infarction: results of a multicenter randomized trial of two dosage regimens. J Am Coll Cardiol 1990; 15: 915-921
    CrossrefPubMedGoogle Scholar
  • 42 Topol EJ. Ultrathrombolysis. J Am Coll Cardiol 1990; 15: 922-924
    CrossrefPubMedGoogle Scholar
  • 43 Cambier P, Van de Werf F, Larsen GR, Collen D. Pharmacokinetics and thrombolytic properties of a nonglycosylated mutant of human tissue- type plasminogen activator, lacking the finger and growth factor domains, in dogs with copper coil-induced coronary artery thrombosis. J Cardiovasc Pharmacol 1988; 11: 468-472
    CrossrefPubMedGoogle Scholar
  • 44 Wu Z, Van de Werf F, Stassen T, Mattsson C, Pohl G, Collen D. Pharmacokinetics and coronary thrombolytic properties of two human tissue-type plasminogen activator variants lacking the finger-like, growth factor-like, and first kringle domains (amino acids 6-173) in a canine model. J Cardiovasc Pharmacol 1990; 16: 197-203
    CrossrefPubMedGoogle Scholar
  • 45 Weinheimer CJ, James HL, Kalyan NK, Wilhelm J, Lee SG, Hung PP, Sobel BE, Bergmann SR. Induction of sustained patency after clot-selective coronary thrombolysis with hybrid-B, a genetically engineered plasminogen activator with a prolonged biological half-life. Circulation 1991; 83: 1429-1436
    CrossrefPubMedGoogle Scholar
  • 46 Jackson CV, Crowe VG, Craft TJ, Sundboom JL, Grinnell BW, Bobbitt JL, Burck PJ, Quay JF, Smith GF. Thrombolytic activity of a novel plasminogen activator, LY210825, compared with recombinant tissue-type plasminogen activator in a canine model of coronary artery thrombosis. Circulation 1990; 82: 930-940
    CrossrefPubMedGoogle Scholar