Bat Plasminogen Activator: Desmoteplase – From Bat to Bench to Bedside of Stroke Victims

  • Wolfgang SöhngenEmail author
  • Karl-Uwe Petersen
  • Mariola Söhngen


Desmoteplase (DSPA) was identified in the salivary venom of Desmodus rotundus (a blood-feeding vampire bat common in Latin America) triggered by observations as early as 1964. The initial interest in DSPA as a therapeutic modality was raised by the success of recombinant tissue plasminogen activator (rt-PA) in acute myocardial infarction (AMI) and the evolving paradigm of fibrin-specificity as the key to safe and effective thrombolysis. The early research on DSPA confirmed an extremely high fibrin specificity and a potential for a lower bleeding propensity, demonstrated in a variety of preclinical studies. Obviously, the unique task in the Vampire Bat – curbing clot formation without disintegrating the other salivary proteins – has led to a protease which serves no other known function than activating plasminogen in the presence of fibrin. This fibrin and substrate specificity distinguishes DSPA from rt-PA, which, apart from clot lysis, has a number of additional physiological roles.

The first clinical trial in AMI confirmed the absence of fibrinogen depletion even at doses of 750 μg/kg (90 μg/kg is effective in acute ischaemic stroke, AIS). DSPA was abandoned by Schering AG for strategic reasons and, in 2001, its further development was redirected by PAION to acute ischemic stroke (AIS), based on the assumption that a more fibrin-specific thrombolytic should pose a lower bleeding risk and allow a longer post-stroke treatment window. Also in 2001, the discovery of the ability of rt-PA to enhance NMDA-induced neurotoxicity (which models the glutamate neurotoxicity known in vivo) gave rise to the speculation that DSPA, by virtue of its high specialization, might be different. The subsequent multi-level research indeed confirmed that DSPA is devoid of any neurotoxic properties. The main reason seems to lie in a structural difference: The deleterious augmentation of NMDA neurotoxicity by rt-PA (and its mutants, shown in vitro) requires the kringle 2 (K2) domain, a moiety lacking in DSPA. This distinction may prove advantageous also in other areas, as, more generally, the kringle 2 seems to capacitate (r)t-PA for numerous mechanisms it is known to operate, sometimes to a harmful end. An important example is its K2-dependent ability to activate platelet-derived growth factor (PDGF), which is instrumental in (r)t-PA induced weakening of the blood brain barrier.

DSPA is now in a global phase III program in AIS, sponsored by PAION’s partner Lundbeck, treating patients up to 9 h after stroke onset, a wide extension of the current window of 3–4.5 h.


Plasminogen Activator Acute Myocardial Infarction Acute Ischemic Stroke Clot Lysis Primary Safety Endpoint 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Belwood, J.J., Morton, P.A., 1991. Vampires: the real story. The truth about the bats people love to hate is even more fascinating than the myths. Bats 9, 11–16.Google Scholar
  2. Benchenane, K., López-Atalaya, J.P., Fernandez-Monreal, M., Touzani, O., Vivien, D., 2004. Equivocal roles of tissue-type plasminogen activator in stroke-induced injury. Trends Neurosci. 27, 155–160.PubMedCrossRefGoogle Scholar
  3. Benchenane, K., Castel, H., Boulouard, M., Bluthé, R., Fernandez-Monreal, M., Roussel, B.D., López-Atalaya, J.P., Butt-Gueulle, S., Agin, V., Maubert, E., Dantzer, R., Touzani, O., Dauphin, F., Vivien, D., Ali, C., 2007. Anti-NR1 N-terminal-domain vaccination unmasks the crucial action of tPA on NMDA-receptor-mediated toxicity and spatial memory. J. Cell. Sci. 120, 578–585.PubMedCrossRefGoogle Scholar
  4. Bergum, P.W., Gardell, S.J., 1992. Vampire bat salivary plasminogen activator exhibits a strict and fastidious requirement for polymeric fibrin as its cofactor, unlike human tissue-type plasminogen activator. A kinetic analysis. J. Biol. Chem. 267, 17726–17731.Google Scholar
  5. Bringmann, P., Gruber, D., Liese, A., Toschi, L., Krätzchmar, J., Schleuning, W.D., Donner, P., 1995. Structural features mediating fibrin selectivity of vampire bat plasminogen activators. J. Biol. Chem. 270, 25596–25603.PubMedCrossRefGoogle Scholar
  6. Busch, E., Krüger, K., Fritze, K., Allegrini, P.R., Hoehn-Berlage, M., Hossmann, K.A., 1997. Blood-brain barrier disturbances after rt-PA treatment of thromboembolic stroke in the rat. Acta Neurochir. Suppl. 70, 206–208.PubMedGoogle Scholar
  7. Collen, D., 1996. Fibrin-selective thrombolytic therapy for acute myocardial infarction. Circulation 93, 857–865.PubMedCrossRefGoogle Scholar
  8. Epple, G., Schleuning, W.D., Kettelgerdes, G., Kottgen, E., Gessner, R., Praus, M., 2004. Prion protein stimulates tissue-type plasminogen activator-mediated plasmin generation via a lysine-binding site on kringle 2. J. Thromb. Haemost. 2, 962–968.PubMedCrossRefGoogle Scholar
  9. Fanne, R.A., Nassar, T., Yarovoi, S., Rayan, A., Lamensdorf, I., Karakoveski, M., Vadim, P., Fanne, R.A., Jamal, M., Cines, D.B., Al-Roof Higazi, A., 2010. Blood-brain barrier permeability and tPA-mediated neurotoxicity. Neuropharmacology 58, 972–980.Google Scholar
  10. Fernández-Monreal, M., López-Atalaya, J.P., Benchenane, K., Cacquevel, M., Dulin, F., Le Caer, J.P., Rossier, J., Jarrige, A.C., Mackenzie, E.T., Colloc’h, N., Ali, C., Vivien, D., 2004. Arginine 260 of the amino-terminal domain of NR1 subunit is critical for tissue-type plasminogen activator-mediated enhancement of N-methyl-D-aspartate receptor signaling. J. Biol. Chem. 279, 50850–508506.PubMedCrossRefGoogle Scholar
  11. Fredriksson, L., Ehnman, M., Fieber, C., Eriksson, U., 2005. Structural requirements for activation of latent platelet-derived growth factor CC by tissue plasminogen activator. J. Biol. Chem. 280, 26856–26862.PubMedCrossRefGoogle Scholar
  12. Furlan, A.J., Eyding, D., Albers, G.W., Al-Rawi, Y., Lees, K.R., Rowley, H.A., Sachara, C., Soehngen, M., Warach, S., Hacke, W., DEDAS Investigators, 2006. Dose escalation of desmoteplase for acute ischemic stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke 37, 1227–1231.PubMedCrossRefGoogle Scholar
  13. Gulba, D.C., Praus, M., Witt, W., 1995. DSPA alpha – properties of the plasminogen activators of the vampire bat Desmodus rotundus. Fibrinolysis 9(Suppl.), 91–96.Google Scholar
  14. Hacke, W., Kaste, M., Fieschi, C., von Kummer, R., Davalos, A., Meier, D,. Larrue, V., Bluhmki, E., Davis, S., Donnan, G., Schneider, D., Diez-Tejedor, E., Trouillas, P., 1998. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet, 352: 1245–1251.CrossRefGoogle Scholar
  15. Hacke, W., Albers, G., Al-Rawi, Y., Bogousslavsky, J., Davalos, A., Eliasziw, M., Fischer, M., Furlan, A., Kaste, M., Lees, K.R., Soehngen, M., Warach, S., for The DIAS Study Group, 2005. The desmoteplase in acute ischemic stroke trial (DIAS). A phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke 36, 66–73PubMedCrossRefGoogle Scholar
  16. Hacke, W., Furlan, A.J., Al-Rawi, Y., Davalos, A., Fiebach, J.B., Gruber, F., Kaste, M., Lipka, L.J., Pedraza, S., Ringleb, P.A., Rowley, H.A., Schneider, D., Schwamm, L.H., Leal, J.S., Söhngen, M., Teal, P.A., Wilhelm-Ogunbiyi, K., Wintermark, M., Warach, S., 2009. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol. 8, 141–50PubMedCrossRefGoogle Scholar
  17. Kassner, A., Roberts, T.P., Moran, B., Silver, F.L., Mikulis, D.J., 2009. Recombinant tissue plasminogen activator increases blood-brain barrier disruption in acute ischemic stroke: an MR imaging permeability study. Am. J. Neuroradiol. 30, 1864–1869.PubMedCrossRefGoogle Scholar
  18. Keyt, B.A., Paoni, N.F., Refino, C.J., Berleau, L., Nguyen, H., Chow, A., Lai, J., Peña, L., Pater, C., Ogez, J., Etcheverry, T., Botstzein, D., Bennett, W.F., 1994. A faster-acting and more potent form of tissue plasminogen activator. Proc. Natl. Acad. Sci. U.S.A. 91, 3670–3674.PubMedCrossRefGoogle Scholar
  19. Kidwell, C.S., Latour, L., Saver, J.L., Alger, J.R., Starkman, S., Duckwiler, G., Jahan, R., Vinuela, F., UCLA Thrombolysis Investigators, Kang, D.W., Warach, S., 2008. Thrombolytic toxicity: blood brain barrier disruption in human ischemic stroke. Cerebrovasc. Dis. 25, 338–343.PubMedCrossRefGoogle Scholar
  20. Krätzschmar, J., Haendler, B., Langer, G., Boidol, W., Bringmann, P., Alagon, A., Donner, P., Schleuning, W.D., 1991. The plasminogen activator family from the salivary gland of the vampire bat Desmodus rotundus: cloning and expression. Gene 105, 229–237.PubMedCrossRefGoogle Scholar
  21. Kruithof, E.K., Schleuning, W.D., 2004. A comparative study of amyloid-beta (1–42) as a cofactor for plasminogen activation by vampire bat plasminogen activator and recombinant human tissue-type plasminogen activator. Thromb. Haemost. 92, 559–567.PubMedGoogle Scholar
  22. Liberatore, G.T., Samson, A., Bladin, C., Schleuning, W.D., Medcalf, R.L., 2003. Vampire bat salivary plasminogen activator (desmoteplase): a unique fibrinolytic enzyme that does not promote neurodegeneration. Stroke 34, 537–543.PubMedCrossRefGoogle Scholar
  23. López-Atalaya, J.P., Roussel, B.D., Ali, C., Maubert, E., Petersen, K.-U., Berezowski, V., Cecchelli, R., Orset, C., Vivien, D., 2007. Recombinant Desmodus rotundus salivary plasminogen activator (desmoteplase) crosses the blood-brain barrier through a LDL receptor-related protein (LRP)-dependent mechanism without exerting neurotoxic effects. Stroke 38, 1036–1043.PubMedCrossRefGoogle Scholar
  24. López-Atalaya, J.P., Roussel, B.D., Levrat, D., Parcq, J., Nicole, O., Hommet, Y., Benchenane, K., Castel, H., Leprince, J., van To, D., Bureau, R., Rault, S., Vaudry, H., Petersen, K.-U., Santos, J.S., Ali, C., Vivien, D., 2008. Toward safer thrombolytic agents in stroke: molecular requirements for NMDA receptor-mediated neurotoxicity. J. Cereb. Blood Flow Metab. 28, 1212–1221.PubMedCrossRefGoogle Scholar
  25. Multicenter Acute Stroke Trial-Europe Study Group, 1996. Thrombolytic therapy with streptokinase in acute ischemic stroke. N. Engl. J. Med. 335, 145–150.CrossRefGoogle Scholar
  26. Muschick, P., Zeggert, D., Donner, P., Witt, W., 1993. Thrombolytic properties of Desmodus (vampire bat) salivary plasminogen activator DSPA alpha1, alteplase and streptokinase following intravenous bolus injection in a rabbit model of carotid artery thrombosis. Fibrinolysis 7, 284–290Google Scholar
  27. NINDS. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, 1995. Tissue plasminogen activator for acute ischemic stroke. N. Engl. J. Med. 33, 1581–1587.Google Scholar
  28. Petersen, K.-U., 2007. Thrombolytics – a field in development. Riv. It. Neurobiologia 53, 7–14.Google Scholar
  29. Reddrop, C., Moldrich, R.X., Beart, P.M., Farso, M., Liberatore, G.T., Howells, D.W., Petersen, K.-U., Schleuning, W.D., Medcalf, R.L., 2005. Vampire bat salivary plasminogen activator (desmoteplase) inhibits tissue-type plasminogen activator-induced potentiation of excitotoxic injury. Stroke 36, 1241–1246.PubMedCrossRefGoogle Scholar
  30. Renatus, M., Stubbs, M.T., Huber, R., Bringmann, P., Donner, P., Schleuning, W.D., Bode, W., 1997. Catalytic domain structure of vampire bat plasminogen activator: a molecular paradigm for proteolysis without activation cleavage. Biochemistry 36, 3483–3493.CrossRefGoogle Scholar
  31. Research Report A315, 1992. Lysis of human plasma and whole blood clots in vitro by ZK 152 387 (DSPA alpha1), ZK 153 786 (DSPA alpha2), ZK 155 278 (DSPA beta), ZK 153 858 (alteplase), ZK 130 932 (scu-PA), ZK 113 905 (urokinase), and ZK 156 552 (anistreplase). (PAION, data on file)Google Scholar
  32. Research Report PN01 PCD 00002/01, 2001. Comparing the therapeutic benefit of desmoteplase, reteplase, and alteplase in a rat model of embolic middle cerebral artery (MCA) occlusion. (PAION, data on file)Google Scholar
  33. Schering Report, Gulba, D., 2002. rDSPA alpha1 in the establishment of early patency in myocardial infarction. (PAION, data on file)Google Scholar
  34. Schleuning, W.D., Alagon, A., Boidol, W., Bringmann, P., Petri, T., Krätzschmar, J., Haendler, B., Langer, G., Baldus, B., Witt, W., Donner, P., 1992. Plasminogen activators from the saliva of Desmodus rotundus (common vampire bat): unique fibrin specificity. Ann. N. Y. Acad. Sci. 667, 395–403.PubMedCrossRefGoogle Scholar
  35. Schleuning, W.D., 2001. Vampire bat plasminogen activator DSPA-alpha-1 (desmoteplase): a thrombolytic drug optimized by natural selection. Haemostasis 31, 118–122.PubMedGoogle Scholar
  36. Stewart, R.J., Fredenburgh, J.C., Weitz, J.I., 1998. Characterization of the interactions of plasminogen and tissue and vampire bat plasminogen activators with fibrinogen, fibrin, and the complex of D-dimer noncovalently linked to fragment E. J. Biol. Chem. 273, 18292–18299.PubMedCrossRefGoogle Scholar
  37. Sobel, B.E., Geltman, E.M., Tiefenbrunn, A.J., Jaffe, A.S., Spadaro, J.J. Jr., Ter-Pogossian, M.M., Collen, D., Ludbrook, P.A., 1984. Improvement of regional myocardial metabolism after coronary thrombolysis induced with tissue-type plasminogen activator or streptokinase. Circulation 69, 983–690.PubMedCrossRefGoogle Scholar
  38. Su, E.J., Fredriksson, L., Geyer, M., Folestad, E., Cale, J., Andrae, J., Gao, Y., Pietras, K., Mann, K., Yepes, M., Strickland, D.K., Betsholtz, C., Eriksson, U., Lawrence, D.A., 2008. Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke. Nat. Med. 14, 731–737.PubMedCrossRefGoogle Scholar
  39. Su, E.J., Fredriksson, L., Schielke, G.P., Eriksson, U., Lawrence, D.A., 2009. Tissue plasminogen activator-mediated PDGF signaling and neurovascular coupling in stroke. J. Thromb. Haemost. 7(Suppl. 1), 155–158.PubMedCrossRefGoogle Scholar
  40. Tebbe, U., Bramlage, P., Graf, A., Lechleitner, P., Bode, C., Riess, F.C., Clemens, N., Al-Rawi, Y., Konstantinides, S., Goldhaber, S.Z., 2009. Desmoteplase in acute massive pulmonary thromboembolism. Thromb. Haemost. 101, 557–562.PubMedGoogle Scholar
  41. Toschi, L., Bringmann, P., Petri, T., Donner, P., Schleuning, W.D., 1998. Fibrin selectivity of the isolated protease domains of tissue-type and vampire bat salivary gland plasminogen activators. Eur. J. Biochem. 252, 108–112.PubMedCrossRefGoogle Scholar
  42. Tsirka, S.E., 2002. Tissue plasminogen activator as a modulator of neuronal survival and function. Biochem. Soc. Trans. 30, 222–225.PubMedCrossRefGoogle Scholar
  43. Yepes, M., Sandkvist, M., Moore, E.G., Bugge, T.H., Strickland, D.K., Lawrence, D.A., 2003. Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein. J. Clin. Invest. 112, 1533–1540.PubMedGoogle Scholar
  44. Yepes, M., Roussel, B.D., Ali, C., Vivien, D., 2009. Tissue-type plasminogen activator in the ischemic brain: more than a thrombolytic. Trends Neurosci. 32, 48–55.PubMedCrossRefGoogle Scholar
  45. Witt, W., Balds, B., Bringmann, P., Cashon, L., Donner, P., Schleuning, W.D., 1992. Thrombolytic properties of Desmodus rotundus (vampire bat) salivary plasminogen activator in experimental pulmonary embolism in rats. Blood 79, 1213–1217.PubMedGoogle Scholar
  46. Witt, W., Maass, B., Baldus, B., Hildebrand, M., Donner, P., Schleuning, W.D., 1994. Coronary thrombolysis with Desmodus salivary plasminogen activator in dogs. Fast and persistent recanalization by intravenous bolus administration. Circulation 90, 421–426.Google Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Wolfgang Söhngen
    • 1
    Email author
  • Karl-Uwe Petersen
    • 1
  • Mariola Söhngen
    • 1
  1. 1.PAION Deutschland GmbHAachenGermany

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