Desmoteplase: Discovery, insights and opportunities for ischaemic stroke

British Journal of Pharmacology

Volumn 165, Issue 1, 2012, Pages 75-89

  Medcalf, Robert L ^a  

^a MONASH UNIVERSITY   (Australia)

Author keywords

desmoteplase; stroke neurotoxicity; thrombolysis; tissue type plasminogen activator; vampire bat

Indexed keywords

ALTEPLASE; DESMODUS SALIVARY PLASMINOGEN ACTIVATOR; DESMOTEPLASE; FIBRIN; PLACEBO; PLASMIN; PLASMINOGEN ACTIVATOR; TISSUE PLASMINOGEN ACTIVATOR; UNCLASSIFIED DRUG;

ARTERY THROMBOSIS; BAT; BLOOD BRAIN BARRIER; BLOOD CLOT LYSIS; BRAIN ISCHEMIA; DISEASE MODEL; DRUG CLEARANCE; DRUG EFFICACY; DRUG ELIMINATION; DRUG HALF LIFE; DRUG MECHANISM; DRUG POTENCY; DRUG SAFETY; GENETIC ANALYSIS; GENOME; GLYCOSYLATION; HEART INFARCTION; HISTORY; HUMAN; LUNG EMBOLISM; NEUROTOXICITY; NONHUMAN; PHYLOGENY; PRIORITY JOURNAL; PROTEIN CLEAVAGE; PROTEIN DOMAIN; REVIEW; VAMPIRE BAT;

ANIMALS; CHIROPTERA; FIBRINOLYTIC AGENTS; HUMANS; PLASMINOGEN ACTIVATORS; SALIVA; STROKE;

EID: 80053651851     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1111/j.1476-5381.2011.01514.x     Document Type: Review

References (99)

1. Abu Fanne R, Nassar T, Yarovoi S, Rayan A, Lamensdorf I, Karakoveski M, et al,. (2010). Blood-brain barrier permeability and tPA-mediated neurotoxicity. Neuropharmacology 58: 972-980.
2. Apitz-Castro R, Beguin S, Tablante A, Bartoli F, Holt JC, Hemker HC, (1995). Purification and partial characterization of draculin, the anticoagulant factor present in the saliva of vampire bats (Desmodus rotundus). Thromb Haemost 73: 94-100.
3. Armstead WM, Cines DB, Higazi AA, (2005). Plasminogen activators contribute to impairment of hypercapnic and hypotensive cerebrovasodilation after cerebral hypoxia/ischemia in the newborn pig. Stroke 36: 2265-2269. (Pubitemid 41429257)
4. Baranes D, Lederfein D, Huang YY, Chen M, Bailey CH, Kandel ER, (1998). Tissue plasminogen activator contributes to the late phase of LTP and to synaptic growth in the hippocampal mossy fiber pathway. Neuron 21: 813-825. (Pubitemid 28498789)
5. Baron A, Montagne A, Casse F, Launay S, Maubert E, Ali C, et al,. (2010). NR2D-containing NMDA receptors mediate tissue plasminogen activator-promoted neuronal excitotoxicity. Cell Death Differ 17: 860-871.
6. Benchenane K, Berezowski V, Ali C, Fernandez-Monreal M, Lopez-Atalaya JP, Brillault J, et al,. (2005). Tissue-type plasminogen activator crosses the intact blood-brain barrier by low-density lipoprotein receptor-related protein-mediated transcytosis. Circulation 111: 2241-2249. (Pubitemid 40632441)
7. Bergum PW, Gardell SJ, (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.
8. Bier OE, (1932). Action anticoagulante et fibrinolytique de l'extract des glands salivaires d'une chauve-souris hematophage (Desmodus rufus). C R Soc Biol (Paris) 110: 129-131.
9. Bringmann P, Gruber D, Liese A, Toschi L, Kratzschmar J, Schleuning WD, et al,. (1995). Structural features mediating fibrin selectivity of vampire bat plasminogen activators. J Biol Chem 270: 25596-25603.
10. Cartwright T, (1974). The plasminogen activator of vampire bat saliva. Blood 43: 317-326.
11. Cartwright T, Hawkey C, (1968). Activation of the blood fibrinolytic mechanism in birds by saliva of the vampire bat (Diaemus youngi). J Physiol 201: 45P-46P.
12. Cesarman-Maus G, Hajjar KA, (2005). Molecular mechanisms of fibrinolysis. Br J Haematol 129: 307-321. (Pubitemid 40646889)
13. Davis SM, Donnan GA, (2009). 4.5 hours: the new time window for tissue plasminogen activator in stroke. Stroke 40: 2266-2267.
14. Donnan GA, Davis SM, (2007). Life after DIAS II. Int J Stroke 2: 236-237. (Pubitemid 350119922)
15. Ellis V, Daniels M, Misra R, Brown DR, (2002). Plasminogen activation is stimulated by prion protein and regulated in a copper-dependent manner. Biochemistry 41: 6891-6896. (Pubitemid 34575659)
16. Epple G, Schleuning WD, 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. (Pubitemid 40185744)
17. Fernandez AZ, Tablante A, Beguin S, Hemker HC, Apitz-Castro R, (1999). Draculin, the anticoagulant factor in vampire bat saliva, is a tight-binding, noncompetitive inhibitor of activated factor X. Biochim Biophys Acta 1434: 135-142. (Pubitemid 29521340)
18. Fredriksson L, Li H, Fieber C, Li X, Eriksson U, (2004). Tissue plasminogen activator is a potent activator of PDGF-CC. EMBO J 23: 3793-3802. (Pubitemid 39389710)
19. 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. (Pubitemid 41040719)
20. Furlan AJ, Eyding D, Albers GW, Al-Rawi Y, Lees KR, Rowley HA, et al,. (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. (Pubitemid 43731867)
21. Gardell SJ, Friedman PA, (1993). Vampire bat salivary plasminogen activator. Methods Enzymol 223: 233-249.
22. Gardell SJ, Duong LT, Diehl RE, York JD, Hare TR, Register RB, et al,. (1989). Isolation, characterization, and cDNA cloning of a vampire bat salivary plasminogen activator. J Biol Chem 264: 17947-17952. (Pubitemid 19279262)
23. Gardell SJ, Hare TR, Bergum PW, Cuca GC, O'Neill-Palladino L, Zavodny SM, (1990). Vampire bat salivary plasminogen activator is quiescent in human plasma in the absence of fibrin unlike human tissue plasminogen activator. Blood 76: 2560-2564.
24. Gardell SJ, Ramjit DR, Stabilito II, Fujita T, Lynch JJ, Cuca GC, et al,. (1991). Effective thrombolysis without marked plasminemia after bolus intravenous administration of vampire bat salivary plasminogen activator in rabbits. Circulation 84: 244-253.
25. Greenhall AM, Schutt WA, (1996). Diaemus youngi. Mamm Species 533: 1-7.
26. Greenhall AM, Joermann G, Schmidt U, Seidel MR, (1983). Desmodus rotundus. Mamm Species 202: 1-6.
27. Greenhall AM, Schmidt U, Joermann G, (1984). Diphylla eucadata. Mamm Species 227: 1-3.
28. Gulba DC, Praus M, Witt W, (1995). DSPA alpha-Properties of the plasminogen activators on the Vampire bat Desmodus rotundus. Fibrinolysis 9: 91-96.
29. Gulba DC, Praus M, Dechend R, Hauck S, Mahler M, Zitvz R, et al,. (1997). Update on the toxicology and pharmacology of rDSPA alpha 1 (Bat-PA) in animals and humans. Fibrinol Proteol 11: 55-62. (Pubitemid 27455944)
30. Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, et al,. (2004). Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 363: 768-774.
31. Hacke W, Albers G, Al-Rawi Y, Bogousslavsky J, Davalos A, Eliasziw M, et al,. (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: 66-73. (Pubitemid 40054177)
32. Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, et al,. (2008). Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 359: 1317-1329.
33. Hacke W, Furlan AJ, Al-Rawi Y, Davalos A, Fiebach JB, Gruber F, et al,. (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: 141-150.
34. Hare TR, Gardell SJ, (1992). Vampire bat salivary plasminogen activator promotes robust lysis of plasma clots in a plasma milieu without causing fluid phase plasminogen activation. Thromb Haemost 68: 165-169.
35. Hastings GA, Coleman TA, Haudenschild CC, Stefansson S, Smith EP, Barthlow R, et al,. (1997). Neuroserpin, a brain-associated inhibitor of tissue plasminogen activator is localized primarily in neurons. Implications for the regulation of motor learning and neuronal survival. J Biol Chem 272: 33062-33067. (Pubitemid 28023647)
36. Hawkey C, (1966). Plasminogen activator in saliva of the vampire bat Desmodus rotundus. Nature 211: 434-435.
37. Hawkey C, (1967). Inhibitor of platelet aggregation present in saliva of the vampire bat Desmodus rotundus. Br J Haematol 13: 1014-1020.
38. 1 (Desmodus rotundus salivary plasminogen activator) in plasma and its application to investigate pharmacokinetics in monkeys. Fibrinolysis 9: 107-111.
39. Hildebrand M, Bhargava AS, Bringmann P, Schutt A, Verhallen P, (1996). Pharmacokinetics of the novel plasminogen activator Desmotus rotundus plasminogen activator and extrapolation to man. Fibrinolysis 10: 269-276.
40. Kassner A, Roberts TP, Moran B, Silver FL, Mikulis DJ, (2009). Recombinant tissue plasminogen activator increases blood-brain barrier disruption in acute ischemic stroke: an MR imaging permeability study. AJNR Am J Neuroradiol 30: 1864-1869.
41. Kidwell CS, Latour L, Saver JL, Alger JR, Starkman S, Duckwiler G, et al,. (2008). Thrombolytic toxicity: blood brain barrier disruption in human ischemic stroke. Cerebrovasc Dis 25: 338-343. (Pubitemid 351555857)
42. Kilic E, Kilic U, Bahr M, Hermann DM, (2005). Tissue plasminogen activator-induced ischemic injury is reversed by NMDA antagonist MK-801 in vivo. Neurodegener Dis 2: 49-55. (Pubitemid 41759074)
43. Kingston IB, Castro MJ, Anderson S, (1995). In vitro stimulation of tissue-type plasminogen activator by Alzheimer amyloid beta-peptide analogues. Nat Med 1: 138-142.
44. Kratzschmar J, Haendler B, Langer G, Boidol W, Bringmann P, Alagon A, et al,. (1991). The plasminogen activator family from the salivary gland of the vampire bat Desmodus rotundus: cloning and expression. Gene 105: 229-237.
45. Kruithof EK, Schleuning WD, (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. (Pubitemid 39248012)
46. Kwon M, MacLeod TJ, Zhang Y, Waisman DM, (2005). S100A10, annexin A2, and annexin a2 heterotetramer as candidate plasminogen receptors. Front Biosci 10: 300-325. (Pubitemid 40543035)
47. Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, et al,. (2010). Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 375: 1695-1703.
48. Liberatore GT, Samson A, Bladin C, Schleuning WD, Medcalf RL, (2003). Vampire bat salivary plasminogen activator (desmoteplase): a unique fibrinolytic enzyme that does not promote neurodegeneration. Stroke 34: 537-543. (Pubitemid 36206361)
49. Liebeskind DS, (2009). Reversing stroke in the 2010s: lessons from Desmoteplase in acute ischemic stroke-2 (DIAS-2). Stroke 40: 3156-3158.
50. Longstaff C, Thelwell C, Williams SC, Silva MM, Szabo L, Kolev K, (2011). The interplay between tissue plasminogen activator domains and fibrin structures in the regulation of fibrinolysis: kinetic and microscopic studies. Blood 117: 661-668.
51. Lopez-Atalaya JP, Roussel BD, Ali C, Maubert E, Petersen KU, Berezowski V, et al,. (2007). Recombinant Desmodus rotundus salivary plasminogen activator crosses the blood-brain barrier through a low-density lipoprotein receptor-related protein-dependent mechanism without exerting neurotoxic effects. Stroke 38: 1036-1043. (Pubitemid 46568471)
52. Lopez-Atalaya JP, Roussel BD, Levrat D, Parcq J, Nicole O, Hommet Y, et al,. (2008). Toward safer thrombolytic agents in stroke: molecular requirements for NMDA receptor-mediated neurotoxicity. J Cereb Blood Flow Metab 28: 1212-1221. (Pubitemid 351733345)
53. Loscalzo J, (1988). Structural and kinetic comparison of recombinant human single- and two-chain tissue plasminogen activator. J Clin Invest 82: 1391-1397.
54. Maas C, Schiks B, Strangi RD, Hackeng TM, Bouma BN, Gebbink MF, et al,. (2008). Identification of fibronectin type I domains as amyloid-binding modules on tissue-type plasminogen activator and three homologs. Amyloid 15: 166-180.
55. Madani R, Hulo S, Toni N, Madani H, Steimer T, Muller D, et al,. (1999). Enhanced hippocampal long-term potentiation and learning by increased neuronal expression of tissue-type plasminogen activator in transgenic mice. EMBO J 18: 3007-3012. (Pubitemid 29255609)
56. Mannaioni G, Orr AG, Hamill CE, Yuan H, Pedone KH, McCoy KL, et al,. (2008). Plasmin potentiates synaptic N-methyl-D-aspartate receptor function in hippocampal neurons through activation of protease-activated receptor-1. J Biol Chem 283: 20600-20611.
57. Matys T, Strickland S, (2003). Tissue plasminogen activator and NMDA receptor cleavage. Nat Med 9: 371-372; author reply 372-373.
58. Medcalf RL, Ruegg M, Schleuning WD, (1990). A DNA motif related to the cAMP-responsive element and an exon-located activator protein-2 binding site in the human tissue-type plasminogen activator gene promoter cooperate in basal expression and convey activation by phorbol ester and cAMP. J Biol Chem 265: 14618-14626.
59. Mellott MJ, Ramjit DR, Stabilito II, Hare TR, Senderak ET, Lynch JJ, et al,. (1995). Vampire bat salivary plasminogen activator evokes minimal bleeding relative to tissue-type plasminogen activator as assessed by a rabbit cuticle bleeding time model. Thromb Haemost 73: 478-483.
60. Montoney M, Gardell SJ, Marder VJ, (1995). Comparison of the bleeding potential of vampire bat salivary plasminogen activator versus tissue plasminogen activator in an experimental rabbit model. Circulation 91: 1540-1544.
61. Mori T, Wang X, Kline AE, Siao CJ, Dixon CE, Tsirka SE, et al,. (2001). Reduced cortical injury and edema in tissue plasminogen activator knockout mice after brain trauma. Neuroreport 12: 4117-4120. (Pubitemid 33152463)
62. 1, alteplase and streptokinase following intravenous bolus injection in a rabbit model of carotid artery thrombosis. Fibrinolysis 7: 284-290. (Pubitemid 23210027)
63. Nicole O, Docagne F, Ali C, Margaill I, Carmeliet P, MacKenzie ET, et al,. (2001). The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling. Nat Med 7: 59-64.
64. Norris EH, Strickland S, (2007). Modulation of NR2B-regulated contextual fear in the hippocampus by the tissue plasminogen activator system. Proc Natl Acad Sci USA 104: 13473-13478. (Pubitemid 47293969)
65. Orth K, Willnow T, Herz J, Gething MJ, Sambrook J, (1994). Low density lipoprotein receptor-related protein is necessary for the internalization of both tissue-type plasminogen activator-inhibitor complexes and free tissue-type plasminogen activator. J Biol Chem 269: 21117-21122. (Pubitemid 24266483)
66. Pawlak R, Magarinos AM, Melchor J, McEwen B, Strickland S, (2003). Tissue plasminogen activator in the amygdala is critical for stress-induced anxiety-like behavior. Nat Neurosci 6: 168-174. (Pubitemid 36182786)
67. Pawlak R, Melchor JP, Matys T, Skrzypiec AE, Strickland S, (2005a). Ethanol-withdrawal seizures are controlled by tissue plasminogen activator via modulation of NR2B-containing NMDA receptors. Proc Natl Acad Sci USA 102: 443-448. (Pubitemid 40116786)
68. Pawlak R, Rao BS, Melchor JP, Chattarji S, McEwen B, Strickland S, (2005b). Tissue plasminogen activator and plasminogen mediate stress-induced decline of neuronal and cognitive functions in the mouse hippocampus. Proc Natl Acad Sci USA 102: 18201-18206. (Pubitemid 41798525)
69. Qian Z, Gilbert ME, Colicos MA, Kandel ER, Kuhl D, (1993). Tissue-plasminogen activator is induced as an immediate-early gene during seizure, kindling and long-term potentiation. Nature 361: 453-457. (Pubitemid 23050134)
70. Reddrop C, Moldrich RX, Beart PM, Farso M, Liberatore GT, Howells DW, et al,. (2005). Vampire bat salivary plasminogen activator (desmoteplase) inhibits tissue-type plasminogen activator-induced potentiation of excitotoxic injury. Stroke 36: 1241-1246. (Pubitemid 40798746)
71. Renatus M, Stubbs MT, Huber R, Bringmann P, Donner P, Schleuning WD, et al,. (1997). Catalytic domain structure of vampire bat plasminogen activator: a molecular paradigm for proteolysis without activation cleavage. Biochemistry 36: 13483-13493. (Pubitemid 27481594)
72. Rogove AD, Siao C, Keyt B, Strickland S, Tsirka SE, (1999). Activation of microglia reveals a non-proteolytic cytokine function for tissue plasminogen activator in the central nervous system. J Cell Sci 112 (Pt 22): 4007-4016. (Pubitemid 30119770)
73. Sakharov DV, Barrertt-Bergshoeff M, Hekkenberg RT, Rijken DC, (1999). Fibrin-specificity of a plasminogen activator affects the efficiency of fibrinolysis and responsiveness to ultrasound: comparison of nine plasminogen activators in vitro. Thromb Haemost 81: 605-612. (Pubitemid 29178950)
74. Samson AL, Medcalf RL, (2006). Tissue-type plasminogen activator: a multifaceted modulator of neurotransmission and synaptic plasticity. Neuron 50: 673-678. (Pubitemid 44218660)
75. Samson AL, Nevin ST, Croucher D, Niego B, Daniel PB, Weiss TW, et al,. (2008). Tissue-type plasminogen activator requires a co-receptor to enhance NMDA receptor function. J Neurochem 107: 1091-1101.
76. Samson AL, Borg RJ, Niego B, Wong CH, Crack PJ, Yongqing T, et al,. (2009). A nonfibrin macromolecular cofactor for tPA-mediated plasmin generation following cellular injury. Blood 114: 1937-1946.
77. Sashindranath M, Samson AL, Downes CE, Crack PJ, Lawrence AJ, Li QX, et al,. (2011). Compartment- and context-specific changes in tissue-type plasminogen activator (tPA) activity following brain injury and pharmacological stimulation. Lab Invest (in press).
78. Schleuning WD, (2001). Vampire bat plasminogen activator DSPA-alpha-1 (desmoteplase): a thrombolytic drug optimized by natural selection. Haemostasis 31: 118-122.
79. 1: a superior thrombolytic created by evolution. In:, Sasahara AA, Loscazo J, (eds). New Therepeutic Agents in Thrombosis and Thrombolysis. Marcel Dekker: New York, pp. 605-625.
80. Schleuning WD, Alagon A, Boidol W, Bringmann P, Petri T, Kratzschmar J, et al,. (1992). Plasminogen activators from the saliva of Desmodus rotundus (common vampire bat): unique fibrin specificity. Ann N Y Acad Sci 667: 395-403. (Pubitemid 23061605)
81. Seeds NW, Williams BL, Bickford PC, (1995). Tissue plasminogen activator induction in Purkinje neurons after cerebellar motor learning. Science 270: 1992-1994. (Pubitemid 26097189)
82. Sipley JD, Alexander DS, Testa JE, Quigley JP, (1997). Introduction of an RRHR motif into chicken urokinase-type plasminogen activator (ch-uPA) confers sensitivity to plasminogen activator inhibitor (PAI)-1 and PAI-2 and allows ch-uPA-mediated extracellular matrix degradation to be controlled by PAI-1. Proc Natl Acad Sci USA 94: 2933-2938.
83. Soehngen W, Petersen KU, Soehngen M, (2010). Bat Plasminogen activator: Desmoteplase-from bat to bench to bedside of stroke victims. In:, Kini RM, (ed.). Toxins and Haemostasis. Springer Science+Business Media B.V.: Dordrecht, Heidelberg, London and New York, pp. 393-407.
84. Stubbs MT, Renatus M, Bode W, (1998). An active zymogen: unravelling the mystery of tissue-type plasminogen activator. Biol Chem 379: 95-103. (Pubitemid 28075968)
85. Su EJ, Fredriksson L, Geyer M, Folestad E, Cale J, Andrae J, et al,. (2008). Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke. Nat Med 14: 731-737.
86. Su EJ, Fredriksson L, Schielke GP, Eriksson U, Lawrence DA, (2009). Tissue plasminogen activator-mediated PDGF signaling and neurovascular coupling in stroke. J Thromb Haemost 7 (Suppl. 1): 155-158.
87. Tellgren-Roth A, Dittmar K, Massey SE, Kemi C, Tellgren-Roth C, Savolainen P, et al,. (2009). Keeping the blood flowing-plasminogen activator genes and feeding behavior in vampire bats. Naturwissenschaften 96: 39-47.
88. Thelwell C, Longstaff C, (2007). The regulation by fibrinogen and fibrin of tissue plasminogen activator kinetics and inhibition by plasminogen activator inhibitor 1. J Thromb Haemost 5: 804-811. (Pubitemid 46563581)
89. Tooyama I, Kawamata T, Akiyama H, Kimura H, Moestrup SK, Gliemann J, et al,. (1995). Subcellular localization of the low density lipoprotein receptor-related protein (alpha 2-macroglobulin receptor) in human brain. Brain Res 691: 235-238.
90. Tsirka SE, Gualandris A, Amaral DG, Strickland S, (1995). Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator. Nature 377: 340-344.
91. Tsirka SE, Rogove AD, Strickland S, (1996). Neuronal cell death and tPA. Nature 384: 123-124.
92. Van de Werf FJ, (1999). The ideal fibrinolytic: can drug design improve clinical results? Eur Heart J 20: 1452-1458. (Pubitemid 29458690)
93. Wang YF, Tsirka SE, Strickland S, Stieg PE, Soriano SG, Lipton SA, (1998). Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice. Nat Med 4: 228-231. (Pubitemid 28138083)
94. Witt W, Baldus B, Bringmann P, Cashion L, Donner P, Schleuning WD, (1992). Thrombolytic properties of Desmodus rotundus (vampire bat) salivary plasminogen activator in experimental pulmonary embolism in rats. Blood 79: 1213-1217.
95. Witt W, Maass B, Baldus B, Hildebrand M, Donner P, Schleuning WD, (1994). Coronary thrombolysis with Desmodus salivary plasminogen activator in dogs. Fast and persistent recanalization by intravenous bolus administration. Circulation 90: 421-426. (Pubitemid 24203707)
96. Wolf BB, Lopes MB, VandenBerg SR, Gonias SL, (1992). Characterization and immunohistochemical localization of alpha 2-macroglobulin receptor (low-density lipoprotein receptor-related protein) in human brain. Am J Pathol 141: 37-42.
97. Yepes M, Lawrence DA, (2004). New functions for an old enzyme: nonhemostatic roles for tissue-type plasminogen activator in the central nervous system. Exp Biol Med (Maywood) 229: 1097-1104. (Pubitemid 39602251)
98. Zavalova LL, Basanova AV, Baskova IP, (2002). Fibrinogen-fibrin system regulators from bloodsuckers. Biochemistry (Mosc) 67: 135-142.
99. van Zonneveld AJ, Veerman H, Pannekoek H, (1986). On the interaction of the finger and the kringle-2 domain of tissue-type plasminogen activator with fibrin. Inhibition of kringle-2 binding to fibrin by epsilon-amino caproic acid. J Biol Chem 261: 14214-14218. (Pubitemid 17196329)