Skip to main content
SpringerLink
Log in

Combination of Thrombolytic Therapy with Antithrombotics and Neuroprotectants

  • Chapter
  • First Online:
Thrombolytic Therapy for Acute Stroke

  • 1568 Accesses

Abstract

Combining rt-PA with other therapies is logical in order to amplify the benefit of rt-PA, which alone does not recanalize all occluded arteries completely and may itself have some cytotoxicity. Even if recanalization occurs, cellular damage may progress during reperfusion. Linking rt-PA to other antithrombotic agents appears to be safe if doses are carefully titrated, and a hands-free device to deliver therapeutic ultrasound has also been developed. Efficacy studies of these novel combinatorial approaches are underway. Future clinical evaluation of combined cytoprotection and thrombolysis must focus on proper trial design to enhance the potential efficacy of treatment. Such factors include: early treatment before or during reperfusion and choice of therapies that are consistently and potently effective in preclinical trials and that target multiple downstream targets of ischemic damage. The most promising of these at the present time is hypothermia, and phase 3 studies are underway.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. The National Institute of Neurological Disorders and Stroke rt-pa Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581–7.

    Article  Google Scholar 

  2. Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317–29.

    Article  CAS  PubMed  Google Scholar 

  3. Saqqur M, Uchino K, Demchuk AM, Molina CA, Garami Z, Calleja S, et al. Site of arterial occlusion identified by transcranial Doppler predicts the response to intravenous thrombolysis for stroke. Stroke. 2007;38:948–54.

    Article  PubMed  Google Scholar 

  4. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, et al. ACC/AHA guidelines for the management of patients with st-elevation myocardial infarction—executive summary: a report of the American college of cardiology/American heart association task force on practice guidelines (writing committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). Circulation. 2004;110:588–636.

    Article  PubMed  Google Scholar 

  5. Basinski A, Naylor CD. Aspirin and fibrinolysis in acute myocardial infarction: meta-analytic evidence for synergy. J Clin Epidemiol. 1991;44:1085–96.

    Article  CAS  PubMed  Google Scholar 

  6. Zinkstok SM, Roos YB. Early administration of aspirin in patients treated with alteplase for acute ischaemic stroke: a randomised controlled trial. Lancet. 2012;380:731–7.

    Article  CAS  PubMed  Google Scholar 

  7. Mousa SA. In-vitro efficacy of different platelet glycoprotein IIb/IIIa antagonists and thrombolytics on platelet/fibrin-mediated clot dynamics in human whole blood using thrombelastography. Blood Coagul Fibrinolysis. 2007;18:55–60.

    Article  CAS  PubMed  Google Scholar 

  8. Nakada MT, Montgomery MO, Nedelman MA, Guerrero JL, Cohen SA, Barnathan ES, et al. Clot lysis in a primate model of peripheral arterial occlusive disease with use of systemic or intraarterial reteplase: addition of abciximab results in improved vessel reperfusion. J Vasc Interv Radiol. 2004;15:169–76.

    Article  PubMed  Google Scholar 

  9. Pancioli AM, Broderick J, Brott T, Tomsick T, Khoury J, Bean J, et al. The combined approach to lysis utilizing eptifibatide and rt-pa in acute ischemic stroke: the clear stroke trial. Stroke. 2008;39:3268–76.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Pancioli A, Adeoye O, Schmit P, Khoury J, Levine S, Tomsick T, et al. Combined approach to lysis utilizing eptifibatide and rt-pa in acute ischemic stroke—enhanced regimen (clear-er) trial. Stroke. 2013;44(9):2381–7.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Di Cera E. Thrombin. Mol Aspects Med. 2008;29:203–54.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Hirano K, Hirano M. Current perspective on the role of the thrombin receptor in cerebral vasospasm after subarachnoid hemorrhage. J Pharmacol Sci. 2010;114:127–33.

    Article  CAS  PubMed  Google Scholar 

  13. Kawai H, Umemura K, Nakashima M. Effect of argatroban on microthrombi formation and brain damage in the rat middle cerebral artery thrombosis model. Jpn J Pharmacol. 1995;69:143–8.

    Article  CAS  PubMed  Google Scholar 

  14. Jang IK, Gold HK, Leinbach RC, Fallon JT, Collen D. In vivo thrombin inhibition enhances and sustains arterial recanalization with recombinant tissue-type plasminogen activator. Circ Res. 1990;67:1552–61.

    Article  CAS  PubMed  Google Scholar 

  15. Lyden P, Pereira B, Chen B, Zhao L, Lamb J, Lei I, et al. Direct thrombin inhibitor argatroban reduces stroke damage in two different models. Stroke. 2014;45(3):896–9.

    Article  CAS  PubMed  Google Scholar 

  16. Morris DC, Zhang L, Zhang ZG, Lu M, Berens KL, Brown PM, et al. Extension of the therapeutic window for recombinant tissue plasminogen activator with argatroban in a rat model of embolic stroke. Stroke. 2001;32:2635–40.

    Article  CAS  PubMed  Google Scholar 

  17. LaMonte MP, Nash ML, Wang DZ, Woolfenden AR, Schultz J, Hursting MJ, et al. Argatroban anticoagulation in patients with acute ischemic stroke (argis-1): a randomized, placebo-controlled safety study. Stroke. 2004;35:1677–82.

    Article  CAS  PubMed  Google Scholar 

  18. Barreto AD, Alexandrov AV, Lyden PD, Lee J, Martin-Schild S, Shen L, et al. The argatroban and rt-PA stroke study: final results of a pilot safety and activity study. Stroke. 2012;43:770–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Barreto A. Randomized controlled trial of argatroban with rt-PA for acute stroke (artss-2). In: ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine (US). 2000- [cited 2013 Oct 16]. Available from: http://clinicaltrials.gov/show/NCT01464788 NLM Identifier: NCT01464788.

    Google Scholar 

  20. Alexandrov AV, Molina CA, Grotta JC, Garami Z, Ford SR, Alvarez-Sabin J, et al. Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med. 2004;351:2170–8.

    Article  CAS  PubMed  Google Scholar 

  21. Daffertshofer M, Gass A, Ringleb P, Sitzer M, Sliwka U, Els T, et al. Transcranial low-frequency ultrasound-mediated thrombolysis in brain ischemia: increased risk of hemorrhage with combined ultrasound and tissue plasminogen activator: results of a phase II clinical trial. Stroke. 2005;36:1441–6.

    Article  PubMed  Google Scholar 

  22. Molina CA, Ribo M, Rubiera M, Montaner J, Santamarina E, Delgado-Mederos R, et al. Microbubble administration accelerates clot lysis during continuous 2-mhz ultrasound monitoring in stroke patients treated with intravenous tissue plasminogen activator. Stroke. 2006;37:425–9.

    Article  CAS  PubMed  Google Scholar 

  23. Molina CA, Barreto AD, Tsivgoulis G, Sierzenski P, Malkoff MD, Rubiera M, et al. Transcranial ultrasound in clinical sonothrombolysis (tucson) trial. Ann Neurol. 2009;66:28–38.

    Article  CAS  PubMed  Google Scholar 

  24. Tsivgoulis G, Eggers J, Ribo M, Perren F, Saqqur M, Rubiera M, et al. Safety and efficacy of ultrasound-enhanced thrombolysis: a comprehensive review and meta-analysis of randomized and nonrandomized studies. Stroke. 2010;41:280–7.

    Article  PubMed  Google Scholar 

  25. Barlinn K, Barreto AD, Sisson A, Liebeskind DS, Schafer ME, Alleman J, et al. Clotbust-hands free: initial safety testing of a novel operator-independent ultrasound device in stroke-free volunteers. Stroke. 2013;44:1641–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Barreto AD, Alexandrov AV, Shen L, Sisson A, Bursaw A, Sahota P, et al. Clotbust—hands free pilot safety study of a novel operator-independent ultrasound device in acute ischemic stroke. Stroke. 2013. doi:10.1161/STROKEAHA.113.002713.

    Article  Google Scholar 

  27. Cerevast Therapeutics I. Phase 3, randomized, placebo-controlled, double-blinded trial of the combined lysis of thrombus with ultrasound and systemic tissue plasminogen activator (rt-PA) for emergent revascularization in acute ischemic stroke (clotbust-er). In: ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine (US). 2000- [cited 2013 Oct 16]. Available from: http://clinicaltrials.gov/show/NCT01098981 NLM Identifier: NCT01098981.

    Google Scholar 

  28. Khatri P, Abruzzo T, Yeatts SD, Nichols C, Broderick JP, Tomsick TA. Good clinical outcome after ischemic stroke with successful revascularization is time-dependent. Neurology. 2009;73:1066–72.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Levy EI, Siddiqui AH, Crumlish A, Snyder KV, Hauck EF, Fiorella DJ, et al. First food and drug administration-approved prospective trial of primary intracranial stenting for acute stroke: Saris (stent-assisted recanalization in acute ischemic stroke). Stroke. 2009;40:3552–6.

    Article  PubMed  Google Scholar 

  30. Broderick JP, Palesch YY, Demchuk AM, Yeatts SD, Khatri P, Hill MD, et al. Endovascular therapy after intravenous t-pa versus t-pa alone for stroke. N Engl J Med. 2013;368:893–903.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Hosomi N, Lucero J, Heo JH, Koziol JA, Copeland BR, del Zoppo GJ. Rapid differential endogenous plasminogen activator expression after acute middle cerebral artery occlusion. Stroke. 2001;32:1341–8.

    Article  CAS  PubMed  Google Scholar 

  32. Matsumoto K, Lo EH, Pierce AR, Halpern EF, Newcomb R. Secondary elevation of extracellular neurotransmitter amino acids in the reperfusion phase following focal cerebral ischemia. J Cereb Blood Flow Metab. 1996;16:114–24.

    Article  CAS  PubMed  Google Scholar 

  33. Traystman RJ, Kirsch JR, Koehler RC. Oxygen radical mechanism of brain injury following ischemia and reperfusion. J Appl Physiol. 1991;71:1185–95.

    CAS  PubMed  Google Scholar 

  34. Aronowski J, Strong R, Grotta J. Reperfusion injury: demonstration of brain damage produced by reperfusion after transient focal ischemia in rats. J Cereb Blood Flow Metab. 1997;17:1048–56.

    Article  CAS  PubMed  Google Scholar 

  35. Zivin JA, deGirolami U, Kochhar A, Lyden P, Mazzarella V, Hemenway CC, et al. A model for quantitative evaluation of embolic stroke therapy. Brain Res. 1987;435:305–9.

    Article  CAS  PubMed  Google Scholar 

  36. Zivin JA, Mazzarella V. Tissue plasminogen activator plus glutamate antagonist improves outcome after embolic stroke. Arch Neurol. 1991;48:1235–8.

    Article  CAS  PubMed  Google Scholar 

  37. Bowes MP, Rothlein R, Fagan SC, Zivin JA. Monoclonal antibodies preventing leukocyte activation reduce experimental neurologic injury and enhance efficacy of thrombolytic therapy. Neurology. 1995;45:815–9.

    Article  CAS  PubMed  Google Scholar 

  38. Zhang RL, Zhang ZG, Chopp M. Increased therapeutic efficacy with rt-PA and anti-CD18 antibody treatment of stroke in the rat. Neurology. 1999;52:273–9.

    Article  CAS  PubMed  Google Scholar 

  39. Tymanski M. Novel approaches to neuroprotection trials in acute ischemic stroke. Stroke. 2013;44:2942–50.

    Article  Google Scholar 

  40. Grotta J. Combination therapy stroke trial: recombinant tissue-type plasminogen activator with/without lubeluzole. Cerebrovasc Dis. 2001;12:258.

    Article  CAS  PubMed  Google Scholar 

  41. Lyden P, Jacoby M, Schim J, Albers G, Mazzeo P, Ashwood T, et al. The clomethiazole acute stroke study in tissue-type plasminogen activator-treated stroke (CLASS-T): final results. Neurology. 2001;57(7):1199–205.

    Article  CAS  PubMed  Google Scholar 

  42. Sacco RL, DeRosa JT, Haley C, Levin B, Ordonneau P, Phillips SJ, et al, for the GAIN Americas Investigators. Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial. JAMA. 2001;285:1719.

    Google Scholar 

  43. Saver JL, Kidwell C, Eckstein M, Starkman S, FAST-MAG Pilot Trial Investigators. Prehospital neuroprotective therapy for acute stroke: results of the Field Administration of Stroke Therapy/Magnesium (FAST-MAG) pilot trial. Stroke. 2004;35(5):e106–8.

    Article  CAS  PubMed  Google Scholar 

  44. Aronowski JA, Strong R, Shrizadi A, Grotta JC. Ethanol plus caffeine (caffeinol) for treatment of ischemic stroke: preclinical experience. Stroke. 2003;34:1246–51.

    Article  CAS  PubMed  Google Scholar 

  45. Piriyawat P, Labiche LA, Burgin WS, Aronowski JA, Grotta JC. A pilot dose-escalation study of caffeine plus ethanol (caffeinol) in acute ischemic stroke. Stroke. 2003;34:1242–5.

    Article  CAS  PubMed  Google Scholar 

  46. Morikawa E, Ginsberg MD, Dietrich WD, Duncan RC, Kraydieh S, Globus MY, et al. The significance of brain temperature in focal cerebral ischemia: histopathological consequences of middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab. 1992;12(3):380–9.

    Article  CAS  PubMed  Google Scholar 

  47. Ridenour TR, Warner DS, Todd MM, McAllister AC. Mild hypothermia reduces infarct size resulting from temporary but not permanent focal ischemia in rats. Stroke. 1992;23(5):733–8.

    Article  CAS  PubMed  Google Scholar 

  48. Zhang RL, Chopp M, Chen H, Garcia JH, Zhang ZG. Postischemic (1 hour) hypothermia significantly reduces ischemic cell damage in rats subjected to 2 hours of middle cerebral artery occlusion. Stroke. 1993;24(8):1235–40.

    Article  CAS  PubMed  Google Scholar 

  49. van der Worp HB, Sena ES, Donnan GA, Howells DW, Macleod MR. Hypothermia in animal models of acute ischaemic stroke: a systematic review and meta-analysis. Brain. 2007;130:3063–74.

    Article  PubMed  Google Scholar 

  50. Kollmar R, Henninger N, Bardutzky J, Schellinger PD, Schabitz WR, Schwab S. Combination therapy of moderate hypothermia and thrombolysis in experimental thromboembolic stroke—an MRI study. Exp Neurol. 2004;190(1):204–12.

    Article  CAS  PubMed  Google Scholar 

  51. Yanamoto H, Nagata I, Nakahara I, Tohnai N, Zhang Z, Kikuchi H. Combination of intraischemic and post-ischemic hypothermia provides potent and persistent neuroprotection against temporary focal ischemia in rats. Stroke. 1999;30(12):2720–6.

    Article  CAS  PubMed  Google Scholar 

  52. Kollmar R, Blank T, Han JL, Georgiadis D, Schwab S. Different degrees of hypothermia after experimental stroke: short- and long-term outcome. Stroke. 2007;38(5):1585–9.

    Article  PubMed  Google Scholar 

  53. Martin-Schild S, Hallevi H, Shaltoni H, Barreto AD, Gonzales NR, Aronowski J, et al. Combined neuroprotective modalities coupled with thrombolysis in acute ischemic stroke: a pilot study of caffeinol and mild hypothermia. J Stroke Cerebrovasc Dis. 2009;18(2):86–96.

    Article  PubMed Central  PubMed  Google Scholar 

  54. Group THCAS. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549–56.

    Article  Google Scholar 

  55. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557–63.

    Article  PubMed  Google Scholar 

  56. Schwab S, Georgiadis D, Berrouschot J, Schellinger PD, Graffagnino C, Mayer SA. Feasibility and safety of moderate hypothermia after massive hemispheric infarction. Stroke. 2001;32(9):2033–5.

    Article  CAS  PubMed  Google Scholar 

  57. Kammersgaard LP, Rasmussen BH, Jorgensen HS, Reith J, Weber U, Olsen TS. Feasibility and safety of inducing modest hypothermia in awake patients with acute stroke through surface cooling: a case-control study: the Copenhagen Stroke Study. Stroke. 2000;31(9):2251–6.

    Article  CAS  PubMed  Google Scholar 

  58. De Georgia MA, Krieger DW, Abou-Chebl A, Devlin TG, Jauss M, Davis SM, et al. Cooling for acute ischemic brain damage (COOL AID): a feasibility trial of endovascular cooling. Neurology. 2004;63(2):312–7.

    Article  PubMed  Google Scholar 

  59. Lyden PD, Allgren RL, Ng K, Akins P, Meyer B, Al-Sanani F, et al. Intravascular cooling in the treatment of stroke (ICTuS): early clinical experience. J Stroke Cerebrovasc Dis. 2005;14(3):107–14.

    Article  PubMed  Google Scholar 

  60. Lyden P, Ernstrom K, Cruz-Flores S, Gomes J, Grotta J, Mullin A, et al. Determinants of effective cooling during endovascular hypothermia. Neurocrit Care. 2012;16:413–20.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, The University of Texas Medical School at Houston, 6431 Fannin, MSB 7.124, Houston, TX, 77030, USA

    Andrew D. Barreto M.D.

  2. Director of Stroke Research and Director Mobile Stroke Unit Consortium, Memorial Hermann Hospital-Texas Medical Center, Houston, TX, USA

    James C. Grotta M.D.

Authors
  1. Andrew D. Barreto M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James C. Grotta M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James C. Grotta M.D. .

Editor information

Editors and Affiliations

  1. Stroke Program, Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California, USA

    Patrick D Lyden

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Barreto, A.D., Grotta, J.C. (2015). Combination of Thrombolytic Therapy with Antithrombotics and Neuroprotectants. In: Lyden, P. (eds) Thrombolytic Therapy for Acute Stroke. Springer, Cham. https://doi.org/10.1007/978-3-319-07575-4_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-07575-4_3

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-07574-7

  • Online ISBN: 978-3-319-07575-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation