Advertisement

Journal of Thrombosis and Thrombolysis

, Volume 49, Issue 1, pp 67–74 | Cite as

ADAMTS13 activity is associated with early neurological improvement in acute ischemic stroke patients treated with intravenous thrombolysis

  • Anne-Sophie Putzer
  • Hans Worthmann
  • Gerrit M. Grosse
  • Friedrich Goetz
  • Jens Martens-Lobenhoffer
  • Meike Dirks
  • Jan T. Kielstein
  • Ralf Lichtinghagen
  • Ulrich Budde
  • Stefanie M. Bode-Böger
  • Karin Weissenborn
  • Ramona SchuppnerEmail author
Article

Abstract

Although intravenous thrombolysis (IVT) with recombinant tissue-plasminogen-activator represents a highly effective treatment in acute ischemic stroke patients, not every patient benefits. We hypothesized that pretreatment levels of mediators of hemostasis (VWF and ADAMTS13) and dimethylarginines (ADMA and SDMA) are associated with early neurological improvement and outcome after IVT in ischemic stroke. Moreover we aimed to investigate the link between ADAMTS13 and markers of inflammation (CRP, IL-6, MMP-9 and MCP-1). In 43 patients with acute ischemic stroke treated with IVT blood samples for determination of the different markers were strictly taken before treatment, as well as at 24 h, 3, 7 and 90 days after symptom onset. Early neurological improvement was assessed using the shift between National Institutes of Health Stroke Scale (NIHSS) at baseline and at 24 h. Outcome at 90 days was assessed using the modified Rankin Scale. The lowest quartile of ADAMTS13 activity was independently associated with less improvement in NIHSS (baseline-24 h) (OR 1.298, p = 0.050). No independent association of ADMA or SDMA levels at baseline with outcome could be shown. Furthermore, IL-6, MCP-1 and CRP levels at 90 days significantly differed between patients with low and high ADAMTS13 activity. Thus, ADAMTS13 might indicate or even influence efficacy of IVT.

Keywords

ADAMTS13 VWF Intravenous thrombolysis Stroke ADMA SDMA 

Notes

Author contributions

Conceptualization: HW, KW and RS; methodology RL; validation HW, FG and RS; formal analysis A-SP, HW, GMG and RS; investigation: A-SP, HW, GMG, FG, MD, JTK, JM-L, SMB-B, UB and RS; data curation: A-SP, HW and RS; writing—original draft preparation, A-SP, HW and RS; writing—review and editing, GMG, FG, JM-L, MD, SMB-B and KW visualization, A-SP and RS; supervision, HW, GMG, KW and RS.

Compliance with ethical standards

Conflict of interests

The authors have no disclosures.

References

  1. 1.
    IST-3 Collaborative Group, Sandercock P, Wardlaw JM, Lindley RI, Dennis M, Cohen G, Murray G, Innes K, Venables G, Czlonkowska A, Kobayashi A, Ricci S, Murray V, Berge E, Slot KB, Hankey GJ, Correia M, Peeters A, Matz K, Lyrer P, Gubitz G, Phillips SJ, Arauz A (2012) The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet 379:2352–2363CrossRefGoogle Scholar
  2. 2.
    Rha JH, Saver JL (2007) The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke 38:967–973CrossRefGoogle Scholar
  3. 3.
    Schuppner R, Dirks M, Grosse GM, Bockmann M, Goetz F, Pasedag T, Bode-Boger SM, Martens-Lobenhoffer J, Budde U, Lanfermann H, Lichtinghagen R, Weissenborn K, Worthmann H (2018) ADAMTS-13 activity predicts outcome in acute ischaemic stroke patients undergoing endovascular treatment. Thromb Haemost 118:758–767PubMedGoogle Scholar
  4. 4.
    Bustamante A, Ning M, Garcia-Berrocoso T, Penalba A, Boada C, Simats A, Pagola J, Ribo M, Molina C, Lo E, Montaner J (2018) Usefulness of ADAMTS13 to predict response to recanalization therapies in acute ischemic stroke. Neurology 90:e995–e1004CrossRefGoogle Scholar
  5. 5.
    Chen J, Chung DW (2018) Inflammation, von Willebrand factor, and ADAMTS13. Blood 132:141–147CrossRefGoogle Scholar
  6. 6.
    Bernardo A, Ball C, Nolasco L, Moake JF, Dong JF (2004) Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow. Blood 104:100–106CrossRefGoogle Scholar
  7. 7.
    Chauhan AK, Kisucka J, Brill A, Walsh MT, Scheiflinger F, Wagner DD (2008) ADAMTS13: a new link between thrombosis and inflammation. J Exp Med 205:2065–2074CrossRefGoogle Scholar
  8. 8.
    Castellanos M, Leira R, Serena J, Pumar JM, Lizasoain I, Castillo J, Davalos A (2003) Plasma metalloproteinase-9 concentration predicts hemorrhagic transformation in acute ischemic stroke. Stroke 34:40–46CrossRefGoogle Scholar
  9. 9.
    Worthmann H, Tryc AB, Goldbecker A, Ma YT, Tountopoulou A, Hahn A, Dengler R, Lichtinghagen R, Weissenborn K (2010) The temporal profile of inflammatory markers and mediators in blood after acute ischemic stroke differs depending on stroke outcome. Cerebrovasc Dis 30:85–92CrossRefGoogle Scholar
  10. 10.
    del Zoppo G, Ginis I, Hallenbeck JM, Iadecola C, Wang X, Feuerstein GZ (2000) Inflammation and stroke: putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia. Brain Pathol 10:95–112CrossRefGoogle Scholar
  11. 11.
    Stoll G, Kleinschnitz C, Nieswandt B (2010) Combating innate inflammation: a new paradigm for acute treatment of stroke? Ann N Y Acad Sci 1207:149–154CrossRefGoogle Scholar
  12. 12.
    Chen S, Li N, Deb-Chatterji M, Dong Q, Kielstein JT, Weissenborn K, Worthmann H (2012) Asymmetric dimethyarginine as marker and mediator in ischemic stroke. Int J Mol Sci 13:15983–16004CrossRefGoogle Scholar
  13. 13.
    Worthmann H, Chen S, Martens-Lobenhoffer J, Li N, Deb M, Tryc AB, Goldbecker A, Dong Q, Kielstein JT, Bode-Boger SM, Weissenborn K (2011) High plasma dimethylarginine levels are associated with adverse clinical outcome after stroke. J Atheroscler Thromb 18:753–761CrossRefGoogle Scholar
  14. 14.
    Schulze F, Carter AM, Schwedhelm E, Ajjan R, Maas R, von Holten RA, Atzler D, Grant PJ, Boger RH (2010) Symmetric dimethylarginine predicts all-cause mortality following ischemic stroke. Atherosclerosis 208:518–523CrossRefGoogle Scholar
  15. 15.
    Iglesias-Rey R, Rodriguez-Yanez M, Rodriguez-Castro E, Pumar JM, Arias S, Santamaria M, Lopez-Dequidt I, Hervella P, Correa-Paz C, Sobrino T, Vivien D, Campos F, Castellanos M, Castillo J (2018) Worse outcome in stroke patients treated with rt-PA without early reperfusion: associated factors. Transl Stroke Res 9:347–355CrossRefGoogle Scholar
  16. 16.
    Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE 3rd (1993) Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24:35–41CrossRefGoogle Scholar
  17. 17.
    Fiorelli M, Bastianello S, von Kummer R, del Zoppo GJ, Larrue V, Lesaffre E, Ringleb AP, Lorenzano S, Manelfe C, Bozzao L (1999) Hemorrhagic transformation within 36 hours of a cerebral infarct: relationships with early clinical deterioration and 3-month outcome in the European Cooperative Acute Stroke Study I (ECASS I) cohort. Stroke 30:2280–2284CrossRefGoogle Scholar
  18. 18.
    van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J (1988) Interobserver agreement for the assessment of handicap in stroke patients. Stroke 19:604–607CrossRefGoogle Scholar
  19. 19.
    Martens-Lobenhoffer J, Bode-Boger SM (2012) Quantification of l-arginine, asymmetric dimethylarginine and symmetric dimethylarginine in human plasma: a step improvement in precision by stable isotope dilution mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 904:140–143CrossRefGoogle Scholar
  20. 20.
    Miyata T, Kokame K, Banno F (2005) Measurement of ADAMTS13 activity and inhibitors. Curr Opin Hematol 12:384–389CrossRefGoogle Scholar
  21. 21.
    Cejka J (1982) Enzyme immunoassay for factor VIII-related antigen. Clin Chem 28:1356–1358PubMedGoogle Scholar
  22. 22.
    Sonneveld MA, Kavousi M, Ikram MA, Hofman A, Rueda Ochoa OL, Turecek PL, Franco OH, Leebeek FW, de Maat MP (2016) Low ADAMTS-13 activity and the risk of coronary heart disease: a prospective cohort study—the Rotterdam Study. J Thromb Haemost 14:2114–2120CrossRefGoogle Scholar
  23. 23.
    Denorme F, Langhauser F, Desender L, Vandenbulcke A, Rottensteiner H, Plaimauer B, Francois O, Andersson T, Deckmyn H, Scheiflinger F, Kleinschnitz C, Vanhoorelbeke K, De Meyer SF (2016) ADAMTS13-mediated thrombolysis of t-PA-resistant occlusions in ischemic stroke in mice. Blood 127:2337–2345CrossRefGoogle Scholar
  24. 24.
    Fan M, Xu H, Wang L, Luo H, Zhu X, Cai P, Wei L, Lu L, Cao Y, Ye R, Fan W, Zhao BQ (2016) Tissue plasminogen activator neurotoxicity is neutralized by recombinant ADAMTS 13. Sci Rep 6:25971CrossRefGoogle Scholar
  25. 25.
    Wang L, Fan W, Cai P, Fan M, Zhu X, Dai Y, Sun C, Cheng Y, Zheng P, Zhao BQ (2013) Recombinant ADAMTS13 reduces tissue plasminogen activator-induced hemorrhage after stroke in mice. Ann Neurol 73:189–198CrossRefGoogle Scholar
  26. 26.
    Shah N, Rutherford C, Matevosyan K, Shen YM, Sarode R (2013) Role of ADAMTS13 in the management of thrombotic microangiopathies including thrombotic thrombocytopenic purpura (TTP). Br J Haematol 163:514–519CrossRefGoogle Scholar
  27. 27.
    Worthmann H, Martens-Lobenhoffer J, Joumaah M, Li N, Lichtinghagen R, Hecker H, Kielstein JT, Ehrenreich H, Bode-Boger SM, Weissenborn K (2013) Asymmetric dimethylarginine in response to recombinant tissue-type plasminogen activator and erythropoietin in acute stroke. Stroke 44:2128–2133CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Anne-Sophie Putzer
    • 1
  • Hans Worthmann
    • 1
  • Gerrit M. Grosse
    • 1
  • Friedrich Goetz
    • 2
  • Jens Martens-Lobenhoffer
    • 3
  • Meike Dirks
    • 1
  • Jan T. Kielstein
    • 4
  • Ralf Lichtinghagen
    • 5
  • Ulrich Budde
    • 6
  • Stefanie M. Bode-Böger
    • 3
  • Karin Weissenborn
    • 1
  • Ramona Schuppner
    • 1
    Email author
  1. 1.Department of NeurologyHannover Medical SchoolHannoverGermany
  2. 2.Institute of Diagnostic and Interventional NeuroradiologyHannover Medical SchoolHannoverGermany
  3. 3.Department of Clinical PharmacologyOtto-Guericke-University of Magdeburg, University HospitalMagdeburgGermany
  4. 4.Medical Clinic VAcademic Teaching Hospital BraunschweigBrunswickGermany
  5. 5.Department of Clinical ChemistryHannover Medical SchoolHannoverGermany
  6. 6.Medilys LaboratoryAsklepios Klinik AltonaHamburgGermany

Personalised recommendations