Advertisement

Heparin Treatment in Aneurysmal Subarachnoid Hemorrhage: A Review of Human Studies

  • Nicolas K. Khattar
  • Esther Bak
  • Andrew C. White
  • Robert F. JamesEmail author
Chapter
Part of the Acta Neurochirurgica Supplement book series (NEUROCHIRURGICA, volume 127)

Abstract

Aneurysmal subarachnoid hemorrhage (aSAH) remains a significant cause of stroke disability despite gradual reductions in physical morbidity and mortality. Heparin is an effective anti-inflammatory agent and may potentially prevent delayed neurological injury in the days to weeks after the hemorrhage. Various human studies have shown the safety of a continuous infusion of low-dose unfractionated heparin in the setting of subarachnoid hemorrhage as well as its efficacy in minimizing delayed neurological deficits including symptomatic cerebral vasospasm, vasospasm-related infarction, and cognitive dysfunction. Studies have also shown mixed results with low-molecular-weight heparin usage in this patient population. Heparin treatment is not associated with significant hemorrhagic complications; however, vigilance is essential for early detection of heparin-induced thrombocytopenia in order to prevent devastating sequelae. Multicenter randomized controlled trials are necessary for objective characterization of the effects of heparin.

Keywords

Low-dose IV heparin Enoxaparin Subarachnoid hemorrhage 

Notes

Conflict of Interest

RFJ is the study chair for ASTROH, a phase 2 clinical trial evaluating heparin treatment in aneurysmal subarachnoid hemorrhage. We delare that we have no other conflicts of interest with the contents of this manuscript.

Source of Funding: None.

References

  1. 1.
    Al-Khindi T, Macdonald RL, Schweizer TA. Cognitive and functional outcome after aneurysmal subarachnoid hemorrhage. Stroke. 2010;41:e519–36.CrossRefGoogle Scholar
  2. 2.
    Bruder M, Won S-YY, Kashefiolasl S, Wagner M, Brawanski N, Dinc N, Seifert V, Konczalla J. Effect of heparin on secondary brain injury in patients with subarachnoid hemorrhage: an additional ‘H’ therapy in vasospasm treatment. J Neurointerv Surg. 2017;9:659–63.CrossRefGoogle Scholar
  3. 3.
    Crowley MG, Liska MG, Borlongan CV. Stem cell therapy for sequestering neuroinflammation in traumatic brain injury: an update on exosome-targeting to the spleen. J Neurosurg Sci. 2017;61:291–302.PubMedGoogle Scholar
  4. 4.
    Girolami B, Prandoni P, Stefani PM, Tanduo C, Sabbion P, Eichler P, Ramon R, Baggio G, Fabris F, Girolami A. The incidence of heparin-induced thrombocytopenia in hospitalized medical patients treated with subcutaneous unfractionated heparin: a prospective cohort study. Blood. 2003;101:2955–9.CrossRefGoogle Scholar
  5. 5.
    Hacker RI, Ritter G, Nelson C, Knobel D, Gupta R, Hopkins K, Marini CP, Barrera R. Subcutaneous heparin does not increase postoperative complications in neurosurgical patients: an institutional experience. J Crit Care. 2012;27:250–4.CrossRefGoogle Scholar
  6. 6.
    Harbrecht U, Bastians B, Kredteck A, Hanfland P, Klockgether T, Pohl C. Heparin-induced thrombocytopenia in neurologic disease treated with unfractionated heparin. Neurology. 2004;62:657–9.CrossRefGoogle Scholar
  7. 7.
    Hellawell DJ, Taylor R, Pentland B. Persisting symptoms and carers’ views of outcome after subarachnoid haemorrhage. Clin Rehabil. 1999;13:333–40.CrossRefGoogle Scholar
  8. 8.
    James RF, Khattar NK, Aljuboori ZS, Page P, Shao EY, Carter LM, Meyer KS, Daniels MJ, Craycroft J, Gaughen JR Jr, Chaudry MI, Rai SN, Everhart DE, Simard JM. Continuous infusion of low-dose unfractionated heparin after aneurysmal subarachnoid hemorrhage: a preliminary study of cognitive outcomes. J Neurosurg. 2018;11:1–8. https://doi.org/10.317.1/2017.11.JNS17894 [Epub ahead of print].
  9. 9.
    Kreiter KT, Copeland D, Bernardini GL, Bates JE, Peery S, Claassen J, Du YE, Stern Y, Connolly ES, Mayer SA. Predictors of cognitive dysfunction after subarachnoid hemorrhage. Stroke. 2002;33:200–8.CrossRefGoogle Scholar
  10. 10.
    Manoel AL, Turkel-Parrella D, Germans M, Kouzmina E, Almendra Pda S, Marotta T, Spears J, Abrahamson S. Safety of early pharmacological thromboprophylaxis after subarachnoid hemorrhage. Can J Neurol Sci. 2014;41:554–61.CrossRefGoogle Scholar
  11. 11.
    Mavaddat N, Sahakian BJ, Hutchinson PJ, Kirkpatrick PJ. Cognition following subarachnoid hemorrhage from anterior communicating artery aneurysm: relation to timing of surgery. J Neurosurg. 1999;91:402–7.CrossRefGoogle Scholar
  12. 12.
    Parra A, Kreiter KT, Williams S, Sciacca R, Mack WJ, Naidech AM, Commichau CS, Fitzsimmons BF, Janjua N, Mayer SA, Connolly ES Jr. Effect of prior statin use on functional outcome and delayed vasospasm after acute aneurysmal subarachnoid hemorrhage: a matched controlled cohort study. Neurosurgery. 2005;56:476–84; discussion 476–84.CrossRefGoogle Scholar
  13. 13.
    Provencio JJ, Vora N. Subarachnoid hemorrhage and inflammation: bench to bedside and back. Semin Neurol. 2005;25:435–44.CrossRefGoogle Scholar
  14. 14.
    Pyne-Geithman GJ, Caudell DN, Prakash P, Clark JF. Glutathione peroxidase and subarachnoid hemorrhage: implications for the role of oxidative stress in cerebral vasospasm. Neurol Res. 2009;31:195–9.CrossRefGoogle Scholar
  15. 15.
    Siironen J, Juvela S, Varis J, Porras M, Poussa K, Ilveskero S, Hernesniemi J, Lassila R. No effect of enoxaparin on outcome of aneurysmal subarachnoid hemorrhage: a randomized, double-blind, placebo-controlled clinical trial. J Neurosurg. 2003;99:953–9.CrossRefGoogle Scholar
  16. 16.
    Simard JM, Aldrich EF, Schreibman D, James RF, Polifka A, Beaty N. Low-dose intravenous heparin infusion in patients with aneurysmal subarachnoid hemorrhage: a preliminary assessment. J Neurosurg. 2013;119:1611–9.CrossRefGoogle Scholar
  17. 17.
    Simard JM, Schreibman D, Aldrich EF, Stallmeyer B, Le B, James RF, Beaty N. Unfractionated heparin: multitargeted therapy for delayed neurological deficits induced by subarachnoid hemorrhage. Neurocrit Care. 2010;13:439–49.CrossRefGoogle Scholar
  18. 18.
    Simard JM, Tosun C, Ivanova S, Kurland DB, Hong C, Radecki L, Gisriel C, Mehta R, Schreibman D, Gerzanich V. Heparin reduces neuroinflammation and transsynaptic neuronal apoptosis in a model of subarachnoid hemorrhage. Transl Stroke Res. 2012;3:155–65.CrossRefGoogle Scholar
  19. 19.
    Stein SC, Levine JM, Nagpal S, LeRoux PD. Vasospasm as the sole cause of cerebral ischemia: how strong is the evidence? Neurosurg Focus. 2006;21:E2.CrossRefGoogle Scholar
  20. 20.
    Vergouwen MD, Vermeulen M, Coert BA, Stroes ES, Roos YB. Microthrombosis after aneurysmal subarachnoid hemorrhage: an additional explanation for delayed cerebral ischemia. J Cereb Blood Flow Metab. 2008;28:1761–70.CrossRefGoogle Scholar
  21. 21.
    Wessell A, Kole MJ, Badjatia N, Parikh G, Albrecht JS, Schreibman DL, Simard JM. High compliance with scheduled nimodipine is associated with better outcome in aneurysmal subarachnoid hemorrhage patients cotreated with heparin infusion. Front Neurol. 2017;8:268.CrossRefGoogle Scholar
  22. 22.
    Wurm G, Tomancok B, Nussbaumer K, Adelwohrer C, Holl K. Reduction of ischemic sequelae following spontaneous subarachnoid hemorrhage: a double-blind, randomized comparison of enoxaparin versus placebo. Clin Neurol Neurosurg. 2004;106:97–103.CrossRefGoogle Scholar
  23. 23.
    Young E. The anti-inflammatory effects of heparin and related compounds. Thromb Res. 2008;122:743–52.CrossRefGoogle Scholar
  24. 24.
    Zachariah J, Snyder KA, Graffeo CS, Khanal DR, Lanzino G, Wijdicks EF, Rabinstein AA. Risk of ventriculostomy-associated hemorrhage in patients with aneurysmal subarachnoid hemorrhage treated with anticoagulant thromboprophylaxis. Neurocrit Care. 2016;25:224–9.CrossRefGoogle Scholar
  25. 25.
    Zhang ZD, Macdonald RL. Contribution of the remodeling response to cerebral vasospasm. Neurol Res. 2006;28:713–20.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Nicolas K. Khattar
    • 1
  • Esther Bak
    • 1
  • Andrew C. White
    • 2
  • Robert F. James
    • 1
    Email author
  1. 1.Department of Neurological SurgerySchool of Medicine, University of LouisvilleLouisvilleUSA
  2. 2.Department of RadiologySchool of Medicine, University of LouisvilleLouisvilleUSA

Personalised recommendations