Neurocritical Care

, 10:28 | Cite as

Risk of Thromboembolism Following Acute Intracerebral Hemorrhage

  • Joshua N. GoldsteinEmail author
  • Louis E. Fazen
  • Lauren Wendell
  • Yuchiao Chang
  • Natalia S. Rost
  • Ryan Snider
  • Kristin Schwab
  • Rishi Chanderraj
  • Christopher Kabrhel
  • Catherine Kinnecom
  • Emilie FitzMaurice
  • Eric E. Smith
  • Steven M. Greenberg
  • Jonathan Rosand



Intracerebral hemorrhage (ICH) is the most feared complication of oral anticoagulant therapy (OAT). While anticoagulated patients have increased severity of bleeding following ICH, they may also be at increased risk for thromboembolic events (TEs) given that they had been prescribed OAT prior to their ICH. We hypothesized that TEs are relatively common following ICH, and that anticoagulated patients are at higher risk for these complications.


Consecutive patients with primary ICH presenting to a tertiary care hospital from 1994 to 2006 were prospectively characterized and followed. Hospital records were retrospectively reviewed for clinically relevant in-hospital TEs and patients were prospectively followed for 90 day mortality.


For 988 patients of whom 218 (22%) were on OAT at presentation, median hospital length of stay was 7 (IQR 4–13) days and 90-day mortality was 36%. TEs were diagnosed in 71 patients (7.2%) including pulmonary embolism (1.8%), deep venous thrombosis (1.1%), myocardial ischemia (1.6%), and cerebrovascular ischemia (3.0%). Mean time to event was 8.4 ± 7.0 days. Rates of TE were 5% among those with OAT-related ICH and 8% among those with non-OAT ICH (P = 0.2). After multivariable Cox regression, the only independent risk factor for developing a TE was external ventricular drain placement (HR 2.1, 95% CI 1.1–4.1, P = 0.03). TEs had no effect on 90-day mortality (HR 0.7, 95% CI 0.5–1.1, P = 0.1).


The incidence of TEs in an unselected ICH population was 7.2%. Patients with OAT-related ICH were not at increased risk of TEs.


Cerebral hemorrhage Warfarin Venous thrombosis Pulmonary embolism Brain ischemia Myocardial ischemia 



This work was supported by an unrestricted research grant from Novo Nordisk A/S, the Miles and Eleanor Shore 50th Anniversary Fellowship Award, the National Institute of Neurological Disorders and Stroke (NIH 1 K23 NS42695, R01 NS04217), and the Jerome Lyle Rappaport Charitable Foundation.


The sponsors had no role in the design or conduct of the study; data collection, management, analysis, or interpretation; or preparation, review, or approval of the manuscript. Dr. Goldstein had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr. Rosand has received research support from NovoNordisk A/S. Dr. Goldstein has received consulting fees from Novo Nordisk A/S, CSL Behring, and Genentech. The remaining authors report no conflict of interest.


  1. 1.
    Towfighi A, Greenberg SM, Rosand J. Treatment and prevention of primary intracerebral hemorrhage. Semin Neurol. 2005;25:445–52. doi: 10.1055/s-2005-923538.PubMedCrossRefGoogle Scholar
  2. 2.
    Silver FL, Norris JW, Lewis AJ, Hachinski VC. Early mortality following stroke: a prospective review. Stroke. 1984;15:492–6.PubMedGoogle Scholar
  3. 3.
    Lacut K, Bressollette L, Le Gal G, Etienne E, De Tinteniac A, Renault A, et al. Prevention of venous thrombosis in patients with acute intracerebral hemorrhage. Neurology. 2005;65:865–9. doi: 10.1212/01.wnl.0000176073.80532.a2.PubMedCrossRefGoogle Scholar
  4. 4.
    Kelly J, Rudd A, Lewis RR, Coshall C, Moody A, Hunt BJ. Venous thromboembolism after acute ischemic stroke: a prospective study using magnetic resonance direct thrombus imaging. Stroke. 2004;35:2320–5. doi: 10.1161/01.STR.0000140741.13279.4f.PubMedCrossRefGoogle Scholar
  5. 5.
    Adams HP Jr, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke. 2007;38:1655–711. doi:10.1161/STROKEAHA.107.181486 Google Scholar
  6. 6.
    Adams HP Jr. Effective prophylaxis for deep vein thrombosis after stroke: low-dose anticoagulation rather than stockings alone: for. Stroke. 2004;35:2911–2. doi: 10.1161/01.STR.0000147720.27350.09.PubMedCrossRefGoogle Scholar
  7. 7.
    Dennis MS. Effective prophylaxis for deep vein thrombosis after stroke: low-dose anticoagulation rather than stockings alone: against. Stroke. 2004;35:2912–3. doi: 10.1161/01.STR.0000147721.75537.ef.PubMedCrossRefGoogle Scholar
  8. 8.
    Bath PM, Iddenden R, Bath FJ. Low-molecular-weight heparins and heparinoids in acute ischemic stroke: a meta-analysis of randomized controlled trials. Stroke. 2000;31:1770–8.PubMedGoogle Scholar
  9. 9.
    Broderick J, Connolly S, Feldmann E, Hanley D, Kase C, Krieger D, et al. Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group. Stroke. 2007;38:2001–23. doi:10.1161/STROKEAHA.107.183689 Google Scholar
  10. 10.
    Steiner T, Kaste M, Forsting M, Mendelow D, Kwiecinski H, Szikora I, et al. Recommendations for the management of intracranial haemorrhage—Part I: spontaneous intracerebral haemorrhage. The European Stroke Initiative Writing Committee and the Writing Committee for the EUSI Executive Committee. Cerebrovasc Dis. 2006;22:294–316.PubMedGoogle Scholar
  11. 11.
    Rosand J, Eckman MH, Knudsen KA, Singer DE, Greenberg SM. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med. 2004;164:880–4. doi: 10.1001/archinte.164.8.880.PubMedCrossRefGoogle Scholar
  12. 12.
    Flaherty ML, Kissela B, Woo D, Kleindorfer D, Alwell K, Sekar P, et al. The increasing incidence of anticoagulant-associated intracerebral hemorrhage. Neurology. 2007;68:116–21. doi: 10.1212/01.wnl.0000250340.05202.8b.PubMedCrossRefGoogle Scholar
  13. 13.
    Bertram M, Bonsanto M, Hacke W, Schwab S. Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation. J Neurol. 2000;247:209–14. doi: 10.1007/s004150050565.PubMedCrossRefGoogle Scholar
  14. 14.
    Goldstein JN, Thomas SH, Frontiero V, Joseph A, Engel C, Snider R, et al. Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage. Stroke. 2006;37:151–5. doi: 10.1161/01.STR.0000195047.21562.23.PubMedCrossRefGoogle Scholar
  15. 15.
    Brody DL, Aiyagari V, Shackleford AM, Diringer MN. Use of recombinant factor VIIa in patients with warfarin-associated intracranial hemorrhage. Neurocrit Care. 2005;2:263–7. doi: 10.1385/NCC:2:3:263.PubMedCrossRefGoogle Scholar
  16. 16.
    Sjoblom L, Hardemark HG, Lindgren A, Norrving B, Fahlen M, Samuelsson M, et al. Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study. Stroke. 2001;32:2567–74. doi: 10.1161/hs1101.098523.PubMedCrossRefGoogle Scholar
  17. 17.
    Diringer MN, Skolnick BE, Mayer SA, Steiner T, Davis SM, Brun NC, et al. Risk of thromboembolic events in controlled trials of rFVIIa in spontaneous intracerebral hemorrhage. Stroke. 2008;39(3):850–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Flaherty ML, Woo D, Haverbusch M, Moomaw CJ, Sekar P, Sauerbeck L, et al. Potential applicability of recombinant factor VIIa for intracerebral hemorrhage. Stroke. 2005;36:2660–4. doi: 10.1161/01.STR.0000189634.08400.82.PubMedCrossRefGoogle Scholar
  19. 19.
    Greenberg SM. Is “compassionate use” compassionate? rFVIIa for intracerebral hemorrhage. Neurology. 2006;67:934. doi: 10.1212/01.wnl.0000239801.90927.80.PubMedCrossRefGoogle Scholar
  20. 20.
    Sugg RM, Gonzales NR, Matherne DE, Ribo M, Shaltoni HM, Baraniuk S, et al. Myocardial injury in patients with intracerebral hemorrhage treated with recombinant factor VIIa. Neurology. 2006;67:1053. doi:10.1212/01.wnl.0000239154.51331.c4 Google Scholar
  21. 21.
    O’Connell KA, Wood JJ, Wise RP, Lozier JN, Braun MM. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA. 2006;295:293–8. doi: 10.1001/jama.295.3.293.PubMedCrossRefGoogle Scholar
  22. 22.
    O’Donnell HC, Rosand J, Knudsen KA, Furie KL, Segal AZ, Chiu RI, et al. Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage. N Engl J Med. 2000;342:240–5. doi: 10.1056/NEJM200001273420403.PubMedCrossRefGoogle Scholar
  23. 23.
    Flibotte JJ, Hagan N, O’Donnell J, Greenberg SM, Rosand J. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology. 2004;63:1059–64.PubMedGoogle Scholar
  24. 24.
    Kopelnik A, Zaroff JG. Neurocardiogenic injury in neurovascular disorders. Crit Care Clin. 2006;22:733–52, abstract ix–x. doi:10.1016/j.ccc.2006.06.002
  25. 25.
    Hemphill JC III, Bonovich DC, Besmertis L, Manley GT, Johnston SC. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke 2001;32:891–7.Google Scholar
  26. 26.
    Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2005;352:777–85. doi: 10.1056/NEJMoa042991.PubMedCrossRefGoogle Scholar
  27. 27.
    Mayer SA, Brun NC, Broderick J, Davis SM, Diringer MN, Skolnick BE, et al. Recombinant activated factor VII for acute intracerebral hemorrhage: US phase IIA trial. Neurocrit Care. 2006;4:206–14. doi: 10.1385/NCC:4:3:206.PubMedCrossRefGoogle Scholar
  28. 28.
    Lyden PD, Shuaib A, Lees KR, Davalos A, Davis SM, Diener HC, et al. Safety and tolerability of NXY–059 for acute intracerebral hemorrhage: the CHANT Trial. Stroke. 2007;38:2262–9. doi: 10.1161/STROKEAHA.106.472746.PubMedCrossRefGoogle Scholar
  29. 29.
    Nadeau JO, Phillips S, Shi HS, Kapral MK, Gladstone DJ, Silver FL, et al. Intracerebral hemorrhage: outcomes and eligibility for factor VIIa treatment in a National Stroke Registry. Cerebrovasc Dis. 2006;22:271–5. doi: 10.1159/000094015.PubMedCrossRefGoogle Scholar
  30. 30.
    Reynolds MW, Shibata A, Zhao S, Jones N, Fahrbach K, Goodnough LT. Impact of clinical trial design and execution-related factors on incidence of thromboembolic events in cancer patients: a systematic review and meta-analysis. Curr Med Res Opin. 2008;24(2):497–505.PubMedCrossRefGoogle Scholar
  31. 31.
    Kelly J, Rudd A, Lewis R, Hunt BJ. Venous thromboembolism after acute stroke. Stroke. 2001;32:262–7.PubMedGoogle Scholar
  32. 32.
    Boeer A, Voth E, Henze T, Prange HW. Early heparin therapy in patients with spontaneous intracerebral haemorrhage. J Neurol Neurosurg Psychiatry. 1991;54:466–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Dickmann U, Voth E, Schicha H, Henze T, Prange H, Emrich D. Heparin therapy, deep-vein thrombosis and pulmonary embolism after intracerebral hemorrhage. Klin Wochenschr. 1988;66:1182–3. doi: 10.1007/BF01727666.PubMedCrossRefGoogle Scholar
  34. 34.
    Khechinashvili G, Asplund K. Electrocardiographic changes in patients with acute stroke: a systematic review. Cerebrovasc Dis. 2002;14:67–76. doi: 10.1159/000064733.PubMedCrossRefGoogle Scholar
  35. 35.
    Maramattom BV, Manno EM, Fulgham JR, Jaffe AS, Wijdicks EF. Clinical importance of cardiac troponin release and cardiac abnormalities in patients with supratentorial cerebral hemorrhages. Mayo Clin Proc. 2006;81:192–6.PubMedCrossRefGoogle Scholar
  36. 36.
    Hays A, Diringer MN. Elevated troponin levels are associated with higher mortality following intracerebral hemorrhage. Neurology. 2006;66:1330–4. doi: 10.1212/01.wnl.0000210523.22944.9b.PubMedCrossRefGoogle Scholar
  37. 37.
    Jensen JK, Kristensen SR, Bak S, Atar D, Hoilund-Carlsen PF, Mickley H. Frequency and significance of troponin T elevation in acute ischemic stroke. Am J Cardiol. 2007;99:108–12. doi: 10.1016/j.amjcard.2006.07.071.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2008

Authors and Affiliations

  • Joshua N. Goldstein
    • 1
    Email author
  • Louis E. Fazen
    • 2
    • 3
  • Lauren Wendell
    • 2
  • Yuchiao Chang
    • 4
  • Natalia S. Rost
    • 2
    • 3
  • Ryan Snider
    • 2
    • 3
  • Kristin Schwab
    • 2
  • Rishi Chanderraj
    • 2
  • Christopher Kabrhel
    • 1
  • Catherine Kinnecom
    • 2
  • Emilie FitzMaurice
    • 2
  • Eric E. Smith
    • 2
  • Steven M. Greenberg
    • 2
  • Jonathan Rosand
    • 2
    • 3
  1. 1.Department of Emergency MedicineMassachusetts General HospitalBostonUSA
  2. 2.Department of NeurologyMassachusetts General HospitalBostonUSA
  3. 3.The Center for Human Genetic ResearchMassachusetts General HospitalBostonUSA
  4. 4.Department of MedicineMassachusetts General HospitalBostonUSA

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