Warfarin-induced intracerebral hemorrhage is a devastating complication of warfarin therapy with high mortality. It accounts for 12-24% of all intracerebral hemorrhages. Immediate management involves reversing the coagulopathy through administering vitamin K and prothrombin complex concentrates to rapidly lower the INR. For select patients, surgical evacuation may be considered after normalization of coagulation. While restarting anticoagulation is important for certain patients, it is generally done 7-14 days after the hemorrhage once the INR has stabilized.

1. Warfarin-induced
Intracerebral Hemorrhage
Ade Wijaya, MD – January 2018

2. Outline:
• Introduction
• Epidemiology
• Pathogenesis
• Clinical Presentation
• Poor prognostic factors
• Management
- Immediate management and surgery
- Reversing the coagulant defect (stop warfarin, Vit K, FFP, PCC, Factor VII A
concentrate)
- Restarting anticoagulation(s)
• Summary

3. Introduction
• Anticoagulation including warfarin is used to prevent stroke In
patients with atrial fibrillation.
• Longterm use in elderly patients associated with increased risk of
warfarin-induced intracerebral hemorrhage (ICH).
• Mortality rate is remain as high as 50-69 % over time.
Aguilar, M. I., Hart, R. G., Kase, C. S., Freeman, W. D., Hoeben, B. J., García, R. C., ... & Steiner, T. (2007, January). Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion. In Mayo Clinic
Proceedings(Vol. 82, No. 1, pp. 82-92). Elsevier.
Appelboam, R., & Thomas, E. O. (2009). Warfarin and intracranial haemorrhage. Blood reviews, 23(1), 1-9.

4. Epidemiology
• 12-24 % of all ICH.
• 8000 to 10,000 cases are estimated to occur annually in the US.
• 8–10 times more frequently than in non-anticoagulated patients.
• Anticoagulation with warfarin increases the risk of ICH 2 to 5 times,
directly related to the intensity of anticoagulation
• The mean age of patients with warfarin-associated ICH is in the 70s
Aguilar, M. I., Hart, R. G., Kase, C. S., Freeman, W. D., Hoeben, B. J., García, R. C., ... & Steiner, T. (2007, January). Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion. In Mayo Clinic
Proceedings(Vol. 82, No. 1, pp. 82-92). Elsevier.
Appelboam, R., & Thomas, E. O. (2009). Warfarin and intracranial haemorrhage. Blood reviews, 23(1), 1-9.

5. Pathogenesis
• Hematoma expansion due to ultra early rebleeding
• Warfarin prolong the time frame over which expansion occurs
• Inflammation, in addition to ischaemia, is also thought to play a role
in a worsened outcome
Yasaka M, Minematsu K, Naritomi H et al. Predisposing factors for enlargement of intracerebral hemorrhage in patients treated with warfarin. Thromb Haemost 2003;89:278–83.
Mayer SA, Lignelli A, Fink ME et al. Perilesional blood flow and edema formation in acute intracerebral hemorrhage: a SPECT study. Stroke 1998;29:1791–8.
Wagner KR, Xi G, Hua Y et al. Lobar intracerebral hemorrhage model in pigs: rapid edema development in perihematomal white matter. Stroke 1996;27:490–7.
Xi G, Wagner KR, Keep RF et al. Role of blood clot formation on early edema development after experimental intracerebral hemorrhage. Stroke 1998;29:2580–6.

6. Clinical Presentation
• Focal neurologic signs
• Headache
• Nausea and vomiting
• Obtundation
• Elevated blood pressure
Aguilar, M. I., Hart, R. G., Kase, C. S., Freeman, W. D., Hoeben, B. J., García, R. C., ... & Steiner, T. (2007, January). Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion. In Mayo Clinic
Proceedings(Vol. 82, No. 1, pp. 82-92). Elsevier.

7. Poor Prognostic Factors
• INRs > 3.0 at presentation
• Large hematoma volume (>50 mL)
• Intraventricular extension
• Shift of midline structures
Neau, JP, Couderq, C, Ingrand, P, Blanchon, P, Gil, R, and VGP Study Group. Intracranial hemorrhage and oral anticoagulant treatment. Cerebrovasc Dis. 2001; 11: 195–200
Sjoblom, L, Hardemark, HG, Lindgren, A et al. Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study. Stroke. 2001;32: 2567–2574
Berwaerts, J, Robb, OJ, Jeffers, TA, and Webster, J. Intracerebral haemorrhages and oral anticoagulation in the north of Scotland. Scott Med J. 2000; 45: 101–104
Eckman, MH, Rosand, J, Knudsen, KA, Singer, DE, and Greenberg, SM. Can patients be anticoagulated after intracerebral hemorrhage? a decision analysis. (Epub 2003 Jun 12.)Stroke.2003 Jul; 34: 1710–1716

8. Management
• Immediate management
• REVERSING THE COAGULATION DEFECT
• Surgery
• Restarting the anticoagulant(s).
Appelboam, R., & Thomas, E. O. (2009). Warfarin and intracranial haemorrhage. Blood reviews, 23(1), 1-9.
Aguilar, M. I., Hart, R. G., Kase, C. S., Freeman, W. D., Hoeben, B. J., García, R. C., ... & Steiner, T. (2007, January). Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion. In Mayo Clinic
Proceedings(Vol. 82, No. 1, pp. 82-92). Elsevier.

9. Immediate Management & Surgery
• Time is Brain
• Standard supportive management
• Surgical treatment after reversing anticoagulation may be appropriate
in select patients, especially if the coagulopathy can be rapidly
corrected
Butler AC, Tait RC. Management of oral anticoagulant induced intracranial haemorrhage. Blood Rev 1998;12: 35–44.
Bertram, M, Bonsanto, M, Hacke, W, and Schwab, S. Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation. J Neurol. 2000;247: 209–214
Mendelow, AD, Gregson, BA, Fernandes, HM..., and STICH Investigators. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical
Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet. 2005; 365: 387–397

10. REVERSING THE COAGULATION DEFECT
Vitamin K Fresh frozen plasma
Prothrombin complex concentrate Factor VIIa concentrate
Discontinuing
Warfarin Therapy

11. Vitamin K
• 6-24 hours to correc INR
• A dose of 5 to 10 mg may be repeated every 12 hours, up to a total
dose of 25 mg
• The infusion rate is 1 mg/min, and it can be diluted in dextrose 5% in
water or dextrose 5% in normal saline.
• Slow rate to avoid anaphylactic reaction.
• Subcutaneous administration may be safer, but the effect is even
slower and less reliable.
Appelboam, R., & Thomas, E. O. (2009). Warfarin and intracranial haemorrhage. Blood reviews, 23(1), 1-9.
Aguilar, M. I., Hart, R. G., Kase, C. S., Freeman, W. D., Hoeben, B. J., García, R. C., ... & Steiner, T. (2007, January). Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion. In Mayo Clinic
Proceedings(Vol. 82, No. 1, pp. 82-92). Elsevier.

12. Fresh Frozen Plasma
• It acts more quickly than vitamin K, though it has a shorter half-life
• At the recommended doses of up to 40 ml/kg
• 2-4 L to normalize INR
• Be careful of volume overload especially in elderly patients
• FFP carries risks associated with transfusion of any blood product,
including allergy, blood-borne infection, and transfusion related acute
lung injury.
Makris M, Watson HG. The management of coumarininduced over anticoagulation. Br J Haematol 2001;114:271–80.
The European stroke initiative writing Committee and the Writing Committee for the EUSI Executive Committee. Recommendations for the management of intracranial haemorrhage. Part 1. Spontaneous Intracerebral
haemorrhage. Cerebrovasc Dis 2006;22:294–316.
Goldstein JN, Thomas SH, Frontiero V et al. Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage. Stroke 2006;37:151–5.
Aguilar, M. I., Hart, R. G., Kase, C. S., Freeman, W. D., Hoeben, B. J., García, R. C., ... & Steiner, T. (2007, January). Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion. In Mayo Clinic
Proceedings(Vol. 82, No. 1, pp. 82-92). Elsevier.

13. PROTHROMBIN COMPLEX CONCENTRATES
• Also known as factor IX concentrate
• Contain a varying combination of prothrombin (factor II), coagulation
factors VII, IX and X, protein C, protein S, and protein Z
• formulated in a concentrated form and do not require compatibility
testing before use
• Normalize INR more rapidly than FFP
• Thrombotic risk
Appelboam, R., & Thomas, E. O. (2009). Warfarin and intracranial haemorrhage. Blood reviews, 23(1), 1-9.
Aguilar, M. I., Hart, R. G., Kase, C. S., Freeman, W. D., Hoeben, B. J., García, R. C., ... & Steiner, T. (2007, January). Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion. In Mayo Clinic
Proceedings(Vol. 82, No. 1, pp. 82-92). Elsevier.

14. Factor VIIa concentrate
• A procoagulant agent
• Doses of 10 to 50 μg/kg
• Side effect: thrombosis
Appelboam, R., & Thomas, E. O. (2009). Warfarin and intracranial haemorrhage. Blood reviews, 23(1), 1-9.
Aguilar, M. I., Hart, R. G., Kase, C. S., Freeman, W. D., Hoeben, B. J., García, R. C., ... & Steiner, T. (2007, January). Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion. In Mayo Clinic
Proceedings(Vol. 82, No. 1, pp. 82-92). Elsevier.

16. Restarting the Anticoagulation
• Valvular heart disease
• Secondary prevention of stroke with AF
• If the INR is corrected to normal using PCCs, it may be sensible to
begin treatment with low-dose subcutaneous heparin or low-dose
low-molecular-weight heparin 48 hours after ICH onset.
• For patients who will resume anticoagulation, it appears that warfarin
therapy can be safely restarted 7 to 14 days after ICH.
Appelboam, R., & Thomas, E. O. (2009). Warfarin and intracranial haemorrhage. Blood reviews, 23(1), 1-9.
Aguilar, M. I., Hart, R. G., Kase, C. S., Freeman, W. D., Hoeben, B. J., García, R. C., ... & Steiner, T. (2007, January). Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion. In Mayo Clinic
Proceedings(Vol. 82, No. 1, pp. 82-92). Elsevier.

17. Summary
• Warfarin-induced intracranial hemorrhage is a devastating condition
with poor outcome
• Early and aggressive INR reversal is crucial in improving outcome
• Vitamin K 5–10 mg i.v. Plus prothrombin complex concentrate is
recommended

18. THANK YOU