Skip to main content Accessibility help
  • Get access
    Check if you have access via personal or institutional login
  • Cited by 1
  • Print publication year: 2009
  • Online publication date: May 2010

Chapter 21 - Hemostatic therapy for intracerebral hemorrhage


This chapter reviews the evidence that blood is readily identifiable on magnetic resonance imaging (MRI). It describes how the use of multiple sequences provides additional information regarding the age of blood products. MRI signal changes on gradient recalled echo (GRE), T1- and T2-weighted images can be used to estimate the age of intracranial blood. MRI is the initial diagnostic procedure of choice for investigation of underlying structural causes of secondary intracerebral hemorrhage (ICH), including vascular malformations and neoplasms. It is generally recognized that MRI is superior to computed tomography (CT) in the evaluation of subarachnoid space diseases of an inflammatory or neoplastic origin. The existence and nature of the penumbra in ICH is arguably the most pressing outstanding information required by clinicians to make rational management decisions in ICH patients. MRI is a valuable tool for investigating the pathophysiology of acute and chronic ICH.

Related content

Powered by UNSILO


1. Hoffman M, Monroe DM. A cell-based model of haemostasis. Thromb Haemost 2001; 85: 958–965.
2. Hoffman M. A cell-based model of coagulation and the role of factor VIIa. Blood Rev 2003; 17(1): S1–5.
3. Rizoli SB, Chughtai T. The emerging role of recombinant activated Factor VII (rFVIIa) in the treatment of blunt traumatic haemorrhage. Expert Opin Biol Ther 2006; 6(1): 73–81.
4. Martinowitz U, Michaelson M. Guidelines for the use of recombinant activated factor VII (rFVIIa) in uncontrolled bleeding: a report by the Israeli Multidisciplinary rFVIIa Task Force. J Thromb Haemost 2005; 3: 640–648.
5. Briede JJ, Heemskerk JW, van't Veer C, Hemker HC, Lindhout T. Contribution of platelet-derived factor Va to thrombin generation on immobilized collagen- and fibrinogen-adherent platelets. Thromb Haemost 2001; 85: 509–513.
6. Drake TA, Morrissey JH, Edgington TS. Selective cellular expression of tissue factor in human tissues: implications for disorders of hemostasis and thrombosis. Am J Pathol 1989; 134: 1087–1097.
7. Fleck RA, Rao LV, Rapaport SI, Varki N. Localization of human tissue factor antigen by immunostaining with monospecific, polyclonal anti-human tissue factor antibody. Thromb Res 1990; 57: 765–781.
8. del Zoppo GJ, Yu JQ, Copeland BR, et al. Tissue factor localization in non-human primate cerebral tissue. Thromb Haemost 1992; 68: 642–647.
9. Antovic J, Bakic M, Zivkovic M, Ilic Z, Blomback M. Blood coagulation and fibrinolysis in acute ischemic and hemorrhagic (intracerebral and subarachnoid hemorrhage) stroke: does decreased plasmin inhibitor indicate increased fibrinolysis in subarachnoid hemorrhage compared to other types of stroke? Scand J Clin Lab Invest 2002; 62: 195–200.
10. Fujii Y, Takeuchi S, Harada A, et al. Hemostatic activation in spontaneous intracerebral hemorrhage. Stroke 2001; 32: 883–890.
11. Takahashi H, Urano T, Nagai N, Takada Y, Takada A. Progressive expansion of hypertensive intracerebral hemorrhage by coagulopathy. Am J Hematol 1998; 59(2): 110–114.
12. Saloheimo P, Juvela S, Riutta A, Pyhtinen J, Hillbom M. Thromboxane and prostacyclin biosynthesis in patients with acute spontaneous intracerebral hemorrhage. Thromb Res 2005; 115: 367–373.
13. FitzGerald GA, Pedersen AK, Patrono C. Analysis of prostacyclin and thromboxane biosynthesis in cardiovascular disease. Circulation 1983; 67: 1174–1177.
14. Svensson J, Hamberg M, Samuelsson B. On the formation and effects of thromboxane A2 in human platelets. Acta Physiol Scand 1976; 98: 285–294.
15. Ellis EF, Oelz O, Roberts LJ II, et al. Coronary arterial smooth muscle contraction by a substance released from platelets: evidence that it is thromboxane A2. Science 1976; 193: 1135–1137.
16. Bunting S, Gryglewski R, Moncada S, Vane JR. Arterial walls generate from prostaglandin endoperoxides a substance (prostaglandin X) which relaxes strips of mesenteric and celiac arteries and inhibits platelet aggregation. Prostaglandins 1976; 12: 897–913.
17. Hammarström S, Falardeau P. Resolution of prostaglandin endoperoxide synthase and thromboxane synthase of human platelets. Proc Natl Acad Sci U S A 1977; 74: 3691–3695.
18. Toyoda K, Okada Y, Minematsu K, et al. Antiplatelet therapy contributes to acute deterioration of intracerebral hemorrhage. Neurology 2005; 65: 1000–1004.
19. Foerch C, Sitzer M, Steinmetz H, Neumann-Haefelin T. Pretreatment with anti-platelet agents is not independently associated with unfavorable outcome in intracerebral hemorrhage. Stroke 2006; 37: 2165–2167.
20. Naidech AM, Bassin SL, Bernstein RA, et al. Reduced platelet activity is more common than reported anti-platelet medication use in patients with intracerebral hemorrhage. Neuroint Care 2009; Apr 21.
21. Naidech AM, Bernstein RA, Levasseur K, et al. Platelet activity and outcome after intracerebral hemorrhage. Ann Neurol 2009; 65(3): 352–356.
22. Lordkipanidze M, Pharand C, Schampaert E, et al. A comparison of six major platelet function tests to determine the prevalence of aspirin resistance in patients with stable coronary artery disease. Eur Heart J 2007; 28: 1702–1708.
23. Mulley GP, Heptinstall S, Taylor PM, Mitchell JRA. ADP-induced platelet release reaction in acute stroke. Thromb Haemost 1983; 50(2): 524–526.
24. Serebruany VL, Gurbel PA, Shustov AR, et al. Depressed platelet status in an elderly patient with hemorragic stroke after thrombolysis for acute myocardial infarction. Stroke 1998; 29: 235–238.
25. Ziai WC, Torbey MT, Kickler T, Wityk RJ. Platelet count and function in spontaneous intracerebral hemorrhage. J Stroke Cerebrovasc Dis 2003; 12(4): 201–206.
26. Liu L, Lin Z, Shen Z, et al. Platelet hyperfunction exists in both acute non-hemorrhagic and hemorrhagic stroke. Thromb Res 1994; 75: 485–490.
27. Brott T, Broderick J, Kothari R, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke 1997; 28: 1–5.
28. Fujitsu K, Muramoto M, Ikeda Y, et al. Indications for surgical treatment of putaminal hemorrhage. Comparative study based on serial CT and time-course analysis. J Neurosurg 1990; 73: 518–525.
29. Kazui S, Naritomi H, Yamamoto H, Sawada T, Yamaguchi T. Enlargement of spontaneous intracerebral hemorrhage. Incidence and time course. Stroke 1996; 27: 1783–1787.
30. Fujii Y, Tanaka R. Predictors of hematoma growth? Stroke 1998; 29: 2442–2443.
31. Chen ST, Chen SD, Hsu CY, Hogan EL. Progression of hypertensive intracerebral hemorrhage. Neurology 1989; 39: 1509–1514.
32. Broderick JP, Brott TG, Tomsick T, Barsan W, Spilker J. Ultra-early evaluation of intracerebral hemorrhage. J Neurosurg 1990; 72: 195–199.
33. Fisher CM. Pathological observations in hypertensive cerebral hemorrhage. J Neuropathol Exp Neurol 1971; 30: 536–550.
34. Mayer SA, Lignelli A, Fink ME, et al. Perilesional blood flow and edema formation in acute intracerebral hemorrhage: a SPECT study. Stroke 1998; 29: 1791–1798.
35. Mayer SA. Intracerebral hemorrhage: natural history and rationale of ultra-early hemostatic therapy. Intensive Care Med 2002; 28 Suppl 2: S235–240.
36. Fujii Y, Tanaka R, Takeuchi S, et al. Hematoma enlargement in spontaneous intracerebral hemorrhage. J Neurosurg 1994; 80: 51–57.
37. Fujii Y, Takeuchi S, Sasaki O, Minakawa T, Tanaka R. Multivariate analysis of predictors of hematoma enlargement in spontaneous intracerebral hemorrhage. Stroke 29: 1160–1166.
38. Murai Y, Takagi R, Ikeda Y, Yamamoto Y, Teramoto A. Three-dimensional computerized tomography angiography in patients with hyperacute intracerebral hemorrhage. J Neurosurg 1999; 91: 424–431.
39. Becker KJ, Baxter AB, Bybee HM, et al. Extravasation of radiographic contrast is an independent predictor of death in primary intracerebral hemorrhage. Stroke 1999; 30: 2025–2032.
40. Mizukami M, Araki G, Mihara H, Tomita T, Fujinaga R. Arteriographically visualized extravasation in hypertensive intracerebral hemorrhage. Report of seven cases. Stroke 1972; 3: 527–537.
41. Komiyama M, Yasui T, Tamura K, et al. Simultaneous bleeding from multiple lenticulostriate arteries in hypertensive intracerebral haemorrhage. Neuroradiology 1995; 37: 129–130.
42. Takasugi S, Ueda S, Matsumoto K. Chronological changes in spontaneous intracerebral hematoma – an experimental and clinical study. Stroke 1985; 16: 651–658.
43. Wagner KR, Xi G, Hua Y, et al. Lobar intracerebral hemorrhage model in pigs: rapid edema development in perihematomal white matter. Stroke 1996; 27(3): 490–497.
44. Tovi D. Fibrinolytic activity of human brain. A histochemical study. Acta Neurol Scand 1973; 49(2): 152–162.
45. Tovi D. Nilsson IM. Increased fibrinolytic activity and fibrin degradation products after experimental intracerebral haemorrhage. Acta Neurol Scand 1972; 48(4): 403–415.
46. Mayer SA, Sacco RL, Shi T, Mohr JP. Neurologic deterioration in noncomatose patients with supratentorial intracerebral hemorrhage. Neurology 1994; 44: 1379–1384.
47. Cartmill M, Dolan G, Byrne JL, Byrne PO. Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies. Br J Neurosurg 2000; 14: 458–461.
48. Kohler M, Hellstern P, Lechler E, Uberfuhr P, Muller-Berghaus G. Thromboembolic complications associated with the use of prothrombin complex and factor IX concentrates. Thromb Haemost 1998; 80: 399–402.
49. Mannucci PM. Hemostatic drugs. N Engl J Med 1998; 339: 245–253.
50. Leipzig TJ, Redelman K, Horner TG. Reducing the risk of rebleeding before early aneurysm surgery: a possible role for antifibrinolytic therapy. J Neurosurg 1997; 86(2): 220–225.
51. Hillman J, Fridriksson S, Nilsson O, et al. Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study. J Neurosurg 2002; 97: 771–778.
52. Henry DA, O'Connell DL. Effects of fibrinolytic inhibitors on mortality from upper gastrointestinal haemorrhage. BMJ 1989; 298: 1142–1146.
53. Walsh PN, Rizza CR, Matthews JM, et al. Epsilon-aminocaproic acid therapy for dental extractions in haemophilia and Christmas disease: a double blind controlled trial. Br J Haematol 1971; 20: 463–475.
54. Piriyawat P, Morgenstern LB, Yawn DH, Hall CE, Grotta JC. Treatment of acute intracerebral hemorrhage with epsilon-aminocaproic acid: a pilot study. Neurocrit Care 2004; 1: 47–52.
55. Levy JH. Overview of clinical efficacy and safety of pharmacologic strategies for blood conservation. Am J Health Syst Pharm. 2005; 62(Suppl 4): S15–19.
56. Paran H, Gutman M, Mayo A. The effect of aprotinin in a model of uncontrolled hemorrhagic shock. Am J Surg 2005; 190(3): 463–466.
57. Levy JH, Bailey JM, Salmenpera M. Pharmacokinetics of aprotinin in preoperative cardiac surgical patients. Anesthesiology 1994; 80(5): 1013–1018.
58. Sedrakyan A, Treasure T, Elefteriades JA. Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. J Thorac Cardiovasc Surg 2004; 128(3): 442–448.
59. Mangano DT, Tidor IC, Dietzel C, for the Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation. The risk associated with aprotinin in cardiac surgery. New Engl J Med 2005; 354: 353–365.
60. Grady RE, Oliver WC Jr, Abel MD, Meyer FB. Aprotinin and deep hypothermic cardiopulmonary bypass with or without circulatory arrest for craniotomy. J Neurosurg Anesthesiol 2002; 14(2): 137–140.
61. Spallone A, Pastore FS, Rizzo A, Guidetti B. Low-dose tranexamic acid combined with aprotinin in the pre-operative management of ruptured intracranial aneurysms. Neurochirurgia (Stuttg) 1987; 30(6): 172–176.
62. Giromini D, Tzonos T. Local use of aprotinin in neurosurgical operations for the prevention of hyperfibrinolytic hemorrhage. Fortschr Med 1981; 99(29): 1153–1156.
63. Levi M, Cromheecke ME, de Jonge E, et al. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet 1999; 354(9194): 1940–1947.
64. Key NS, Aledort LM, Beardsley D, et al. Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (Novoseven) in haemophiliacs with inhibitors. Thromb Haemost 1998; 80: 912–918.
65. Monroe DM, Hoffman M, Oliver JA, Roberts HR. Platelet activity of high-dose factor VIIa is independent of tissue factor. Br J Haematol 1997; 99: 542–547.
66. Hoffman M, Monroe DM III, Roberts HR. Activated factor VII activates factors IX and X on the service of activated platelets: thoughts on the mechanism of action of high-dose activated factor VII. Blood Coagul Fibrinolysis 1998; 9(Suppl 1): 56–65.
67. Jurlander B, Thim L, Klausen NK, et al. Recombinant activated factor VII (rFVIIa): characterization, manufacturing, and clinical development. Semin Thromb Hemost 2001; 27(4): 373–384.
68. Hedner U. Recombinant activated factor VII as a universal haemostatic agent. Blood Coagul Fibrinolysis 1998; 9(Suppl 1): S147–152.
69. Hedner U, Ingerslev J. Clinical use of recombinant FVIIa (rFVIIa). Transfus Sci 1998; 19: 163–176.
70. Rice KM, Savidge GF. Novo Seven (recombinant factor VIIa) in central nervous systems bleeds. Haemostasis 1996; 26(Suppl 1): 131–134.
71. Erhardtsen E. Pharmacokinetics of recombinant activated factor VII. Semin Thromb Hemost 2000; 26: 385–391.
72. Fridberg, MJ, Hedner U, Robertshr, Erhardsten E. A study of the pharmacokinetics and safety of recombinant activated factor VII in healthy Caucasian and Japanese subjects. Blood Coagul Fibrinolysis 2005; 16(4): 259–266.
73. Villar A, Aronis S, Morfini M, et al. Pharmacokinetics of activated recombinant coagulation Factor VII (NovoSeven) in children versus adults with haemophilia A. Haemophilia 2004; 10(4): 352–359.
74. Abshire T, Kenet G. Recombinant factor VIIa: a review of efficacy, dosing regimens and safety in patients with congenital and acquired factor VII or IX inhibitors. J Thromb Haemost 2004; 2: 899–909.
75. Parameswaran R, Shapiro AD, Gill JC, et al. Dose effect and efficacy of rFVIIa in the treatment of haemophilia patients with inhibitors: analysis from the Hemophilia and Thrombosis Research Society Registry. Haemophilia 2005; 11: 100–106.
76. Key NS, Aledort LM, Beardsley D, et al. Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (NovoSeven) in haemophiliacs with inhibitors. Thromb Haemost 1998; 80: 912–918.
77. Lusher JM, Roberts HR, Davignon G, et al. A randomized, double-blind comparison of two dosage levels of recombinant factor VIIa in the treatment of joint, muscle and mucocutaneous haemorrhages in persons with haemophilia A and B, with and without inhibitors. rFVIIa Study Group. Haemophilia 1998; 4: 790–798.
78. Erhardtsen E. Ongoing Novoseven trials. Intensive Care Med 2002; 28: S248–255.
79. Laffan MA, Cummins M. Recombinant factor VIIa for intractable surgical bleeding. Blood 2000; 96(Suppl 1, Abstract 4048): 85b.
80. Fewel ME, Park P. The emerging role of recombinant-activated factor VII in neurocritical care. Neurocrit Care 2004; 1: 19–30.
81. Park P, Fewel ME, Garton HJ, Thompson BG, Hoff JT. Recombinant activated factor VII for the rapid correction of coagulopathy in nonhemophilic neurosurgical patients. Neurosurgery 2003; 53: 34–38; discussion 38–39.
82. Pickard JD, Kirkpatrick PJ, Melsen T, et al. Potential role of Novoseven in the prevention of rebleeding following aneurysmal subarachnoid hemorrhage. Blood Coagul Fibrinolysis 2000; 11(Suppl 1): S117–120.
83. Peerlinck K, Vermylen J. Acute myocardial infarction following administration of recombinant activated factor VII (NovoSeven) in a patient with haemophilia A and inhibitor. Thromb Haemost 1999; 82: 1775–1776.
84. Rosenfeld SB, Watkinson KK, Thompson BH, Macfarlane DE, Lentz SR. Pulmonary embolism after sequential use of recombinant factor VIIa and activated prothrombin complex concentrate in a factor VIII inhibitor patient. Thromb Haemost 2002; 87: 925–926.
85. Roberts HR. Recombinant factor VIIa: how safe is the stuff? Can J Anaesth 2005; 52(1): 8–11.
86. Levi M, Peters M, Buller HR. Efficacy and safety of recombinant factor VIIa for treatment of severe bleeding: a systematic review. Crit Care Med 2005; 33: 883–890.
87. 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: 293–298.
88. Mayer SA, Brun N, Broderick J, et al. Safety and feasibility of recombinant factor VIIa for acute intracerebral hemorrhage. Stroke 2005; 36: 74–79.
89. Mayer SA, Brun NC, Begtrup K, et al. Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005; 352(8): 777–785.
90. Mayer SA, Brun NC. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005; 352: 2134.
91. Diringer MN, Skolnick BE, Mayer SA, et al. Risk of thromboembolic events in controlled trials of rFVIIa in spontaneous intracerebral hemorrhage. Stroke 2008; 39(3): 850–856.
92. Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. New Engl J Med 2008; 358: 2127–2137.
93. Mayer SA, Davis SA, Skolnick BE, et al. on behalf of the FAST trial investigators. Can a subset of intracerebral hemorrhage patients benefit from hemostatic therapy with recombinant activated factor VII? Stroke 2009; 40(3): 833–840.
94. Wada R, Aviv RI, Fox AJ, et al. CT angiography “spot sign” predicts hematoma expansion in acute intracerebral hemorrhage. Stroke 2007; 38: 1257–1262.
95. Goldstein JN, Fazen LE, Snider R, et al. Contrast extravasation on CT angiography predicts hematoma expansion in intracerebral hemorrhage. Neurology 2007; 68: 889–894.
96. Albers GW, Sherman DG, Gress DR, Paulseth JE, Petersen P. Stroke prevention in nonvalvular atrial fibrillation: a review of prospective randomized trials. Ann Neurol 1991; 30: 511–518.
97. Wintzen AR, de Jonge H, Loeliger EA, Bots GT. The risk of intracerebral hemorrhage during oral anticoagulant therapy: a population study. Ann Neurol 1984; 16: 553–558.
98. Flibotte JJ, Hagan N, O'Donnell J, Greenberg SM, Rosand J. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology 2004; 63: 1059–1064.
99. Ansell J, Hirsh J, Dalen J, et al. Managing oral anticoagulant therapy. Chest 2001; 119: 22S–38S.
100. Hart RG. Management of warfarin associated intracerebral hemorrhage. In: Rose BD, ed. UpToDate. Wellesley, MA: UpToDate; 2009.
101. Mayer SA, Rincon F. Management of intracerebral hemorrhage. Lancet Neurol 2005; 4: 662–672.
102. 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: 151–155.
103. Steiner T, Rosand J, Diringer M. Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions. Stroke 2006; 37: 256–262.
104. Boulis NM, Bobek MP, Schmaier A, Hoff JT. Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery 1999; 45: 1113–1118; discussion 1118–1119.
105. Freeman WD, Brott TG, Barrett KM, et al. Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. Mayo Clin Proc 2004; 79: 1495–1500.
106. Deveras RE, Kessler CM. Reversal of warfarin induced excessive anticoagulation with recombinant human factor VIIa concentrate. Ann Intern Med 2002; 137: 884–888.
107. Erhardtsen E, Nony P, Dechavanne M, et al. The effect of recombinant factor VIIa (NovoSeven) in healthy volunteers receiving acenocoumarol to an International Normalized Ratio above 2.0. Blood Coagul Fibrinolysis 1998; 9: 741–748.
108. Sorensen B, Johansen P, Nielsen GL, Sorensen JC, Ingerslev J. Reversal of the International Normalized Ratio with recombinant activated factor VII in central nervous system bleeding during warfarin thromboprophylaxis: clinical and biochemical aspects. Blood Coagul Fibrinolysis 2003; 14(5): 469–477.
109. Fredriksson K, Norrving B, Stromblad LG. Emergency reversal of anticoagulation after intracerebral hemorrhage. Stroke 1992; 23(7): 972–977.
110. Wakefield TW, Stanley JC. Intraoperative heparin anticoagulation and its reversal. Semin Vasc Surg 1996; 9(4): 296–302.
111. Mannucci PM, Remuzzi G, Pusineri F, et al. Deamino-8-D-arginine vasopressin shortens the bleeding time in uremia. N Engl J Med 1983; 308(1): 8–12.
112. Ananthasubramaniam K, Beattie JN, Rosman HS, Jayam V, Borzak S. How safely and for how long can warfarin therapy be withheld in prosthetic heart valve patients hospitalized with a major hemorrhage? Chest 2001; 119(2): 478–484.
113. Phan TG, Koh M, Wijdicks EF. Safety of discontinuation of anticoagulation in patients with intracranial hemorrhage at high thromboembolic risk. Arch Neurol 2000; 57: 1710–1713.
114. Morgenstern LB, Demchuk AM, Kim DH, Frankowski RF, Grotta JC. Rebleeding leads to poor outcome in ultra-early craniotomy for intracerebral hemorrhage. Neurology 2001; 56(10): 1294–1299.