The Evidence for the Use of Recombinant Human Activated Factor VII in the Treatment of Bleeding Patients With Quantitative and Qualitative Platelet Disorders

Transfusion Medicine Reviews

Volumn 21, Issue 3, 2007, Pages 223-236

  Poon, Man Chiu ^a,b,c  

^a UNIVERSITY OF CALGARY   (Canada)

^b UNIVERSITY OF CALGARY   (Canada)

^c Southern Alberta Clinic   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ANTITHROMBIN; BLOOD CLOTTING FACTOR 10; BLOOD CLOTTING FACTOR 11; BLOOD CLOTTING FACTOR 5; BLOOD CLOTTING FACTOR 7; BLOOD CLOTTING FACTOR 8; BLOOD CLOTTING FACTOR 9; FIBRIN; GLYCOPROTEIN IB; PROTHROMBIN; RECOMBINANT BLOOD CLOTTING FACTOR 7A; THROMBOPLASTIN; VON WILLEBRAND FACTOR;

ACUTE HEART INFARCTION; ARTICLE; BLEEDING DISORDER; BRAIN INFARCTION; CATHETER THROMBOSIS; CEREBROVASCULAR ACCIDENT; CONTINUOUS INFUSION; DEEP VEIN THROMBOSIS; DISSEMINATED INTRAVASCULAR CLOTTING; DRUG DOSE COMPARISON; DRUG EFFICACY; DRUG INDICATION; DRUG MEGADOSE; DRUG SAFETY; DRUG USE; EPISTAXIS; EVIDENCE BASED MEDICINE; GANGRENE; GASTROINTESTINAL HEMORRHAGE; GLANZMANN DISEASE; HEMOPHILIA; HUMAN; LUNG EMBOLISM; OCCLUSIVE CEREBROVASCULAR DISEASE; RECOMMENDED DRUG DOSE; SINGLE DRUG DOSE; SYSTEMATIC REVIEW; THROMBIN TIME; THROMBOCYTE ADHESION; THROMBOCYTE DISORDER; THROMBOCYTOPENIA; THROMBOPHLEBITIS; THROMBOTIC THROMBOCYTOPENIC PURPURA; VEIN THROMBOSIS;

BLOOD COAGULATION FACTORS; BLOOD PLATELET DISORDERS; CLINICAL TRIALS; FACTOR VII; HUMANS; PLATELET ACTIVATION; RECOMBINANT PROTEINS;

EID: 34250193640     PISSN: 08877963     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tmrv.2007.03.003     Document Type: Article

References (102)

1. Gelb A.B., and Leavitt A.D. Crossmatch-compatible platelets improve corrected count increments in patients who are refractory to randomly selected platelets. Transfusion 37 (1997) 624-630
2. Dodd R.Y., Notari E.P., and Stramer S.L. Current prevalence and incidence of infectious disease markers and estimated window-period risk in the American Red Cross blood donor population. Transfusion 42 (2002) 975-979
3. Jacobs M.R., Palavecino E., and Yomtovian R. Don't bug me: the problem of bacterial contamination of blood components-Challenges and solutions. Transfusion 41 (2001) 1331-1334
4. Engelfriet C.P., Reesink H.W., Blajchman M.A., et al. Bacterial contamination of blood components. Vox Sang 78 (2000) 59-67
5. Poon M.C., Demers C., Jobin F., et al. Recombinant factor VIIa is effective for bleeding and surgery in patients with Glanzmann thrombasthenia. Blood 94 (1999) 3951-3953
6. Poon M.C., d'Oiron R., von Depka M., et al. Prophylactic and therapeutic recombinant factor VIIa administration to patients with Glanzmann's thrombasthenia: Results of an international survey. J Thromb Haemost 2 (2004) 1096-1103
7. Jurlander B., Thim L., Klausen N.K., et al. Recombinant activated factor VII (rFVIIa): Characterization, manufacturing, and clinical development. Semin Thromb Hemost 27 (2001) 373-384
8. Lindley C.M., Sawyer W.T., Macik B.G., et al. Pharmacokinetics and pharmacodynamics of recombinant factor VIIa. Clin Pharmacol Ther 55 (1994) 638-648
9. Villar A., Aronis S., Morfini M., et al. Pharmacokinetics of activated recombinant coagulation factor VII (NovoSeven) in children vs. adults with haemophilia A. Haemophilia 10 (2004) 352-359
10. Shirahata A., Kamiya T., Takamatsu J., et al. Clinical trial to investigate the pharmacokinetics, pharmacodynamics, safety, and efficacy of recombinant factor VIIa in Japanese patients with hemophilia with inhibitors. Int J Hematol 73 (2001) 517-525
11. Berrettini M., Mariani G., Schiavoni M., et al. Pharmacokinetic evaluation of recombinant, activated factor VII in patients with inherited factor VII deficiency. Haematologica 86 (2001) 640-645
12. Morrissey J.H., and Mutch N.J. Tissue factor structure and function. Hemostasis and thrombosis. In: Colman R.E., Marder V.J., Clowes A.W., et al. (Eds). Basic principles and clinical practice. ed 5 (2006), Lippincott Williams & Wilkins, Philadelphia 91-106
13. Hedner U., Glazer S., Pingel K., et al. Successful use of recombinant factor VIIa in patient with severe haemophilia A during synovectomy. Lancet 2 (1988) 1193
14. Hay C.R., Negrier C., and Ludlam C.A. The treatment of bleeding in acquired haemophilia with recombinant factor VIIa: A multicentre study. Thromb Haemost 78 (1997) 1463-1467
15. Lusher J.M., Roberts H.R., 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 4 (1998) 790-798
16. Shapiro A.D., Gilchrist G.S., Hoots W.K., et al. Prospective, randomised trial of two doses of rFVIIa (NovoSeven) in haemophilia patients with inhibitors undergoing surgery. Thromb Haemost 80 (1998) 773-778
17. Baudo F., Redaelli R., Caimi T.M., et al. The continuous infusion of recombinant activated factor VIIa (rFVIIa) in patients with factor VIII inhibitors activates the coagulation and fibrinolytic systems without clinical complications. Thromb Res 99 (2000) 21-24
18. van't Veer C., Golden N.J., and Mann K.G. Inhibition of thrombin generation by the zymogen factor VII: Implications for the treatment of hemophilia A by factor VIIa. Blood 95 (2000) 1330-1335
19. Butenas S., Brummel K.E., Branda R.F., et al. Mechanism of factor VIIa-dependent coagulation in hemophilia blood. Blood 99 (2002) 923-930
20. Monroe D.M., Hoffman M., Oliver J.A., et al. Platelet activity of high-dose factor VIIa is independent of tissue factor. Br J Haematol 99 (1997) 542-547
21. Butenas S., Brummel K.E., Bouchard B.A., et al. How factor VIIa works in hemophilia. J Thromb Haemost 1 (2003) 1158-1160
22. He S., Blomback M., Jacobsson E.G., et al. The role of recombinant factor VIIa (FVIIa) in fibrin structure in the absence of FVIII/FIX. J Thromb Haemost 1 (2003) 1215-1219
23. Lisman T., Mosnier L.O., Lambert T., et al. Inhibition of fibrinolysis by recombinant factor VIIa in plasma from patients with severe hemophilia A. Blood 99 (2002) 175-179
24. Kjalke M., Ezban M., Monroe D.M., et al. High-dose factor VIIa increases initial thrombin generation and mediates faster platelet activation in thrombocytopenia-like conditions in a cell-based model system. Br J Haematol 114 (2001) 114-120
25. Galán A.M., Tonda R., Pino M., et al. Increased local procoagulant action: a mechanism contributing to the favorable hemostatic effect of recombinant FVIIa in PLT disorders. Transfusion 43 (2003) 885-892
26. Lisman T., Adelmeijer J., Cauwenberghs S., et al. Recombinant factor VIIa enhances platelet adhesion and activation under flow conditions at normal and reduced platelet count. J Thromb Haemost 3 (2005) 742-751
27. Reverter J.C., Beguin S., Kessels H., et al. Inhibition of platelet-mediated, tissue factor-induced thrombin generation by the mouse/human chimeric 7E3 antibody. Potential implications for the effect of c7E3 Fab treatment on acute thrombosis and "clinical restenosis". J Clin Invest 98 (1996) 863-874
28. Poon M.-C. Factor VIIa. In: Michelson A.A. (Ed). Platelets. ed 2 (2006), Elsevier Science, Boston 1251-1261
29. Lisman T., Moschatsis S., Adelmeijer J., et al. Recombinant factor VIIa enhances deposition of platelets with congenital or acquired alpha IIb beta 3 deficiency to endothelial cell matrix and collagen under conditions of flow via tissue factor-independent thrombin generation. Blood 101 (2003) 1864-1870
30. Niewiarowski S., Levy-Toledano S., and Caen J.P. Platelet interaction with polymerizing fibrin in Glanzmann's thrombasthenia. Thromb Res 23 (1981) 457-463
31. McGregor L., Hanss M., Sayegh A., et al. Aggregation to thrombin and collagen of platelets from a Glanzmann thrombasthenic patient lacking glycoproteins IIb and IIIa. Thromb Haemost 62 (1989) 962-967
32. Osdoit S., and Rosa J.-P. Polymeric fibrin interacts with platelets independently from integrin aIIob3. Blood 98 (2001) 518a (suppl, abstr)
33. Lisman T., Adelmeijer J., Heijnen H.F., et al. Recombinant factor VIIa restores aggregation of alphaIIbbeta3-deficient platelets via tissue factor-independent fibrin generation. Blood 103 (2004) 1720-1727
34. Soslau G., Class R., Morgan D.A., et al. Unique pathway of thrombin-induced platelet aggregation mediated by glycoprotein Ib. J Biol Chem 276 (2001) 21173-21183
35. Hedner U., Bergqvist D., Ljungberg J., et al. Haemostatic effect of factor VIIa in thrombocytopenic rabbits. Blood 86 (1985) 1043 (suppl 1, abstr)
36. Tranholm M., Rojkjaer R., Pyke C., et al. Recombinant factor VIIa reduces bleeding in severely thrombocytopenic rabbits. Thromb Res 109 (2003) 217-223
37. Kristensen J., Killander A., Hippe E., et al. Clinical experience with recombinant factor VIIa in patients with thrombocytopenia. Haemostasis 26 (1996) 159-164 (suppl 1)
38. Brenner B., Hoffman R., Balashov D., et al. Control of bleeding caused by thrombocytopenia associated with hematologic malignancy: An audit of the clinical use of recombinant activated factor VII. Clin Appl Thromb Hemost 11 (2005) 401-410
39. Gerotziafas G.T., Zervas C., Gavrielidis G., et al. Effective hemostasis with rFVIIa treatment in two patients with severe thrombocytopenia and life-threatening hemorrhage. Am J Hematol 69 (2002) 219-222
40. Waddington D.P., McAuley F.T., Hanley J.P., et al. The use of recombinant factor VIIa in a Jehovah's witness with auto-immune thrombocytopenia and post-splenectomy haemorhage. Br J Haematol 119 (2002) 286-288
41. Culic S. Recombinant factor VIIa for refractive haemorrhage in autoimmune idiopathic thrombocytopenic purpura. Br J Haematol 120 (2003) 909-910
42. Virchis A., Hughes C., and Berney S. Severe gastrointestinal haemorrhage responding to recombinant factor VIIa in a Jehovah's Witness with refractory immune thrombocytopenia. Hematol J 5 (2004) 281-282
43. Busani S., Marietta M., Pasetto A., et al. Use of recombinant factor VIIa in a thrombocytopenic patient with spontaneous intracerebral haemorrhage. Thromb Haemost 93 (2005) 381-382
44. Barnes C., Blanchette V., Canning P., et al. Recombinant FVIIa in the management of intracerebral haemorrhage in severe thrombocytopenia unresponsive to platelet-enhancing treatment. Transfus Med 15 (2005) 145-150
45. Vidarsson B., and Onundarson P.T. Recombinant factor VIIa for bleeding in refractory thrombocytopenia. Thromb Haemost 83 (2000) 634-635
46. Billio A., Morello E., Amaddii G., et al. Treatment of refractory thrombocytopenic bleeding with rFVIIa: a case report. Blood 100 (2002) 83 (suppl 1, abstr)
47. Watson H., Salamat A., Tait J., et al. Successful treatment of life threatening haemorrhage with rVIIa during autologous peripheral blood stem cell transplantation complicated by platelet refractoriness. Blood 100 (2002) 78 (suppl 1, abstr)
48. Hoffman R., Eliakim R., Zuckerman T., et al. Successful use of recombinant activated factor VII in controlling upper gastrointestinal bleeding in a patient with relapsed acute myeloid leukemia. J Thromb Haemost 1 (2003) 606-608
49. Culligan D.J., Salamat A., Tait J., et al. Use of recombinant factor VIIa in life-threatening bleeding following autologous peripheral blood stem cell transplantation complicated by platelet refractoriness. Bone Marrow Transplant 31 (2003) 1183-1184
50. De Fabritiis P., Dentamaro T., Picardi A., et al. Recombinant factor VIIa for the management of severe hemorrhages in patients with hematologic malignancies. Haematologica 89 (2004) 243-245
51. Zulfikar B., and Kayran S.M. Successful treatment of massive gastrointestinal hemorrhage in acute biphenotypic leukemia with recombinant factor VIIa (NovoSeven). Blood Coagul Fibrinolysis 15 (2004) 261-263
52. Osborne W., Bhandari S., Tait R.C., et al. Immediate haemostasis with recombinant factor VIIa for haemorrhage following Hickman line insertion in acute myeloid leukaemia. Clin Lab Haematol 26 (2004) 229-231
53. Kurekci A.E., Atay A.A., Okutan V., et al. Recombinant activated factor VII for severe gastrointestinal bleeding after chemotherapy in an infant with acute megakaryoblastic leukemia. Blood Coagul Fibrinolysis 16 (2005) 145-147
54. Savani B.N., Dunbar C.E., and Rick M.E. Combination therapy with rFVIIa and platelets for hemorrhage in patients with severe thrombocytopenia and alloimmunization. Am J Hematol 81 (2006) 218-219
55. Sokolic V., Bukovic D., Fures R., et al. Recombinant factor VIIa (rFVIIa) is effective at massive bleeding after caesarean section-A case report. Coll Antropol 26 (2002) 155-157 (suppl)
56. Zupancic-Salek S., Sokolic V., Viskovic T., et al. Successful use of recombinant factor VIIa for massive bleeding after caesarean section due to HELLP syndrome. Acta Haematol 108 (2002) 162-163
57. Dart B.W., Cockerham W.T., Torres C., et al. A novel use of recombinant factor VIIa in HELLP syndrome associated with spontaneous hepatic rupture and abdominal compartment syndrome. J Trauma 57 (2004) 171-174
58. Merchant S.H., Mathew P., Vanderjagt T.J., et al. Recombinant factor VIIa in management of spontaneous subcapsular liver hematoma associated with pregnancy. Obstet Gynecol 103 (2004) 1055-1058
59. Thomas A.E., and Plews D.E. Use of recombinant factor VIIa in platelet disorders-A single centre experience. Blood Coagul Fibrinolysis 12 (2001) A14
60. Heuer L., and Blumenberg D. Management of bleeding in a multi-transfused patient with positive HLA class I alloantibodies and thrombocytopenia associated with platelet dysfunction refractory to transfusion of cross-matched platelets. Blood Coagul Fibrinolysis 16 (2005) 287-290
61. Minniti C., and Weinthal J. Use of recombinant activated factor VII (rFVIIa) in two children with idiopathic thrombocytopenic purpura (ITP). Blood 98 (2001) 62b (suppl 1, abstr)
62. Conesa V., Navarro-Ruiz A., Borras-Blasco J., et al. Recombinant factor VIIa is an effective therapy for abdominal surgery and severe thrombocytopenia: A case report. Int J Hematol 81 (2005) 75-76
63. Klamroth R., Gottstein S., and Landgraf H. Successful use of recombinant factor VIIa to prevent bleeding during major surgery in a patient with severe immune thrombocytopenia. Blood 100 (2002) 77b (suppl 1, abstr)
64. Pihusch M., Bacigalupo A., Szer J., et al. Recombinant activated factor VII in treatment of bleeding complication following hematopoietic stem cell transplantation. J Thromb Haemost 3 (2005) 1935-1944
65. Blatt J., Gold S.H., Wiley J.M., et al. Off-label use of recombinant factor VIIa in patients following bone marrow transplantation. Bone Marrow Transplant 28 (2001) 405-407
66. Phelan J.T., Broder J., and Kouides P.A. Near-fatal uterine hemorrhage during induction chemotherapy for acute myeloid leukemia: A case report of bilateral uterine artery embolization. Am J Hematol 77 (2004) 151-155
67. Eller P., Pechlaner C., and Wiedermann C.J. Ineffective off-label use of recombinant activated factor VII in a case of bone-marrow transplantation-related gastrointestinal bleeding. J. Thromb 4 (2006) 1
68. Tengborn L., and Petruson B. A patient with Glanzmann thrombasthenia and epistaxis successfully treated with recombinant factor VIIa. [letter]. Thromb Haemost 75 (1996) 981-982
69. Chuansumrit A., Sangkapreecha C., and Hathirat P. Successful epistaxis control in a patient with Glanzmann thrombasthenia by increased bolus injection dose of recombinant factor VIIa. Thromb Haemost 82 (1999) 1778
70. Robinson K.L., Savoia H., and Street A.M. Thrombotic complications in two patients receiving NovoSeven. Haemophilia 6 (2000) 349 (abstr)
71. d'Oiron R., Menart C., Trzeciak M.C., et al. Use of recombinant factor VIIa in 3 patients with inherited type I Glanzmann's thrombasthenia undergoing invasive procedures. Thromb Haemost 83 (2000) 644-647
72. Monte S., and Lyons G. Peripartum management of a patient with Glanzmann's thrombasthenia using Thrombelastograph. Br J Anaesth 88 (2002) 734-738
73. vanBuuren H.R., and Wielenga J.J. Successful surgery using recombinant factor VIIa for recurrent, idiopathic nonulcer duodenal bleeding in a patient with Glanzmann's thrombasthenia. Dig Dis Sci 47 (2002) 2134-2136
74. Almeida A.M., Khair K., Hann I., et al. The use of recombinant factor VIIa in children with inherited platelet function disorders. Br J Haematol 121 (2003) 477-481
75. Chuansumrit A., Suwannuraks M., Sri-Udomporn N., et al. Recombinant activated factor VII combined with local measures in preventing bleeding from invasive dental procedures in patients with Glanzmann thrombasthenia. Blood Coagul Fibrinolysis 14 (2003) 187-190
76. Caglar K., Cetinkaya A., Aytac S., et al. Use of recombinant factor VIIa for bleeding in children with Glanzmann thrombasthenia. Pediatr Hematol Oncol 20 (2003) 435-438
77. Bell J.A., and Savidge G.F. Glanzmann's thrombasthenia proposed optimal management during surgery and delivery. Clin Appl Thromb Hemost 9 (2003) 167-170
78. Kaleelrahman M., Minford A., and Parapia L.A. Use of recombinant factor VIIa in inherited platelet disorders. Br J Haematol 125 (2004) 95-96
79. Kale A., Bayhan G., Yalinkaya A., et al. The use of recombinant factor VIla in a primigravida with Glanzmann's thrombasthenia during delivery. J Perinat Med 32 (2004) 456-458
80. Uzunlar H.I., Eroglu A., Senel A.C., et al. A patient with Glanzmann's thrombasthenia for emergent abdominal surgery. Anesth Analg 99 (2004) 1258-1260
81. Coppola A., Tufano A., Cimino E., et al. Recombinant factor VIIa in a patient with Glanzmann's thrombasthenia undergoing gynecological surgery: open issues in light of successful treatment. Thromb Haemost 92 (2004) 1450-1452
82. Yilmaz B.T., Alioglu B., Ozyurek E., et al. Successful use of recombinant factor VIIa (NovoSeven) during cardiac surgery in a pediatric patient with Glanzmann thrombasthenia. Pediatr Cardiol 26 (2005) 843-845
83. Dargaud Y., Bordet J.C., Trzeciak M.C., et al. A case of Glanzmann's thrombasthenia successfully treated with recombinant factor VIIa during a surgical procedure: Observations on the monitoring and the mechanism of action of this drug. Haematologica 91 (2006) 17-20 (suppl)
84. Musso R., Cultrera D., Russo M., et al. Recombinant activated factor VII as haemostatic agent in Glanzmann's thrombasthenia. Thromb Haemost 82 (1999) 621 (suppl, abstr)
85. Devecioglu O., Unuvar A., Anak S., et al. Pyelolithotomy in a patient with Glanzmann thrombasthenia and antiglycoprotein IIb/IIIa antibodies: the shortest possible duration of treatment with recombinant activated factor VII and platelet transfusions. Turk J Pediatr 45 (2003) 64-66
86. Ito K., Yoshida H., Hatoyama H., et al. Antibody removal therapy used successfully at delivery of a pregnant patient with Glanzmann's thrombasthenia and multiple anti-platelet antibodies. Vox Sang 61 (1991) 40-46
87. Martin I., Kriaa F., Proulle V., et al. Protein A Sepharose immunoadsorption can restore the efficacy of platelet concentrates in patients with Glanzmann's thrombasthenia and anti-glycoprotein IIb-IIIa antibodies. Br J Haematol 119 (2002) 991-997
88. Poon M.C., Zotz R., Di M.G., et al. Glanzmann's thrombasthenia treatment: A prospective observational registry on the use of recombinant human activated factor VII and other hemostatic agents. Semin Hematol 43 (2006) S33-S36
89. Peters M., and Heijboer H. Treatment of a patient with Bernard-Soulier syndrome and recurrent nosebleeds with recombinant factor VIIa. [letter]. Thromb Haemost 80 (1998) 352
90. Ozelo M.C., Svirin P., and Larina L. Use of recombinant factor VIIa in the management of severe bleeding episodes in patients with Bernard-Soulier syndrome. Ann Hematol 84 (2005) 816-822
91. PozoPozo A.I., Jimenez-Yuste V., Villar A., et al. Successful thyroidectomy in a patient with Hermansky-Pudlak syndrome treated with recombinant activated factor VII and platelet concentrates. Blood Coagul Fibrinolysis 13 (2002) 551-553
92. Langendonck L., and Appel I.M. Modification of biological parameters after treatment with recombinant factor VIIa in a patient with thrombocytopathy due to storage pool disease. Pediatr Blood Cancer 44 (2005) 676-678
93. Fressinaud E., Sigaud-Fiks M., Le Boterff C., et al. Use of recombinant factor VIIa (NovoSeven) for dental extraction in a patient affected by platelet-type (pseudo-) von Willebrand disease. Haemophilia 4 (1998) 299 (abstr)
94. Inagaki M., Mori T., Tsunematsu Y., et al. Use of recombinant activated factor VII to control bleeding in a young child with qualitative platelet disorder: A case report. Blood Coagul Fibrinolysis 17 (2006) 317-322
95. Meijer K., Sieders E., Slooff M.J., et al. Effective treatment of severe bleeding due to acquired thrombocytopathia by single dose administration of activated recombinant factor VII [letter]. Thromb Haemost 80 (1998) 204-205
96. Révész T., Arets B., and Bierings M. Recombinant factor VIIa in severe uremic bleeding. [letter]. Thromb Haemost 80 (1998) 353
97. Cervera J.S., Mena-Duran A.V., and Piqueras C.S. The use of recombinant factor VIIa in a patient with essential thrombocythaemia with uncontrolled surgical bleeding. Thromb Haemost 93 (2005) 383-384
98. Aledort L.M. Comparative thrombotic event incidence after infusion of recombinant factor VIIa versus factor VIII inhibitor bypass activity. J Thromb Haemost 2 (2004) 1700-1708
99. Abshire T., and Kenet G. Recombinant factor VIIa: Review of efficacy, dosing regimens and safety in patients with congenital and acquired factor VIII or IX inhibitors. J Thromb Haemost 2 (2004) 899-909
100. Sallah S., Isaksen M., Seremetis S., et al. Comparative thrombotic event incidence after infusion of recombinant factor VIIa vs. factor VIII inhibitor bypass activity-A rebuttal. J Thromb Haemost 3 (2005) 820-822
101. O'connell N.M., Perry D.J., Hodgson A.J., et al. Recombinant FVIIa in the management of uncontrolled hemorrhage. Transfusion 43 (2003) 1711-1716
102. Mayer S.A., Brun N.C., Begtrup K., et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 352 (2005) 777-785