1. Lee CA, Berntorp E & Hoots K. Textbook of Hemophilia. 2nd edn (Wiley-Blackwell, 2010.
2. Coppola A, Tagliaferri A, Di Capua M, Franchini M. Prophylaxis in children with hemophilia: evidence-based achievements, old and new challenges. Semin Thromb Hemos. 2012;38(1):79-94.
3. Franchini M, Mannucci PM. The history of hemophilia. Semin Thromb Hemost. 2014;40(5):571-576.
4. Tabor E. The epidemiology of virus transmission by plasma derivatives: clinical studies verifying the lack of transmission of hepatitis B and C viruses and HIV type 1. Transfusion. 1999;39(11-12):1160-1168.
5. Nilsson IM, Berntorp E, Lofqvist T, Pettersson H. Twenty-five years’ experience of prophylactic treatment in severe haemophilia A and B. J Intern Med. 1992;232:25-32.
6. Manco-Johnson MJ, Kempton CL, Reding MT et al. Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand treatment with sucrose-formulated recombinant factor VIII in adults with severe hemophilia A (SPINART). J Thromb Haemost. 2013;11(6):1119-27.
7. Manco-Johnson MJ, Abshire TC, Shapiro AD et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357(6):535-44.
8. Hacker MR, Geraghty S, Manco-Johnson M. Barriers to compliance with prophylaxis therapy in haemophilia. Haemophilia. 2001;7:392-396.
9. Franchini M, Mannucci PM. Hemophilia A in the third millennium. Blood Rev. 2013; 27: 179-84.
10. Collins PW, Blanchette VS, Fischer K et al. Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A. J Thromb Haemost. 2009;7:413-420.
11. Collins PW, Bjorkman S, Fischer K et al. Factor VIII requirement to maintain a target plasma level in the prophylactic treatment of severe hemophilia A: influences of variance in pharmacokinetics and treatment regimens. J Thromb Haemost. 2010;8:269-275.
12. Walsh CE, Soucie JM, Miller CH. Impact of inhibitors on hemophilia A mortality in the United States. Am J Hematol. 2015;90(5):400-5.
13. Oldenburg J, Pavlova A. Genetic risk factors for inhibitors to factors VIII and IX. Haemophilia. 2006;12(Suppl6):15-22.
14. Astermark J, Altisent y col. Non-genetic risk factors and the development of inhibitors in haemophilia: a comprehensive review and consensus report. Haemophilia. 2010;16,747-766.
15. Astermark J, Donfield SM y col. E. A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA 10 - NovoSeven Comparative (FENOC) Study. Blood. 2007;109, 546-551.
16. Peyvandi F, Mannucci P y col. A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. New England Journal of Medicine. 2016;374,2054-2064.
17. Pipe SW, Montgomery RR, Pratt KP, Lenting PJ, Lillicrap D. Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A. Blood. 2016;128(16):2007-2016.
18. Pabinger-Fasching I. The story of a unique molecule in hemophilia A: recombinant single-chain factor VIII. Thromb Res. 2016;141 (suppl 3):S2-S4.
19. Zollner S, Raquet E, Claar P et al. Non-clinical pharmacokinetics and pharmacodynamics of rVIII-SingleChain, a novel recombinant singlechain factor VIII. Thromb Res. 2014;134(1):125-131.
20. Liesner et al Immunogenicity, efficacy and safety of Nuwiq® (human-cl rhFVIII) in previously untreated patients with severe haemophilia A—Interim results from the NuProtect Study. Haemophilia. 2018;24:211-220.
21. Mahlangu J, Powell JS, Ragni MV et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood. 2014;123:317-325.
22. Konkle BA, Stasyshyn O, Chowdary P et al. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood. 2015;126:1078-1085.
23. Reding MT, Ng HJ, Poulsen LH et al. Safety and efficacy of BAY 94-9027, a prolonged-half - life factor VIII. J Thromb Haemost. 2017;15:411-419.
24. Giangrande P, Andreeva T, Chowdary P et al. Clinical evaluation of glycoPEGylated recombinant FVIII: efficacy and safety in severe haemophilia A. Thromb Haemost. 2017;117:252-261.
25. Santagostino E, Martinowitz U, Lissitchkov T et al. Long acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood. 2016;127:1761-1769.
26. Young G, Mahlangu JN. Extended half-life clotting factor concentrates: results from published clinical trials. Haemophilia. 2016;22(Suppl 5):25-30.
27. Oldenburg J, Kulkarni R, Srivastava A et al. Improved joint health in subjects with severe haemophilia A treated prophylactically with recombinant factor VIII Fc fusion protein. Haemophilia. 2018;24:77-84.
28. Mancuso ME, Santagostino E. Outcome of clinical trials with new extended half-life FVIII/ IX concentrates. J Clin Med. 2017, April 6 (4): E39.
29. Monahan PE. Emerging genetic and pharmacologic therapies for controlling hemostasis: beyond recombinant clotting factors. Hematol Am Soc Hematol Educ Program. 2015;2015:33-40.
30. Ragni MV. Novel alternate hemostatic agents for patients with inhibitors: beyond bypass therapy. Hematol Am Soc Hematol Educ Program. 2017;2017:605-609.
31. Sampei Z, Igawa T, Soeda T, Okuyama-Nishida Y,Moriyama C, Wakabayashi T, Tanaka E, Muto A, KojimaT, Kitazawa T, Yoshihashi K, Harada A, Funaki M, Haraya K, Tachibana T, Suzuki S, Esaki K, Nabuchi Y, Hattori K. Identification and multidimensional optimization of an asymmetric bispecific IgG antibody mimicking the function of factor VIII cofactor activity. PloS One. 2013; 8:e57479.
32. Uchida N, Sambe T, Yoneyama K, Fukazawa N, Kawanishi T, Kobayashi S, Shima M. A first-in-human phase 1 study of ACE910, a novel factor VIII-mimetic bispecific antibody, in healthy subjects. Blood. 2016;127:1633-1641.
33. Muto A, Yoshihashi K, Takeda M, Kitazawa T, SoedaT, Igawa T, Sampei Z, Kuramochi T, Sakamoto A,Haraya K, Adachi K, Kawabe Y, Nogami K, Shima M, Hattori K. Anti-factor IXa/X bispecific antibody ACE910 prevents joint bleeds in a long-term primate model of acquired hemophilia A. Blood. 2014;124:3165-3171.
34. Oldenburg J et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med. 377,809-818 (2017).
35. Collins W, Liesner R, Makris M, Talks K, Chowdary P, Chalmers E, Hall G, Ridell A, Percy C, Hay C, Hart D, Collins et al. Haemophilia. 2018;24:344-347.
36. Mahlangu J, Oldenburg J, Paz-Priel I, Negrier C, Niggli M, Mancuso M, Schmitt C, Jimenez Yuste V, Kempton C, Dhalluin C, Callaghan M, Bujan W, Shima M, Adamkewicz JI, Asikanius E, Levy GG, Kruse Jarres R. Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors. N Engl J Med. 2018;379:811-22.
37. Ishiguro, K et al. Complete antithrombin deficiency in mice results in embryonic lethality. J Clin Invest. 106,873-878 (2000).
38. Pasi KJ, Rangarajan S, Georgiev P et al. Targeting of antithrombin in hemophilia A or B with RNAi therapy. N Engl J Med. 2017;377:819-828.
39. Pasi KJ, Georgiev P, Mant T et al. Fitusiran, an investigational RNAi therapeutic targeting antithrombin for the treatment of hemophilia: interim results from a phase 2 extension study in patients with hemophilia A or B with and without inhibitors. Res Pract Thromb Haemost. 2017;1(suppl 1).
40. Chowdary P et al. Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial. J Thromb Haemost. 2015;13,743-754.
41. Waters EK, Sigh J, Friedrich U, Hilden I, Sorensen BB. Concizumab, an anti-tissue factor pathway inhibitor antibody, induces increased thrombin generation in plasma from haemophilia patients and healthy subjects measured by the thrombin generation assay. Haemophilia. 2017;23:769-776.
42. Yegneswaran S et al. BAY 1093884 binds to the kunitz 1 and 2 domain interface of tissue factor pathway inhibitor and inhibits its function [abstract]. Res Pract Thromb Haemost. 2017;1 (Suppl. 1), PB 892.
43. Hough C, Lillicrap D. Gene therapy for hemophilia: an imperative to succeed. J Thromb Haemost. 2005;3:1195-1205.
44. Manno CS, Chew AJ, Hutchison S et al. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood. 2003;101:2963-2972.
45. Manno CS, Pierce GF, Arruda VR et al. Successful transduction of liver in hemophilia by AAV-factor IX and limitations imposed by the host immune response. Nat Med. 2006;12:342-347.
46. Mingozzi F, Maus MV, Hui DJ et al. CD8(+) T-cell responses to adeno-associated virus capsid in humans. Nat Med. 2007;13:419-422.
47. Nathwani AC, Tuddenham EG, Rangarajan S et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011;365:2357-2365.
48. Nathwani AC, Reiss UM, Tuddenham EG et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med. 2014;371:1994-2004.
49. George LA, Sullivan SK, Giermasz A et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N Engl J Med. 2017;377:2215-2227.
50. Miesbach W, Meijer K, Coppens M et al. Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. Blood. 2018;131:1022-1031.
51. Rangarajan S, Walsh L, Lester W et al. AAV5-factor VIII gene transfer in severe hemophilia A. N Engl J Med. 2017;377:2519-2530.
52. Favaloro EJ. Von Willebrand disease: local diagnosis and management of a globally distributed bleeding disorder. Semin Thromb Hemost. 2011; 37: 425-6.
53. Mannucci PM, Kempton C, Millar C et al. rVWF Ad Hoc Study Group Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial. Blood. 2013; 122: 648-57.
54. Gill JC, Castaman G, Windyga J et al. Hemostatic efficacy, safety and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood. 2013; 126: 2038-46.
55. Franchini M, Mannucci PM. Von Willebrand factor (Vonvendi®): the first recombinant product licensed for the treatment of von Willebrand disease. Expert Rev Hematol. 2016;9(9):825-830
56. Favaloro EJ. Towards personalized therapy for von Willebrand disease: a future role for recombinant products. Blood Transfus. 2016;14(2):262-276.
57. Skinner MW. WFH: closing the global gap-achieving optimal care. Haemophilia. 2012;18(Suppl 4):1-12.
2. Coppola A, Tagliaferri A, Di Capua M, Franchini M. Prophylaxis in children with hemophilia: evidence-based achievements, old and new challenges. Semin Thromb Hemos. 2012;38(1):79-94.
3. Franchini M, Mannucci PM. The history of hemophilia. Semin Thromb Hemost. 2014;40(5):571-576.
4. Tabor E. The epidemiology of virus transmission by plasma derivatives: clinical studies verifying the lack of transmission of hepatitis B and C viruses and HIV type 1. Transfusion. 1999;39(11-12):1160-1168.
5. Nilsson IM, Berntorp E, Lofqvist T, Pettersson H. Twenty-five years’ experience of prophylactic treatment in severe haemophilia A and B. J Intern Med. 1992;232:25-32.
6. Manco-Johnson MJ, Kempton CL, Reding MT et al. Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand treatment with sucrose-formulated recombinant factor VIII in adults with severe hemophilia A (SPINART). J Thromb Haemost. 2013;11(6):1119-27.
7. Manco-Johnson MJ, Abshire TC, Shapiro AD et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357(6):535-44.
8. Hacker MR, Geraghty S, Manco-Johnson M. Barriers to compliance with prophylaxis therapy in haemophilia. Haemophilia. 2001;7:392-396.
9. Franchini M, Mannucci PM. Hemophilia A in the third millennium. Blood Rev. 2013; 27: 179-84.
10. Collins PW, Blanchette VS, Fischer K et al. Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A. J Thromb Haemost. 2009;7:413-420.
11. Collins PW, Bjorkman S, Fischer K et al. Factor VIII requirement to maintain a target plasma level in the prophylactic treatment of severe hemophilia A: influences of variance in pharmacokinetics and treatment regimens. J Thromb Haemost. 2010;8:269-275.
12. Walsh CE, Soucie JM, Miller CH. Impact of inhibitors on hemophilia A mortality in the United States. Am J Hematol. 2015;90(5):400-5.
13. Oldenburg J, Pavlova A. Genetic risk factors for inhibitors to factors VIII and IX. Haemophilia. 2006;12(Suppl6):15-22.
14. Astermark J, Altisent y col. Non-genetic risk factors and the development of inhibitors in haemophilia: a comprehensive review and consensus report. Haemophilia. 2010;16,747-766.
15. Astermark J, Donfield SM y col. E. A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA 10 - NovoSeven Comparative (FENOC) Study. Blood. 2007;109, 546-551.
16. Peyvandi F, Mannucci P y col. A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. New England Journal of Medicine. 2016;374,2054-2064.
17. Pipe SW, Montgomery RR, Pratt KP, Lenting PJ, Lillicrap D. Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A. Blood. 2016;128(16):2007-2016.
18. Pabinger-Fasching I. The story of a unique molecule in hemophilia A: recombinant single-chain factor VIII. Thromb Res. 2016;141 (suppl 3):S2-S4.
19. Zollner S, Raquet E, Claar P et al. Non-clinical pharmacokinetics and pharmacodynamics of rVIII-SingleChain, a novel recombinant singlechain factor VIII. Thromb Res. 2014;134(1):125-131.
20. Liesner et al Immunogenicity, efficacy and safety of Nuwiq® (human-cl rhFVIII) in previously untreated patients with severe haemophilia A—Interim results from the NuProtect Study. Haemophilia. 2018;24:211-220.
21. Mahlangu J, Powell JS, Ragni MV et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood. 2014;123:317-325.
22. Konkle BA, Stasyshyn O, Chowdary P et al. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood. 2015;126:1078-1085.
23. Reding MT, Ng HJ, Poulsen LH et al. Safety and efficacy of BAY 94-9027, a prolonged-half - life factor VIII. J Thromb Haemost. 2017;15:411-419.
24. Giangrande P, Andreeva T, Chowdary P et al. Clinical evaluation of glycoPEGylated recombinant FVIII: efficacy and safety in severe haemophilia A. Thromb Haemost. 2017;117:252-261.
25. Santagostino E, Martinowitz U, Lissitchkov T et al. Long acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood. 2016;127:1761-1769.
26. Young G, Mahlangu JN. Extended half-life clotting factor concentrates: results from published clinical trials. Haemophilia. 2016;22(Suppl 5):25-30.
27. Oldenburg J, Kulkarni R, Srivastava A et al. Improved joint health in subjects with severe haemophilia A treated prophylactically with recombinant factor VIII Fc fusion protein. Haemophilia. 2018;24:77-84.
28. Mancuso ME, Santagostino E. Outcome of clinical trials with new extended half-life FVIII/ IX concentrates. J Clin Med. 2017, April 6 (4): E39.
29. Monahan PE. Emerging genetic and pharmacologic therapies for controlling hemostasis: beyond recombinant clotting factors. Hematol Am Soc Hematol Educ Program. 2015;2015:33-40.
30. Ragni MV. Novel alternate hemostatic agents for patients with inhibitors: beyond bypass therapy. Hematol Am Soc Hematol Educ Program. 2017;2017:605-609.
31. Sampei Z, Igawa T, Soeda T, Okuyama-Nishida Y,Moriyama C, Wakabayashi T, Tanaka E, Muto A, KojimaT, Kitazawa T, Yoshihashi K, Harada A, Funaki M, Haraya K, Tachibana T, Suzuki S, Esaki K, Nabuchi Y, Hattori K. Identification and multidimensional optimization of an asymmetric bispecific IgG antibody mimicking the function of factor VIII cofactor activity. PloS One. 2013; 8:e57479.
32. Uchida N, Sambe T, Yoneyama K, Fukazawa N, Kawanishi T, Kobayashi S, Shima M. A first-in-human phase 1 study of ACE910, a novel factor VIII-mimetic bispecific antibody, in healthy subjects. Blood. 2016;127:1633-1641.
33. Muto A, Yoshihashi K, Takeda M, Kitazawa T, SoedaT, Igawa T, Sampei Z, Kuramochi T, Sakamoto A,Haraya K, Adachi K, Kawabe Y, Nogami K, Shima M, Hattori K. Anti-factor IXa/X bispecific antibody ACE910 prevents joint bleeds in a long-term primate model of acquired hemophilia A. Blood. 2014;124:3165-3171.
34. Oldenburg J et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med. 377,809-818 (2017).
35. Collins W, Liesner R, Makris M, Talks K, Chowdary P, Chalmers E, Hall G, Ridell A, Percy C, Hay C, Hart D, Collins et al. Haemophilia. 2018;24:344-347.
36. Mahlangu J, Oldenburg J, Paz-Priel I, Negrier C, Niggli M, Mancuso M, Schmitt C, Jimenez Yuste V, Kempton C, Dhalluin C, Callaghan M, Bujan W, Shima M, Adamkewicz JI, Asikanius E, Levy GG, Kruse Jarres R. Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors. N Engl J Med. 2018;379:811-22.
37. Ishiguro, K et al. Complete antithrombin deficiency in mice results in embryonic lethality. J Clin Invest. 106,873-878 (2000).
38. Pasi KJ, Rangarajan S, Georgiev P et al. Targeting of antithrombin in hemophilia A or B with RNAi therapy. N Engl J Med. 2017;377:819-828.
39. Pasi KJ, Georgiev P, Mant T et al. Fitusiran, an investigational RNAi therapeutic targeting antithrombin for the treatment of hemophilia: interim results from a phase 2 extension study in patients with hemophilia A or B with and without inhibitors. Res Pract Thromb Haemost. 2017;1(suppl 1).
40. Chowdary P et al. Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial. J Thromb Haemost. 2015;13,743-754.
41. Waters EK, Sigh J, Friedrich U, Hilden I, Sorensen BB. Concizumab, an anti-tissue factor pathway inhibitor antibody, induces increased thrombin generation in plasma from haemophilia patients and healthy subjects measured by the thrombin generation assay. Haemophilia. 2017;23:769-776.
42. Yegneswaran S et al. BAY 1093884 binds to the kunitz 1 and 2 domain interface of tissue factor pathway inhibitor and inhibits its function [abstract]. Res Pract Thromb Haemost. 2017;1 (Suppl. 1), PB 892.
43. Hough C, Lillicrap D. Gene therapy for hemophilia: an imperative to succeed. J Thromb Haemost. 2005;3:1195-1205.
44. Manno CS, Chew AJ, Hutchison S et al. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood. 2003;101:2963-2972.
45. Manno CS, Pierce GF, Arruda VR et al. Successful transduction of liver in hemophilia by AAV-factor IX and limitations imposed by the host immune response. Nat Med. 2006;12:342-347.
46. Mingozzi F, Maus MV, Hui DJ et al. CD8(+) T-cell responses to adeno-associated virus capsid in humans. Nat Med. 2007;13:419-422.
47. Nathwani AC, Tuddenham EG, Rangarajan S et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011;365:2357-2365.
48. Nathwani AC, Reiss UM, Tuddenham EG et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med. 2014;371:1994-2004.
49. George LA, Sullivan SK, Giermasz A et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N Engl J Med. 2017;377:2215-2227.
50. Miesbach W, Meijer K, Coppens M et al. Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. Blood. 2018;131:1022-1031.
51. Rangarajan S, Walsh L, Lester W et al. AAV5-factor VIII gene transfer in severe hemophilia A. N Engl J Med. 2017;377:2519-2530.
52. Favaloro EJ. Von Willebrand disease: local diagnosis and management of a globally distributed bleeding disorder. Semin Thromb Hemost. 2011; 37: 425-6.
53. Mannucci PM, Kempton C, Millar C et al. rVWF Ad Hoc Study Group Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial. Blood. 2013; 122: 648-57.
54. Gill JC, Castaman G, Windyga J et al. Hemostatic efficacy, safety and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood. 2013; 126: 2038-46.
55. Franchini M, Mannucci PM. Von Willebrand factor (Vonvendi®): the first recombinant product licensed for the treatment of von Willebrand disease. Expert Rev Hematol. 2016;9(9):825-830
56. Favaloro EJ. Towards personalized therapy for von Willebrand disease: a future role for recombinant products. Blood Transfus. 2016;14(2):262-276.
57. Skinner MW. WFH: closing the global gap-achieving optimal care. Haemophilia. 2012;18(Suppl 4):1-12.
- Resumen visto - 170 veces
- pdf descargado - 205 veces
Descargas
La descarga de datos todavía no está disponible.
Copyright
© G Arbesú, 2018
Afiliaciones
G Arbesú
Servicio de Hematología. Hospital Humberto Notti. Mendoza
Nuevos tratamientos en hemofilia y enfermedad de von Willebrand
Vol. 22 Núm. Extraordin (2018): Extraordinario II Jornadas Latinoamericanas
Enviado: ene 20, 2019
Publicado: ene 21, 2019
Resumen
La hemofilia es una enfermedad hemorrágica ligada al cromosoma X, producida por la deficiencia del factor VIII (hemofilia A) o IX (hemofilia B)
Las manifestaciones clínicas de la enfermedad sin adecuado tratamiento son los sangrados prolongados, principalmente hemartrosis. Tobillos, rodillas y codos se afectan con mayor frecuencia.
La hemorragia puede ocurrir en cualquier órgano o tejido, particularmente después de un trauma.
El sangrado musculoesquelético es característico en la hemofilia, aunque también puede ocurrir en mucosas, particularmente epistaxis.