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Clinical manifestations and diagnosis of hemophilia

W Keith Hoots, MD
Amy D Shapiro, MD
Section Editors
Lawrence LK Leung, MD
Donald H Mahoney, Jr, MD
Deputy Editor
Jennifer S Tirnauer, MD


Hemophilia A and B are X-linked recessive diseases that present in male children of carrier females. However, hemophilia must sometimes be differentiated from other bleeding disorders when the family history is negative or unknown. Differentiation between hemophilia and other conditions, such as some types of von Willebrand disease or acquired factor inhibitors, and distinction between hemophilia A and B are crucial for appropriate management.

The clinical manifestations and diagnosis of hemophilia A and B will be reviewed here, along with a discussion of obstetrical issues. Other issues related to care for people with hemophilia are presented separately.

Routine care including prophylaxis – (See "Hemophilia A and B: Routine management including prophylaxis".)

Treatment of bleeding and perioperative management – (See "Treatment of bleeding and perioperative management in hemophilia A and B".)

Inhibitors – (See "Factor VIII and factor IX inhibitors in patients with hemophilia".)

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Literature review current through: Nov 2017. | This topic last updated: Dec 05, 2017.
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  1. Blanchette VS, Key NS, Ljung LR, et al. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2014; 12:1935.
  2. White GC 2nd, Rosendaal F, Aledort LM, et al. Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 2001; 85:560.
  3. Franchini M, Favaloro EJ, Lippi G. Mild hemophilia A. J Thromb Haemost 2010; 8:421.
  4. Carcao MD. The diagnosis and management of congenital hemophilia. Semin Thromb Hemost 2012; 38:727.
  5. Shetty S. Haemophilia - diagnosis and management challenges. Mol Cytogenet 2014; 7:I44.
  6. Venkateswaran L, Wilimas JA, Jones DJ, Nuss R. Mild hemophilia in children: prevalence, complications, and treatment. J Pediatr Hematol Oncol 1998; 20:32.
  7. Santagostino E, Mancuso ME, Tripodi A, et al. Severe hemophilia with mild bleeding phenotype: molecular characterization and global coagulation profile. J Thromb Haemost 2010; 8:737.
  8. Lee DH, Walker IR, Teitel J, et al. Effect of the factor V Leiden mutation on the clinical expression of severe hemophilia A. Thromb Haemost 2000; 83:387.
  9. Shetty S, Vora S, Kulkarni B, et al. Contribution of natural anticoagulant and fibrinolytic factors in modulating the clinical severity of haemophilia patients. Br J Haematol 2007; 138:541.
  10. van Dijk K, van der Bom JG, Fischer K, et al. Do prothrombotic factors influence clinical phenotype of severe haemophilia? A review of the literature. Thromb Haemost 2004; 92:305.
  11. Escuriola Ettingshausen C, Halimeh S, Kurnik K, et al. Symptomatic onset of severe hemophilia A in childhood is dependent on the presence of prothrombotic risk factors. Thromb Haemost 2001; 85:218.
  12. Mauser Bunschoten EP, van Houwelingen JC, Sjamsoedin Visser EJ, et al. Bleeding symptoms in carriers of hemophilia A and B. Thromb Haemost 1988; 59:349.
  13. Kulkarni R, Soucie JM, Lusher J, et al. Sites of initial bleeding episodes, mode of delivery and age of diagnosis in babies with haemophilia diagnosed before the age of 2 years: a report from The Centers for Disease Control and Prevention's (CDC) Universal Data Collection (UDC) project. Haemophilia 2009; 15:1281.
  14. Kulkarni R, Presley RJ, Lusher JM, et al. Complications of haemophilia in babies (first two years of life): a report from the Centers for Disease Control and Prevention Universal Data Collection System. Haemophilia 2017; 23:207.
  15. Ljung R, Petrini P, Nilsson IM. Diagnostic symptoms of severe and moderate haemophilia A and B. A survey of 140 cases. Acta Paediatr Scand 1990; 79:196.
  16. Pollmann H, Richter H, Ringkamp H, Jürgens H. When are children diagnosed as having severe haemophilia and when do they start to bleed? A 10-year single-centre PUP study. Eur J Pediatr 1999; 158 Suppl 3:S166.
  17. Rizza CR. The clinical features of clotting factor deficiencies. In: Human Blood Coagulation Haemostasis and Thrombosis, 2nd ed, Biggs R (Ed), Blackwell Scientific Publications, Oxford 1976. p.238.
  18. Kitchens CS. Occult hemophilia. Johns Hopkins Med J 1980; 146:255.
  19. Eyster ME, Gill FM, Blatt PM, et al. Central nervous system bleeding in hemophiliacs. Blood 1978; 51:1179.
  20. Klinge J, Auberger K, Auerswald G, et al. Prevalence and outcome of intracranial haemorrhage in haemophiliacs--a survey of the paediatric group of the German Society of Thrombosis and Haemostasis (GTH). Eur J Pediatr 1999; 158 Suppl 3:S162.
  21. Kulkarni R, Lusher JM. Intracranial and extracranial hemorrhages in newborns with hemophilia: a review of the literature. J Pediatr Hematol Oncol 1999; 21:289.
  22. Tarantino MD, Gupta SL, Brusky RM. The incidence and outcome of intracranial haemorrhage in newborns with haemophilia: analysis of the Nationwide Inpatient Sample database. Haemophilia 2007; 13:380.
  23. Richards M, Lavigne Lissalde G, Combescure C, et al. Neonatal bleeding in haemophilia: a European cohort study. Br J Haematol 2012; 156:374.
  24. Koch JA. Haemophilia in the newborn. A case report and literature review. S Afr Med J 1978; 53:721.
  25. Plummer ES, Crary SE, Buchanan GR. Prominent forehead hematomas ("goose-eggs") as an initial manifestation of hemophilia. J Pediatr 2013; 163:1781.
  26. Franchini M, Mannucci PM. Hemophilia A in the third millennium. Blood Rev 2013; 27:179.
  27. Ljung RC. Intracranial haemorrhage in haemophilia A and B. Br J Haematol 2008; 140:378.
  28. Witmer C, Presley R, Kulkarni R, et al. Associations between intracranial haemorrhage and prescribed prophylaxis in a large cohort of haemophilia patients in the United States. Br J Haematol 2011; 152:211.
  29. Nelson MD Jr, Maeder MA, Usner D, et al. Prevalence and incidence of intracranial haemorrhage in a population of children with haemophilia. The Hemophilia Growth and Development Study. Haemophilia 1999; 5:306.
  30. Nuss R, Soucie JM, Evatt B, Hemophilia Surveillance System Project Investigators. Changes in the occurrence of and risk factors for hemophilia-associated intracranial hemorrhage. Am J Hematol 2001; 68:37.
  31. Aviña-Zubieta JA, Galindo-Rodriguez G, Lavalle C. Rheumatic manifestations of hematologic disorders. Curr Opin Rheumatol 1998; 10:86.
  32. Steven MM, Yogarajah S, Madhok R, et al. Haemophilic arthritis. Q J Med 1986; 58:181.
  33. Querol F, Rodriguez-Merchan EC. The role of ultrasonography in the diagnosis of the musculo-skeletal problems of haemophilia. Haemophilia 2012; 18:e215.
  34. Fernandez-Palazzi F, Hernandez SR, De Bosch NB, De Saez AR. Hematomas within the iliopsoas muscles in hemophilic patients: the Latin American experience. Clin Orthop Relat Res 1996; :19.
  35. Jaovisidha S, Ryu KN, Hodler J, et al. Hemophilic pseudotumor: spectrum of MR findings. Skeletal Radiol 1997; 26:468.
  36. Bogdan CJ, Strauss M, Ratnoff OD. Airway obstruction in hemophilia (factor VIII deficiency): a 28-year institutional review. Laryngoscope 1994; 104:789.
  37. Jones JJ, Kitchens CS. Spontaneous intra-abdominal hemorrhage in hemophilia. Arch Intern Med 1984; 144:297.
  38. McCoy HE 3rd, Kitchens CS. Small bowel hematoma in a hemophiliac as a cause of pseudoappendicitis: diagnosis by CT imaging. Am J Hematol 1991; 38:138.
  39. Small S, Rose PE, McMillan N, et al. Haemophilia and the kidney: assessment after 11-year follow-up. Br Med J (Clin Res Ed) 1982; 285:1609.
  40. Prentice CR, Lindsay RM, Barr RD, et al. Renal complications in haemophilia and Christmas disease. Q J Med 1971; 40:47.
  41. MERSKEY C. The occurrence of haemophilia in the human female. Q J Med 1951; 20:299.
  42. Panarello C, Acquila M, Caprino D, et al. Concomitant Turner syndrome and hemophilia A in a female with an idic(X)(p11) heterozygous at locus DXS52. Cytogenet Cell Genet 1992; 59:241.
  43. Pavlova A, Brondke H, Müsebeck J, et al. Molecular mechanisms underlying hemophilia A phenotype in seven females. J Thromb Haemost 2009; 7:976.
  44. Mori PG, Pasino M, Vadalà CR, et al. Haemophilia 'A' in a 46,X,i(Xq) female. Br J Haematol 1979; 43:143.
  45. Staber J, Croteau SE, Davis J, et al. The spectrum of bleeding in women and girls with haemophilia B. Haemophilia 2017.
  46. Plug I, Mauser-Bunschoten EP, Bröcker-Vriends AH, et al. Bleeding in carriers of hemophilia. Blood 2006; 108:52.
  47. Aledort LM, Haschmeyer RH, Pettersson H. A longitudinal study of orthopaedic outcomes for severe factor-VIII-deficient haemophiliacs. The Orthopaedic Outcome Study Group. J Intern Med 1994; 236:391.
  48. Mazepa MA, Monahan PE, Baker JR, et al. Men with severe hemophilia in the United States: birth cohort analysis of a large national database. Blood 2016; 127:3073.
  49. Luck JV Jr, Silva M, Rodriguez-Merchan EC, et al. Hemophilic arthropathy. J Am Acad Orthop Surg 2004; 12:234.
  50. Jansen NW, Roosendaal G, Lafeber FP. Understanding haemophilic arthropathy: an exploration of current open issues. Br J Haematol 2008; 143:632.
  51. Madhok R, Bennett D, Sturrock RD, Forbes CD. Mechanisms of joint damage in an experimental model of hemophilic arthritis. Arthritis Rheum 1988; 31:1148.
  52. Hakobyan N, Kazarian T, Jabbar AA, et al. Pathobiology of hemophilic synovitis I: overexpression of mdm2 oncogene. Blood 2004; 104:2060.
  53. Horowitz B, Prince AM, Hamman J, Watklevicz C. Viral safety of solvent/detergent-treated blood products. Blood Coagul Fibrinolysis 1994; 5 Suppl 3:S21.
  54. Mannucci PM. Clinical evaluation of viral safety of coagulation factor VIII and IX concentrates. Vox Sang 1993; 64:197.
  55. Troisi CL, Hollinger FB, Hoots WK, et al. A multicenter study of viral hepatitis in a United States hemophilic population. Blood 1993; 81:412.
  56. Kumar A, Kulkarni R, Murray DL, et al. Serologic markers of viral hepatitis A, B, C, and D in patients with hemophilia. J Med Virol 1993; 41:205.
  57. Kroner BL, Rosenberg PS, Aledort LM, et al. HIV-1 infection incidence among persons with hemophilia in the United States and western Europe, 1978-1990. Multicenter Hemophilia Cohort Study. J Acquir Immune Defic Syndr 1994; 7:279.
  58. Soucie JM, Richardson LC, Evatt BL, et al. Risk factors for infection with HBV and HCV in a largecohort of hemophiliac males. Transfusion 2001; 41:338.
  59. Arnold DM, Julian JA, Walker IR, Association of Hemophilia Clinic Directors of Canada. Mortality rates and causes of death among all HIV-positive individuals with hemophilia in Canada over 21 years of follow-up. Blood 2006; 108:460.
  60. Morfini M, Mannucci PM, Ciavarella N, et al. Prevalence of infection with the hepatitis C virus among Italian hemophiliacs before and after the introduction of virally inactivated clotting factor concentrates: a retrospective evaluation. Vox Sang 1994; 67:178.
  61. Tradati F, Colombo M, Mannucci PM, et al. A prospective multicenter study of hepatocellular carcinoma in italian hemophiliacs with chronic hepatitis C. The Study Group of the Association of Italian Hemophilia Centers. Blood 1998; 91:1173.
  62. Eyster ME, Diamondstone LS, Lien JM, et al. Natural history of hepatitis C virus infection in multitransfused hemophiliacs: effect of coinfection with human immunodeficiency virus. The Multicenter Hemophilia Cohort Study. J Acquir Immune Defic Syndr 1993; 6:602.
  63. Santagostino E, Mannucci PM, Gringeri A, et al. Transmission of parvovirus B19 by coagulation factor concentrates exposed to 100 degrees C heat after lyophilization. Transfusion 1997; 37:517.
  64. Gaboulaud V, Parquet A, Tahiri C, et al. Prevalence of IgG antibodies to human parvovirus B19 in haemophilia children treated with recombinant factor (F)VIII only or with at least one plasma-derived FVIII or FIX concentrate: results from the French haemophilia cohort. Br J Haematol 2002; 116:383.
  65. Morfini M, Longo G, Rossi Ferrini P, et al. Hypoplastic anemia in a hemophiliac first infused with a solvent/detergent treated factor VIII concentrate: the role of human B19 parvovirus. Am J Hematol 1992; 39:149.
  66. Donfield SM, Lynn HS, Lail AE, et al. Delays in maturation among adolescents with hemophilia and a history of inhibitors. Blood 2007; 110:3656.
  67. Favaloro EJ, Meijer P, Jennings I, et al. Problems and solutions in laboratory testing for hemophilia. Semin Thromb Hemost 2013; 39:816.
  68. Thompson AR, Bajaj SP, Chen SH, MacGillivray RT. "Founder" effect in different families with haemophilia B mutation. Lancet 1990; 335:418.
  69. Lawn RM. The molecular genetics of hemophilia: blood clotting factors VIII and IX. Cell 1985; 42:405.
  70. Kleinveld HA, Andersson NE, van Voorthuizen H, et al. Determination of coagulation factor VIII activity by a chromogenic substrate method on STA, an automated coagulation analyzer. Scand J Clin Lab Invest 1999; 59:335.
  71. Bowyer AE, Van Veen JJ, Goodeve AC, et al. Specific and global coagulation assays in the diagnosis of discrepant mild hemophilia A. Haematologica 2013; 98:1980.
  72. Potgieter JJ, Damgaard M, Hillarp A. One-stage vs. chromogenic assays in haemophilia A. Eur J Haematol 2015; 94 Suppl 77:38.
  73. Hellstern P, Miyashita C, Köhler M, et al. Measurement of factor VIII procoagulant antigen in normal subjects and in hemophilia A patients by an immunoradiometric assay and by an enzyme-linked immunosorbent assay. Haemostasis 1987; 17:173.
  74. Keeling DM, Sukhu K, Kemball-Cook G, et al. Diagnostic importance of the two-stage factor VIII:C assay demonstrated by a case of mild haemophilia associated with His1954-->Leu substitution in the factor VIII A3 domain. Br J Haematol 1999; 105:1123.
  75. Rudzki Z, Duncan EM, Casey GJ, et al. Mutations in a subgroup of patients with mild haemophilia A and a familial discrepancy between the one-stage and two-stage factor VIII:C methods. Br J Haematol 1996; 94:400.
  76. Goodeve AC. Advances in carrier detection in haemophilia. Haemophilia 1998; 4:358.
  77. Kazazian HH Jr. The molecular basis of hemophilia A and the present status of carrier and antenatal diagnosis of the disease. Thromb Haemost 1993; 70:60.
  78. Poon MC, Chui DH, Patterson M, et al. Hemophilia B (Christmas disease) variants and carrier detection analyzed by DNA probes. J Clin Invest 1987; 79:1204.
  79. http://www.mylifeourfuture.org/ (Accessed on August 29, 2014).
  80. http://www.genetests.org/search/tests.php?search=hemophilia&submit=Search&start=0 (Accessed on August 29, 2014).
  81. Antonarakis SE, Waber PG, Kittur SD, et al. Hemophilia A. Detection of molecular defects and of carriers by DNA analysis. N Engl J Med 1985; 313:842.
  82. Lakich D, Kazazian HH Jr, Antonarakis SE, Gitschier J. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nat Genet 1993; 5:236.
  83. Antonarakis SE, Rossiter JP, Young M, et al. Factor VIII gene inversions in severe hemophilia A: results of an international consortium study. Blood 1995; 86:2206.
  84. Jenkins PV, Collins PW, Goldman E, et al. Analysis of intron 22 inversions of the factor VIII gene in severe hemophilia A: implications for genetic counseling. Blood 1994; 84:2197.
  85. Bagnall RD, Waseem N, Green PM, Giannelli F. Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A. Blood 2002; 99:168.
  86. Gouw SC, van den Berg HM, Oldenburg J, et al. F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis. Blood 2012; 119:2922.
  87. Klein HG, Aledort LM, Bouma BN, et al. A co-operative study for the detection of the carrier state of classic hemophilia. N Engl J Med 1977; 296:959.
  88. Kadir RA, Davies J, Winikoff R, et al. Pregnancy complications and obstetric care in women with inherited bleeding disorders. Haemophilia 2013; 19 Suppl 4:1.
  89. Tsui NB, Kadir RA, Chan KC, et al. Noninvasive prenatal diagnosis of hemophilia by microfluidics digital PCR analysis of maternal plasma DNA. Blood 2011; 117:3684.
  90. Hudecova I, Jiang P, Davies J, et al. Noninvasive detection of F8 int22h-related inversions and sequence variants in maternal plasma of hemophilia carriers. Blood 2017; 130:340.
  91. James AH, Hoots K. The optimal mode of delivery for the haemophilia carrier expecting an affected infant is caesarean delivery. Haemophilia 2010; 16:420.
  92. Ljung R. The optimal mode of delivery for the haemophilia carrier expecting an affected infant is vaginal delivery. Haemophilia 2010; 16:415.
  93. Towner D, Castro MA, Eby-Wilkens E, Gilbert WM. Effect of mode of delivery in nulliparous women on neonatal intracranial injury. N Engl J Med 1999; 341:1709.
  94. Chalmers E, Williams M, Brennand J, et al. Guideline on the management of haemophilia in the fetus and neonate. Br J Haematol 2011; 154:208.
  95. https://www.hemophilia.org/Researchers-Healthcare-Providers/Medical-and-Scientific-Advisory-Council-MASAC/All-MASAC-Recommendations/Guidelines-for-Perinatal-Management-of-Women-with-Bleeding-Disorders-and-Carriers-of-Hemophilia-A-and-B (Accessed on September 22, 2014).
  96. http://www.hemophilia.org/Researchers-Healthcare-Providers/Medical-and-Scientific-Advisory-Council-MASAC/All-MASAC-Recommendations/Guidelines-for-Perinatal-Management-of-Women-with-Bleeding-Disorders-and-Carriers-of-Hemophilia-A-and-B (Accessed on August 28, 2014).