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Semin Thromb Hemost 2012; 38(07): 727-734
DOI: 10.1055/s-0032-1326786
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The Diagnosis and Management of Congenital Hemophilia

Manuel D. Carcao
1   Division of Haematology/Oncology and Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
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Publication History

Publication Date:
25 September 2012 (online)

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Abstract

Hemophilia is the most common, severe, inherited bleeding disorder recognized in humans and makes up the largest proportion of patients followed in most bleeding disorders' clinics. Persons with hemophilia have a life-long bleeding tendency that roughly correlates to their endogenous coagulant factor VIII (FVIII) or factor IX (FIX) level (FVIII:C and FIX:C). The hallmark of bleeding in severe hemophilia is musculoskeletal bleeds (soft tissue, muscle and joint bleeds) but persons with hemophilia are also prone to other bleeds including intracranial bleeds. The neonatal period is a particularly vulnerable period for persons with severe hemophilia. Diagnosing hemophilia is mainly based on measuring FVIII:C and FIX:C levels and on distinguishing hemophilia from other conditions that can cause a low FVIII:C or FIX:C level. Management involves preventing bleeds and rapidly treating those that occur. Bleed prevention in severe hemophilia can be accomplished by avoiding high-risk activities, taking appropriate precautions and early commencement of life-long prophylaxis. With proper management, persons with severe hemophilia can now live an essentially normal life. The development of an inhibitor does however complicate management. This review will summarize the very complex and multifaceted aspects of diagnosing and managing persons with hemophilia.

Keywords

hemophilia - diagnosis - management - prophylaxis
 

  • References

  • 1 Stonebraker JS, Bolton-Maggs PHB, Soucie JM, Walker I, Brooker M. A study of variations in the reported haemophilia A prevalence around the world. Haemophilia 2010; 16 (1) 20-32
    PubMedGoogle Scholar
  • 2 Stonebraker JS, Bolton-Maggs PHB, Michael Soucie J, Walker I, Brooker M. A study of variations in the reported haemophilia B prevalence around the world. Haemophilia 2012; 18 (3) e91-e94
    CrossrefPubMedGoogle Scholar
  • 3 Bowen DJ. Haemophilia A and haemophilia B: molecular insights. Mol Pathol 2002; 55 (1) 1-18
    CrossrefPubMedGoogle Scholar
  • 4 Do H, Healey JF, Waller EK, Lollar P. Expression of factor VIII by murine liver sinusoidal endothelial cells. J Biol Chem 1999; 274 (28) 19587-19592
    CrossrefPubMedGoogle Scholar
  • 5 Jacquemin M, Neyrinck A, Hermanns MI , et al. FVIII production by human lung microvascular endothelial cells. Blood 2006; 108 (2) 515-517
    CrossrefPubMedGoogle Scholar
  • 6 Shen BW, Spiegel PC, Chang C-H , et al. The tertiary structure and domain organization of coagulation factor VIII. Blood 2008; 111 (3) 1240-1247
    PubMedGoogle Scholar
  • 7 Fang H, Wang L, Wang H. The protein structure and effect of factor VIII. Thromb Res 2007; 119 (1) 1-13
    CrossrefPubMedGoogle Scholar
  • 8 Terraube V, O'Donnell JS, Jenkins PV. Factor VIII and von Willebrand factor interaction: biological, clinical and therapeutic importance. Haemophilia 2010; 16 (1) 3-13
    PubMedGoogle Scholar
  • 9 Lillicrap D. The molecular basis of haemophilia B. Haemophilia 1998; 4 (4) 350-357
    CrossrefPubMedGoogle Scholar
  • 10 Weston BW, Monahan PE. Familial deficiency of vitamin K-dependent clotting factors. Haemophilia 2008; 14 (6) 1209-1213
    CrossrefPubMedGoogle Scholar
  • 11 Rodgers SE, Duncan EM, Barbulescu DM, Quinn DM, Lloyd JV. In vitro kinetics of factor VIII activity in patients with mild haemophilia A and a discrepancy between one-stage and two-stage factor VIII assay results. Br J Haematol 2007; 136 (1) 138-145
    CrossrefPubMedGoogle Scholar
  • 12 Mazurier C. von Willebrand disease masquerading as haemophilia A. Thromb Haemost 1992; 67 (4) 391-396
    PubMedGoogle Scholar
  • 13 Spreafico M, Peyvandi F. Combined FV and FVIII deficiency. Haemophilia 2008; 14 (6) 1201-1208
    CrossrefPubMedGoogle Scholar
  • 14 Zhang B, McGee B, Yamaoka JS , et al. Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2. Blood 2006; 107 (5) 1903-1907
    CrossrefPubMedGoogle Scholar
  • 15 Picketts DJ, Mueller CR, Lillicrap D. Transcriptional control of the factor IX gene: analysis of five cis-acting elements and the deleterious effects of naturally occurring hemophilia B Leyden mutations. Blood 1994; 84 (9) 2992-3000
    PubMedGoogle Scholar
  • 16 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 (6) 2206-2212
    PubMedGoogle Scholar
  • 17 Rossiter JP, Young M, Kimberland ML , et al. Factor VIII gene inversions causing severe hemophilia A originate almost exclusively in male germ cells. Hum Mol Genet 1994; 3 (7) 1035-1039
    CrossrefPubMedGoogle Scholar
  • 18 Kulkarni R, Lusher JM. Intracranial and extracranial hemorrhages in newborns with hemophilia: a review of the literature. J Pediatr Hematol Oncol 1999; 21 (4) 289-295
    CrossrefPubMedGoogle Scholar
  • 19 Ljung RC. Intracranial haemorrhage in haemophilia A and B. Br J Haematol 2008; 140 (4) 378-384
    CrossrefPubMedGoogle Scholar
  • 20 Kulkarni R, Lusher J. Perinatal management of newborns with haemophilia. Br J Haematol 2001; 112 (2) 264-274
    CrossrefPubMedGoogle Scholar
  • 21 van Dijk K, van der Bom JG, Fischer K, Grobbee DE, van den Berg HM. Do prothrombotic factors influence clinical phenotype of severe haemophilia? A review of the literature. Thromb Haemost 2004; 92 (2) 305-310
    PubMedGoogle Scholar
  • 22 van Dijk K, Fischer K, van der Bom JG, Grobbee DE, van den Berg HM. Variability in clinical phenotype of severe haemophilia: the role of the first joint bleed. Haemophilia 2005; 11 (5) 438-443
    CrossrefPubMedGoogle Scholar
  • 23 Valentino LA. Blood-induced joint disease: the pathophysiology of hemophilic arthropathy. J Thromb Haemost 2010; 8 (9) 1895-1902
    CrossrefPubMedGoogle Scholar
  • 24 Robertson JD, Connolly B, Hilliard P, Wedge J, Babyn P, Carcao M. Acute haemarthrosis of the hip joint: rapid convalescence following ultrasound-guided needle aspiration. Haemophilia 2009; 15 (1) 390-393
    CrossrefPubMedGoogle Scholar
  • 25 Khawaji M, Astermark J, Akesson K, Berntorp E. Physical activity for prevention of osteoporosis in patients with severe haemophilia on long-term prophylaxis. Haemophilia 2010; 16 (3) 495-501
    PubMedGoogle Scholar
  • 26 Mannucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood 1997; 90 (7) 2515-2521
    PubMedGoogle Scholar
  • 27 Nolan B, White B, Smith J, O'Reily C, Fitzpatrick B, Smith OP. Desmopressin: therapeutic limitations in children and adults with inherited coagulation disorders. Br J Haematol 2000; 109 (4) 865-869
    CrossrefPubMedGoogle Scholar
  • 28 Das P, Carcao M, Hitzler J. DDAVP-induced hyponatremia in young children. J Pediatr Hematol Oncol 2005; 27 (6) 330-332
    CrossrefPubMedGoogle Scholar
  • 29 Collins PW, Björkman 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 (2) 269-275
    CrossrefPubMedGoogle Scholar
  • 30 Barnes C, Lillicrap D, Pazmino-Canizares J , et al. Pharmacokinetics of recombinant factor VIII (Kogenate-FS) in children and causes of inter-patient pharmacokinetic variability. Haemophilia 2006; 12 (Suppl 4) 40-49
    CrossrefPubMedGoogle Scholar
  • 31 Monahan PE, Liesner R, Sullivan ST, Ramirez ME, Kelly P, Roth DA. Safety and efficacy of investigator-prescribed BeneFIX prophylaxis in children less than 6 years of age with severe haemophilia B. Haemophilia 2010; 16 (3) 460-468
    PubMedGoogle Scholar
  • 32 Batorova A, Martinowitz U. Intermittent injections vs. continuous infusion of factor VIII in haemophilia patients undergoing major surgery. Br J Haematol 2000; 110 (3) 715-720
    CrossrefPubMedGoogle Scholar
  • 33 Negrier C, Knobe K, Tiede A, Giangrande P, Møss J. Enhanced pharmacokinetic properties of a glycoPEGylated recombinant factor IX: a first human dose trial in patients with hemophilia B. Blood 2011; 118 (10) 2695-2701
    CrossrefPubMedGoogle Scholar
  • 34 Nilsson IM, Berntorp E, Löfqvist T, Pettersson H. Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B. J Intern Med 1992; 232 (1) 25-32
    CrossrefPubMedGoogle Scholar
  • 35 Aledort LM, Haschmeyer RH, Pettersson H ; The Orthopaedic Outcome Study Group. A longitudinal study of orthopaedic outcomes for severe factor-VIII-deficient haemophiliacs. J Intern Med 1994; 236 (4) 391-399
    CrossrefPubMedGoogle Scholar
  • 36 Feldman BM, Pai M, Rivard GE , et al; Association of Hemophilia Clinic Directors of Canada Prophylaxis Study Group. Tailored prophylaxis in severe hemophilia A: interim results from the first 5 years of the Canadian Hemophilia Primary Prophylaxis Study. J Thromb Haemost 2006; 4 (6) 1228-1236
    CrossrefPubMedGoogle Scholar
  • 37 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) 535-544
    CrossrefPubMedGoogle Scholar
  • 38 Valentino LA, Ewenstein B, Navickis RJ, Wilkes MM. Central venous access devices in haemophilia. Haemophilia 2004; 10 (2) 134-146
    CrossrefPubMedGoogle Scholar
  • 39 Astermark J, Petrini P, Tengborn L, Schulman S, Ljung R, Berntorp E. Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized. Br J Haematol 1999; 105 (4) 1109-1113
    CrossrefPubMedGoogle Scholar
  • 40 Pavlova A, Delev D, Lacroix-Desmazes S , et al. Impact of polymorphisms of the major histocompatibility complex class II, interleukin-10, tumor necrosis factor-alpha and cytotoxic T-lymphocyte antigen-4 genes on inhibitor development in severe hemophilia A. J Thromb Haemost 2009; 7 (12) 2006-2015
    CrossrefPubMedGoogle Scholar
  • 41 Iorio A, Halimeh S, Holzhauer S , et al. Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review. J Thromb Haemost 2010; 8 (6) 1256-1265
    CrossrefPubMedGoogle Scholar
  • 42 Mancuso ME, Mannucci PM, Rocino A, Garagiola I, Tagliaferri A, Santagostino E. Source and purity of factor VIII products as risk factors for inhibitor development in patients with hemophilia A. J Thromb Haemost 2012; 10 (5) 781-790
    CrossrefPubMedGoogle Scholar
  • 43 Mannucci PM, Gringeri A, Peyvandi F, Santagostino E. Factor VIII products and inhibitor development: the SIPPET study (survey of inhibitors in plasma-product exposed toddlers). Haemophilia 2007; 13 (Suppl 5) 65-68
    CrossrefPubMedGoogle Scholar
  • 44 Konkle BA, Ebbesen LS, Erhardtsen E , et al. Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors. J Thromb Haemost 2007; 5 (9) 1904-1913
    CrossrefPubMedGoogle Scholar
  • 45 Leissinger C, Gringeri A, Antmen B , et al. Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors. N Engl J Med 2011; 365 (18) 1684-1692
    CrossrefPubMedGoogle Scholar
  • 46 Hay CR, DiMichele DM ; International Immune Tolerance Study. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood 2012; 119 (6) 1335-1344
    CrossrefPubMedGoogle Scholar