RSS-Feed abonnieren
DOI: 10.1055/s-0032-1326786
The Diagnosis and Management of Congenital Hemophilia
Publikationsverlauf
Publikationsdatum:
25. September 2012 (online)
![](https://www.thieme-connect.de/media/sth/201207/lookinside/thumbnails/10.1055-s-0032-1326786-1.jpg)
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.
-
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
- 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
- 3 Bowen DJ. Haemophilia A and haemophilia B: molecular insights. Mol Pathol 2002; 55 (1) 1-18
- 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
- 5 Jacquemin M, Neyrinck A, Hermanns MI , et al. FVIII production by human lung microvascular endothelial cells. Blood 2006; 108 (2) 515-517
- 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
- 7 Fang H, Wang L, Wang H. The protein structure and effect of factor VIII. Thromb Res 2007; 119 (1) 1-13
- 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
- 9 Lillicrap D. The molecular basis of haemophilia B. Haemophilia 1998; 4 (4) 350-357
- 10 Weston BW, Monahan PE. Familial deficiency of vitamin K-dependent clotting factors. Haemophilia 2008; 14 (6) 1209-1213
- 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
- 12 Mazurier C. von Willebrand disease masquerading as haemophilia A. Thromb Haemost 1992; 67 (4) 391-396
- 13 Spreafico M, Peyvandi F. Combined FV and FVIII deficiency. Haemophilia 2008; 14 (6) 1201-1208
- 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
- 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
- 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
- 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
- 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
- 19 Ljung RC. Intracranial haemorrhage in haemophilia A and B. Br J Haematol 2008; 140 (4) 378-384
- 20 Kulkarni R, Lusher J. Perinatal management of newborns with haemophilia. Br J Haematol 2001; 112 (2) 264-274
- 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
- 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
- 23 Valentino LA. Blood-induced joint disease: the pathophysiology of hemophilic arthropathy. J Thromb Haemost 2010; 8 (9) 1895-1902
- 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
- 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
- 26 Mannucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood 1997; 90 (7) 2515-2521
- 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
- 28 Das P, Carcao M, Hitzler J. DDAVP-induced hyponatremia in young children. J Pediatr Hematol Oncol 2005; 27 (6) 330-332
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 38 Valentino LA, Ewenstein B, Navickis RJ, Wilkes MM. Central venous access devices in haemophilia. Haemophilia 2004; 10 (2) 134-146
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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