Download PDF
Semin Thromb Hemost 2015; 41(08): 826-831
DOI: 10.1055/s-0034-1395349
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Phenotypic Heterogeneity of Hemostasis in Severe Hemophilia

Keiji Nogami
1   Department of Pediatrics, Nara Medical University, Nara, Japan
,
Midori Shima
1   Department of Pediatrics, Nara Medical University, Nara, Japan
› Author Affiliations
Further Information

Publication History

Publication Date:
23 January 2015 (online)

    Permissions and Reprints

Abstract

A reduction in bleeding pattern and arthropathy appears to be observed in approximately 10% of the patients with severe hemophilia (< 1% clotting factor activity). These patients rarely bleed and do not always need prophylactic therapy of therapeutic products, resulting in the wide range of joint damage seen in patients with severe hemophilia. The cause(s) of this phenotypic heterogeneity has been investigated in many studies till date, but remains to be completely solved. The large heterogeneity of the clinical phenotype in severe hemophilia seems to be multifactorial, including variation in the levels of various procoagulant and anticoagulant factors, the balance between the coagulation and fibrinolysis systems, pharmacokinetics of therapeutic products, environmental factors including lifestyle activity, and the limitation of measurement at lower levels of clotting factors. As an approach toward clarification, studies should be designed to evaluate a homogenous cohort of hemophilic A patients with an intron 22 inversion who produce no factor VIII. In the future, by a combination of the measurement of lower levels of clotting factors and the evaluation of global clotting function, it might be possible to better grasp the potential of hemostatic coagulation in individual hemophilia patients, which should in turn be useful for the prediction of bleeding phenotype and the designation of adequate and long-term hemostatic management throughout their life.

Keywords

clinical phenotype - severe hemophilia - heterogeneity
 

  • References

  • 1 White II GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J ; Factor VIII and Factor IX Subcommittee. 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 (3) 560
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Schramm W, Royal S, Kroner B , et al; European haemophilia economic study group. Clinical outcomes and resource utilization associated with haemophilia care in Europe. Haemophilia 2002; 8 (1) 33-43
    PubMedGoogle Scholar
  • 3 Molho P, Rolland N, Lebrun T , et al. Epidemiological survey of the orthopaedic status of severe haemophilia A and B patients in France. The French Study Group. secretariat.haemophiles@cch.ap-hop-paris.fr. Haemophilia 2000; 6 (1) 23-32
    CrossrefPubMedGoogle Scholar
  • 4 Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. Lancet 2003; 361 (9371) 1801-1809
    CrossrefPubMedGoogle Scholar
  • 5 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
  • 6 Jayandharan GR, Srivastava A. The phenotypic heterogeneity of severe hemophilia. Semin Thromb Hemost 2008; 34 (1) 128-141
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 van den Berg HM, De Groot PH, Fischer K. Phenotypic heterogeneity in severe hemophilia. J Thromb Haemost 2007; 5 (Suppl. 01) 151-156
    CrossrefPubMedGoogle Scholar
  • 8 Hemker HC, Giesen P, Al Dieri R , et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33 (1) 4-15
    CrossrefPubMedGoogle Scholar
  • 9 Shima M, Matsumoto T, Fukuda K , et al. The utility of activated partial thromboplastin time (aPTT) clot waveform analysis in the investigation of hemophilia A patients with very low levels of factor VIII activity (FVIII:C). Thromb Haemost 2002; 87 (3) 436-441
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Onwuzurike N, Warrier I, Lusher JM. Types of bleeding seen during the first 30 months of life in children with severe haemophilia A and B. Haemophilia 1996; 2: 137-140
    PubMedGoogle Scholar
  • 11 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
  • 12 Plug I, van der Bom JG, Peters M , et al. Thirty years of hemophilia treatment in the Netherlands, 1972-2001. Blood 2004; 104 (12) 3494-3500
    CrossrefPubMedGoogle Scholar
  • 13 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 (2) 196-200
    PubMedGoogle Scholar
  • 14 Fischer K, van der Bom JG, Mauser-Bunschoten EP , et al. Endogenous clotting factor activity and long-term outcome in patients with moderate haemophilia. Thromb Haemost 2000; 84 (6) 977-980
    PubMedGoogle Scholar
  • 15 Rainsford SG, Hall A. A three-year study of adolescent boys suffering from haemophilia and allied disorders. Br J Haematol 1973; 24 (5) 539-551
    CrossrefPubMedGoogle Scholar
  • 16 Bertina RM, Koeleman BP, Koster T , et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369 (6475) 64-67
    CrossrefPubMedGoogle Scholar
  • 17 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 (2) 218-220
    PubMedGoogle Scholar
  • 18 Nichols WC, Amano K, Cacheris PM , et al. Moderation of hemophilia A phenotype by the factor V R506Q mutation. Blood 1996; 88 (4) 1183-1187
    PubMedGoogle Scholar
  • 19 Nowak-Göttl U, Escuriola C, Kurnik K , et al. Haemophilia and thrombophilia. What do we learn about combined inheritance of both genetic variations?. Hamostaseologie 2003; 23 (1) 36-40
    PubMedGoogle Scholar
  • 20 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 (3) 387-391
    PubMedGoogle Scholar
  • 21 Grünewald M, Siegemund A, Grünewald A, Konegan A, Koksch M, Griesshammer M. Paradoxical hyperfibrinolysis is associated with a more intensely haemorrhagic phenotype in severe congenital haemophilia. Haemophilia 2002; 8 (6) 768-775
    CrossrefPubMedGoogle Scholar
  • 22 van Dijk K, van der Bom JG, Fischer K, de Groot PG, van den Berg HM. Phenotype of severe hemophilia A and plasma levels of risk factors for thrombosis. J Thromb Haemost 2007; 5 (5) 1062-1064
    CrossrefPubMedGoogle Scholar
  • 23 Jayandharan GR, Nair SC, Poonnoose PM , et al. Polymorphism in factor VII gene modifies phenotype of severe haemophilia. Haemophilia 2009; 15 (6) 1228-1236
    CrossrefPubMedGoogle Scholar
  • 24 Foley JH, Nesheim ME, Rivard GE, Brummel-Ziedins KE. Thrombin activatable fibrinolysis inhibitor activation and bleeding in haemophilia A. Haemophilia 2012; 18 (3) e316-e322
    CrossrefPubMedGoogle Scholar
  • 25 Mosnier LO, Lisman T, van den Berg HM, Nieuwenhuis HK, Meijers JC, Bouma BN. The defective down regulation of fibrinolysis in haemophilia A can be restored by increasing the TAFI plasma concentration. Thromb Haemost 2001; 86 (4) 1035-1039
    PubMedGoogle Scholar
  • 26 Oldenburg J. Mutation profiling in haemophilia A. Thromb Haemost 2001; 85 (4) 577-579
    PubMedGoogle Scholar
  • 27 Jayandharan G, Shaji RV, Baidya S, Nair SC, Chandy M, Srivastava A. Identification of factor VIII gene mutations in 101 patients with haemophilia A: mutation analysis by inversion screening and multiplex PCR and CSGE and molecular modelling of 10 novel missense substitutions. Haemophilia 2005; 11 (5) 481-491
    CrossrefPubMedGoogle Scholar
  • 28 Jayandharan GR, Shaji RV, Baidya S, Nair SC, Chandy M, Srivastava A. Molecular characterization of factor IX gene mutations in 53 patients with haemophilia B in India. Thromb Haemost 2005; 94 (4) 883-886
    PubMedGoogle Scholar
  • 29 Goodeve AC, Preston FE, Peake IR. Factor VIII gene rearrangements in patients with severe haemophilia A. Lancet 1994; 343 (8893) 329-330
    CrossrefPubMedGoogle Scholar
  • 30 Bertina RM. Elevated clotting factor levels and venous thrombosis. Pathophysiol Haemost Thromb 2003; 33 (5-6) 395-400
    CrossrefPubMedGoogle Scholar
  • 31 Iacoviello L, Di Castelnuovo A, De Knijff P , et al. Polymorphisms in the coagulation factor VII gene and the risk of myocardial infarction. N Engl J Med 1998; 338 (2) 79-85
    CrossrefPubMedGoogle Scholar
  • 32 Frère C, Morange PE, Saut N , et al. Quantification of thrombin activatable fibrinolysis inhibitor (TAFI) gene polymorphism effects on plasma levels of TAFI measured with assays insensitive to isoform-dependent artefact. Thromb Haemost 2005; 94 (2) 373-379
    PubMedGoogle Scholar
  • 33 Frosst P, Blom HJ, Milos R , et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10 (1) 111-113
    CrossrefPubMedGoogle Scholar
  • 34 Fijnvandraat K, Peters M, ten Cate JW. Inter-individual variation in half-life of infused recombinant factor VIII is related to pre-infusion von Willebrand factor antigen levels. Br J Haematol 1995; 91 (2) 474-476
    CrossrefPubMedGoogle Scholar
  • 35 Vlot AJ, Mauser-Bunschoten EP, Zarkova AG , et al. The half-life of infused factor VIII is shorter in hemophiliac patients with blood group O than in those with blood group A. Thromb Haemost 2000; 83 (1) 65-69
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 van Dijk K, van der Bom JG, Lenting PJ , et al. Factor VIII half-life and clinical phenotype of severe hemophilia A. Haematologica 2005; 90 (4) 494-498
    PubMedGoogle Scholar
  • 37 Hilberg T, Herbsleb M, Puta C, Gabriel HH, Schramm W. Physical training increases isometric muscular strength and proprioceptive performance in haemophilic subjects. Haemophilia 2003; 9 (1) 86-93
    CrossrefPubMedGoogle Scholar
  • 38 Harris S, Boggio LN. Exercise may decrease further destruction in the adult haemophilic joint. Haemophilia 2006; 12 (3) 237-240
    CrossrefPubMedGoogle Scholar
  • 39 Czepa D, von Mackensen S, Hilberg T. Haemophilia & Exercise Project (HEP): the impact of 1-year sports therapy programme on physical performance in adult haemophilia patients. Haemophilia 2013; 19 (2) 194-199
    CrossrefPubMedGoogle Scholar
  • 40 Barnes C, Blanchette V, Lillicrap D , et al. Different clinical phenotype in triplets with haemophilia A. Haemophilia 2007; 13 (2) 202-205
    CrossrefPubMedGoogle Scholar
  • 41 Verhoef CM, van Roon JA, Vianen ME, Bijlsma JW, Lafeber FP. Interleukin 10 (IL-10), not IL-4 or interferon-gamma production, correlates with progression of joint destruction in rheumatoid arthritis. J Rheumatol 2001; 28 (9) 1960-1966
    PubMedGoogle Scholar
  • 42 Matsumoto T, Shima M, Takeyama M , et al. The measurement of low levels of factor VIII or factor IX in hemophilia A and hemophilia B plasma by clot waveform analysis and thrombin generation assay. J Thromb Haemost 2006; 4 (2) 377-384
    CrossrefPubMedGoogle Scholar
  • 43 Shima M, Matsumoto T, Ogiwara K. New assays for monitoring haemophilia treatment. Haemophilia 2008; 14 (Suppl. 03) 83-92
    CrossrefPubMedGoogle Scholar
  • 44 Trossaërt M, Regnault V, Sigaud M, Boisseau P, Fressinaud E, Lecompte T. Mild hemophilia A with factor VIII assay discrepancy: using thrombin generation assay to assess the bleeding phenotype. J Thromb Haemost 2008; 6 (3) 486-493
    CrossrefPubMedGoogle Scholar
  • 45 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 (4) 737-743
    CrossrefPubMedGoogle Scholar
  • 46 Gilmore R, Harmon S, Gannon C, Byrne M, O'Donnell JS, Jenkins PV. Thrombin generation in haemophilia A patients with mutations causing factor VIII assay discrepancy. Haemophilia 2010; 16 (4) 671-674
    PubMedGoogle Scholar
  • 47 Dargaud Y, Béguin S, Lienhart A , et al. Evaluation of thrombin generating capacity in plasma from patients with haemophilia A and B. Thromb Haemost 2005; 93 (3) 475-480
    PubMedGoogle Scholar
  • 48 Matsumoto T, Nogami K, Ogiwara K, Shima M. A modified thrombin generation test for investigating very low levels of factor VIII activity in hemophilia A. Int J Hematol 2009; 90 (5) 576-582
    CrossrefPubMedGoogle Scholar
  • 49 Yada K, Nogami K, Wakabayashi H, Fay PJ, Shima M. The mild phenotype in severe hemophilia A with Arg1781His mutation is associated with enhanced binding affinity of factor VIII for factor X. Thromb Haemost 2013; 109 (6) 1007-1015
    Article in Thieme ConnectPubMedGoogle Scholar