The Phenotypic Heterogeneity of Severe Hemophilia

ABSTRACT

It has been long recognized that 10 to 15% of patients with “phenotypically characterized” severe hemophilia (< 1% clotting factor activity) have relatively mild disease clinically. Not all these patients have frequent spontaneous bleeding, and even among those who bleed, the extent of joint damage tends to vary considerably. The basis for this difference has not been completely understood. This article reviews the literature on possible determinants of phenotypic variation in patients with severe hemophilia. Apart from the well-recognized associations of the level of residual clotting factor activity, pharmacokinetics of administered clotting factor concentrates, and presence of prothrombotic markers, there is evidence to suggest that variations in other coagulation proteins as assessed in tests of global hemostasis as well as the fibrinolytic system can affect the clinical severity of bleeding. We also hypothesize that mediators of the inflammatory response in the synovium are likely to impact the severity of joint damage in these patients. One of the major issues in the management of hemophilia today is to decide on ways in which therapy, particularly the initiation and intensity of prophylaxis, can be individualized. A detailed understanding of all factors that may contribute to joint damage in severe hemophilia could help us in tailoring therapy for these individuals.

Hemophilia - phenotype - heterogeneity

REFERENCES

• 1 Schramm W, Royal S, Kroner B et al.. Clinical outcomes and resource utilization associated with haemophilia care in Europe.  Haemophilia. 2002;  8 33-43
• 2 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. [e-mail].  Haemophilia. 2000;  6 23-32
• 3 Aledort L M, Haschmeyer R H, Pettersson H. A longitudinal study of orthopaedic outcomes for severe factor-VIII-deficient haemophiliacs. The Orthopaedic Outcome Study Group.  J Intern Med. 1994;  236 391-399
• 4 Bolton-Maggs P H, Pasi K J. Haemophilias A and B.  Lancet. 2003;  361 1801-1809
• 5 Beutler E. Discrepancies between genotype and phenotype in hematology: an important frontier.  Blood. 2001;  98 2597-2602
• 6 Astermark J, Oldenburg J, Escobar M, White II G C, Berntorp E. The Malmo International Brother Study (MIBS). Genetic defects and inhibitor development in siblings with severe hemophilia A.  Haematologica. 2005;  90 924-931
• 7 Vandenbroucke J P, Koster T, Briet E, Reitsma P H, Bertina R M, Rosendaal F R. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation.  Lancet. 1994;  344 1453-1457
• 8 van Dijk K, van der Bom J G, Fischer K, Grobbee D E, van den Berg H M. Do prothrombotic factors influence clinical phenotype of severe haemophilia? A review of the literature.  Thromb Haemost. 2004;  92 305-310
• 9 van Dijk K, van der Bom J G, Lenting P J et al.. Factor VIII half-life and clinical phenotype of severe hemophilia A.  Haematologica. 2005;  90 494-498
• 10 Handelsman J E. The knee joint in hemophilia.  Orthop Clin North Am. 1979;  10 139-173
• 11 Hoskinson J, Duthie R B. Management of musculoskeletal problems in the hemophilias.  Orthop Clin North Am. 1978;  9 455-480
• 12 Stein H, Duthie R B. The pathogenesis of chronic haemophilic arthropathy.  J Bone Joint Surg Br. 1981;  63B 601-609
• 13 Hooiveld M J, Roosendaal G, Jacobs K M et al.. Initiation of degenerative joint damage by experimental bleeding combined with loading of the joint: a possible mechanism of hemophilic arthropathy.  Arthritis Rheum. 2004;  50 2024-2031
• 14 Arnold W D, Hilgartner M W. Hemophilic arthropathy. Current concepts of pathogenesis and management.  J Bone Joint Surg Am. 1977;  59 287-305
• 15 van den Berg H M, De Groot P H, Fischer K. Phenotypic heterogeneity in severe hemophilia.  J Thromb Haemost. 2007;  5(Suppl 1) 151-156
• 16 Fischer K, van der Bom J G, Mauser-Bunschoten E P et al.. The effects of postponing prophylactic treatment on long-term outcome in patients with severe hemophilia.  Blood. 2002;  99 2337-2341
• 17 Pollmann H, Richter H, Ringkamp H, Jurgens 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-S170
• 18 Ramgren O. Haemophilia in Sweden. III. Symptomatology, with special reference to differences between haemophilia A and B.  Acta Med Scand. 1962;  171 237-242
• 19 Rainsford S G, Hall A. A three-year study of adolescent boys suffering from haemophilia and allied disorders.  Br J Haematol. 1973;  24 539-551
• 20 van Dijk K, Fischer K, van der Bom J G, Grobbee D E, van den Berg H M. Variability in clinical phenotype of severe haemophilia: the role of the first joint bleed.  Haemophilia. 2005;  11 438-443
• 21 Blanchette P, Rivard G, Israels S et al.. A survey of factor prophylaxis in the Canadian haemophilia A population.  Haemophilia. 2004;  10 679-683
• 22 Grunewald M, Siegemund A, Grunewald A, Konegan A, Koksch M, Griesshammer M. Paradoxical hyperfibrinolysis is associated with a more intensely haemorrhagic phenotype in severe congenital haemophilia.  Haemophilia. 2002;  8 768-775
• 23 Arbini A A, Mannucci P M, Bauer K A. Low prevalence of the factor V Leiden mutation among “severe” hemophiliacs with a “milder” bleeding diathesis.  Thromb Haemost. 1995;  74 1255-1258
• 24 Beltran-Miranda C P, Khan A, Jaloma-Cruz A R, Laffan M A. Thrombin generation and phenotypic correlation in haemophilia A.  Haemophilia. 2005;  11 326-334
• 25 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;  138 541-544
• 26 Srivastava A. Dose and response in haemophilia-optimization of factor replacement therapy.  Br J Haematol. 2004;  127 12-25
• 27 Gilbert M S. Prophylaxis: musculoskeletal evaluation.  Semin Hematol. 1993;  30 3-6
• 28 Pettersson H, Ahlberg A, Nilsson I M. A radiologic classification of hemophilic arthropathy.  Clin Orthop Relat Res. 1980;  149 153-159
• 29 Poonnoose P M, Srivastava A. Functional assessment of arthropathy-an international perspective.  Semin Hematol. 2006;  43 S27-S32
• 30 Dargaud Y, Meunier S, Negrier C. Haemophilia and thrombophilia: an unexpected association!.  Haemophilia. 2004;  10 319-326
• 31 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;  87 436-441
• 32 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;  85 218-220
• 33 Ghosh K, Shetty S, Mohanty D. Milder clinical presentation of haemophilia A with severe deficiency of factor VIII as measured by one-stage assay.  Haemophilia. 2001;  7 9-12
• 34 Sorensen B, Ingerslev J. Whole blood clot formation phenotypes in hemophilia A and rare coagulation disorders. Patterns of response to recombinant factor VIIa.  J Thromb Haemost. 2004;  2 102-110
• 35 Dargaud Y, Beguin S, Lienhart A et al.. Evaluation of thrombin generating capacity in plasma from patients with haemophilia A and B.  Thromb Haemost. 2005;  93 475-480
• 36 Siegemund T, Petros S, Siegemund A, Scholz U, Engelmann L. Thrombin generation in severe haemophilia A and B: the endogenous thrombin potential in platelet-rich plasma.  Thromb Haemost. 2003;  90 781-786
• 37 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;  4 377-384
• 38 Chandler W L, Rodgers G M, Sprouse J T, Thompson A R. Elevated hemostatic factor levels as potential risk factors for thrombosis.  Arch Pathol Lab Med. 2002;  126 1405-1414
• 39 Lee D H, Walker I R, Teitel J et al.. Effect of the factor V Leiden mutation on the clinical expression of severe hemophilia A.  Thromb Haemost. 2000;  83 387-391
• 40 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 36-40
• 41 Jayandharan G R, Nair S C, Poonoose P et al.. Polymorphisms in coagulant and inflammatory genes modify the phenotype of severe hemophilia A and B.  J Thomb Haemost. 2007;  5(Suppl 1) P_W_681
• 42 van Dijk K, van der Bom J G, Fischer K, de Groot P G, van den Berg H M. Phenotype of severe hemophilia A and plasma levels of risk factors for thrombosis.  J Thromb Haemost. 2007;  5 1062-1064
• 43 Mosnier L O, Lisman T, van den Berg H M, Nieuwenhuis H K, Meijers J C, Bouma B N. The defective down regulation of fibrinolysis in haemophilia A can be restored by increasing the TAFI plasma concentration.  Thromb Haemost. 2001;  86 1035-1039
• 44 Jayandharan G, Shaji R V, Baidya S, Nair S C, 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;  11 481-491
• 45 Jayandharan G R, Shaji R V, Baidya S, Nair S C, Chandy M, Srivastava A. Molecular characterization of factor IX gene mutations in 53 patients with haemophilia B in India.  Thromb Haemost. 2005;  94 883-886
• 46 Goodeve A C, Peake I R. The molecular basis of hemophilia A: genotype-phenotype relationships and inhibitor development.  Semin Thromb Hemost. 2003;  29 23-30
• 47 Bertina R M. Elevated clotting factor levels and venous thrombosis.  Pathophysiol Haemost Thromb. 2003/2004;  33 395-400
• 48 Endler G, Mannhalter C. Polymorphisms in coagulation factor genes and their impact on arterial and venous thrombosis.  Clin Chim Acta. 2003;  330 31-55
• 49 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 79-85
• 50 Frere C, Morange P E, 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;  94 373-379
• 51 Frosst P, Blom H J, Milos R et al.. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.  Nat Genet. 1995;  10 111-113
• 52 Hooiveld M, Roosendaal G, Vianen M, van den Berg M, Bijlsma J, Lafeber F. Blood-induced joint damage: longterm effects in vitro and in vivo.  J Rheumatol. 2003;  30 339-344
• 53 Roosendaal G, Vianen M E, Wenting M J et al.. Iron deposits and catabolic properties of synovial tissue from patients with haemophilia.  J Bone Joint Surg Br. 1998;  80 540-545
• 54 Hakobyan N, Kazarian T, Jabbar A A, Jabbar K J, Valentino L A. Pathobiology of hemophilic synovitis I: overexpression of mdm2 oncogene.  Blood. 2004;  104 2060-2064
• 55 Nishiya K. Stimulation of human synovial cell DNA synthesis by iron.  J Rheumatol. 1994;  21 1802-1807
• 56 Morris C J, Blake D R, Wainwright A C, Steven M M. Relationship between iron deposits and tissue damage in the synovium: an ultrastructural study.  Ann Rheum Dis. 1986;  45 21-26
• 57 Wen F Q, Jabbar A A, Chen Y X, Kazarian T, Patel D A, Valentino L A. c-myc proto-oncogene expression in hemophilic synovitis: in vitro studies of the effects of iron and ceramide.  Blood. 2002;  100 912-916
• 58 Petrovic-Rackov L, Pejnovic N. Clinical significance of IL-18, IL-15, IL-12 and TNF-alpha measurement in rheumatoid arthritis.  Clin Rheumatol. 2006;  25 448-452
• 59 Aguillon J C, Cruzat A, Aravena O, Salazar L, Llanos C, Cuchacovich M. Could single-nucleotide polymorphisms (SNPs) affecting the tumour necrosis factor promoter be considered as part of rheumatoid arthritis evolution?.  Immunobiology. 2006;  211 75-84
• 60 Poli F, Boschiero L, Giannoni F et al.. Tumour necrosis factor-alpha gene polymorphism: implications in kidney transplantation.  Cytokine. 2000;  12 1778-1783
• 61 Vinasco J, Beraun Y, Nieto A et al.. Polymorphism at the TNF loci in rheumatoid arthritis.  Tissue Antigens. 1997;  49 74-78
• 62 Huizinga T W, Keijsers V, Yanni G et al.. Are differences in interleukin 10 production associated with joint damage?.  Rheumatology (Oxford). 2000;  39 1180-1188
• 63 Kirkham B W, Lassere M N, Edmonds J P et al.. Synovial membrane cytokine expression is predictive of joint damage progression in rheumatoid arthritis: A two-year prospective study (the DAMAGE study cohort).  Arthritis Rheum. 2006;  54 1122-1131
• 64 Ghosh K, Shankarkumar U, Shetty S, Mohanty D. Chronic synovitis and HLA B27 in patients with severe haemophilia.  Lancet. 2003;  361 933-934
• 65 van Lent P L, Nabbe K, Blom A B et al.. Role of activatory Fc gamma RI and Fc gamma RIII and inhibitory Fc gamma RII in inflammation and cartilage destruction during experimental antigen-induced arthritis.  Am J Pathol. 2001;  159 2309-2320
• 66 Roosendaal G, Lafeber F P. Pathogenesis of haemophilic arthropathy.  Haemophilia. 2006;  12(Suppl 3) 117-121
• 67 McDonald A, Hoffman M, Hedner U, Roberts H R, Monroe D M. Restoring hemostatic thrombin generation at the time of cutaneous wounding does not normalize healing in hemophilia B.  J Thromb Haemost. 2007;  5 1577-1583
• 68 Conway E M, Collen D, Carmeliet P. Molecular mechanisms of blood vessel growth.  Cardiovasc Res. 2001;  49 507-521
• 69 Ollivier V, Chabbat J, Herbert J M, Hakim J, de Prost D. Vascular endothelial growth factor production by fibroblasts in response to factor VIIa binding to tissue factor involves thrombin and factor Xa.  Arterioscler Thromb Vasc Biol. 2000;  20 1374-1381
• 70 Jazwa A, Loboda A, Golda S et al.. Effect of heme and heme oxygenase-1 on vascular endothelial growth factor synthesis and angiogenic potency of human keratinocytes.  Free Radic Biol Med. 2006;  40 1250-1263
• 71 Fearon U, Reece R, Smith J, Emery P, Veale D J. Synovial cytokine and growth factor regulation of MMPs/TIMPs: implications for erosions and angiogenesis in early rheumatoid and psoriatic arthritis patients.  Ann N Y Acad Sci. 1999;  878 619-621
• 72 Drouart M, Saas P, Billot M et al.. High serum vascular endothelial growth factor correlates with disease activity of spondylarthropathies.  Clin Exp Immunol. 2003;  132 158-162
• 73 Butt C, Lim S, Greenwood C, Rahman P. VEGF, FGF1, FGF2 and EGF gene polymorphisms and psoriatic arthritis.  BMC Musculoskelet Disord. 2007;  8 1
• 74 Oen K, Malleson P N, Cabral D A et al.. Cytokine genotypes correlate with pain and radiologically defined joint damage in patients with juvenile rheumatoid arthritis.  Rheumatology (Oxford). 2005;  44 1115-1121
• 75 Bond G L, Hu W, Bond E E et al.. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans.  Cell. 2004;  119 591-602
• 76 Mura C, Nousbaum J B, Verger P et al.. Phenotype-genotype correlation in haemochromatosis subjects.  Hum Genet. 1997;  101 271-276
• 77 Alizadeh B Z, Njajou O T, Hazes J M et al.. The H63D variant in the HFE gene predisposes to arthralgia, chondrocalcinosis and osteoarthritis.  Ann Rheum Dis. 2007;  66 1436-1442
• 78 Cruz E, Porto G, Morais S, Campos M, de Sousa M. HFE mutations in the pathobiology of hemophilic arthropathy.  Blood. 2005;  105 3381-3382
• 79 Barnes C, Blanchette V, Lillicrap D et al.. Different clinical phenotype in triplets with haemophilia A.  Haemophilia. 2007;  13 202-205
• 80 Fraga M F, Ballestar E, Paz M F et al.. Epigenetic differences arise during the lifetime of monozygotic twins.  Proc Natl Acad Sci U S A. 2005;  102 10604-10609
• 81 Buzzard B M. Sports and hemophilia: antagonist or protagonist.  Clin Orthop Relat Res. 1996;  328 25-30
• 82 Sahyoun N R, Hochberg M C, Helmick C G, Harris T, Pamuk E R. Body mass index, weight change, and incidence of self-reported physician-diagnosed arthritis among women.  Am J Public Health. 1999;  89 391-394
• 83 Ahmed R, Kannan M, Choudhry V P, Saxena R. Does the MTHFR 677T allele alter the clinical phenotype in severe haemophilia A?.  Thromb Res. 2003;  109 71-72
• 84 Petkova R, Chakarov S, Horvath A, Ganev V, Kremensky I. Coexistence of a common prothrombotic risk factor and hemophilia in the Bulgarian hemophilic population:genotype/phenotype correlations.  Balkan J Med Genet. 2001;  4 37-39
• 85 Yee D L. Platelets as modifiers of clinical phenotype in hemophilia.  Sci World J. 2006;  6 661-668
• 86 Skogen B, Bellissimo D B, Hessner M J et al.. Rapid determination of platelet alloantigen genotypes by polymerase chain reaction using allele-specific primers.  Transfusion. 1994;  34 955-960
• 87 Poort S R, Rosendaal F R, Reitsma P H, Bertina R M. A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.  Blood. 1996;  88 3698-3703
• 88 Bertina R M, Koeleman B P, Koster T et al.. Mutation in blood coagulation factor V associated with resistance to activated protein C.  Nature. 1994;  369 64-67
• 89 Di Castelnuovo A, D'Orazio A, Amore C et al.. Genetic modulation of coagulation factor VII plasma levels: contribution of different polymorphisms and gender-related effects.  Thromb Haemost. 1998;  80 592-597
• 90 Kangsadalampai S, Board P. The Val34Leu polymorphism in the A subunit of coagulation factor XIII contributes to the large normal range in activity and demonstrates that the activation peptide plays a role in catalytic activity.  Blood. 1998;  92 2766-2770
• 91 Brouwers G J, Leebeek F W, Tanck M W, Wouter Jukema J, Kluft C, de Maat M P. Association between thrombin-activatable fibrinolysis inhibitor (TAFI) and clinical outcome in patients with unstable angina pectoris.  Thromb Haemost. 2003;  90 92-100
• 92 von Depka M, Czwalinna A, Eisert R et al.. Prevalence of a 23bp insertion in exon 3 of the endothelial cell protein C receptor gene in venous thrombophilia.  Thromb Haemost. 2001;  86 1360-1362
• 93 Marsik C, Endler G, Halama T et al.. Polymorphism in the tissue factor region is associated with basal but not endotoxin-induced tissue factor-mRNA levels in leukocytes.  J Thromb Haemost. 2006;  4 745-749
• 94 Heltianu C, Costache G, Azibi K, Poenaru L, Simionescu M. Endothelial nitric oxide synthase gene polymorphisms in Fabry's disease.  Clin Genet. 2002;  61 423-429
• 95 Kim H S, Hwang K Y, Chung I K et al.. Tissue plasminogen activator and plasminogen activator inhibitor type 1 gene polymorphism in patients with gastric ulcer complicated with bleeding.  J Korean Med Sci. 2003;  18 58-64
• 96 Martiskainen M, Pohjasvaara T, Mikkelsson J et al.. Fibrinogen gene promoter -455 A allele as a risk factor for lacunar stroke.  Stroke. 2003;  34 886-891
• 97 Amini-Nekoo A, Futers T S, Moia M, Mannucci P M, Grant P J, Ariens R. Analysis of the tissue factor pathway inhibitor gene and antigen levels in relation to venous thrombosis.  Br J Haematol. 2001;  113 537-543
• 98 Spek C A, Koster T, Rosendaal F R, Bertina R M, Reitsma P. Genotypic variation in the promoter region of the protein C gene is associated with plasma protein C levels and thrombotic risk.  Arterioscler Thromb Vasc Biol. 1995;  15 214-218
• 99 Leroy-Matheron C, Duchemin J, Levent M, Gouault-Heilmann M. Genetic modulation of plasma protein S levels by two frequent dimorphisms in the PROS1 gene.  Thromb Haemost. 1999;  82 1088-1092
• 100 Doggen C J, Kunz G, Rosendaal F R et al.. A mutation in the thrombomodulin gene, 127G to A coding for Ala25Thr, and the risk of myocardial infarction in men.  Thromb Haemost. 1998;  80 743-748
• 101 Tiret L, Rigat B, Visvikis S et al.. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels.  Am J Hum Genet. 1992;  51 197-205
• 102 Addas-Carvalho M, Origa A F, Saad S T. Interleukin 1 beta and tumor necrosis factor levels in stored platelet concentrates and the association with gene polymorphisms.  Transfusion. 2004;  44 996-1003
• 103 Barber M D, Powell J J, Lynch S F, Fearon K C. J.A. R. A polymorphism of the interleukin-1 beta gene influences survival in pancreatic cancer.  Br J Cancer. 2000;  83 1443-1447
• 104 Tarlow J K, Blakemore A I, Lennard A et al.. Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat.  Hum Genet. 1993;  91 403-404
• 105 Messer G, Spengler U, Jung M C et al.. Polymorphic structure of the tumor necrosis factor (TNF) locus: an NcoI polymorphism in the first intron of the human TNF-beta gene correlates with a variant amino acid in position 26 and a reduced level of TNF-beta production.  J Exp Med. 1991;  173 209-219
• 106 Rocha V, Franco R F, Porcher R et al.. Host defense and inflammatory gene polymorphisms are associated with outcomes after HLA-identical sibling bone marrow transplantation.  Blood. 2002;  100 3908-3918
• 107 Chae Y S, Kim J G, Sohn S K et al.. Investigation of vascular endothelial growth factor gene polymorphisms and its association with clinicopathologic characteristics in gastric cancer.  Oncology. 2006;  71 266-272