The Phenotypic Heterogeneity of Severe Hemophilia

 

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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.

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
  PubMedGoogle Scholar
• 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. secretariat.haemophiles@cch.ap-hop-paris.fr.  Haemophilia. 2000;  6 23-32
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 4 Bolton-Maggs P H, Pasi K J. Haemophilias A and B.  Lancet. 2003;  361 1801-1809
  CrossrefPubMedGoogle Scholar
• 5 Beutler E. Discrepancies between genotype and phenotype in hematology: an important frontier.  Blood. 2001;  98 2597-2602
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 10 Handelsman J E. The knee joint in hemophilia.  Orthop Clin North Am. 1979;  10 139-173
  PubMedGoogle Scholar
• 11 Hoskinson J, Duthie R B. Management of musculoskeletal problems in the hemophilias.  Orthop Clin North Am. 1978;  9 455-480
  PubMedGoogle Scholar
• 12 Stein H, Duthie R B. The pathogenesis of chronic haemophilic arthropathy.  J Bone Joint Surg Br. 1981;  63B 601-609
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 14 Arnold W D, Hilgartner M W. Hemophilic arthropathy. Current concepts of pathogenesis and management.  J Bone Joint Surg Am. 1977;  59 287-305
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 26 Srivastava A. Dose and response in haemophilia-optimization of factor replacement therapy.  Br J Haematol. 2004;  127 12-25
  CrossrefPubMedGoogle Scholar
• 27 Gilbert M S. Prophylaxis: musculoskeletal evaluation.  Semin Hematol. 1993;  30 3-6
  PubMedGoogle Scholar
• 28 Pettersson H, Ahlberg A, Nilsson I M. A radiologic classification of hemophilic arthropathy.  Clin Orthop Relat Res. 1980;  149 153-159
  PubMedGoogle Scholar
• 29 Poonnoose P M, Srivastava A. Functional assessment of arthropathy-an international perspective.  Semin Hematol. 2006;  43 S27-S32
  PubMedGoogle Scholar
• 30 Dargaud Y, Meunier S, Negrier C. Haemophilia and thrombophilia: an unexpected association!.  Haemophilia. 2004;  10 319-326
  CrossrefPubMedGoogle Scholar
• 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
  Article in Thieme ConnectPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 47 Bertina R M. Elevated clotting factor levels and venous thrombosis.  Pathophysiol Haemost Thromb. 2003/2004;  33 395-400
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 55 Nishiya K. Stimulation of human synovial cell DNA synthesis by iron.  J Rheumatol. 1994;  21 1802-1807
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 60 Poli F, Boschiero L, Giannoni F et al.. Tumour necrosis factor-alpha gene polymorphism: implications in kidney transplantation.  Cytokine. 2000;  12 1778-1783
  CrossrefPubMedGoogle Scholar
• 61 Vinasco J, Beraun Y, Nieto A et al.. Polymorphism at the TNF loci in rheumatoid arthritis.  Tissue Antigens. 1997;  49 74-78
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 64 Ghosh K, Shankarkumar U, Shetty S, Mohanty D. Chronic synovitis and HLA B27 in patients with severe haemophilia.  Lancet. 2003;  361 933-934
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 66 Roosendaal G, Lafeber F P. Pathogenesis of haemophilic arthropathy.  Haemophilia. 2006;  12(Suppl 3) 117-121
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 68 Conway E M, Collen D, Carmeliet P. Molecular mechanisms of blood vessel growth.  Cardiovasc Res. 2001;  49 507-521
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 76 Mura C, Nousbaum J B, Verger P et al.. Phenotype-genotype correlation in haemochromatosis subjects.  Hum Genet. 1997;  101 271-276
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 79 Barnes C, Blanchette V, Lillicrap D et al.. Different clinical phenotype in triplets with haemophilia A.  Haemophilia. 2007;  13 202-205
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 81 Buzzard B M. Sports and hemophilia: antagonist or protagonist.  Clin Orthop Relat Res. 1996;  328 25-30
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 85 Yee D L. Platelets as modifiers of clinical phenotype in hemophilia.  Sci World J. 2006;  6 661-668
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar

Alok SrivastavaM.D. 

Professor of Medicine, Head, Department of Hematology, Christian Medical College

Vellore 632004, India

Email: aloks@cmcvellore.ac.in