Elevated factor VIII in hereditary haemorrhagic telangiectasia (HHT): Association with venous thromboembolism

Summary

Hereditary haemorrhagic telangiectasia (HHT) causes chronic nasal and gastrointestinal haemorrhage. Prothrombotic agents are commonly used for severe haemorrhage. Thrombotic risks have not been defined. In order to identify prothrombotic variables in HHT patients, and assess their potential functional significance, a pilot ELISA-based study comparing plasma proteins in healthy individuals with HHT to age/sex-matched non-HHT controls was validated in a full study of 309 consecutive HHTaffected individuals. In the pilot study, factor VIII (FVIII) and von Willebrand factor antigen concentrations were elevated in the HHT group compared to non-HHT controls (p<0.0013, Mann- Whitney). Service laboratory measurements confirmed high FVIII:Ag in 125 HHT-affected individuals with no recent illhealth, intervention or venous thromboemboli. FVIII:Ag levels increased with age. Logistic regression also suggested an age-independent association with HHT-associated pulmonary arteriovenous malformations (AVMs). No association was demonstrated between FVIII:Ag and acute phase response, disseminated intravascular coagulation, ABO group, pulmonary artery pressure, or markers of HHT haemorrhage. Elevated FVIII:Ag were associated with shortened activated partial thromboplastin times (APTTs), andVTE:VTE affected 20/309 (6.5%) HHT-affected individuals, at median age 61(36–71) years. Four VTE occurred in factorV Leiden heterozygotes in the months following PAVM-associated brain abscess. The strongest association with VTE was with log-transformed FVIII:Ag measured 10–132 months from VTE (odds ratio 2.41, 95% confidence intervals 1.254, 4.612, p=0.008). Age made no additional contribution to VTE risk once adjusted for FVIII:Ag. In conclusion, HHT-related elevation of FVIII:Ag levels may influence thrombotic risk in HHT. Individualised risk-benefit considerations may be helpful in HHT management.

Keywords

Brain abscess - DIC - pulmonary AVMs - tranexamic acid - VWF

• References

• 1 Bideau A, Brunet G, Heyer E. et al. An abnormal concentration of cases of Rendu-Osler disease in the Valserine valley of the French Jura: a geneological and demographic study. Ann Hum Biol 1992; 19: 233-247.
• 2 Kjeldsen AD, Vase P, Green A. Hereditary hemorrhagic telangiectasia (HHT): a population-based study of prevalence and mortality in Danish HHT patients. J Intern Med 1999; 245: 31-39.
• 3 Guttmacher AE, Marchuk DA, White RI. Hereditary hemorrhagic telangiectasia. New Engl J Med 1995; 333: 918-924.
• 4 Begbie ME, Wallace GMF, Shovlin CL. Hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): A view from the 21st century. Postgrad Med J 2003; 79: 18-24.
• 5 Girola SS, Cusa C, DiGiulio G. et al. Lung angiodysplasia and von Willebrand’s disease in a family with Rendu-Osler disease. Recenti Prog Med 1996; 87: 589-591.
• 6 Maggi CA, Ballarin E, Comin U. et al. Hemorrhagic telangiectasia and hemophilia A: an occasional association?. Haematologica 1983; 68: 399-404.
• 7 Sudarshan A, Natelson EA, Gordon C. Hereditary hemorrhagic telangiectasia and factor VIII inhibitor. South Med J 1985; 78: 623-624.
• 8 Ferran M, Arderiu A, Vilardell M. et al. Hereditary hemorrhagic telangiectasia and congenital factor XI deficiency. Med Clin (Barc) 1986; 86: 425-427.
• 9 Muckle JJ. Low in-vivo adhesive platelet count in hereditary haemorrhagic telangiectasia. Lancet 1964; 2: 880-882.
• 10 Larsson SO. Osler’s disease with impaired adhesion and aggregation of platelets. Acta Med Scand 1974; 196: 133-136.
• 11 Maire R, Schnewlin G, Bollinger A. Videomikroskopische Untersuchungen von Telangiektasien bei Morbus Osler und Sclerodermie. Schweiz Med Wschr 1986; 116: 335-338.
• 12 Braverman IM, Keh A, Jacobson BS. Ultrastructure and three-dimensional organization of the telangiectases of hereditary hemorrhagic telangiectasia. J Invest Dermatol 1990; 95: 422-427.
• 13 McAllister KA, Grogg KM, Johnson DW. et al. Endoglin, a TGF-β binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nature Genet 1994; 8: 345-351.
• 14 Johnson DW, Berg JN, Baldwin MA. et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nature Genet 1996; 13: 189-195.
• 15 Gallione C, Repetto GM, Legius E. et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia is associated with mutations in MADH4 (SMAD4). Lancet 2004; 363: 852-859.
• 16 Cole SG, Begbie ME, Wallace GMF. et al. A new locus for hereditary haemorrhagic telangiactasia (HHT3) maps to chromosome 5. J Med Genet 2005; 42: 577-582.
• 17 Bayrak-Toydemir P, McDonald J, Akarsu N. et al. A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7. Am J Med Genet 2006; 140: 2155-2162.
• 18 Bick RL. Hereditary hemorrhagic telangiectasia and disseminated intravascular coagulation: a new clinical syndrome. Ann NY Acad Sci 1981; 370: 851-854.
• 19 Blaustein A. Treatment of thrombosis in individuals with hereditary hemorrhagic telangiectasis: report of three cases including two members of one family. Angiology 1956; 7: 55-60.
• 20 Sturm W, Gaenzer H, Heiniger-Rothbucher D. et al. Unsuspected mesenteric vein thrombosis in a patient with a hereditary bleeing disorder. Blood Coagul Fibrinolysis 2003; 14: 599-600.
• 21 Shovlin CL, Jackson JE. Pulmonary arteriovenous malformations. In: Pulmonary Circulation, 2nd edn 2004. Arnold; London:
• 22 Oger E. Incidence of venous thromboembolism: a community-based study in Western France. Thromb Haemost 2000; 83: 657-660.
• 23 Heit JA, Silverstein MD, Mohr DN. The epidemiology of thromboembolism in the community. Thromb Haemost 2001; 86: 452-463.
• 24 Shovlin CL, Guttmacher AE, Buscarini E. et al. Diagnostic criteria for hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet 2000; 91: 66-67.
• 25 Gupta P, Mordin C, Curtiss J. et al. PAVMs: Effect of embolisation on right-to-left shunt, hypoxaemia and exercise tolerance in 66 patients. Am J Roent 2002; 179: 347-355.
• 26 Dahlback B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognised mechanism characterised by poor anticoagulant response to activated protein C: Prediction of a co-factor to activated protein C. Proc Natl Acad Sci 1993; 90: 1004-1008.
• 27 Poort SR, Rosendaal FR, Reitsma PH. et al. 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.
• 28 Letamandía A, Lastres P, Botella L. et al. Role of endoglin in cellular responses to transforming growth factor-β. J Biol Chem 1998; 273: 33011-33019.
• 29 Seigneur M, Constans J, Blann A. et al. Soluble adhesion molecules and endothelial cell damage in HIV infected patients. Thromb Haemost 1997; 77: 646-649.
• 30 van Mourik JA, Boertjes R, Huisveld IA. et al. von Willebrand factor propeptide in vascular disorders: A tool to distinguish between acute and chronic endothelial cell perturbation. Blood 1999; 94: 179-185.
• 31 Kraaijenhagen RA, in ’tAnker PS, Koopman MM. et al. High plasma concentration of Factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost 2000; 83: 5-9.
• 32 Begbie M, Notley C, Tinlin S. et al. The Factor VIII acute phase response requires the participation of NFkappaB and C/EBP. Thromb Haemost 2000; 84: 216-222.
• 33 van den Burg PJ, Hospers JE, van Vliet B. et al. Changes in haemostatic factors and activation products after exercise in healthy subjects with different ages. Thromb Haemost 1995; 74: 1457-1464.
• 34 Bonderman D, Turecek PL, Jakowitsch J. et al. High prevalence of elevated clotting factor VIII in chronic thromboembolic pulmonary hypertension. Thromb Haemost 2003; 90: 372-376.
• 35 O’Donnell J, Laffan MA. The relationship between ABO histo-blood group, factor VIII and von Willebrand factor. Transfus Med 2001; 11: 343-351.
• 36 Trembath R, Thomson J, Machado R. et al. Clinical and molecular features of pulmonary hypertension in hereditary hemorrhagic telangiectasia. New Engl J Med 2001; 345: 325-334.
• 37 Benjamini Y, Hochberg Y. Controlling the False Discovery Rate: a practical and powerful approach to multiple testing. J Roy Stats Soc (B) 1995; 57: 289-300.
• 38 Plauchu H, de Chadarévian J-P, Bideau A. et al. Age-related profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet 1989; 32: 291-297.
• 39 Tripodi A, Chantaranqkul V, Martinelli I. et al. A shortened activated partial thromboplastin time is associated with the risk of venous thromboembolism. Blood 2004; 104: 3631-3634.
• 40 Bowen DJ, Bowley S, John M. et al. Factor V Leiden (G1691A), the prothrombin 3‘-untranslated region variant (G20210A) and thermolabile methylenetetrahydrofolate reductase (C677T): a single genetic test genotypes all three loci- determination of frequencies in the S.Wales population of the UK. Thromb Haemost 1998; 79: 949-954.
• 41 Dargaud Y, Meunier S, Negrier C. Haemophilia and thrombophilia: an unexpected association!. Haemophilia 2004; 10: 319-326.
• 42 Cottin V, Plauchu H, Bayle JY. et al. Pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia. Am J Respir Crit Care Med 2004; 169: 994-1000.
• 43 Rumley A, Emberson JR, Wannamethee SG. et al. Effects of older age on fibrin D-dimer, C-reactive protein, and other hemostatic and inflammatory variables in men aged 60–79 years. J Thromb Haemost 2006; 4: 982-987.
• 44 Kyrle PA, Eichinger S. The risk of recurrent venous thromboembolism: the Austrian study on recurrent venous thromboembolism. Wien Klin Wochenschr 2003; 115: 471-474.
• 45 Shovlin CL, Jackson JE, Bamford KB. et al. Primary determinants of ischaemic stroke / brain abscess risks are independent of severity of pulmonary arteriovenous malformations in HHT. Thorax 2007; in press.
• 46 Sargeant IR, Loizou LA, Rampton D. et al. Laser ablation of upper gastrointestinal vascular ectasias: long term results. Gut 1993; 34: 470-475.
• 47 Van Cutsem E, Rutgeerts P, Vantrappen G. Treatment of bleeding gastrointestinal vascular malformations with oestrogen-progesterone. Lancet 1990; 335: 953-955.
• 48 Sabba C, Gallitelli M, Palasciano G. Efficacy of unusually high doses of tranexamic acid for the treatment of epistaxis in hereditary hemorrhagic telangiectasia. N Engl J Med 2001; 345: 926.
• 49 Saba HI, Morelli GA, Logrono LA. Treatment of bleeding in hereditary hemorrhagic telangiectasia with aminocaproic acid. New Engl J Med 1994; 330: 1789-1790.