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Published online before print December 5, 2007
Eur Respir J 2007, doi:10.1183/09031936.00055107
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ORIGINAL ARTICLE

Fibrinogen A{alpha}Thr312Ala polymorphism is associated with Chronic Thromboembolic Pulmonary Hypertension

J. Suntharalingam 1, K. Goldsmith 2, V. van Marion 3, L. Long 4, C.M. Treacy 1, F. Dudbridge 2, M.R. Toshner 1, J. Pepke-Zaba 1, J.C.J. Eikenboom 3, N.W. Morrell 4*

1 Pulmonary Vascular Diseases Unit, Papworth Hospital, Papworth Everard, Cambridgeshire, CB3 8RE
2 MRC Biostatistics Unit, Robinson Way, Cambridge, CB2 2SR
3 Dept of Hematology, Subdepartment of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, Netherlands
4 University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ


  Abstract

Although Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is characterised by the persistence of organised thrombus, few prothrombotic risk factors have been identified in subjects with the disease.

This study compares the prevalence of eight functionally relevant haemostatic polymorphisms between CTEPH subjects and healthy controls.

Genomic DNA was isolated from 214 CTEPH and 200 healthy controls and analysed for Factor V Leiden, Prothrombin G20210A, PAI-1 4G/5G, tPA C7351T, Factor XIII G100T, Fibrinogen A{alpha}Thr312Ala, Fibrinogen B{beta}Arg448Lys and Fibrinogen B{beta}G455A polymorphisms.

A significant difference was demonstrated in Fibrinogen A{alpha}Thr312Ala genotype (p=0.03) and allele (p=0.01) frequencies between CTEPH subjects and controls. Presence of the Ala allele significantly increased the risk of CTEPH (OR 1.68; p=0.01 95%CI 1.13, 2.49).

The Fibrinogen A{alpha}312 Ala allele alters fibrinogen {alpha}-{alpha} chain cross-linkage and has previously been associated with both an increased risk of embolisation and an increased resistance to thrombolysis. An association between this polymorphism and CTEPH therefore supports an embolic aetiology for this disease, and may provide a mechanism by which thrombus persists following an acute event.

Keywords:  Coagulation, fibrinolysis, polymorphisms, pulmonary hypertension, thromboembolic




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