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Fibrinogen A Thr312Ala polymorphism is associated with chronic thromboembolic pulmonary hypertension

¹ Pulmonary Vascular Diseases Unit, Papworth Hospital, Papworth Everard, ² Medical Research Council Biostatistics Unit, and ⁴ University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Cambridge, UK. ³ Dept of Haematology, Subdepartment of Thrombosis and Haemostasis, Leiden University Medical Centre, Leiden, The Netherlands.

CORRESPONDENCE: N. W. Morrell, University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 2QQ, UK. Fax: 44 1223762007. E-mail: nwm23{at}cam.ac.uk

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

Received: May 7, 2007
Accepted November 21, 2007

Although chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by the persistence of organised thrombus, few pro-thrombotic risk factors have been identified in subjects with the disease. The aim of the present study was to compare the prevalence of eight functionally relevant haemostatic polymorphisms between CTEPH subjects and healthy controls.

Genomic DNA was isolated from 214 CTEPH subjects and 200 healthy controls, and analysed for Factor V Leiden, prothrombin guanine (G) to adenine (A) substitution at nucleotide 20210 (20210G>A), plasminogen activator inhibitor-1 4G/5G, tissue plasminogen activator 7351 cytosine (C)>thymidine (T), Factor XIII 100G>T, fibrinogen A substitution of threonine with alanine at position 312 (Thr312Ala), fibrinogen Bβ substitution of arginine with lysine at position 448 (Arg448Lys) and fibrinogen Bβ 455G>A polymorphisms.

A significant difference was demonstrated in fibrinogen A Thr312Ala genotype and allele frequencies between CTEPH subjects and controls. The presence of the alanine allele significantly increased the risk of CTEPH.

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