Association of Estrogen Receptor-Alpha Gene Polymorphisms with Deep Vein Thrombosis; Results of the Mega Study

Abstract number: OR236

O'Connell^1,2 NM, Riddell² AF, Lee² CA, Perry² DJ

^1,21The Adelaide and Meath Hospital and Trinity College Dublin, Tallaght, Dublin 24, Ireland ²²The Royal Free and University College Medical School, Pond Street, London NW3 2QG, UK

Factor XI (FXI) deficiency is characterized by a variable bleeding phenotype which correlates poorly with FXI coagulant activity but may correlate more closely with endogenous thrombin potential (ETP). Thrombin generation in FXI deficient plasma from patients with a known bleeding phenotype was studied using two thrombin generation assays.

Method:  In the chromogenic method, thrombin generation was initiated in defibrinated, platelet poor plasma with 10 pg/mL recombinant tissue factor (TF; Recombiplastin) and detected using the chromogenic substrate CBS 00.68 (Diagnostica Stago). In the fluorogenic method (Thrombinoscope BV), recombinant TF (Innovin; final concentration 1 pM) was used to initiate coagulation in platelet poor plasma and the substrate used was Z-Gly-Gly-Arg-AMC. The bleeding phenotype was characterized using a standard scoring system.

Results:  Fifty FXI deficient patient plasmas (11 severe, 29 partial deficiency) were analysed using the chromogenic method. The ETP in severely deficient plasmas was markedly lower than in partially deficient plasmas (median 9.4% versus 60.7%). The median ETP of 11 partially deficient bleeders was 50% while 16 non-bleeders had a median ETP of 72.5%, which approached significance (P= 0.09). Using the fluorogenic method, 15 FXI deficient plasmas were analysed. The median ETP was lower in severely deficient versus partially deficient plasma (63% versus 101%) but there was no difference between partially deficient and normal plasma. Amongst partially deficient patients, there was no difference between bleeders and non-bleeders (ETP 108% versus 95%).

Conclusions:  Differences in ETP are seen between severe and partially FXI deficient plasma at low TF concentrations in both methods. However, differences in ETP relating to phenotype were only seen with the lower TF concentrations used in the chromogenic method. TF concentration and assay method are critical when comparing ETP in FXI deficient plasma.