Advances in Understanding Mechanisms of Thrombophilic Disorders

Abstract

Venous thromboembolism constitutes a major medical problem afflicting millions of individuals worldwide each year. Its pathogenesis is multifactorial, involving both environmental and genetic risk factors. The most common genetic risk factor known to date is a mutation in the factor V (FV) gene (R506Q or FV Leiden), which impairs the normal regulation of FV by activated protein C (APC). APC is an important regulator of blood coagulation, cleaving and inactivating not only FV/FVa but also activated factor VIII (FVIIIa). In FVa, APC cleaves several sites, Arg506 (R506) being one of them. The R506Q mutation results in the APC resistance phenotype and a lifelong hypercoagulable state. A prothrombin gene mutation is another relatively frequent thrombosis risk factor, whereas deficiencies of the anticoagulant proteins antithrombin, protein C, or protein S are less common. As a result of the high prevalence of FV and prothrombin mutations in the general population, combinations of genetic defects are relatively common. Such individuals have highly increased risk of thrombosis.

Quantitative measurement of APC-Resistant factor V clotting activity (FV-Leiden) and potential graduation of the associated thrombo-embolic risk

“…Thrombin activated FV-L has then an increased activity survival time in plasmas from patients with this R506Q mutation, and this can propagate activation of coagulation pathways. APC resistance and FV-L were rapidly identified as the major hereditary diathesis associated with an increased thrombotic risk 15,[20][21][22][23] , although for patients with the R506Q mutation odds ratios for occurrence of thrombosis are lower than those associated with AT, PC or PS deficiencies 4,[23][24][25][26] . Since these discoveries, testing for APC-R with clotting assays and for the FVa mutation with molecular biology, have become major parameters of the thrombosis check-up.…”

“…Diagnosis of individuals carrying the R506Q mutation is then very important and useful for understanding the diathesis favoring the development of thrombotic diseases. It is yet of higher usefulness for investigating patients with unprovoked thrombotic events, along with the measurement of other anticoagulant factors, such as Antithrombin, PC, FPS, and eventually Plasminogen 3,4 . Whilst AT, PC, FPS deficiencies contribute to about 15% of total unprovoked thrombosis, especially in younger patients, APC-R and the FV-L mutation are involved in about 60 % of these events 24 .…”

“…The complementary action of these functions is of essence for keeping the procoagulant pathways at the right sites, and for a delayed dissolution of the clot once the healing function is achieved. Abnormal concentration or activity of these anticoagulant mechanisms favors occurrence of thromboembolic diseases 3,4 . FV plays then a key role in this process, being at the crossroads of blood coagulation pathways.…”

64th Annual Congress of the Gesellschaft für Thrombose- und Hämostaseforschung e.V. in Bremen

“…In a historical perspective, Dr Dahlbäck gives a summary of his discovery of the most important genetic risk factors for venous thromboembolism (VTE). 1 He also summarises our present understanding of the biochemistry and physiology of pro-and anticoagulant systems that control thrombosis and haemostasis, respectively.…”

Συμβολή Της Κληρονομικής Θρομβοφιλίας Στην Κλινική Πορεία Της Σήψης

“…Σχηματική απεικόνιση της μετάλλαξης G20210A του γονιδίου της προθρομβίνης. 51 59 60 Από το σύνολο των μεταλλάξεων του γονιδίου του παράγοντα V, μόνο οι μεταλλάξεις G1691A και H1299R σχετίζονται με κληρονομική θρομβοφιλία.…”