The prothrombin factor ii g20210a mutation with pulmonary thromboembolism and a normal level of fibrin degradation products

Diagnosis of pulmonary thromboembolism (PTE) usually includes clinical pretest probability assessment, testing for specific degradation products of cross-linked fibrin (D-dimer) and imaging studies. Patients with radiological findings attributable to pulmonary infarction and normal D-dimer level, may present a diagnostic and therapeutic challenge. A 37-year-old Caucasian female had episodes of hemoptysis, and bilateral pulmonary nodular infiltrates on chest radiograph and computerized tomography. The plasma D-dimer level was normal, perfusion lung scan was not conclusive and histological examination of an open lung biopsy revealed recent thrombotic pulmonary infarction. She deteriorated and more perfusion defects were detected on perfusion lung scan. Genetic analysis revealed her to be a carrier of the prothrombin factor II (FII) G20210A mutation

Inherited thrombophilia influences localization and extent of pregnancy related deep venous thrombosis

Background:Venous thromboembolism is one of the leading causes ofmaternal morbidity and mortality. The role of inherited thrombophiliain occurrence and localization of pregnancy related thrombosis is notclear.Aims:To investigate the influence of hereditary thrombophilia onlocalization and extent of thrombosis in women with thromboemboliccomplications during pregnancy and puerperium.Methods:We conducted a retrospective analysis of 212 consecutivewomen with pregnancy related deep vein thrombosis of lower extremi-ties (LE) or pulmonary embolism (PE) who were referred to our insti-tution for thrombophilia testing from January 2004 to December2015. When DVT of LE was present with PE, the event was accountedas PE. Thrombosis of superficial veins was excluded. All thromboticepisodes were confirmed with duplex ultrasonography and CT pneu-moangiography. In all women following causes of hereditary throm-bophilia were tested: factor V Leiden and prothrombin G20210Amutations, antithrombin, protein C and protein S deficiency. Bloodfor thrombophilia testing was obtained at least 3 months after cessa-tion of anticoagulant therapy.Results:Out of 212 women with pregnancy related thrombosis, 33(15,6%) developed PE, 73 (34,4%) developed unilateral thrombosis ofboth proximal and distal veins, 63 (29,7%) of proximal, and 36 (17%)of distal veins. Seven women (3,3%) developed concomitant bilateralthrombosis of deep veins of lower extremities. Hereditary throm-bophilia testing was positive in 82/212 (38,7%) women. Prevalence ofinherited thrombophilia was significantly higher in women with mas-sive DVT (proximal+distal veins) and in women with isolated DVT ofproximal veins than in women with PE and isolated DVT of distalveins.Conclusions:According to our results, inherited thrombophilia influ-ences localization and extent of pregnancy related thrombosis. Surpris-ingly, prevalence of thrombophilia was low in women who developedpregnancy related pulmonary embolism

The Silence Speaks, but We Do Not Listen: Synonymous c.1824C gt T Gene Variant in the Last Exon of the Prothrombin Gene as a New Prothrombotic Risk Factor

BACKGROUND: Thrombosis is a major global disease burden with almost 60% of cases related to underlying heredity and most cases still idiopathic. Synonymous single nucleotide polymorphisms (sSNPs) are considered silent and phenotypically neutral. Our previous study revealed a novel synonymous FII c.1824C gt T variant as a potential risk factor for pregnancy loss, but it has not yet been associated with thrombotic diseases. METHODS: To determine the frequency of the FII c.1824C gt T variant we have sequenced patients' DNA. Prothrombin RNA expression was measured by quantitative PCR. Functional analyses included routine hemostasis tests, western blotting and ELISA to determine prothrombin levels in plasma, and global hemostasis assays for thrombin and fibrin generation in carriers of the FII c.1824C gt T variant. Scanning electron mi- croscopy was used to examine the structure of fibrin clots. RESULTS: Frequency of the FII c.1824C gt T variant was significantly increased in patients with venous thromboembolism and cerebrovascular insult. Examination in vitro demonstrated increased expression of prothrombin mRNA in FII c.1824C gt T transfected cells. Our ex vivo study of FII c.1824C gt T carriers showed that the presence of this variant was associated with hyperprothrom-binemia, hypofibrinolysis, and formation of densely packed fibrin clots resistant to fibrinolysis. CONCLUSION: Our data indicate that FII c.1824C gt T, although a synonymous variant, leads to the development of a prothrombotic phenotype and could represent a new prothrombotic risk factor. As a silent variant, FII c.1824C gt T would probably be overlooked during genetic screening, and our results show that it could not be detected in routine laboratory tests