Fibrinogen, an abundant plasma glycoprotein, is involved in the final stage of blood coagulation. Decreased fibrinogen levels, which may be caused by mutations, are manifested mainly in bleeding and thrombotic disorders. Clinically relevant mutations of fibrinogen are listed in the Human Fibrinogen Database. For the αC-connector (amino acids Aα240-410, nascent chain numbering), we have extended this database, with detailed descriptions of the clinical manifestations among members of reported families. This includes the specification of bleeding and thrombotic events and results of coagulation assays. Where available, the impact of a mutation on clotting and fibrinolysis is reported. The collected data show that the Human Fibrinogen Database reports considerably fewer missense and synonymous mutations than the general COSMIC and dbSNP databases. Homozygous nonsense or frameshift mutations in the αC-connector are responsible for most clinically relevant symptoms, while heterozygous mutations are often asymptomatic. Symptomatic subjects suffer from bleeding and, less frequently, from thrombotic events. Miscarriages within the first trimester and prolonged wound healing were reported in a few subjects. All mutations inducing thrombotic phenotypes are located at the identical positions within the consensus sequence of the tandem repeats.
- Klíčová slova
- Human Fibrinogen Database, afibrinogenemia, dysfibrinogenemia, fibrinogen, hypodysfibrinogenemia, hypofibrinogenemia, mutations, αC-connector,
- MeSH
- fibrinogen genetika MeSH
- hemokoagulace genetika MeSH
- krvácení genetika MeSH
- lidé MeSH
- mutace genetika MeSH
- trombóza genetika MeSH
- vyšetření krevní srážlivosti metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- fibrinogen MeSH
BACKGROUND: Factor V Leiden (FVL) supposedly carries relatively higher risk of deep vein thrombosis (DVT), compared to the risk of pulmonary embolism (PE). AIM: To prove this paradox in a group of patients with various clinical presentation of venous thromboembolism (VTE). MATERIALS AND METHODS: We retrospectively evaluated clinical pattern of VTE in patients who had been referred to vascular clinic shortly after an acute VTE event. In FVL positive and FVL negative groups we compared the prevalence of isolated symptomatic DVT (proximal or distal) and symptomatic PE with/without DVT, and, moreover, asymptomatic DVT or PE. RESULTS: Of 575 patients (mean age 57 years, 50.1% women), 120 were FVL positive and those had significantly higher prevalence of isolated symptomatic DVT, compared to symptomatic PE with/without DVT. Proximal DVT location was significantly more frequent in FVL carriers. The prevalence of asymptomatic PE did not differ between the two groups. The rate of asymptomatic DVT tended to be higher in FVL negative group. In a multivariate analysis, we confirmed FVL to be positively associated with isolated DVT presentation (odds ratio OR 1.757; 95% confidence interval (CI) 1.148-2.690). On the contrary, increasing age and unprovoked nature of VTE event carried a higher risk of symptomatic PE. CONCLUSIONS: We confirmed FVL to be significantly associated with isolated symptomatic DVT despite higher prevalence of proximal DVT in FVL carriers. The fact of relatively lower risk of PE in FVL positive patients might have clinical implication. However, mechanisms of FVL paradox remain to be elucidated.
- MeSH
- asymptomatické nemoci epidemiologie MeSH
- bodová mutace MeSH
- detekce genetických nosičů MeSH
- dospělí MeSH
- faktor V genetika MeSH
- hemokoagulace genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- plicní embolie * epidemiologie genetika patofyziologie MeSH
- prevalence MeSH
- retrospektivní studie MeSH
- senioři MeSH
- žilní trombóza * epidemiologie genetika patofyziologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Irsko MeSH
- Názvy látek
- factor V Leiden MeSH Prohlížeč
- faktor V MeSH
BACKGROUND: Molecular genetic methods were implemented in the detection of thrombophilic disorders in the 1990's with the discovery of coagulation inhibitors antithrombin III (AT III), protein C (PC) and S (PS). The discovery of the molecular cause of activated protein C (APC) resistance by Bertina in 1994 greatly expanded their utilization. METHODS AND RESULTS: Currently, a broad group of molecular genetic markers with a clearly demonstrated risk of thrombophilia are used--mutation of FV Leiden 506R/Q, mutation of prothrombin (F II) 20210G/A, mutation of methylenetetrahydrofolate reductase (MTHFR) 677C/T in homozygous form, mutation of plasminogen activator inhibitor (PAI-1) 4G/5G, mutations of single coagulation inhibitors as well as a number of polymorphisms with controversial thrombophilic risk such as F XIII Val34Leu, platelet glycoproteins, endothelial protein C receptor and thrombomodulin. Another area utilizing molecular genetic methods is research of the pathophysiology of individual coagulation processes. To date, the greatest advances in regard to APC resistance have been achieved here. Although the molecular cause of APC resistance was clearly demonstrated in the 1990's, its clinical variability has not yet been fully explained. The same is true for the second most widespread mutation, prothrombin gene mutation, where only the latest research has hinted at a possible mechanism of expression of the genetic changes in the actual coagulation process. CONCLUSIONS: The future of molecular genetic methods is in achieving a complex understanding of the pathophysiology of thrombophilia and not only in its utilization as a method for detecting many polymorphisms with a very low risk of thrombosis.
- MeSH
- antithrombin III genetika MeSH
- faktor V genetika fyziologie MeSH
- hemokoagulace genetika fyziologie MeSH
- hyperhomocysteinemie genetika MeSH
- lidé MeSH
- mutace MeSH
- protein C genetika MeSH
- protein S genetika MeSH
- protrombin genetika MeSH
- rezistence k aktivovanému proteinu C genetika MeSH
- trombofilie krev chemicky indukované genetika patofyziologie MeSH
- trombóza krev genetika patofyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- antithrombin III MeSH
- factor V Leiden MeSH Prohlížeč
- faktor V MeSH
- protein C MeSH
- protein S MeSH
- protrombin MeSH
OBJECTIVE: A 22-yr-old woman had abnormal preoperative coagulation test results and congenital dysfibrinogenaemia was suspected. PATIENTS AND METHODS: The patient from Liberec (Czech Republic) had a low fibrinogen plasma level as determined by Clauss method, normal fibrinogen level as determined by immunoturbidimetrical method, and prolonged thrombin time. To identify the genetic mutation responsible for this dysfibrinogen, genomic DNA extracted from the blood was analysed. Fibrin polymerisation measurement, kinetics of fibrinopeptide release, fibrinogen clottability measurement and scanning electron microscopy were performed. RESULTS: DNA sequencing showed the heterozygous fibrinogen gamma Y262C mutation. Kinetics of fibrinopeptide release was normal, however fibrin polymerisation was impaired. Fibrinogen clottability measurement showed that only about 45% molecules of fibrinogen are involved in the clot formation. Scanning electron microscopy revealed thicker fibres, which were significantly different from the normal control. CONCLUSION: A case of dysfibrinogenaemia, found by routine coagulation testing, was genetically identified as a novel fibrinogen variant (gamma Y262C) that has been named Liberec.
- MeSH
- afibrinogenemie genetika MeSH
- dospělí MeSH
- fibrinogeny abnormální genetika MeSH
- hemokoagulace genetika MeSH
- lidé MeSH
- missense mutace * MeSH
- mutační analýza DNA MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Názvy látek
- fibrinogeny abnormální MeSH
