Intracardiac hemostasis and fibrinolysis parameters in patients with atrial fibrillation

Aims. To identify intracardiac hemostasis or fibrinolysis abnormalities, which are associated with atrial fibrillation (AF) and increase the risk of thromboembolism. Patients and Methods. Patient group consisted of 24 patients with AF and control group included 14 individuals with other supraventricular tachycardia undergoing transcatheter radiofrequency ablation. Blood samples were drawn from the femoral vein (FV), left atrium (LA), and left atrial appendage (LAA) before the ablation procedure. Fibrinogen, factor VIII (FVIII) and factor XIII activity, von Willebrand factor (VWF) antigen, thrombin-antithrombin (TAT) complex, quantitative fibrin monomer (FM), plasminogen, α2-plasmin inhibitor, plasmin-α2-antiplasmin (PAP) complex, PAI-1 activity, and D-dimer were measured from all samples. Results. Levels of FVIII and VWF were significantly elevated in the FV and LA of AF patients as compared to controls. TAT complex, FM, PAP complex, and D-dimer levels were significantly elevated in the LA as compared to FV samples in case of both groups, indicating a temporary thrombotic risk associated with the catheterization procedure. Conclusions. None of the investigated hemostasis or fibrinolysis parameters showed significant intracardiac alterations in AF patients as compared to non-AF controls. AF patients have elevated FVIII and VWF levels, most likely due to endothelial damage, presenting at both intracardiac and systemic level

Antithrombin Debrecen (p.Leu205Pro) - Clinical and molecular characterization of a novel mutation associated with severe thrombotic tendency

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Intracardiac Fibrinolysis and Endothelium Activation Related to Atrial Fibrillation Ablation with Different Techniques

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Laboratory Diagnosis, Molecular Genetic and Protein Biochemical Analysis of Rare Hemostasis Disorders

Az öröklött hemosztázis rendellenességek ritka kórképek, az adott egyénre nézve életveszélyes, vagy az életminőséget jelentősen rontó, <2-5:10 000 fő prevalenciájú kórképek. A véralvadási rendszer pro-vagy anticoaguláns oldalának érintettségétől függően hemorrhagiás diathesisek, vagy thrombophiliák alakulhatnak ki. Jelen értekezésben a coagulopathiák közül az V-ös (FV) és a XIII-as (FXIII) véralvadási faktorok zavarait, a thrombophiliák közül a protein C deficienciát tárgyaljuk esetbemutatásokon és in vitro kísérleteken keresztül. Valamennyi esetben meghatároztuk a háttérben álló okozati mutáció(ka)t, és lehetőség szerint vizsgáltuk a talált mutációk előfordulását a betegek elérhető családtagjaiban. Az új, vagy korábban nem karakterizált genetikai eltérések esetén fehérje biokémiai vizsgálatokat, és/ vagy molekulamodellezést végeztünk. FV deficiencia: • a 34 éves mérsékelten vérzékeny nőbetegnél és egyelőre tünetmentes egyik lánygyermekénél a p.Gly493Arg mutációt detektáltuk heterozigóta formában; • a mutáció a molekulamodellezés alapján lokális konformáció változást okozva instabilitáshoz, az A2 domén kóros foldingjához vezet. FXIII deficiencia: • két, súlyos FXIII-A deficienciában szenvedő esetet mutattunk be, ahol elvégeztük a deficiencia komplex laboratóriumi karakterizálását. Az újszülött proband1 összetett heterozigóta volt a c.980G>A, p.Arg326Gln és az új, splice-hely defektust eredményező c.1112+2T>C mutációkra. A 13 éves proband2-nél egy új nukleotid deléció (c.212delA) vezetett korai stop kodonhoz csupán a molekula egy kis N-terminalis részének transzlációját téve lehetővé. Protein C deficiencia: • két, thrombosisban szenvedő beteg PROC génjében detektált három mutáció következményeit vizsgáltuk, egy újszülött összetett heterozigóta volt és purpura fulminánsban szenvedett, egy 50 éves nőnek recidív mélyvénás thrombosisai voltak; • a 163-as pozícióban lévő mutációk (p.Ala163Glu és p.Ala163Val) kóros foldinghoz és következményesen károsodott szekrécióhoz vezetnek; • a 77-es pozíciót érintő mutáció (p.Asp77Gly) esetében feltehetően vagy az intermolekuláris interakciók megváltozása, vagy a fehérje fokozott eliminációja lehet felelős a deficienciáért.Inherited hemostatic disorders are rare and they can be life-threatening to the affected person or might be disabling; their prevalence is <2-5:10 000. Depending on whether the pro-or the anticoagulant part of the hemostatic system is affected, hemorrhagic diatheses or thrombophilias might develop. In the present thesis we focus on factor V (FV) and factor XIII (FXIII) deficiencies among coagulopathies, and protein C deficiency leading to thrombophilia. The above-mentioned diseases are presented via case reports and in vitro studies. The causative mutations are described in all cases and if possible, the molecular genetic testing of the family members has been also carried out. The consequences of the novel or previously not characterized mutations are investigated in protein biochemistry experiments and/ or molecular modelling. FV deficiency: • the p.Gly493Arg mutation was detected in heterozygous form in a 34-year-old female with moderate bleeding symptomes and in one of her asymptomatic daughters; • molecular modelling studies suggest that the mutation leads to local conformational changes, instability of the affected region and inproper folding of the A2 domain. FXIII deficiency: • We presented two cases of severe FXIII-A deficiency. The newborn proband1 was compound heterozygote for the c.980G>A, p.Arg326Gln and the novel c.1112+2T>C mutations, the latter leads to splice site defect. The 13-year-old proband2 carried the novel c.212delA single nucleotid deletion causing early stop codon enabling the translation of only small portion of the N-terminal part of the molecule. Protein C deficiency: • we examined the molecular consequences of three PROC mutations found in two patients suffering from venous thromboembolism. A neonate was a compound heterozygote and had purpura fulminans, a 50-year-old female had multiple severe deep venous thrombotic events; • the mutations affecting the 163 position (p.Ala163Glu and p.Ala163Val) cause abnormal folding and as a consequence impaired secretion; • the mutation affecting position 77 (p.Asp77Gly) probably influences the intermolecular interactions in which PC takes part and/or leads to increased elimination of the mutant protein.N

Hemorrhagic Transformation of Ischemic Strokes

Ischemic stroke, resulting from insufficient blood supply to the brain, is among the leading causes of death and disability worldwide. A potentially severe complication of the disease itself or its treatment aiming to restore optimal blood flow is hemorrhagic transformation (HT) increasing morbidity and mortality. Detailed summaries can be found in the literature on the pathophysiological background of hemorrhagic transformation, the potential clinical risk factors increasing its chance, and the different biomarkers expected to help in its prediction and clinical outcome. Clinicopathological studies also contribute to the improvement in our knowledge of hemorrhagic transformation. We summarized the clinical risk factors of the hemorrhagic transformation of ischemic strokes in terms of risk reduction and collected the most promising biomarkers in the field. Also, auxiliary treatment options in reperfusion therapies have been reviewed and collected. We highlighted that the optimal timing of revascularization treatment for carefully selected patients and the individualized management of underlying diseases and comorbidities are pivotal. Another important conclusion is that a more intense clinical follow-up including serial cranial CTs for selected patients can be recommended, as clinicopathological investigations have shown HT to be much more common than clinically suspected

Uninterrupted Dabigatran Administration Provides Greater Inhibition against Intracardiac Activation of Hemostasis as Compared to Vitamin K Antagonists during Cryoballoon Catheter Ablation of Atrial Fibrillation

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