Publications by authors named "Zsuzsa Bagoly"

50 Publications

Decreased clot burden is associated with factor XIII Val34Leu polymorphism and better functional outcomes in acute ischemic stroke patients treated with intravenous thrombolysis.

PLoS One 2021 7;16(7):e0254253. Epub 2021 Jul 7.

Division of Clinical Laboratory Sciences, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

Background: Intravenous thrombolysis using recombinant tissue plasminogen activator remains the mainstay treatment of acute ischemic stroke (AIS), although endovascular treatment is becoming standard of care in case of large vessel occlusions (LVO). To quantify the thrombus burden in LVO, a semiquantitative CT angiography (CTA) grading system, the clot burden score (CBS) can be used. Here we aimed to study the association between CBS and various hemostasis parameters, and to evaluate which parameters are major determinants of thrombolysis outcome.

Methods: In this single-centered prospective observational case-control study, 200 anterior circulation AIS patients receiving intravenous thrombolysis treatment without thrombectomy were enrolled: 100 AIS patients with LVO (CBS 0-9) and 100 age- and sex-matched AIS patients without LVO (CBS 10). Fibrinogen, α2-plasmin inhibitor, plasminogen, factor XIII and D-dimer were assessed from blood samples taken before and 24 h after thrombolysis, and FXIII-A Val34Leu was genotyped. CBS was calculated using admission CTA. Short-term outcomes were defined based on the change in NIHSS by day 7, long-term outcomes were assessed according to the modified Rankin scale at 3 months post-event.

Results: Poor outcomes were significantly more frequent in the CBS 0-9 group. Plasminogen activity on admission was significantly higher in the CBS 0-9 group. In a univariate analysis, significant protective effect of the Leu34 allele against developing larger clots (CBS 0-9) could be demonstrated (OR:0.519; 95%CI:0.298-0.922, p = 0.0227). Multivariate regression analysis revealed that CBS is an independent predictor of short- and long-term functional outcomes, while such effect of the studied hemostasis parameters could not be demonstrated.

Conclusions: CBS was found to be a significant independent predictor of thrombolysis outcomes. FXIII-A Leu34 carrier status was associated with smaller thrombus burden, which is consistent with the in vitro described whole blood clot mass reducing effects of the allele, but the polymorphism had no effect on thrombolysis outcomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254253PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263307PMC
July 2021

A modified in vitro clot lysis assay predicts outcomes and safety in acute ischemic stroke patients undergoing intravenous thrombolysis.

Sci Rep 2021 Jun 16;11(1):12713. Epub 2021 Jun 16.

Division of Clinical Laboratory Sciences, Department of Laboratory Medicine, Faculty of Medicine, Kálmán Laki Doctoral School, University of Debrecen, 98 Nagyerdei krt., Debrecen, 4032, Hungary.

The outcome of intravenous thrombolysis using recombinant tissue plasminogen activator (rt-PA) is only favorable in ≈ 40% of acute ischemic stroke (AIS) patients. Moreover, in ≈ 6-8% of cases, intracerebral hemorrhage (ICH) develops. We tested whether a modification of clot lysis assay (CLA), might predict therapy outcomes and safety. In this prospective observational study, blood samples of 231 AIS patients, all receiving intravenous rt-PA, were taken before thrombolysis. Cell-free DNA (cfDNA), CLA and CLA supplemented with cfDNA and histones (mCLA) were determined from the blood samples. Stroke severity was determined by NIHSS on admission. ICH was classified according to ECASSII. Short- and long-term outcomes were defined at 7 and 90 days post-event according to ΔNIHSS and by the modified Rankin Scale, respectively. Stroke severity demonstrated a step-wise positive association with cfDNA levels, while a negative association was found with the time to reach 50% lysis (50%CLT) parameter of CLA and mCLA. ROC analysis showed improved diagnostic performance of the mCLA. Logistic regression analysis proved that 50%CLT is a predictor of short-term therapy failure, while the AUC parameter predicts ICH occurrence. A modified CLA, supplemented with cfDNA and histones, might be a promising tool to predict short-term AIS outcomes and post-lysis ICH.
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http://dx.doi.org/10.1038/s41598-021-92041-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208992PMC
June 2021

Multimodal hyperspectroscopy – the use of digital technology in cervical cancer screening

Orv Hetil 2021 05 16;162(20):790-799. Epub 2021 May 16.

1 Debreceni Egyetem, Általános Orvostudományi Kar, Szülészeti és Nőgyógyászati Intézet, Debrecen, Nagyerdei krt. 98., 4032.

Összefoglaló. Bevezetés: Bevezetés: A citológiai alapú méhnyakrákszűrés átmeneti kategóriáinak optimális menedzselése a humán papillomavírus (HPV) szűrése és tipizálása ellenére jelenleg is kihívás. Vizsgálatunk célja a modern cervixspektroszkópiának (multimodális hiperspektroszkópia - MHS), egy azonnali eredményt nyújtó, digitális technológiára épülő módszernek a vizsgálata volt a citológiai alapú méhnyakszűrés találati biztonságának javítására. Betegek és módszer: Vizsgálatainkat 208, 18 és 75 év közötti nőbeteg bevonásával végeztük, akiknél már indikálásra került valamely, a méhnyakon végzendő műtét, citológiai eredményük rendelkezésre állt (a HPV-tesztet, amennyiben nem történt meg, elvégeztük), valamint valamennyi betegnél elvégeztük a műtét előtt az MHS-vizsgálatot. A szövettani mintavétel 166 betegnél történt meg. Eredmények: A citológiai vizsgálatot (az összes betegre tekintve) magas álpozitív arány jellemezte (69,28%), amely megfigyelések mindenképpen utalnak az újabb komponens alkalmazásának igényére a triázsban. Az összes citológiai kategóriára nézve az MHS-eredmények közül kiemelendő az álnegatív leletek rendkívül alacsony aránya (3/166 = 1,8%), mely a HPV-teszt esetén ennél magasabb volt (11/165 = 6,66%). A spektroszkópiás vizsgálat álpozitív aránya ugyanakkor kedvezőtlenebbnek bizonyult (91/166 = 54,81%) a HPV-vizsgálat álpozitív arányánál (40/165 = 24,24%). Az atípusos laphámsejt (ASC-US/ASC-H) citológiai kategória esetén a spektroszkópia álnegatív eredményeinek aránya (3/126 = 2,38%) szintén kedvezőbb volt, mint a HPV-vizsgálaté (9/126 = 7,14%). A cervicalis intraepithelialis neoplasia-2 vagy súlyosabb fokozatú hámelváltozások azonosításában a spektroszkópia szenzitivitása 94% (95% CI = 0,84-0,99), specificitása 22% (95% CI = 0,15-0,31), negatív prediktív értéke 90% (95% CI = 0,73-0,98), pozitív prediktív értéke 34% (95% CI = 0,26-0,43) volt (p = 0,00130). Következtetés: Az MHS fejlett innovatív technológián alapuló, azonnali eredményt adó vizsgálóeljárás, amely kiemelkedően alacsony álnegatív eredménye miatt nagy segítséget nyújt a citológiai eltéréssel rendelkező betegek további vizsgálatában. Orv Hetil. 2021; 162(20): 790-799.

Summary:

Introduction: Despite the use of human papillomavirus (HPV) testing, the management of the transitional categories of cytology-based screening still remains a challenge. The modern multimodal hyperspectroscopy (MHS) of the cervix is a novel digital technology based on artificial intelligence, providing an instant result in the assessment of cytology-based screening abnormalities.

Patients And Methods: 208 women (age 18-75) were enrolled. The patients already had cytology results and an operation on the cervix indicated at the time of inclusion. HPV and the hyperspectroscopy examination was performed pre-operatively. The pre-indicated operation was performed on 166 patients.

Results: Cytology-based screening alone (in the category of all patients) resulted in a high false-positive rate (69.28%). In this category, the MHS had an outstanding false-negative rate (3/166 = 1.80%) compared to the HPV (11/165 = 6.66%). The false-positive rate of the spectroscopy examination (91/166 = 54.81%) was higher than that of the HPV testing (40/165 = 24.24%). In the atypical squamous cell (ASC-US/ASC-H) category, the false-negative rate of the spectroscopy (3/126 = 2.38%) was also lower than that of the HPV test (9/126 = 7.14%). In the detection of high-grade abnormalities (cervical intraepithelial neoplasia 2 and worse), the spectroscopy had a 94% sensitivity (95% CI = 0.84-0.99), with a 22% specificity (95% CI = 0.15-0.31), an 90% negative predictive value (95% CI = 0.73-0.98), and a 34% positive predictive value (95% CI = 0.26-0.43) (p = 0.00130).

Conclusion: In the case of cytological abnormality, the MHS provides an immediate result based on advanced digital technology, and because of its outstanding false negative rate it is a great aid and should be considered in the triage of such patients. Orv Hetil. 2021; 162(20): 790-799.
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http://dx.doi.org/10.1556/650.2021.32096DOI Listing
May 2021

A Modified Clot Lysis Assay Predicts Outcomes in Non-traumatic Intracerebral Hemorrhage Stroke Patients-The IRONHEART Study.

Front Neurol 2021 20;12:613441. Epub 2021 Apr 20.

Division of Clinical Laboratory Sciences, Department of Laboratory Medicine, Faculty of Medicine, Kálmán Laki Doctoral School University of Debrecen, Debrecen, Hungary.

Non-traumatic intracerebral hemorrhage (ICH) accounts for 10-15% of all strokes and results in a higher rate of mortality as compared to ischemic strokes. In the IRONHEART study, we aimed to find out whether a modified clot lysis assay method, that includes the effect of neutrophil extracellular traps (NETs) might predict ICH outcomes. In this prospective, observational study, 89 consecutive non-traumatic ICH patients were enrolled. Exclusion criteria included aneurysm rupture, cancer, liver- or kidney failure or hemorrhagic diathesis. On admission, detailed clinical and laboratory investigations were performed. ICH volume was estimated based on CT performed on admission, day 14 and 90. A conventional clot lysis assay (CLA) and a modified CLA (mCLA) including cell-free-DNA and histones were performed from stored platelet-free plasma taken on admission. Clot formation and lysis in case of both assays were defined using the following variables calculated from the turbidimetric curves: maximum absorbance, time to maximum absorbance, clot lysis times (CLT) and area under the curve (CLA AUC). Long-term ICH outcomes were defined 90 days post-event by the modified Rankin Scale (mRS). All patients or relatives provided written informed consent. Patients with more severe stroke (NIHSS>10) presented significantly shorter clot lysis times of the mCLA in the presence of DNA and histone as compared to patients with milder stroke [10%CLT: NIHSS 0-10: median 31.5 (IQR: 21.0-40.0) min vs. NIHSS>10: 24 (18-31.0) min, = 0.032]. Shorter clot lysis times of the mCLA showed significant association with non-survival by day 14 and with unfavorable long-term outcomes [mRS 0-1: 36.0 (22.5.0-51.0) min; mRS 2-5: 23.5 (18.0-36.0) min and mRS 6: 22.5 (18.0-30.5) min, = 0.027]. Estimated ICH volume showed significant negative correlation with mCLA parameters, including 10%CLT ( = -0.3050, = 0.009). ROC analysis proved good diagnostic performance of mCLA for predicting poor long-term outcomes [AUC: 0.73 (0.57-0.89)]. In a Kaplan-Meier survival analysis, those patients who presented with an mCLA 10%CLT result of >38.5 min on admission showed significantly better survival as compared to those with shorter clot lysis results (=0.010). Parameters of mCLA correlate with ICH bleeding volume and might be useful to predict ICH outcomes.
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http://dx.doi.org/10.3389/fneur.2021.613441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093390PMC
April 2021

Prognostic Value of Various Hemostasis Parameters and Neurophysiological Examinations in Spontaneous Intracerebral Hemorrhage: The IRONHEART Study Protocol.

Front Neurol 2021 17;12:615177. Epub 2021 Mar 17.

Department of Neurology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

Stroke is one of the leading causes of death in all developed countries. In Hungary, more than 10,000 patients die annually due to cerebrovascular diseases according to the WHO Mortality Database. Of these patients, 10-15 % suffer non-traumatic intracerebral hemorrhage (ICH). ICH results in a higher rate of mortality as compared to ischemic stroke and outcomes are difficult to predict. In the IRONHEART study, we aim to test various hemostasis parameters and clinical neurophysiological examinations in evaluating outcome in ICH. In this prospective, observational study, we plan to enroll consecutive patients with non-traumatic spontaneous ICH admitted to a single Stroke Center (Department of Neurology, University of Debrecen, Hungary). The protocol of the IRONHEART study includes the investigation of detailed clinical, laboratory investigations, and various neurophysiological examinations. Stroke severity is quantified based on the National Institutes of Health Stroke Scale (NIHSS) on admission and day 7, 14, and 90 after the onset of stroke. Cranial CT is performed on admission, day 14, and 90 to estimate the ICH volume. Modified Rankin Scale (mRS) is used for evaluating the long-term outcome (90 days post-event). Blood is drawn immediately on admission for specific hemostasis tests. Digital and quantitative EEG techniques and motor evoked potential (MEP) are performed to evaluate the prognosis of cerebral hemorrhage on admission (within 24-48 h), immediately before discharge (~10-14 days later), and 3 months after the event. The following outcomes are investigated: primary outcomes: mortality by day 14 and day 90, secondary long-term outcome at 90 days post-event where mRS 0-2 is defined as favorable long-term outcome. If associations between outcomes and the investigated parameters (hemostasis and neurophysiological examinations) are confirmed, results might aid prognosis assessment in this subtype of stroke with particularly high mortality. Improving clinical grading systems on ICH severity and outcomes by including the investigated parameters could help to better guide the management of these patients in the future.
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http://dx.doi.org/10.3389/fneur.2021.615177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010310PMC
March 2021

Resolving Differential Diagnostic Problems in von Willebrand Disease, in Fibrinogen Disorders, in Prekallikrein Deficiency and in Hereditary Hemorrhagic Telangiectasia by Next-Generation Sequencing.

Life (Basel) 2021 Mar 5;11(3). Epub 2021 Mar 5.

Division of Clinical Laboratory Science and Specialist Clinical Hemostasis Laboratory, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.

Diagnosis of rare bleeding disorders is challenging and there are several differential diagnostics issues. Next-generation sequencing (NGS) is a useful tool to overcome these problems. The aim of this study was to demonstrate the usefulness of molecular genetic investigations by summarizing the diagnostic work on cases with certain bleeding disorders. Here we report only those, in whom NGS was indicated due to uncertainty of diagnosis or if genetic confirmation of initial diagnosis was required. Based on clinical and/or laboratory suspicion of von Willebrand disease (vWD, = 63), hypo-or dysfibrinogenemia ( = 27), hereditary hemorrhagic telangiectasia (HHT, = 10) and unexplained activated partial thromboplastin time (APTT) prolongation ( = 1), NGS using Illumina platform was performed. Gene panel covered 14 genes (, , , , , , , , , , , , and ) selected on the basis of laboratory results. We identified forty-seven mutations, = 29 (6 novel) in vWD, = 4 mutations leading to hemophilia A, = 10 (2 novel) in fibrinogen disorders, = 2 novel mutations in HHT phenotype and two mutations (1 novel) leading to prekallikrein deficiency. By reporting well-characterized cases using standardized, advanced laboratory methods we add new pieces of data to the continuously developing "bleeding disorders databases", which are excellent supports for clinical patient management.
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http://dx.doi.org/10.3390/life11030202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999415PMC
March 2021

Incorporation of α2-Plasmin Inhibitor into Fibrin Clots and Its Association with the Clinical Outcome of Acute Ischemic Stroke Patients.

Biomolecules 2021 02 25;11(3). Epub 2021 Feb 25.

Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.

Cross-linking of α2-plasmin inhibitor (α2-PI) to fibrin by activated factor XIII (FXIIIa) is essential for the inhibition of fibrinolysis. Little is known about the factors modifying α2-PI incorporation into the fibrin clot and whether the extent of incorporation has clinical consequences. Herein we calculated the extent of α2-PI incorporation by measuring α2-PI antigen levels from plasma and serum obtained after clotting the plasma by thrombin and Ca. The modifying effect of FXIII was studied by spiking of FXIII-A-deficient plasma with purified plasma FXIII. Fibrinogen, FXIII, α2-PI incorporation, in vitro clot-lysis, soluble fibroblast activation protein and α2-PI p.Arg6Trp polymorphism were measured from samples of 57 acute ischemic stroke patients obtained before thrombolysis and of 26 healthy controls. Increasing FXIII levels even at levels above the upper limit of normal increased α2-PI incorporation into the fibrin clot. α2-PI incorporation of controls and patients with good outcomes did not differ significantly (49.4 ± 4.6% vs. 47.4 ± 6.7%, = 1.000), however it was significantly lower in patients suffering post-lysis intracranial hemorrhage (37.3 ± 14.0%, = 0.004). In conclusion, increased FXIII levels resulted in elevated incorporation of α2-PI into fibrin clots. In stroke patients undergoing intravenous thrombolysis treatment, α2-PI incorporation shows an association with the outcome of therapy, particularly with thrombolysis-associated intracranial hemorrhage.
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http://dx.doi.org/10.3390/biom11030347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996613PMC
February 2021

A proposed Common Training Framework for Specialists in Laboratory Medicine under EU Directive 2013/55/EC (The Recognition of Professional Qualifications).

Clin Chem Lab Med 2021 Feb 30;59(3):505-512. Epub 2020 Nov 30.

European Federation of Clinical Chemistry and Laboratory Medicine, Brussels/Milan, Belgium/Italy.

European Union (EU) Directive 2013/55/EC (The Recognition of Professional Qualifications) allows Member States to decide on a common set of minimum knowledge, skills and competences that are needed to pursue a given profession through a Common Training Framework. To be adopted the framework must combine the knowledge, skills and competences of at least one third of the Member States. Professionals who have gained their qualifications under a Common Training Framework will be able to have these recognised automatically within the Union. The backbone of the European Federation of Clinical Chemistry and Laboratory Medicine's (EFLM) proposed Common Training Framework for non-medical is outlined here. It is based on an Equivalence of Standards in education, training, qualifications, knowledge, skills, competences and the professional conduct associated with specialist practice. In proposing the recognition of specialist practice EFLM has identified 15 EU Member States able to meet Equivalence and in whom the profession and/or its training is regulated (an additional EU Commission requirement). The framework supports and contributes to the Directive's enabling goals for increasing professional mobility, safeguarding consumers and ensuring a more equitable distribution of skills and expertise across the Member States. It represents EFLM's position statement and provides a template for professional societies and/or competent authorities to engage with the EU Commission.
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http://dx.doi.org/10.1515/cclm-2020-1504DOI Listing
February 2021

Neuropsychiatric symptoms, quality of life and caregivers' burden in dementia.

Open Med (Wars) 2020 14;15(1):905-914. Epub 2020 Sep 14.

Department of Psychiatry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

The objective of this research is to identify the relationship between the neuropsychiatric symptoms (NPSs) of patients with major neurocognitive disorder (mNCD), their quality of life, illness intrusiveness and the caregiver's burden. We assessed 131 patients with mNCD. Examination methods included WHO well-being index short version, illness intrusiveness rating scale, Alzheimer's Disease Assessment Scale-Cog, Mini Mental State Examination and neuropsychiatric inventory. The results were analysed using standard statistical tests. In our sample, the prevalence of NPSs is 100%. A significant correlation ( < 0.0001) was observed with quality of life and illness intrusiveness. Additionally, a strong relationship was observed between NPSs and the caregiver's burden ( = 0.9). The result is significantly twice as much stronger in comparison to the relationship between NPS and cognitive symptoms ( = 0.4). This is the first study in Hungary to assess the impact of NPS on the burden of relatives and quality of life. NPS had twice stronger impact on caregivers' burden than cognitive decline. However, further studies are needed to assess the sub-syndromes in mNCD in relation to NPS.
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http://dx.doi.org/10.1515/med-2020-0124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718626PMC
September 2020

Stroke as a Potential Complication of COVID-19-Associated Coagulopathy: A Narrative and Systematic Review of the Literature.

J Clin Med 2020 Sep 28;9(10). Epub 2020 Sep 28.

Division of Clinical Laboratory Sciences, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 98 Nagyerdei krt., 4032 Debrecen, Hungary.

Coronavirus disease 2019 (COVID-19) is the most overwhelming medical threat of the past few decades. The infection, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can cause serious illness leading to respiratory insufficiency, and, in severely ill patients, it can progress to multiple organ failure leading to death. It has been noted from the earliest reports that the disease influences the hemostasis system and a hallmark of severe infection is elevated D-dimer levels. The profound coagulation changes in COVID-19 seem to be linked to inflammation-related events and severe endothelial cell injury. Besides the high incidence of venous thromboembolic events in SARS-CoV-2 infections, arterial events, including cerebrovascular events, were found to be associated with the disease. In this review, we aimed to summarize the available literature on COVID-19-associated coagulopathy and thrombosis. Furthermore, we performed a systematic search of the literature to identify the characteristics of stroke in COVID-19. Our findings showed that acute ischemic stroke (AIS) is the most frequent type of stroke occurring in infected patients. In most cases, stroke was severe (median NIHSS:16) and most of the patients had one or more vascular risk factors. Laboratory findings in AIS patients were consistent with COVID-19-associated coagulopathy, and elevated D-dimer levels were the most common finding. The outcome was unfavorable in most cases, as a large proportion of the reported patients died or remained bedridden. Limited data are available as yet on outcomes after acute vascular interventions in COVID-19 patients. In the future, well-designed studies are needed to better understand the risk of stroke in COVID-19, to optimize treatment, and to improve stroke care.
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http://dx.doi.org/10.3390/jcm9103137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599722PMC
September 2020

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

J Clin Med 2020 Sep 22;9(9). Epub 2020 Sep 22.

Department of Cardiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.

Background: Cerebral thromboembolism is a rare but feared complication of transcatheter ablation in patients with atrial fibrillation (AF). Here, we aimed to test which pre-procedural anticoagulation strategy results in less intracardiac activation of hemostasis during ablation.

Patients And Methods: In this observational study, 54 paroxysmal/persistent AF patients undergoing cryoballoon ablation were grouped according to their periprocedural anticoagulation strategy: no anticoagulation (oral anticoagulation (OAC) free; = 24), uninterrupted vitamin K antagonists (VKA) ( = 11), uninterrupted dabigatran ( = 17). Blood was drawn from the left atrium before and immediately after the ablation procedure. Cryoablations were performed according to standard protocols, during which heparin was administered. Heparin-insensitive markers of hemostasis and endothelial damage were tested from intracardiac samples: D-dimer, quantitative fibrin monomer (FM), plasmin-antiplasmin complex (PAP), von Willebrand factor (VWF) antigen, chromogenic factor VIII (FVIII) activity.

Results: D-dimer increased significantly in all groups post-ablation, with lowest levels in the dabigatran group (median [interquartile range]: 0.27 [0.36] vs. 1.09 [1.30] and 0.74 [0.26] mg/L in OAC free and uninterrupted VKA groups, respectively, < 0.001). PAP levels were parallel to this observation. Post-ablation FM levels were elevated in OAC free (26.34 [30.04] mg/L) and VKA groups (10.12 [16.01] mg/L), but remained below cut-off in all patients on dabigatran (3.98 [2.0] mg/L; < 0.001). VWF antigen and FVIII activity increased similarly post-ablation in all groups, suggesting comparable procedure-related endothelial damage.

Conclusion: Dabigatran provides greater inhibition against intracardiac activation of hemostasis as compared to VKAs during cryoballoon catheter ablation.
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http://dx.doi.org/10.3390/jcm9093050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563747PMC
September 2020

Factors Affecting Dental Service Utilisation in Indonesia: A Population-Based Multilevel Analysis.

Int J Environ Res Public Health 2020 07 22;17(15). Epub 2020 Jul 22.

Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4028 Debrecen, Hungary.

This study aimed to examine the prevalence of dental service utilisation in Indonesia and its association with social determinants at individual and community levels. Cross-sectional data from the 2014 Indonesian Family Life Survey (IFLS-5) was analysed. Individual independent variables included age, sex, marital status, educational attainment, economic status, health insurance, dental pain, self-reported mouth ulcers, self-rated health status, unmet healthcare needs and smoking status, while community independent variables included cognitive, structural social capital and residential area. Multilevel logistic regressions were performed to explore the associations between independent variables at different levels and the outcome of dental service utilisation. Of the total sample of 16,860 adults aged 15 years or older in our study, around 86.4% never visited a dentist. Dental service utilisation was associated with older age, female, currently not married, higher education level and economic status, health insurance, dental pain, self-reported mouth ulcers, met healthcare needs, never smoking, living in urban areas and communities with high structural social capital. Both individual and broader social determinants influenced dental service utilisation in Indonesia. These factors should be considered in the formulation of oral health policies and programmes aiming to improve dental service utilisation in the country.
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http://dx.doi.org/10.3390/ijerph17155282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432444PMC
July 2020

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

Cardiol Res Pract 2020 12;2020:1570483. Epub 2020 Feb 12.

Institute of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

Objective: The effect of pulmonary vein isolation (PVI) on fibrinolytic and endothelial activation with currently applied periprocedural anticoagulation has not been explored. We measured markers of fibrinolysis and endothelium activation before and after PVI with the second-generation cryoballoon (Cryo), pulmonary vein ablation catheter (PVAC-Gold), and irrigated radiofrequency (IRF).

Methods: Markers of fibrinolysis and endothelium activation in left atrial (LA) blood samples were measured in 31 patients before and after PVI (Cryo:10, PVAC-Gold: 7, IRF: 14). Periprocedural anticoagulation included uninterrupted vitamin K antagonist and iv heparin (ACT≥300 sec) during LA dwelling.

Results: Levels of (median; interquartile range, mgFEU/L) increased with all techniques (PVAC: 0.34; 0.24-0.50 versus 0.70; 0.61-1.31; =0.0313, Cryo: 0.33; 0.28-0.49 versus 0.79; 0.65-0.93; =0.0313, Cryo: 0.33; 0.28-0.49 versus 0.79; 0.65-0.93; =0.0313, Cryo: 0.33; 0.28-0.49 versus 0.79; 0.65-0.93; (ng/ml) increased after Cryo (247.3, 199.9-331.6 versus 270.9, 227.9-346.7; =0.0313, Cryo: 0.33; 0.28-0.49 versus 0.79; 0.65-0.93; =0.0313, Cryo: 0.33; 0.28-0.49 versus 0.79; 0.65-0.93; =0.0313, Cryo: 0.33; 0.28-0.49 versus 0.79; 0.65-0.93; (%) decreased with the PVAC (1.931; 0.508-3.859 versus 0.735, 0.240-2.707; =0.0313, Cryo: 0.33; 0.28-0.49 versus 0.79; 0.65-0.93; =0.0313, Cryo: 0.33; 0.28-0.49 versus 0.79; 0.65-0.93; =0.0313, Cryo: 0.33; 0.28-0.49 versus 0.79; 0.65-0.93; and increased after PVI with all the 3 techniques. The levels of (ng/ml) did not change after PVAC procedures, but increased after Cryo (542, 6; 428.5-753.1 versus 619.2; 499.8-799.0; =0.0313, Cryo: 0.33; 0.28-0.49 versus 0.79; 0.65-0.93; =0.0313, Cryo: 0.33; 0.28-0.49 versus 0.79; 0.65-0.93.

Conclusion: PVI with contemporary ablation techniques and periprocedural antithrombotic treatment induces coagulation and endothelium activation of similar magnitude with different ablation methods.
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http://dx.doi.org/10.1155/2020/1570483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037955PMC
February 2020

The factor XIII-A Val34Leu polymorphism decreases whole blood clot mass at high fibrinogen concentrations.

J Thromb Haemost 2020 04 28;18(4):885-894. Epub 2020 Feb 28.

Department of Pathology and Laboratory Medicine and UNC Blood Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background: Factor XIII (FXIII) promotes fibrin crosslinking and red blood cell (RBC) retention in clots. The FXIII-A polymorphism, Val34Leu, is associated with protection against venous thrombosis. This effect is hypothesized to result from fibrinogen concentration-dependent changes in fibrin structure. Effects of the FXIII-A Val34Leu polymorphism in whole blood clots have not been investigated.

Aim: Characterize effects of FXIII-A Val34Leu polymorphism and fibrinogen on whole blood clots.

Methods: We isolated platelet-poor plasmas from human donors (FXIII , FXIII , FXIII ), reconstituted plasmas with platelets and RBCs, and triggered clotting. We assessed contributions of gender, age, clotting times, thrombin generation, FXIII activity, FXIII-A Val34Leu polymorphism, and fibrinogen to clot mass. We also reconstituted FXIII-depleted plasma with platelets, RBCs, and purified FXIII or FXIII , varied fibrinogen, and characterized effects on clot mass.

Results: Clot mass was associated with age, fibrinogen, prothrombin time, and thrombin generation. Clots reconstituted with plasmas from individuals with FXIII-A and FXIII-A did not differ in mass from clots with FXIII-A . However, clots containing a 34Val allele demonstrated a fibrinogen concentration-dependent increase in mass, whereas clots with homozygous 34Leu did not. In plasmas with high fibrinogen, mass was higher for clots with 34Val alleles compared with clots with homozygous 34Leu. In clots reconstituted with purified FXIII, increasing fibrinogen enhanced clot mass in the presence of 34Val, but decreased mass in the presence of 34Leu.

Conclusions: FXIII 34Leu mitigates the effect of elevated fibrinogen on whole blood clot mass. The Val34Leu polymorphism may protect against venous thrombosis by reducing clot mass.
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http://dx.doi.org/10.1111/jth.14744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059250PMC
April 2020

Antiphospholipid syndrome and the risk of myocardial infarction: current evidence and uncertainties.

Kardiol Pol 2020 01 6;78(1):6-14. Epub 2019 Dec 6.

Antiphospholipid syndrome (APS) encompasses a wide spectrum of disease manifestations that may prevail in the form of venous or arterial thrombosis or lead to pregnancy complications in the presence of persisting antiphospholipid antibodies (aPL). Unlike in the case of congenital thrombophilias, in which venous thromboses are more likely to occur as compared with arterial events, aPL may cause thrombosis in both types of vascular systems. Arterial thrombosis in APS is fairly common and often involve coronary or cerebral arteries leading to myocardial infarction (MI) or stroke. In this review, we summarize the complex pathomechanisms leading to aPL‑associated thrombosis and list challenges during the laboratory detection of these antibodies. Specific features of MI in patients with APS are summarized based on a comprehensive literature search of available case reports. Preventive and treatment strategies are discussed based on the current recommendations and most recent evidence. We conclude that the risk of MI in patients with APS is considerable and MI may be the first manifestation of the disease. MI in APS shows specific clinical features including relatively young age at presentation, no sex dominance, often normal coronaries without the sign of atherosclerosis, high risk of recurrent thrombotic events. Treatment of acute MI in patients with APS is often challenging and adverse events, including stent thrombosis, are more frequent as compared with patients without APS. Preventive strategies in APS should be personalized and include strict management of additional cardiovascular risk factors and long‑term anticoagulation with vitamin K antagonists. Current evidence does not support the use of direct oral anticoagulants in the management of patients with APS with arterial thrombosis due to the high risk of recurrent events.
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http://dx.doi.org/10.33963/KP.15090DOI Listing
January 2020

Sex-specific alteration to α2-antiplasmin incorporation in patients with type 2 diabetes.

Thromb Res 2020 01 21;185:55-62. Epub 2019 Oct 21.

Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland; John Paul II Hospital, Krakow, Poland. Electronic address:

Background: Type 2 diabetes mellitus (T2DM) is associated with hypofibrinolysis and increased factor XIII-mediated α2-antiplasmin incorporation into the fibrin clot. It is unclear whether there are sex-related differences in α2-antiplasmin incorporation in relation to impaired clot lysis in T2DM.

Aim: We investigated α2-antiplasmin incorporation into fibrin clots as a determinant of clot lysability in patients of both sexes with T2DM.

Methods: In a group of 113 T2DM patients, 54 (47.8%) of which were women, we investigated α2-antiplasmin incorporation using an in-house sandwich enzyme-linked immunoassay and plasma clot lysis by turbidimetry, along with fibrinogen and thrombin generation using calibrated automated thrombogram and factor XIII activity.

Results: Female patients had 15.2% greater α2-antiplasmin incorporation into the fibrin clot (p = 0.008) and slightly higher plasma α2-antiplasmin concentration (p = 0.005) along with 8.4% longer time to 50% lysis (Lys50, p = 0.012) compared with men. Female patients had enhanced thrombin generation represented by shorter lag phase (p = 0.042), shorter time to peak (p = 0.033), and higher endogenous thrombin potential (p = 0.003) compared with men, while factor XIII activity was comparable between sexes (p = 0.085). On multivariate regression, patient sex and glycated hemoglobin (HbA1c) level were the predictors of α2-antiplasmin incorporation in the entire patient group, while α2-antiplasmin incorporation was associated with Lys50, as were fibrinogen, male sex and body-mass index.

Conclusions: This study suggests that a more compromised fibrinolysis in diabetic women when compared with men could be in part mediated by increased α2-antiplasmin incorporation into the fibrin.
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http://dx.doi.org/10.1016/j.thromres.2019.09.032DOI Listing
January 2020

PAI-1 5G/5G genotype is an independent risk of intracranial hemorrhage in post-lysis stroke patients.

Ann Clin Transl Neurol 2019 11 21;6(11):2240-2250. Epub 2019 Oct 21.

Faculty of Medicine, Department of Laboratory Medicine, Division of Clinical Laboratory Sciences, University of Debrecen, 98 Nagyerdei krt., Debrecen, 4032, Hungary.

Objective: Thrombolysis by recombinant tissue plasminogen activator (rt-PA) is the main pharmacological therapy in acute ischemic stroke (IS); however, it is only effective in a subset of patients. Here we aimed to investigate the role of plasminogen activator inhibitor-1 (PAI-1), an effective inhibitor of t-PA, and its major polymorphism (PAI-1 4G/5G) in therapy outcome.

Methods: Study population included 131 consecutive IS patients who all underwent thrombolysis. Blood samples were taken on admission, 1 and 24 h after rt-PA infusion. PAI-1 activity and antigen levels were measured from all blood samples and the PAI-1 4G/5G polymorphism was determined. Clinical data including NIHSS were registered on admission and day 1. ASPECTS was assessed using CT images taken before and 24 h after thrombolysis. Intracranial hemorrhage (ICH) was classified according to ECASS II. Long-term outcome was defined 90 days post-event by the modified Rankin Scale (mRS).

Results: PAI-1 activity levels dropped transiently after thrombolysis, while PAI-1 antigen levels remained unchanged. PAI-1 4G/5G polymorphism had no effect on PAI-1 levels and did not influence stroke severity. PAI-1 activity/antigen levels as measured on admission were significantly elevated in patients with worse 24 h ASPECTS (<7). Logistic regression analysis including age, sex, NIHSS on admission, BMI, history of arterial hypertension, and hyperlipidemia conferred a significant, independent risk for developing ICH in the presence of 5G/5G genotype (OR:4.75, 95%CI:1.18-19.06). PAI-1 levels and PAI-1 4G/5G polymorphism had no influence on long-term outcomes.

Interpretation: PAI-1 5G/5G genotype is associated with a significant risk for developing ICH in post-lysis stroke patients.
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http://dx.doi.org/10.1002/acn3.50923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856768PMC
November 2019

Markers of Coagulation and Fibrinolysis Predicting the Outcome of Acute Ischemic Stroke Thrombolysis Treatment: A Review of the Literature.

Front Neurol 2019 21;10:513. Epub 2019 Jun 21.

MTA-DE Cerebrovascular and Neurodegenerative Research Group, University of Debrecen, Debrecen, Hungary.

Intravenous administration of recombinant tissue plasminogen activator (rt-PA) has been proven to be safe and effective in the treatment of acute ischemic stroke. Little is known, however, why this treatment is less effective in some patients while in others life-threatening side-effects, e.g., symptomatic intracerebral hemorrhage might occur. Clinical failure of thrombolysis related to absent or partial recanalization or reocclusion as well as hemorrhagic complications of thrombolysis are possibly related to hemostatic events. Data on markers of coagulation and/or fibrinolysis in acute stroke patients are numerous and may provide indications regarding therapy outcomes. Better understanding of the hemostatic and fibrinolytic system during rt-PA therapy might be clinically useful and ultimately might lead to an improvement in the efficacy or safety of this treatment. Studies on thrombus composition retrieved from cerebral arteries may also advance our knowledge and provide a key to improve acute stroke therapy. Here we provide a comprehensive review on a wide range of factors and markers of coagulation and fibrinolysis that have been studied in the context of thrombolysis outcome in ischemic stroke patients. Moreover, a brief summary is given on the most recent research on thrombus composition having a potential influence on outcomes.
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http://dx.doi.org/10.3389/fneur.2019.00513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611415PMC
June 2019

A new ELISA method for the measurement of total α-plasmin inhibitor level in human body fluids.

J Immunol Methods 2019 08 24;471:27-33. Epub 2019 May 24.

Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 98. Nagyerdei krt., Debrecen H-4032, Hungary. Electronic address:

The ever-increasing research efforts to develop new antithrombotic therapies have led to the reassessment of the role of alpha-2-plasmin inhibitor (α-PI) in pathological conditions. In particular, experimental stroke studies have suggested correlation between increased free α2-PI level and mortality. However there are only a small number of well-characterized and specific assays available for the measurements of free α-PI. In plasma α-PI undergoes both N- and/or C-terminal cleavages resulting four isoforms with modified susceptibility to FXIII catalyzed cross-linking to fibrin and/or loss of plasmin(ogen) binding. Present paper describes a new sandwich ELISA method for the determination of free total α-PI in plasma and other body fluids. A newly generated biotinylated monoclonal antibody recognizes and captures all the four N- and/or C-terminally modified isoforms of α-PI while HRPO-labeled polyclonal anti-α-PI antibody detects the captured antigen. Performing the 2-step assay in streptavidin-coated microplate can be completed within three hours. The assay is well reproducible, total (within laboratory) imprecision in the normal, pathological and very low ranges were 7.4%, 9.1% and < 19%, respectively. When examining the plasma samples of 197 healthy volunteers, 100 acute ischemic stroke patients and 102 patients with venous thrombosis, strong correlation was observed between total α2-PI antigen levels and α2-PI activity for each group. Using the assay a reference interval of 45-86 mg/L was established for total α-PI mass concentration in the plasma. α-PI levels were also measured in cerebrospinal fluid samples of 47 individuals the median value and range was 132 (36-379) μg/L. In conclusion, our ELISA enables accurate and fast measurement of total free α-PI in human body fluids.
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http://dx.doi.org/10.1016/j.jim.2019.05.004DOI Listing
August 2019

Inherited thrombophilia and the risk of myocardial infarction: current evidence and uncertainties.

Kardiol Pol 2019 Apr 25;77(4):419-429. Epub 2019 Apr 25.

Division of ClinicalLaboratory Sciences, Department ofLaboratory Medicine, University of Debrecen,Faculty of Medicine, Debrecen, Hungary

Atherothrombotic diseases (ATEs) and venous thromboembolism (VTE) have been traditionally considered to have a distinct pathogenesis. Today, a growing body of evidence on the pathophysiology of thrombus formation has convincingly proved that they share more mutual risk factors than previously recognized. It has been shown in a number of case‑control studies that there is a significant risk for a subsequent cardiovascular disease after VTE, although this risk is low or at most moderate. In the past 2 decades, the role of each inherited risk factor for VTE in relation to ATE has been intensively studied. Unfortunately, a large body of contradictory findings has been published that hinders consensus and transformation of knowledge into clinical practice. Complicated gene‑gene interactions, small sample sizes, heterogeneous genetic and environmental patient backgrounds, confounding factors, and varied methodological designs may have contributed to opposing findings. In the case of rare thrombophilias, conclusions must be summarized based on case reports or case series, as only few case‑control and cohort studies are available. In this review we focus on available evidence and controversies regarding the relationship between the classic inherited VTE risk factors (factor V Leiden, prothrombin 20210A, deficiencies of antithrombin, protein C, and protein S) and the risk of myocardial infarction (MI). We conclude that the risk of MI in patients with common inherited thrombophilia is generally modest. However, in patients with deficiencies of antithrombin, protein C, or protein S, the risk of MI or other ATEs is not negligible. A personalized clinical approach is suggested when testing for inherited thrombophilia in a patient with MI.
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http://dx.doi.org/10.33963/KP.14804DOI Listing
April 2019

Factor XIII: What does it look like?

J Thromb Haemost 2019 05;17(5):714-716

Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

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http://dx.doi.org/10.1111/jth.14431DOI Listing
May 2019

Altered fibrin clot phenotype as predictor of the risk of recurrent venous thromboembolism: evidence is growing.

Authors:
Zsuzsa Bagoly

Pol Arch Intern Med 2018 10 31;128(10):569-571. Epub 2018 Oct 31.

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http://dx.doi.org/10.20452/pamw.4356DOI Listing
October 2018

Low factor XIII levels after intravenous thrombolysis predict short-term mortality in ischemic stroke patients.

Sci Rep 2018 05 16;8(1):7662. Epub 2018 May 16.

Division of Clinical Laboratory Sciences, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

In this observational study we investigated whether levels of factor XIII (FXIII) and its major polymorphisms affect the outcome of thrombolysis by recombinant tissue plasminogen activator (rtPA) in acute ischemic stroke (AIS) patients. Study cohort included 132 consecutive AIS patients undergoing i.v. thrombolysis within 4.5 h of symptom onset. Blood samples taken on admission, immediately after and 24 h after therapy were analyzed for FXIII activity and antigen levels. FXIII-A p.Val34Leu, p.Tyr204Phe, FXIII-B p.His95Arg and intron K(IVS11 + 144) polymorphisms were genotyped. Neurological deficit was assessed using the National Institutes of Health Stroke Scale. Intracranial hemorrhage was classified according to ECASSII criteria. Long-term functional outcome was defined at 3 months post-event by the modified Rankin scale. FXIII levels showed a gradual decrease immediately after thrombolysis and 24 h later, which was not related to therapy-associated bleeding. In a multiple logistic regression model, a FXIII level in the lowest quartile 24 h post-lysis proved to be an independent predictor of mortality by 14 days post-event (OR:4.95, 95% CI:1.31-18.68, p < 0.05). No association was found between the investigated FXIII polymorphisms and therapeutic outcomes. In conclusion, our findings indicate that FXIII levels 24 h after thrombolysis might help to identify patients at increased risk for short-term mortality.
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http://dx.doi.org/10.1038/s41598-018-26025-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955963PMC
May 2018

Elevated Factor VIII and von Willebrand Factor Levels Predict Unfavorable Outcome in Stroke Patients Treated with Intravenous Thrombolysis.

Front Neurol 2017 23;8:721. Epub 2018 Jan 23.

Division of Clinical Laboratory Sciences, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

Introduction: Plasma factor VIII (FVIII) and von Willebrand factor (VWF) levels have been associated with the rate and severity of arterial thrombus formation and have been linked to outcomes following thrombolytic therapy in acute myocardial infarction patients. Here, we aimed to investigate FVIII and VWF levels during the course of thrombolysis in acute ischemic stroke (AIS) patients and to find out whether they predict long-term outcomes.

Materials And Methods: Study population included 131 consecutive AIS patients (median age: 69 years, 60.3% men) who underwent i.v. thrombolysis with recombinant tissue plasminogen activator (rt-PA). Blood samples were taken on admission, 1 and 24 h after rt-PA administration to measure FVIII activity and VWF antigen levels. Neurological deficit of patients was determined according to the National Institutes of Health Stroke Scale (NIHSS). ASPECT scores were assessed using computer tomography images taken before and 24 h after thrombolysis. Intracranial hemorrhage was classified according to the European Cooperative Acute Stroke Study (ECASS) II criteria. Long-term functional outcome was determined at 90 days after the event by the modified Rankin scale (mRS).

Results: VWF levels on admission were significantly elevated in case of more severe AIS [median and IQR values: NIHSS <6:189.6% (151.9-233.2%); NIHSS 6-16: 199.6% (176.4-250.8%); NIHSS >16: 247.8% (199.9-353.8%),  = 0.013]; similar, but non-significant trend was observed for FVIII levels. FVIII and VWF levels correlated well on admission ( = 0.748,  < 0.001) but no significant correlation was found immediately after thrombolysis ( = 0.093,  = 0.299), most probably due to plasmin-mediated FVIII degradation. VWF levels at all investigated occasions and FVIII activity before and 24 h after thrombolysis were associated with worse 24 h post-lysis ASPECT scores. In a binary backward logistic regression analysis including age, gender, high-sensitivity C-reactive protein, active smoking, diabetes, and NIHSS >5 on admission, elevated FVIII and VWF levels after thrombolysis were independently associated with poor functional outcomes (mRS ≥ 3) at 90 days (immediately after thrombolysis: FVIII: OR: 7.10, 95% CI: 1.77-28.38,  = 0.006, VWF: OR: 6.31, 95% CI: 1.83-21.73,  = 0.003; 24 h after thrombolysis: FVIII: OR: 4.67, 95% CI: 1.42-15.38,  = 0.011, VWF: OR: 19.02, 95% CI: 1.94-186.99,  = 0.012).

Conclusion: Elevated FVIII activity and VWF antigen levels immediately after lysis and at 24 h post-therapy were shown to have independent prognostic values regarding poor functional outcomes at 90 days.
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http://dx.doi.org/10.3389/fneur.2017.00721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787073PMC
January 2018

Clot Structure and Fibrinolysis in Thrombosis and Hemostasis.

Biomed Res Int 2017;2017:4645137. Epub 2017 Nov 15.

Department of Pathology and Laboratory Medicine and McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.

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http://dx.doi.org/10.1155/2017/4645137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705862PMC
October 2018

Uncovering the genetic background of natural anticoagulant deficiencies: time to look behind the scenes.

Authors:
Zsuzsa Bagoly

Pol Arch Intern Med 2017 08 3;127(7-8):465-467. Epub 2017 Sep 3.

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http://dx.doi.org/10.20452/pamw.4069DOI Listing
August 2017

Intracardiac Hemostasis and Fibrinolysis Parameters in Patients with Atrial Fibrillation.

Biomed Res Int 2017 21;2017:3678017. Epub 2017 Jun 21.

Division of Clinical Laboratory Sciences, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

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, -plasmin inhibitor, plasmin--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.
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http://dx.doi.org/10.1155/2017/3678017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497646PMC
April 2018

Low thrombin generation predicts poor prognosis in ischemic stroke patients after thrombolysis.

PLoS One 2017 10;12(7):e0180477. Epub 2017 Jul 10.

Department of Laboratory Medicine, Division of Clinical Laboratory Sciences, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

Thrombolysis by intravenous recombinant tissue plasminogen activator (rt-PA) is an effective therapy in acute ischemic stroke (AIS). Thrombin generation test (TGT) is a global hemostasis test providing information about the speed and amount of generated thrombin in plasma. Here we aimed to find out whether results of this test before the initiation of thrombolysis might predict outcomes. Study population included 120 consecutive AIS patients, all within 4.5 hours of their symptom onset, who underwent thrombolysis by rt-PA. Blood samples were collected from all patients upon admission and TGT was performed using platelet poor plasma. Clinical data of patients including the NIHSS were registered at admission, day 1 and 7 after therapy. The ASPECT score was assessed using CT images taken before and 24 hours after thrombolysis. Long-term functional outcome was defined 3 months after the event by the modified Rankin Scale. Endogenous Thrombin Potential (ETP) and Peak Thrombin were significantly lower in patients with cardioembolic IS. Symptomatic intracranial hemorrhage (SICH) was found in 6 patients and was significantly associated with low ETP and Peak Thrombin levels. A multiple logistic regression model revealed that an ETP result in the lower quartile is an independent predictor of mortality within the first two weeks (OR: 6.03; 95%CI: 1.2-30.16, p<0.05) and three months after the event (OR: 5.28; 95%CI: 1.27-21.86, p<0.05). Low levels of ETP and Peak Thrombin parameters increase the risk of therapy associated SICH. A low ETP result is an independent predictor of short- and long-term mortality following thrombolysis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180477PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503253PMC
September 2017

Regulation of plasma factor XIII levels in healthy individuals; a major impact by subunit B intron K c.1952+144 C>G polymorphism.

Thromb Res 2016 Dec 27;148:101-106. Epub 2016 Oct 27.

Division of Clinical Laboratory Science, Department of Laboratory Medicine, University of Debrecen, Faculty of Medicine, Debrecen, Hungary; Vascular Biology, Thrombosis and Hemostasis Research Group of the Hungarian Academy of Sciences, University of Debrecen, Hungary. Electronic address:

Background: The regulation of plasma factor XIII (FXIII) levels in healthy individuals has been only partially explored. The identification of major non-genetic and genetic regulatory factors might provide important information on the contribution of FXIII to the risk of cardio/cerebrovascular diseases.

Objectives: To determine the effect of age, smoking, BMI, fibrinogen concentration on plasma FXIII activity, complex FXIII antigen (FXIII-AB) and total FXIII-B subunit (tFXIII-B) level, to correlate FXIII-B level with the other two FXIII parameters and to assess the variation of FXIII levels in carriers of major FXIII subunit polymorphisms.

Methods: 268 healthy individuals were enrolled in the study. FXIII activity was measured by the ammonia release assay; FXIII-AB and tFXIII-B were determined by ELISAs. FXIII-A p.Val34Leu, FXIII-B p.His95Arg and FXIII-B intron K c.1952+144 C>G polymorphisms were identified by RT-PCR using melting point analysis with fluorescence resonance energy transfer detection.

Results: All investigated FXIII parameters showed significant positive correlation with age and fibrinogen level; gender and BMI influenced only tFXIII-B. A highly significant positive correlation was demonstrated between tFXIII-B and the other FXIII parameters. FXIII-A p.Val34Leu polymorphism had only slight, if any effect on FXIII levels. The FXIII-B Arg95 allele moderately increased all three FXIII parameters, but the effect became statistically significant only after adjustment. The FXIII-B intron K G allele drastically decreased FXIII levels, and it seemed to be in synergism with the FXIII-A Leu34 allele.

Conclusions: Plasma FXIII levels are subjected to multifactorial regulation, in which age, fibrinogen level and FXIII-B intron K polymorphism are major determinants.
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http://dx.doi.org/10.1016/j.thromres.2016.10.025DOI Listing
December 2016

Protein cross-linking by chlorinated polyamines and transglutamylation stabilizes neutrophil extracellular traps.

Cell Death Dis 2016 08 11;7(8):e2332. Epub 2016 Aug 11.

Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary.

Neutrophil extracellular trap (NET) ejected from activated dying neutrophils is a highly ordered structure of DNA and selected proteins capable to eliminate pathogenic microorganisms. Biochemical determinants of the non-randomly formed stable NETs have not been revealed so far. Studying the formation of human NETs we have observed that polyamines were incorporated into the NET. Inhibition of myeloperoxidase, which is essential for NET formation and can generate reactive chlorinated polyamines through hypochlorous acid, decreased polyamine incorporation. Addition of exogenous primary amines that similarly to polyamines inhibit reactions catalyzed by the protein cross-linker transglutaminases (TGases) has similar effect. Proteomic analysis of the highly reproducible pattern of NET components revealed cross-linking of NET proteins through chlorinated polyamines and ɛ(γ-glutamyl)lysine as well as bis-γ-glutamyl polyamine bonds catalyzed by the TGases detected in neutrophils. Competitive inhibition of protein cross-linking by monoamines disturbed the cross-linking pattern of NET proteins, which resulted in the loss of the ordered structure of the NET and significantly reduced capacity to trap bacteria. Our findings provide explanation of how NETs are formed in a reproducible and ordered manner to efficiently neutralize microorganisms at the first defense line of the innate immune system.
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http://dx.doi.org/10.1038/cddis.2016.200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5108309PMC
August 2016
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