Publications by authors named "Ewa Wypasek"

85 Publications

Relationships between circulating galectin-3, extracellular matrix fibrosis and outcomes in dilated cardiomyopathy.

Adv Clin Exp Med 2021 Mar;30(3):245-253

Department of Cardiac and Vascular Disease, John Paul II Hospital, Jagiellonian University Medical College, Kraków, Poland.

Background: Galectin-3 is an emerging biomarker in cardiovascular disease. Myocardial galectin-3 is involved in the pathology of cardiac fibrosis; however, the role of circulating galectin-3 is not yet established.

Objectives: To assess the relationships between circulating galectin-3, fibrosis and outcomes in dilated cardiomyopathy (DCM).

Material And Methods: We included 70 patients (age: 48 ±12.1 years, ejection fraction (EF) 24.4 ±7.4%) with new-onset DCM (n = 35, ≤6 months). Galectin-3 and procollagen type I and III (PICP, PINP, PIIICP, and PIIINP), transforming growth factor β (TGF-β), connective tissue growth factor (CTGF), osteopontin (OPN), matrix metalloproteinases (MMP-2 and -9), and tissue inhibitor (TIMP-1) were determined in serum at baseline and after 3 and 12 months. Patients underwent endomyocardial biopsy. The endpoint was a combination of death and urgent hospitalization at 12 months.

Results: Galectin-3 did not correlate with biopsy-determined fibrosis. Baseline galectin-3 correlated with OPN,, TIMP-1, PIIICP, and MMP-2. In new-onset DCM, galectin-3 levels at baseline were higher than at 3 and 12 months, whereas in chronic DCM there was no difference. Galectin-3 was a predictor of the endpoint (hazard ratio (HR) = 1.115; 95% confidence interval (95% CI) = 1.009-1.231; p < 0.05). The best cut-off value was 14.54 ng/mL (area under the curve (AUC) = 0.67). Patients with galectin-3 ≥14.54 ng/mL had an increased risk of events (HR = 2.569; 95% CI = 1.098-6.009; p < 0.05).

Conclusions: Circulating galectin-3 is unrelated to fibrosis. Serial measurements of galectin-3 correlated with markers of fibrosis, including markers of collagen synthesis and OPN. Circulating galectin-3 was independently associated with cardiovascular (CV) outcomes in DCM.
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http://dx.doi.org/10.17219/acem/115081DOI Listing
March 2021

Elements of Immunoglobulin E Network Associate with Aortic valve Area in Patients with Acquired Aortic Stenosis.

Biomedicines 2020 Dec 31;9(1). Epub 2020 Dec 31.

Krakow Center for Medical Research and Technology, John Paul II Hospital, 31-202 Krakow, Poland.

Allergic mechanisms are likely involved in atherosclerosis and its clinical presentations, such as coronary artery disease (CAD). It has been previously reported that CAD severity associates with serum levels of immunoglobulin E (IgE), the molecule that, along with its high-affinity receptor (FcԑRI), plays a central role in allergic reactions. Considering multiple pathophysiological similarities between atherosclerosis and acquired aortic (valve) stenosis (AS), we speculated that allergic pathways could also contribute to the AS mechanisms and grading. To validate this hypothesis, we first checked whether total serum IgE levels associate with echocardiographic markers of AS severity. Having found a positive correlation between serum IgE and aortic valve area (AVA), we further speculated that also total IgE-determining genetic polymorphisms in , a locus encoding an allergen-biding FcԑRI subunit, are related to acquired AS severity. Indeed, the major allele of rs2251746 polymorphism, known to associate with higher IgE levels, turned out to correlate with larger AVA, a marker of less severe AS. Our findings surprisingly suggest a protective role of IgE pathways against AS progression. IgE-mediated protective mechanisms in AS require further investigations.
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http://dx.doi.org/10.3390/biomedicines9010023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824289PMC
December 2020

Afibrinogenemia caused by a novel homozygous missense mutation, FGB p.Cys241Tyr, in a male patient with recurrent intracranial bleeding: case report and review of literature.

Haemophilia 2021 Jan 27;27(1):26-32. Epub 2020 Nov 27.

Krakow Specialist Hospital named after John Paul II, Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland.

Introduction: Congenital afibrinogenemia is a severe bleeding disorder, sometimes manifesting as thrombosis and/or pregnancy complications. Intracranial haemorrhage (ICH) constitutes the major cause of death in this disease.

Methods: We present the case of a male patient with congenital afibrinogenemia, who presented with recurrent intracranial hemorrhages, despite prophylactic fibrinogen substitution. We also review the literature for the risk of intracranial hemorrhages in afibrinogenemia.

Result: Molecular analysis revealed a novel homozygous missense mutation in FGB exon 5, p.Cys241 Tyr, that was named "Fibrinogen Krakow V".

Discussion And Conclusion: Intracranial hemorrhage is a severe manifestation of afibrinogenemia, also in children. The clinical presentation of afibrinogenemia is variable. Fibrinogen substitution carries a risk of thrombotic complications.
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http://dx.doi.org/10.1111/hae.14211DOI Listing
January 2021

Novel Splice Site Mutation in the Gene in a Polish Patient with Venous Thromboembolism: c.602-2delA, Splice Acceptor Site of Exon 7.

Medicina (Kaunas) 2020 Sep 22;56(9). Epub 2020 Sep 22.

The John Paul II Hospital, 80 Prądnicka Street, 31-202 Krakow, Poland.

We identified a novel splice site mutation of the gene in a Polish family with protein S (PS) deficiency and explored the molecular pathogenesis of this previously undescribed variant. A novel mutation was detected in a 26-year-old woman with a history of venous thromboembolism (VTE) provoked by oral contraceptives. Her family history of VTE was positive. The sequence analysis of the gene was performed in the proband and the proband's family. The proband and their asymptomatic father had lower free PS levels (45% and 50%, respectively) and PS activity (48% and 44%, respectively). Total PS levels were normal (65.6% and 62.4%, respectively). The sequence analysis of the gene revealed the presence of heterozygous deletion at the nucleotide position c.602-2 in intron 6, just upstream of exon 7, detected in the proband and her father. This variant alters the splice acceptor site of exon 7, and, according to the in silico prediction, it is highly likely to cause in-frame exon 7 skipping. We also presented follow-up data of two other Polish patients with PS deficiency associated with splice site mutations in gene.
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http://dx.doi.org/10.3390/medicina56090485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558706PMC
September 2020

Interaction between functional polymorphisms in FCER1A and TLR2 and the severity of atopic dermatitis.

Hum Immunol 2020 Dec 1;81(12):709-713. Epub 2020 Sep 1.

Krakow Center for Medical Research and Technology, John Paul II Hospital, Krakow, Poland; Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Krakow University, Krakow, Poland. Electronic address:

Dendritic cell toll-like receptors (TLRs) and the high-affinity immunoglobulin E (IgE) receptor (FcεRI) may biologically interact with regard to atopic dermatitis (AD) development and, especially, severity. Our aim here was to test if such interaction can be detected on the genetic level. The combined effect of the TLR2 gene (TLR2) rs4696480 and the FcεRI α-chain gene (FCER1A) rs2252226 and rs2251746 polymorphisms on the AD severity as measured by SCORAD was assessed. The FCER1A rs2252226 and TLR2 rs4696480 polymorphisms interacted with regard to SCORAD. Higher SCORAD was observed in patients being the TLR2 rs4696480 major homozygotes and carrying at the same time the FCER1A rs2252226 minor allele, compared to those characterized by (any other of) the remaining combined rs2252226 and rs4696480 genotypes. The observation of the epistatic effect of TLR2 and FCER1A genetic variants on SCORAD is in line with the involvement of the interaction TLRs-FcεRI in the pathophysiology of AD.
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http://dx.doi.org/10.1016/j.humimm.2020.08.002DOI Listing
December 2020

Impaired Fibrinolysis in Patients with Isolated Aortic Stenosis is Associated with Enhanced Oxidative Stress.

J Clin Med 2020 Jun 25;9(6). Epub 2020 Jun 25.

Institute of Cardiology, Jagiellonian University Medical College, 31-202 Krakow, Poland.

Aortic stenosis (AS) has been associated with impaired fibrinolysis and increased oxidative stress. This study aimed to investigate whether oxidative stress could alter fibrin clot properties in AS. We studied 173 non-diabetic patients, aged 51-79 years, with isolated AS. We measured plasma protein carbonylation (PC) and thiobarbituric acid reactive substances (TBARS), along with plasma clot permeability (K), thrombin generation, and fibrinolytic efficiency, which were evaluated by two assays: clot lysis time (CLT) and lysis time (Lys50). Coagulation factors and fibrinolytic proteins were also determined. Plasma PC showed an association with AS severity, reflected by the aortic valve area and the mean and maximum aortic gradients. Plasma PC was positively correlated with CLT, Lys50, plasminogen activator inhibitor-1 (PAI-1), and tissue factor (TF) antigens. TBARS were positively correlated with maximum aortic gradient, Lys50, and TF antigen. Regression analysis showed that PC predicted prolonged CLT (>104 min; odds ratio (OR) 6.41, 95% confidence interval (CI) 2.58-17.83, < 0.001) and Lys50 (>565 s; OR 5.83, 95% CI 2.23-15.21, < 0.001). Multivariate regression analysis showed that mean aortic gradient, PC, α2-antiplasmin, PAI-1, and triglycerides were predictors of prolonged CLT, while PC, α2-antiplasmin, and fibrinogen were predictors of Lys50. Our findings suggest that elevated oxidative stress contributes to impaired fibrinolysis in AS and is associated with AS severity.
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http://dx.doi.org/10.3390/jcm9062002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355626PMC
June 2020

Effects of rivaroxaban and dabigatran on local expression of coagulation and inflammatory factors within human aortic stenotic valves.

Vascul Pharmacol 2020 07 7;130:106679. Epub 2020 May 7.

John Paul II Hospital, Cracow, Poland; Institute of Cardiology, Jagiellonian University Medical College, Cracow, Poland.

Background: Treatment with non-vitamin K antagonist oral anticoagulants (NOACs) such as dabigatran (a direct thrombin inhibitor) or rivaroxaban (a direct inhibitor of factor [F] Xa) attenuates atherosclerotic plaque progression in hypercholesterolemic mice.

Purpose: To evaluate the effect of NOACs application on the expression of coagulation proteins in loco within stenotic aortic valves and in valve interstitial cells (VICs) from patients with severe aortic stenosis (AS).

Methods: Primary cultures of VICs obtained from 90 patients undergoing aortic valve replacement were stimulated with TNF-α (50 ng/mL) and pre-treated with rivaroxaban (1 and 10 ng/mL) or dabigatran (25 and 250 ng/mL). The expression of coagulation proteins was analyzed by immunofluorescence. Cytokine levels were measured by ELISA.

Results: FX, FXa, FVII, thrombin and PAR1/2 were present in loco within human aortic stenotic valves. Cultured VICs exhibited constant expression of FX, TF, PAR1/2. Exposure of VICs to TNF-α caused the upregulated expression of TF, PAR1/2 and induced expression of thrombin, FVII and FXa. FX was expressed by 80% of VICs, regardless of stimulation. Cultured VICs were able to synthesize metalloproteinases 1-3, IL-6, IL-32, IL-34, osteopontin and osteocalcin, the levels of which increased under TNF-α stimulation. NOACs added to culture inhibited coagulation factor and PAR1/2 expression. Moreover, NOACs down-regulated VIC-derived proteins responsible for valve calcification and extracellular matrix remodeling.

Conclusions: NOACs at therapeutic concentrations may inhibit the effects of FXa and thrombin at in vitro level. It might be speculated that long-term treatment with rivaroxaban or dabigatran could attenuate the progression of AS in humans.
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http://dx.doi.org/10.1016/j.vph.2020.106679DOI Listing
July 2020

Determinants of elevated factor VIII in patients screened for thrombophilia.

Thromb Res 2020 04 29;188:28-30. Epub 2020 Jan 29.

Krakow Center for Medical Research and Technology, John Paul II Hospital, 80 Prądnicka Str., 31-202 Kraków, Poland; Faculty od Medicine and Health Sciences, Andrzej Frycz Modrzewski Krakow University, 1 Gustav Herling-Grudziński Str., 30-705 Kraków, Poland. Electronic address:

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http://dx.doi.org/10.1016/j.thromres.2020.01.027DOI Listing
April 2020

A prothrombotic state and denser clot formation in patients following acute limb ischemia of unknown cause.

Thromb Res 2020 03 10;187:32-38. Epub 2020 Jan 10.

Krakow Center for Medical Research and Technology, John Paul II Hospital, Krakow, Poland; Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland. Electronic address:

Introduction: Fibrin clot structure differs between healthy individuals and those following thromboembolic events. Dense and poorly lysable fibrin clots have also been reported in peripheral artery disease. We studied fibrin clot properties and its determinants in individuals with a history of acute lower limb ischemia (ALI) of unknown cause.

Materials And Methods: In this case-control study, we enrolled 43 patients who experienced ALI of unknown cause, and two age-and sex-matched reference groups: (1) patients with cryptogenic non-lacunar stroke (n = 43) and (2) individuals without any history of thromboembolism (n = 43, control group). Plasma fibrin clot properties, along with thrombin generation and fibrinolysis markers were assessed following ≥3 months of anticoagulation.

Results: Compared with the control group, the ALI group exhibited more compact plasma fibrin clots (13.4% lower permeability [K], p = .001), decreased formed clot lysis (12.5% lower D-D, p = .001) and unaltered clot lysis potential, along with enhanced thrombin generation potential (49% higher peak thrombin concentration, p < .0001). There were no differences in these variables between ALI and stroke patients. Patients with ALI had slightly higher α-antiplasmin and lower plasminogen activator inhibitor 1 levels compared with the stroke and control groups (all p < .01).

Conclusions: Patients who experienced ALI of unknown cause display a prothrombotic fibrin clot phenotype, including increased clot density and hypofibrinolysis associated with higher thrombin generation, which might suggest potential benefits from prolonged anticoagulation in this disease.
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http://dx.doi.org/10.1016/j.thromres.2020.01.008DOI Listing
March 2020

Identification of a variant hotspot in MYBPC3 and of a novel CSRP3 autosomal recessive alteration in a cohort of Polish patients with hypertrophic cardiomyopathy.

Pol Arch Intern Med 2020 02 9;130(2):89-99. Epub 2020 Jan 9.

Division of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.

Introduction: Hypertrophic cardiomyopathy (HCM) is a heart disorder caused by autosomal dominant alterations affecting both sarcomeric genes and other nonsarcomeric loci in a minority of cases. However, in some patients, the occurrence of the causal pathogenic variant or variants in homozygosity, compound heterozygosity, or double heterozygosity has also been described. Most of the HCM pathogenic variants are missense and unique, but truncating mutations of the MYBPC3 gene have been reported as founder pathogenic variants in populations from Finland, France, Japan, Iceland, Italy, and the Netherlands.

Objectives: This study aimed to assess the genetic background of HCM in a cohort of Polish patients.

Patients And Methods: Twenty‑nine Polish patients were analyzed by a next generation sequencing panel including 404 cardiovascular genes.

Results: Pathogenic variants were found in 41% of the patients, with ultra‑ rare MYBPC3 c.2541C>G (p.Tyr847Ter) mutation standing for a variant hotspot and correlating with a lower age at HCM diagnosis. Among the nonsarcomeric genes, the CSRP3 mutation was found in a single case carrying the novel c.364C>T (p.Arg122Ter) variant in homozygosity. With this finding, the total number of known HCM cases with human CSRP3 knockout cases has reached 3.

Conclusions: This report expands the mutational spectrum and the inheritance pattern of HCM.
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http://dx.doi.org/10.20452/pamw.15130DOI Listing
February 2020

Fibrinogen Łódź: a new cause of dysfibrinogenemia associated with recurrent thromboembolic arterial events.

Pol Arch Intern Med 2019 12 9;129(12):934-935. Epub 2019 Oct 9.

John Paul II Hospital, Kraków, Poland; Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland

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http://dx.doi.org/10.20452/pamw.15014DOI Listing
December 2019

Vascular Ehlers-Danlos syndrome in 2 Polish patients: identification of 2 novel COL3A1 gene mutations.

Kardiol Pol 2019 Nov 1;77(11):1070-1073. Epub 2019 Oct 1.

Department of Cardiac Surgery, Anesthesiology and Experimental Cardiology, Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland

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http://dx.doi.org/10.33963/KP.15005DOI Listing
November 2019

Genetic and clinical characterization of congenital fibrinogen disorders in Polish patients: Identification of three novel fibrinogen gamma chain mutations.

Thromb Res 2019 Oct 24;182:133-140. Epub 2019 Aug 24.

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

Introduction: Congenital fibrinogen disorders are poorly explored in Slavic populations. The aim of this study was to characterize the genetic background and clinical manifestations of fibrinogen disorders in the Polish case series.

Materials And Methods: In 27 unrelated patients (mean [SD] age, 30.4 [19.2] years, 30% men) with fibrinogen concentration (von Clauss method) < 1.8 g/L, exons and intron-exon junctions of the fibrinogen alpha chain (FGA), fibrinogen beta chain (FGB), and fibrinogen gamma chain (FGG) genes were analyzed using polymerase chain reaction (PCR) amplification followed by sequencing.

Results: At enrollment, 15 (55.6%) and 2 (7.4%) of patients experienced bleeding and thrombotic events, respectively, and the remainder were asymptomatic. The following congenital fibrinogen disorders were identified: 1A. afibrinogenemia, n = 1; 2A. severe hypofibrinogenemia, n = 2; 2B. moderate hypofibrinogenemia, n = 4; 2C. mild hypofibrinogenemia, n = 6; 3A. dysfibrinogenemia, n = 12; 3B. thrombotic related-dysfibrinogenemia, n = 1; 4C. mild hypodysfibrinogenemia, n = 1. Eight dysfibrinogenemic patients (62%) were carriers of hotspot mutations. Fifteen patients were heterozygous and one (afibrinogenemia) homozygous for known causative mutations. Three new heterozygous mutations were detected, all affecting splicing in FGG: fibrinogen Poznan II, a 177 bp deletion eliminating parts of intron 6 and exon 7 in a dysfibrinogenemic woman with recurrent bleeding; fibrinogen Zakopane, (intron 2 acceptor splice site) and fibrinogen Belchatow (intron 1 donor splice site), found in hypofibrinogenemic patients. During follow-up (median 60, interquartile range 10-60 months), bleeding episodes, mainly menorrhagia and easy bruising were reported in 15 (55.6%) patients. One thromboembolic event was observed.

Conclusion: This study of the largest cohort of Slavic patients with congenital fibrinogen disorders has enabled the identification of 3 new FGG mutations and shows a high prevalence of bleeding manifestations with recurrences.
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http://dx.doi.org/10.1016/j.thromres.2019.08.012DOI Listing
October 2019

Direct oral anticoagulants in the treatment of cerebral venous sinus thrombosis: a single institution's experience.

Neurol Neurochir Pol 2019 27;53(5):384-387. Epub 2019 Aug 27.

John Paul II Hospital, 80 Prądnicka St, Kraków, Poland.

Aim Of The Study: Oral anticoagulants, preferentially vitamin K antagonists (VKA), are recommended for 3-12 months in patients with cerebral venous sinus thrombosis (CVST). We present a series of patients with CVST treated with direct oral anticoagulants (DOAC).

Materials And Methods: We prospectively recruited 36 patients with CVST (aged 40.3 ± 9.2 years, 58.3% female) treated with DOAC based on the physician's or patient's preferences. Functional outcome was assessed with modified Rankin Scale. Recanalisation was assessed on imaging at 3-6 months post the event. Patients were followed for a median of 30 [interquartile range (IQR) 25-37] months.

Results: After use of heparin (median: 6 days; IQR 5-8.75), patients received dabigatran (150 mg bid, n = 16 or 110 mg bid, n = 2), rivaroxaban (20 mg qd, n = 10) or apixaban (5 mg bid, n = 8) for a median of 8.5 months (IQR 6.25-12). Complete or partial recanalisation was observed in 34 cases (94.4%). Three patients (8.3%) experienced major bleeding: menorrhagia on rivaroxaban (n = 2) and gastrointestinal bleeding on dabigatran (n = 1). A favourable functional outcome was observed in 24 (66.7%) patients, without any fatality. CSVT recurred in two patients (5.6%) and two venous thromboses developed in two other patients with inherited thrombophilia after anticoagulation withdrawal.

Conclusions And Clinical Implications: DOACs could be an alternative to VKA in CVST patients.
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http://dx.doi.org/10.5603/PJNNS.a2019.0037DOI Listing
November 2019

A series of 10 Polish patients with thromboembolic events and antithrombin deficiency: two new c.1154-1 G>C and c.1219-534 A>G SERPINC1 gene splicing mutations.

Blood Coagul Fibrinolysis 2019 Jul;30(5):193-198

John Paul II Hospital, Krakow, Poland.

: Inherited antithrombin (AT) deficiency, with prevalence in the general population ranging 0.02-0.17%, is an autosomal dominant disorder associated with a high risk of venous thromboembolism. In most cases, deficiency is caused by mutations in the AT-coding gene (SERPINC1). Only 24 splicing defects have been described causing AT deficiency, all affecting exon flanking regions. The aim of the current study was to characterize the mutations underlying AT deficiency in 10 venous thromboembolism Polish patients aged 42.9 (14-63) years. Whole SERPINC1 gene sequencing was done by next generation sequencing methods. Eight cases had mutations previously described. However, we identified two new intronic mutations that might affect the correct splicing of exon 6 according to in-silico predictions: c.1154-1 G>C, which strongly disturbs the acceptor sequence and c.1219-534 A>G, a deep intronic mutation that might generate a cryptic donor sequence; both might compete with the wild-type donor sequence and explain the associated moderate AT deficiency of carriers. In conclusion, we show the molecular base of AT deficiency in 10 new Polish patients, including two novel SERPINC1 gene mutations potentially affecting splicing.
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http://dx.doi.org/10.1097/MBC.0000000000000816DOI Listing
July 2019

High prevalence of inherited thrombophilia and antiphospholipid syndrome in myocardial infarction with non-obstructive coronary arteries: Comparison with cryptogenic stroke.

Int J Cardiol 2019 09 18;290:1-6. Epub 2019 May 18.

Department of Experimental Cardiac Surgery, Anesthesiology and Cardiology, Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland; Krakow Center for Medical Research and Technology, John Paul II Hospital, Krakow, Poland. Electronic address:

Background: A role of thrombophilia in myocardial infarction with non-obstructive coronary arteries (MINOCA) is unclear. We investigated thrombophilic factors in MINOCA patients versus those following cryptogenic stroke (CS), a well-established indication for thrombophilia screening.

Methods: In a prospective cross-sectional study, we assessed 84 consecutive patients (median age: 45.5 years) at least 3 months after MINOCA. Age-matched CS patients (n = 84) and published data on general population served as controls. Thrombophilia screening involved inherited thrombophilia (factor V Leiden, prothrombin G20210A mutation, deficiency of protein C, protein S or antithrombin), antiphospholipid syndrome (APS), along with factor VIII >150%, homocysteine ≥15 μM and lipoprotein (a) >30 mg/dl.

Results: Compared to CS, MINOCA were more often males (60.7 vs 33.3%, P < 0.001), obese (34.5 vs 17.9%, P = 0.014), smokers (51.2 vs 35.7%, P = 0.043) and had family history of myocardial infarction (27.4 vs 6.0%, P < 0.001). Inherited thrombophilia occurred in 20 (23.8%) MINOCA patients and in 13 (15.5%) with CS (P = 0.17), without any difference in the parameters except for elevated lipoprotein (a) that was less common in MINOCA (21.4 vs 39.3%, P = 0.012). APS was found in 13 (15.5%) of MINOCA patients, mostly in a single-positive form. APS was diagnosed less frequently in STEMI (2.5 vs 27.3% for NSTEMI, P = 0.002) and MINOCA patients aged ≤50 years (5.7 vs 32.3% for older subjects, P = 0.003).

Conclusions: MINOCA patients exhibit high prevalence of thrombophilia including APS, similar to that in CS. Our first comprehensive thrombophilia testing in MINOCA supports its clinical relevance and the need for long-term anticoagulation for some abnormalities, especially APS.
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http://dx.doi.org/10.1016/j.ijcard.2019.05.037DOI Listing
September 2019

High detection rates of antithrombin deficiency and antiphospholipid syndrome in outpatients aged over 50 years using the standardized protocol for thrombophilia screening.

Thromb Res 2019 Apr 11;176:67-73. Epub 2019 Feb 11.

Krakow Center for Medical Research and Technology, John Paul II Hospital, Krakow, Poland; Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland. Electronic address:

Introduction: Thrombophilia screening has limited detection efficiency. We assessed the detection rate when a standardized approach to thrombophilia-screened outpatients was used.

Methods: We analyzed 1185 patients (36.5% males, median age: 43 years [IQR 33-54]) referred to a single center from January 2014 to October 2017 with 11 different clinical indications for thrombophilia screening, which was performed in the adherence to published guidelines. Factor V Leiden, prothrombin G20210A mutation, antithrombin (AT), protein C, protein S deficiencies and antiphospholipid syndrome (APS) were determined.

Results: The overall positivity rate was 37.1% (95% CI 34.3%-39.7%). The highest positivity rate was found in women following VTE during pregnancy/childbirth (64.1%) and provoked VTE patients with positive family history (52.9%). In patients aged >50 years (32.5%), APS was found at a similar rate as in younger subjects (11.4% vs 10.1%), while AT deficiency was detected more frequently in the older group (5.7% vs 2.4%, p = 0.003).

Conclusions: Standard indications for thrombophilia screening lead to detection rates of 37% or more. Frequent detection of APS and AT deficiency among older patients, which often implies a need for long-term anticoagulation and could impact clinical practice patterns, suggests a benefit of thrombophilia screening in this population in selected clinical circumstances.
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http://dx.doi.org/10.1016/j.thromres.2019.02.008DOI Listing
April 2019

MPI-CDG with transient hypoglycosylation and antithrombin deficiency.

Haematologica 2019 02 13;104(2):e79-e82. Epub 2018 Dec 13.

Institute of Cardiology, Jagiellonian University Medical College, John Paul II Hospital, Kraków, Poland.

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http://dx.doi.org/10.3324/haematol.2018.211326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355499PMC
February 2019

Kinetics of selected serum markers of fibrosis in patients with dilated cardiomyopathy and different grades of diastolic dysfunction of the left ventricle.

Cardiol J 2020 28;27(6):726-734. Epub 2018 Nov 28.

Collegium Medicum of Jagiellonian University, Department of Cardiac and Vascular Diseases, John Paul II Hospital, Kraków, Poland, ul.Prądnicka 80, 31-202 Cracow, Poland.

Background: Fibrosis of the extracellular matrix (ECM) in dilated cardiomyopathy (DCM) is common and compromises both systolic and diastolic function. The aim of this study was to investigate the kinetics of ECM fibrosis markers over a 12 month follow-up in patients with DCM based on the severity of diastolic dysfunction (DD).

Methods: Seventy consecutive DCM patients (48 ± 12.1 years, ejection fraction 24.4 ± 7.4%) were included in the study. The grade of DD was determined using the ASE/EACVI algorithm. Markers of ECM fibrosis were measured at baseline and at 3 and 12 month follow-ups: collagen type I and III (PICP, PINP, PIIICP, PIIINP), transforming growth factor beta-1 (TGF1-b), connective tissue growth factor (CTGF) and galectin-3 were measured.

Results: Patients were divided into three groups according to DD severity: 30 patients with grade I, 18 with grade II and 22 with grade III of DD. Levels of PICP, PINP were increased over a 12-month period, while PIIINP decreased and PIIICP unchanged. Levels of TGF1-b decreased from the 3 to the 12-month points in grade I and II DD, and in grade III they remained unchanged. Levels of CTGF decreased over 12 months in grade III DD but were unchanged in grades I and II. Galectin-3 levels remained the same over all observation periods, irrespective of DD grade.

Conclusions: Regardless of the DD grade, markers of collagen type I synthesis increased, markers of collagen type III decreased. Levels of TGF and CTGF had a tendency to decrease. Galectin-3 was revealed not to be a marker discriminating the severity of DD.
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http://dx.doi.org/10.5603/CJ.a2018.0143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079113PMC
November 2018

Non-classical and intermediate monocytes in patients following venous thromboembolism: Links with inflammation.

Adv Clin Exp Med 2019 Jan;28(1):51-58

Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland.

Background: Monocyte subsets are involved in atherosclerotic vascular disease and its thromboembolic complications. Moreover, the role of monocytes has been suggested in the pathogenesis of venous thromboembolism (VTE).

Objectives: We hypothesized that pro-inflammatory non-classical and intermediate monocytes are increased in the first months following VTE.

Material And Methods: We enrolled 70 patients aged 18-65 years (mean age 41.6 ±11.6) with the firstever provoked (n = 32; 45.7%) or unprovoked (n = 38; 54.28%) VTE episode, and 46 healthy controls. The exclusion criteria were: acute infection, cancer, autoimmune disorders, previous myocardial infarction (MI), or stroke. Monocyte subsets were assessed 12 (8.5-21.5) months after VTE using flow cytometry and were defined as classical (CD14++CD16-), intermediate (CD14++CD16+) and non-classical (CD14+CD16++).

Results: Patients with VTE had higher intermediate and non-classical monocyte counts compared to the control group (16.8 ±9.3 vs 10.4 ±4.0 cells/μL, and 64.1 ±25.2 vs 44.1 ±19.2 cells/μL, respectively, both p < 0.001). Increased non-classical monocyte counts were observed in patients who experienced a VTE incident within 12 months prior to enrollment (71.5 ±27.4 vs 56.03 ±20.6 cells/μL; p = 0.01) and those with unprovoked VTE (70.2 ±4.1 vs 58.8 ±4.3 cells/μL; p = 0.06). There were no differences in monocyte subsets related to the current anticoagulation.

Conclusions: Our data has shown for the first time that VTE is associated with an increased number of nonclassical and intermediate monocytes, which may indicate the involvement of monocyte-related mechanisms in the pathophysiology of this disease.
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http://dx.doi.org/10.17219/acem/76262DOI Listing
January 2019

Defects of splicing in antithrombin deficiency.

Res Pract Thromb Haemost 2017 Oct 14;1(2):216-222. Epub 2017 Jul 14.

Servicio de Hematología y Oncología Médica Hospital Universitario Morales Meseguer Centro Regional de Hemodonación Universidad de Murcia IMIB-Arrixaca Murcia Spain.

Background: There is increasing evidence supporting the relevance of aberrant splicing in multiple disorders. In antithrombin deficiency only 22 intronic mutations affecting splicing sites (7% of mutations) are considered as splicing mutations.

Methods: was analyzed by Sanger sequencing and MLPA in 141 unrelated cases with antithrombin deficiency. Plasma antithrombin was studied by functional and western blot assays, purified by FPLC and characterized by proteomic analysis. predictions on splicing was done with the Human Splicing Finder software.

Results: We detected 89 different defects, 13 with potential effect on splicing. Ten cases presented 9 mutations disturbing splicing sites, 5 new. Three gross or small gene defects also disturbed a correct splicing. Interestingly, the first duplication of a single exon ever described (c.1154-13_1218+115dup), caused mild deficiency (75%). A deeper intronic mutation (c.1154-14G>A), identified in three unrelated patients with traces of disulphide dimers of antithrombin in plasma, created a cryptic splicing site that might generate a variant with 4 additional in frame residues according to predictions. This aberrant splicing was confirmed by proteomic analysis of the dimer purified from plasma.

Conclusions: A high proportion of cases with antithrombin deficiency (up to 13%) may be explained by an aberrant splicing. Up to 15% of mutations in : splicing site variations, gross gene defects and deep intronic mutations, may affect a correct splicing with three potential consequences type I, type II, and even moderate antithrombin deficiency.
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http://dx.doi.org/10.1002/rth2.12025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058262PMC
October 2017

The New *G29A and G1222A of , 5-HTTLPR of Polymorphisms and Hypocretin-1, Serotonin Concentrations in Migraine Patients.

Front Mol Neurosci 2018 5;11:191. Epub 2018 Jun 5.

Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, Poznan, Poland.

Migraine is one of the most common primary headache disorders that affects 11% of the adult population. The disease is divided into two main clinical subtypes: migraine with aura (MA) and migraine without aura (MO). Both serotonergic and hypocretinergic systems are involved in the migraine pathomechanism. Polymorphisms in the serotonin transporter gene () and the hypocretin receptor 1 gene () may be risk factors for migraine development due to their ability to affect serotonin and hypocretin-1 (HCRT-1) concentrations. The aim of the study was to analyze, for the first time in the Polish population, the 5-HT transporter linked polymorphic region (5-HTTLPR) in , G1222A (rs2271933) and the never before studied *G29A (rs41263963) polymorphisms in the gene, as well as the 5-HT and hypocretin-1 plasma concentrations in migraine patients (MA, MO) and control subjects. The study included 123 patients that were diagnosed with migraine and 123 control subjects. Methods such as PCR, HRMA and sequencing were used for genotyping, while 5-HT was determined by HPLC/EC and hypocretin-1 by ELISA. No significant differences were observed in 5-HTTLPR frequencies. The A allele of G1222A occurred more often in MO, while the GA genotype of *G29A was more frequent among MA when compared to control group ( < 0.05). The mean age of migraine onset in individuals with *G29A was 18 years old for patients with MA and 26 years old for MO patients. The localization and type of polymorphisms (G1222A-missense variant in exon 7, *G29A-3'UTR variant) may predispose patients to the clinical subtype of migraine: MO or MA, respectively. In control subjects, the short allele of 5-HTTLPR tended to decrease the 5-HT concentration, while the A allele of G1222A decreased both 5-HT and hypocretin-1 levels. Serotonin concentrations differed in terms of clinical features of migraine. The relation between genotypes of 5-HTTLPR, G1222A, and 5-HT concentrations may bedisturbed in migraine. It seems that *G29A is more strongly associated with regulating the 5-HT in patients with MA than MO, and therefore may contribute to the early age of onset for migraine.
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http://dx.doi.org/10.3389/fnmol.2018.00191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996111PMC
June 2018

Genetic causes of resistance to vitamin K antagonists in Polish patients: a novel p.Ile123Met mutation in VKORC1 gene.

Blood Coagul Fibrinolysis 2018 Jul;29(5):429-434

Krakow Centre for Medical Research and Technologies.

: Mutations in the genes encoding vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) largely contribute to the inter-individual variations in vitamin K antagonists (VKAs) dose requirements. Up to 50% of the dosage variability can be explained by genetic polymorphisms in these genes. We sought to identify the mutations responsible for VKA resistance in a series of Polish patients. Of the 607 patients treated with VKA, 35 (6%) individuals with the VKA resistance defined as a daily dose of acenocoumarol more than 8 mg (n = 15, 43%) or warfarin more than 10 mg (n = 20, 57%) were selected for further mutational analysis using Sanger sequencing (VKORC1) or real-time PCR genotyping (CYP2C9). The indications for anticoagulant treatment were venous thromboembolism (n = 28, 80%), atrial fibrillation (n = 6, 17%), or artificial heart valve (n = 1, 3%). Patients taking medication interfering with VKA were ineligible. Almost all of VKA-resistant patients (n = 34, 97%) possessed at least one VKORC1*3 (n = 29, 83%) or VKORC1*4 (n = 15, 43%) haplotypes. In a 70-year-old man atrial fibrillation patient on the daily acenocoumarol dose of 16 mg, a novel p.Ile123Met (c.369C>G) VKORC1 mutation was found. In-silico analysis showed that the p.Ile123Met can functionally underlie the acenocoumarol resistance, presumably by altering VKA binding. To our knowledge this is the first cohort of Polish patients resistant to VKA evaluated for the causal genetic background. We found one new detrimental mutation underlying VKA resistance. Our study highlights a key role of unidentified environmental factors in VKA resistance in daily clinical practice.
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http://dx.doi.org/10.1097/MBC.0000000000000737DOI Listing
July 2018

Lymphocyte and monocyte subpopulations in severe aortic stenosis at the time of surgical intervention.

Cardiovasc Pathol 2018 Jul - Aug;35:1-7. Epub 2018 Apr 7.

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

Introduction: Aortic stenosis (AS) is the most common acquired valvular heart disease in adults. Immune system involvement becomes evident during AS development. We sought to investigate the role of different circulating lymphocyte and monocyte subpopulations, with focus on CD4CD8 and natural killer T (NKT) cells, in AS.

Material And Methods: Blood samples and aortic valves were obtained from patients undergoing elective aortic valve surgery. Valves were dissected and underwent genetic analyses and calcium content assessment. Lymphocytes and monocytes subsets were assessed by flow cytometry.

Results: Thirty-eight AS patients were studied. Maximal transvalvular pressure gradient (PG) as well as mean transvalvular pressure gradient (PG) correlated with the CD4CD8 lymphocyte count (r=0.35, P=.03 and r=0.43, P=.006, respectively) and fraction (r=0.43, P=.007 and r=0.48, P=.002, respectively). PG and PG correlated with CD16CD56CD3 NKT cell count (r=0.39, P=.01 and r=0.43, P=.007, respectively) and fraction (r=0.49, P=.002 and r=0.47, P=.003, respectively). The classical monocyte subpopulation increased after the surgery by 68% (P<.0001). Patients after mini-sternotomy surgery had 47% lower nonclassical monocyte counts than those with full-sternotomy (P=.03). Patients treated with statins had significantly lower postoperative levels of both classical (-25%, P=.04) and nonclassical monocytes (-37%, P=.004) than nontreated individuals.

Conclusions: In patients with severe isolated AS, CD4CD8 T cells and CD16CD56CD3 NKT cells are associated with AV pressure gradients. Postoperative monocyte levels are affected by procedure invasiveness and use of statins.
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http://dx.doi.org/10.1016/j.carpath.2018.03.004DOI Listing
December 2018

Identification of a New Mechanism of Antithrombin Deficiency Hardly Detected by Current Methods: Duplication of SERPINC1 Exon 6.

Thromb Haemost 2018 05 21;118(5):939-941. Epub 2018 Mar 21.

Servicio de Hematología y Oncología Médica, Centro Regional de Hemodonación, Hospital Universitario Morales Meseguer, Universidad de Murcia, IMIB-Arrixaca, CIBERER, Murcia, Spain.

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http://dx.doi.org/10.1055/s-0038-1637721DOI Listing
May 2018

Bleeding predictors in patients following venous thromboembolism treated with vitamin K antagonists: Association with increased number of single nucleotide polymorphisms.

Vascul Pharmacol 2018 07 9;106:22-27. Epub 2018 Feb 9.

Institute of Cardiology, Jagiellonian University School of Medicine, Cracow, Poland; John Paul II Hospital, Cracow, Poland. Electronic address:

Introduction: Single nucleotide polymorphisms (SNP) in genes encoding proteins involved in metabolism and action of vitamin K antagonists (VKA) affect anticoagulation stability. We investigated how those polymorphisms influence bleeding rates in patients following venous thromboembolism (VTE).

Materials And Methods: In 324 patients following unprovoked VTE, 143 (44%) on warfarin and 181 (56%) on acenocoumarol, we recorded bleeds within the preceding 24 months. We assessed eight SNP, including those in cytochrome P450 isoform 2C9 (CYP2C9) and isoform 4F2 (CYP4F2), vitamin K epoxide reductase complex subunit 1 (VKORC1), gamma-glutamyl carboxylase (GGCX), apolipoprotein E (APOE) and multidrug resistance gene 1 (MDR1).

Results: Within 48 months before enrolment, bleeding events occurred in 80 (25%) patients, including 14 (4%) major bleeds. Patients with bleeds had 16.2% lower median time in therapeutic range (TTR) and were more often carriers of CYP2C9*3 variant (26 [33%] vs. 19 [8%], p < 0.001) compared with the remainder. Bleeding occurred more frequently in patients with ≥4 SNP compared with the remainder (27 [34%] vs. 47 [19%], p = 0.009) with no intergroup differences of TTR. Number of SNP was one of the predictors of any bleeding. The regression model for major bleeding including factors such as CYP2C9*3 c. 1075 C, VKORC1 c. -1639 A and APOE c. 388 C showed good predictive ability (area under the curve - 0.79).

Conclusions: In VTE patients on the maintenance treatment with VKA, bleeding episodes are associated with CYP2C9 gene variations and increased number of SNP of genes involved in the action and metabolism of VKA.
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http://dx.doi.org/10.1016/j.vph.2018.02.002DOI Listing
July 2018

Venous thromboembolism associated with protein S deficiency due to Arg451* mutation in PROS1 gene: a case report and a literature review.

J Genet 2017 Dec;96(6):1047-1051

The John Paul II Hospital, 31-202 Kraków, Poland.

Protein S (PS) is a vitaminK-dependent glycoproteinwhich plays an important role in the regulation of blood coagulation. PS deficiency has been found in 1.5-7% of thrombophilic patients. Here, we report the first Polish case with PS deficiency caused by the p.Arg451* in the PROS1 gene detected in a 21-year-old man with trauma-induced venous thromboembolism. To our knowledge, we provided the review of all the available data on this mutation (a total of 56 cases). The proband, his mother and his sister were screened for thrombophilia. To elucidate genetic background of PS deficiency, all PROS1 genes were subjected to direct sequencing. The free PS levels were 35% in the proband, 21% in the proband's mother and 28% in the proband's sister and their PS total levels were 37.1, 47.5 and 55.1%, respectively. Type I PS deficiency was diagnosed. In all patients, genetic analysis revealed the presence of heterozygous nonsense mutation (c.1351C>T; p.Arg451*) located in exon 12 of PROS1 gene. This mutation interrupts the reading frame by premature termination codon at position 451 and may lead to the production of truncated protein. The present case combined with the review of the literature suggests that p.Arg451* in the PROS1 gene mainly leads to clinically evident thrombosis following trauma, surgery or serious comorbidities especially malignancy.
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http://dx.doi.org/10.1007/s12041-017-0865-9DOI Listing
December 2017