Publications by authors named "Joanna Natorska"

56 Publications

Aortic valvular stenosis: Novel therapeutic strategies.

Eur J Clin Invest 2021 Feb 23:e13527. Epub 2021 Feb 23.

John Paul II Hospital, Kraków, Poland.

Background: Aortic stenosis (AS) prevalence is estimated to reach 4.5 million cases worldwide by the year 2030. AS is a progressive disease without a pharmacological treatment. In the current review, we aimed to investigate novel therapeutic approaches for non-surgical AS treatment, at least in patients with mild-to-moderate AS.

Materials And Methods: The most recent and relevant papers concerned with novel molecular pathways that have potential as therapeutic targets in AS were selected from searches of PubMed and Web of Science up to February 2021.

Results: Growing evidence indicates that therapies using proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, simvastatin/ezetimibe combination, cholesteryl ester transfer protein inhibitors or antisense oligonucleotides targeting apolipoprotein(a) reduce the risk of AS progression. It has been shown that enhanced valvular lipid oxidation may drive AS development by leading to the activation of valvular interstitial cells (VICs), the most abundant valvular cells having a major contribution to valve calcification. Since VICs are able to release pro-inflammatory cytokines, clotting factors and proteins involved in calcification, strategies targeting these cell activations seem promising as therapeutic interventions. Recently, non-vitamin K antagonist oral anticoagulants (NOACs) have been shown to inhibit activation of VICs.

Conclusion: Several novel molecular pathways of AS development have been identified over the past few years. Therapies using PCSK9 inhibitors, simvastatin/ezetimibe combination, lipoprotein(a)-lowering therapy are highly promising candidates as therapeutics in the prevention of mild AS progression, while preclinical studies show that NOACs may inhibit valvular inflammation and coagulation activation and slower the rate of AS progression.
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http://dx.doi.org/10.1111/eci.13527DOI Listing
February 2021

Factor XIII and Fibrin Clot Properties in Acute Venous Thromboembolism.

Int J Mol Sci 2021 Feb 5;22(4). Epub 2021 Feb 5.

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

Coagulation factor XIII (FXIII) is converted by thrombin into its active form, FXIIIa, which crosslinks fibrin fibers, rendering clots more stable and resistant to degradation. FXIII affects fibrin clot structure and function leading to a more prothrombotic phenotype with denser networks, characterizing patients at risk of venous thromboembolism (VTE). Mechanisms regulating FXIII activation and its impact on fibrin structure in patients with acute VTE encompassing pulmonary embolism (PE) or deep vein thrombosis (DVT) are poorly elucidated. Reduced circulating FXIII levels in acute PE were reported over 20 years ago. Similar observations indicating decreased FXIII plasma activity and antigen levels have been made in acute PE and DVT with their subsequent increase after several weeks since the index event. Plasma fibrin clot proteome analysis confirms that clot-bound FXIII amounts associated with plasma FXIII activity are decreased in acute VTE. Reduced FXIII activity has been associated with impaired clot permeability and hypofibrinolysis in acute PE. The current review presents available studies on the role of FXIII in the modulation of fibrin clot properties during acute PE or DVT and following these events. Better understanding of FXIII's involvement in the pathophysiology of acute VTE might help to improve current therapeutic strategies in patients with acute VTE.
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http://dx.doi.org/10.3390/ijms22041607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914915PMC
February 2021

The Effect of Direct Oral Anticoagulants on Antithrombin Activity Testing Is Abolished by DOAC-Stop in Venous Thromboembolism Patients.

Arch Pathol Lab Med 2021 01;145(1):99-104

From the Institute of Cardiology, Jagiellonian University Medical College and John Paul II Hospital, Kraków, Poland (Ząbczyk, Natorska, Kopytek, Undas).

Context.—: Direct oral anticoagulants (DOACs) may cause false negative results of antithrombin (AT) deficiency screening.

Objective.—: To evaluate the impact of DOAC-Stop, an agent reversing in vitro effects of DOACs, on AT testing in anticoagulated patients.

Design.—: We assessed 130 venous thromboembolism patients aged 46.7 ± 13.5 years. Blood samples were collected 2 to 27 hours after DOAC intake from 49 patients on rivaroxaban, 54 on apixaban, and 27 on dabigatran. Antithrombin activity was assessed using the activated factor X (FXa)-based and the activated factor II (FIIa)-based method twice, before and after DOAC-Stop treatment, together with plasma DOAC levels using coagulometric assays.

Results.—: The use of DOAC-Stop did not influence AT activity measured using the FIIa-based assay, whereas there was a marked decrease in AT activity determined using the FXa-based assay (ΔAT = 16.9%; 95% CI, 12.9%-19.1%). The AT-FIIa assay revealed decreased AT level (<79%) in all 10 (7.7%) genetically confirmed AT-deficient patients treated with rivaroxaban or apixaban (n = 5 each), whereas the AT-FXa assay showed decreased AT activity (<83%) in 2 subjects on rivaroxaban and 1 on apixaban with low plasma DOAC concentrations (<90 ng/mL). After DOAC-Stop median AT-FXa activity lowered from 83.5% (interquartile range, 66%-143%) to 65.5% (interquartile range, 57%-75%; P = .005; ΔAT = 18%) in AT-deficient patients, without any false negative results. The ΔAT in the FXa-based assay correlated with rivaroxaban and apixaban concentrations in the AT-deficient patients (r = 0.99, P < .001).

Conclusions.—: Application of DOAC-Stop enables reliable evaluation of AT deficiency screening in patients taking rivaroxaban or apixaban and tested using the FXa-based method.
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http://dx.doi.org/10.5858/arpa.2020-0021-OADOI Listing
January 2021

Von Willebrand factor in aortic or mitral valve stenosis and bleeding after heart valve surgery.

Thromb Res 2021 02 16;198:190-195. Epub 2020 Dec 16.

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

Objectives: Low von Willebrand factor (VWF) increases the risk of bleeding. The objective was to assess the influence of VWF on bleeding after valvular surgery.

Methods: We studied 82 consecutive patients in median age of 65.5 years with severe isolated aortic stenosis (AS, n = 62) or mitral stenosis (MS, n = 20), undergoing heart valve surgery in extracorporeal circulation. Preoperatively, we assessed VWF antigen (VWF:Ag) and activity (VWF:RCo), a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), and fibrinolysis inhibitors.

Results: Compared with AS, MS patients were more frequently female (80 vs. 55%, p = 0.045) with atrial fibrillation (AF) (80 vs. 8%, p < 0.0001), with no difference in age or comorbidities. Median postoperative drainage was 420 ml for AS, and 425 ml for MS (p = 0.37). Patients with AS had lower VWF:RCo (125.8 [88.5-160.8] vs. 188.0 [140.3-207.3] IU/dl, p = 0.003) and VWF:Ag (135.8 [112.0-171.2] vs. 191.7 [147.3-236.4] IU/dl, p = 0.01) than MS patients. Mean VWF:RCo/Ag ratio was 0.88 ± 0.17, with no intergroup differences. ADAMTS13 levels and activity were similar in both groups. In AS, both VWF:RCo and VWF:Ag correlated inversely with maximal (r = -0.39, p = 0.0003 and r = -0.39, p = 0.0004, respectively) and mean (r = -0.40, p = 0.0004 and r = -0.39, p = 0.0006, respectively) transvalvular pressure gradients. There was no difference in perioperative bleeding between patients following mitral and aortic valve surgery, and bleeding was not associated with VWF:Ag or VWF:RCo.

Conclusions: In severe AS, VWF levels and activity correlate inversely with transvalvular pressure gradients, and are lower than in severe degenerative MS, but do not affect blood loss after valvular surgery in extracorporeal circulation.
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http://dx.doi.org/10.1016/j.thromres.2020.12.005DOI Listing
February 2021

Fibrin clot susceptibility to lysis is impaired after on-pump coronary artery by-pass grafting with tranexamic acid: clinical implications.

Blood Coagul Fibrinolysis 2021 Jan;32(1):29-36

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

Coronary artery bypass grafting (CABG) done on-pump may cause a significant blood loss. Low fibrinogen is associated with perioperative bleeding. The influence of cardiopulmonary bypass on fibrin clot properties is poorly investigated. We studied 55 patients with isolated coronary artery disease on aspirin undergoing on-pump CABG with tranexamic acid. Fibrinogen levels, fibrinolytic capacity expressed as clot lysis time (CLT), thrombin generation potential and platelet count were assessed before and after the surgery (prior to admission to the intensive care unit). A postoperative drop in haemoglobin (-30% from baseline), haematocrit (-31% from baseline) and platelet count (-42% from baseline) was observed (all, P < 0.0001). Postoperative fibrinogen level was lower by 57%, compared with preoperative value (1.5 [1.3-1.8] vs. 3.5 [2.8-3.9] g/l, P < 0.0001). Postoperative CLT was longer by 48 min, compared with preoperative (182 [170-218] vs. 134 [122-165] min, P < 0.0001). Thrombin generation was impaired postoperatively: both lag time and time to peak thrombin were prolonged by 44 and 45%, respectively, whereas endogenous thrombin potential and peak thrombin generation decreased by 45 and 78%, respectively (all P < 0.0001). Median postoperative drainage at 12 h was 400 [290-570] ml. Predictors of blood loss at 12 h identified in multivariable linear regression model adjusted for sex and preoperative fibrinogen level were: BMI (b = -23.4, P = 0.048) and postoperative CLT (b = -2.4, P = 0.042). Despite decreased fibrinogen levels after on-pump CABG with tranexamic acid, fibrin clot susceptibility to lysis is impaired, as reflected by prolonged CLT. Postoperative CLT is associated with mediastinal drainage at 12 h.
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http://dx.doi.org/10.1097/MBC.0000000000000980DOI Listing
January 2021

Loose Fibrin Clot Structure and Increased Susceptibility to Lysis Characterize Patients with Central Acute Pulmonary Embolism: The Impact of Isolated Embolism.

Thromb Haemost 2021 Apr 13;121(4):529-537. Epub 2020 Nov 13.

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

Background:  Prothrombotic fibrin clot properties are associated with higher early mortality risk in acute pulmonary embolism (PE) patients. It is unknown whether different types of PE are associated with particular clot characteristics.

Methods:  We assessed 126 normotensive, noncancer acute PE patients (median age: 59 [48-70] years; 52.4% males), who were categorized into central versus peripheral PE with or without concomitant deep vein thrombosis (DVT). Plasma fibrin clot permeability (), clot lysis time (CLT), thrombin generation, platelet-derived markers, and fibrinolytic parameters were measured on admission. Plasma fibrin clot morphology was assessed by scanning electron microscopy (SEM).

Results:  Patients with central PE ( = 76; 60.3%) compared with peripheral PE ( = 50; 39.7%) had 17.8% higher and 14.3% shortened CLT (both  < 0.01 after adjustment for potential confounders including fibrinogen), with no differences between segmental and subsegmental PE. SEM analysis demonstrated larger fibrin fiber diameter and pore size in central PE compared with peripheral PE (both  < 0.01). For isolated PE, there was 23.3% higher in central PE than in peripheral PE ( = 24; 19%) with no differences in other variables. Central PE combined with DVT ( = 45; 35.7%), as compared with central isolated PE ( = 31; 24.6%), was associated with shortened CLT (all  < 0.05).

Conclusion:  Our findings suggest that looser fibrin networks composed of thicker fibers with increased susceptibility to lysis characterize patients with central PE, suggesting that fibrin clot phenotype affects the size of thrombi occluding the pulmonary arteries, highlighting the role of fibrin structures in thrombus formation and stability.
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http://dx.doi.org/10.1055/s-0040-1718762DOI Listing
April 2021

Left internal mammary artery skeletonization reduces bleeding - a randomized controlled trial.

Ann Thorac Surg 2020 Nov 7. Epub 2020 Nov 7.

Department of Cardiovascular Surgery and Transplantology, John Paul II Hospital, Krakow, Poland; Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland.

Background: The objective was to compare the impact of skeletonized vs. pedicled left internal mammary artery (LIMA) harvesting on bleeding after coronary artery by-pass grafting (CABG).

Methods: In a randomized single-blinded trial with parallel group design and equal allocation, we randomly assigned 62 patients undergoing primary elective CABG in a tertiary cardiac center to skeletonized or pedicled LIMA dissection. Preoperatively, all aspects of coagulation were assessed. Patients were blinded to LIMA dissection technique and monitored for cumulative drainage at 12h (primary outcome) and myocardial necrosis markers.

Results: With recruitment complete, there were 31 patients in each group and all patients were analyzed. Median postoperative drainage was 395 ml at 12h in all patients, and was lower by 28% at 12h (p=0.02) in patients with skeletonized LIMA (Cohen's d [95% CI], 0.6 [0.09-1.11]). Patients with LIMA pedicle received more fresh frozen plasma transfusions than skeletonized LIMA group (3 [3-5] vs. 3 [3-3], p=0.03). Study arms did not differ in blood coagulation. LIMA skeletonization (OR [95% CI], 0.04 [0.003-0.44], p=0.009) and higher body mass index (OR [95% CI], 0.63 [0.45-0.89], p=0.008) decreased the odds of being in the top drainage quartile at 12h (≥550 ml). Creatine kinase was lower in skeletonized LIMA directly after surgery (218 [175-310] vs. 424 [256-510] U/l, p=0.0001), at 6h (324 [239-424] vs. 529 [374-707] U/l, p=0.0003) and 12h postoperatively (351 [277-552] vs. 695 [509-1067] U/l, p=0.0001).

Conclusions: LIMA skeletonization results in a lower mediastinal drainage after CABG than pedicled LIMA harvesting. Jagiellonian University grant No. K/ZDS/007961. NCT03622671.
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http://dx.doi.org/10.1016/j.athoracsur.2020.10.024DOI Listing
November 2020

Increased levels of histidine-rich glycoprotein are associated with the development of post-thrombotic syndrome.

Sci Rep 2020 09 2;10(1):14419. Epub 2020 Sep 2.

Krakow Centre for Medical Research and Technologies, John Paul II Hospital, Krakow, Poland.

Denser fibrin networks which are relatively resistant to lysis can predispose to post-thrombotic syndrome (PTS). Histidine-rich glycoprotein (HRG), a blood protein displaying antifibrinolytic properties, is present in fibrin clots. We investigated whether HRG may affect the risk of PTS in relation to alterations to fibrin characteristics. In venous thromboembolism (VTE) patients, we evaluated plasma HRG levels, plasma clot permeability, maximum absorbance, clot lysis time and maximum rate of increase in D-dimer levels released from clots after 3 months of the index event. We excluded patients with cancer and severe comorbidities. After 2 years of follow-up, 48 patients who developed PTS had 18.6% higher HRG at baseline. Baseline HRG positively correlated with clot lysis time, maximum absorbance, and thrombin-activatable fibrinolysis inhibitor (TAFI) activity but was inversely correlated with plasma clot permeability and maximum rate of increase in D-dimer levels released from clots. On multivariate regression model adjusted for age, fibrinogen and glucose, independent predictors of PTS were recurrent VTE, baseline HRG level, and TAFI activity. VTE recurred in 45 patients, including 30 patients with PTS, and this event showed no association with elevated HRG. Our findings suggest that increased HRG levels might contribute to the development of PTS, in part through prothrombotic fibrin clot properties.
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http://dx.doi.org/10.1038/s41598-020-71437-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468120PMC
September 2020

Intraoperative Thrombophilia-Associated Thrombosis of Both Saphenous Veins during Harvesting for Coronary Artery Bypass Grafting.

TH Open 2020 Jul 23;4(3):e197-e202. Epub 2020 Aug 23.

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

 Intraoperative thrombosis of saphenous veins (SV) during open harvesting is very rare.  We present a case of a 60-year-old male patient with multivessel coronary artery disease and a history of a non-ST elevation acute coronary syndrome, and type-2 diabetes mellitus admitted for coronary artery bypass grafting, in whom bilateral intraoperative SV thrombosis occurred during graft harvesting. Routine thrombophilia screening showed no abnormalities and cancer was excluded. Compared with healthy controls, we observed prolonged fibrin clot lysis time and increased thrombin generation reflected by endogenous thrombin potential. Scanning electron microscopy of the thrombosed material revealed compact and thick fibrin layer on the clot surface with a solid mass of unusually compressed platelets and erythrocytes underneath. The patient was tested for fibrinogen and factor (F) XIII polymorphisms, and was found to be heterozygous for β-fibrinogen HaeIII (-455G > A) and FXIII Val34Leu (100G > T).  β-fibrinogen HaeIII and FXIII Val34Leu polymorphisms are reflected in reduced clot permeability and susceptibility to lysis, and might contribute to intraoperative SV thrombosis during vascular grafting procedures. Carriers of those are at risk of primary venous graft failure after bypass procedures.
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http://dx.doi.org/10.1055/s-0040-1715657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443364PMC
July 2020

Effect of enoxaparin on plasma fibrin clot properties and fibrin structure in patients with acute pulmonary embolism.

Vascul Pharmacol 2020 Oct - Nov;133-134:106783. Epub 2020 Aug 22.

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

Background: Low-molecular-weight heparins (LMWHs) influence the fibrin network structure in in vitro models. There have been no reports on LMWH-induced modifications of fibrin clot characteristics and their determinants in acute pulmonary embolism (PE).

Aim: We investigated how enoxaparin alters fibrin clot properties in acute PE patients.

Methods: Clots were generated from plasma of 46 acute PE patients, aged 47-77 years treated with enoxaparin 1 mg/kg bid. Fibrin clot permeability (K) and clot lysis time (CLT), along with coagulation and fibrinolysis proteins were determined. Plasma fibrin clot nanostructure was assessed using scanning electron microscopy (SEM).

Results: Both K and CLT were associated with anti-factor (F)Xa activity (r = 0.75, p < 0.0001 and r = -0.37, p = 0.011). Anti-FXa was positively associated with fibrin fiber diameter and the pore area, and inversely with fibrin fiber density on SEM images. Multiple regression analysis adjusted for age, body-mass index, and fibrinogen levels showed that anti-FXa activity, antithrombin activity, and FVIII activity determined K, while anti-FXa activity, plasminogen activator inhibitor-1 level, and presence of right ventricular dysfunction determined CLT.

Conclusions: We identified new laboratory and clinical factors contributing to prothrombotic plasma fibrin clot characteristics during enoxaparin treatment, which might help elucidate mechanisms underlying therapy failure in patients with acute PE.
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http://dx.doi.org/10.1016/j.vph.2020.106783DOI Listing
October 2020

Interaction of glycated and acetylated human α2-antiplasmin with fibrin clots.

Blood Coagul Fibrinolysis 2020 Sep;31(6):393-396

John Paul II Hospital, Krakow.

: In type 2 diabetes mellitus (T2DM), increased α2-antiplasmin incorporation in fibrin and impaired fibrinolysis have been reported. Acetylsalicylic acid (ASA), used in cardiovascular prevention, modulates fibrinolysis and exerts weaker therapeutic effect in this disease. We investigated how glycation and acetylation of α2-antiplasmin affects its interaction with fibrin. Using surface plasmon resonance, we analyzed fibrin binding by α2-antiplasmin incubated with no β-D-glucose or ASA (control); incubated with β-D-glucose (5, 10, 50 mmol/l); (3) incubated with 1.6 mmol/l acetylsalicylic acid (ASA) and (4) incubated with 1.6 mmol/l ASA and 50 mmol/l β-D-glucose. Incubation with glucose decreased affinity of α2-antiplasmin for fibrin compared with control α2-antiplasmin in a glucose concentration-depending manner. α2-Antiplasmin incubation with ASA did not affect its affinity to fibrin. α2-Antiplasmin incubation with ASA and glucose resulted in 4.2-fold increased affinity to fibrin compared with α2-antiplasmin incubated with 50 mmol/l glucose (P < 0.001). In conclusion, α2-antiplasmin incubation with glucose at concentrations encountered in T2DM is associated with decreased binding affinity of α2-antiplasmin to fibrin. ASA alone does not affect the binding affinity of α2-antiplasmin to fibrin, but partly reverses the effect introduced by the incubation with 50 mmol/l glucose. This study suggests new mechanisms involved in regulating fibrinolysis efficiency in hyperglycemia.
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http://dx.doi.org/10.1097/MBC.0000000000000935DOI Listing
September 2020

Plasma fibrin clot proteomics in patients with acute pulmonary embolism: Association with clot properties.

J Proteomics 2020 10 16;229:103946. Epub 2020 Aug 16.

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

It has been reported that 476 proteins can be detected in plasma fibrin clots from patients with venous thromboembolism. Plasma fibrin clots proteomic composition in relation to their properties has not been studied in acute pulmonary embolism (PE). Clots generated from plasma of 20 PE patients and 20 healthy controls were assessed using mass spectrometry, clot permeability (K), and clot lysis time (CLT). The proteomic composition of plasma fibrin clots from acute PE patients differed from that of control subjects in regard to 198 clot-bound proteins. In the acute PE group, we observed increased clot-bound fibrinogen, apolipoprotein B-100, platelet glycoprotein Ib, lipopolysaccharide-binding protein, and histones H3 + 4 and reduced fibronectin, α2-antiplasmin, α2-macroglobulin, factor (F)XIII, histidine-rich glycoprotein, antithrombin, von Willebrand Factor, plasminogen, and prothrombin. Among PE patients, low K (≤3.83 × 10 cm) was associated with increased clot-bound C-reactive protein, kininogen-1, protein S, β-2-microglobulin, and thromboxane-A synthase when compared with patients having K > 3.83 × 10 cm. K correlated inversely with FIX and FV, thrombin-activatable fibrinolysis inhibitor, complement C1s, C7, C8, and apolipoprotein A-I. The specific protein composition in plasma fibrin clots from acute PE patients is associated with denser clot formation. Several proteins unrelated to the coagulation system can modulate fibrin phenotype in acute thrombotic states. SIGNIFICANCE: Our study significantly advances the field of thrombosis and hemostasis. The plasma fibrin clot proteomics findings fill the gap of knowledge about the presence and the role of other proteins to the plasma fibrin clot in the acute phase of pulmonary embolism, aside fibrinogen, which is the main component of fibrin. The reported methodology, which involves the sample preparation using Multienzyme Digestion-Filter Aided Sample Preparation (MED FASP), data acquisition with the Quadrupole-Orbitrap mass spectrometer, and data analysis using the advanced tools such as MaxQuant, Total Protein Approach and Perseus, allows to gain not only the qualitative, but also the quantitative insights into the microworld of proteins entangled among the fibrin network. By comparing the clots formed from plasma of patients with acute pulmonary embolism with the clots from healthy control, we provide the specific protein composition associated with unfavorable clot properties observed in this disease. Moreover, our findings emphasize that several proteins unrelated to the coagulation system, can modulate fibrin phenotype in acute thrombotic states.
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http://dx.doi.org/10.1016/j.jprot.2020.103946DOI Listing
October 2020

Prothrombotic fibrin clot properties associated with NETs formation characterize acute pulmonary embolism patients with higher mortality risk.

Sci Rep 2020 07 10;10(1):11433. Epub 2020 Jul 10.

Institute of Cardiology, Jagiellonian University Medical College, 80 Pradnicka St.,, 31-202, Krakow, Poland.

Venous thromboembolism is associated with formation of denser fibrin clots resistant to lysis. We investigated whether prothrombotic plasma clot properties are associated with the severity of acute pulmonary embolism (PE). We enrolled 126 normotensive acute PE patients (aged 58 ± 14 years) and 25 age- and sex-matched healthy controls. Plasma fibrin clot permeability (K), clot lysis time (CLT), endogenous thrombin potential (ETP), plasminogen activator inhibitor-1 (PAI-1), and citrullinated histone H3 (citH3) were evaluated on admission. PE patients compared to controls had 370% higher citH3 levels, 41% higher ETP, 16.5% reduced K, and 25.6% prolonged CLT. Patients with intermediate-high (n = 29) and intermediate-low (n = 77) PE mortality risk had reduced K and prolonged CLT, increased PAI-1 and ETP as compared to low-risk PE (n = 20) patients. Prolonged CLT was predicted by PAI-1 and citH3, while low K by C-reactive protein. During a 12-month follow-up 9 (7.1%) patients who had 24% higher ETP, 45% higher citH3 levels, and 18% prolonged CLT at baseline died. High ETP combined with elevated citH3 levels and prolonged CLT was associated with eightfold increased risk of PE-related death. Prothrombotic fibrin clot properties and enhanced neutrophil extracellular traps formation are associated with higher early mortality risk in acute PE patients, which suggests a prognostic role of these biomarkers.
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http://dx.doi.org/10.1038/s41598-020-68375-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351737PMC
July 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

Accumulation of advanced glycation end products (AGEs) is associated with the severity of aortic stenosis in patients with concomitant type 2 diabetes.

Cardiovasc Diabetol 2020 06 17;19(1):92. Epub 2020 Jun 17.

John Paul II Hospital, Kraków, Poland.

Background: Accumulation of advanced glycation end products (AGEs) leads to chronic glycation of proteins and tissue damage, particularly in patients with diabetes mellitus (DM). We aimed to evaluate whether increased accumulation of AGEs in patients with aortic stenosis (AS) and concomitant type 2 diabetes (DM) is associated with AS severity.

Methods: We prospectively enrolled 76 patients with severe AS (47.1% males; nonDM), aged 68 [66-72] years, and 50 age-matched DM patients with a median blood glucose level of 7.5 [5.9-9.1] mM and glycated hemoglobin (HbA1c) of 6.8 [6.3-7.8]%, scheduled for aortic valve replacement. Valvular expression of AGEs, AGEs receptor (RAGE), interleukin-6 (IL-6), and reactive oxygen species (ROS) induction were evaluated ex vivo by immunostaining and calculated as the extent of positive immunoreactive areas/total sample area. Plasma levels of AGEs and soluble RAGE (sRAGE) were assessed by ELISAs.

Results: Subjects with DM had increased valvular expression of both AGEs (6.6-fold higher, 15.53 [9.96-23.28]%) and RAGE (1.8-fold higher, 6.8 [4.9-8.45]%) compared to nonDM patients (2.05 [1.21-2.58]% and 2.4 [1.56-3.02]%, respectively; both p < 0.001). Plasma levels of AGEs (12-fold higher) and sRAGE (1.3-fold higher) were elevated in DM patients, compared to nonDM (both p < 0.0001). The percentage of valvular ROS-positive (2.28 [1.6-3.09] vs. 1.15 [0.94-1.4]%, p < 0.0001) but not IL-6-positive areas was higher within DM, compared to nonDM valves. In DM patients, the percentage of valvular AGEs- and RAGE-positive areas correlated with HbA1c (r = 0.77, p < 0.0001 and r = 0.30, p = 0.034). Similarly, plasma AGEs and sRAGE levels were associated with HbA1c in the DM group (r = 0.32, p = 0.024 and r = 0.33, p = 0.014, respectively). In all DM patients, we found an association between the amount of valvular AGEs and the disease severity measured as aortic valve area (AVA; r = 0.68, p < 0.0001). Additionally, in DM patients with HbA1c > 7% (n = 24, 48%) we found that valvular expression of AGEs correlated with mean transvalvular pressure gradient (PG; r = 0.45, p = 0.027). Plasma AGEs levels in the whole DM group correlated with AVA (r = - 0.32, p = 0.02), PG (r = 0.31, p = 0.023), and PG (r = 0.30, p = 0.03).

Conclusions: Our study suggests that poorly-controlled diabetes leads to increased AGEs and RAGE valvular accumulation, which at least partially, might result in AS progression in DM patients.
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http://dx.doi.org/10.1186/s12933-020-01068-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301463PMC
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

Elevated Lactate Levels in Acute Pulmonary Embolism Are Associated with Prothrombotic Fibrin Clot Properties: Contribution of NETs Formation.

J Clin Med 2020 Mar 30;9(4). Epub 2020 Mar 30.

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

Background: Elevated plasma lactate levels correlate with high mortality rate in acute pulmonary embolism (PE) patients. We hypothesized that elevated lactate levels correlate with prothrombotic fibrin clot properties and enhanced neutrophil extracellular trap (NET) formation in acute PE.

Methods: As many as 126 normotensive acute PE patients (aged 58 ± 14 years) were enrolled. Plasma fibrin clot permeability (K), clot lysis time (CLT), endogenous thrombin potential (ETP), citrullinated histone H3 (citH3), and plasminogen activator inhibitor-1 antigen (PAI-1), together with plasma L-lactate levels were evaluated on admission.

Results: Lactate levels ≥2 mM were found in 70 (55.6%) patients in whom we observed 29% higher neutrophil count and 45% elevated plasma citH3 levels. Elevated lactate levels were associated with more prothrombotic fibrin properties as reflected by 11% reduced K, 13% longer CLT, along with 11% increased ETP. Lactate levels were positively associated with plasma citH3 concentrations, ETP, CLT, and PAI-1 ( < 0.05). An increase of lactate levels by 1 mM leading to the prolongation of CLT by 8.82 minutes was shown in the linear regression.

Conclusions: Our findings suggest a new mechanism contributing to a negative impact of elevated lactate levels on prognosis in acute PE patients, in particular hypofibrinolysis, associated with enhanced NET formation.
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http://dx.doi.org/10.3390/jcm9040953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231195PMC
March 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

Elevated thrombin generation and factor VIII activity during angioedema attack in patients with hereditary C1 inhibitor deficiency.

Pol Arch Intern Med 2019 12 9;129(12):936-938. Epub 2019 Dec 9.

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

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http://dx.doi.org/10.20452/pamw.15096DOI Listing
December 2019

Coagulation factors and fibrinolytic activity in the left atrial appendage and other heart chambers in patients with atrial fibrillation: is there a local intracardiac prothrombotic state? (HEART-CLOT study).

Int J Cardiol 2020 02 20;301:103-107. Epub 2019 Oct 20.

Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA.

Introduction: Atrial fibrillation (AF), a risk factor for stroke and systemic thromboembolism, is associated with unfavorable fibrin clot properties and increased thrombus formation in peripheral blood. The left atrial appendage (LAA) is known to be the primary site of thrombus formation.

Aim: We investigated the relative differences in plasma fibrin clot features including plasma fibrin clot permeability (K) and clot lysis time (CLT) between the right atrium (RA), right ventricle (RV), left atrium (LA), left ventricle (LV), LAA, and peripheral blood.

Methods: Sixteen patients with nonvalvular AF who stopped oral anticoagulant therapy at least 2 days before a LARIAT procedure participated in a single-center prospective study. We measured fibrinogen and plasminogen levels along with K, CLT, and endogenous thrombin potential (ETP) during the LARIAT procedure in blood obtained from the right femoral vein, RA, RV, LA, LV and LAA.

Results: LAA clot porosity was reduced by 16.2% compared to peripheral blood (p = 0.026), also after adjustment for fibrinogen levels (p = 0.038). K was similar for the RA, RV, LA, LV, and LAA (all p > 0.05). We found 14.7% prolonged CLT for clots prepared from blood samples obtained from the LAA compared to those prepared from peripheral blood, but no differences between the RA, RV, LA and LV (all p > 0.05) were found. There were no significant differences in other parameters, including ETP, between heart chambers.

Conclusions: Patients with AF are characterised by a local prothrombotic state as reflected by formation of compact fibrin clots in the LAA compared to peripheral blood, which may contribute to LAA thrombus formation and device-related thrombi.
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http://dx.doi.org/10.1016/j.ijcard.2019.09.053DOI Listing
February 2020

Fibrin Clot Properties and Thrombin Generation in Hypertrophic Cardiomyopathy.

Thromb Haemost 2020 01 28;120(1):181-183. Epub 2019 Oct 28.

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

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http://dx.doi.org/10.1055/s-0039-1697956DOI Listing
January 2020

DOAC-Remove abolishes the effect of direct oral anticoagulants on activated protein C resistance testing in real-life venous thromboembolism patients.

Clin Chem Lab Med 2020 02;58(3):430-437

John Paul II Hospital, Kraków, Poland.

Background Direct oral anticoagulants (DOACs) may cause false results of activated protein C resistance (APC-R) ratio. DOAC-Remove, a new reagent based on activated carbon, has been designed to eliminate the interference of DOACs on coagulation assays. The aim of the study was to investigate whether the use of DOAC-Remove enables to determine APC-R in patients treated with DOACs. Methods We assessed 74 venous thromboembolism (VTE) patients, including 25 on rivaroxaban, 25 on apixaban and 24 taking dabigatran. APC-R was determined using the Russell Viper Venom Time (RVVT)-based clotting test. APC-R and DOAC concentrations were tested at baseline and following DOAC-Remove. Thrombophilia, including factor V Leiden (FVL) mutation was tested. Results FVL mutation was found in 20 (27%) patients. The APC-R ratio at baseline was measurable in 43 patients (58.1%), including 20 (80%) on rivaroxaban, 19 (76%) on apixaban and four (16.7%) on dabigatran. In patients with measurable APC-R at baseline, the ratio >2.9 was found in 23 patients (53.5%). In 16 (37.2%) subjects APC-R ratio <1.8 suggested FVL mutation which was genetically confirmed. Four (9.3%) FVL carriers on dabigatran showed negative/equivocal APC-R results. In 11 (14.9%) patients taking rivaroxaban or apixaban, in whom blood was collected 2-5 h since the last dose, we observed unmeasurable APC-R. DOAC-Remove almost completely eliminated all plasma DOACs. After addition of DOAC-Remove all APC-R ratios were measurable. In four FVL carriers on dabigatran with false negative APC-R, DOAC-Remove resulted in APC-R ratios <1.8. Conclusions DOAC-Remove effectively reduces DOACs concentration in plasma, which enables FVL testing using APC-R.
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http://dx.doi.org/10.1515/cclm-2019-0650DOI Listing
February 2020

Plasma fibrin clot proteomics in healthy subjects: Relation to clot permeability and lysis time.

J Proteomics 2019 09 16;208:103487. Epub 2019 Aug 16.

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: Little is known about fibrin clot composition in relation to its structure and lysability. We investigated plasma clots protein composition and its associations with clot properties.

Methods: We studied 20 healthy subjects aged 31-49 years in whom plasma fibrin clot permeability (K) and clot lysis time (CLT) were determined. A proteomic analysis of plasma fibrin clots was based on quantitative liquid chromatography-mass spectrometry.

Results: Among 494 clot-bound proteins identified in all clots, the highest concentrations were for fibrinogen chains (about 64% of the clot mass) and fibronectin (13%). α-antiplasmin (2.7%), factor XIIIA (1.2%), complement component C3 (1.2%), and histidine-rich glycoprotein (HRG, 0.61%) were present at relatively high concentrations. Proteins present in concentrations <0.5% included (pro)thrombin, plasminogen, apolipoproteins, or platelet factor 4 (PF4). Fibrinogen-α and -γ chains were associated with age, while body-mass index with clot-bound apolipoproteins (all p < .05). K correlated with fibrinogen-γ and PF4 amounts within plasma clots. CLT was associated with fibrinogen-α and -γ, PF4, and HRG (all p < .05).

Conclusions: This study is the first to show associations of two key measures of clot properties with protein content within plasma clots, suggesting that looser fibrin clots with enhanced lysability contain less fibrinogen-γ chain, platelet-derived PF4, and HRG.

Significance: Our study for the first time suggests that more permeable fibrin clots with enhanced lysability contain less fibrinogen-γ chain, platelet-derived factor 4, and histidine-rich glycoprotein, which is related to accelerated clot lysis. The current findings might have functional consequences regarding clot structure, stability, and propagation of thrombin generation, and detailed proteomic analysis of clots in various disorders opens new perspective for coagulation and fibrin research.
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http://dx.doi.org/10.1016/j.jprot.2019.103487DOI Listing
September 2019

Improving fibrinolysis in venous thromboembolism: impact of fibrin structure.

Expert Rev Hematol 2019 08 5;12(8):597-607. Epub 2019 Jul 5.

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

. Fibrinolysis is of key importance in maintaining vessel patency. Impaired fibrinolysis associated with more compact fibrin structure has been shown in patients with venous thromboembolism (VTE), including deep-vein thrombosis and pulmonary embolism (PE). Currently, recombinant or modified plasminogen activators are the only commonly available thrombolytic agents. However, they are fraught with side effects and suboptimal effectiveness. . Based on the available literature, the current evidence linking fibrinolysis with VTE and potential therapeutic targets among fibrinolysis proteins are presented. . Prolonged clot lysis time has been reported as a new predictor of first-time and recurrent VTE, including PE. Anticoagulant therapy, including non-vitamin K antagonist oral anticoagulants, has a favorable impact on fibrinolysis in VTE patients. Several VTE risk factors are also related to lower efficiency of fibrinolysis and their treatment improve fibrinolysis, in part by alterations to fibrin properties. There is an increasing number of studies aiming at developing novel profibrinolytic therapeutic agents for treatment of VTE patients, mostly targeting the antifibrinolytic proteins, i.e. antiplasmin, plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor.
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http://dx.doi.org/10.1080/17474086.2019.1627193DOI Listing
August 2019

NETosis is associated with the severity of aortic stenosis: Links with inflammation.

Int J Cardiol 2019 07 26;286:121-126. Epub 2019 Mar 26.

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

Background: An involvement of neutrophil extracellular traps (NETs) in the aortic stenosis (AS) pathogenesis is unknown.

Methods: We enrolled 50 patients, median age 66.5 years with isolated severe AS, after aortic valve replacement and 20 healthy sex/age-matched controls. Autopsy-derived aortic valves from 5 healthy donors served as controls. Valvular expression of citrullinated histone H3 (citH3), myeloperoxidase (MPO), and neutrophil elastase (NE) and macrophages (CD68) were evaluated by immunostaining. Plasma citH3 and interleukin 6 (IL-6) were also determined.

Results: All stenotic and healthy valves expressed citH3 in the leaflets' endothelial and sub-endothelial layers at the aortic side. Amount of valvular citH3-positive cells was higher in AS patients compared with controls (53.5 [33-62]% vs. 5.7 [4.1-9.0]%, p < 0.0001) and correlated with aortic valve area (AVA; r = -0.69, p < 0.0001) and mean transvalvular gradient (r = 0.6, p < 0.0001). Double-staining revealed that in AS valves 27.2 ± 9.8% of cells were citH3/MPO- and 25.3 ± 8.9% citH3/NE-positive. Within stenotic valves, 6.4 ± 2.5% of cells showed citH3/CD68 double-positivity and were identified as macrophages. AS patients compared to controls had 83% higher plasma citH3 (p < 0.0001). In AS, plasma citH3 correlated with IL-6 (r = 0.39, p = 0.0054) levels and AVA (r = -0.45, p = 0.0009).

Conclusions: The presence of NETs in stenotic valves and association with AS severity suggest novel mechanisms involved in the disease progression.
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http://dx.doi.org/10.1016/j.ijcard.2019.03.047DOI Listing
July 2019

The effect of DOAC-Stop on lupus anticoagulant testing in plasma samples of venous thromboembolism patients receiving direct oral anticoagulants.

Clin Chem Lab Med 2019 08;57(9):1374-1381

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

Background Direct oral anticoagulants (DOACs) cause false positive lupus anticoagulant (LA) results. We assessed the impact of DOAC-Stop, reversing in vitro effects of DOACs, on LA testing in anticoagulated patients. Methods We assessed 75 venous thromboembolism patients aged 44.5±14.6 years. Blood samples were collected 2-28 h since intake of DOACs, including 50 patients on rivaroxaban, 20 on dabigatran and five on apixaban. LA testing was performed at baseline and after DOAC-Stop treatment. Positive LA was defined as the normalized (patient/standard plasma clotting time) LA screening and screening (LA1)/confirmation (LA2) ratios exceeding 1.2. Results LA diluted Russell's viper venom time (dRVVT) normalized screening test revealed abnormal results in 73 (97.3%) and activated partial thromboplastin time (APTT)-LA in 49 (65.3%) patients. In six (8%) patients, antiphospholipid syndrome (APS) was diagnosed. dRVVT LA1/LA2 was abnormal in 35 (50.7%) patients taking DOACs. The APTT ratio was normal in all studied subjects. DOAC-Stop completely removed dabigatran and reduced by 98% rivaroxaban and by 92.3% apixaban concentrations (all p<0.05). After DOAC-Stop screening dRVVT remained prolonged in 34 (49.3%) patients (p<0.001), while dRVVT LA1/LA2 was abnormal in six (8.7%) subjects, with no association with DOAC concentrations at baseline and after DOAC-Stop. The APTT-LA screening test remained prolonged in five (7.2%) patients, while the APTT LA1/LA2 ratio was normal in those subjects. DOAC-Stop did not influence LA testing in APS patients. Conclusions Application of DOAC-Stop effectively reduced plasma DOAC concentrations leading to appropriate dRVVT results in up to 97% of VTE patients.
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http://dx.doi.org/10.1515/cclm-2018-1197DOI Listing
August 2019

A Prothrombotic State in Patients With a History of Left Ventricular Thrombus.

Am J Cardiol 2019 04 24;123(8):1358-1363. Epub 2019 Jan 24.

Institute of Cardiology, Jagiellonian University Medical College, Cracow, Poland; John Paul II Hospital, Cracow, Poland; Faculty of Medicine and Health Sciences, Jan Kochanowski University, Kielce, Poland. Electronic address:

Left ventricular thrombus (LVT) is associated with a hypercoagulable state and occurs most frequently after myocardial infarction (MI). Blood prothrombotic alterations might predispose to LVT formation, its recurrence, and subsequent cerebrovascular events. We investigated 58 patients with a history of LVT unrelated to recent MI or LV ejection fraction <25% and 58 well-matched control subjects. We determined plasma clot permeability, fibrinolytic efficiency, thrombin generation, and endothelial markers after 3 to 6 months of anticoagulant treatment. During follow-up we recorded LVT and thromboembolic events. Patients with LVT more often had LV akinesia, congestive heart failure, and prothrombotic state as evidenced by increased endogenous thrombin potential, lower antithrombin, lower clot permeability, and longer clot lysis time associated with lower antiplasmin, higher plasminogen activator inhibitor-1, thrombin activatable fibrinolysis inhibitor, and von Willebrand factor. During follow-up (57.5 ± 8.1 months for LVT patients and 59.6 ± 5.3 months for controls) strokes, transient ischemic attacks, or LVT occurred in 18 (31%) LVT patients and in 6 (10.3%) control subjects (4.1 vs 1.4% per year, p = 0.006). LVT recurred in 10 (2.3%/year) patients, who had higher risk of stroke/transient ischemic attacks (relative risk = 4.73, 95% confidence interval 1.8 to 40.4). The most compact clot formation at baseline, defined as the lowest quartile of clot permeability (≤5.4 × 10 cm) was a predictor of recurrent LVT (relative risk = 4.67, 95% confidence interval 1.32 to 18.37). This study shows that a persistent prothrombotic state involving enhanced thrombin generation, hypofibrinolysis, and formation of more compact fibrin clots characterizes patients who develop LVT not related to MI and those prone to its recurrence.
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http://dx.doi.org/10.1016/j.amjcard.2019.01.007DOI Listing
April 2019

Fibrin biofilm can be detected on intracoronary thrombi aspirated from patients with acute myocardial infarction.

Cardiovasc Res 2019 05;115(6):1026-1028

Institute of Cardiology, Jagiellonian University Medical College, 80 Pradnicka St., Krakow, Poland.

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http://dx.doi.org/10.1093/cvr/cvz019DOI Listing
May 2019

Unfavourably altered plasma clot properties in patients with primary Raynaud's phenomenon: association with venous thromboembolism.

J Thromb Thrombolysis 2019 Feb;47(2):248-254

John Paul II Hospital, Krakow, Poland.

Associations of Raynaud's phenomenon (RP) with venous thromboembolism (VTE) are unclear. We investigated the occurrence of RP together with prothrombotic state markers and fibrin clot properties in VTE patients. In this prospective cohort study we enrolled 360 patients free of known autoimmune disease. D-dimer, von Willebrand factor (vWF), plasma clot permeability (K), clot lysis time (CLT) along with fibrinolysis activators and inhibitors were determined at least 3 months since the VTE event. The presence/absence of RP was diagnosed at least 6 months before VTE. Primary RP occurred in 57 subjects (17%) with a 3.6-fold higher prevalence among women. Patients with RP had 11% higher fibrinogen, 16% higher vWF, 5% lower K, and 10% longer CLT (all p < 0.05). Females with RP (21%) had 6.6% lower K, 11.2% longer CLT, and 18.5% higher vWF (all p < 0.05) compared with men. CLT was predicted by PAI-1 and vWF levels. Regression analysis showed that RP was a predictor of prolonged CLT in the whole patient group (OR 3.46, 95% CI 1.92-6.24) and in women following VTE (OR 2.75, 95% CI 1.31-5.78). Primary RP patients tend to form denser plasma fibrin clots displaying impaired lysability and increased endothelial damage. RP might be a novel risk factor for VTE, especially in women.
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http://dx.doi.org/10.1007/s11239-019-01805-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394442PMC
February 2019

Differences in plasma fibrin clot composition in patients with thrombotic antiphospholipid syndrome compared with venous thromboembolism.

Sci Rep 2018 11 23;8(1):17301. Epub 2018 Nov 23.

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

The prothrombotic fibrin clot phenotype has been reported in patients with thrombotic antiphospholipid syndrome (APS) and venous thromboembolism (VTE). Protein composition of plasma fibrin clots in APS has not been studied. We evaluated 23 patients with thrombotic APS, 19 with VTE alone, and 20 well-matched controls. A proteomic analysis of fibrin clots generated from citrated plasma was based on liquid chromatography-mass spectrometry. Plasma levels of thrombospondin-1 (TSP1), apolipoprotein(a), A-I, and B-100, complement components (C)3a, C5b-C9, histidine-rich glycoprotein (HRG), and prothrombin were evaluated using immunoenzymatic tests. In plasma fibrin clots of APS patients, compared with VTE subjects and controls, we identified decreased amounts of (pro)thrombin, antithrombin-III, apolipoprotein A-I, and HRG with no differences in plasma levels of antithrombin, prothrombin, along with lower plasma HRG and apolipoprotein A-I. In APS patients, plasma HRG positively correlated with amounts of clot-bound HRG, while apolipoprotein A-I was inversely associated with clot-bound levels of this protein. The most predominant proteins within the clots of APS patients were bone marrow proteoglycan, C5-C9, immunoglobulins, apolipoprotein B-100, platelet-derived proteins, and TSP1. Our study is the first to demonstrate differences in the protein composition of fibrin clots generated from plasma of thrombotic APS patients versus those with VTE alone.
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http://dx.doi.org/10.1038/s41598-018-35034-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251889PMC
November 2018