Publications by authors named "Anetta Undas"

474 Publications

A new editor in Polish Archives of Internal Medicine: welcome to Professor Tomasz Stompór.

Authors:
Anetta Undas

Pol Arch Intern Med 2021 Apr 29;131(4):320-321. Epub 2021 Apr 29.

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http://dx.doi.org/10.20452/pamw.15976DOI Listing
April 2021

Via Medica comes back as the publisher of Kardiologia Polska.

Authors:
Anetta Undas

Kardiol Pol 2021 04 23;79(4):371-372. Epub 2021 Apr 23.

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

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http://dx.doi.org/10.33963/KP.15947DOI Listing
April 2021

Fibrinolysis in Venous Thromboembolism.

Authors:
Anetta Undas

Semin Thromb Hemost 2021 Apr 20. Epub 2021 Apr 20.

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

Fibrinolysis is of paramount importance in maintaining or regaining the patency of veins and pulmonary arteries obstructed by thrombi. Growing experimental and clinical evidence indicates that impaired fibrinolysis mediated by multiple complex mechanisms is involved in venous thromboembolism (VTE). Global plasma fibrin clot lysis markers, especially clot lysis time, have been reported to predict recurrent deep-vein thrombosis and pulmonary embolism. The current overview summarizes available data linking fibrinolysis to VTE and its long-term sequelae.
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http://dx.doi.org/10.1055/s-0041-1725094DOI Listing
April 2021

Right ventricular echocardiographic parameters associated with prothrombotic abnormalities in normotensive patients with acute pulmonary embolism.

Int J Cardiol 2021 Jun 5;333:195-201. Epub 2021 Mar 5.

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

Background: In acute pulmonary embolism (PE) right ventricular (RV) pressure overload negatively affects prognosis. Recently we have shown that RV dilatation is associated with a prothrombotic state in PE. We investigated which RV echocardiographic parameters best indicate prothrombotic alterations in acute PE.

Methods: In 121 normotensive, noncancer PE patients, markers of RV dilatation and dysfunction were evaluated on admission using transthoracic echocardiography, along with prothrombotic state markers, i.e. increased endogenous thrombin generation (ETP), low fibrin clot permeability (K, a measure of clot density), and prolonged clot lysis time (CLT).

Results: RV parasternal long axis (RVOT PLAX) >30 mm was associated with ETP (OR 3.86; 95% CI 1.55-9.62; p = 0.004) and CLT (OR 4.08; 95% CI 1.58-10.54; p = 0.004) in the top quartiles, but not with K. RV short parasternal axis (RVOT PSAX) >27 mm showed similar associations with higher ETP (OR 3.54; 95% CI 1.50-8.37; p = 0.004) and prolonged CLT (OR 2.78; 95% CI 1.17-6.62; p = 0.021). RV basal diameter >41 mm solely predicted prolonged CLT (OR 2.93; 95% CI 1.23-6.99; p = 0.016). The right atrium area, pulmonary trunk diameter, and tricuspid regurgitation maximum velocity were not related to prothrombotic markers, except for tricuspid annular plane systolic excursion weakly associated with ETP. Multivariable analysis showed that RVOT PSAX is independently associated with prolonged CLT (OR 1.16; 95% CI 1.04-1.30; p = 0.007), low K (OR 1.21; 95% CI 1.02-1.44; p = 0.029), and higher ETP (OR 1.14; 95% CI 1.03-1.26; p = 0.009).

Conclusions: Among RV echocardiographic parameters, the RVOT dilatation measured in PSAX best predicts prothrombotic alterations in PE patients.
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http://dx.doi.org/10.1016/j.ijcard.2021.02.087DOI Listing
June 2021

Professor Franciszek Kokot and his successor, Professor Andrzej Januszewicz: the Polish Co-Chair of the Scientific Board of Polish Archives of Internal Medicine.

Authors:
Anetta Undas

Pol Arch Intern Med 2021 02 26;131(2):114-115. Epub 2021 Feb 26.

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.15837DOI Listing
February 2021

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

Plasma fibrin clot properties and cardiovascular mortality in patients with type 2 diabetes: a long-term follow-up study.

Cardiovasc Diabetol 2021 Feb 18;20(1):47. Epub 2021 Feb 18.

John Paul II Hospital, Krakow, Poland.

Background: Patients with type 2 diabetes mellitus (T2DM) are at high risk of cardiovascular mortality, but the mechanisms behind this remain unclear. Prothrombotic fibrin clot properties have been shown in T2DM and cardiovascular disease. We hypothesized that formation of denser clots, which are resistant to fibrinolysis, has a negative impact on cardiovascular mortality in T2DM.

Methods: We studied 133 T2DM patients aged 43-83 years. Plasma fibrin clot turbidity, permeation, compaction, and efficiency of clot lysis using 3 assays including the determination of maximum concentration (D-D) and rate of increase in D-dimer concentration (D-D) released during tissue plasminogen activator-induced degradation, were evaluated at the time of enrollment, along with thrombin generation and fibrinolytic proteins. During a median follow-up period of 72 months, cardiovascular mortality was recorded.

Results: Cardiovascular deaths (n = 16, 12%) occurred more frequently in patients with increased D-D (> 4.26 mg/l, hazard ratio [HR] 5.43, 95% confidence interval [CI] 1.99-14.79), or decreased D-D (< 0.07 mg/l/min, HR 2.97, 95% CI 1.07-8.23), or increased peak thrombin (> 283.5 nM, HR 5.65, 95% CI 2.07-15.51). These predictors had an even more potent impact on cardiovascular mortality in patients with prior cardiovascular disease (64.7%) and with corresponding risks as follows: HR 6.18, 95% CI 2.02-18.96; HR 8.98, 95% CI 2.99-26.96; and HR 5.35, 95% CI 1.62-17.72, respectively. Other investigated fibrin variables and fibrinolytic proteins did not associate with cardiovascular mortality. In multivariable analysis, cardiovascular mortality was predicted by D-D > 4.26 mg/l, age > 65 years, prior cardiovascular disease, and C-reactive protein > 3 mg/l.

Conclusions: This study is the first to show that formation of denser fibrin clots resistant to fibrinolysis could be a risk factor for long-term cardiovascular mortality in T2DM.
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http://dx.doi.org/10.1186/s12933-021-01230-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893920PMC
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

Will 2021 be the year of the triumph of science?

Pol Arch Intern Med 2021 01 28;131(1):1-2. Epub 2020 Dec 28.

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http://dx.doi.org/10.20452/pamw.15729DOI Listing
January 2021

Correction to: Direct oral anticoagulants in patients with severe inherited thrombophilia: a single-center cohort study.

Int J Hematol 2021 Mar;113(3):464-465

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

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http://dx.doi.org/10.1007/s12185-020-03052-zDOI 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

The year 2020 in Kardiologia Polska.

Authors:
Anetta Undas

Kardiol Pol 2020 12 23;78(12):1192-1193. Epub 2020 Dec 23.

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http://dx.doi.org/10.33963/KP.15717DOI Listing
December 2020

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

Glycation and acetylation sites on fibrinogen in plasma fibrin clot of patients with type 2 diabetes: Effects of low-dose acetylsalicylic acid.

Thromb Res 2021 02 28;198:93-98. Epub 2020 Nov 28.

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

Acetylsalicylic acid (ASA) and type 2 diabetes mellitus (T2DM) affect fibrin clot properties through fibrinogen acetylation or glycation. We aimed to identify glycation and acetylation sites on fibrinogen in plasma fibrin clot of T2DM patients with respect to effects of ASA and fibrin clot properties. In fibrin clots generated from plasma of 9 T2DM patients, we performed mass-spectrometric analysis of Nε-fructosyl-(FL), Nε-carboxyethyl-(CEL) and Nε-carboxymethyl-lysine (CML), and acetylation sites, before and after one-month administration of 75 mg/d ASA confirmed with determination of thromboxane B2 concentration (TXB), along with clot permeability and lysis time, and thrombin generation. In the proteomic analysis, 216 proteins were identified. Among 10 glycation sites identified in α, 10 in β and 6 in γ fibrinogen chain, there were 17 FL, 5 CEL and 4 CML sites. Some of glycation sites in fibrinogen were previously reported to be involved in cross-linking by factor XIII (αK-208, αK-448 and αK-539) and plasmin cleavage (αK-81). There were 7 acetylation sites in α and β chains, and none in fibrinogen γ chain. Two acetylation sites were identical with FL sites (αK-195 and β-247), while one with CML site (βK-353). In 7 patients with low post-ASA TXB, intensity of acetylation, as well as clot properties were unaffected by ASA. This study identifies glycation and acetylation sites on fibrinogen in plasma fibrin clot of T2DM and supports the view that low-dose ASA does not increase fibrinogen acetylation in T2DM. Our findings suggest that glycation may block sites previously identified to be acetylated in vitro.
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http://dx.doi.org/10.1016/j.thromres.2020.11.031DOI Listing
February 2021

Cellular fibronectin promotes deep vein thrombosis in diet-induced obese mice.

J Thromb Haemost 2021 03 27;19(3):814-821. Epub 2020 Dec 27.

Division of Hematology/Oncology, Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.

Background: Overweight and obesity are significant risk factors for deep vein thrombosis (DVT). Cellular fibronectin containing extra domain A (Fn-EDA), an endogenous ligand for toll-like-receptor 4 (TLR4), contributes to thrombo-inflammation. The role of Fn-EDA in the modulation of DVT is not elucidated yet.

Objective: To determine whether Fn-EDA promotes DVT in the context of diet-induced obesity.

Methods: Wild-type (WT) and Fn-EDA-deficient mice were either fed control or high-fat (HF) diet for 12 weeks. DVT was induced by inferior vena cava (IVC) stenosis and evaluated after 48 hours. Cellular Fn-EDA levels in the plasma of venous thromboembolism (VTE) patients were measured by sandwich ELISA.

Results: We found that cellular Fn-EDA levels were significantly elevated in VTE patients' plasma and positively correlated with body mass index. HF diet-fed WT mice exhibited increased DVT susceptibility compared with control diet-fed WT mice. In contrast, HF diet-fed Fn-EDA-deficient mice exhibited significantly reduced thrombus weight and decreased incidence (%) of DVT compared with HF diet-fed WT mice concomitant with reduced neutrophil content and citrullinated histone H3-positive cells (a marker of NETosis) in IVC thrombus. Exogenous cellular Fn-EDA potentiated NETosis in neutrophils stimulated with thrombin-activated platelets via TLR4. Genetic deletion of TLR4 in Fn-EDA mice (constitutively express Fn-EDA in plasma and tissues), but not in Fn-EDA-deficient mice, reduced DVT compared with respective controls.

Conclusion: These results demonstrate a previously unknown role of Fn-EDA in the DVT exacerbation, which may be an essential mechanism promoting DVT in the setting of diet-induced obesity.
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http://dx.doi.org/10.1111/jth.15206DOI Listing
March 2021

Efficacy and Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and Chronic Kidney Disease Stage G4: A Single-Center Experience.

J Cardiovasc Pharmacol 2020 12;76(6):671-677

John Paul II Hospital, Krakow, Poland.

Atrial fibrillation (AF) is associated with increased stroke and bleeding risk in patients with chronic kidney disease (CKD). Little is known about the real-life use of non-vitamin K antagonist oral anticoagulants (NOACs) in CKD stage G4. In a retrospective cohort study, we enrolled 182 consecutive AF patients with CKD stage G4 including 90 (49%) subjects on NOAC, ie, 61 on apixaban 2.5 mg bid and 29 on rivaroxaban 15 mg qd, and 92 (51%) subjects on warfarin. Thromboembolic and bleeding events were recorded during a mean follow-up of 26.3 months. There were no differences in demographic, clinical, and laboratory variables at baseline between the 2 treatment groups. During follow-up, arterial thromboembolic events occurred in 11 (12.22%) subjects on NOAC and 7 (7.61%) on warfarin, (hazard ratio [HR] 1.70; 95% CI, 0.65-4.42), with similar risk of ischemic stroke (9 [10%] vs. 7 [7.61%], P = 0.56, respectively). Major bleedings or clinically relevant nonmajor bleeding occurred in 14 (15.56%) on NOAC and 13 (14.13%) on warfarin, (HR 1.12; 95% CI, 0.53-2.39), with similar risk of gastrointestinal bleeding (HR 0.70; 95% CI, 0.20-2.47). We observed no difference in all-cause mortality related to the type of anticoagulants, but it tended to be lower in the apixaban group compared with rivaroxaban group (14.7% vs. 31%, P = 0.07), without any differences in thromboembolic and bleeding events. The study suggests that AF patients with CKD stage G4 receiving reduced-dose NOAC or warfarin have similar risk of thromboembolism and bleeding in everyday practice of a tertiary anticoagulation center.
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http://dx.doi.org/10.1097/FJC.0000000000000911DOI Listing
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

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

Determinants of plasma fibrin clot lysis measured using three different assays in healthy subjects.

Thromb Res 2021 01 15;197:1-7. Epub 2020 Oct 15.

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

Introduction: Several methods for measuring fibrinolytic capacity in plasma have been developed yielding frequently inconsistent results. We investigated which factors determine fibrinolytic capacity in three plasma-based assays.

Material And Methods: In 80 apparently healthy controls (aged 43 ± 10 years, 50 women [62.5%]) we evaluated fibrinolysis using three assays: (1) by Pieters et al. (CLT2018), (2) by Lisman et al. (CLT), and (3) by Carter et al. (Lys50). Coagulation factors and fibrinolytic proteins, including histidine-rich glycoprotein (HRG) and γ'-fibrinogen, were determined. Regression models were performed to identify determinants of lysis times.

Results: Positive correlations were observed between CLT2018 and both CLT (r = 0.73) and Lys50 (r = 0.61), as well as between CLT and Lys50 (r = 0.46, all p < 0.001). The main determinants of both CLT2018 and CLT were plasminogen activator inhibitor-1 (PAI-1), followed by thrombin-activatable fibrinolysis inhibitor (TAFI) and α-antiplasmin. Histidine-rich glycoprotein was a predictor of the longest-normal CLT2018 alone (OR 1.04, 95% CI 1.02-1.06). α-Antiplasmin and fibrinogen levels, followed by PAI-1 and TAFI determined Lys50. After adjustment for age, sex, and body mass index, C-reactive protein (CRP) was an independent predictor of the top quartiles of the three lysis times.

Conclusions: We showed that apart from PAI-1, TAFI, and α-antiplasmin, several other factors, in particular CRP, can affect the results of global fibrinolysis tests used in research. Our findings may help understand why the choice of a specific fibrinolysis assay can affect the presence and/or magnitude of intergroup differences in fibrinolytic capacity in a given disease state.
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http://dx.doi.org/10.1016/j.thromres.2020.10.014DOI Listing
January 2021

Antiplatelet and anticoagulant agents for secondary prevention of stroke and other thromboembolic events in people with antiphospholipid syndrome.

Cochrane Database Syst Rev 2020 10 12;10:CD012169. Epub 2020 Oct 12.

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

Background: Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by arterial or venous thrombosis (or both), and/or pregnancy morbidity in association with the presence of antiphospholipid antibodies. The prevalence of APS is estimated at 40 to 50 cases per 100,000 people. The most common sites of thrombosis are cerebral arteries and deep veins of the lower limbs. People with a definite APS diagnosis have an increased lifetime risk of recurrent thrombotic events.

Objectives: To assess the effects of antiplatelet (AP) or anticoagulant agents, or both, for the secondary prevention of recurrent thrombosis, particularly ischemic stroke, in people with APS.

Search Methods: We last searched the MEDLINE, Embase, CENTRAL, Cochrane Stroke Group Trials Register, and ongoing trials registers on 22 November 2019. We checked reference lists of included studies, systematic reviews, and practice guidelines. We also contacted experts in the field.

Selection Criteria: We included randomized controlled trials (RCTs) that evaluated any anticoagulant or AP agent, or both, in the secondary prevention of thrombosis in people with APS, according to the criteria valid when the study took place. We did not include studies specifically addressing women with obstetrical APS.

Data Collection And Analysis: Pairs of review authors independently worked on each step of the review, following Cochrane methods. We summarized the evidence using the GRADE approach.

Main Results: We identified eight studies including 811 participants that compared different AP or anticoagulant agents. NOAC (non-VKA oral anticoagulant: rivaroxaban 15 or 20 mg/d) versus standard-dose VKA (vitamin K antagonist: warfarin at moderate International Normalized Ratio [INR] - 2.5) or adjusted [INR 2.0-3.0] dose): In three studies there were no differences in any thromboembolic event (including death) and major bleeding (moderate-certainty evidence), but an increased risk of stroke (risk ratio [RR] 14.13, 95% confidence interval [CI] 1.87 to 106.8; moderate-certainty evidence). One of the studies reported a small benefit of rivaroxaban in terms of quality of life at 180 days measured as health state on Visual Analogue Scale (mean difference [MD] 7 mm, 95% CI 2.01 to 11.99; low-certainty evidence), but not measured as health utility on a scale from 0 to 1 (MD 0.04, 95% CI -0.02 to 0.10; low-certainty evidence). High-dose VKA (warfarin with a target INR of 3.1 to 4.0 [mean 3.3] or 3.5 [mean 3.2]) versus standard-dose VKA (warfarin with a target INR of 2.0 to 3.0 [mean 2.3] or 2.5 [mean 2.5]): In two studies there were no differences in the rates of thrombotic events and major bleeding (RR 2.22, 95% CI 0.79 to 6.23, low-certainty evidence), but an increased risk of minor bleeding in one study during a mean of 3.4 years (standard deviation [SD] 1.2) of follow-up (RR 2.55, 95% CI 1.07 to 6.07). In both trials there was evidence of a higher risk of any bleeding (hazard ratio [HR] 2.03 95% CI 1.12 to 3.68; low-certainty evidence) in the high-dose VKA group, and for this outcome (any bleeding) the incidence is not different, only the time to event is showing an effect. Standard-dose VKA plus a single AP agent (warfarin at a target INR of 2.0 to 3.0 plus aspirin 100 mg/d) versus standard-dose VKA (warfarin at a target INR of 2.0 to 3.0): One high-risk-of-bias study showed an increased risk of any thromboembolic event with combined treatment (RR 2.14, 95% CI 1.04 to 4.43; low-certainty evidence) and reported on major bleeding with five cases in the combined treatment group and one case in the standard-dose VKA treatment group, resulting in RR 7.42 (95% CI 0.91 to 60.7; low-certainty evidence) and no differences for secondary outcomes (very low- to low-certainty evidence). Single/dual AP agent and standard-dose VKA (pooled results): Two high-risk-of-bias studies compared a combination of AP and VKA (aspirin 100 mg/d plus warfarin or unspecified VKA at a target INR of 2.0 to 3.0 or 2.0 to 2.5) with a single AP agent (aspirin 100 mg/d), but did not provide any conclusive evidence regarding the effects of those drugs in people with APS (very low-certainty evidence). One of the above-mentioned studies was a three-armed study that compared a combination of AP and VKA (aspirin 100 mg/d plus warfarin at a target INR of 2.0 to 2.5) with dual AP therapy (aspirin 100 mg/d plus cilostazol 200 mg/d) and dual AP therapy (aspirin 100 mg/d plus cilostazol 200 mg/d) versus a single AP treatment (aspirin 100 mg/d). This study reported on stroke (very low-certainty evidence) but did not report on any thromboembolic events, major bleeding, or any secondary outcomes. We identified two ongoing studies and three studies are awaiting classification.

Authors' Conclusions: The evidence identified indicates that NOACs compared with standard-dose VKAs may increase the risk of stroke and do not appear to alter the risk of other outcomes (moderate-certainty evidence). Using high-dose VKA versus standard-dose VKA did not alter the risk of any thromboembolic event or major bleeding but may increase the risk of any form of bleeding (low-certainty evidence). Standard-dose VKA combined with an AP agent compared with standard-dose VKA alone may increase the risk of any thromboembolic event and does not appear to alter the risk of major bleeding or other outcomes (low-certainty evidence). The evidence is very uncertain about the benefit or harm of using standard-dose VKA plus AP agents versus single or dual AP therapy, or dual versus single AP therapy, for the secondary prevention of recurrent thrombosis in people with APS (very low-certainty evidence).
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http://dx.doi.org/10.1002/14651858.CD012169.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094585PMC
October 2020

Direct oral anticoagulants in patients with severe inherited thrombophilia: a single-center cohort study.

Int J Hematol 2021 Feb 11;113(2):190-198. Epub 2020 Oct 11.

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

We investigated the safety and efficacy of direct oral anticoagulants (DOACs) in patients with venous thromboembolism (VTE) associated with severe inherited thrombophilia. In this single-center cohort study, we enrolled 56 consecutive VTE patients with severe inherited thrombophilia, defined as the presence of antithrombin (n = 18), protein C (n = 12) and protein S (n = 12) deficiencies, homozygous Factor V Leiden (n = 3) and prothrombin G20210AA (n = 4) mutations, or combined defects (n = 7). During a median follow-up of 44.5 (IQR 30-52.5) months, rivaroxaban was used in 30 (53.6%), apixabanin 14 (25%), and dabigatran in 12 (21.4%) subjects. Recurrent nonfatal VTE was observed in 5 (8.9%) patients (2.4 per 100 patient-years), treated with rivaroxaban (n = 4) and apixaban (n = 1). Major bleeding and clinically relevant non-major bleeding (CRNMB) occurred in 2 (3.5%) and 4 (7%) subjects, respectively (0.96 per 100 patient-years and 1.92 per 100 patient-years, respectively), including 4 patients on rivaroxaban. The event-free survival analysis showed that the use of rivaroxaban was associated with increased risk of recurrent VTE or bleeding, compared with apixaban or dabigatran (HR 2.76, 95% CI 1.26-3.92, p = 0.039). In conclusion, the results of our cohort study indicate that full-dose dabigatran or apixaban are effective and safe in patients with severe inherited thrombophilia.
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http://dx.doi.org/10.1007/s12185-020-03012-7DOI Listing
February 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

Direct oral anticoagulants in the prevention of stroke in breast cancer patients with atrial fibrillation during adjuvant endocrine therapy: A cohort study.

Int J Cardiol 2021 Feb 12;324:78-83. Epub 2020 Sep 12.

Department of Internal Medicine, Jagiellonian University, Medical College, Kraków, Poland. Electronic address:

Background: Atrial fibrillation (AF) is a frequent comorbidity in malignant patients. Anticancer therapies complicate anticoagulant strategy. We evaluated the safety and efficacy of long-term use of direct oral anticoagulants (DOACs) in breast cancer women.

Methods: In a prospective cohort study we enrolled 48 consecutive radically treated breast cancer women with AF (median age 63 [interquartile range 56-69] years, CHADS-VASc 2 [2,3]) score) and adjuvant hormonal therapy. Thromboembolic complications (stroke, transient ischemic attack [TIA], venous thromboembolism [VTE]) and bleeding events (major and clinically relevant non-major bleeding [CRNMB]) were recorded in follow-up.

Results: During a median follow-up of 40 (interquartile range 28-50.5) months 13 (27%) patients received apixaban, 22 (46%) rivaroxaban, and 13 (27%) dabigatran. One stroke (2.3%/year) and two CRNMBs (4.6%/year) were observed on apixaban. One TIA (1.3%/year), three major bleedings and two CRNMBs (6.7%/year, combined) were reported on rivaroxaban. Three VTE were documented in dabigatran treated individuals (7.8%/year), without any bleeding or cerebrovascular events. Women with thromboembolic events had higher body mass index (32 [29-33]) vs. 26 [24-29]) kg/m, p = 0.02) and CHADS-VASc score (3 [3]) vs. 2 [1-3]), p = 0.02). Most thromboembolic complications (n = 4, 80%) and all three major bleedings were observed in tamoxifen users, while three of four CRNMBs occurred on aromatase inhibitors. Mortality rates were low (apixaban, n = 1 [2.3%/year], rivaroxaban, n = 3 [5.22%/ year], and dabigatran, n = 2 [4%/ year]). No death was related to bleeding.

Conclusions: This study suggests that DOACs are an effective and safe therapeutic option in breast cancer patients with AF during adjuvant hormonal therapy.
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http://dx.doi.org/10.1016/j.ijcard.2020.09.037DOI Listing
February 2021

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

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

A new impact factor of Kardiologia Polska.

Authors:
Anetta Undas

Kardiol Pol 2020 08 25;78(7-8):653-654. Epub 2020 Aug 25.

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

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http://dx.doi.org/10.33963/KP.15562DOI Listing
August 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