Journal of Investigational Allergology and Clinical Immunology, Oct 22, 2021
Inclusion and exclusion criteria Severity of asthma was categorized according to the Global Initi... more Inclusion and exclusion criteria Severity of asthma was categorized according to the Global Initiative for Asthma (GINA) (1) guidelines."Mild" asthma was defined as mild disease, treated with low daily dose of inhaled corticosteroids (ICS) (<250 g of fluticasone propionate [FP] [dry powder inhaler] or equivalent) and/or short acting β2-agonists on demand. "Moderate" asthma was defined as mild persistent disease treated with low (combined with long-acting β2-agonists) or medium dose of ICS (250-500 g of FP or equivalent). "Severe" asthma was defined as asthma that requires high dose of ICS (>500 g of FP or equivalent) with long-acting β2-agonist to prevent it from becoming uncontrolled or asthma that remains poorly controlled despite that treatment. Arterial hypertension was defined based on a history of hypertension (blood pressure >140/90 mmHg), or administration of antihypertensive treatment. Hypercholesterolemia was defined as the previously diagnosed and treated with statins, or serum total cholesterol >5.2 mmol/l. Diabetes mellitus was defined as the current use of insulin, or oral hypoglycemic medications, or fasting serum glucose >7.0 mmol/l. Congestive heart failure was defined as the left ventricular ejection fraction below 40%. Coronary heart disease was defined as a clinical manifestation of angina pectoris or myocardial infarct in the past. Liver injury was defined as the liver enzymes above the upper limit of the reference range. Ultrasound examinations Flow-mediated dilatation (FMD) of the right brachial artery was assessed using Celermayer' method (2), as described previously (3,4). A baseline sagittal diameter (D1) of a
W ostatnich latach dokonano odkryć, które pozwalają lepiej opisać podłoże molekularne i obraz kli... more W ostatnich latach dokonano odkryć, które pozwalają lepiej opisać podłoże molekularne i obraz kliniczny heterogennej skazy krwotocznej, jaką jest choroba von Willebranda (vWD). W artykule przedstawiono kluczowe, opublikowane w ostatnich latach, doniesienia dotyczące tego schorzenia o największym znaczeniu-zarówno z naukowego, jak i praktycznego punktu widzenia. Dotyczą one przede wszystkim mutacji sprawczych w obrębie genu czynnika von Willebranda (vWF), patogenezy choroby typu 1, nowych możliwości oceny aktywności vWF w osoczu oraz standaryzacji wywiadu krwotocznego jako podstawowego narzędzia przesiewowego w diagnostyce vWD. Słowa kluczowe: czynnik von Willebranda, choroba von Willebranda, skaza krwotoczna, propeptyd czynnika von Willebranda
Background: The role of autoimmune factors in the etiology of coronary artery disease (CAD) was s... more Background: The role of autoimmune factors in the etiology of coronary artery disease (CAD) was suggested in numerous studies but has not been definitively determined. Objectives: To assess the possible influence of antiphospholipid and antinuclear antibodies on atherosclerosis development in young patients after myocardial revascularization procedures. Methods: The study group included 39 patients younger than 45 years with CAD who underwent myocardial revascularization. Serum levels of antiphospholipid (aPL), antinuclear (ANA) and antineutrophil cytoplasmatic (ANCA) antibodies were tested within 1 month after the procedure. Results: All three types of aPL were significantly higher in CAD patients when compared to healthy controls: anti-β2-glycoprotein I (aβ2GPI), both immunoglobulin (Ig)G and IgM classes (median 4.10 SGU, range 3.45-21.63 vs. 0.76, 0.12-6.01, P < 0.001, and 2.82 SGU, 1.44-11.70 vs. 1.08, 0.44-3.64, P < 0.001, respectively); anticardiolipin antibodies (aCL) both IgG and IgM classes (3.13 GPL, 1.32-14.03 vs. 2.42, 0.96-18.45, P = 0.0037, and 6.94 MPL, 1.90-26.40 vs. 4.32, 1.9-28.73, P < 0.008, respectively); and lupus anticoagulant (LA) (27.7% vs. 0%, P = 0.005). ANA were elevated in one patient and ANCA in 23 (60%). The levels of aPL did not correlate with the presence of a clot in a coronary vessel detected during angiography or with exacerbation of coronary artery atherosclerosis. Conclusions: In young patients with CAD who underwent myocardial revascularization the levels of aPL were significantly higher than in young healthy subjects. Thus, besides the classic risk factors for CAD, autoimmunity may play an important role in atherosclerotic plaque formation and progression.
Objective To assess the association of genetic polymorphisms of signal transducer and activator o... more Objective To assess the association of genetic polymorphisms of signal transducer and activator of transcription (STAT) 4 with thrombotic manifestations in patients with autoimmune diseases, including antiphospholipid syndrome (APS). Methods A group of 395 adult, non-related patients (331 women and 64 men) with autoimmune diseases and 150 healthy control subjects were genotyped for 4 STAT4 single-nucleotide polymorphisms (SNPs): rs7574865, rs10181656, rs7582694 and rs11684030. The risk alleles associations with antiphospholipid antibodies (APLA) and the occurrence of thrombotic events were then analysed in the group of patients. Results Among 395 patients almost half were diagnosed with APS: 97 with primary (PAPS) and 83 with secondary (SAPS). Differences in frequencies of the risk alleles for the following 3 SNPs: G/C rs7582694, rs10181656 C/G, and rs7574865 G/T were stronger associated with APS than with systemic lupus erythematosus or other autoimmune diseases. All 3 SNPs were associated with prothrombotic, triple positive APLA pro le: OR = 1.68 (1.04 to 2.70, 95% CI), p = 0.032; OR = 1.61 (1.1 to 2.59, 95% CI), p = 0.048; and OR = 1.61 (1.0 to 2.59, 95% CI), p = 0.048; respectively. The association of the 2 STAT4 risk alleles, i.e., SNP rs7582694 (C) and rs10181656 (G) was stronger for venous thromboembolism: OR = 1.6 (1.1 to 2.5, 95% CI), p = 0.03 and OR = 1.5 (1.1 to 2.5, 95% CI), p = 0.02; respectively. Conclusions SNPs in the STAT4 gene, i.e., rs7582694(C), rs1018165(G), and rs7574865(T) are associated with venous thromboembolic events in autoimmune disease patients, therefore they might identify subjects at risk of venous thromboembolism.
In antiphospholipid syndrome (APS) the presence of anti-β2-glycoprotein I (β2GPI) antibodies is s... more In antiphospholipid syndrome (APS) the presence of anti-β2-glycoprotein I (β2GPI) antibodies is strongly associated with thromboembolic complications. It has been suggested that the common β2GPI Valine/Leucine247(Val/Leu247)polymorphism could be found more commonly in APS and might influence the generation of anti-β2GPI antibodies. Therefore we studied β2GPI Val/Leu247single-nucleotide polymorphism (SNP) by PCR in 338 patients with various autoimmune diseases (46 with secondary and 84 with primary APS) and 147 sex and age-matched healthy controls. In all patients lupus anticoagulant, anticardiolipin and anti-β2GPI antibodies (both IgG and IgM) were also determined. All patients and controls were Caucasians. Frequencies of the SNP genotypes in patients did not depart from genetic equilibrum and did not differ from those found in controls. There was also no association between the presence of β2GPI Val/Leu247genotypes and the presence or absence of lupus anticoagulant, anticardiolipin antibodies, anti-β2GPI antibodies or clinical APS symptoms in all patients studied. In conclusion, among the exclusively Caucasian, Polish population of autoimmune patients β2GPI Val/Leu247SNP has the same distribution as in healthy subjects and does not influence the production of anti-β2GPI antibodies.
Unfortunately, the country information for co-authors F. Conti and G. Valesini was incorrectly pu... more Unfortunately, the country information for co-authors F. Conti and G. Valesini was incorrectly published in the affiliation of the original publication. It should be Italy instead of Serbia. The corrected affiliation is presented with this erratum.
Research and Practice in Thrombosis and Haemostasis
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Introduction: COVID-19 is associated with an increased thromboembolic risk. However, the mechanis... more Introduction: COVID-19 is associated with an increased thromboembolic risk. However, the mechanisms triggering clot formation in those patients remain unknown. Patients and methods: In 118 adult Caucasian severe but non-critically ill COVID-19 patients (median age 58 years; 73 % men) and 46 controls, we analyzed in vitro plasma thrombin generation profile (calibrated automated thrombogram [CAT assay]) and investigated thrombophilia-related factors, such as protein C and antithrombin activity, free protein S level, presence of antiphospholipid antibodies and factor V Leiden R506Q and prothrombin G20210A mutations. We also measured circulating von Willebrand factor (vWF) antigen and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) antigen and activity. In patients, blood samples were collected on admission to the hospital before starting any therapy, including heparin. Finally, we examined the relationship between observed alterations and disease follow-up, such as thromboembolic complications. Results: COVID-19 patients showed 17 % lower protein C activity, 22 % decreased free protein S levels, and a higher prevalence of positive results for IgM anticardiolipin antibodies. They also had 151 % increased vWF, and 27 % decreased ADAMTS13 antigens compared with controls (p < 0.001, all). On the contrary, thrombin generation potential was similar to controls. In the follow-up, pulmonary embolism (PE) occurred in thirteen (11 %) patients. They were characterized by a 55 % elevated D-dimer (p = 0.04) and 2.7-fold higher troponin I (p = 0.002) during hospitalization and 29 % shorter time to thrombin peak in CAT assay (p = 0.009) compared to patients without PE. Conclusions: In COVID-19, we documented prothrombotic abnormalities of peripheral blood. PE was characterized by more dynamic thrombin generation growth in CAT assay performed on admittance to the hospital.
Objective: Sarcoidosis is a multisystem inflammatory granulomatous disease of unknown cause that ... more Objective: Sarcoidosis is a multisystem inflammatory granulomatous disease of unknown cause that most commonly affects lungs and lymph nodes, with frequent yet asymptomatic cardiac involvement. The epidemiologically associated cardiovascular risk suggests an underlying prothrombotic state and endothelial dysfunction, currently understudied in the available literature. Therefore, we aimed to investigate prothrombotic plasma properties together with selected echocardiographic and laboratory biomarkers of cardiovascular injury in that disease.Methods: N=53 patients with pulmonary sarcoidosis in clinical remission and N=66 matched controls were assessed for inflammatory and endothelial injury biomarkers, plasma thrombin generation profile, and echocardiographic and lung function parameters.Results: Sarcoidosis cases had impaired systolic and diastolic left ventricular function, higher concentrations of inflammatory markers, D-dimer and factor VIII activity compared to the controls. The coexistence of extrapulmonary disease was associated with elevated circulating vascular cell adhesion molecule (VCAM)-1, while cases with hypercalcemia had higher thrombomodulin concentration. Sarcoidosis was characterized by the unfavorably altered thrombin generation profile, reflected by the 16% higher endogenous thrombin potential (ETP), 24% increased peak thrombin concentration, and 12% shorter time to thrombin peak in comparison to the control group. ETP was higher in cases with proxies of pulmonary restriction, extrapulmonary-extracutaneous manifestation and need for corticosteroids use.Conclusions: Despite the clinical remission, sarcoidosis is related to prothrombotic plasma properties and signs of endothelial injury, likely contributing to the higher risk of cardiovascular events. In addition, subclinical cardiac involvement may play an additional role, although further clinical and experimental studies are needed to verify these findings.
Objective. Systemic sclerosis (SSc) is a rare immune-mediated heterogenous entity characterised b... more Objective. Systemic sclerosis (SSc) is a rare immune-mediated heterogenous entity characterised by excessive tissue fibrosis and vascular injury. Recently, increased risk of thromboembolic events has been documented in that disease. Our aim was to investigate prothrombotic plasma properties together with selected laboratory biomarkers of endothelial injury in SSc. Methods. In 56 clinically stable SSc patients and 67 well-matched controls we assessed plasma thrombin generation profile and measured circulating vascular cell adhesion molecule-1 (VCAM-1), cellular fibronectin (cFN), and thrombomodulin, as well as analysed their relationships with disease clinical parameters and autoimmune antibody profile. Results. SSc was characterised by 18.3% increased endogenous thrombin potential (ETP), 14.5% higher thrombin peak (p<0.001 both, also after adjustment for potential confounders), and similar endothelial damage biomarkers, as compared to controls. Surprisingly, raised thrombin generation was related to the lower thrombomodulin and VCAM-1. Inflammatory markers, factor VIII activity, and blood eosinophilia predicted positively ETP, whereas platelet count and thrombomodulin had negative impact on that parameter in a multiple regression model. Intriguingly, patient group had also 6.7% extended lag-time (p=0.01 after adjustment for confounders) which was independently determined by higher thrombomodulin and cFN, as well as lower VCAM-1. Former cyclophosphamide therapy, thus more severe type of the disease was referred to the increased thrombin generation. Conclusion. SSc is characterised by enhanced thrombin generation potential which might contribute to the higher risk of thromboembolic events in that disease. Endothelium may play hereby an additional role, although large observational and experimental studies are needed to verify this hypothesis.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Nabyta hemofilia jest rzadkim, potencjalnie śmiertelnym, nabytym schorzeniem autoimmunologicznym,... more Nabyta hemofilia jest rzadkim, potencjalnie śmiertelnym, nabytym schorzeniem autoimmunologicznym, z wytworzeniem przeciwciał blokujących aktywność własnych czynników krzepnięcia. To obniżenie aktywności prowadzi do rozwoju skazy krwotocznej. Najczęściej wytwarzane są przeciwciała przeciwko czynnikowi VIII – określane jako nabyta hemofilia A. W blisko połowie przypadków ma ona charakter pierwotny i nie towarzyszy żadnym innym zmia nom patologicznym, w 35–40% jest wtórna do innych schorzeń autoimmunologicznych, nowotworowych lub reakcji polekowych, a w 10–15% dotyczy młodych kobiet w okresie połogu. Leczenie nabytej hemofilii polega na opanowaniu czynnego krwawienia oraz eliminacji z krążenia aktywnego inhibitora. Autorzy przedstawiają przypadek 55-letniej chorej na reumatoidalne zapalenie stawów z nabytą hemofilią typu A (ryc. 1 i 2). Objawy skazy krwotocznej ustąpiły po dożylnym podaniu rekombinowanego aktyw nego czynnika VII oraz prednizonu i cyklofosfamidu. Celem pracy jest zwróce...
Afibrinogenemia is an autosomal recessive bleeding disorder with a prevalence of about 1: 1,000,0... more Afibrinogenemia is an autosomal recessive bleeding disorder with a prevalence of about 1: 1,000,000, characterized by complete absence of fibrinogen. 1 It is usually caused by null mutations of the FGA gene such as large deletions, frameshift and splice-site mutations. The most common mutation causing afibrinogenemia in Europe is a donor splice mutation in intron 4, c.510+1G>T. 1-3 Over 80% of afibrinogenemia cases manifest in the early neonatal period with umbilical cord bleeding. 3 Menorrhagia, gastrointestinal and skin bleeds are frequent, whereas joint and muscle bleeds are uncommon. Women with afibrinogenemia are at risk of
Coronary artery bypass grafting (CABG) done on-pump may cause a significant blood loss. Low fibri... more 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). Th...
Background: Treatment with non-vitamin K antagonist oral anticoagulants (NOACs) such as dabigatra... more 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.
Aim: To compare the effect of two low-calorie diets with high-protein or standard-protein on adip... more Aim: To compare the effect of two low-calorie diets with high-protein or standard-protein on adipokine plasma concentration and its association with changes in cardiometabolic markers in subjects with diabetes mellitus type 2 and overweight or obesity. Methods: 73 women (55.6±8.37 aged and 32.8±3.67 of BMI) were randomized to follow one of two calorie-restricted diets with the following distribution of calories from protein, carbohydrates and fat, respectively: 18%, 52% and 30%; 35%, 35%, and 30%, during six months. Plasma adipokines (leptin, adiponectin and Retinol Binding Protein 4; RBP4) levels and cardiometabolic markers were assessed at baseline and after 3 and 6 months of dietary intervention. Results: Weight loss homogenously decreased among diets. RBP4 and leptin significantly decreased in both diets although no differences were found between them. Adiponectin significantly increased in both diets; it changed by 6.05% and 29.9% at 3-months in 18%-and 35%-protein diets, respectively (P¼0.167), and 23.7% and 53.5% at 6-months in 18%-and 35%-protein diets, respectively (P¼0.219). Adiponectin variation inversely correlated to glycated hemoglobin (R¼-0.431; P<0.001), insulin (R¼-0.267; P¼0.043) and HOMA-IR (R¼-0.262; P¼0.047) changes at 6-months visit. Conclusions: RBP4 and leptin significantly improved after an energyrestricted intervention regardless of protein content. Adiponectin levels showed a higher increase after 35%-protein diet although statistical significance was not found. This change was inversely associated to glycated hemoglobin, HOMA index and insulin variations. Our findings suggest that glycemic improvement after high-protein diets is not explained by changes in plasma concentrations of adipokines.
Journal of Investigational Allergology and Clinical Immunology, Oct 22, 2021
Inclusion and exclusion criteria Severity of asthma was categorized according to the Global Initi... more Inclusion and exclusion criteria Severity of asthma was categorized according to the Global Initiative for Asthma (GINA) (1) guidelines."Mild" asthma was defined as mild disease, treated with low daily dose of inhaled corticosteroids (ICS) (<250 g of fluticasone propionate [FP] [dry powder inhaler] or equivalent) and/or short acting β2-agonists on demand. "Moderate" asthma was defined as mild persistent disease treated with low (combined with long-acting β2-agonists) or medium dose of ICS (250-500 g of FP or equivalent). "Severe" asthma was defined as asthma that requires high dose of ICS (>500 g of FP or equivalent) with long-acting β2-agonist to prevent it from becoming uncontrolled or asthma that remains poorly controlled despite that treatment. Arterial hypertension was defined based on a history of hypertension (blood pressure >140/90 mmHg), or administration of antihypertensive treatment. Hypercholesterolemia was defined as the previously diagnosed and treated with statins, or serum total cholesterol >5.2 mmol/l. Diabetes mellitus was defined as the current use of insulin, or oral hypoglycemic medications, or fasting serum glucose >7.0 mmol/l. Congestive heart failure was defined as the left ventricular ejection fraction below 40%. Coronary heart disease was defined as a clinical manifestation of angina pectoris or myocardial infarct in the past. Liver injury was defined as the liver enzymes above the upper limit of the reference range. Ultrasound examinations Flow-mediated dilatation (FMD) of the right brachial artery was assessed using Celermayer' method (2), as described previously (3,4). A baseline sagittal diameter (D1) of a
W ostatnich latach dokonano odkryć, które pozwalają lepiej opisać podłoże molekularne i obraz kli... more W ostatnich latach dokonano odkryć, które pozwalają lepiej opisać podłoże molekularne i obraz kliniczny heterogennej skazy krwotocznej, jaką jest choroba von Willebranda (vWD). W artykule przedstawiono kluczowe, opublikowane w ostatnich latach, doniesienia dotyczące tego schorzenia o największym znaczeniu-zarówno z naukowego, jak i praktycznego punktu widzenia. Dotyczą one przede wszystkim mutacji sprawczych w obrębie genu czynnika von Willebranda (vWF), patogenezy choroby typu 1, nowych możliwości oceny aktywności vWF w osoczu oraz standaryzacji wywiadu krwotocznego jako podstawowego narzędzia przesiewowego w diagnostyce vWD. Słowa kluczowe: czynnik von Willebranda, choroba von Willebranda, skaza krwotoczna, propeptyd czynnika von Willebranda
Background: The role of autoimmune factors in the etiology of coronary artery disease (CAD) was s... more Background: The role of autoimmune factors in the etiology of coronary artery disease (CAD) was suggested in numerous studies but has not been definitively determined. Objectives: To assess the possible influence of antiphospholipid and antinuclear antibodies on atherosclerosis development in young patients after myocardial revascularization procedures. Methods: The study group included 39 patients younger than 45 years with CAD who underwent myocardial revascularization. Serum levels of antiphospholipid (aPL), antinuclear (ANA) and antineutrophil cytoplasmatic (ANCA) antibodies were tested within 1 month after the procedure. Results: All three types of aPL were significantly higher in CAD patients when compared to healthy controls: anti-β2-glycoprotein I (aβ2GPI), both immunoglobulin (Ig)G and IgM classes (median 4.10 SGU, range 3.45-21.63 vs. 0.76, 0.12-6.01, P < 0.001, and 2.82 SGU, 1.44-11.70 vs. 1.08, 0.44-3.64, P < 0.001, respectively); anticardiolipin antibodies (aCL) both IgG and IgM classes (3.13 GPL, 1.32-14.03 vs. 2.42, 0.96-18.45, P = 0.0037, and 6.94 MPL, 1.90-26.40 vs. 4.32, 1.9-28.73, P < 0.008, respectively); and lupus anticoagulant (LA) (27.7% vs. 0%, P = 0.005). ANA were elevated in one patient and ANCA in 23 (60%). The levels of aPL did not correlate with the presence of a clot in a coronary vessel detected during angiography or with exacerbation of coronary artery atherosclerosis. Conclusions: In young patients with CAD who underwent myocardial revascularization the levels of aPL were significantly higher than in young healthy subjects. Thus, besides the classic risk factors for CAD, autoimmunity may play an important role in atherosclerotic plaque formation and progression.
Objective To assess the association of genetic polymorphisms of signal transducer and activator o... more Objective To assess the association of genetic polymorphisms of signal transducer and activator of transcription (STAT) 4 with thrombotic manifestations in patients with autoimmune diseases, including antiphospholipid syndrome (APS). Methods A group of 395 adult, non-related patients (331 women and 64 men) with autoimmune diseases and 150 healthy control subjects were genotyped for 4 STAT4 single-nucleotide polymorphisms (SNPs): rs7574865, rs10181656, rs7582694 and rs11684030. The risk alleles associations with antiphospholipid antibodies (APLA) and the occurrence of thrombotic events were then analysed in the group of patients. Results Among 395 patients almost half were diagnosed with APS: 97 with primary (PAPS) and 83 with secondary (SAPS). Differences in frequencies of the risk alleles for the following 3 SNPs: G/C rs7582694, rs10181656 C/G, and rs7574865 G/T were stronger associated with APS than with systemic lupus erythematosus or other autoimmune diseases. All 3 SNPs were associated with prothrombotic, triple positive APLA pro le: OR = 1.68 (1.04 to 2.70, 95% CI), p = 0.032; OR = 1.61 (1.1 to 2.59, 95% CI), p = 0.048; and OR = 1.61 (1.0 to 2.59, 95% CI), p = 0.048; respectively. The association of the 2 STAT4 risk alleles, i.e., SNP rs7582694 (C) and rs10181656 (G) was stronger for venous thromboembolism: OR = 1.6 (1.1 to 2.5, 95% CI), p = 0.03 and OR = 1.5 (1.1 to 2.5, 95% CI), p = 0.02; respectively. Conclusions SNPs in the STAT4 gene, i.e., rs7582694(C), rs1018165(G), and rs7574865(T) are associated with venous thromboembolic events in autoimmune disease patients, therefore they might identify subjects at risk of venous thromboembolism.
In antiphospholipid syndrome (APS) the presence of anti-β2-glycoprotein I (β2GPI) antibodies is s... more In antiphospholipid syndrome (APS) the presence of anti-β2-glycoprotein I (β2GPI) antibodies is strongly associated with thromboembolic complications. It has been suggested that the common β2GPI Valine/Leucine247(Val/Leu247)polymorphism could be found more commonly in APS and might influence the generation of anti-β2GPI antibodies. Therefore we studied β2GPI Val/Leu247single-nucleotide polymorphism (SNP) by PCR in 338 patients with various autoimmune diseases (46 with secondary and 84 with primary APS) and 147 sex and age-matched healthy controls. In all patients lupus anticoagulant, anticardiolipin and anti-β2GPI antibodies (both IgG and IgM) were also determined. All patients and controls were Caucasians. Frequencies of the SNP genotypes in patients did not depart from genetic equilibrum and did not differ from those found in controls. There was also no association between the presence of β2GPI Val/Leu247genotypes and the presence or absence of lupus anticoagulant, anticardiolipin antibodies, anti-β2GPI antibodies or clinical APS symptoms in all patients studied. In conclusion, among the exclusively Caucasian, Polish population of autoimmune patients β2GPI Val/Leu247SNP has the same distribution as in healthy subjects and does not influence the production of anti-β2GPI antibodies.
Unfortunately, the country information for co-authors F. Conti and G. Valesini was incorrectly pu... more Unfortunately, the country information for co-authors F. Conti and G. Valesini was incorrectly published in the affiliation of the original publication. It should be Italy instead of Serbia. The corrected affiliation is presented with this erratum.
Research and Practice in Thrombosis and Haemostasis
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Introduction: COVID-19 is associated with an increased thromboembolic risk. However, the mechanis... more Introduction: COVID-19 is associated with an increased thromboembolic risk. However, the mechanisms triggering clot formation in those patients remain unknown. Patients and methods: In 118 adult Caucasian severe but non-critically ill COVID-19 patients (median age 58 years; 73 % men) and 46 controls, we analyzed in vitro plasma thrombin generation profile (calibrated automated thrombogram [CAT assay]) and investigated thrombophilia-related factors, such as protein C and antithrombin activity, free protein S level, presence of antiphospholipid antibodies and factor V Leiden R506Q and prothrombin G20210A mutations. We also measured circulating von Willebrand factor (vWF) antigen and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) antigen and activity. In patients, blood samples were collected on admission to the hospital before starting any therapy, including heparin. Finally, we examined the relationship between observed alterations and disease follow-up, such as thromboembolic complications. Results: COVID-19 patients showed 17 % lower protein C activity, 22 % decreased free protein S levels, and a higher prevalence of positive results for IgM anticardiolipin antibodies. They also had 151 % increased vWF, and 27 % decreased ADAMTS13 antigens compared with controls (p < 0.001, all). On the contrary, thrombin generation potential was similar to controls. In the follow-up, pulmonary embolism (PE) occurred in thirteen (11 %) patients. They were characterized by a 55 % elevated D-dimer (p = 0.04) and 2.7-fold higher troponin I (p = 0.002) during hospitalization and 29 % shorter time to thrombin peak in CAT assay (p = 0.009) compared to patients without PE. Conclusions: In COVID-19, we documented prothrombotic abnormalities of peripheral blood. PE was characterized by more dynamic thrombin generation growth in CAT assay performed on admittance to the hospital.
Objective: Sarcoidosis is a multisystem inflammatory granulomatous disease of unknown cause that ... more Objective: Sarcoidosis is a multisystem inflammatory granulomatous disease of unknown cause that most commonly affects lungs and lymph nodes, with frequent yet asymptomatic cardiac involvement. The epidemiologically associated cardiovascular risk suggests an underlying prothrombotic state and endothelial dysfunction, currently understudied in the available literature. Therefore, we aimed to investigate prothrombotic plasma properties together with selected echocardiographic and laboratory biomarkers of cardiovascular injury in that disease.Methods: N=53 patients with pulmonary sarcoidosis in clinical remission and N=66 matched controls were assessed for inflammatory and endothelial injury biomarkers, plasma thrombin generation profile, and echocardiographic and lung function parameters.Results: Sarcoidosis cases had impaired systolic and diastolic left ventricular function, higher concentrations of inflammatory markers, D-dimer and factor VIII activity compared to the controls. The coexistence of extrapulmonary disease was associated with elevated circulating vascular cell adhesion molecule (VCAM)-1, while cases with hypercalcemia had higher thrombomodulin concentration. Sarcoidosis was characterized by the unfavorably altered thrombin generation profile, reflected by the 16% higher endogenous thrombin potential (ETP), 24% increased peak thrombin concentration, and 12% shorter time to thrombin peak in comparison to the control group. ETP was higher in cases with proxies of pulmonary restriction, extrapulmonary-extracutaneous manifestation and need for corticosteroids use.Conclusions: Despite the clinical remission, sarcoidosis is related to prothrombotic plasma properties and signs of endothelial injury, likely contributing to the higher risk of cardiovascular events. In addition, subclinical cardiac involvement may play an additional role, although further clinical and experimental studies are needed to verify these findings.
Objective. Systemic sclerosis (SSc) is a rare immune-mediated heterogenous entity characterised b... more Objective. Systemic sclerosis (SSc) is a rare immune-mediated heterogenous entity characterised by excessive tissue fibrosis and vascular injury. Recently, increased risk of thromboembolic events has been documented in that disease. Our aim was to investigate prothrombotic plasma properties together with selected laboratory biomarkers of endothelial injury in SSc. Methods. In 56 clinically stable SSc patients and 67 well-matched controls we assessed plasma thrombin generation profile and measured circulating vascular cell adhesion molecule-1 (VCAM-1), cellular fibronectin (cFN), and thrombomodulin, as well as analysed their relationships with disease clinical parameters and autoimmune antibody profile. Results. SSc was characterised by 18.3% increased endogenous thrombin potential (ETP), 14.5% higher thrombin peak (p<0.001 both, also after adjustment for potential confounders), and similar endothelial damage biomarkers, as compared to controls. Surprisingly, raised thrombin generation was related to the lower thrombomodulin and VCAM-1. Inflammatory markers, factor VIII activity, and blood eosinophilia predicted positively ETP, whereas platelet count and thrombomodulin had negative impact on that parameter in a multiple regression model. Intriguingly, patient group had also 6.7% extended lag-time (p=0.01 after adjustment for confounders) which was independently determined by higher thrombomodulin and cFN, as well as lower VCAM-1. Former cyclophosphamide therapy, thus more severe type of the disease was referred to the increased thrombin generation. Conclusion. SSc is characterised by enhanced thrombin generation potential which might contribute to the higher risk of thromboembolic events in that disease. Endothelium may play hereby an additional role, although large observational and experimental studies are needed to verify this hypothesis.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Nabyta hemofilia jest rzadkim, potencjalnie śmiertelnym, nabytym schorzeniem autoimmunologicznym,... more Nabyta hemofilia jest rzadkim, potencjalnie śmiertelnym, nabytym schorzeniem autoimmunologicznym, z wytworzeniem przeciwciał blokujących aktywność własnych czynników krzepnięcia. To obniżenie aktywności prowadzi do rozwoju skazy krwotocznej. Najczęściej wytwarzane są przeciwciała przeciwko czynnikowi VIII – określane jako nabyta hemofilia A. W blisko połowie przypadków ma ona charakter pierwotny i nie towarzyszy żadnym innym zmia nom patologicznym, w 35–40% jest wtórna do innych schorzeń autoimmunologicznych, nowotworowych lub reakcji polekowych, a w 10–15% dotyczy młodych kobiet w okresie połogu. Leczenie nabytej hemofilii polega na opanowaniu czynnego krwawienia oraz eliminacji z krążenia aktywnego inhibitora. Autorzy przedstawiają przypadek 55-letniej chorej na reumatoidalne zapalenie stawów z nabytą hemofilią typu A (ryc. 1 i 2). Objawy skazy krwotocznej ustąpiły po dożylnym podaniu rekombinowanego aktyw nego czynnika VII oraz prednizonu i cyklofosfamidu. Celem pracy jest zwróce...
Afibrinogenemia is an autosomal recessive bleeding disorder with a prevalence of about 1: 1,000,0... more Afibrinogenemia is an autosomal recessive bleeding disorder with a prevalence of about 1: 1,000,000, characterized by complete absence of fibrinogen. 1 It is usually caused by null mutations of the FGA gene such as large deletions, frameshift and splice-site mutations. The most common mutation causing afibrinogenemia in Europe is a donor splice mutation in intron 4, c.510+1G>T. 1-3 Over 80% of afibrinogenemia cases manifest in the early neonatal period with umbilical cord bleeding. 3 Menorrhagia, gastrointestinal and skin bleeds are frequent, whereas joint and muscle bleeds are uncommon. Women with afibrinogenemia are at risk of
Coronary artery bypass grafting (CABG) done on-pump may cause a significant blood loss. Low fibri... more 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). Th...
Background: Treatment with non-vitamin K antagonist oral anticoagulants (NOACs) such as dabigatra... more 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.
Aim: To compare the effect of two low-calorie diets with high-protein or standard-protein on adip... more Aim: To compare the effect of two low-calorie diets with high-protein or standard-protein on adipokine plasma concentration and its association with changes in cardiometabolic markers in subjects with diabetes mellitus type 2 and overweight or obesity. Methods: 73 women (55.6±8.37 aged and 32.8±3.67 of BMI) were randomized to follow one of two calorie-restricted diets with the following distribution of calories from protein, carbohydrates and fat, respectively: 18%, 52% and 30%; 35%, 35%, and 30%, during six months. Plasma adipokines (leptin, adiponectin and Retinol Binding Protein 4; RBP4) levels and cardiometabolic markers were assessed at baseline and after 3 and 6 months of dietary intervention. Results: Weight loss homogenously decreased among diets. RBP4 and leptin significantly decreased in both diets although no differences were found between them. Adiponectin significantly increased in both diets; it changed by 6.05% and 29.9% at 3-months in 18%-and 35%-protein diets, respectively (P¼0.167), and 23.7% and 53.5% at 6-months in 18%-and 35%-protein diets, respectively (P¼0.219). Adiponectin variation inversely correlated to glycated hemoglobin (R¼-0.431; P<0.001), insulin (R¼-0.267; P¼0.043) and HOMA-IR (R¼-0.262; P¼0.047) changes at 6-months visit. Conclusions: RBP4 and leptin significantly improved after an energyrestricted intervention regardless of protein content. Adiponectin levels showed a higher increase after 35%-protein diet although statistical significance was not found. This change was inversely associated to glycated hemoglobin, HOMA index and insulin variations. Our findings suggest that glycemic improvement after high-protein diets is not explained by changes in plasma concentrations of adipokines.
Uploads
Papers by Teresa Iwaniec