Plasminogen Activator Inhibitor-1 Levels Research Articles

Association of Metabolically Healthy and Unhealthy Obesity Phenotype with Markers Related to Obesity, Diabetes among Young, Healthy Adult Men. Analysis of MAGNETIC Study.

Adipose tissue secretes many regulatory factors called adipokines. Adipokines affect the metabolism of lipids and carbohydrates. They also influence the regulation of the immune system and inflammation. The current study aimed to evaluate the association between markers related to obesity, diabesity and adipokines and metabolically healthy and unhealthy obesity in young men. The study included 98 healthy participants. We divided participants into three subgroups based on body mass index and metabolic health definition: 49 metabolically healthy normal-weight patients, 27 metabolically healthy obese patients and 22 metabolically unhealthy obese patients. The 14 metabolic markers selected were measured in serum or plasma. The analysis showed associations between markers related to obesity, diabesity and adipokines in metabolically healthy and unhealthy obese participants. The decreased level of adipsin (p < 0.05) was only associated with metabolically healthy obesity, not with metabolically unhealthy obesity. The decreased level of ghrelin (p < 0.001) and increased level of plasminogen activator inhibitor-1 (p < 0.01) were only associated with metabolically unhealthy obesity, not with metabolically healthy obesity. The decreased level of adiponectin and increased levels of leptin, c-peptide, insulin and angiopoietin-like 3 protein were associated with metabolically healthy and unhealthy obesity. In conclusion, our data show that metabolically healthy obesity was more similar to metabolically unhealthy obesity in terms of the analyzed markers related to obesity and diabesity.

Altered fibrin clot structure and dysregulated fibrinolysis contribute to thrombosis risk in severe COVID-19

AbstractThe high incidence of thrombotic events suggests a possible role of the contact system pathway in COVID-19 pathology. In this study, we determined the altered levels of factor XII (FXII) and its activation products in critically ill patients with COVID-19 in comparison with patients with severe acute respiratory distress syndrome related to the influenza virus (acute respiratory distress syndrome [ARDS]-influenza). Compatible with those data, we found rapid consumption of FXII in COVID-19 but not in ARDS-influenza plasma. Interestingly, the lag phase in fibrin formation, triggered by the FXII activator kaolin, was not prolonged in COVID-19, as opposed to that in ARDS-influenza. Confocal and electron microscopy showed that increased FXII activation rate, in conjunction with elevated fibrinogen levels, triggered formation of fibrinolysis-resistant, compact clots with thin fibers and small pores in COVID-19. Accordingly, clot lysis was markedly impaired in COVID-19 as opposed to that in ARDS-influenza. Dysregulated fibrinolytic system, as evidenced by elevated levels of thrombin-activatable fibrinolysis inhibitor, tissue-plasminogen activator, and plasminogen activator inhibitor-1 in COVID-19 potentiated this effect. Analysis of lung tissue sections revealed widespread extra- and intravascular compact fibrin deposits in patients with COVID-19. A compact fibrin network structure and dysregulated fibrinolysis may collectively contribute to a high incidence of thrombotic events in COVID-19.

Porphyromonas gingivalis Gingipains-Mediated Degradation of Plasminogen Activator Inhibitor-1 Leads to Delayed Wound Healing Responses in Human Endothelial Cells

Plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor, is constitutively produced by endothelial cells and plays a vital role in maintaining vascular homeostasis. Chronic periodontitis is an inflammatory disease characterized by bleeding of periodontal tissues that support the tooth. In this study, we aimed to determine the role of PAI-1 produced by endothelial cells in response to infections caused by the primary periodontal pathogen Porphyromonas gingivalis. We demonstrated that P. gingivalis infection resulted in significantly reduced PAI-1 levels in human endothelial cells. This reduction in PAI-1 levels could be attributed to the proteolysis of PAI-1 by P. gingivalis proteinases, especially lysine-specific gingipain-K (Kgp). We demonstrated the roles of these degradative enzymes in the endothelial cells using a Kgp-specific inhibitor and P. gingivalis gingipain-null mutants, in which the lack of the proteinases resulted in the absence of PAI-1 degradation. The degradation of PAI-1 by P. gingivalis induced a delayed wound healing response in endothelial cell layers via the low-density lipoprotein receptor-related protein. Our results collectively suggested that the proteolysis of PAI-1 in endothelial cells by gingipains of P. gingivalis might lead to the deregulation of endothelial homeostasis, thereby contributing to the permeabilization and dysfunction of the vascular endothelial barrier.

Abstract 11929: PAI-1 is Cardioprotective in Human Inflammatory Cardiomyopathy

Introduction: Preclinical data indicate that plasminogen activator inhibitor-1 (PAI-1) is cardioprotective by repressing fibrosis through TGF-β and plasminogen mediated pathways. Moreover, PAI-1 is suggested to be involved in the recruitment and polarization of M2 macrophages. Hypothesis: Elevated myocardial PAI-1 expression protects from fibrosis and acute inflammatory response. Methods: Endomyocardial biopsies (EMBs) of patients with dilated cardiomyopathy (DCM, n=27) and inflammatory dilated cardiomyopathy (DCMi, n=149) were retrospectively analyzed for PAI-1 expression, markers of fibrosis and M1/M2 macrophage polarization. Results: Patients with high-grade myocardial inflammation (DCMi-high, CD3 + lymphocytes &gt; 30 cells/mm 2 ) had significantly increased PAI-1 levels compared to DCM and low-grade DCMi patients (DCMi-low, CD3 + lymphocytes = 14 - 30 cells/mm 2 ) (15.5 ± 0.4 % vs. 1.0 ± 0.1 % and 4.0 ± 0.1 %, p ≤ 0.001). Elevated PAI-1 expression in DCMi-high subjects was associated with a diminished degree of tissue fibrosis, accompanied by decreased levels of TGF-β and a reduced number of cardiac myofibroblasts. In addition, elevation of PAI-1 led to a shift from M1 to M2 macrophages. Conclusions: Our findings give evidence that increased expression of PAI-1 in DCMi patients suppresses cardiac fibrosis and promotes M2 macrophage polarization. Thus, PAI-1 could serve as a potential prognostic biomarker of cardiac fibrosis and inflammation, as well as possible therapeutic target in inflammatory cardiomyopathies.

The relationship between Dietary approaches to stop hypertension diet adherence and inflammatory factors and insulin resistance in overweight and obese women: A cross-sectional study

BackgroundAlthough there is abundant evidence for an association between dietary pattern, weight, and other related factors, such as homeostatic model assessment for insulin resistance (HOMA-IR) and inflammatory markers; there is limited information pertaining to levels of plasminogen activator inhibitor-1 (PAI-1) and Monocyte Chemoattractant Protein −1 (MCP-1). Therefore, this study sought to examine the association between adherence to the dietary approaches to stop hypertension (DASH) diet and levels of inflammatory factors PAI-1, MCP-1, and HOMA-IR. MethodsThis cross-sectional study was performed on 305 obese and overweight women. The typical food intake of individuals was assessed using the 147 items semi-quantitative food frequency questionnaire (FFQ). Body components were measured for all participants. Insulin resistance was estimated by homeostasis model assessment (HOMA), and biochemical parameters were examined. ResultsNo significant relationship was observed between the DASH diet and MCP-1 (P-trend = 0.70), PAI-1 (P-trend = 0.92), or HOMA-IR (P-trend = 0.08) in the crude model. However, there was a significant inverse relationship between the DASH diet and HOMA-IR (P-trend = 0.03) after adjusting for age, BMI, and physical activity. ConclusionThis study showed that higher adherence to DASH pattern is inversely correlated with HOMA-IR in overweight and obese women.

Delayed Plasma Clot Lysis in Adult Patients with Primary Immune Thrombocytopenia (ITP)

Introduction: Primary immune thrombocytopenia (ITP) is an orphan disease characterized by very low platelet counts. Patients have heterogeneous bleeding phenotypes, which are not only determined by platelet counts, also a paradoxically increased thrombotic risk has been observed.Aim: To investigate, whether the fibrinolysis inhibitors plasminogen activator inhibitor-1 (PAI-1) and α2-antiplasmin are associated with impaired plasma clot lysis in primary ITP patients in comparison to non-immunologic thrombocytopenic controls (TPC) and healthy controls (HC). Furthermore, associations with bleeding severity and previous thrombotic events were investigated.Methods: Patients from the Vienna ITP biobank (EC 1843/2016), a multi-centric study including adult patients with primary ITP were investigated and compared to age- and sex-matched control groups: TPC with thrombocytopenia after chemotherapy and HC. Informed consent was obtained from all individuals before study inclusion. A clot formation and lysis assay (CLA) was performed according to the recommendations of the ISTH SSC. Platelet poor plasma samples were measured in duplicates for each patient and control. PAI-1 (PAI-1 Actibind ELISA, Technoclone, Vienna, Austria) and α2-antiplasmin by the chromogenic STA Stachrom antiplasmin assay (Diagnostic Stago, Asnieres, France) were measured. Bleeding severity was measured using the ITP-specific ITP-ISTH BAT (Rodeghiero et al. 2013).Results: In total, 37 primary ITP patients, 18 TPC and 156 healthy controls were analyzed (Table 1). Primary ITP patients had a higher BMI than HC. Bleeding severity was higher and more ITP patients had a thrombosis history compared to HC, whereas there was no difference in comparison to TPC. PAI-1 activity was highest in ITP patients, with a statistically significant difference in comparison to HC. α2-antiplasmin activity was higher in ITP patients than in TPC, whereas there was no difference in comparison to HC.After adjustment for sex, age, BMI and fibrinogen, primary ITP patients had a reduced clot formation rate (V max) and significantly delayed plasma clot lysis compared to TPC and HC (Table 2). Also, the lag phase and time to peak absorbance (TTP) were prolonged with a significant difference in comparison to HC.To investigate outliers of PAI-1 and α2-antiplasmin, we calculated cut-offs at the 75 th percentile of healthy controls (PAI-1: ≥ 3.1 U/mL, α2-antiplasmin: ≥ 107.0 %). 14 (37.8 %) ITP patients had PAI-1 levels and 10 (27.0 %) ITP patients had α2-antiplasmin activity above the cut-off. ITP patients with high PAI-1 levels had mildly delayed clot lysis in comparison to those below with a significantly lower maximal lysis rate (mLR). ITP patients with α2-antiplasmin activity above the cut-off had a significantly shorter lag phase, faster V max and shorter TTP than patients below the cut-off, whereas there was no difference in clot lysis. No differences between ITP patients above or below the respective cut-offs of PAI-1 and α2-antiplasmin regarding their bleeding severity and thrombosis incidence were observed (Table 3).Conclusion: Primary ITP patients have a tendency towards increased PAI-1 activity, which is associated with considerably delayed plasma clot lysis. Albeit an association with the bleeding score could not be identified, this impaired lysis could be seen as a counter-regulation and at least contribute to the relatively mild bleeding tendency in patients with ITP. [Display omitted] DisclosuresPabinger: CSL Behring: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Research Funding; Bayer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Daiichi Sanchyo: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

Prothrombotic and Inflammatory Markers in Elderly Patients with Non-Alcoholic Hepatic Liver Disease before and after Weight Loss: A Pilot Study.

Background: Non-alcoholic fatty liver disease (NAFLD) is a pathological condition, ranging from fatty liver to chronic steatohepatitis (NASH), liver cirrhosis, and eventually to hepatocellular carcinoma. Recent findings suggest that patients with NAFLD have an increased risk of cardiovascular events and thromboembolism, which is independent of metabolic diseases that are frequently associated with NAFLD, such as diabetes, hyperlipidemia, and obesity. Methods: We evaluated 30 NAFLD patients, before and after weight loss. Plasma levels of C-reactive protein (CRP), fibrinogen, plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (VWF), homocysteine, coagulation protein S, Thrombin activable fibrinolysis inhibitor (TAFI), and factor VII (FVII) were assessed to evaluate whether they should be responsible of the prothrombotic state of NAFLD after weight loss. Results: At baseline, patients affected by NAFLD had a significantly higher levels of CRP, fibrinogen, PAI-1, VWF antigen, and FVII levels. After weight reduction, we observed a significant drop of inflammatory and prothrombotic markers, as well as glucometabolic, lipid profile. Conclusion: These findings provide evidence for a link between NAFLD/NASH and thromboembolism. The association seems to be linked with primitive thrombotic state and hypercoagulation due to increased levels of coagulation factors and reduced levels of PAI-1. This hypercoagulation state might explain increased levels of thrombosis and splanchnic thrombosis observed in NASH correlated cirrhosis.

Insights into Fibrinogen-Mediated COVID-19 Hypercoagubility in Critically Ill Patients.

Coronavirus disease-2019 (COVID-19) is associated with hypercoagulability that may cause thromobembolic complications. We describe our recent studies investigating the mechanisms of hypercoagulability in patients with severe COVID-19 requiring mechanical ventilation during the COVID-19 crisis in New York City in spring 2020. Using rotational thombelastometry we found that almost all patients with severe COVID-19 had signs of hypercoagulability compared with non-COVID-19 controls. Specifically, the maximal clot firmness in the fibrin-based extrinsically activated test was almost twice the upper limit of normal in COVID patients, indicating a fibrin-mediated cause for hypercoagulability. To better understand the mechanism of this hypercoagulability we measured the components of the fibrinolytic pathways. Fibrinogen, tissue plasminogen activator and plasminogen activator inhibitor-1, but not plasminogen levels were elevated in patients with severe COVID-19. Our studies indicate that hypercoagulability in COVID-19 may be because of decreased fibrinolysis resulting from inhibition of plasmin through high levels of plasminogen activator inhibitor-1. Clinicians creating treatment protocols for anticoagulation in critically ill COVID-19 patients should consider these potential mechanisms of hypercoaguability.

Coagulation Factor Activity and Hemostatic Markers of Endothelial Dysfunction in Patients with Peripheral Arterial Disease

Purpose We aimed to evaluate the impact of intrinsic coagulation factors and hemostatic markers of endothelial dysfunction on complications in patients with atherosclerotic peripheral arterial disease (PAD). Materials and Methods This prospective study enrolled 120 PAD patients at Fontaine stages 2b to 3 who underwent open surgical, endovascular, or conservative treatment. Coagulation factors (FVIII, FIX, and FXI) and endothelial hemostatic markers, including von Willebrand factor (vWF) activity and level, soluble endothelial protein C receptor, and plasminogen activator inhibitor-1 (PAI-1) levels, were assessed. Results At 3 months after open bypass grafting, activity of FVIII significantly increased from a median of 175% to 233% (P<0.001). At 3 months after endovascular treatment, the activities of FVIII, FIX, and FXI significantly increased from medians of 157%, 180%, and 156% to 184%, 218%, and 181%, respectively (P<0.05). Six patients with increased FVIII activity developed bypass graft thrombosis. Four patients in the endovascular group and three patients in the conservative treatment group with increased activity of vWF developed myocardial infarction (P=0.049). The subjects who developed restenosis had increased vWF activity (P=0.023) and decreased nitric oxide metabolite levels (P=0.003). Three subjects who received conservative treatment and developed PAD progression at 12 months had increased PAI-1 activity (P=0.028). Conclusion Patients with advanced PAD had a hypercoagulable status, and performance of open or endovascular revascularization was associated with further hypercoagulability. Increased activity of coagulation factors and altered levels of hemostatic markers of endothelial dysfunction were associated with PAD complications such as graft thrombosis, myocardial infarction, disease progression, and restenosis.

Prognostic difficulties of men with breast cancer.

Most adequately powered studies confirm a worse prognosis for males versus matched females with breast cancer. There is in-stage migration for stage I cancers with a different ratio of tumor/normal breast tissue in males. Younger men have a better prognosis, largely the result of increased morbidity in the elderly, exacerbated by smoking, low socioeconomic differences, and ethnic disparity. BRCA2 carriers with MBC have a worse outcome than noncarriers as do men with amplification of EMSY. Men with tumors having a high cytosol level of plasminogen activator inhibitor 1 (PAI-1) may have more invasive cancers leading to earlier spread and hence a worse outcome. PREDICT+ is a useful prognostic model for MBC and multigene testing enables more specific systemic therapies to be used.

Fibrinolytic system activation immediately following trauma was quickly and intensely suppressed in a rat model of severe blunt trauma

In severe trauma, excessive fibrinolytic activation is associated with an increase in the transfusion volume and mortality rate. However, in the first several hours after a blunt trauma, changes in fibrinolytic activation, suppression, and activation–suppression balance have not yet been elucidated, which the present study aimed to clarify. Anesthetized 9-week-old male Wistar S/T rats experienced severe blunt trauma while being placed inside the Noble–Collip drum. Rats were randomly divided into four groups of seven. The no-trauma group was not exposed to any trauma; the remaining groups were analysed 0, 60, and 180 min after trauma. Immediately following trauma, total tissue-plasminogen activator (tPA) levels significantly increased in the plasma, and the balance of active tPA and active plasminogen activator inhibitor-1 (PAI-1) significantly tipped toward fibrinolytic activation. After trauma, both tPA and PAI-1 levels increased gradually in various organs and active and total PAI-1 levels increased exponentially in the plasma. Total plasma tPA levels 60 min after trauma returned quickly to levels comparable to those in the no-trauma group. In conclusion, fibrinolytic activation was observed only immediately following trauma. Therefore, immediately after trauma, the fibrinolytic system was activated; however, its activation was quickly and intensely suppressed.

Growth differentiation factor-15 and plasminogen activator inhibitor-1 are possible predictors of cardiovascular events in atrial fibrillation patients after elective PCI

Abstract Introduction Patients (pts) with AF (atrial fibrillation), undergoing elective PCI (percutaneous coronary intervention), receiving combined antithrombotic therapy (AT) have high risk of stroke/systemic embolism, coronary events and bleedings. Minimizing the duration of combined AT is the main way to improve the safety of treatment. However, due to the high risk of thrombotic events, patient stratification is necessary. Biomarkers of high risk cardiovascular events (CVE) could be the rational reason to prolong combined AT for some pts. The search for them is relevant. There is data on relationship between growth differentiation factor-15 (GDF-15) level, plasminogen activator inhibitor-1 (PAI-1) level and adverse CVE. Purpose To investigate the prognostic value of GDF-15 and PAI-1 levels in AF pts after elective PCI during 1 year follow up. Methods 150 pts (104 males), aged 70.8±8.5 years, with AF after elective PCI were enrolled in the prospective study. All pts received direct oral anticoagulants and double (89.3%) or single (10.7%) antiplatelet therapy. Median duration of follow up period was 11.5 months [IQR 8.0; 12.0]. Efficacy endpoint of the study was the sum of CVE: ACS (acute coronary syndrome), ischemic stroke (IS), VTE (venous thrombotic events), cardiovascular death and need for unplanned PCI. Plasma samples for GDF-15 and PAI-1 were taken before PCI and analyzed using ELISA. Results AF pts receiving combined AT demonstrated high thrombotic risk (CHA2DS2-VASc, Med 5 [IQR 4; 6]), high rate of comorbidity (index Charlson, Med 7 [IQR 5; 9]). Frequency of CVE during follow up period was 16% (ACS 2; fatal IS 2; VTE 2, include 1 fatal pulmonary embolism; cardiovascular death 2; pts needed an unplanned PCI 16). Median GDF-15 level was 1270 pg/ml [IQR 953; 1778]. Median PAI-1 level was 10.15 U/ml [6,3; 17,0]. By linear correlation analysis (r=0.24; p=0.0037) and by regression model (F-ratio 157.4, p&amp;lt;0.0001) GFD-15 and PAI-1 are exhibited a relation. According to ROC analysis GDF-15 level &amp;gt;1191 pg/ml (sensitivity 83.0, specifity 50.0) and PAI-1 level &amp;gt;13.2 U/ml (sensitivity 58.3, specifity 68.6) increases the probability of the development of CVE (AUC=0.647, p=0.0076, CI 0.565–0.723; AUC=0.652, p=0.0135, CI 0.569–0.728 respectively). Kaplan-Meier curves demonstrated significant difference in CVE free survival between the patients with GDF-15 level &amp;gt; and ≤1191 pg/ml (75.9% and 94.0% respectively, p=0.0032 [HR 4.36, CI 1.50–7.48]); and with PAI-1 level &amp;gt; and ≤13.2 U/ml (74% and 89% respectively, p=0.0112 [HR 2.73, CI 1.28–6.98]). The multivariable Cox regression model demonstrated that GDF-15 (p=0.0363) and PAI-1 (p=0.0074), were independently associated with an increased risk of CVE (op=0.0022). Conclusions GDF-15 and PAI-1 are correlated, and they are new markers of CVE in AF pts after elective PCI. Funding Acknowledgement Type of funding sources: None.

Plasminogen activator inhibitor-1 (PAI-1) is anti-fibrogenic in human inflammatory cardiomyopathy

Abstract Background/Introduction Preclinical data indicate that plasminogen activator inhibitor-1 (PAI-1) is cardioprotective by repressing cardiac fibrosis through TGF-β and plasminogen mediated pathways. In addition it is linked to the recruitment and polarization of non-classical M2 macrophages in cancer. Purpose The role of cardiac PAI-1 in fibrogenesis and macrophage polarization is investigated in patients with dilated cardiomyopathy (DCM) and inflammatory dilated cardiomyopathy (DCMi). Methods We retrospectively analyzed endomyocardial biopsies (EMBs) of patients with DCM (n=27) and DCMi (n=149) for PAI-1 expression, number of activated myofibroblasts and M1/M2 macrophage polarization. Results Patients with high-grade DCMi (DCMi-high, CD3+ lymphocytes &amp;gt;30 cells/mm2) had significantly increased PAI-1 levels compared to DCM and low grade DCMi patients (DCMi-low, CD3+ lymphocytes = 14 - 30 cells/mm2) (15.5±0.4% vs. 1.0±0.1% and 4.0±0.1%, p≤0.001). Elevated PAI-1 expression in DCMi-high subjects was accompanied by a reduced number of alpha smooth muscle actin (α-SMA) positive myofibroblasts and an increased number of CD16+ CD68+ M2 macrophages, indicating anti-fibrogenic and M2 macrophage-favoring properties of PAI-1 in DCMi. Conclusion Our findings give evidence that elevated expression of PAI-1 suppresses cardiac fibrosis and promotes M2 macrophage polarization. Thus, PAI-1 could serve as a potential prognostic biomarker of cardiac fibrosis and inflammation, as well as possible therapeutic target in inflammatory cardiomyopathies. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): ERA-Net on Cardiovascular Diseases (ERA-CVD) of the German Research Foundation (DFG)Transregional Collaborative Research Center “Inflammatory Cardiomyopathy-Molecular Pathogenesis and Therapy”

Post-hysteroscopy Duration of the Cook Balloon Uterine Stent Effect on the Re-adhesion Formation.

To compare duration of Cook balloon uterine stent on re-adhesions formation, and observe its effect on serum transforming growth factor β1 (TGF-β1) and plasminogen activator inhibitor-1 (PAI-1) levels in patients with intrauterine adhesions (IUA) undergoing hysteroscopic transcervical resection of adhesion (TCRA). Randomised controlled trial. No. 215 Hospital of Shaanxi Nuclear Industry, Shaanxi Province, China, from January 2018 to January 2019. A total of 98 patients with IUA, who underwent hysteroscopic TCRA with cold scissors, were randomly divided into Group A (n=49) and Group B (n=49). Cook balloon uterine stent was placed for 37 days in Group A and 7 days in Group B. Efficacy of two groups was compared. Total effective rate in Group A was higher than that in Group B (p=0.021). After treatment, levels of serum TGF-β1 and PAI-1 in Group A were lower than those in Group B (p <0.001, and p=0.001, respectively). Recurrence rate of IUA at three months after treatment and total incidence of complications in Group A were lower than those in Group B (p=0.012, and 0.037, respectively). Pregnancy rate in the 2-year follow-up period in Group A was higher than that in Group B (p= 0.043). Placement of Cook balloon uterine stent for 37 days after hysteroscopic TCRA in patients with IUA can effectively prevent postoperative intrauterine re-adhesion, have few complications, low recurrence rate of IUA and high re-pregnancy rate, and reduce levels of serum TGF-β1 and PAI-1. Key Words: Intrauterine adhesions (IUA), Transcervical resection of adhesion (TCRA), Transforming growth factor β1 (TGF-β1), Plasminogen activator inhibitor-1 (PAI-1), Pregnancy.

Application of Machine Learning to Assess Interindividual Variability in Rapid-Acting Insulin Responses After Subcutaneous Injection in People With Type 1 Diabetes

ObjectivesCirculating insulin concentrations mediate vascular-inflammatory and prothrombotic factors. However, it is unknown whether interindividual differences in circulating insulin levels are associated with different inflammatory and prothrombotic profiles in type 1 diabetes (T1D). We applied an unsupervised machine-learning approach to determine whether interindividual differences in rapid-acting insulin levels associate with parameters of vascular health in patients with T1D. MethodsWe re-analyzed baseline pretreatment meal-tolerance test data from 2 randomized controlled trials in which 32 patients consumed a mixed-macronutrient meal and self-administered a single dose of rapid-acting insulin individualized by carbohydrate counting. Postprandial serum insulin, tumour necrosis factor (TNF)-alpha, plasma fibrinogen, human tissue factor (HTF) activity and plasminogen activator inhibitor-1 (PAI-1) were measured. Two-step clustering categorized individuals based on shared clinical characteristics. For analyses, insulin pharmacokinetic summary statistics were normalized, allowing standardized intraindividual comparisons. ResultsDespite standardization of insulin dose, individuals exhibited marked interpersonal variability in peak insulin concentrations (48.63%), time to peak (64.95%) and insulin incremental area under the curve (60.34%). Two clusters were computed: cluster 1 (n=14), representing increased serum insulin concentrations; and cluster 2 (n=18), representing reduced serum insulin concentrations (cluster 1: 389.50±177.10 pmol/L/IU h−1; cluster 2: 164.29±41.91 pmol/L/IU h−1; p<0.001). Cluster 2 was characterized by increased levels of fibrinogen, PAI-1, TNF-alpha and HTF activity; higher glycated hemoglobin; increased body mass index; lower estimated glucose disposal rate (increased insulin resistance); older age; and longer diabetes duration (p<0.05 for all analyses). ConclusionsReduced serum insulin concentrations are associated with insulin resistance and a prothrombotic milieu in individuals with T1D, and therefore may be a marker of adverse vascular outcome.

Abstract P270: Covid19 Hypertension In Primary Care

One of the symptoms of Sars-cov-2 is hypertension with diastolic dysfunction. Out of 432 patients, 112 had hypertension and 102 of them had diastolic hypertension that helped identify early infection despite having a negative PCR test. Diastolic hypertension led to pulmonary edema. The use of spironolactone, an aldosterone antagonist selective diuretic, at a dose of 25-50mg po q d reduced the effects of hypertension and pulmonary edema in 94/112 of the treated patients. This treatment was added to the regimen the patient was on for previously diagnosed hypertension or initiated due to Sars-cov-2 infection causing hypertension. The key to this medication is in the renin aldosterone system. Uncontrolled aldosterone promotes myocardial fibrosis and is most likely why many people have long haul covid19 cardiac complications. Aldosterone also causes perivascular fibrosis, blocks the myocardial uptake of norepinephrine, and increases plasminogen activator inhibitor levels. In conjunction with angiotensin II, aldosterone causes vascular damage that sends coagulation signals to platelets, endothelial dysfunction, and decreased vascular compliance. Therefore, aldosterone management plays a major role in the development of both hypertension and heart failure in Sars-cov-2 and a key target for therapeutic interventions.

Association of Plasminogen Activator Inhibitor-1 and Cardiovascular Events Development in Patients with Prediabetes

Background. Plasminogen activator inhibitor-1(PAI-1) is a marker of endothelial dysfunction(ED) and a predictor of both the development of type 2 diabetes mellitus, and a cardiovascular event(CVE). Its role in the CVE development was sufficiently studied in patients without carbohydrate metabolism disorders, and understudied in patients with prediabetes.&#x0D; Aim: the research interest is the study of PAI-1 in patients with prediabetes and its effect on the CVE development.&#x0D; Materials and methods. The case-control study of 168 patients aged from 18 to 65 was carried out among the local population from January to December 2019.After clinical examination, patients were divided into 3 groups: group 1 (n=55)– patients with prediabetes and with CVE; group 2 (n=93) - patients with prediabetes and without CVE; the control group n=20.&#x0D; Results. Differences in PAI-1 level were found in groups 1 (Me=30718.6 pg/ml) and 2 (Me=24692.0 pg/ml; p≤0.001), even greater differences were found in both groups compared to the control one (p≤0.001).&#x0D; The correlation analysis has found in both group influence such IR indicators as fasting glucose, IR-HOMA index, glucagon, C-peptide to elevation of PAI-1. These findings indicate that with an elevation of the PAI-1 level, the concentration of fasting glucose, glucagon, C-peptide and scores of IR-HOMA index increase in both group.&#x0D; The Binary regression analysis has demonstrated, that an elevation of the PAI-1 biomarker increases the likelihood of CVE by 3.3 fold in patients with prediabetes (p≤0.01). In addition to, a model has been derived for assessing the risk of cardiovascular events in patients with prediabetes.&#x0D; Conclusions. Elevation of PAI-1 concentration is associated with insulin resistance which leads to ED, and further development risk of CVE in patients with prediabetes.

Mechanisms affecting brain remodeling in depression: do all roads lead to impaired fibrinolysis?

Fibrinolysis occurs when plasminogen activators, such as tissue plasminogen activator (tPA), convert plasminogen to plasmin, which dissolves the fibrin clot. The proteolytic activity of tPA and plasmin is not restricted to fibrin degradation. In the extravascular space, these two proteases modify a variety of substrates other than fibrin, playing a crucial role in physiological and pathological tissue remodeling. In the brain, for example, tPA and plasmin mediate the conversion of brain-derived neurotrophic factor precursor (proBDNF) to mature brain-derived neurotrophic factor precursor (BDNF). Thus, the fibrinolytic system influences processes reported to be dysfunctional in depression, including neurogenesis, synaptic plasticity, and reward processing. The hypothesis that decreased fibrinolytic activity is an important element in the pathogenesis of depression is supported by the association between depression and increased levels of plasminogen activator inhibitor (PAI)-1, the main inhibitor of tPA. Also, various biochemical markers of depression induce PAI-1 synthesis, including hypercortisolism, hyperinsulinemia, hyperleptinemia, increased levels of cytokines, and hyperhomocysteinemia. Moreover, hypofibrinolysis provides a link between depression and emotional eating, binge eating, vegetarianism, and veganism. This paper discusses the role of reduced fibrinolytic activity in the bidirectional interplay between depression and its somatic manifestations and complications. It also reviews evidence that abnormal fibrinolysis links heterogeneous conditions associated with treatment-resistant depression. Understanding the role of hypofibrinolysis in depression may open new avenues for its treatment.

More Pronounced Hypercoagulable State and Hypofibrinolysis in Patients With Cirrhosis With Versus Without HCC.

In patients with cirrhosis, particularly those with hepatocellular carcinoma (HCC), hypercoagulability may be associated with purported increased risks of portal vein thrombosis and cirrhosis progression. In this study, we extensively investigated hemostatic alterations potentially responsible for the thrombotic tendency in HCC, and evaluated whether such alterations were predictive of hepatic decompensation. Patients with cirrhosis at all stages were prospectively recruited and underwent an extensive hemostatic assessment, including all procoagulant factors and inhibitors, thrombin generation with and without thrombomodulin (TG), profibrinolytic and antifibrinolytic factors, and plasmin‐antiplasmin complex. In study part 1 (case control), we compared alterations of coagulation and fibrinolysis in patients with cirrhosis with versus without HCC. In study part 2 (prospective), the subgroup of patients with decompensated cirrhosis was followed for development of further decompensation, and predictors of outcome were assessed by multivariate analysis. One‐hundred patients were recruited (50 each with and without HCC). Severity of cirrhosis was comparable between groups. Median HCC volume was 9 cm3 (range: 5‐16). Compared with controls, patients with HCC demonstrated a significantly more prothrombotic hemostatic profile due to increased TG and reduced activation of fibrinolysis, independent of cirrhosis stage. During a median follow‐up of 175 days, 20 patients with decompensated cirrhosis developed further episodes of decompensation that were predicted by low FVII and high plasminogen activator inhibitor‐1 levels, independent of Model for End‐Stage Liver Disease score. Conclusion: Patients with cirrhosis with HCC have profound hyper‐coagulable changes that can account for their increased thrombotic tendency. In contrast, hypercoagulability in patients with decompensated cirrhosis is more likely a consequence of chronic liver disease rather than a driver for cirrhosis progression.

Longitudinal Assessment of Cytokine Expression and Plasminogen Activation in Hantavirus Cardiopulmonary Syndrome Reveals Immune Regulatory Dysfunction in End-Stage Disease.

Pathogenic New World orthohantaviruses cause hantavirus cardiopulmonary syndrome (HCPS), a severe immunopathogenic disease in humans manifested by pulmonary edema and respiratory distress, with case fatality rates approaching 40%. High levels of inflammatory mediators are present in the lungs and systemic circulation of HCPS patients. Previous studies have provided insights into the pathophysiology of HCPS. However, the longitudinal correlations of innate and adaptive immune responses and disease outcomes remain unresolved. This study analyzed serial immune responses in 13 HCPS cases due to Sin Nombre orthohantavirus (SNV), with 11 severe cases requiring extracorporeal membrane oxygenation (ECMO) treatment and two mild cases. We measured viral load, levels of various cytokines, urokinase plasminogen activator (uPA), and plasminogen activator inhibitor-1 (PAI-1). We found significantly elevated levels of proinflammatory cytokines and PAI-1 in five end-stage cases. There was no difference between the expression of active uPA in survivors’ and decedents’ cases. However, total uPA in decedents’ cases was significantly higher compared to survivors’. In some end-stage cases, uPA was refractory to PAI-1 inhibition as measured by zymography, where uPA and PAI-1 were strongly correlated to lymphocyte counts and IFN-γ. We also found bacterial co-infection influencing the etiology and outcome of immune response in two cases. Unsupervised Principal Component Analysis and hierarchical cluster analyses resolved separate waves of correlated immune mediators expressed in one case patient due to a sequential co-infection of bacteria and SNV. Overall, a robust proinflammatory immune response, characterized by an imbalance in T helper 17 (Th17) and regulatory T-cells (Treg) subsets, was correlated with dysregulated inflammation and mortality. Our sample size is small; however, the core differences correlated to survivors and end-stage HCPS are instructive.