scholarly journals Induction of soluble platelet activation markers and FXIII deficiency promote COVID-19 severity

2021 ◽  
Author(s):  
Abaher O. Al-Tamimi ◽  
Ayesha M. Yusuf ◽  
Manju N. Jayakumar ◽  
Abdul W. Ansari ◽  
Mona Elhassan ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Platelet Activation ◽  
Molecular Mechanisms ◽  
Plasminogen Activator Inhibitor ◽  
Cd40 Ligand ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activation Markers ◽  
Pathway Activation ◽  
Coagulation Dysfunction ◽  
Fxiii Deficiency

Coagulation dysfunction and thromboembolism emerge as strong comorbidity factors in severe COVID-19 patients. However, the underlying pathomechanisms are largely undefined. Here, we sought to identify the potential molecular mechanisms of SARS-CoV-2 mediated coagulopathy and thromboembolism. A broader investigation was conducted including hospitalized COVID-19 patients with (severe cases that required intensive care) or without pneumonia (moderate cases). Phenotypic and molecular characterizations were performed employing basic coagulation tests, flow cytometry-based multiplex assays, and ELISA. The investigations revealed induction of plasma P-selectin and CD40 ligand (sCD40L) in moderate COVID-19 cases which were significantly abolished with the progression of COVID-19 severity. Moreover, a profound reduction in plasma tissue factor pathway inhibitor (TFPI) and FXIII were identified particularly in the severe COVID-19. Further analysis revealed a profound induction of fibrinogen in both moderate and severe patients. Interestingly, an elevated plasminogen activator inhibitor-1 more prominently in moderate, and tissue plasminogen activator (tPA) particularly in severe COVID-19 cases were observed. Particularly, the levels of fibrinogen and tPA directly correlated with the severity of COVID-19. In summary, SARS-CoV-2 infection induces the levels of platelet activation markers soluble P-selectin and sCD40L in hospitalized COVID-19 patients. Furthermore, an attenuated level of TFPI indicates TF pathway activation and, acquired FXIII deficiency likely plays a key role in thrombus instability and promotes thromboembolism in severe cases. The progression of COVID-19 severity could be limited with anti-platelet in combination with recombinantTFPI treatment. Furthermore, thromboembolic events in severe COVID-19 patients could be minimized if treated with recombinantFXIII in combination with LMW heparin.

Abstract P357: Induction Of Soluble P-selectin And CD40 Ligand And, FXIII Deficiency Promote Aberrant Coagulation And Thromboembolism In Severe COVID-19

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Abaher O Al-Tamimi ◽  
Ayesha M Yusuf ◽  
Manju N Jayakumar ◽  
Abdul W Ansari ◽  
Mona Elhassan ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Platelet Activation ◽  
Molecular Mechanisms ◽  
Thrombus Formation ◽  
Plasminogen Activator Inhibitor ◽  
Cd40 Ligand ◽  
Control Group ◽  
Soluble P ◽  
D Dimer ◽  
Fxiii Deficiency

Coagulation dysfunction and thromboembolism emerge as strong comorbidity factors in severe COVID-19. However, the underlying pathomechanisms are largely undefined. Here, we sought to identify the potential underlying molecular mechanisms of SARS-CoV-2 mediated coagulopathy and thromboembolism. In this series, 30 hospitalized COVID-19 patients presenting elevated D-dimer with (severe cases that required intensive care) or without pneumonia (moderate cases) were included in the study. Patients with anticoagulant/ antiplatelet therapy or with a history of cardiovascular diseases were excluded. Phenotypic and molecular characterizations were carried out employing basic coagulation tests, flow cytometry-based multiplex assays, and ELISA. The findings revealed slightly higher prothrombin and activated partial thromboplastin times (aPTT) with normal platelet counts. Elevated levels of plasma P-selectin and CD40 ligand (CD40L), markers of platelet activation, were observed in the moderate COVID-19 cases which were significantly abolished with the progression of COVID-19 severity. Moreover, analysis of the coagulation pathways revealed comparable FIX, prothrombin, and anti-thrombin levels, and a significantly higher level of fibrinogen was observed in both the moderate and severe patients vs. control group. Interestingly, the levels of plasma tissue factor pathway inhibitor (TFPI) and FXIII, a regulator of stable thrombus formation, were significantly lower particularly in the severe COVID-19 cases. Moreover, a dysregulated fibrinolysis was indicated by elevated tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI), and D-dimer levels in COVID-19 cases. In summary, SARS-CoV-2 infection-mediated endothelial cell lining damage potentially enhances soluble P-selectin and CD40L levels inducing platelet activation. Furthermore, in severe COVID-19, a decreased level of TFPI possibly contributes to additional thrombin generation through activation of the TF pathway and provides positive feedback to platelet activation and thrombus formation. FXIII deficiency plays a key role in thrombus instability which most likely promotes thromboembolism in the severe COVID-19.

Genetic and environmental influences on the fibrinolytic system: a twin study

2004 ◽  
Vol 92 (08) ◽  
pp. 344-351 ◽  
Author(s):  
Anja Victor ◽  
Petra Adams ◽  
Hilde Erbes ◽  
Gerd Hafner ◽  
Karl Lackner ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Single Gene ◽  
Environmental Influences ◽  
Plasminogen Activator Inhibitor ◽  
Genetic Influence ◽  
Fibrinolytic System ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activation Markers ◽  
Interaction Terms ◽  
Pai 1

SummaryThe determination of heritability is a key issue to assess the predictive power of polymorphisms for disease in clinical studies. The aim of this study was to determine the heritability of proteins and activation markers of the fibrinolytic system in a large cohort of healthy twins. Heritability was calculated as 0.76 for thrombin activatable fibrinolysis inhibitor (TAFI), 0.44 for plasminogen activator inhibitor-1 (PAI-1), and 0.43 for tissue plasminogen activator. No significant genetic influence was observed for α2-antiplasmin-plasmin-complex and D-dimer. Heritability explained by single gene polymorphisms was 25.2% for TAFI 505G>A, 31.5% for 1542C>G, and 50.0% for combination of both. The influence on TAFI levels of 1542C>G (CC→GG, median: −280.5%) was considerably stronger than that of 505G>A (GG→AA, median: +49.3%) and in both cases there seems to be a dose-response relationship. Significant environmental influences on TAFI levels were observed for combined interaction terms (age*sex and bmi*sex). The PAI-1 4G/5G polymorphism explained 56.4% of the calculated heritability. The genetic variables accounting for the 43% heritability of tPA remain unknown. Our data show that the production of several key components of the fibrinolytic system is strongly genetically determined. This genetic influence is accounted for in large part but not completely by a limited number of polymorphisms within the respective genes associated with plasma levels of the gene products.

Can Biomarkers of Coagulation, Platelet Activation, and Inflammation Predict Venous Thromboembolism in Patients with Haematological Malignancies?

2019 ◽  
Vol 141 (4) ◽  
pp. 245-253 ◽  
Author(s):  
Shereef Elmoamly ◽  
Mervat Mattar ◽  
Maha F. Yacoub ◽  
Alaa Afif
Keyword(s):  
Venous Thromboembolism ◽  
Platelet Activation ◽  
Statistical Significance ◽  
Central Venous Access ◽  
Plasminogen Activator Inhibitor ◽  
Venous Access ◽  
Inflammatory Biomarkers ◽  
Haematological Malignancies ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activation Markers

Background: The incidence of venous thromboembolism (VTE) in haematological malignancies varies according to the type and grade of the disease and clinical variables, and there is a need to develop a tool to predict the occurrence of VTE in cancer patients at diagnosis to tailor prophylactic anticoagulation use during treatment. Objective: To study the incidence of VTE in haematological malignancies and clarify whether vascular and inflammatory biomarkers could be used as predictors of VTE in those patients. Methods: This was a prospective observational cohort study. Hypercoagulability and inflammatory biomarkers were assayed in a group of 171 patients with haematological malignancies at diagnosis. These markers included (1) coagulation and fibrinolysis activation markers (D-dimer, fibrinogen, antithrombin, plasminogen activator inhibitor 1), (2) endothelial and platelet activation markers (von Willebrand factor and soluble P-selectin), and (3) inflammatory markers (tumour necrosis factor αand interleukin 6). The end point was mortality or symptomatic VTE. Results/Conclusion: The incidence of symptomatic VTE was 7%. None of the tested biomarkers showed statistical significance as predictors for the occurrence of VTE in haematological malignancies. However, there were statistically significant associations between the occurrence of VTE and central venous access device insertion, the prothrombin time, and the erythrocyte sedimentation rate. An ESR above 106.5 mm/h is associated with increased VTE occurrence.

scholarly journals Prothrombotic markers and early spontaneous recanalization in ST-segment elevation myocardial infarction

2007 ◽  
Vol 98 (08) ◽  
pp. 420-426 ◽  
Author(s):  
Emilie Lanoy ◽  
Didier Tcheche ◽  
Laurent Feldman ◽  
Annie Bezeaud ◽  
Eduardo Anglès-Cano ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Plasminogen Activator ◽  
Platelet Activation ◽  
Plasminogen Activator Inhibitor ◽  
Platelet Glycoprotein ◽  
Activation Markers ◽  
St Segment Elevation ◽  
St Segment ◽  
Circulating Microparticles ◽  
The Difference

SummaryWe tested the hypothesis that selected prothrombotic biomarkers might be associated with early spontaneous coronary recanalization in patients with ST-segment elevation acute myocardial infarction (STEMI). We prospectively enrolled 123 patients with STEMI including 53 patients with spontaneous coronary recanalization (cases) and 70 patients with persistent occlusion (controls) at the time of emergent coronary angiography and before angioplasty. All had received aspirin and heparin. Blood samples were collected immediately before angioplasty to measure soluble P-selectin, circulating microparticles originating from platelets (PMPs), granulocytes (GMPs), endothelial cells (EMPs); tissue factor-associated MP (TF-MP); soluble platelet glycoprotein V (sGPV) and prothrombin F1+2; tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI-1) and plasmin-antiplasmin (PAP). A sub-group of 70 patients (35 cases, 35 controls) was available for flow cytometry analysis of platelet P-selectin and activated GPIIb-IIIa. Baseline clinical characteristics did not differ between groups except for more frequent hypertension and dyslipidemia in controls. Platelet activation markers and PMP did not differ between the two groups. Controls had higher numbers of EMPs and GMPs compared to cases, but the difference was no longer significant when corrected for risk factors. Controls differed from cases by higher plasma levels of sGPV [64 (47–84) ng/ml vs. 53 (44–63) ng/ml] and PAP [114(65–225) ng/ml vs. 88 (51–147) ng/ml].The difference persisted after adjustment for risks factors (p=0.031 and 0.037, respectively). Persistent occlusion of the infarct related artery is associated with some markers related to higher thrombin (sGPV) and plasmin (PAP) production but is not associated with markers of platelet activation.

scholarly journals Biomarkers of Inflammation, Thrombogenesis, and Collagen Turnover in Patients With Atrial Fibrillation

2018 ◽  
Vol 24 (5) ◽  
pp. 718-723 ◽  
Author(s):  
Sallu Jabati ◽  
Jawed Fareed ◽  
Jeffrey Liles ◽  
Abigail Otto ◽  
Debra Hoppensteadt ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Plasminogen Activator ◽  
Medical Center ◽  
Normal Population ◽  
Plasminogen Activator Inhibitor ◽  
Cd40 Ligand ◽  
Collagen Turnover ◽  
Plasminogen Activator Inhibitor 1 ◽  
Pai 1 ◽  
Procollagen Iii

The purpose of this study was to determine whether there are any differences in the levels of inflammatory, thrombotic, and collagen turnover biomarkers between individuals with atrial fibrillation (AF) and healthy volunteers. Circulating plasma levels of plasminogen activator inhibitor 1 (PAI-1), CD40-ligand (CD40-L), nucleosomes (which are indicators of cell death), C-reactive protein (CRP), procollagen III N-terminal propeptide (PIIINP), procollagen III C-terminal propeptide (PIIICP), procollagen I N-terminal propeptide, tissue plasminogen activator, and von Willebrand factor were analyzed as potential biomarkers of AF. Baseline plasma was collected from patients with AF prior to ablation surgery at Loyola University Medical Center. Individuals with AF had statistically significantly increased levels of PAI-1, CD40-L, and nucleosomes, when compared to the normal population ( P < .0001). Additionally, there was a statistically significant increase in the CRP ( P = .01), PIIINP ( P = .04), and PIIICP ( P = .0008) when compared to normal individuals. From this study, it is concluded that the prothrombotic, inflammatory, and collagen turnover biomarkers PAI-1, CD40-L, nucleosomes, CRP, PIIICP, and PIIINP are elevated in AF.

scholarly journals p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway

2007 ◽  
Vol 177 (6) ◽  
pp. 1119-1132 ◽  
Author(s):  
Benjamin D. Sachs ◽  
George S. Baillie ◽  
Julianne R. McCall ◽  
Melissa A. Passino ◽  
Christian Schachtrup ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Plasminogen Activator Inhibitor ◽  
Neurotrophin Receptor ◽  
Matrix Remodeling ◽  
P75 Neurotrophin Receptor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Pka Pathway

Clearance of fibrin through proteolytic degradation is a critical step of matrix remodeling that contributes to tissue repair in a variety of pathological conditions, such as stroke, atherosclerosis, and pulmonary disease. However, the molecular mechanisms that regulate fibrin deposition are not known. Here, we report that the p75 neurotrophin receptor (p75NTR), a TNF receptor superfamily member up-regulated after tissue injury, blocks fibrinolysis by down-regulating the serine protease, tissue plasminogen activator (tPA), and up-regulating plasminogen activator inhibitor-1 (PAI-1). We have discovered a new mechanism in which phosphodiesterase PDE4A4/5 interacts with p75NTR to enhance cAMP degradation. The p75NTR-dependent down-regulation of cAMP results in a decrease in extracellular proteolytic activity. This mechanism is supported in vivo in p75NTR-deficient mice, which show increased proteolysis after sciatic nerve injury and lung fibrosis. Our results reveal a novel pathogenic mechanism by which p75NTR regulates degradation of cAMP and perpetuates scar formation after injury.

943: Plasminogen Activator Inhibitor 1 (PAI-1) is Increased in Human Peyronie's Disease

2005 ◽  
Vol 173 (4S) ◽  
pp. 255-255 ◽  
Author(s):  
Hugo H. Davila ◽  
Thomas R. Magee ◽  
Freddy Zuniga ◽  
Jacob Rajfer ◽  
Nestor F. GonzalezCadavid
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Peyronie’S Disease ◽  
Plasminogen Activator Inhibitor 1 ◽  
Peyronie's Disease ◽  
Activator Inhibitor ◽  
Pai 1

Relationship of Plasminogen Activator Inhibitor-1 Levels following Thrombolytic Therapy with rt-PA as Compared to Streptokinase and Patency of Infarct Related Coronary Artery

1999 ◽  
Vol 82 (07) ◽  
pp. 104-108 ◽  
Author(s):  
Franck Paganelli ◽  
Marie Christine Alessi ◽  
Pierre Morange ◽  
Jean Michel Maixent ◽  
Samuel Lévy ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Thrombolytic Therapy ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Control Group ◽  
Plasminogen Activator Inhibitor 1 ◽  
Vessel Patency ◽  
Activator Inhibitor ◽  
Pai 1

Summary Background: Type 1 plasminogen activator inhibitor (PAI-1) is considered to be risk factor for acute myocardial infarction (AMI). A rebound of circulating PAI-1 has been reported after rt-PA administration. We investigated the relationships between PAI-1 levels before and after thrombolytic therapy with streptokinase (SK) as compared to rt-PA and the patency of infarct-related arteries. Methods and Results: Fifty five consecutive patients with acute MI were randomized to strep-tokinase or rt-PA. The plasma PAI-1 levels were studied before and serially within 24 h after thrombolytic administration. Vessel patency was assessed by an angiogram at 5 ± 1days. The PAI-1 levels increased significantly with both rt-PA and SK as shown by the levels obtained from a control group of 10 patients treated with coronary angioplasty alone. However, the area under the PAI-1 curve was significantly higher with SK than with rt-PA (p <0.01) and the plasma PAI-1 levels peaked later with SK than with rt-PA (18 h versus 3 h respectively). Conversely to PAI-1 levels on admission, the PAI-1 levels after thrombolysis were related to vessel patency. Plasma PAI-1 levels 6 and 18 h after SK therapy and the area under the PAI-1 curve were significantly higher in patients with occluded arteries (p <0.002, p <0.04 and p <0.05 respectively).The same tendency was observed in the t-PA group without reaching significance. Conclusions: This study showed that the PAI-1 level increase is more pronounced after SK treatment than after t-PA treatment. There is a relationship between increased PAI-1 levels after thrombolytic therapy and poor patency. Therapeutic approaches aimed at quenching PAI-1 activity after thrombolysis might be of interest to improve the efficacy of thrombolytic therapy for acute myocardial infarction.

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