Coagulation abnormalities in SARS-CoV-2 infection: overexpression tissue factor

AbstractAmong the pathways and mediators that may be dysregulated in COVID-19 infection, there are proinflammatory cytokines, lymphocyte apoptosis, and the coagulation cascade. Venous and arterial thromboembolisms also are frequent in COVID-19 patients with the increased risk of some life-threatening complications such as pulmonary embolism, myocardial infarction, and ischemic stroke. In this regard, overproduction of proinflammatory cytokines such as IL-6, IL-1β, and TNF-α induce cytokine storms, increase the risk of clot formation, platelet activation, and multiorgan failure that may eventually lead to death among these patients. Surface S protein of SARS-CoV-2 binds to its target transmembrane receptor, named as angiotensin converting enzyme 2 (ACE2(, on various cells such as lymphocyte, alveolar cells, monocytes/macrophages, and platelets. Notably, the activation of the coagulation cascade occurs through tissue factor (TF)/FVIIa-initiated hemostasis. Accordingly, TF plays the major role in the activation of coagulation system during viral infection. In viral infections, the related coagulopathy multiple factors such as inflammatory cytokines and viral specific TLRs are involved, which consequently induce TF expression aberrantly. SARS-COV-2 may directly infect monocytes/ macrophages. In addition, TF expression/release from these cells may play a critical role in the development of COVID-19 coagulopathy. In this regard, the use of TF- VIIa complex inhibitor may reduce the cytokine storm and mortality among COVID-19 patients.

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Imbalance in Coagulation/Fibrinolysis Inhibitors Resulting in Extravascular Thrombin Generation in Gliomas of Varying Levels of Malignancy

Biomolecules ◽

10.3390/biom11050663 ◽

2021 ◽

Vol 11 (5) ◽

pp. 663

Author(s):

Marek Z. Wojtukiewicz ◽

Marta Mysliwiec ◽

Elwira Matuszewska ◽

Stanislaw Sulkowski ◽

Lech Zimnoch ◽

...

Keyword(s):

Tissue Factor ◽

Blood Coagulation ◽

Tissue Factor Pathway Inhibitor ◽

Protein S ◽

Systemic Circulation ◽

Coagulation System ◽

Lower Grade ◽

Increased Risk ◽

Tissue Factor Pathway ◽

Pai 1

Neoplastic processes are integrally related to disturbances in the mechanisms regulating hemostatic processes. Brain tumors, including gliomas, are neoplasms associated with a significantly increased risk of thromboembolic complications, affecting 20–30% of patients. As gliomas proliferate, they cause damage to the brain tissue and vascular structures, which leads to the release of procoagulant factors into the systemic circulation, and hence systemic activation of the blood coagulation system. Hypercoagulability in cancer patients may be, at least in part, a result of the inadequate activity of coagulation inhibitors. The aim of the study was to evaluate the expression of the inhibitors of the coagulation and fibrinolysis systems (tissue factor pathway inhibitor, TFPI; tissue factor pathway inhibitor-2 TFPI-2; protein C, PC; protein S, PS, thrombomodulin, TM; plasminogen activators inhibitor, PAI-1) in gliomas of varying degrees of malignancy. Immunohistochemical studies were performed on 40 gliomas, namely on 13 lower-grade (G2) gliomas (8 astrocytomas, 5 oligodendrogliomas) and 27 high-grade gliomas (G3–12 anaplastic astrocytomas, 4 anaplastic oligodendrogliomas; G4–11 glioblastomas). A strong expression of TFPI-2, PS, TM, PAI-1 was observed in lower-grade gliomas, while an intensive color immunohistochemical (IHC) reaction for the presence of TFPI antigens was detected in higher-grade gliomas. The presence of PC antigens was found in all gliomas. Prothrombin fragment 1+2 was observed in lower- and higher-grade gliomas reflecting local activation of blood coagulation. Differences in the expression of coagulation/fibrinolysis inhibitors in the tissues of gliomas with varying degrees of malignancy may be indicative of their altered role in gliomas, going beyond that of their functions in the hemostatic system.

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Pharmacokinetics and Safety of Intravenous Cidofovir for Life-Threatening Viral Infections in Pediatric Hematopoietic Stem Cell Transplant Recipients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04348-14 ◽

2015 ◽

Vol 59 (7) ◽

pp. 3718-3725 ◽

Cited By ~ 26

Author(s):

Amy E. Caruso Brown ◽

Mindy N. Cohen ◽

Suhong Tong ◽

Rebecca S. Braverman ◽

James F. Rooney ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell ◽

Half Life ◽

Viral Infections ◽

Multiorgan Failure ◽

Kidney Injury ◽

Cell Transplant ◽

Open Label ◽

Hematopoietic Stem ◽

Life Threatening

ABSTRACTChildren undergoing hematopoietic stem cell transplantation (HSCT) are at risk for life-threatening viral infections. Cidofovir is often used as a first-line agent for adenovirus infections, despite the absence of randomized controlled trials with HSCT patients, and as a second-line agent for resistant herpesvirus infections. The frequency and severity of adverse effects, particularly nephrotoxicity, in pediatric HSCT recipients are unclear, and pharmacokinetics (PK) of cidofovir in children have not previously been reported. This study was an open-label, nonrandomized, single-dose pilot study to determine the safety and PK of cidofovir in pediatric HSCT recipients with symptomatic adenovirus, nucleoside-resistant cytomegalovirus (CMV) or herpes simplex virus (HSV), and/or human papovavirus infections. Subsequent dosing and frequency were determined by clinical response and side effects, as assessed by the treating physician. Blood and urine samples were obtained from patients for PK studies and assessment of toxicity and virologic response. Twelve patients were enrolled (median age, 9 years; 33.5 days posttransplantation). Four of seven patients with adenovirus infection were successfully treated and eventually cleared their infections. Four of twelve patients died of disseminated viral disease and multiorgan failure. Two of twelve patients had evidence of acute kidney injury after the first dose, and one of these patients developed chronic kidney disease; two other patients developed late nephrotoxicity. The mean drug half-life was 9.5 h. There was no correlation between nephrotoxicity and plasma maximum concentration, clearance, or half-life. PK were similar to those reported for adults, although the drug half-life was significantly longer than that for adults. Cidofovir was well tolerated in the majority of patients. However, effective therapeutic strategies are urgently needed to support patients until immune reconstitution is achieved.

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Glioblastoma cell populations with distinct oncogenic programs release podoplanin as procoagulant extracellular vesicles

Blood Advances ◽

10.1182/bloodadvances.2020002998 ◽

2021 ◽

Vol 5 (6) ◽

pp. 1682-1694

Author(s):

Nadim Tawil ◽

Rayhaan Bassawon ◽

Brian Meehan ◽

Ali Nehme ◽

Laura Montermini ◽

...

Keyword(s):

Cancer Cells ◽

Tissue Factor ◽

Extracellular Vesicles ◽

Coagulation System ◽

Platelet Factor ◽

Increased Risk ◽

Cell Subpopulations ◽

Cancer Associated Thrombosis

Abstract Vascular anomalies, including local and peripheral thrombosis, are a hallmark of glioblastoma (GBM) and an aftermath of deregulation of the cancer cell genome and epigenome. Although the molecular effectors of these changes are poorly understood, the upregulation of podoplanin (PDPN) by cancer cells has recently been linked to an increased risk for venous thromboembolism (VTE) in GBM patients. Therefore, regulation of this platelet-activating protein by transforming events in cancer cells is of considerable interest. We used single-cell and bulk transcriptome data mining, as well as cellular and xenograft models in mice, to analyze the nature of cells expressing PDPN, as well as their impact on the activation of the coagulation system and platelets. We report that PDPN is expressed by distinct (mesenchymal) GBM cell subpopulations and downregulated by oncogenic mutations of EGFR and IDH1 genes, along with changes in chromatin modifications (enhancer of zeste homolog 2) and DNA methylation. Glioma cells exteriorize their PDPN and/or tissue factor (TF) as cargo of exosome-like extracellular vesicles (EVs) shed from cells in vitro and in vivo. Injection of glioma-derived podoplanin carrying extracelluar vesicles (PDPN-EVs) activates platelets, whereas tissue factor carrying extracellular vesicles (TF-EVs) activate the clotting cascade. Similarly, an increase in platelet activation (platelet factor 4) or coagulation (D-dimer) markers occurs in mice harboring the corresponding glioma xenografts expressing PDPN or TF, respectively. Coexpression of PDPN and TF by GBM cells cooperatively affects tumor microthrombosis. Thus, in GBM, distinct cellular subsets drive multiple facets of cancer-associated thrombosis and may represent targets for phenotype- and cell type–based diagnosis and antithrombotic intervention.

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QTY Code-designed Water-soluble Fc-fusion Cytokine Receptors Bind to their Respective Ligands

QRB Discovery ◽

10.1017/qrd.2020.4 ◽

2020 ◽

Vol 1 ◽

Cited By ~ 2

Author(s):

Shilei Hao ◽

David Jin ◽

Shuguang Zhang ◽

Rui Qing

Keyword(s):

Chemokine Receptors ◽

Protein Modification ◽

Viral Infections ◽

Critical Role ◽

Water Soluble ◽

Cytokine Receptors ◽

Interleukin Receptors ◽

Physiological Properties ◽

Life Threatening ◽

Hydrophobic Amino Acids

AbstractCytokine release syndrome (CRS), or ‘cytokine storm’, is the leading side effect during chimeric antigen receptor (CAR)-T therapy that is potentially life-threatening. It also plays a critical role in viral infections such as Coronavirus Disease 2019 (COVID-19). Therefore, efficient removal of excessive cytokines is essential for treatment. We previously reported a novel protein modification tool called the QTY code, through which hydrophobic amino acids Leu, Ile, Val and Phe are replaced by Gln (Q), Thr (T) and Tyr (Y). Thus, the functional detergent-free equivalents of membrane proteins can be designed. Here, we report the application of the QTY code on six variants of cytokine receptors, including interleukin receptors IL4Rα and IL10Rα, chemokine receptors CCR9 and CXCR2, as well as interferon receptors IFNγR1 and IFNλR1. QTY-variant cytokine receptors exhibit physiological properties similar to those of native receptors without the presence of hydrophobic segments. The receptors were fused to the Fc region of immunoglobulin G (IgG) protein to form an antibody-like structure. These QTY code-designed Fc-fusion receptors were expressed in Escherichia coli and purified. The resulting water-soluble fusion receptors bind to their respective ligands with Kd values affinity similar to isolated native receptors. Our cytokine receptor–Fc-fusion proteins potentially serve as an antibody-like decoy to dampen the excessive cytokine levels associated with CRS and COVID-19 infection.

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Monocyte Tissue Factor Expression Is Enhanced in Women who Smoke and Use Oral Contraceptives

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614888 ◽

1999 ◽

Vol 82 (12) ◽

pp. 1614-1620 ◽

Cited By ~ 20

Author(s):

Helma-Meta Terhalle ◽

Ute Zakel ◽

Ulrich Maus ◽

Behnoush Parviz ◽

Harald Tillmanns ◽

...

Keyword(s):

Tissue Factor ◽

Oral Contraceptives ◽

Transcriptional Activation ◽

Contraceptive Use ◽

Coagulation Cascade ◽

Blood Monocytes ◽

Inhibitor Molecule ◽

Increased Risk ◽

Menopausal Women ◽

Tf Gene

SummaryThe association between use of oral contraceptives (OCs) and increased risk of thromboembolic disease has been firmly established. This risk increases when use of OCs is combined with cigarette smoking. The cellular mechanism favoring an hypercoagulable state under these behaviours is not known. Circulating monocytes are potent activators of the coagulation cascade through their ability to synthesize procoagulant tissue factor (TF). In the present study we report that monocyte TF expression is increased in women who use OCs and smoke.We studied monocyte TF expression in 4 groups of healthy pre-menopausal women (n = 15 each): (1) non-smoking OC non-users, (2) nonsmoking current OC users, (3) smoking OC non-users and (4) smoking OC users. TF expression was assessed on both mRNA and protein levels in unstimulated and LPS-stimulated cells. Transcriptional activation of the TF gene was assessed by analysis of the transcription factor NF-κB and its inhibitor molecule IκBα. Monocyte TF generation was significantly higher in OC users than in women who did not use OCs. Enhanced monocyte TF generation was also observed in smoking women when compared to non-smokers. Strongest monocyte TF expression occurred in women with combined smoking and use of OCs. The enhanced TF expression in monocytes from women using OCs or smoking was based on an increased TF gene transcription following activation of NF-κB. Experiments on cultured monocytes/macrophages demonstrated enhanced IκBα degradation in the presence of estradiol, suggesting that a direct hormone effect is responsible for the observed increase in monocyte TF expression.This study demonstrates that use of OCs and smoking is associated with an increase in monocyte TF expression in pre-menopausal women. Aberrant TF expression by blood monocytes may favour intravascular clotting activation in women with OC therapy. The further enhancement of TF activity observed in women who smoke and use OCs may explain the synergistic effect of smoking on risk of thromboembolic events associated with contraceptive use.

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Should We Replace the Terms Intrinsic and Extrinsic Coagulation Pathways With Tissue Factor Pathway?

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029616673733 ◽

2016 ◽

Vol 23 (8) ◽

pp. 922-927 ◽

Cited By ~ 5

Author(s):

Jan F. Vojacek

Keyword(s):

Tissue Factor ◽

Coagulation Cascade ◽

Coagulation System ◽

Bleeding Complications ◽

Antithrombotic Agents ◽

Risk Of Bleeding ◽

Tissue Factor Pathway ◽

The Common ◽

Coagulation Pathway

Present review highlights some new aspects of the role of individual components of blood coagulation process and proposes a modified concept of hemocoagulation cascade. The role of FXII in the initiation of the so-called intrinsic coagulation system is currently questioned. Its role has been recently demonstrated mainly in the thrombus propagation and final stabilization together with factors XI and XIII. The edited concept underlines the common part of the tissue factor (TF) in the initiation of both the intrinsic and extrinsic pathways of the coagulation system and therefore may make it not improperly be called the TF coagulation pathway. The search for new antithrombotic agents shows that the level of the coagulation system blockade depends on which step in the coagulation cascade is targeted and results in different degrees of the antithrombotic efficiency and the risk of bleeding complications.

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First Reported Case of Hemopericardium Related to Dabigatran Use Reversed by New Antidote Idarucizumab

Case Reports in Cardiology ◽

10.1155/2017/6458636 ◽

2017 ◽

Vol 2017 ◽

pp. 1-3 ◽

Cited By ~ 2

Author(s):

Steven Song ◽

Joselle Cook ◽

Clive Goulbourne ◽

Matthew Meade ◽

Louis Salciccioli ◽

...

Keyword(s):

Paradigm Shift ◽

Multiorgan Failure ◽

Nonvalvular Atrial Fibrillation ◽

Reversal Agent ◽

Reversal Agents ◽

Risk Of Bleeding ◽

Increased Risk ◽

Novel Oral Anticoagulant ◽

Hemorrhagic Events ◽

Life Threatening

Dabigatran, the first novel oral anticoagulant (NOAC) with a reversal agent, heralded a paradigm shift in the treatment of nonvalvular atrial fibrillation. The potential for life-threatening hemorrhagic events with the use of NOACs has been highly debated since the effectiveness of reversal agents such as idarucizumab is based primarily on pharmacologic data. It is known that cancer patients are at an increased risk of bleeding with anticoagulation, though specific studies demonstrating the risks or efficacy of NOACs in this population are lacking. We provide the first report of hemopericardium resulting in multiorgan failure related to dabigatran use that was successfully reversed by idarucizumab in a man with prostate cancer on chemotherapy.

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Tissue Factor: A Critical Role in Inflammation and Cancer

Biological Research For Nursing ◽

10.1177/1099800407305733 ◽

2007 ◽

Vol 9 (2) ◽

pp. 97-107 ◽

Cited By ~ 16

Author(s):

Bashir A. Lwaleed ◽

Alan J. Cooper ◽

David Voegeli ◽

Kathryn Getliffe

Keyword(s):

Tissue Factor ◽

Vascular Endothelium ◽

Critical Role ◽

Vascular Diseases ◽

The Body ◽

Coagulation Cascade ◽

Enzymatic Reactions ◽

Blood Proteins ◽

Disease States ◽

Enzyme Cascade

A series of coordinated enzymatic reactions takes place in the body whenever blood clots. The major physiological initiator of these reactions is a membrane-bound glycoprotein known as tissue factor (TF), which is normally separated from the bloodstream by the vascular endothelium. Bleeding, caused by injury or tissue damage, activates a complex enzyme cascade as TF becomes exposed to the bloodstream. In disease states, leukocytes or the vascular endothelium may abnormally express TF to cause intravascular coagulation. The blood-coagulation cascade is also relevant to diseases such as hemophilia, in which patients are deficient in blood proteins necessary for clotting, and is linked to vascular diseases such as heart attack and stroke, in which clotting can lead to the occlusion of blood vessels. Coagulation is also activated in inflammation and cancer. In this article, we discuss characteristics of TF and review its role in inflammation and cancer.

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When Manual Analysis of 12-Lead ECG Holter Plays a Critical Role in Discovering Unknown Patterns of Increased Arrhythmogenic Risk: A Case Report of a Patient Treated with Tamoxifen and Subsequent Pneumonia in COVID-19

Cardiovascular Toxicology ◽

10.1007/s12012-021-09659-w ◽

2021 ◽

Author(s):

Donatella Brisinda ◽

Barbara Merico ◽

Peter Fenici ◽

Riccardo Fenici

Keyword(s):

Ventricular Myocytes ◽

Therapeutic Option ◽

Critical Role ◽

Holter Monitoring ◽

Ventricular Repolarization ◽

Cancer Therapies ◽

Qtc Interval ◽

Increased Risk ◽

Repolarization Reserve ◽

Life Threatening

AbstractSeveral medicines, including cancer therapies, are known to alter the electrophysiological function of ventricular myocytes resulting in abnormal prolongation and dispersion of ventricular repolarization (quantified by multi-lead QTc measurement). This effect could be amplified by other concomitant factors (e.g., combination with other drugs affecting the QT, and/or electrolyte abnormalities, such as especially hypokalemia, hypomagnesaemia, and hypocalcemia). Usually, this condition results in higher risk of torsade de point and other life-threatening arrhythmias, related to unrecognized unpaired cardiac ventricular repolarization reserve (VRR). Being VRR a dynamic phenomenon, QT prolongation might often not be identified during the 10-s standard 12-lead ECG recording at rest, leaving the patient at increased risk for life-threatening event. We report the case of a 49-year woman, undergoing tamoxifen therapy for breast cancer, which alteration of ventricular repolarization reserve, persisting also after correction of concomitant recurrent hypokalemia, was evidenced only after manual measurements of the corrected QT (QTc) interval from selected intervals of the 12-lead ECG Holter monitoring. This otherwise missed finding was fundamental to drive the discontinuation of tamoxifen, shifting to another “safer” therapeutic option, and to avoid the use of potentially arrhythmogenic antibiotics when treating a bilateral pneumonia in recent COVID-19.

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A Novel Tail-Associated O91-Specific Polysaccharide Depolymerase from a Podophage Reveals Lytic Efficacy of Shiga Toxin-Producing Escherichia coli

Applied and Environmental Microbiology ◽

10.1128/aem.00145-20 ◽

2020 ◽

Vol 86 (9) ◽

Cited By ~ 2

Author(s):

Yibao Chen ◽

Xiangmin Li ◽

Shuang Wang ◽

Lingyu Guan ◽

Xinxin Li ◽

...

Keyword(s):

Escherichia Coli ◽

Hemolytic Uremic Syndrome ◽

Proinflammatory Cytokines ◽

Shiga Toxin ◽

Hemorrhagic Colitis ◽

Content Type ◽

Increased Risk ◽

Specific Polysaccharide ◽

Life Threatening ◽

Uremic Syndrome

ABSTRACT Shiga toxin-producing Escherichia coli (STEC) strains are important zoonotic foodborne pathogens, causing diarrhea, hemorrhagic colitis, and life-threatening hemolytic uremic syndrome (HUS) in humans. However, antibiotic treatment of STEC infection is associated with an increased risk of HUS. Therefore, there is an urgent need for early and effective therapeutic strategies. Here, we isolated lytic T7-like STEC phage PHB19 and identified a novel O91-specific polysaccharide depolymerase (Dep6) in the C terminus of the PHB19 tailspike protein. Dep6 exhibited strong hydrolase activity across wide ranges of pH (pH 4 to 8) and temperature (20 to 60°C) and degraded polysaccharides on the surface of STEC strain HB10. In addition, both Dep6 and PHB19 degraded biofilms formed by STEC strain HB10. In a mouse STEC infection model, delayed Dep6 treatment (3 h postinfection) resulted in only 33% survival, compared with 83% survival when mice were treated simultaneously with infection. In comparison, pretreatment with Dep6 led to 100% survival compared with that of the control group. Surprisingly, a single PHB19 treatment resulted in 100% survival in all three treatment protocols. Moreover, a significant reduction in the levels of proinflammatory cytokines was observed at 24 h postinfection in Dep6- or PHB19-treated mice. These results demonstrated that Dep6 or PHB19 might be used as a potential therapeutic agent to prevent STEC infection. IMPORTANCE Shiga toxin-producing Escherichia coli (STEC) is an important foodborne pathogen worldwide. The Shiga-like toxin causes diarrhea, hemorrhagic colitis, and life-threatening hemolytic uremic syndrome (HUS) in humans. Although antibiotic therapy is still used for STEC infections, this approach may increase the risk of HUS. Phages or phage-derived depolymerases have been used to treat bacterial infections in animals and humans, as in the case of the “San Diego patient” treated with a phage cocktail. Here, we showed that phage PHB19 and its O91-specific polysaccharide depolymerase Dep6 degraded STEC biofilms and stripped the lipopolysaccharide (LPS) from STEC strain HB10, which was subsequently killed by serum complement in vitro. In a mouse model, PHB19 and Dep6 protected against STEC infection and caused a significant reduction in the levels of proinflammatory cytokines. This study reports the use of an O91-specific polysaccharide depolymerase for the treatment of STEC infection in mice.

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