Transcriptional Expression of Tissue Factor Pathway Inhibitor, Thrombomodulin and von Willebrand Factor in Normal Human Tissues

1999 ◽  
Vol 82 (09) ◽  
pp. 1047-1052 ◽  
Author(s):  
M. N. Kuppuswamy ◽  
A. N. Manepalli ◽  
S. P. Bajaj ◽  
M. S. Bajaj
Keyword(s):  
Skeletal Muscle ◽  
Tissue Factor ◽  
Von Willebrand Factor ◽  
Tissue Factor Pathway Inhibitor ◽  
Northern Blotting ◽  
Transcriptional Expression ◽  
Microvascular Endothelium ◽  
Tissue Factor Pathway ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryUnder normal physiologic conditions, tissue factor pathway inhibitor (TFPI) is synthesized primarily by the microvascular endothelium. Using Northern blotting, we studied its transcriptional expression in different organs and compared it with the expression of two other endothelial specific proteins, namely thrombomodulin (TM) and von Willebrand factor (vWF). The order of mRNA expression for each protein was: TFPI–placenta>lung>liver>kidney>heart>skeletal muscle≥pancreas>brain; TM–heart>pancreas>lung>skeletal muscle>kidney≥liver>placenta>brain; and vWF–heart>skeletal muscle>pancreas>lung≥kidney>placenta>brain>liver. Notably, heart expressed TM and vWF mRNA in large amounts and only small amounts of TFPI whereas lung expressed all three mRNAs in significant amounts. Placenta, on the contrary, expressed large amounts of TFPI but only small amounts of TM and vWF mRNAs. Brain by this technique was found to express undetectable amounts of TFPI and TM mRNAs but small amounts of vWF mRNA. The expression of TFPI mRNA in the brain was however detected by RT/PCR and the antigen was localized to the endothelium of microvessels as well as to the astrocytes and oligodendrocytes. Since ultimate expression of proteins is linked to the expression of their mRNAs, our data support a concept that vascular endothelium is made up of phenotypically diverse groups of cells and that endothelial cells of different vascular beds express specific sets of genes that enable them to carry out tissue-specific functions. Importantly, since astrocytes are known to express tissue factor, the TFPI expression by these cells may control coagulation in their microenvironment and their response to injury and inflammation.

scholarly journals Effects of Melatonin and Luzindole on Plasma Levels of Tissue Factor, Tissue Factor Pathway Inhibitor and Von Willebrand Factor in Rats

2015 ◽  
Vol 47 (1) ◽  
pp. 64
Author(s):  
Negrin Negrev ◽  
Yuri Nyagolov ◽  
Antoaneta Zarkova ◽  
Irina Ilieva Pashalieva ◽  
Emiliya Stancheva ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Von Willebrand Factor ◽  
Plasma Levels ◽  
Tissue Factor Pathway Inhibitor ◽  
Tissue Factor Pathway ◽  
Von Willebrand ◽  
Willebrand Factor

scholarly journals The Tissue Factor Pathway Inhibitor Antibody, PF-06741086, Increases Thrombin Generation in Rare Bleeding Disorder and Von Willebrand Factor Deficient Plasmas

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2462-2462 ◽  
Author(s):  
Swapnil Rakhe ◽  
Sunita R. Patel-Hett ◽  
Sheryl Bowley ◽  
John E. Murphy ◽  
Debra D Pittman
Keyword(s):  
Tissue Factor ◽  
Thrombin Generation ◽  
Tissue Factor Pathway Inhibitor ◽  
Coagulation Factor ◽  
Bleeding Disorders ◽  
Tissue Factor Pathway ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Donor Plasma

Abstract Hemophilia A and B are hereditary bleeding disorders that result from deficiencies in the intrinsic coagulation pathway leading to insufficient generation of Factor Xa (FXa) and thrombin to promote stable hemostasis. Coagulation defects are also observed in other inherited rare factor bleeding disorders. The extrinsic pathway of coagulation in these disorders cannot generate sufficient levels of FXa due to the regulation by Tissue Factor Pathway Inhibitor (TFPI). TFPI is a Kunitz-type serine protease inhibitor that negatively regulates thrombin generation by inhibiting the FXa/tissue factor (TF)/Factor VIIa (FVIIa) complex. PF-06741086, a fully human inhibitory monoclonal antibody, binds the Kunitz-2 domain and is currently under development as a potential prophylactic treatment to prevent bleeding episodes in hemophilia A and hemophilia B patients with and without inhibitors. The addition of PF-06741086 in vitro to donor plasma from both healthy normal volunteers and hemophilia patients promoted thrombin generation and restored hemostasis in vivo in murine hemophilia bleeding models. Pharmacological effects of PF-06741086 on thrombin generation were also observed in a healthy volunteer Phase 1 study. Other rare disease coagulopathies also result in the insufficient generation of thrombin. In this study, the potential of PF-06741086 to restore thrombin generation in rare disease plasma was explored. Thrombin generation was measured in citrated platelet poor Factor XI (FXI), Factor V (FV), FVII, von Willebrand Factor (vWF) deficient (Type 1, 2A, 2B and 3) congenital donor plasma following the in vitro addition of PF-06741086 (0, 1, 10 or 100 nM) or a human IgG1 antibody; initiated with 1 pM TF and 4 µM phospholipid. FXI, FV, and FVII donors had less than 1% coagulation factor activity. Non-hemophilic plasma from healthy donors alone was also included in the analysis. In FXI deficient plasmas, a concentration-dependent increase in peak thrombin and a shortening of the lag time was observed with the addition of PF-06741086 normalizing and restoring levels to those observed in the non-hemophilic plasma. A similar response was also observed in all of the vWF deficient plasmas. In one FVII deficient plasma, an increase in peak thrombin was observed at dose of 100 nM PF-06741086, however, the lag time (20 minutes) was significantly extended, relative to healthy volunteer non-hemophilic plasma. As expected, the addition of PF-06741086 to FV deficient plasma did not increase thrombin generation at any concentration. The in vitro addition of the TFPI antibody, PF-06741086, improved thrombin generation in selected coagulation factor deficient plasmas, including vWF deficiency, to the levels observed in normal plasma. This data suggestion that the inhibition of TFPI may promote hemostasis in rare bleeding disorders such as FXI deficiency and vWF deficiencies. Disclosures Rakhe: Pfizer: Employment. Patel-Hett:Pfizer: Employment. Bowley:Pfizer: Employment. Murphy:Pfizer: Employment. Pittman:Pfizer: Employment.

Tissue Factor Firmly Immobilized on Surfaces Promotes Platelet Adhesion and Fibrin Formation in Studies with Circulating Human Blood: Importance of Shear Rate Conditions and FVIIa.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3925-3925
Author(s):  
Raul Tonda ◽  
Irene Lopez-Vilchez ◽  
Ana M. Galan ◽  
Fulgencio Navalon ◽  
Marcos Pino ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Statistical Significance ◽  
Low Molecular Weight ◽  
Shear Rates ◽  
Fibrin Formation ◽  
Closure Time ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract While procoagulant activity of tissue factor (TF) has been widely investigated, its possible proadhesive properties towards platelets have not been studied in detail. We explored the interaction of platelets with human TF (hTF) firmly attached to a surface using anticoagulated blood with low molecular weight heparin (20 U/ml) at different shear rates. For studies at 250 s−1 and 600 s−1, TF adsorbed on a synthetic surface was exposed to circulating blood in flat perfusion devices. Deposition of platelets and fibrin formation were evaluated by morphometric, immunocytochemical and ultrastructural methods. For experiments at 5000 s−1, we used the PFA-100™ with experimental cartridges with collagen or collagen-hTF. Effect of rFVIIa was assessed in all experimental settings. Prothrombin fragment F1+2 levels were also measured. At 250 and 600 s−1 platelet interaction was 19.84±1.33% and 26.12±3.42% of the total surface respectively. Our inmunocytochemical results suggest that von Willebrand factor could mediate these interactions. Fibrin formation was significantly higher at 250 s−1 than at 600 s−1 (p<0.05). FVIIa tended to increase platelet deposition without reaching statistical significance, and raised fibrin formation and thrombin generation (p<0.05). Our At 5000 s−1, closure times in the PFA-100 were significantly shortened in the presence of hTF (154.09 ±14.69 s vs 191.45± 16.09 s with collagen alone; p<0.05). Addition of rFVIIa did not result in a further reduction of closure time. Our studies demonstrate that hTF is reactive for platelets. von Willebrand factor could mediate these interactions. Recombinant FVIIa enhances the procoagulant action of hTF at low and intermediate shear rates, but has no impact on the hemostatic performance at very elevated shear rates.

scholarly journals COVID-19 and Acute Coronary Syndromes: From Pathophysiology to Clinical Perspectives

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Luca Esposito ◽  
Francesco Paolo Cancro ◽  
Angelo Silverio ◽  
Marco Di Maio ◽  
Patrizia Iannece ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Tissue Factor ◽  
Von Willebrand Factor ◽  
Acute Coronary Syndromes ◽  
Oxygen Supply ◽  
Thrombus Formation ◽  
Cellular Damage ◽  
Coronary Syndromes ◽  
Von Willebrand ◽  
Willebrand Factor

Acute coronary syndromes (ACS) are frequently reported in patients with coronavirus disease 2019 (COVID-19) and may impact patient clinical course and mortality. Although the underlying pathogenesis remains unclear, several potential mechanisms have been hypothesized, including oxygen supply/demand imbalance, direct viral cellular damage, systemic inflammatory response with cytokine-mediated injury, microvascular thrombosis, and endothelial dysfunction. The severe hypoxic state, combined with other conditions frequently reported in COVID-19, namely sepsis, tachyarrhythmias, anemia, hypotension, and shock, can induce a myocardial damage due to the mismatch between oxygen supply and demand and results in type 2 myocardial infarction (MI). In addition, COVID-19 promotes atherosclerotic plaque instability and thrombus formation and may precipitate type 1 MI. Patients with severe disease often show decrease in platelets count, higher levels of d-dimer, ultralarge von Willebrand factor multimers, tissue factor, and prolongation of prothrombin time, which reflects a prothrombotic state. An endothelial dysfunction has been described as a consequence of the direct viral effects and of the hyperinflammatory environment. The expression of tissue factor, von Willebrand factor, thromboxane, and plasminogen activator inhibitor-1 promotes the prothrombotic status. In addition, endothelial cells generate superoxide anions, with enhanced local oxidative stress, and endothelin-1, which affects the vasodilator/vasoconstrictor balance and platelet aggregation. The optimal management of COVID-19 patients is a challenge both for logistic and clinical reasons. A deeper understanding of ACS pathophysiology may yield novel research insights and therapeutic perspectives in higher cardiovascular risk subjects with COVID-19.

A Comprehensive Study on Hemostasis in CAPD Patients Treated with Erythropoietin

2002 ◽  
Vol 22 (5) ◽  
pp. 582-592 ◽  
Author(s):  
Jolanta Malyszko ◽  
Ewa Suchowierska ◽  
Jacek S. Malyszko ◽  
Michal Mysliwiec
Keyword(s):  
Platelet Aggregation ◽  
Tissue Factor ◽  
Von Willebrand Factor ◽  
Factor Vii ◽  
Clot Lysis ◽  
Control Group ◽  
Primary Role ◽  
Baseline Values ◽  
Von Willebrand ◽  
Willebrand Factor

Objective Bleeding diathesis and simultaneous thrombotic complications may be seen in dialyzed patients. Erythropoietin (EPO) may shift the precarious balance of the hemostatic system toward thrombosis. Platelets and tissue factor (TF) play a major role in plug formation. Tissue factor pathway inhibitor (TFPI) appears to play a primary role in regulating TF-induced coagulation. Thrombin activatable fibrinolysis inhibitor (TAFI) is a key protein linking coagulation and fibrinolysis. The aim of the study was to assess whether 6 months of EPO therapy affects platelet function, that is, platelet aggregation and P-selectin level; moieties of the extrinsic coagulation pathway: TF, TFPI, and TFPI/Xa complexes, and factors VII and X; markers of ongoing coagulation: thrombin–antithrombin complexes (TAT) and prothrombin fragments 1+2; a marker of ongoing fibrinolysis: plasmin–antiplasmin complexes (PAP); fibrinolytic activity: euglobulin clot lysis time (ECLT); and markers of endothelial cell injury: von Willebrand factor, thrombomodulin, E-selectin, and TAFI, in continuous ambulatory peritoneal dialysis (CAPD) patients. Patients and Methods 22 patients on CAPD were given EPO 6000 U/week. 12 patients with chronic renal failure and 12 healthy volunteers served as control groups. All parameters were studied before, and after 1, 3, and 6 months of EPO therapy. Setting Department of Nephrology and Internal Medicine, Medical Academy of Bialystok, Poland. Results Platelet aggregation in whole blood did not change significantly during EPO treatment. A significant rise in arachidonic acid-induced platelet aggregation in platelet-rich plasma was observed after 3 and 6 months, and in collagen-induced platelet aggregation after 6 months of EPO therapy, compared to the baseline values. The TFPI concentration decreased significantly after 6 months of EPO therapy. The activity of factor VII increased transiently after 1 month of EPO therapy, compared to the baseline values. The TAFI concentration and activity in the CAPD group were significantly higher than in the control group. Erythropoietin therapy resulted in a significant decrease in TAFI concentration and activity after 6 months of EPO treatment. The ECLT was shortened significantly as early as after 1 month of EPO therapy. Thrombomodulin, von Willebrand factor concentration and activity, PAP, TAT, TFPI/Xa complexes, prothrombin fragments 1+2, factor X activity, P-selectin, E-selectin, and lipoprotein(a) did not change significantly during EPO treatment. Conclusion Erythropoietin treatment has a minimal effect on hemostasis in CAPD patients. A tendency toward a decline in TAFI is of unknown clinical relevance so far, and awaits further research.

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