scholarly journals Impact of Tissue Factor Localization on Blood Clot Structure and Resistance under Venous Shear

2018 ◽  
Vol 114 (4) ◽  
pp. 978-991 ◽  
Author(s):  
Vijay Govindarajan ◽  
Shu Zhu ◽  
Ruizhi Li ◽  
Yichen Lu ◽  
Scott L. Diamond ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Blood Clot ◽  
Clot Structure

scholarly journals Dusart syndrome: a new concept of the relationship between fibrin clot architecture and fibrin clot degradability: hypofibrinolysis related to an abnormal clot structure

Blood ◽  
1993 ◽  
Vol 82 (8) ◽  
pp. 2462-2469 ◽  
Author(s):  
JP Collet ◽  
J Soria ◽  
M Mirshahi ◽  
M Hirsch ◽  
FB Dagonnet ◽  
...  
Keyword(s):  
Blood Clot ◽  
Fibrin Clot ◽  
Important Change ◽  
High Incidence ◽  
Gel Porosity ◽  
Clot Structure ◽  
The Relationship ◽  
Dose Dependent ◽  
Thrombotic Disorder

Fibrinogen Dusart is a congenital dysfibrinogenemia (A-alpha 554 Arginine-->Cysteine) associated with severe thrombotic disorder, high incidence of thrombotic embolism, and abnormal fibrin polymerization. This thrombotic disorder was attributed to an abnormal clot thrombolysis with reduced plasminogen binding to fibrin and defective plasminogen activation by tissue plasminogen activator. The purpose of this work was to assess whether clot architecture could be involved in the thromboresistance of the fibrin Dusart and the high incidence of embolism. An important change in Dusart fibrin clot structure was identified with dramatic decrease of gel porosity (Ks), fiber diameters (d), and fiber mass-length ratios (mu) derived from permeation analysis. In addition, rigidity of the Dusart clot was found to be greatly increased compared with normal fibrin. We provide evidence that both thrombolysis resistance and abnormal rigidity of the fibrin Dusart are related to this abnormal architecture, which impairs the access of fibrinolytic enzymes to the fibrin and which is responsible for a brittle clot that breaks easily, resulting in a high incidence of embolism. Indeed, when restoring a normal clot structure by adding dextran 40 (30 mg/mL) before coagulation, clot thrombolysis and clot rigidity recovered normal values. This effect was found to be dose- dependent. We conclude that clot architecture is crucial for the propensity of blood clot to be degraded and that abnormal clot structure can be highly thrombogenic in vivo. The alpha-C domains of fibrinogen are determinant in fibrin clot structure.

scholarly journals Understanding the Dynamics of Full-Length Tissue Factor (TF1-263) in the Context of Allosteric Modulation of Factor VIIa : A Molecular Dynamics Simulation Approach

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4949-4949
Author(s):  
Ramesh Prasad ◽  
Prosenjit Sen
Keyword(s):  
Endothelial Cell ◽  
Tissue Factor ◽  
Vascular Injury ◽  
Blood Clot ◽  
Allosteric Modulation ◽  
Full Length ◽  
Dynamics Simulation ◽  
Factor Vii ◽  
Dynamic Changes ◽  
Structural Modulation

Abstract Tissue factor (TF) mediated blood clot is the key event in cellular physiology. During vascular injury or endothelial cell rupture, factor VII (FVII) which is present normally in flowing blood as zymogenic form, upon binding with its cofactor TF (present beneath endothelial cell), get converted into its activated form, FVIIa; makes TF-FVIIa protease complex for the conversion of downstream protease members into activated form. Upon successful transformation of FX to FXa, prothrombin to thrombin, soluble fibrinogen get converted into its insoluble form fibrin, which accumulates at the site of vascular injury in the presence of platelets, resulting into the blood clot. Recent studies have shown that TF is solely responsible for the structural modulation of FVIIa. However, due to lack of well-resolved crystal structure of the zymogenic form of FVII and full-length TF-FVIIa binary complex, the actual allosteric mechanism induced by TF and structural changes observed in FVIIa is not fully understood at atomic resolution. Molecular dynamic simulation is the only way to visual the potential interaction between protein-protein and protein-lipid at atomistic resolution. Here we did the simulation of complex and free FVIIa to understand the causative effect of TF in terms of allosteric modulation occurred in FVIIa. The present study was carried out to investigate the domain-wise structural modulation of FVIIa in the presence of full-length TF. We have done the comparative study among full-length (FL) TF1-263-FVIIa, sTF1-219-FVIIa and free FVIIa. Measurements of intrinsic dynamic changes clearly suggest that TF not only made changes in the allosteric modulation of FVIIa but inter as well intradomain communication made between FLTF and FVIIa is also responsible for the structural modulation in the protease domain of FVIIa. Among interdomain communication, two interactions between EGF2 domain and FLTF (Glu94-Ser47 and Asp104-Thr51) guide the potential effect of TF in the structural modulation of FVIIa. Examining the catalytic triad localization reveals that single as well as double interaction regulates the dynamism of protease part in substrate recognition and substrate catalysis, however in the case of no interaction the movement of CT is much higher and in a wide range. In a case of sTF-FVIIa complex, few inter-domain communications ware missing, which causes reduced affinity of sTF towards FVIIa and thus sTF-FVIIa shows less activity compare to FLTF. We proposed the hypothesis that binding of FLTF not only changes the allosteric alteration of SP domain but also induces the structural alteration in each domain of FVIIa, and these alterations in combination contribute to the enhancement of FLTF-FVIIa activity in which two interactions may be the controller for such dynamic changes in FVIIa. In summary, our study provides valuable information to understand the blood coagulation more intrinsically. Disclosures No relevant conflicts of interest to declare.

The Pleiotropic Effects of Tissue Factor: a Possible Role for Factor VIIa-induced Intracellular Signalling?

2001 ◽  
Vol 86 (12) ◽  
pp. 1353-1359 ◽  
Author(s):  
Maikel Peppelenbosch ◽  
Arnold Spek ◽  
Henri Versteeg
Keyword(s):  
Tissue Factor ◽  
Map Kinases ◽  
Factor Viia ◽  
Blood Clot ◽  
Calcium Signalling ◽  
Small Gtpases ◽  
Pleiotropic Effects ◽  
Intracellular Signalling ◽  
Coagulation Cascade ◽  
Extrinsic Pathway

SummaryTissue factor, a 47 kDa membrane glycoprotein, lies at the basis of the extrinsic pathway of the coagulation cascade. Interaction of TF with factor VIIa results in the formation of fibrin from fibrinogen, thereby inducing the formation of a blood clot. In addition to this well-established role in blood coagulation, TF is associated with various other physiological processes such as sepsis, inflammation, angiogenesis, metastasis and atherosclerosis. The molecular basis of the latter events is slowly emerging. It has become clear that TF-FVIIa interaction elicits a variety of intracellular signalling events that may be implicated in these actions. These events include the sequential activation of Src-like kinases, MAP kinases, small GTPases and calcium signalling. How this progress in the understanding of TF associated signal transduction may generate answers as to the mechanism through which TF exerts it pleiotropic effects will be focus of this review.

Blood Clot Contraction (Retraction) Is Impaired in Acute Ischemic Stroke

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4998-4998 ◽  
Author(s):  
Valerie Tutwiler ◽  
Alina Peshkova ◽  
Dina Khasanova ◽  
John W. Weisel ◽  
Rustem I. Litvinov
Keyword(s):  
Platelet Count ◽  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Tissue Factor ◽  
Healthy Subjects ◽  
Blood Clot ◽  
Severe Stroke ◽  
Clot Contraction

Abstract Obstructive thrombi or thrombotic emboli of cerebral arteries are the pathogenic basis of ischemic stroke, which is a leading cause of death and disability worldwide. Blood clots undergo volume shrinkage due to the contractile forces that are generated by platelets and propagated through the clot volume due to platelet-fibrin interactions and elasticity of the fibrin network. This process is designed clot contraction (retraction) which remains one of the least studied steps of blood clotting. Importantly, this phenomenon has been shown to occur not only in vitro but also in in vivo thrombi. Clot contraction has been shown to be important in the volume reduction of otherwise obstructive thrombi and has the potential to reduce occlusion and restore blood flow past emboli or thrombi. Despite the potential medical significance of clot contraction, it has not been examined systemically in a clinical setting. This aim of this work was to examine the potential pathogenic role of clot contraction in ischemic stroke. Here we employed a novel automated method to quantify the time of initiation, extent and rate of clot contraction in vitro to compare clot contraction in the blood of healthy subjects with patients suffering a recent ischemic stroke (<6 hours from the onset of symptoms) who had not yet received any treatment with anticoagulants, antiplatelet drugs or thrombolytics.. Parameters of clot contraction were correlated with the severity and etiological types of stroke as well as with hematological, coagulation, and biochemical tests to examine the clinical significance of clot contraction. The main finding of this work is that clot contraction in blood from patients with acute ischemic stroke is reduced on average by ~60% (p<0.0001) when compared to that of healthy subjects. The reduction in clot contraction is correlated with a lower platelet count and platelet dysfunction, higher fibrinogen level, higher hematocrit, leukocytosis as well as other changes in the blood composition of patients with ischemic stroke that may alter the properties of the blood clot. We propose that these changes in the composition of the blood contribute to the impaired mechanism of clot contraction, which may exaggerate vessel occlusion and brain infarct. While stroke severity is determined mainly by the diameter and location of the obstructed cerebral artery, the ability of the thrombi to contract more or less may augment or ease the course of brain damage. Clinical correlations with respect to severity and stroke etiology indicate that reduced clot contraction has the potential to be a pathogenic factor in ischemic stroke. Paradoxically, the extent of clot contraction marginally improved in patients with a more severe stroke (NIHSS>15 vs. NIHSS<15, p<0.01), while it was still significantly reduced compared to healthy subjects. This finding can be presumably explained by the fact that in severe brain damage a massive amount of tissue factor is released into the systemic circulation, which can induce the activation of blood coagulation. We propose that this release of tissue factor results in a secondary wave of thrombin generation that causes patients with more severe stroke to have hyperactivity of platelets. In combination with a higher platelet count (p<0.01) this can enhance contraction of obstructive clots or thrombi, which may be a compensatory mechanism resulting in the recanalization of an otherwise occluded blood vessel. In support of this hypothetical scenario, it was also found that patients with atherothrombotic strokes have an increased extent of clot contraction compared to patients with cardioembolic stroke (p<0.05), and atherothrombotic patients are reported to have increased tissue factor as a consequence of atherosclerotic lesions. In summary, the clinical pathophysiological importance of clot contraction in a thrombotic state has been examined for the first time and the modulation of the ability of clots or thrombi to shrink in volume may be a novel and unappreciated mechanism that aggravates or alleviates the course and outcomes of thrombosis, such as ischemic stroke. The clinical importance of clot or thrombus remodeling in vivo as well as the diagnostic and prognostic value of this blood test for clot contraction needs further exploration. Disclosures Weisel: Bayer: Research Funding.

Clot properties and cardiovascular disease

2014 ◽  
Vol 112 (11) ◽  
pp. 901-908 ◽  
Author(s):  
Katherine Bridge ◽  
Helen Philippou ◽  
Robert Ariëns
Keyword(s):  
Cardiovascular Disease ◽  
Blood Clot ◽  
Fibrin Clot ◽  
Disease States ◽  
Inflammatory Conditions ◽  
Number Of Factors ◽  
Venous Diseases ◽  
Cardiovascular Medications ◽  
Clot Structure

SummaryFibrinogen is cleaved by thrombin to fibrin, which provides the blood clot with its essential structural backbone. As an acute phase protein, the plasma levels of fibrinogen are increased in response to inflammatory conditions. In addition to fibrinogen levels, fibrin clot structure is altered by a number of factors. These include thrombin levels, treatment with common cardiovascular medications, such as aspirin, anticoagulants, statins and fibrates, as well as metabolic disease states such as diabetes mellitus and hyperhomocysteinaemia. In vitro studies of fibrin clot structure can provide information regarding fibre density, clot porosity, the mechanical strength of fibres and fibrinolysis. A change in fibrin clot structure, to a denser clot with smaller pores which is more resistant to lysis, is strongly associated with cardiovascular disease. This pathological change is present in patients with arterial as well as venous diseases, and is also found in a moderate form in relatives of patients with cardiovascular disease. Pharmacological therapies, aimed at both the treatment and prophylaxis of cardiovascular disease, appear to result in positive changes to the fibrin clot structure. As such, therapies aimed at ‘normalising’ fibrin clot structure may be of benefit in the prevention and treatment of cardiovascular disease.

scholarly journals Pathogenesis of Trousseau’s syndrome

2015 ◽  
Vol 64 (4) ◽  
pp. 85-94
Author(s):  
Alexander Viktorovich Vorobev ◽  
Alexander Davidovich Makatsaria ◽  
Andrey Mikhailovich Chabrov ◽  
Alexander Anatol’evich Savchenko
Keyword(s):  
Cancer Patients ◽  
Tissue Factor ◽  
Tumor Cells ◽  
Blood Clot ◽  
Coagulation Cascade ◽  
Severe Bleeding ◽  
Trousseau’S Syndrome ◽  
Thrombotic Complications ◽  
Significant Release ◽  
Coagulation Pathway

Malignancies and thrombosis have common pathogenetic features that was shown by A. Trousseau in 1865. There is now no doubt that the cancer patients occur much more frequently thromboembolism, and migratory venous thrombosis is a manifestation of paraneoplastic syndrome in cancer patients. In general, any manifestation of thrombohemorrhagic complications in cancer patients called Trousseau’s syndrome. While thrombotic complications such as venous thromboembolism are most frequent in cancer patients, may also experience severe bleeding symptoms due to systemic coagulopathies, including disseminated intravascular coagulation, haemolytic thrombotic microangiopathy, and hyperfibrinolysis. The basis of the pathophysiology of Trousseau’s syndrome, except the classic triad of Virchow, is overproduction of tissue factor (TF), the main initiator of extrinsic coagulation pathway. Thus a significant release of microparticles from tumor cells bearing tissue factor is critical not only for the formation of a blood clot, but the growth and progression of tumors. Tumor cells activate the coagulation cascade or fibrinolysis system, providing conditions for its further spread, stimulation of angiogenesis, increased vascular permeability, which in turn promotes metastasis.

Characterization of Platelet TFPI.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1937-1937
Author(s):  
Susan A. Maroney ◽  
Paul Friese ◽  
Sarah Alliman ◽  
George L. Dale ◽  
Alan Mast
Keyword(s):  
Flow Cytometry ◽  
Tissue Factor ◽  
Factor Viia ◽  
Blood Clot ◽  
Calcium Ionophore ◽  
Full Length ◽  
Pcr Analysis ◽  
Factor X ◽  
Platelet Surface ◽  
Endothelial Surface

Abstract The accumulation of blood borne tissue factor within a blood clot is thought to be important for normal fibrin generation and may cause propagation of the blood clot into an occlusive thrombus. Tissue factor pathway inhibitor (TFPI), the primary inhibitor of tissue factor activity, is present in platelets where it may have an important role in down regulating the activity of circulating tissue factor. Western blot analysis of gel filtered platelet lysates demonstrates the presence of full-length, 43 kDa TFPI. The lower molecular weight, C-terminally truncated forms of TFPI present in plasma are not present in platelet lysates suggesting that full length TFPI is selectively adsorbed from plasma or that TFPI is synthesized within megakaryocytes. Real time PCR analysis of cDNA produced from highly purified platelet mRNA demonstrates transcripts for both TFPI and TFPI-beta, a truncated form of TFPI produced by alternative splicing. TFPI mRNA is about 3000-fold more abundant than TFPI-beta mRNA. TFPI is not released from platelets following stimulation with the thrombin receptor activating peptide SFLLRN (TRAP) indicating that it is not stored as a soluble alpha-granule protein. Instead, it appears to be associated with platelet membranes. It remains largely insoluble following lysis of platelets by repeated freeze thaw or exposure to hypotonic buffer. There is little to no expression of TFPI on the surface of quiescent platelets as assessed by flow cytometry. TRAP stimulated platelets have surface TFPI that is detected by flow cytometry, but the amount varies between experiments. TFPI is consistently detectable by flow cytometry on the surface of coated-platelets that are produced by stimulation with thrombin/convulxin or thrombin/calcium ionophore. Platelet TFPI activity was measured in eight individuals by determining the rate of factor X activation by factor VIIa/tissue factor. Comparison of quiescent and coated-platelets demonstrates a significant increase in the amount of TFPI activity on the surface the coated-platelets (11.0+/−0.3 vs. 38.7+/−17.2 pmole/10 million platelets; p<0.005), but no significant increase in platelets activated with 20 or 200 micromolar TRAP. Since TFPI associates with the endothelial surface through a GPI-anchor, coated-platelets were treated with phospahtidyl inositol specific phospholipase C (PIPLC) to determine if it would remove TFPI. In experiments where PIPLC removed 56% of the CD59 from the platelet surface, only 22% of the TFPI was removed indicating that if platelet TFPI is GPI-anchored, it is expressed in a manner that is relatively protected from PIPLC. Confocal and electron microscopy studies demonstrate that TFPI is distributed throughout the cytoplasm of quiescent platelets without localization to granules suggesting that it may associate with the platelet cytoskeleton.

The Interactions of Fibrin and Endothelial Cells within a Fibrin Clot

1997 ◽  
Vol 3 (S2) ◽  
pp. 233-234
Author(s):  
W. G. Jerome ◽  
R.R. Hantgan ◽  
S. Handt
Keyword(s):  
Endothelial Cells ◽  
Blood Clot ◽  
Direct Interaction ◽  
Fibrin Clot ◽  
Clot Lysis ◽  
Heart Attacks ◽  
Microscopic Studies ◽  
Life Threatening ◽  
Inhibitory Molecules ◽  
Clot Structure

A life threatening blood clot is the major cause of heart attacks. Thrombolytic therapy attempts to restore blood flow by activating the body's own fibrinolytic system at the site of the occlusive thrombus. However, for unknown reasons, therapy is unsuccessful in greater than 20% of patients. We have previously shown that the endothelial cells lining the wall of the vessel can play a substantial role in inhibiting clot lysis. This is due chiefly to the secretion of inhibitory molecules by endothelial cells. However, endothelial cells also have receptors for fibrin and little is known about how the direct interaction of fibrin with cells may influence lysis. To investigate this we have undertaken a series of microscopic studies to analyse the influence of endothelial cells on clot structure. We report here that endothelial cells can organize clot fibers into tight assemblies. We also show that, at least in culture, fibrin can act in concert with antithrombotic molecules to dramatically affect endothelial structure

scholarly journals Correlation between LncRNA Profiles in the Blood Clot Formed on Nano-Scaled Implant Surfaces and Osseointegration

Nanomaterials ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 674
Author(s):  
Long Bai ◽  
Peiru Chen ◽  
Bin Tang ◽  
Ruiqiang Hang ◽  
Yin Xiao
Keyword(s):  
Signaling Pathways ◽  
Cellular Response ◽  
De Novo ◽  
Blood Clot ◽  
Cell Metabolism ◽  
Osteoclast Differentiation ◽  
Vegf Signaling ◽  
Titania Nanotube Arrays ◽  
Pathway Analyses ◽  
Clot Structure

Implant surfaces with a nanoscaled pattern can dominate the blood coagulation process resulting in a defined clot structure and its degradation behavior, which in turn influence cellular response and the early phase of osseointegration. Long non-coding (Lnc) RNAs are known to regulate many biological processes in the skeletal system; however, the link between the LncRNA derived from the cells within the clot and osseointegration has not been investigated to date. Hence, the sequence analysis of LncRNAs expressed within the clot formed on titania nanotube arrays (TNAs) with distinct nano-scaled diameters (TNA 15 of 15 nm, TNA 60 of 60 nm, TNA 120 of 120 nm) on titanium surfaces was profiled for the first time. LncRNA LOC103346307, LOC103352121, LOC108175175, LOC103348180, LOC108176660, and LOC108176465 were identified as the pivotal players in the early formed clot on the nano-scaled surfaces. Further bioinformatic prediction results were used to generate co-expression networks of LncRNAs and mRNAs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that distinct nano-scaled surfaces could regulate the biological functions of target mRNAs in the clot. LOC103346307, LOC108175175, and LOC108176660 upregulated mRNAs related to cell metabolism and Wnt, TGF-beta, and VEGF signaling pathways in TNA 15 compared with P-Ti, TNA 60, and TNA 120, respectively, whereas LOC103352121, LOC103348180, and LOC108176465 downregulated mRNAs related to bone resorption and inflammation through negatively regulating osteoclast differentiation, TNF, and NF-kappa signaling pathways. The results indicated that surface nano-scaled characteristics can significantly influence the clot-derived LncRNAs expression profile, which affects osseointegration through multiple signaling pathways of the targeted mRNAs, thus paving a way for better interpreting the link between the properties of a blood clot formed on the nano-surface and de novo bone formation.

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