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 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

Abstract 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 Fibrinopeptide A release is necessary for effective B:b interactions in polymerisation of variant fibrinogens with impaired A:a interactions

2013 ◽  
Vol 109 (02) ◽  
pp. 221-228 ◽  
Author(s):  
Keisuke Soya ◽  
Fumiko Terasawa ◽  
Nobuo Okumura
Keyword(s):  
Electron Microscopy ◽  
Scanning Electron Microscopy ◽  
Fibrin Clot ◽  
Fibrinopeptide A ◽  
Thrombin Cleavage ◽  
No Release ◽  
Per Se ◽  
Clot Structure ◽  
Dose Dependent ◽  
Scanning Electron

SummaryFibrin polymerisation is mediated by interactions between knobs ‘A’ and ‘B’ exposed by thrombin cleavage, and holes ‘a’ and ‘b’. We demonstrated markedly delayed thrombin-catalysed fibrin polymerisation, through B:b interactions alone, of recombinant γD364H-fibrinogen with impaired hole ‘a’. To determine whether recombinant variant fibrinogens with no release of fibrinopeptide A (FpA) polymerise similarly to γD364H-fibrinogen, we examined two variant fibrinogens with substitutions altering knob ‘A’, Aα17A- and Aα17C-fibrinogen. We examined thrombin- or batroxobin-catalysed fibrinopeptide release by HPLC, fibrin clot formation by turbidity and fibrin clot structure by scanning electron microscopy (SEM) and compared the results of the variants with those for γD364H-fibrinogen. Thrombin-catalysed FpA release of Aα17A-fibrinogen was substantially delayed and none observed for Aα17C-fibrinogen; fibrinopeptide B (FpB) release was delayed for all variants. All variant fibrinogens showed substantially impaired thrombin-catalysed polymerisation; for Aα17A-fibrinogen it was delayed less, and for Aα17C more than for γD364H-fibrinogen. No variants polymerised with batroxobin, which exposed only knob ‘A’. The inhibition of variant fibrinogens’ polymerisation was dose-dependent on the concentration of either GPRP or GHRP, and both peptides that block holes ‘b’. SEM showed that the variant clots from Aα17A- and γD364H-fibrinogen had uniform, ordered fibres, thicker than normal, whereas Aα17C-fibrinogen formed less organised clots with shorter, thinner, and tapered ends. These results demonstrate that FpA release per se is necessary for effective B:b interactions during polymerisation of variant fibrinogens with impaired A:a interactions.

Factor XIIa regulates the structure of the fibrin clot independently of thrombin generation through direct interaction with fibrin

Blood ◽  
2011 ◽  
Vol 118 (14) ◽  
pp. 3942-3951 ◽  
Author(s):  
Joke Konings ◽  
José W. P. Govers-Riemslag ◽  
Helen Philippou ◽  
Nicola J. Mutch ◽  
Julian I. Borissoff ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Thrombus Formation ◽  
Coagulation Factor ◽  
Direct Interaction ◽  
Fibrin Clot ◽  
Fiber Density ◽  
Contact Pathway ◽  
Clot Structure ◽  
Fibrin Structure

Abstract Recent data indicate an important contribution of coagulation factor (F)XII to in vivo thrombus formation. Because fibrin structure plays a key role in clot stability and thrombosis, we hypothesized that FXII(a) interacts with fibrin(ogen) and thereby regulates clot structure and function. In plasma and purified system, we observed a dose-dependent increase in fibrin fiber density and decrease in turbidity, reflecting a denser structure, and a nonlinear increase in clot stiffness with FXIIa. In plasma, this increase was partly independent of thrombin generation, as shown in clots made in prothrombin-deficient plasma initiated with snake venom enzyme and in clots made from plasma deficient in FXII and prothrombin. Purified FXII and α-FXIIa, but not β-FXIIa, bound to purified fibrinogen and fibrin with nanomolar affinity. Immunostaining of human carotid artery thrombi showed that FXII colocalized with areas of dense fibrin deposition, providing evidence for the in vivo modulation of fibrin structure by FXIIa. These data demonstrate that FXIIa modulates fibrin clot structure independently of thrombin generation through direct binding of the N-terminus of FXIIa to fibrin(ogen). Modification of fibrin structure by FXIIa represents a novel physiologic role for the contact pathway that may contribute to the pathophysiology of thrombosis.

scholarly journals Quantification of the Relationship between Bacterial Kinetics and Host Response for Monkeys Exposed to AerosolizedFrancisella tularensis

2010 ◽  
Vol 77 (2) ◽  
pp. 485-490 ◽  
Author(s):  
Yin Huang ◽  
Charles N. Haas
Keyword(s):  
Survival Data ◽  
Count Data ◽  
Host Response ◽  
Growth Curves ◽  
Bacterial Count ◽  
Extensive Literature ◽  
Schu S4 ◽  
The Relationship ◽  
Dose Dependent

ABSTRACTFrancisella tularensiscan be disseminated via aerosols, and once inhaled, only a few microorganisms may result in tularemia pneumonia. Effective responses to this threat depend on a thorough understanding of the disease development and pathogenesis. In this study, a class of time-dose-response models was expanded to describe quantitatively the relationship between the temporal probability distribution of the host response and thein vivobacterial kinetics. An extensive literature search was conducted to locate both the dose-dependent survival data and thein vivobacterial count data of monkeys exposed to aerosolizedF. tularensis. One study reporting responses of monkeys to four different sizes of aerosol particles (2.1, 7.5, 12.5, and 24.0 μm) of the SCHU S4 strain and three studies involving fivein vivogrowth curves of various strains (SCHU S4, 425, and live vaccine strains) initially delivered to hosts in aerosol form (1 to 5 μm) were found. The candidate models exhibited statistically acceptable fits to the time- and dose-dependent host response and provided estimates for the bacterial growth distribution. The variation pattern of such estimates with aerosol size was found to be consistent with the reported pathophysiological and clinical observations. The predicted growth curve for 2.1-μm aerosolized bacteria was highly consistent with the available bacterial count data. This is the first instance in which the relationship between thein vivogrowth ofF.tularensisand the host response can be quantified by mechanistic mathematical models.

scholarly journals Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation

Blood ◽  
2012 ◽  
Vol 119 (25) ◽  
pp. 5972-5979 ◽  
Author(s):  
James H. Morrissey ◽  
Sharon H. Choi ◽  
Stephanie A. Smith
Keyword(s):  
Blood Clotting ◽  
Molecular Mechanisms ◽  
Fibrin Clot ◽  
Human Platelets ◽  
Factor V ◽  
Inorganic Polyphosphate ◽  
Contact Pathway ◽  
Anticoagulant Function ◽  
Clot Structure

AbstractInorganic polyphosphate is widespread in biology and exhibits striking prohemostatic, prothrombotic, and proinflammatory effects in vivo. Long-chain polyphosphate (of the size present in infectious microorganisms) is a potent, natural pathophysiologic activator of the contact pathway of blood clotting. Medium-chain polyphosphate (of the size secreted from activated human platelets) accelerates factor V activation, completely abrogates the anticoagulant function of tissue factor pathway inhibitor, enhances fibrin clot structure, and greatly accelerates factor XI activation by thrombin. Polyphosphate may have utility as a hemostatic agent, whereas antagonists of polyphosphate may function as novel antithrombotic/anti-inflammatory agents. The detailed molecular mechanisms by which polyphosphate modulates blood clotting reactions remain to be elucidated.

scholarly journals Nanomechanics of Blood Clot and Thrombus Formation

2022 ◽  
Vol 51 (1) ◽  
Author(s):  
Marco M. Domingues ◽  
Filomena A. Carvalho ◽  
Nuno C. Santos
Keyword(s):  
Mechanical Properties ◽  
Thrombus Formation ◽  
Blood Clot ◽  
Fibrin Clot ◽  
Annual Review ◽  
Publication Date ◽  
New Methods ◽  
Fibrin Network ◽  
Protein Cell

Mechanical properties have been extensively studied in pure elastic or viscous materials; however, most biomaterials possess both physical properties in a viscoelastic component. How the biomechanics of a fibrin clot is related to its composition and the microenvironment where it is formed is not yet fully understood. This review gives an outline of the building mechanisms for blood clot mechanical properties and how they relate to clot function. The formation of a blood clot in health conditions or the formation of a dangerous thrombus go beyond the mere polymerization of fibrinogen into a fibrin network. The complex composition and localization of in vivo fibrin clots demonstrate the interplay between fibrin and/or fibrinogen and blood cells. Studying these protein–cell interactions and clot mechanical properties may represent new methods for the evaluation of cardiovascular diseases (the leading cause of death worldwide), creating new possibilities for clinical diagnosis, prognosis, and therapy. Expected final online publication date for the Annual Review of Biophysics, Volume 51 is May 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Comparative Fibrinolytic Properties of Staphylokinase and Streptokinase in Animal Models of Venous Thrombosis

1991 ◽  
Vol 66 (04) ◽  
pp. 468-473 ◽  
Author(s):  
H R Lijnen ◽  
J M Stassen ◽  
I Vanlinthout ◽  
H Fukao ◽  
K Okada ◽  
...  
Keyword(s):  
Human Plasma ◽  
Pulmonary Embolus ◽  
Blood Clot ◽  
B Value ◽  
Clot Lysis ◽  
Maximal Rate ◽  
Pharmacokinetic Properties ◽  
Z Value ◽  
Dose Dependent

SummaryThe thrombolytic and pharmacokinetic properties of staphylokinase were compared with those of streptokinase in hamsters with a pulmonary embolus produced from human plasma or from hamster plasma, and in rabbits with a jugular vein blood clot produced from rabbit blood. In both models, a continuous intravenous infusion of staphylokinase and streptokinase over 60 min in hamsters or over 4 h in rabbits, induced dose-dependent progressive clot lysis in the absence of significant systemic activation of the fibrinolytic system. The results of thrombolytic potency (clot lysis at 30 min after the end of the infusion, in percent, versus dose administered, in mg/kg) were fitted with an exponentially transformed sigmoidal function and the maximal percent clot lysis (c), the maximal rate of lysis (z = ¼ac · e b ) and the dose at which the maximal rate of lysis is achieved (b) were determined. In hamsters with a pulmonary embolus produced from human plasma, streptokinase had a somewhat higher thrombolytic potency than staphylokinase, as revealed by a higher z value (2,100 ± 1,100% lysis per mg/kg streptokinase administered versus 1,100 ± 330% lysis per mg/kg for staphylokinase). In hamsters with a pulmonary embolus produced from hamster plasma, staphylokinase had a somewhat higher thrombolytic potency than streptokinase (z = 1,600 ± 440 versus 1,200 ± 370% lysis per mg/kg). Staphylokinase had a higher thrombolytic potency than streptokinase in rabbits, as revealed by a higher z-value (950 ± 350% lysis per mg/kg staphylokinase administered versus 330 ± 39% lysis per mg/kg for streptokinase) and a lower b-value (0.035 ± 0.010 mg/kg staphylokinase versus 0.091 ± 0.008 mg/kg for streptokinase). The plasma clearance following bolus injection of staphylokinase or streptokinase in hamsters or rabbits was comparably rapid (1.1 to 1.4 ml/min in hamsters and 14 to 15 ml/min in rabbits) as a result of a short initial half-life (1.8 to 1.9 min in hamsters and 1.7 to 2.0 min in rabbits). These results in two quantitative rodent models of thrombolysis suggest that staphylokinase is a potent thrombolytic agent with an in vivo thrombolytic potency that is comparable to that of streptokinase. Further investigation of the thrombolytic potential of staphylokinase seems to be warranted.

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.

How can We Predict Efficacy of rFVIIa in Hemophilia Patients with Inhibitors?

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3487-3487
Author(s):  
Yesim Dargaud ◽  
Jean C Bordet ◽  
Chantal Huchon ◽  
Claude Negrier
Keyword(s):  
Thrombin Generation ◽  
Fibrin Clot ◽  
Bypassing Agents ◽  
The Stability ◽  
Clot Structure ◽  
Dose Dependent ◽  
Clot Stability ◽  
Scanning Electron ◽  
Fibrin Clots

Abstract Abstract 3487 Poster Board III-424 Hemophilia patients with inhibitors are treated with bypassing agents for which hemostatic efficacy is unpredictable. While both activated prothrombin complex concentrate and recombinant activated factor VII (rFVIIa) have demonstrated excellent safety profiles, neither product is a universal hemostatic agent and the variability of response to bypassing agents complicates the treatment in these patients. Moreover, the lack of a validated laboratory assay to measure the effectiveness of bypassing agents dramatically limits the optimisation of treatment strategies. As the final enzyme generated by bypassing agents is thrombin, thrombin generation assay (TGA) could theoretically be used for monitoring rFVIIa. However, TGA does not reflect the stability of the fibrin clot and its resistance to fibrinolysis which are essential parameters of hemostasis. We have therefore evaluated the use of an additional method that might provide complementary information on fibrin clot structure and stability, and would allow a better prediction of the biological efficacy of rFVIIa. In the absence of FVIII/FIX, fibrin fibres are abnormally thick and clots are overly susceptible to fibrinolysis. After treatment with rFVIIa, clots are less porous and fibrin fibres are thinner as assessed using scanning electron microscopy. Using whole blood thromboelastography (TEG) measuring viscoelastic changes of fibrin throughout clot initiation, formation and fibrinolysis, we developed an in vitro model to assess fibrin clot stability and resistance to fibrinolysis. The aim of the present study was to evaluate the correlation between the modifications of the fibrin clot structure and the stability of the fibrin clots obtained in the presence of rFVIIa. METHODS The in vitro effect of rFVIIa was tested in 6 severe hemophilia A patients at doses of 90 – 180 – 270 μg/kg. Thrombin generation (TG) was measured in platelet rich plasma using the CAT method in the presence of TF 1pM. After addition of rFVIIa, the improvement in TG capacity was compared to normal values obtained from 80 control males. Fibrin clots obtained from the TG measurements were studied by scanning electron microscopy (SEM) and fibrin diametres were measured (700 measurements on each sample). In the same samples, the stability of fibrin clots obtained before and after addition of rFVIIa was assessed using TEG-5000™. Clot resistance to fibrinolysis was recorded in the presence of TF 0.5pM and tPA 0.125μM. TEG-tPA and SEM results were compared to those obtained in 30 healthy control males. RESULTS A dose dependent increase of TG was observed in the presence of increasing doses of rFVIIa (p<0.0001; ANOVA). In the presence of rFVIIa 90μg/kg, TG capacity was significantly improved in all patients (p=0.0023; Mann Whitney), and was completely normalized in 4 patients while 2 others needed higher doses of rFVIIa to normalize their TG. The fibrin fibre diameters were thicker (217±16 nm; p<0.0001) in all hemophilia patients in comparison with controls (170±24 nm). After addition of rFVIIa 90μg/kg, the fibrin clot structure was modified and the diameter of fibrin fibres was dramatically decreased in all patients (184±11 nm; p=0.006). A further improvement of fibrin clot structure was observed with rFVIIa 180μg/kg in only one patient. TEG-tPA showed a dose-dependent improvement of fibrin clot stability in the presence of rFVIIa (p<0.0001; ANOVA). A reverse correlation was observed between fibrin fibre diametres and resistance of fibrin clots to fibrinolysis (r=-0.68, p=0.001; Spearman test). CONCLUSION This data demonstrates a statistically significant correlation between clot structure and its stability. The combined use of TGA with TEG-tPA may allow physicians to better evaluate the individual response of patients to bypassing agents. The clinical validity of the minimal individual dose of rFVIIa normalizing both TGA and TEG-tPA needs to be verified in clinical studies. Disclosures: No relevant conflicts of interest to declare.

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

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