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 Microbiota-independent immunological effects of non-digestible oligosaccharides in the context of inflammatory bowel diseases

2020 ◽  
Vol 79 (4) ◽  
pp. 468-478 ◽  
Author(s):  
Stefania Del Fabbro ◽  
Philip C. Calder ◽  
Caroline E. Childs
Keyword(s):  
Inflammatory Bowel Diseases ◽  
Immune Cell ◽  
Intestinal Inflammation ◽  
Mechanisms Of Action ◽  
Mucosal Inflammation ◽  
Disease States ◽  
Inflammatory Conditions ◽  
Bowel Diseases ◽  
Inflammatory Bowel

The aim of the present paper is to review the effects of non-digestible oligosaccharides (NDO) on immunity, focusing on their microbiota-independent mechanisms of action, as well as to explore their potential beneficial role in inflammatory bowel diseases (IBD). IBD are chronic, inflammatory conditions of the gastrointestinal tract. Individuals with IBD have an aberrant immune response to commensal microbiota, resulting in extensive mucosal inflammation and increased intestinal permeability. NDO are prebiotic fibres well known for their role in supporting intestinal health through modulation of the gut microbiota. NDO reach the colon intact and are fermented by commensal bacteria, resulting in the production of SCFA with immunomodulatory properties. In disease states characterised by increased gut permeability, prebiotics may also bypass the gut barrier and directly interact with intestinal and systemic immune cells, as demonstrated in patients with IBD and in infants with an immature gut. In vitro models show that fructooligosaccharides, inulin and galactooligosaccharides exert microbiota-independent effects on immunity by binding to toll-like receptors on monocytes, macrophages and intestinal epithelial cells and by modulating cytokine production and immune cell maturation. Moreover, animal models and human supplementation studies demonstrate that some prebiotics, including inulin and lactulose, might reduce intestinal inflammation and IBD symptoms. Although there are convincing preliminary data to support NDO as immunomodulators in the management of IBD, their mechanisms of action are still unclear and larger standardised studies need to be performed using a wider range of prebiotics.

scholarly journals Synergistic Effect of Bypassing Agents and Sequence Identical Analogue of Emicizumab and Fibrin Clot Structure in the In Vitro Model of Hemophilia A

TH Open ◽  
2020 ◽  
Vol 04 (02) ◽  
pp. e94-e103
Author(s):  
Yanan Zong ◽  
Aleksandra Antovic ◽  
Nida Mahmoud Hourani Soutari ◽  
Jovan Antovic ◽  
Iva Pruner
Keyword(s):  
In Vitro Model ◽  
Hemophilia A ◽  
Fibrin Clot ◽  
Substantial Improvement ◽  
Activated Prothrombin Complex Concentrate ◽  
Bypassing Agents ◽  
Vitro Model ◽  
Clot Structure ◽  
Fibrin Clots

AbstractDevelopment of inhibitors to factor VIII (FVIII) occurs in approximately 30% of severe hemophilia A (HA) patients. These patients are treated with bypassing agents (activated prothrombin complex concentrate [aPCC] and recombinant activated FVII-rFVIIa). Recently, a bispecific FIX/FIXa- and FX/FXa-directed antibody (emicizumab) has been approved for the treatment of HA patients with inhibitors. However, the data from clinical studies imply that coadministration of emicizumab and bypassing agents, especially aPCC, could have a thrombotic effect.This study was aimed to address the question of potential hypercoagulability of emicizumab and bypassing agents' coadministration, we have investigated fibrin clot formation and structure in the in vitro model of severe HA after adding sequence-identical analogue (SIA) of emicizumab and bypassing agents.Combined overall hemostasis potential (OHP) and fibrin clot turbidity assay was performed in FVIII-deficient plasma after addition of different concentrations of SIA, rFVIIa, and aPCC. Pooled normal plasma was used as control. The fibrin clots were analyzed by scanning electron microscopy (SEM).OHP and turbidity parameters improved with the addition of aPCC, while therapeutic concentrations of rFVIIa did not show substantial improvement. SIA alone and in combination with rFVIIa or low aPCC concentration improved OHP and turbidity parameters and stabilized fibrin network, while in combination with higher concentrations of aPCC expressed hypercoagulable pattern and generated denser clots.Our in vitro model suggests that combination of SIA and aPCC could potentially be prothrombotic, due to hypercoagulable changes in fibrin clot turbidity and morphology. Additionally, combination of SIA and rFVIIa leads to the formation of stable clots similar to normal fibrin clots.

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 Clot Structure and Implications for Bleeding and Thrombosis

2019 ◽  
Vol 46 (01) ◽  
pp. 096-104 ◽  
Author(s):  
Emily Mihalko ◽  
Ashley C. Brown
Keyword(s):  
Wound Healing ◽  
Structural Changes ◽  
Fiber Diameter ◽  
Structural Characteristics ◽  
Critical Role ◽  
Fibrin Clot ◽  
Therapeutic Strategies ◽  
Disease States ◽  
Clot Structure ◽  
Coagulation And Fibrinolysis

AbstractThe formation of a fibrin clot matrix plays a critical role in promoting hemostasis and wound healing. Fibrin dynamics can become disadvantageous in the formation of aberrant thrombus development. Structural characteristics of clots, such as fiber diameter, clot density, stiffness, or permeability, can determine overall clot integrity and functional characteristics that have implications on coagulation and fibrinolysis. This review examines known factors that contribute to changes in clot structure and the presence of structural clot changes in various disease states. These insights provide valuable information in forming therapeutic strategies for disease states where alterations in clot structure are observed. Additionally, the implications of structural changes in clot networks on bleeding and thrombus development in terms of disease states and clinical outcomes are also examined in this review.

Clot Accumulation Characteristics of Plasminogen-bearing Liposomes in a Flow-system

1998 ◽  
Vol 79 (01) ◽  
pp. 144-149 ◽  
Author(s):  
H. Feitsma ◽  
C. Kluft ◽  
J. L. M. Heeremans ◽  
R. Prevost ◽  
D. J. A. Crommelin
Keyword(s):  
Closed System ◽  
Whole Blood ◽  
Surface Density ◽  
Closed Loop ◽  
Flow System ◽  
Blood Clot ◽  
Fibrin Clot ◽  
Partial Degradation ◽  
Accumulation Characteristics

SummaryIn this study, the clot accumulation properties of liposome-coupled plasminogen were compared to those of free (non-liposomal) plasminogen in an in vitro, closed-loop, flow-system. After introduction of a clot into the closed system, double-radiolabelled plasminogen-liposomes were administered and the accumulation of radiolabel on the entire clot was measured.Liposomal plasminogen showed improved accumulation over free plasminogen, on both a fibrin clot and a whole blood clot. Moreover, once liposomal plasminogen was fibrin associated, it could not be washed away with buffer, in contrast to free plasminogen. Liposomal plasminogen was able to compete successfully with an excess of free plasminogen. The plateau levels for the accumulated amount of plasminogen depended on the incubated amount of plasminogen and were influenced by partial degradation of the clot. Furthermore, it was shown that a threshold liposomal plasminogen surface-density was needed for optimum clot accumulation.

Pharmacogenomics and Cardiovascular Disease

2019 ◽  
pp. 184-197
Author(s):  
Emily K. Dornblaser ◽  
Craig P. Worby ◽  
Daniel Alan Brazeau
Keyword(s):  
Cardiovascular Disease ◽  
Genetic Variation ◽  
Cardiovascular Disorders ◽  
Disease States ◽  
Clinical Literature ◽  
Prevention And Treatment ◽  
Prevalent Disease ◽  
Cardiovascular Medications ◽  
The Relationship ◽  
The U.S

Cardiovascular disease is one of the most prevalent disease states in the U.S. and contributes substantially to overall morbidity and mortality. The ability to effectively optimize the treatment of cardiovascular disease has a significant impact on overall disease prevention and treatment. This chapter discusses the relationship between genetic variations and their impact on medications used for the treatment of cardiovascular disorders. Key medications that are susceptible to genetic variation have been identified. The chapter describes the mechanisms by which genetic variation may contribute to altered medication concentrations or effects and briefly reviews the place in therapy for the cardiovascular medications. In addition, this chapter reviews current clinical literature to determine the overall impact these variations may have on clinical outcomes.

Berries of many colours

2009 ◽  
Vol 311 ◽  
pp. 1-4 ◽  
Keyword(s):  
Cardiovascular Disease ◽  
Clinical Trials ◽  
Chronic Disease ◽  
Clinical Applications ◽  
Food Sources ◽  
Disease States ◽  
Vitro Data ◽  
In Vitro Data

In a nutshellBerries are one of the richest food sources of antioxidants.There is quite a bit of animal and in vitro data supporting clinical applications for berries in chronic disease states such as cancer, dementia and cardiovascular disease, and as an anti-microbial. A few human clinical trials are just now starting to appear.

scholarly journals Recombinant Destabilase from Hirudo medicinalis Is Able to Dissolve Human Blood Clots In Vitro

2021 ◽  
Vol 43 (3) ◽  
pp. 2068-2081
Author(s):  
Pavel Bobrovsky ◽  
Valentin Manuvera ◽  
Izolda Baskova ◽  
Svetlana Nemirova ◽  
Alexandr Medvedev ◽  
...  
Keyword(s):  
Response Curve ◽  
Blood Clot ◽  
Morphological Characteristics ◽  
Fibrin Clot ◽  
Blood Clots ◽  
Isopeptide Bonds ◽  
Isopeptidase Activity ◽  
Stabilized Fibrin ◽  
Poisonous Animals

Leeches are amazing animals that can be classified as conditionally poisonous animals since the salivary cocktail they produce is injected directly into the victim, and its components have strictly defined biological purposes, such as preventing blood clot formation. Thrombolytic drugs are mainly aimed at treating newly formed blood clots. Aged clots are stabilized by a large number of isopeptide bonds that prevent the action of thrombolytics. These bonds are destroyed by destabilase, an enzyme of the leech’s salivary glands. Here, we conducted a pilot study to evaluate the feasibility and effectiveness of the use of destabilase in relation to blood clots formed during real pathological processes. We evaluated the isopeptidase activity of destabilase during the formation of a stabilized fibrin clot. We showed that destabilase does not affect the internal and external coagulation cascades. We calculated the dose–response curve and tested the ability of destabilase to destroy isopeptide bonds in natural blood clots. The effect of aged and fresh clots dissolving ability after treatment with destabilase coincided with the morphological characteristics of clots during surgery. Thus, recombinant destabilase can be considered as a potential drug for the treatment of aged clots, which are difficult to treat with known thrombolytics.

scholarly journals Force-Independent Cleavage of Talin by Calpain Promotes Platelet-Mediated Fibrin Clot Contraction

2021 ◽  
Author(s):  
Karen P. Fong ◽  
Kathleen S. Molnar ◽  
Nicholas J. Agard ◽  
Rustem I Litvinov ◽  
Oleg V. Kim ◽  
...  
Keyword(s):  
Binding Sites ◽  
Blood Clot ◽  
Tensile Force ◽  
Structural Rearrangement ◽  
Fibrin Clot ◽  
Clot Retraction ◽  
Clot Contraction ◽  
Α Helix ◽  
Unstructured Regions

Blood clot contraction is driven by traction forces generated by the platelet cytoskeleton that are transmitted to fibrin fibers via the integrin αIIbβ3. Here we show that clot contraction is impaired by inhibitors of the platelet cytosolic protease calpain. We used subtiligase-mediated labeling of amino-termini and mass spectrometry to identify proteolytically-cleaved platelet proteins involved in clot contraction. Of 32 calpain-cleaved proteins after TRAP stimulation, fourteen were cytoskeletal, most prominently talin and vinculin. A complex of talin and vinculin constitutes a "mechanosensitive clutch" connecting integrins bound to the extracellular matrix to the actin cytoskeleton. Accordingly, we focused on talin and vinculin. Talin is composed of an N-terminal head domain and a C-terminal rod domain organized into a series of four- and five-helix bundles. The bundles contain 11 vinculin binding sites (VBS), each of which is an α-helix packed into a bundle interior and requiring a structural rearrangement to initiate vinculin binding. We detected 8 calpain-mediated cleavages in talin, 2 previously identified in unstructured regions and 6 in α-helical regions in proximity to a VBS. There is evidence in vitro that applying mechanical force across talin enables vinculin binding to the talin rod. However, we found that inhibiting platelet cytoskeletal contraction had no effect on talin cleavage, indicating that talin cleavage by calpain in platelets does not require cytoskeleton-generated tensile force. Thus, it is likely that calpain acts in the later stages of clot retraction through focal adhesion disassembly.

Fibrinogen Bβ polymorphisms do not directly contribute to an altered in vitro clot structure in humans

2003 ◽  
Vol 90 (12) ◽  
pp. 1021-1028 ◽  
Author(s):  
Stephen Brennan ◽  
Peter George ◽  
Ghassan Maghzal
Keyword(s):  
Myocardial Infarction ◽  
Fibrin Clot ◽  
Mass Spectrometry Analysis ◽  
Protein Coding ◽  
Spectrometry Analysis ◽  
Atherothrombotic Disease ◽  
Clot Structure ◽  
Permeation Properties ◽  
Fibrinolysis Kinetics

SummaryFibrinogen Bβ polymorphisms, such as the -455 G/A and the Arg448Lys amino acid substitution, have been shown to increase the risk of atherothrombotic disease. Although these polymorphisms are related to fibrinogen concentrations, their effect on fibrin clot structure has not been extensively studied. We examined the frequency of the fibrinogen Bβ -455 G/A polymorphism in a group of myocardial infarction (MI) patients. There was no association between this polymorphism and MI. However, we found that patients homozygous for the rare -455 A allele had a higher average age at first MI. A similar result was found for individuals homozygous for the Bβ 448 Lys allele who also had a higher age at first MI.We subsequently studied the clotting properties of purified Arg448 and Lys448 fibrinogens in vitro and found that these fibrinogens did not significantly differ in their polymerisation, fibrinolysis kinetics or in their clot permeation properties. Mass spectrometry analysis of endoproteinase Asp-N digests of Bβ chains revealed that the Lys448 and the Arg448 chains were expressed in approximately equal proportions in a heterozygote Arg448Lys individual. Our results demonstrate that the fibrinogen Bβ –455 G/A polymorphism is not associated with myocardial infarction and furthermore the closely linked Bβ Arg448Lys protein coding variation does not have an influence on the function nor the structure of the protein in a purified system.

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