Evidence That Fibrinogen Inhibits Leukocyte Adhesion to Fibrin Clot and Immobilized Fibrinogen by Binding to the Substrate but Not to Integrins.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2631-2631
Author(s):  
Valeryi K. Lishko ◽  
Tatiana P. Ugarova
Keyword(s):  
Leukocyte Adhesion ◽  
Fibrin Clot ◽  
Plasma Fibrinogen ◽  
Flow Conditions ◽  
Fibrin Gel ◽  
Surface Receptors ◽  
High Concentrations ◽  
Adhesive Interactions ◽  
Adhesive Effect

Abstract The recruitment of phagocytic leukocytes to sites of injured vessel wall plays an important role in thrombus remodeling during normal vascular repair and in the pathophysiology of thrombosis. Fibrin and fibrinogen, present in the thrombus, are potent adhesive substrates for neutrophils and monocytes. They support cellular attachment by binding cell surface receptors that belong to the β2 subfamily of integrins. Adhesive interactions of neutrophils and monocytes with polymerized fibrin and insoluble fibrinogen matrix in vivo occur in the presence of high concentrations of circulating plasma fibrinogen (~2–4 mg/ml). One important property of fibrinogen that would have a major bearing on leukocyte adhesion is its capacity to form complexes with fibrin. Therefore, by virtue of its binding to the fibrin clot and/or immobilized fibrinogen, soluble plasma fibrinogen can influence leukocyte adhesion to these substrates. In this study, the possibility that soluble fibrinogen could protect fibrin from adhesion of leukocytes was examined. Fibrinogen was an efficient inhibitor of adhesion of U937 monocytoid cells and neutrophils to fibrin gel and immobilized fibrin(ogen). An investigation of the mechanism by which fibrinogen exerts its influence on leukocyte adhesion indicated that it did not block integrins but rather associated non-covalently and weakly with fibrin(ogen) substrates. Consequently, leukocyte integrins that engage fibrinogen molecules loosely bound to the fibrin(ogen) matrix are not able to consolidate their grip on the substrate; subsequently, cells detach. This conclusion is based on the evidence obtained in adhesion studies using various β2-integrin bearing cells and performed under static and flow conditions. Furthermore, surface plasmon resonance studies, undertaken to determine the Kd of fibrinogen-fibrin interactions under flow conditions, indicated that fibrinogen formed complexes with fibrin(ogen) with micromolar affinities. Thus, these findings reveal a new role of fibrinogen in integrin-mediated leukocyte adhesion. They also imply that the anti-adhesive effect of fibrinogen may protect the thrombus from an excessive leukocyte accumulation and premature dissolution at the early stages of wound healing when hemostatic plug integrity is critical for preventing blood loss.

scholarly journals Antiadhesive effect of fibrinogen: a safeguard for thrombus stability

Blood ◽  
2006 ◽  
Vol 109 (4) ◽  
pp. 1541-1549 ◽  
Author(s):  
Valeryi K. Lishko ◽  
Timothy Burke ◽  
Tatiana Ugarova
Keyword(s):  
Wound Healing ◽  
Vessel Wall ◽  
Potent Inhibitor ◽  
Leukocyte Adhesion ◽  
Fibrin Clot ◽  
Flow Conditions ◽  
High Concentration ◽  
Fibrin Gel ◽  
Wall Injury

Abstract The recruitment of phagocytic leukocytes to sites of vessel wall injury plays an important role in thrombus dissolution by proteases elaborated on their adhesion. However, leukocyte adhesion to the fibrin clot can be detrimental at the early stages of wound healing when hemostatic plug integrity is critical for preventing blood loss. Adhesion of circulating leukocytes to the insoluble fibrin(ogen) matrix is mediated by integrins and occurs in the presence of a high concentration of plasma fibrinogen. In this study, the possibility that soluble fibrinogen could protect fibrin from excessive adhesion of leukocytes was examined. Fibrinogen was a potent inhibitor of adhesion of U937 monocytoid cells and neutrophils to fibrin gel and immobilized fibrin(ogen). An investigation of the mechanism by which soluble fibrinogen exerts its influence on leukocyte adhesion indicated that it did not block integrins but rather associated with the fibrin(ogen) substrate. Consequently, leukocytes that engage fibrinogen molecules loosely bound to the surface of fibrin(ogen) matrix are not able to consolidate their grip on the substrate; subsequently, cells detach. This conclusion is based on the evidence obtained in adhesion studies using various cells and performed under static and flow conditions. These findings reveal a new role of fibrinogen in integrin-mediated leukocyte adhesion and suggest that this mechanism may protect the thrombus from premature dissolution.

Pulmonary microcirculatory kinetics of neutrophils deficient in leukocyte adhesion-promoting glycoproteins

1990 ◽  
Vol 69 (1) ◽  
pp. 207-213 ◽  
Author(s):  
M. C. Yoder ◽  
L. L. Checkley ◽  
U. Giger ◽  
W. L. Hanson ◽  
K. R. Kirk ◽  
...  
Keyword(s):  
Leukocyte Adhesion ◽  
Surface Membrane ◽  
Pulmonary Sequestration ◽  
Membrane Expression ◽  
Transit Times ◽  
Wide Range ◽  
Activated Neutrophils ◽  
Adhesive Interactions ◽  
Pulmonary Microcirculation

The mechanism that causes neutrophils to sequester in the pulmonary circulation is unknown. Because the CD11/CD18 glycoprotein family on the surface membrane of neutrophils participates in many adhesive interactions with the endothelium, we investigated the role of these proteins in the intravascular sequestration of pulmonary neutrophils. Neutrophils were isolated from normal dogs and from the only living dog known to have leukocyte adhesion deficiency disease, an inherited deficiency of the CD11/CD18 adhesion family. The neutrophils were labeled with fluorescein dye, injected into normal recipient dogs, and their passage through the pulmonary microcirculation was recorded by in vivo videofluorescence microscopy through a transparent thoracic window. Transit times for normal and deficient neutrophils were similar over a wide range of hemo-dynamic conditions. Activation by zymosan-activated plasma, which increases the surface membrane expression of CD11/CD18, prolonged the transit of normal neutrophils but did not alter the transit time of the deficient neutrophils. These results indicate that neutrophil CD11/CD18 adhesion-promoting glycoproteins are not involved in the normal pulmonary sequestration of neutrophils but have a significant role in the arrest of activated neutrophils in the pulmonary capillaries.

Control of Platelet Adhesion by Rigidity Sensing at the Surface of Fibrin Clot.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3906-3906
Author(s):  
Nataly P. Podolnikova ◽  
Benjamin Bowen ◽  
Valeryi K. Lishko ◽  
Andriy V. Podolnikov ◽  
Tatiana Ugarova
Keyword(s):  
Platelet Adhesion ◽  
Leukocyte Adhesion ◽  
Thrombus Formation ◽  
Focal Adhesions ◽  
Fibrin Clot ◽  
Fibrin Gel ◽  
Vessel Occlusion ◽  
Leukocyte Integrins ◽  
Low Concentrations ◽  
Platelet Spreading

Abstract Thrombus formation at sites of vascular injury must occur quickly to reduce blood loss, but is carefully controlled to limit vessel occlusion. Arrest of bleeding is mediated by adhesion and aggregation of platelets and the formation of the fibrin clot. While the interactions responsible for platelet adhesion and thrombus growth have been extensively researched, the mechanisms that limit platelet adhesion are not clear. We have previously demonstrated that plasma fibrinogen is a potent inhibitor of integrin-mediated leukocyte adhesion to fibrin clots and surface-bound fibrinogen, and have provided evidence that fibrinogen reduces cell adhesion by binding to the surface of fibrin rather than blocking leukocyte integrins. Accordingly, cells that engage fibrinogen molecules loosely bound to fibrin (soft substrate) are not able to consolidate their grip on the surface; subsequently, cells detach. Conversely, cells that adhere to the naked fibrin clot (rigid substrate) adhere firmly. Since fibrin and immobilized fibrinogen support platelet adhesion, we examined the effect of soluble fibrinogen on integrin αIIbβ3-mediated adhesion. We show that the anti-adhesive fibrinogen layer formed on the surface of fibrin inhibits platelet adhesion. We also demonstrate that fibrinogen immobilized on plastic at high densities (>20 μg/ml) supports weak platelet adhesion whereas at low concentrations (∼2 μg/ml) it is highly adhesive. An investigation of the mechanism underlying differential platelet adhesion indicates that platelet adhesion to rigid substrates (low-density fibrinogen and naked fibrin gel) induces much stronger phosphorylation of FAK and Syk kinases than that to soft substrates (high-density fibrinogen and fibrin exposed to soluble fibrinogen). Furthermore, the rigid, but not the soft substrates induce recruitment of signaling molecules talin and skelemin to αIIbβ3-containing focal adhesions. Consistent with their limited ability to induce sufficient signaling, soft substrates do not support platelet spreading. These data suggest that circulating fibrinogen prevents stable platelet adhesion by modifying the mechanical properties of the fibrin clot’s surface which results in reduced force generation and insufficient signaling.

scholarly journals Neutrophil-activating protein 1/interleukin 8 stimulates the binding activity of the leukocyte adhesion receptor CD11b/CD18 on human neutrophils.

1990 ◽  
Vol 171 (4) ◽  
pp. 1155-1162 ◽  
Author(s):  
P A Detmers ◽  
S K Lo ◽  
E Olsen-Egbert ◽  
A Walz ◽  
M Baggiolini ◽  
...  
Keyword(s):  
Leukocyte Adhesion ◽  
Binding Activity ◽  
Receptor Expression ◽  
Human Neutrophils ◽  
Adhesion Receptor ◽  
Biological Responses ◽  
Specific Granules ◽  
Inflammatory Stimuli ◽  
Adhesive Interactions

The cytokine NAP-1/IL-8 is produced by a variety of different cells in response to inflammatory stimuli and elicits several biological responses from PMN. Experiments presented here demonstrate that PMN exposed to NAP-1/IL-8 expressed increased amounts of CD11b/CD18, as well as CD11c/CD18 and CR1, on their cell surface, while expression of Fc gamma RIII and HLA-A,B,C remained essentially unchanged. Increased CD11b/CD18 and CD11c/CD18 appears to correspond with the release of specific granules by NAP-1/IL-8. NAP-1/IL-8 was also a potent stimulator of several of the binding activities of CD11b/CD18. Ligation of EC3bi by CD11b/CD18 was rapidly enhanced by NAP-1/IL-8, but phagocytosis of the ligated particles was not induced by the agonist. In addition, enhanced binding of EC3bi was observed in the absence of an increase in receptor expression as shown with PMN cytoplasts. NAP-1/IL-8 promoted additional adhesive interactions between CD11b/CD18 and the biosynthetic precursor of LPS, lipid IVa, fibrinogen, and endothelial cells, suggesting that NAP-1/IL-8 may promote leukocyte adhesion in vivo that could lead to recruitment of PMN to sites of tissue inflammation.

Comparative Studies Of Purified Poloxamer 188 Using ClotBased and Viscoelastic Measurements Of Coagulation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4770-4770
Author(s):  
Jawed Fareed ◽  
Debra Hoppensteadt ◽  
Omer Iqbal ◽  
Schuharazad Abro ◽  
Martin Emanuele
Keyword(s):  
Blood Coagulation ◽  
Whole Blood ◽  
Maximum Amplitude ◽  
Fibrin Clot ◽  
Clotting Time ◽  
Poloxamer 188 ◽  
Biochemical Systems ◽  
High Concentrations ◽  
Adhesive Interactions ◽  
Clinically Significant

Background Poloxamer 188 (P188; Mast Therapeutics, Inc.) is a surface-active, non-ionic block copolymer which binds to hydrophobic surfaces on damaged cells improving membrane hydration and lowering adhesion and viscosity.  It is known to improve microvascular function in various pathologic states.  Currently, this agent is under investigation in a phase 3 clinical trial for treatment of sickle cell disease patients experiencing acute vaso-occlusive crisis.  The effect of P188 on blood coagulation and platelet function has been evaluated in several clinical trials where no clinically significant effect has been observed.   In these trials, coagulation studies were based on standard clot based methods (e.g., PT and aPTT) and did not include viscoelastic measurements such as thromboelastography (TEG).   Given P188 alters viscosity, we compared the effect of this agent using various clotbased, chromogenic and viscoelastic measurements of blood coagulation. Materials and Methods Whole blood activated clotting time studies were carried out in groups of healthy individuals (n=10) at a concentration range of 1.872-15.0mg/mL. TEG analysis on native and citratedwhole blood was carried out on TEG 5000 (Haemoscope Corp, Niles, IL) at concentrations of 0-0.45 mg/mL. The effect of P188 on normal plasma clotting parameters, such as PT and aPTT, was measured at a concentration range of 0-10 mg/mL. The effect of P188 on thrombin-induced clot formation was investigated using a fibrinokinetic method. The effect of P188 on thrombin generation was measured using the fluormetric method (Technoclone, Vienna, Austria). The anti-protease effects of P188 were studied using chromogenic substrate methods using isolated biochemical systems. Results At concentrations up to 10 mg/mL, P188 did not produce any modification of Celiteactivated clotting time (Celite-ACT).  At all concentrations the Celite-ACT values remained comparable to saline (138-140 sec for P188 vs. 140 sec for saline).  In the TEG analysis, P188 produced a concentrationdependent hypocoagulant effect in both native and citratedblood as evidenced by increased angle and shortening of maximum amplitude (MA).   In standard PT and aPTT tests, P188 did not produce any effect on the clotting profile at concentrations up to 20 mg/mL.  In fibrinokinetic studies, P188 produced an increase in the fibrin clot density and rate of fibrin polymerization. Discussion These studies demonstrate that even at very high concentrations, P188 does not produce an effect on whole blood clotting as measured by the Celite-ACT assay;   this result was confirmed in other standard assays.  Fibrinokinetic studies revealed an increase in the rate of fibrin formation and clot density.   However, at relatively low concentrations, P188 exhibited a hypocoagulant profile in TEG analysis.  The marked discordance between TEG and other coagulation tests suggest that P188’s effect on viscosity and adhesive interactions result in an artifact in TEG analysis and an incorrect indication of a hypocoagulant effect.  This effect may be due to the viscoelastic endpoint in the TEG assay. Further studies are needed to confirm this hypothesis. Disclosures: Fareed: Mast Therapeutics: Research Funding. Emanuele:Mast Therapeutics: Employment.

Immunoblockade of PSGL-1 attenuates established experimental murine colitis by reduction of leukocyte rolling

2004 ◽  
Vol 287 (1) ◽  
pp. G115-G124 ◽  
Author(s):  
Emile M. Rijcken ◽  
Mike G. Laukoetter ◽  
Christoph Anthoni ◽  
Stephanie Meier ◽  
Rudolf Mennigen ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Activity Index ◽  
Leukocyte Adhesion ◽  
Combined Treatment ◽  
Disease Activity Index ◽  
Leukocyte Recruitment ◽  
Leukocyte Rolling ◽  
Chronic Colitis ◽  
Adhesive Interactions

Recruitment of circulating leukocytes into the colonic tissue is a key feature of intestinal inflammation. P-selectin glycoprotein ligand-1 (PSGL-1) and very late antigen-4 (VLA-4) are expressed on leukocytes and play an important role in leukocyte-endothelial cell adhesive interactions. We examined the effects of immunoneutralization of PSGL-1 and VLA-4 on leukocyte recruitment in vivo in the development and treatment of experimental colitis. Chronic colitis was induced in balb/c mice by oral administration of dextran sodium sulfate (DSS). Monoclonal antibodies 2PH1 (anti-PSGL-1) and PS/2 (anti-VLA-4) or the combination of both were injected intravenously, and leukocyte adhesion was observed for 60 min in colonic submucosal venules by intravital microscopy (IVM) under isoflurane/N2O anesthesia. In addition, mice with established colitis were treated by daily intraperitoneal injections of 2PH1, PS/2, or the combination of both over 5 days. Disease activity index (DAI), histology, and myeloperoxidase (MPO) levels were compared with sham-treated DSS controls. We found that 2PH1 reduced the number of rolling leukocytes (148.7 ± 29.8 vs. 36.9 ± 8.7/0.01 mm2/30 s, P < 0.05), whereas leukocyte velocity was increased (24.0 ± 3.6 vs. 127.8 ± 11.7 μm/s, P < 0.05). PS/2 reduced leukocyte rolling to a lesser extent. Leukocyte firm adhesion was not influenced by 2PH1 but was strongly reduced by PS/2 (24.1 ± 2 vs. 4.4 ± 0.9/0.01 mm2/30 s, P < 0.05). Combined application did not cause additional effects on leukocyte adhesion. Treatment of chronic colitis with 2PH1 or PS/2 reduced DAI, mucosal injury, and MPO levels significantly. Combined treatment led to a significantly better reduction of DAI (0.4 ± 0.1 vs. 2.1 ± 0.2 points) and histology (9.7 ± 0.9 vs. 21.4 ± 4.6 points). In conclusion, PSGL-1 and VLA-4 play an important role for leukocyte recruitment during intestinal inflammation. Therapeutic strategies designed to disrupt interactions mediated by PSGL-1 and/or VLA-4 may prove beneficial in treatment of chronic colitis.

A fundamental role of mAbp1 in neutrophils: impact on β2 integrin–mediated phagocytosis and adhesion in vivo

Blood ◽  
2009 ◽  
Vol 114 (19) ◽  
pp. 4209-4220 ◽  
Author(s):  
Jürgen Schymeinsky ◽  
Ronald Gerstl ◽  
Ingrid Mannigel ◽  
Katy Niedung ◽  
David Frommhold ◽  
...  
Keyword(s):  
Leukocyte Adhesion ◽  
Green Fluorescence Protein ◽  
Actin Binding ◽  
Neutrophil Adhesion ◽  
Flow Conditions ◽  
Down Regulation ◽  
Β2 Integrin ◽  
Factor Α

Abstract The mammalian actin-binding protein 1 (mAbp1, Hip-55, SH3P7) is phosphorylated by the nonreceptor tyrosine kinase Syk that has a fundamental effect for several β2 integrin (CD11/CD18)–mediated neutrophil functions. Live cell imaging showed a dynamic enrichment of enhanced green fluorescence protein–tagged mAbp1 at the phagocytic cup of neutrophil-like differentiated HL-60 cells during β2 integrin–mediated phagocytosis of serum-opsonized Escherichia coli. The genetic absence of Syk or its pharmacologic inhibition using piceatannol abrogated the proper localization of mAbp1 at the phagocytic cup. The genetic absence or down-regulation of mAbp1 using the RNA interference technique significantly compromised β2 integrin–mediated phagocytosis of serum-opsonized E coli or Salmonella typhimurium in vitro as well as clearance of S typhimurium infection in vivo. Moreover, the genetic absence of mAbp1 almost completely abrogated firm neutrophil adhesion under physiologic shear stress conditions in vitro as well as leukocyte adhesion and extravasation in inflamed cremaster muscle venules of mice treated with tumor-necrosis factor α. Functional analysis showed that the down-regulation of mAbp1 diminished the number of β2 integrin clusters in the high-affinity conformation under flow conditions. These unanticipated results define mAbp1 as a novel molecular player in integrin biology that is critical for phagocytosis and firm neutrophil adhesion under flow conditions.

Effects of Epsilon-Aminocaproic Acid on Fibrin Clot Lysis

1966 ◽  
Vol 15 (01/02) ◽  
pp. 173-191 ◽  
Author(s):  
K Egeblad
Keyword(s):  
Trypsin Inhibitor ◽  
Aminocaproic Acid ◽  
Inhibitory Effect ◽  
Fibrin Clot ◽  
Clot Lysis ◽  
Thrombin Time ◽  
Low Concentrations ◽  
Plasma Factor ◽  
High Concentrations

SummaryThe inhibitory effect of EACA on plasmin, urokinase, and SK-activator was investigated by means of fibrin clot lysis. Clot formation and resolution was followed by thrombelastography.Lysis of the simple fibrin clot by plasmin is inhibited by low concentrations of EACA. There is a dual effect of EACA on urokinase induced fibrinolysis. Low concentrations of EACA enhanced, whereas high concentrations inhibited urokinase activity. Assayed in the simple fibrin clot the SK-activator was the most sensitive to EACA inhibition, urokinase fibrinolysis the least.Several factors influence the inhibitory effect of EACA, and the effect depends on the fibrinolytic agent used. The inhibitory effect of EACA on urokinase was strongly potentiated by a plasma factor present in the euglobulin fraction. The effect of EACA on SK-activator was only slightly potentiated by the plasma factor, and there was no effect on plasmin inhibition.In presence of the urinary trypsin inhibitor mingin the inhibitory effect of EACA on urokinase induced fibrinolysis was enormously increased and the enhancing effect of EACA was reversed. Assayed against SK-activator the effect of mingin was less pronounced, and was only slight when assayed against plasmin. The inhibitory effects of the soy bean trypsin inhibitor, the ox lung trypsin inhibitor pulmin, and the pancreas inhibitor of Kunitz on the urokinase fibrinolysis were all slightly decreased in presence of EACA.The thrombin generation in recalcified human plasma, the tissue thromboplastin time, and the thrombin time were all unaffected by even high concentrations of EACA, However, in the thrombelastographie assay, EACA influenced fibrin formation or structure when present together with activators of plasminogen.The multiple effects of EACA on fibrinolysis makes it difficult to elucidate its action in vivo.

scholarly journals The alpha 4-integrin supports leukocyte rolling and adhesion in chronically inflamed postcapillary venules in vivo.

1996 ◽  
Vol 183 (5) ◽  
pp. 1995-2006 ◽  
Author(s):  
B Johnston ◽  
T B Issekutz ◽  
P Kubes
Keyword(s):  
Polymorphonuclear Leukocytes ◽  
Mononuclear Cells ◽  
Leukocyte Adhesion ◽  
Systemic Vasculitis ◽  
Significant Proportion ◽  
Leukocyte Rolling ◽  
Peripheral Blood Mononuclear ◽  
Beta 2 ◽  
Adhesive Interactions

A role for the alpha 4-integrin (alpha 4 beta 1 or alpha 4 beta 7), has been implicated in the recruitment of peripheral blood mononuclear cells (PBMCs) to sites of inflammation. However, the adhesive interactions (i.e., tethering, rolling, and adhesion) mediated by the alpha 4-integrin have not been characterized in vivo. The objective of this study was to establish a model wherein postcapillary venules were chronically inflamed, and then use intravital microscopy to identify the adhesive interactions mediated by the alpha 4-integrin in vivo. Between 4 and 20 d after immunization with Mycobacterium butyricum, animals developed a systemic vasculitis characterized by large increases in the numbers of rolling and adhering leukocytes within mesenteric venules. The selectins could only account for approximately 50% of the leukocyte rolling whereas the remaining cells rolled exclusively via the alpha 4-integrin. Anti-alpha 4 therapy also eliminated the increase in leukocyte adhesion observed in this model, whereas selectin therapies and an anti-CD18 (beta 2-integrin) monoclonal antibody (mAb) did not reduce adhesion. A serum against polymorphonuclear leukocytes (PMNs) was used to confirm that a significant proportion of rolling cells, and most of the adhering cells were PBMCs. Sequential treatment with anti-PMN serum and the anti-alpha 4 mAb demonstrated that alpha 4-dependent rolling was distinct from PMN rolling populations. Initial leukocyte tethering via the alpha 4-integrin could not be demonstrated in this model, whereas L-selectin did support leukocyte tethering. These data suggest that the alpha 4-integrin can mediate both rolling and adhesion in the multistep recruitment of PMBCs in vivo, and these interactions occur independently of the selectins and beta 2-integrins.

Epistatic and pleiotropic effects of polymorphisms in the fibrinogen and coagulation factor XIII genes on plasma fibrinogen concentration, fibrin gel structure and risk of myocardial infarction

2006 ◽  
Vol 95 (03) ◽  
pp. 420-427 ◽  
Author(s):  
Per Eriksson ◽  
Carl-Göran Ericsson ◽  
Anders Hamsten ◽  
Angela Silveira ◽  
Maria Mannila
Keyword(s):  
Myocardial Infarction ◽  
Factor Xiii ◽  
Coagulation Factor ◽  
Fibrin Clot ◽  
Pleiotropic Effects ◽  
Plasma Fibrinogen ◽  
Fibrinogen Concentration ◽  
Fibrin Gel ◽  
Coagulation Factor Xiii ◽  
Clot Structure

SummaryAn intricate interplay between the genes encoding fibrinogen gamma (FGG), alpha (FGA) and beta (FGB), coagulation factor XIII (F13A1) and interleukin6 (IL6) and environmental factors is likely to influence plasma fibrinogen concentration, fibrin clot structure and risk of myocardial infarction (MI). In the present study, the potential contribution of SNPs harboured in the fibrinogen, IL6 and F13A1 genes to these biochemical and clinical phenotypes was examined. A database and biobank based on 387 survivors ofa first MI and population-based controls were used. Sixty controls were selected according to FGG 9340T>C [rs1049636] genotype for studies on fibrin clot structure using the liquid permeation method. The multifactor dimensionality reduction method was used for interaction analyses. We here report that the FGA 2224G>A [rs2070011] SNP (9.2%), plasma fibrinogen concentration (13.1%) and age (8.1%) appeared as independent determinants of fibrin gel porosity. The FGA 2224G>A SNP modulated the relation between plasma fibrinogen concentration and fibrin clot porosity. The FGG-FGA*4 haplotype, composed of the minor FGG 9340C and FGA 2224A alleles, had similar effects, supporting its reported protective role in relation to MI. Significant epistasis on plasma fibrinogen concentration was detected between the FGA 2224G>A and F13A1 Val34Leu [rs5985] SNPs (p<0.001).The FGG 9340T>C and FGB 1038G>A [rs1800791] SNPs appeared to interact on MI risk, explaining the association of FGG-FGB haplotypes with MI in the absence of effects of individual SNPs. Thus, epistatic and pleiotropic effects of polymorphisms contribute to the variation in plasma fibrinogen concentration, fibrin clot structure and risk of MI.

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