Fibrinogen Molecule Research Articles

Quantitative Modeling of Fibrinogen Adsorption on Different Biomaterials

Adsorption processes of biological macromolecules on solid surfaces, e.g. on implant materials, are of scientific, medical and technological interest. The adsorption process of the blood plasma protein fibrinogen from aqueous solutions on biomaterial surfaces is simulated by solving the diffusion equation in one dimension in combination with a two dimensional cellular automaton model. The adsorption/desorption kinetics of fibrinogen on different metallic biomaterials is tracked until a dynamic equilibrium is reached. In addition to mass transfer towards the surface, adsorption of fibrinogen molecules and surface diffusion of single fibrinogen molecules and clusters the algorithm also accounts for the desorption of single molecules. By varying the desorption behavior in the simulation calculation, the equilibrium surface coverage changes in the range of 0.2–0.85, implying more flexible and higher surface coverage than previous models. The influences of surface properties of the biomaterials and of the initial concentration of fibrinogen on the adsorption process are quantified. Experimental results from the literature on fibrinogen adsorption kinetics are compared with our simulation results and illustrate good quantitative agreement that is only achievable using desorption as essential model component.

USAGE OF MONOCLONAL ANTIBODIES FOR DETERMINATION OF LOCALIZATION OF ANTIGENIC DETERMINANTS AND FIBRIN POLYMERIZATION SITES WITHIN FIBRINOGEN AND FIBRIN MOLECULES AND THEIR APPLICATION IN TEST--SYSTEMS FOR DIAGNOSTICS AND THE THREAT OF THROMBUS FORMATION

33 Fibrinogen (Fg) is a protein playing the main role in functioning of blood coagulation system [1]. It has a dimeric structure where two subunits are formed by three polypeptide chains: Aα, Bβ and γ. The fibrinogen molecule consists of a central E, two peripheral Dregions and two extended αC-regions. The E-region, consisting of (Aα1-104, Bβ1133, γ1-72)2, is formed by the N-terminal segments of all six polypeptide chains. The two Dregions, each comprising of Aα105-219, Bβ134-461 and γ73-411 in the C part of the molecule, have the globular βC232-461 and γC170-411 nodules. The extended αC-regions UDK 547.962.4

AFM/TIRFM Study of Individual Fibrin Fibers

Colocalized imaging of individual fibrin fibers by combined atomic force microscopy (AFM) and total internal reflection fluorescence microscopy (TIRFM) was used to gain insights into the structure and the effects of the degree of hydration. In AFM images obtained under buffer conditions, fibrin fibers appear flattened, with heights one order of magnitude smaller (tens of nm) than diameters (hundreds of nm), with thicker fibers more flattened. All fibers present thickness variations along their length, of up to 3 nm in diameter per 10 nm length of fiber. Branching of fibers, at angles between 0-900 was also observed. High resolution imaging reveals the periodic structure of fibers, with a periodicity of 23 nm corresponding to half-staggering of protofibrils. Exchange of the physiological buffer with water increases the cross-sectional area of individual fibers to more than double. In dehydration and rehydration experiments, identical fibers show large variations in cross-sectional area. Upon drying, cross sections decrease by up to more than 80% while upon rehydration the same cross sections increase by a factor of up to three, relative to the dry value. TIRFM imaging of the same fibers showed that fibers fluorescence correlated with the topographical features imaged by AFM, suggesting that labeled protein is uniformly distributed throughout the fibers. Single-molecule TIRFM imaging of fibrinogen molecules, basic constituents of fibers, allows for a molecular calibration that determines the number of molecules in individual fibers; correlated with AFM topographical data informs to the degree of hydration of the fibers - a major question in the fibrin fiber structure.

The Effect of Reagents Mimicking Oxidative Stress on Fibrinogen Function

Fibrinogen is one of the plasma proteins most susceptible to oxidative modification. It has been suggested that modification of fibrinogen may cause thrombotic/bleeding complications associated with many pathophysiological states of organism. We exposed fibrinogen molecules to three different modification reagents—malondialdehyde, sodium hypochlorite, and peroxynitrite—that are presented to various degrees in different stages of oxidative stress. We studied the changes in fibrin network formation and platelet interactions with modified fibrinogens under flow conditions. The fastest modification of fibrinogen was caused by hypochlorite. Fibers from fibrinogen modified with either reagent were thinner in comparison with control fibers. We found that platelet dynamic adhesion was significantly lower on fibrinogen modified with malondialdehyde and significantly higher on fibrinogen modified either with hypochlorite or peroxynitrite reflecting different prothrombotic/antithrombotic properties of oxidatively modified fibrinogens. It seems that, in the complex reactions ongoing in living organisms at conditions of oxidation stress, hypochlorite modifies proteins (e.g., fibrinogen) faster and more preferentially than malondialdehyde. It suggests that the prothrombotic effects of prior fibrinogen modifications may outweigh the antithrombotic effect of malondialdehyde-modified fibrinogen in real living systems.

Fibrinogen interaction with the red blood cell membrane

A brief review of the fibrinogen molecule composition and structure is presented like as an introduction to the effects of this plasma protein on the red blood cell hemorheoplogical properties namely erythrocyte aggregation tendency and deformability ability. The protein membrane RBC target for fibrinogen is also highlight as well as the erythrocyte signal transduction pathway associated with nitric oxide mobilization resulting from its binding.

Tuning conformations of fibrinogen monolayers on latex particles by pH of adsorption

Adsorption of fibrinogen on polystyrene latex particles was studied using the micro-electrophoretic and the concentration depletion methods. Measurements were carried out for pH 3.5, 7.4 and ionic strength of 0.15M, NaCl. Electrophoretic mobility of latex was determined as a function of the amount of adsorbed fibrinogen, expressed as a surface concentration. A monotonic increase in the electrophoretic mobility (zeta potential) of the latex was observed, indicating a significant adsorption of fibrinogen on latex for pH equal to 3.5 and 7.4, respectively. The anomalous adsorption in the latter case was explained in terms of the heterogeneous charge distribution on the fibrinogen molecule. The stability of fibrinogen monolayers formed on latex was also determined in pH cycling between 3.5 and 9.7. These measurements revealed that fibrinogen adsorption was irreversible, governed by the two main adsorption mechanisms: (i) the unoriented (random) mechanism prevailing for pH=3.5 where adsorbing molecules significantly penetrate the latex particle core and (ii) the side-on adsorption mechanism prevailing for pH equal to 7.4. In both cases, variations in the zeta potential with the fibrinogen coverage were adequately described in terms of the electrokinetic model, previously formulated for particle adsorption on planar substrates. Based on these experimental data, an efficient procedure of preparing fibrinogen monolayers on latex particles of controlled conformations and coverage was envisaged.

The value of numerical modeling of aquifers in data-poor regions

The adsorption and desorption of plasma proteins—albumin, γ-globulin, and fibrinogen—on copolypeptide and silicone surfaces have been studied. The process is characterized by three stages; an initial brief period where adsorption is reversible; a second phase where the adsorbed proteins undergo a slow conformation change based on the period of adsorption and where protein is essentially irreversibly adsorbed; in the final stage, denatured material is slowly desorbed. In the second stage the process is essentially irreversible, desorption being very slow; the third stage is essentially irreversible, adsorption of denatured material being improbable. The adsorption process may be represented by a two-state Oreskes/Singer plot, there being an apparent surface phase change at 50–60% surface coverage. Albumin and fibrinogen molecules are adsorbed side-on; γ-globulin is adsorbed in an end-on configuration. Surface denaturation seems to be driven by a need to increase hydrophobic bonding with the surface and adsorption is heavily entropic in nature. In the desorbed material, albumin and fibrinogen sustain a marked decrease in α-helical content; γ-globulin loses most of its β-sheet structure.

Resolving Two-dimensional Kinetics of the Integrin αIIbβ3-Fibrinogen Interactions Using Binding-Unbinding Correlation Spectroscopy

Using a combined experimental and theoretical approach named binding-unbinding correlation spectroscopy (BUCS), we describe the two-dimensional kinetics of interactions between fibrinogen and the integrin αIIbβ3, the ligand-receptor pair essential for platelet function during hemostasis and thrombosis. The methodology uses the optical trap to probe force-free association of individual surface-attached fibrinogen and αIIbβ3 molecules and forced dissociation of an αIIbβ3-fibrinogen complex. This novel approach combines force clamp measurements of bond lifetimes with the binding mode to quantify the dependence of the binding probability on the interaction time. We found that fibrinogen-reactive αIIbβ3 pre-exists in at least two states that differ in their zero force on-rates (k(on1) = 1.4 × 10(-4) and k(on2) = 2.3 × 10(-4) μm(2)/s), off-rates (k(off1) = 2.42 and k(off2) = 0.60 s(-1)), and dissociation constants (K(d)(1) = 1.7 × 10(4) and K(d)(2) = 2.6 × 10(3) μm(-2)). The integrin activator Mn(2+) changed the on-rates and affinities (K(d)(1) = 5 × 10(4) and K(d)(2) = 0.3 × 10(3) μm(-2)) but did not affect the off-rates. The strength of αIIbβ3-fibrinogen interactions was time-dependent due to a progressive increase in the fraction of the high affinity state of the αIIbβ3-fibrinogen complex characterized by a faster on-rate. Upon Mn(2+)-induced integrin activation, the force-dependent off-rates decrease while the complex undergoes a conformational transition from a lower to higher affinity state. The results obtained provide quantitative estimates of the two-dimensional kinetic rates for the low and high affinity αIIbβ3 and fibrinogen interactions at the single molecule level and offer direct evidence for the time- and force-dependent changes in αIIbβ3 conformation and ligand binding activity, underlying the dynamics of fibrinogen-mediated platelet adhesion and aggregation.

Association of vitamin D with cardiometabolic risk factors in rheumatoid arthritis

Individuals with rheumatoid arthritis (RA) are at a greater risk for cardiovascular disease (CVD). Vitamin D deficiency is a potential risk factor for CVD and metabolic syndrome. Since patients with RA have a high prevalence of vitamin D deficiency, we investigated the association of vitamin D levels with cardiometabolic risk factors in a cohort of RA patients with no prior history of CVD. Serum 25-hydroxyvitamin D (25[OH]D) levels were measured among RA patients enrolled in a cohort study of subclinical CVD. The cross-sectional associations of 25(OH)D levels with traditional CVD risk factors such as insulin resistance (IR; estimated using the homeostatic model assessment [HOMA]), adipokines, markers of systemic inflammation, and endothelial activation were explored, adjusting for pertinent sociodemographic, lifestyle, and RA characteristics. Among 179 RA patients, 73 (41%) had a 25(OH)D level <30 ng/ml. Only 23 patients (13%) had a 25(OH)D level ≥45 ng/ml. After adjusting for demographics and body mass index (BMI), 25(OH)D remained significantly associated with high-density lipoprotein (HDL) cholesterol and inversely associated with HOMA-IR, fibrinogen, E-selectin, and soluble intercellular adhesion molecule 1 (sICAM-1). Significant associations with HDL cholesterol, E-selectin, and sICAM-1 were maintained after adjusting for the Disease Activity Score in 28 joints (DAS28) and autoantibody status. These associations were similar between the groups subdivided by sex, ethnicity, BMI, DAS28 level, and autoantibody status. These data suggest that vitamin D deficiency is common in RA and may be independently associated with several cardiometabolic intermediates in this population.

Molecular Interaction of Poly(acrylic acid) Gold Nanoparticles with Human Fibrinogen

The binding of fibrinogen to various nanoparticles can result in protein unfolding and exposure of cryptic epitopes that subsequently interact with cell surface receptors. This response is dependent on the size, charge, and concentration of the nanoparticle. Here we examine the binding kinetics of human fibrinogen to negatively charged poly(acrylic acid)-coated gold nanoparticles ranging in size from 7 to 22 nm. These particles have previously been shown to elicit an inflammatory response in human cells. The larger nanoparticles bound fibrinogen with increasing affinity and a slower dissociation rate. Each fibrinogen molecule could accommodate two 7 nm nanoparticles but only one when the diameter increased to 10 nm. Nanoparticles larger than 12 nm bound multiple fibrinogen molecules in a positively cooperative manner. However, in the presence of excess nanoparticle, fibrinogen induced aggregation of the larger particles that could bind more than one protein molecule. This is consistent with interparticle bridging by the fibrinogen. Taken together, these results demonstrate that subtle changes in nanoparticle size can influence protein binding both with the surface of the nanoparticle and within the protein corona.

Fibrinogen, Riboflavin, and UVA to Immobilize a Corneal Flap – Molecular Mechanisms

Tissue glue containing fibrinogen (FIB) and riboflavin (RF), upon exposure to long wavelength ultraviolet light (UVA, 365 nM) has been proposed potentially to solve long-standing problems presented by corneal wound and epithelial ingrowth side-effects from laser-assisted in situ keratomileuis (LASIK). Data presented in a previous study demonstrated an ability of FIB + RF + UVA to adhere two stromal surfaces; however, to our knowledge no molecular mechanisms have been proposed to account for interactions occurring between corneal extracellular matrix (ECM) and tissue glue molecules. Here, we document several covalent and noncovalent interactions between these classes of macromolecules. SDS-PAGE and Western blot techniques were used to identify covalent interactions between tissue glue molecules and corneal ECM molecules in either the presence or absence of RF and UVA, in vitro and ex vivo. Surface plasmon resonance (SPR) was used to characterize noncovalent interactions, and obtain k(a), k(d), and K(D) binding affinity values. SDS-PAGE and Western blot analyses indicated that covalent interactions occurred between neighboring FIB molecules, as well as between FIB and collagen type I (Coll-I) proteins (in vitro and ex vivo). These interactions occurred only in the presence of RF and UVA. SPR data demonstrated the ability of FIB to bind noncovalently to corneal stroma molecules, Coll-I, decorin, dermatan sulfate, and corneal basement membrane molecules, laminin and heparan sulfate--only in the presence of Zn(2+). Covalent and (zinc-mediated) noncovalent mechanisms involving FIB and stromal ECM molecules contribute to the adhesion created by FIB + RF + UVA.

Interaction of Serum Proteins with Surface of Hemodialysis Fiber Membranes

The poly(vinyl pyrrolidone)-covered hydrophilic surface of hollow-fiber membranes (fiber membrane, hereafter) for hemodialysis was mechanically probed using modified tips on an atomic force microscope (AFM) with covalent crosslinkers and several types of serum protein. The retraction part of many of the force extension (F–E) curves obtained with AFM tips coated with serum albumin had a long and smooth extension up to 200–300 nm indicating forced elongation of poly(vinyl pyrrolidone) chains. When fibrinogen-coated tips were used, long extension F–E curves up to 500 nm with multiple peaks were obtained in addition to smooth curves most likely reflecting the unfolding of fibrinogen molecules. The results indicated that individual polymer chains had a significant affinity toward serum proteins. The adhesion frequency of tips coated with serum proteins was lower on the poly(vinyl pyrrolidone) surface than on the uncoated hydrophobic polysulfone surface.

Interaction of Serum Proteins with Surface of Hemodialysis Fiber Membranes

The poly(vinyl pyrrolidone)-covered hydrophilic surface of hollow-fiber membranes (fiber membrane, hereafter) for hemodialysis was mechanically probed using modified tips on an atomic force microscope (AFM) with covalent crosslinkers and several types of serum protein. The retraction part of many of the force extension (F–E) curves obtained with AFM tips coated with serum albumin had a long and smooth extension up to 200–300 nm indicating forced elongation of poly(vinyl pyrrolidone) chains. When fibrinogen-coated tips were used, long extension F–E curves up to 500 nm with multiple peaks were obtained in addition to smooth curves most likely reflecting the unfolding of fibrinogen molecules. The results indicated that individual polymer chains had a significant affinity toward serum proteins. The adhesion frequency of tips coated with serum proteins was lower on the poly(vinyl pyrrolidone) surface than on the uncoated hydrophobic polysulfone surface.

Fibrinogen conformations and charge in electrolyte solutions derived from DLS and dynamic viscosity measurements

Hydrodynamic properties of fibrinogen molecules were theoretically calculated. Their shape was approximated by the bead model, considering the presence of flexible side chains of various length and orientation relative to the main body of the molecule. Using the bead model, and the precise many-multipole method of solving the Stokes equations, the mobility coefficients for the fibrinogen molecule were calculated for arbitrary orientations of the arms whose length was varied between 12 and 18nm. Orientation averaged hydrodynamic radii and intrinsic viscosities were also calculated by considering interactions between the side arms and the core of the fibrinogen molecule. Whereas the hydrodynamic radii changed little with the interaction magnitude, the intrinsic viscosity exhibited considerable variation from 30 to 60 for attractive and repulsive interactions, respectively. These theoretical results were used for the interpretation of experimental data derived from sedimentation and diffusion coefficient measurements as well as dynamic viscosity measurements. Optimum dimensions of the fibrinogen molecule derived in this way were the following: the contour length 84.7nm, the side arm length 18nm, and the total volume 470nm3, which gives 16% hydration (by volume). Our calculations enabled one to distinguish various conformational states of the fibrinogen molecule, especially the expanded conformation, prevailing for pH<4 and lower ionic strength, characterized by high intrinsic viscosity of 50 and the hydrodynamic radius of 10.6nm. On the other hand, for the physiological condition, that is, pH=7.4 and the ionic strength of 0.15M NaCl, the semi-collapsed conformation dominates. It is characterized by the average angle equal to <φ>=55°, intrinsic viscosity of 35, and the hydrodynamic radius of 10nm. Additionally, the interaction energy between the arms and the body of the molecule was predicted to be −4kT units, confirming that they are oppositely charged than the central nodule. Results obtained in our work confirm an essential role of the side chains responsible for a highly anisotropic charge distribution in the fibrinogen molecule. These finding can be exploited to explain anomalous adsorption of fibrinogen on various surfaces.

Anticoagulant activity of Moon jellyfish (Aurelia aurita) tentacle extract

Moon jellyfish (Aurelia aurita) tentacle extract was studied for its anticoagulant activity in vitro. The Jellyfish Tentacle Extract (JFTE) showed very strong fibrinogenolytic activity by cleaving Aα and Bβ chain of fibrinogen molecule. The fibrinogenolytic activity was found to be stronger than some snake venom derived anticoagulants. JFTE also completely liquefied fibrin clots in 24 h. JFTE was found to contain both high and low molecular weight proteins/peptides. The fibrinogenolysis appears to be caused by high molecular weight fractions of the extract. It has been also noted that PMSF significantly reduced fibrinogenolytic activity and heating totally abolished it. Autolytic degradation of the high molecular weight protein was also noted. Autolysis slowed down, but did not abolish the fibrinogenolytic activity of the extract.

Molecular analysis of afibrinogenemic mutations caused by a homozygous FGA1238 bp deletion, and a compound heterozygous FGA1238 bp deletion and novel FGA c.54+3A&gt;C substitution

We identified two afibrinogenemic girls in two Japanese families and performed molecular analysis to clarify the mechanisms of fibrinogen defects. Genetic analyses were performed by PCR amplification of the fibrinogen gene and DNA sequence analysis. To analyze the mechanisms of mature fibrinogen defects in plasma, we cloned minigenes from the proposita’s PCR-amplified DNA, transfected them into CHO cells, and sequenced the cDNA amplified with the RT reaction followed by PCR. Sequence analyses indicated that one was caused by a homozygous 1238 bp deletion of the fibrinogen Aα-chain gene (FGAΔ1238) and the other was a compound heterozygous FGAΔ1238 and novel FGA c.54+3A>C substitution. The minigene corresponding to FGAΔ1238 generates two aberrant mRNAs, both of which may induce a frameshift and terminate prematurely. In contrast, the minigene corresponding to FGA c.54+3A>C generates two aberrant mRNAs, one of which may induce a frameshift and terminate prematurely, and the other uses a cryptic 5′ splice site in exon 1, resulting in the deletion of six amino acids in signal peptides. Molecular analyses of both genetic variants suggest that the lack of a mature Aα-chain, impaired assembly, and/or secretion of the fibrinogen molecule may lead to afibrinogenemia.

The anchoring of fibrinogen to a bioactive glass investigated by FT-IR spectroscopy

The attachment of fibrinogen on the bioactive glass surface is investigated by means of Fourier transform infrared spectroscopy (FT-IR). The β-sheet/β-turn ratio estimated from the deconvolution of the amide I band of adsorbed fibrinogen indicates a good biocompatibility of the substrate. In vitro study shows the bioactive character of bioactive glass with attached fibrinogen, and at the same time severe conformational changes in secondary structures of the adsorbed fibrinogen molecules were identified. These changes were found to be determined by electrostatic interaction between the positive charged site of the protein and negative charges on bioactive glass surface, and, by interaction between protein carboxyls and, the phosphate and calcium ions from simulated body fluid (SBF). The most pronounced conformational modifications were observed in the first three days of immersion in SBF; after seven days of immersion these changes were attenuated. FT-IR imaging measurements were also performed to understand the role played by the attached fibrinogen on the hydroxyapatite (HA) layer formation on the glass surface. The HA layer was observed during the first days in relation to the sample without fibrinogen.

Control of Anti-Thrombogenic Properties: Surface-Induced Self-Assembly of Fibrinogen Fibers

Wound healing is a complex process initiated by the formation of fibrin fibers and endothelialization. Normally, this process is triggered in a wound by thrombin cleavage of fibrinopeptides on fibrinogen molecules, which allows them to self spontaneously-assemble into large fibers that provide the support structure of the clot and promote healing. We have found that the fibrous structures can also form without thrombin on most polymer or metal surfaces, including those commonly used for stents. We show that the relatively hydrophobic E and D regions of the fibrinogen molecule are adsorbed on these surfaces, exposing the αC domains, which in turn results in the formation of large fiber structures that promote endothelial cell adhesion. We show that the entire process can be suppressed when stents or other substrates are coated with polymers that are functionalized to bind the αC domains, leading to the development of potentially nonthrombogenic implant materials.

Protective effects of (−)-epicatechin against nitrative modifications of fibrinogen

Fibrinogen appears to be particularly sensitive to toxic action of peroxynitrite; a potent oxidizing and nitrating species. An increased nitration of fibrinogen has been reported in cardiovascular diseases. The defense mechanisms against PN are crucial for complex hemostasis process. Flavonoids have antioxidative properties and could protect biomolecules against action of peroxynitrite. The aim of our studies was to establish, if (−)-epicatechin may in vitro protect fibrinogen molecule against peroxynitrite-induced nitration of tyrosines and change its thrombin-catalyzed polymerization. The exposure of purified fibrinogen (6μM) to peroxynitrite (1–100μM) resulted in both structural modifications and clotting ability of this glycoprotein. Peroxynitrite at the concentration of 1μM increased maximum velocity of Fg polymerization, whereas exposure to 100μM PN resulted in a significant decrease of Vmax. (−)-Epicatechin (1–100μM) caused a dose-dependent inhibition of 3-nitrotyrosine formation in fibrinogen treated with peroxynitrite (100μM) in both Western blot assays and C-ELISA assays. At the highest concentration of (−)-epicatechin (100μM) the level of 3-NT in fibrinogen reached the control values. At lower doses (−)-epicatechin reduced tyrosine nitration by approx. 23% and 40% at the concentration of 1μM and 10μM, respectively. (−)-Epicatechin also abolished the pro-thrombotic effect of peroxynitrite on fibrinogen clotting. The presented in vitro results demonstrated for the first time that (−)-epicatechin might have protective effects against the impairment of structure and properties of Fg, caused by action of the strong biologic oxidant/nitration and inflammatory mediators.

Exercise intervention and inflammatory markers in coronary artery disease: A meta-analysis

Inflammatory activity plays a role in the development and progression of coronary artery disease (CAD), and exercise confers survival benefit. We performed a meta-analysis of changes in inflammatory biomarkers over the course of exercise interventions in patients with CAD. We searched MEDLINE, Embase, the Cochrane Collaboration, AMED, and CINAHL for studies reporting peripheral inflammatory biomarker concentrations before and after exercise interventions of ≥ 2 weeks in patients with CAD. Data were summarized using standard mean differences (SMD) and 95% CIs. Twenty-three studies were included. Concentrations of C-reactive protein (CRP; SMD -0.345, 95% CI -0.444 to -0.246, n = 1,466, P < .001), interleukin 6 (SMD -0.546, 95% CI -0.739 to -0.353, n = 280, P < .001), fibrinogen (SMD -0.638, 95% CI -0.953 to -0.323, n = 247, P < .001), and vascular cell adhesion molecule 1 (SMD -0.413, 95% CI -0.778 to -0.048, n = 187, P = .027) were lower postintervention. Higher total cholesterol (B = -0.328, 95% CI -0.612 to -0.043, P = .026) and higher total/high-density lipoprotein cholesterol ratios (B = -0.250, 95% CI -0.425 to -0.076, P = .008) at baseline were associated with greater reductions in CRP. In controlled studies, follow-up concentrations of CRP (SMD -0.500, 95% CI -0.844 to -0.157, n(exercise/control) = 485/284, P = .004), and fibrinogen (SMD -0.544, 95% CI -1.058 to -0.030, n(exercise/control) = 148/100, P = .038) were lower in subjects who exercised compared with controls. Exercise training is associated with reduced inflammatory activity in patients with CAD. C-reactive protein and fibrinogen have provided the strongest evidence. Higher baseline CRP and adverse baseline lipid profiles predicted greater reductions in CRP.