Quantile-specific heritability of plasma fibrinogen concentrations

Background Fibrinogen is a moderately heritable blood protein showing different genetic effects by sex, race, smoking status, pollution exposure, and disease status. These interactions may be explained in part by “quantile-dependent expressivity”, where the effect size of a genetic variant depends upon whether the phenotype (e.g. plasma fibrinogen concentration) is high or low relative to its distribution. Purpose Determine whether fibrinogen heritability (h2) is quantile-specific, and whether quantile-specific h2 could account for fibrinogen gene-environment interactions. Methods Plasma fibrinogen concentrations from 5689 offspring-parent pairs and 1932 sibships from the Framingham Heart Study were analyzed. Quantile-specific heritability from offspring-parent (βOP, h2 = 2βOP/(1+rspouse)) and full-sib regression slopes (βFS, h2 = {(1+8rspouseβFS)0.05–1}/(2rspouse)) were robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples. Results Quantile-specific h2 (±SE) increased with increasing percentiles of the offspring’s age- and sex-adjusted fibrinogen distribution when estimated from βOP (Ptrend = 5.5x10-6): 0.30±0.05 at the 10th, 0.37±0.04 at the 25th, 0.48±0.05 at the 50th, 0.61±0.06 at the 75th, and 0.65±0.08 at the 90th percentile, and when estimated from βFS (Ptrend = 0.008): 0.28±0.04 at the 10th, 0.31±0.04 at the 25th, 0.36±0.03 at the 50th, 0.41±0.05 at the 75th, and 0.50±0.06 at the 90th percentile. The larger genetic effect at higher average fibrinogen concentrations may contribute to fibrinogen’s greater heritability in women than men and in Blacks than Whites, and greater increase from smoking and air pollution for the FGB -455G>A A-allele. It may also explain greater fibrinogen differences between: 1) FGB -455G>A genotypes during acute phase reactions than usual conditions, 2) GTSM1 and IL-6 -572C>G genotypes in smokers than nonsmokers, 3) FGB -148C>T genotypes in untreated than treated diabetics, and LPL PvuII genotypes in macroalbuminuric than normoalbuminuric patients. Conclusion Fibrinogen heritability is quantile specific, which may explain or contribute to its gene-environment interactions. The analyses do not disprove the traditional gene-environment interpretations of these examples, rather quantile-dependent expressivity provides an alternative explanation that warrants consideration.

Risks of Cardiovascular Events in Patients with Inflammatory Bowel Disease in China: A Retrospective Multicenter Cohort Study

Background Inflammatory bowel disease (IBD) is a complex chronic disorder characterized by systemic inflammation, which may cause abnormal state of coagulation, resulting in cardiac events. This study aimed to investigate the incidences and risks of cardiac events in patients with IBD in China. Methods A retrospective cohort study was performed comprising 1,435 patients with IBD from 12 IBD centers in China. Cases were matched with 1,588 eligible participants without IBD from 12 medical centers according to age, sex, and laboratory parameters. Results Patients with IBD in China exhibited significantly higher incidences of ischemic heart disease (IHD) (coronary heart disease included) but lower frequencies of right bundle branch block and premature contraction than those of matched controls. The risk of IHD increased in patients with IBD, peaking at the age of 18−35 years. Female patients with IBD were more likely to experience IHD than male patients. C-reactive protein (CRP) levels and neutrophil count in the peripheral blood were positively related with the risk of IHD among patients with Crohn’s disease (CD), whereas plasma fibrinogen levels were negatively related with the risk of IHD both in patients with CD and UC. Conclusions The risk of IHD is increased in patients with IBD, especially in young female patients with IBD when compared to matched non-IBD subjects. CRP and plasma fibrinogen levels and neutrophil count in the peripheral blood may be potential predictors associated with the occurrence of IHD in patients with IBD. The study’s findings have significant implications for the management and prevention of cardiac events in patients with IBD.

Prognostic Significance of the Combined Score of Plasma Fibrinogen and Neutrophil-Lymphocyte Ratio in Patients with Spontaneous Intracerebral Hemorrhage

Background. The combination of plasma fibrinogen and neutrophil to lymphocyte ratio (F-NLR) score is a novel inflammatory marker constituted by peripheral blood fibrinogen concentration and neutrophil to lymphocyte ratio. In the current study, we aim to explore the relationship between admission F-NLR score and intracerebral hemorrhage (ICH) and assess its prognostic predictive ability in ICH patients. Methods. The original cohort was consecutively recruited from August 2014 to September 2017, and the validation cohort was consecutively recruited between October 2018 and March 2020. The primary outcomes were 3-month functional outcome and 1-month mortality. All statistical analyses were performed using SPSS and R software. Results. A total of 431 and 251 ICH patients were included in original cohort and validation cohort, respectively. In the original cohort, F-NLR score could independently predict the 3-month functional outcome (adjusted OR 2.013, 95% CI 1.316-3.078, p = 0.001 ) and 1-month mortality (adjusted OR 3.036, 95% CI 1.965-4.693, p < 0.001 ). Receiver operation characteristic (ROC) analyses and predictive model comparison indicated that F-NLR score had a stronger predictive ability in the 3-month outcome and 1-month mortality. Validation cohort verified the results. Conclusion. F-NLR score was an independent indicator for both the 3-month functional outcome and 1-month mortality, and its prognostic predictive ability was superior to fibrinogen and NLR in both the original and the validation cohort.

Suppression of fibrin(ogen)-driven pathologies through controlled knockdown by lipid nanoparticle delivery of siRNA

Fibrinogen plays a pathologic role in multiple diseases. It contributes to thrombosis and modifies inflammatory and immune responses, supported by studies in mice expressing fibrinogen variants with altered function or with a germline fibrinogen deficiency. However, therapeutic strategies to safely and effectively tailor plasma fibrinogen concentration are lacking. Here, we developed a strategy to tune fibrinogen expression by administering lipid nanoparticle (LNP)-encapsulated siRNA targeting the fibrinogen α chain (siFga). Three distinct LNP-siFga reagents reduced both hepatic Fga mRNA and fibrinogen levels in platelets and plasma, with plasma levels decreased to 42%, 16% and 4% of normal within one-week of administration. Using the most potent siFga, circulating fibrinogen was controllably decreased to 32%, 14%, and 5% of baseline with a 0.5, 1, and 2 mg/kg dose, respectively. Whole blood from mice treated with siFga formed clots with significantly decreased clot strength ex vivo, but siFga treatment did not compromise hemostasis following saphenous vein puncture or tail transection. In an endotoxemia model, siFga suppressed the acute phase response and decreased plasma fibrinogen, D-dimer, and proinflammatory cytokine levels. In a sterile peritonitis model, siFga restored normal macrophage migration in plasminogen-deficient mice. Finally, treatment of mice with siFga decreased the metastatic potential of tumour cells in a manner comparable to that observed in fibrinogen-deficient mice. The results indicate that siFga causes robust and controllable depletion of fibrinogen and provide the proof-of-concept that this strategy can modulate the pleiotropic effects of fibrinogen in relevant disease models.

Nitric oxide and fibrinogen in patients with subclinical hypothyroidism and their possible relation to cardiovascular damage

Endothelial dysfunction as well as hypercoagulability have been described as the initial triggers of atherosclerosis and cardiovascular damage and have been associated with subclinical hypothyroidism (SHC). The aim of this research was to determine the concentration of nitric oxide (NO), fibrinogen and circulating lipids in patients with subclinical hypothyroidism and to correlate these variables with thyrotropin (TSH) concentration to establish their possible association with the development of cardiovascular damage. A descriptive, cross-sectional, correlational study was conducted at the IESS Hospital in Riobamba, Ecuador, in the period from January 2019 to September 2021. Ninety-five subjects were studied (65 patients with CAH and 30 controls). The concentration of total cholesterol, triglycerides, HDL cholesterol and LDL cholesterol, TSH, free thyroxine, ON and fibrinogen were determined. Results: We found a decrease in the concentration of ON (p<0.001), accompanied by an increase in the concentration of total cholesterol (p<0.0001), LDL cholesterol (p<0.01) and fibrinogen (p<0.0001) in patients with CAH vs. controls. A negative correlation (p<0.0001; r= -0.5020) was observed between TSH and ON and a positive correlation (p<0.0001; r= 5412) between TSH and plasma fibrinogen in patients with CAH. Conclusion: patients with CAH showed a decrease in serum ON levels and an elevation in plasma fibrinogen concentration. Both measurements correlated significantly with TSH concentration. These parameters associated with an increase in total cholesterol and LDL cholesterol could favor vascular dysfunction, the development of atherosclerosis and consequent cardiovascular damage.

Measurement of Plasma Fibrinogen Levels, PT and APTT among HIV Infected Patients: A Critical Bio-Marker for Coagulation Dysfunctions

Background: The literature stated that Human immunodeficiency virus (HIV) infection led to activation of coagulation, and habitually linked with an augmented risk of venous and arterial thrombosis. So the purpose of the study was to determine the plasma fibrinogen level in Sudanese HIV-infected patients. Materials and Methods: A total of one hundred participants were recruited, and classified into two groups; the case group include (50) HIV patients, and the control group enrolled (50) healthy individuals. Three ml of blood was collected. Fresh Poor Plasma was prepared from citrated venous blood by centrifuged for 15 minutes at 3000 pm. Fibrinogen levels were measured by an automated coagulation analyzer (Thrombolyzer XRC Germany). Data were collected using a directly structured questionnaire. Data were analyzed using SPSS Version 21. Results: The present study showed that the mean of plasma fibrinogen levels was statistically significantly higher in HIV infection in comparison with those normal healthy control (470.50 ±67.75 vs 214.75±21.25 with P-value 0.00). There was a significantly decreased level of PT, and PTT among the HIV group comparing with the control (9.575±0.64, and 22.39±4.94) VS (12.483±0.72, and 30.78±3.55) consequently, (P-value ≤0.001). Fibrinogen levels were significantly increased with the progression of HIV disease (469.84 ±67.15, 472.74 ±87.75, 478.47 ±61.92) in stage I, stage II, and stage III respectively. Conclusions: An HIV-infected patient had elevated plasma fibrinogen levels, as well as other coagulation dysfunctions.

Hypofibrinogenemia with preserved hemostasis and protection from thrombosis in mice with a Fga truncation mutation

Genetic variants within the fibrinogen Aa-chain encoding the aC-region commonly result in hypodysfibrinogenemia in patients. However, the (patho)physiological consequences and underlying mechanisms of such mutations remain undefined. Here, we generated Fga270 mice carrying a premature termination codon within the Fga gene at residue 271. The Fga270 mutation was compatible with Mendelian inheritance for offspring of heterozygous crosses. Adult Fga270/270 mice were hypofibrinogenemic with ~10% plasma fibrinogen levels relative to FgaWT/WTmice, linked to 90% reduction in hepatic Fga mRNA due to nonsense-mediated decay of the mutant mRNA. Fga270/270 mice had preserved hemostatic potential in vitro and in vivo in models of tail bleeding and laser-induced saphenous vein injury, while Fga-/- mice had continuous bleeding. Platelets from FgaWT/WTandFga270/270 mice displayed comparable initial aggregation following ADP stimulation, but Fga270/270 platelets quickly disaggregated. Despite ~10% plasma fibrinogen, the fibrinogen level in Fga270/270 platelets was ~30% of FgaWT/WT platelets with a compensatory increase in fibronectin. Notably, Fga270/270 mice showed complete protection from thrombosis in the inferior vena cava stasis model. In a model of Staphylococcus aureus peritonitis, Fga270/270 mice supported local, fibrinogen-mediated bacterial clearance and host survival comparable to FgaWT/WT, unlike Fga-/- mice. Decreasing the normal fibrinogen levels to ~10% with siRNA in mice also provided significant protection from venous thrombosis without compromising hemostatic potential and antimicrobial function. These findings both reveal novel molecular mechanisms underpinning fibrinogen aC-region truncation mutations and highlight the concept that selective fibrinogen reduction may be efficacious for limiting thrombosis while preserving hemostatic and immune protective functions.

Albumin and fibrinogen kinetics in sepsis: a prospective observational study

Background The measurement of circulating substrate concentrations does not provide information about substrate kinetics. It, therefore, remains unclear if a decrease in plasma concentration of albumin, as seen during critical illness, is a consequence of suppressed production in the liver or increased peripheral clearance. In this study, using stable isotope tracer infusions, we measured albumin and fibrinogen kinetics in septic patients and in a control group of non-septic subjects. Methods With the approval from the institutional Research Ethics Board and after obtaining written informed consent from patients or their substitute decision maker, mechanically ventilated patients with sepsis and patients scheduled for elective coronary artery bypass grafting were enrolled. Patients in the non-sepsis group were studied on the day before surgery. The stable isotope L-[ring-2H5]phenylalanine was used to measure absolute synthesis rates (ASR) of albumin and fibrinogen. A priming dose of L-[ring-2H5]phenylalanine (4 µmol/kg) was given followed by a six-hour infusion at a rate of 0.15 µmol/kg/min. At baseline and hourly thereafter, blood was drawn to measure isotope enrichments by gas chromatography/mass spectrometry. Very low density lipoprotein apolipoprotein-B 100 isotopic enrichment was used to represent the isotopic enrichment of the phenylalanine precursor pool from which the liver synthesizes proteins. Plasma albumin and fibrinogen concentrations were also measured. Results Mean plasma albumin in septic patients was decreased when compared to non-septic patients, while synthesis rates were comparable. Mean plasma fibrinogen and ASR in septic patients was increased when compared to non-septic patients. In non-septic patients, no statistically significant correlation between plasma albumin and ASR was observed but plasma fibrinogen significantly correlated with ASR. In septic patients, plasma albumin and fibrinogen significantly correlated with ASR. Conclusions While septic patients showed lower plasma albumin levels than non-septic patients, albumin synthesis was similar in the two groups suggesting that hypoalbuminemia during sepsis was not caused by suppressed hepatic production but a result of enhanced clearance from the circulation. Hyperfibrinogenemia in septic patients was a consequence of increased fibrinogen production. Trial registration: ClinicalTrials.gov: NCT02865408 (registered on August 12, 2016) and ClinicalTrials.gov: NCT02549443 (registered on September 15, 2015).

Study of Levels of Plasma Fibrinogen and its Association with Disease Severity in Patients with Chronic Obstructive Pulmonary Disease

COPD has been recognized as a component of the systemic inflammatory syndrome. A commonly used indicator of the severity and progression of the disease in COPD is expiratory volume per second (FEV1). However, it is weakly associated with symptoms and administration difficulties in elderly patients. Therefore, there is a need for other markers that are better and easy to apply to sick and elderly patients. Plasma fibrinogen can be used as a marker of disease severity. Aim: To estimate the plasma fibrinogen level in patients with COPD and Relationship of levels of plasma fibrinogen with the severity of chronic obstructive pulmonary disease using the BODE classification and GOLD staging. Place and Duration: In the Medicine Unit-II of Jinnah Hospital Lahore for one-year duration from August 2020 to August 2021. Methods: In this cross-sectional study, 110 COPD patients were assessed by measuring plasma fibrinogen correlated with disease severity using the GOLD scale, BODE index and the 6-minute walk test. Results: Plasma fibrinogen is present in all COPD patients. A significant correlation was observed between the BODE index (r = 0.69, p <0.001), gold grading (r = 0.95, p <0.001) and plasma fibrinogen levels. Most of the 110 subjects (34.5%) were Grade II, then Grade III 30.9%, 18.1% Grade IV and 14.5% Grade I. In our study, it was found that the average level of fibrinogen increased with the increase in the GOLD stage, which was statistically significant, and the p value was 0.01. Conclusions: Plasma fibrinogen levels are significantly higher in COPD and can be used as a marker correlating with disease severity in COPD. Keywords: COPD; plasma fibrinogen; GOLDEN stage; BODE index.