1 / 17

Role of γ' fibrinogen in Cardiovascular Disease: Implications and Limitations

This study examines the role of γ' fibrinogen in cardiovascular disease, including its association with traditional risk factors and its potential as a diagnostic marker. The study also discusses the limitations of using long-term frozen banked plasma for assessing reference intervals and diagnostic decision thresholds.

charlottea
Download Presentation

Role of γ' fibrinogen in Cardiovascular Disease: Implications and Limitations

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Introduction • High fibrinogen is a risk factor for CVDMeta-analyses show a two times higher risk for each 1 g/L increase • Fibrinogen is heterogeneous with different isoforms≈ 90% contain only A chains • ≈ 10% contain a ' chain

  2. Introduction (cont) • ' Fibrinogen has an altered ' chain • Arises from alternative mRNA processing • Contains a high affinity thrombin binding site • Results in altered clot ultrastructure • Results in a decreased rate of fibrinolysis

  3. Introduction (cont) • Increased ' fibrinogen is independently associated with CVD and stroke in case/control studies • Coronary artery disease: n = 133, OR = 7.16 (95% CI = 1.82 - 27.7) • per A/’ fibrinogen quartile (Lovely RS, Falls LA, Al-Mondhiry HA, Chambers CE, Sexton GJ, Ni H, Farrell DH. Thromb Haemost 2002:88:26-31) • Myocardial infarction: n = 774, OR = 1.24 (95% CI = 1.01 - 1.52). (Mannila MN, Lovely RS, Kazmierczak SC, Eriksson P, Samnegård A, Farrell DH, et al. J Thromb Haemost 2007;5:766-73) • Stroke: n = 249, elevated in cases vs. controls (0.42 mg/ml vs. 0.34 mg/ml). (Cheung EY, Uitte de Willige S, Vos HL, Leebeek FW, • Dippel DW, Bertina RM, de Maat MP. Stroke 2008;39:1033-5)

  4. Question • Is ' fibrinogen simply a surrogate marker • for total fibrinogen?

  5. Results • Assay precision • Respective within-run, run-to-run, and total imprecision estimates: • 13.4%, 28.6%, and 29.1% at 0.127 g/L of ' fibrinogen • 4.8%, 11.2%, and 11.6% at 0.416 g/L of ' fibrinogen

  6. Results (cont) • Analytical specificity • ' fibrinogen shows 99.9% sequence homology with A/A fibrinogen • Serial dilutions of anti-' monoclonal antibody 2.G2.H9 showed no measurable activity against A/A fibrinogen

  7. Figure 1. Analytical specificity of 2.G2.H9 towards ' fibrinogen. The analytical specificity of anti-' fibrinogen monoclonal antibody 2.G2.H9 and its ability to differentiate ' fibrinogen from fibrinogen lacking ' chains was determined by incubating the indicated dilutions of the antibody with A/A or A/' fibrinogen in microtiter wells. Goat anti-mouse IgG/HRP conjugate was added for detection, followed by O-phenylenediamine, and the absorbance was quantitated at 450 nm.

  8. Figure 3. Limit of quantification for the ' fibrinogen ELISA. The limit of quantification of the assay for measurement of ' fibrinogen concentrations in plasma was determined using 8 separate pools of patient plasma. The limit of quantification for the assay was 0.10 g/L, defined as that concentration of ' fibrinogen giving a within-run CV of 20% or less.

  9. Question • What are some possible limitations of using • long-term frozen banked plasma for assessing reference intervals and diagnostic decision thresholds? • The Framingham Offspring cohort samples were collected during the 7th examination cycle from 1998-2001 and stored frozen until analysis.

  10. Results (cont) • ' fibrinogen concentrations in humans • Central 95th percentile limits (median value) determined from various studies • Framingham offspring controls (n = 2879): 0.088–0.551 g/L (0.234 g/L) • Healthy blood donors (n = 120): 0.115–0.460 g/L (0.281 g/L) • Control subjects from study on CAD (see ref. 7) (n = 42): 0.125–0.676 g/L (0.242 g/L)

  11. Figure 4. ' fibrinogen concentrations in healthy individuals from the Framingham Offspring Study. ' fibrinogen was measured in 2879 participants from the Framingham Offspring Study with no previous history of cardiovascular disease. The reference interval of ' fibrinogen varied nearly 40-fold, from a low of 0.037 g/L to a high of 1.443 g/L. The 2.5th and 97.5th percentile limits for ' fibrinogen were 0.088 to 0.551 g/L. The median concentration was 0.234 g/L and the mean concentration was 0.255  0.119 g/L (SD).

  12. Figure 5. Receiver-operating characteristic curve for ' fibrinogen in CAD patients. ' fibrinogen concentrations were measured in a prior study in 133 patients referred for elective diagnostic cardiac catheterization. The receiver-operating characteristic curve of ' fibrinogen concentrations in CAD cases and controls showed an area under the curve of 0.76. A maximum diagnostic accuracy of 0.78 was found at a decision threshold of 0.30 g/L.

  13. Table 1. Association of ' Fibrinogen with Traditional Cardiovascular Risk Factors. aResults are unadjusted mean (1 standard deviation) or %. bP values assess the significance of the difference in mean/% across fibrinogen tertiles and are age and sex-adjusted. (P value for age is sex-adjusted only, and P value for sex is age-adjusted only.)

  14. Association of ' Fibrinogen with Traditional Cardiovascular Risk Factors • Factors showing significant positive association • Age, gender, BMI, smoking, diabetes, glucose, and triglycerides • Factors showing significant inverse correlation • HDL cholesterol • ' Fibrinogen does not show significant association with systolic blood pressure and total cholesterol • Total fibrinogen does show a significant association with systolic blood pressure and total cholesterol. • Addition of ' fibrinogen to total cholesterol and hsCRP may provide additional predictive value for assessment of the risk of CVD

  15. Question • What future studies should be performed to further investigate the association between ' fibrinogen and cardiovascular disease risk?

  16. Conclusions • The ' fibrinogen ELISA has within-run CVs of 13.4% at 0.127 g/L and 4.8% at 0.416 g/L • ROC curve analysis of results from patients with coronary artery disease yielded an area under the curve of 0.76, with a diagnostic accuracy of 0.78 at a decision threshold of 0.30 g/L • ' fibrinogen shows excellent prognostic utility for cardiovascular risk analysis

More Related