Cheung, E.Y.L.

The role of fibrinogen variants in cardiovascular diseases and wound healing (Doctoral Thesis)

2012-06-26T00:00:00Z

Maintaining the integrity and patency of the vascular system is essential for the viability of humans. When vascular injury has occurred, fast formation of a thrombus at the site of injury is essential to seal the wound, resulting in haemostasis. Haemostasis is a tightly regulated process, which involves the activation of endothelial cells, platelets, procoagulants and the inhibition of fibrinolytic factors. Haemostasis can be separated in two phases called primary and secondary haemostasis, which occur simultaneously.1 In primary haemostasis, a platelets plug is rapidly formed at the site of injury, whereas in secondary haemostasis, blood coagulation is initiated, either with negatively charged surfaces (intrinsic pathway) or with tissue factor (extrinsic pathway). The cascade leads to the generation of thrombin and the formation of a fibrin network.2 The thrombus provides an effective restriction for bleeding. Hence, an imbalance of normal haemostasis caused by pathologic disorders may lead to thrombosis or hemorrhage, which may account for morbidity and mortality. Fibrinogen is a central protein in the hemostatic system. At the final stage of the blood coagulation system, thrombin converts the soluble fibrinogen into fibrin monomers, which then polymerize to an insoluble fibrin clot. Furthermore, fibrinogen induces platelet adhesion and aggregation via the αIIbβ3 integrin, thus promoting blood coagulation. In addition to their primary function in blood clotting, fibrinogen and fibrin also play a role in various physiological reactions including fibrinolysis, cellular and matrix interactions, wound healing and neoplasia.

Fibrinogen γ' levels in patients with intracerebral hemorrhage (Article)

2011-09-13T00:00:00Z

Background: The fibrinogen γ' variant (γ') has both antithrombotic and prothrombotic properties when compared to normal fibrinogen. It may therefore be of relevance in intracerebral hemorrhage and intraventricular extension of the bleeding. Objective: To study the role of γ' in intracerebral hemorrhage, and in intraventricular extension of the hemorrhage. Patients/Methods: We performed a case-control study in 156 controls and 55 patients with intracerebral hemorrhage, with and without intraventricular extension. Levels of fibrinogen γ' and the γ'/total fibrinogen ratio were measured in all participants. Results: Levels of γ' were increased in patients with intracerebral hemorrhage when compared with controls (0.40 vs 0.32 g/l, p < 0.001). The γ'/total fibrinogen ratio was similar in patients and controls (0.092 vs 0.096 p = 0.42). There was evidence for an unfavorable outcome in patients with fibrinogen levels in the highest tertile compared with the lowest tertile (OR 4.0, 95%CI 1.1-15.2), and a nonsignificant trend toward unfavorable outcome with higher levels of γ' (p-value for trend = 0.06). Conclusions: Our study shows that absolute levels of fibrinogen γ' are increased in patients with intracerebral hemorrhage, but relative levels are similar in patients and controls, suggesting that the absolute rise in γ' is an acute phase response.

Elevated fibrinogen γ′ ratio is associated with cardiovascular diseases and acute phase reaction but not with clinical outcome (Article)

2009-11-12T00:00:00Z

Strongly increased levels of fibrinogen elastase degradation products in patients with ischemic stroke (Article)

2008-12-01T00:00:00Z

Ischemic stroke is associated with leucocyte activation. Activated leucocytes release elastase, an enzyme that can degrade fibrinogen. Fibrinogen elastase degradation products (FgEDP) may serve as a specific marker of elastase proteolytic activity. In a case-control study of 111 ischemic stroke patients and 119 controls, significantly higher FgEDP levels were observed in cases than in controls, both in the acute phase and in the convalescent phase. Results were only slightly affected by adjustment for cardiovascular risk factors, C-reactive protein and fibrinogen. Our findings suggest that FgEDP might be involved in the pathogenesis of stroke.

Variation in fibrinogen FGG and FGA genes and risk of stroke: The Rotterdam study (Article)

2008-08-01T00:00:00Z

Haplotypes of the fibrinogen gamma and alpha (FGG and FGA) genes are associated with the structure of the fibrin network and may therefore influence the risk of stroke. We investigated the relationship between common variation in these genes with ischemic and haemorrhagic stroke. The study was based on 6,275 participants of the prospective population-based Rotterdam Study who at baseline (1990-1993) were aged 55 years or over, free from stroke, and had successful assessment of at least one FGG or FGA single nucleotide polymorphisms (SNP). Common haplotypes were estimated using seven tagging SNPs across a 30 kb region containing the FGG and FGA genes. Follow-up for incident stroke was complete until January 1, 2005. Associations between constructed haplotypes and risk of stroke were estimated with an age- and sex-adjusted logistic regression model. We observed 668 strokes, of which 393 were ischemic and 62 haemorrhagic, during a median follow-up time of 10.1 years. FGG+FGA haplotype 3 (H3) was associated with an increased risk of ischemic stroke (odds ratio [OR] 1.36, 95% confidence interval [CI] 1.09-1.69) and the risk estimate for hemorrhagic stroke was 0.71 (95% CI 0.46-1.09) compared to the most frequent H1. The FGG and FGA genes were not associated with stroke or its subtypes when analyzed separately. In conclusion, risk of ischemic stroke was higher in FGG+FGA H3 than in H1. The results suggested that an opposite association may exist for haemorrhagic stroke.

Haplotypes of the fibrinogen gene and cerebral small vessel disease: The Rotterdam scan study (Article)

2008-07-01T00:00:00Z

Objective: Fibrinogen levels and fibrinogen clot structure have been implicated in the pathogenesis of vascular disease. We examined fibrinogen levels and variation in fibrinogen genes (fibrinogen γ (FGG), α (FGA) and β (FGB)), which have been associated with fibrin clot structure and fibrinogen levels, in relation to cerebral small vessel disease (SVD). Methods and results: This study was performed as part of the Rotterdam Scan Study, a population based study in 1077 elderly patients undergoing cerebral MRI. Plasma fibrinogen levels and haplotypes were determined. We examined the association between fibrinogen levels and haplotype with silent brain infarcts and white matter lesions using logistic regression models. We constructed seven haplotypes (frequency >0.01) that describe the total common variation in the FGG and FGA genes. Haplotype 2 (GATAGTG) was associated with the presence of silent brain infarcts compared with the most frequent haplotype (GGTGGTA) (OR 1.41, 95% CI 1.03 to 1.94). Haplotype 3 (GGCGATA) was associated with periventricular white matter lesions in the highest fertile of the distribution (OR 1.40, 95% CI 1.01 to 1.92). No association was found between plasma fibrinogen levels and SVD. Conclusions: Our study provides evidence for an association of common variation in the FGG and FGA genes with cerebral SVD. It is possible that the structure of the fibrin clot rather than plasma fibrinogen levels plays a role in the pathogenesis of cerebral SVD.

Fibrinogen γ′ in ischemic stroke: A case-control study (Article)

2008-03-01T00:00:00Z

BACKGROUND AND PURPOSE - To determine the contribution of fibrinogen γ′ levels and FGG haplotypes to ischemic stroke. METHODS - Associations between fibrinogen γ′ levels, fibrinogen γ′/total fibrinogen ratio, and FGG haplotypes with the risk of ischemic stroke were determined in 124 cases and 125 controls. RESULTS - Fibrinogen γ′/total fibrinogen ratio was higher in patients than in controls during the acute phase of the stroke and lower in the convalescent phase 3 months after the stroke. FGG haplotype 3 (H3) was associated with a reduced risk of ischemic stroke (odds ratio 0.60; 95% CI, 0.38 to 0.94), but not with the fibrinogen γ′/total fibrinogen ratio. In contrast, FGG-H2 was associated with a decreased fibrinogen γ′/total fibrinogen ratio, but not with risk of stroke. CONCLUSIONS - Fibrinogen γ′/total fibrinogen ratio is associated with ischemic stroke, especially in the acute phase of the disease. In addition, FGG-H3 haplotype appears to be protective against ischemic stroke.