BβArg448Lys polymorphism is associated with altered fibrin clot structure and fibrinolysis in type 2 diabetes

Both type 2 diabetes (T2DM) and Bβ448Lys variant of fibrinogen are associated with dense fibrin clots, impaired fibrinolysis and increased cardiovascular risk. It was our objective to investigate whether BβArg448Lys adds to vascular risk by modulating fibrin network structure and/or fibrinolysis in diabetes. The primary aim was to study effects of BβArg448Lys on fibrin network characteristics in T2DM. Secondary aims investigated interactions between gender and BβArg448Lys substitution in relation to fibrin clot properties and vascular disease. Genotyping for BβArg448Lys and dynamic clot studies were carried out on 822 T2DM patients enrolled in the Edinburgh Type 2 Diabetes Study. Turbidimetric assays of individual plasma samples analysed fibrin clot characteristics with additional experiments conducted on clots made from purified fibrinogen, further examined by confocal and electron microscopy. Plasma clot lysis time in Bβ448Lys was longer than Bβ448Arg variant (mean ± SD; 763 ± 322 and 719 ± 351 seconds [s], respectively; p<0.05). Clots made from plasma-purified fibrinogen of individuals with Arg/Arg, Arg/Lys and Lys/Lys genotypes showed differences in fibre thickness (46.75 ± 8.07, 38.40 ± 6.04 and 25 ± 4.99 nm, respectively; p<0.001) and clot lysis time (419 ± 64, 442 ± 87 and 517 ± 65 s, respectively; p=0.02), directly implicating the polymorphism in the observed changes. Women with Bβ448Lys genotype had increased risk of cerebrovascular events and were younger compared with Bβ448Arg variant (67.2 ± 4.0 and 68.2 ± 4.4 years, respectively; p=0.035). In conclusion, fibrinogen Bβ448Lys variant is associated with thrombotic fibrin clots in diabetes independently of traditional risk factors. Prospective studies are warranted to fully understand the role of BβArg448Lys in predisposition to vascular ischaemia in T2DM with the potential to develop individualised antithrombotic management strategies

In Vivo Near-Infrared Imaging of Fibrin Deposition in Thromboembolic Stroke in Mice

imaging of activated factor XIII (FXIIIa), an important mediator of thrombosis or fibrinolytic resistance. The present study was to investigate the fibrin deposition in a thromboembolic stroke mice model by FXIIIa–targeted near-infrared fluorescence (NIRF) imaging., which were correlated with histology after animal euthanasia. NIRF images and lesion volume.Non-invasive detection of fibrin deposition in ischemic mouse brain using NIRF imaging is feasible and this technique may provide an in vivo experimental tool in studying the role of fibrin in stroke

Genes influencing coagulation and the risk of aneurysmal subarachnoid hemorrhage, and subsequent complications of secondary cerebral ischemia and rebleeding

We investigated whether genes influencing coagulation are associated with the occurrence of aneurysmal subarachnoid hemorrhage (SAH) and with secondary cerebral ischemia and rebleeding in patients with aneurysmal SAH. Genotyping for factor V Leiden (G1691A), prothrombin G20210A, methylenetetetrahydrofolate reductase (MTHFR) C677T, factor XIII subunit A Val34Leu, Tyr204Phe and Pro564Leu, and factor XIII subunit B His95Arg was performed in 208 patients with aneurysmal SAH and in 925 controls. Secondary cerebral ischemia occurred in 49 (24%) patients and rebleeding in 28 (14%) during their clinical course of 3 months after the aneurysmal SAH. The risk of aneurysmal SAH was assessed as odds ratio (OR) with 95% confidence interval (95% CI). The risk of secondary cerebral ischemia and rebleeding was assessed as hazard ratio (HR) with 95% CI using Cox regression. Carriers of the subunit B His95Arg factor XIII polymorphism had an increased risk of aneurysmal SAH with 23% of the patients homozygous or heterozygous for the variant allele compared to 17% of control subjects (OR 1.5, 95% CI 1.0-2.2). For the remaining genetic variants no effect on the risk of aneurysmal SAH could be demonstrated. A clear relation with the risk of secondary cerebral ischemia and of rebleeding could not be established for any of the genetic variants. We found that aneurysmal SAH patients are more often carriers of the subunit B His95Arg factor XIII polymorphism compared to controls. This suggests that carriers of the subunit B His95Arg factor XIII polymorphism have an increased risk of aneurysmal SAH. Larger studies should confirm our results. As aneurysmal SAH patients who died soon after admission could not be included in the present study, our results only apply to a population of patients who survived the initial hours after the hemorrhage. For the other studied genetic factors involved in coagulation, no association with the occurrence of aneurysmal SAH or with the occurrence of secondary cerebral ischemia or rebleeding after aneurysmal SAH could be demonstrated

Duration of fever and serious bacterial infections in children: a systematic review

Background: Parents of febrile children frequently contact primary care. Longer duration of fever has been related to increased risk for serious bacterial infections (SBI). However, the evidence for this association remains controversial. We assessed the predictive value of duration of fever for SBI. Methods: Studies from MEDLINE, Embase and Cochrane databases (from January 1991 to December 2009) were retrieved. We included studies describing children aged 2 months to 6 years in countries with high Haemophilus influenzae type b vaccination coverage. Duration of fever had to be studied as a predictor for serious bacterial infections. Results: Seven studies assessed the association between duration of fever and serious bacterial infections; three of these found a relationship. Conclusion: The predictive value of duration of fever for identifying serious bacterial infections in children remains inconclusive. None of these seven studies was performed in primary care. Studies evaluating the duration of fever and its predictive value in children in primary care are required

Prognostic factors for disability claim duration due to musculoskeletal symptoms among self-employed persons

<p>Abstract</p> <p>Background</p> <p>Employees and self-employed persons have, among others, different personal characteristics and different working conditions, which may influence the prognosis of sick leave and the duration of a disability claim. The purpose of the current study is to identify prognostic factors for the duration of a disability claim due to non-specific musculoskeletal disorders (MSD) among self-employed persons in the Netherlands.</p> <p>Methods</p> <p>The study population consisted of 276 self-employed persons, who all had a disability claim episode due to MSD with at least 75% work disability. The study was a cohort study with a follow-up period of 12 months. At baseline, participants filled in a questionnaire with possible individual, work-related and disease-related prognostic factors.</p> <p>Results</p> <p>The following prognostic factors significantly increased claim duration: age > 40 years (Hazard Ratio 0.54), no similar symptoms in the past (HR 0.46), having long-lasting symptoms of more than six months (HR 0.60), self-predicted return to work within more than one month or never (HR 0.24) and job dissatisfaction (HR 0.54).</p> <p>Conclusions</p> <p>The prognostic factors we found indicate that for self-employed persons, the duration of a disability claim not only depends on the (history of) impairment of the insured, but also on age, self-predicted return to work and job satisfaction.</p