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Bone formation during fracture repair inevitably initiates within or around extravascular deposits of a fibrin-rich matrix. In addition to a central role in hemostasis, fibrin is thought to enhance bone repair by supporting inflammatory and mesenchymal progenitor egress into the zone of injury. However, given that a failure of efficient fibrin clearance can impede normal wound repair, the precise contribution of fibrin to bone fracture repair, whether supportive or detrimental, is unknown. Here, we employed mice with genetically and pharmacologically imposed deficits in the fibrin precursor fibrinogen and fibrin-degrading plasminogen to explore the hypothesis that fibrin is vital to the initiation of fracture repair, but impaired fibrin clearance results in derangements in bone fracture repair. In contrast to our hypothesis, fibrin was entirely dispensable for long-bone fracture repair, as healing fractures in fibrinogen-deficient mice were indistinguishable from those in control animals. However, failure to clear fibrin from the fracture site in plasminogen-deficient mice severely impaired fracture vascularization, precluded bone union, and resulted in robust heterotopic ossification. Pharmacological fibrinogen depletion in plasminogen-deficient animals restored a normal pattern of fracture repair and substantially limited heterotopic ossification. Fibrin is therefore not essential for fracture repair, but inefficient fibrinolysis decreases endochondral angiogenesis and ossification, thereby inhibiting fracture repair.
Chronic pain may be related to cardiovascular disease (CVD) risk. The current study examined whether persistent bodily pain was related to cardiovascular disease risk factors, whether these effects were moderated by body mass index (BMI), and, if not, whether chronic pain accounted for unique variance in CVD risk factors. Participants were women (N = 2,135) in the Study of Women's Health Across the Nation. A high pain frequency variable (high pain in 0 through 4 assessments) was coded to reflect the frequency of high levels of bodily pain across the first 3 years of the study. Six CVD risk factors and BMI were measured at follow-up year 3. High pain frequency and BMI were correlated significantly with risk factors, although effects for the former were small. Hierarchical multiple regressions revealed high pain frequency × BMI interactions for 5 of 6 CVD risk factors. Dissecting the interactions revealed a similar pattern across 4 risk factors: for women with normal BMI, there was a "dose-response" in which increasing frequency of high pain revealed increasingly worse CVD risk factor levels, whereas for women with obese BMI, high pain frequency was unrelated to risk factors. For obese women, increasing frequency of high pain was associated with higher blood glucose. Although BMI is a well-established CVD risk factor, evaluation of CVD risk level may be improved by considering the incidence of persistent pain, particularly in normal weight women (BMI < 25 kg/m(2)) lower BMI.
The Gram-negative bacterium Yersinia pestis causes plague, a rapidly progressing and often fatal disease. The formation of fibrin at sites of Y. pestis infection supports innate host defense against plague, perhaps by providing a nondiffusible spatial cue that promotes the accumulation of inflammatory cells expressing fibrin-binding integrins. This report demonstrates that fibrin is an essential component of T cell-mediated defense against plague but can be dispensable for Ab-mediated defense. Genetic or pharmacologic depletion of fibrin abrogated innate and T cell-mediated defense in mice challenged intranasally with Y. pestis. The fibrin-deficient mice displayed reduced survival, increased bacterial burden, and exacerbated hemorrhagic pathology. They also showed fewer neutrophils within infected lung tissue and reduced neutrophil viability at sites of liver infection. Depletion of neutrophils from wild-type mice weakened T cell-mediated defense against plague. The data suggest that T cells combat plague in conjunction with neutrophils, which require help from fibrin to withstand Y. pestis encounters and effectively clear bacteria.
Bradykinin increases during cardiopulmonary bypass (CPB) and stimulates the release of nitric oxide, inflammatory cytokines, and tissue-type plasminogen activator (t-PA), acting through its B2 receptor. This study tested the hypothesis that endogenous bradykinin contributes to the fibrinolytic and inflammatory response to CPB and that bradykinin B2 receptor antagonism reduces fibrinolysis, inflammation, and subsequent transfusion requirements. Patients (N = 115) were prospectively randomized to placebo, ε-aminocaproic acid (EACA), or HOE 140, a bradykinin B2 receptor antagonist. Bradykinin B2 receptor antagonism decreased intraoperative fibrinolytic capacity as much as EACA, but only EACA decreased D-dimer formation and tended to decrease postoperative bleeding. Although EACA and HOE 140 decreased fibrinolysis and EACA attenuated blood loss, these treatments did not reduce the proportion of patients transfused. These data suggest that endogenous bradykinin contributes to t-PA generation in patients undergoing CPB, but that additional effects on plasmin generation contribute to decreased D-dimer concentrations during EACA treatment.
INTRODUCTION - Pulmonary thromboembolism (PTE) may increase D-dimer and decrease fibrinogen levels. However, in settings such as intensive care units (ICU) and in long-term hospitalised patients, several factors may influence D-dimer and fibrinogen concentrations and make them unreliable indicators for the diagnosis of PTE. The aim of this study was to evaluate the accuracy of D-dimer:fibrinogen ratio (DDFR) for the diagnosis of PTE in ICU patients.
METHODS - ICU patients who were suspected of having a first PTE and had no history of using anti-coagulants and contraceptives were included in the study. Levels of D-dimer and fibrinogen were measured for each patient prior to any intervention. Angiography or CT angiography was done in order to establish a definite diagnosis for each patient. Suitable analytical tests were performed to compare means.
RESULTS - Eighty-one patients were included in the study, of whom 41 had PTE and 40 did not. Mean values of D-dimer and fibrinogen were 3.97 ± 3.22 µg/ml and 560.6 ± 197.3 mg/dl, respectively. Significantly higher levels of D-dimer (4.65 ± 3.46 vs 2.25 ± 2.55 µg/ml, p = 0.006) and DDFR (0.913 ± 0.716 vs 483 ± 0.440 × 10-(3), p = 0.003) were seen in PTE patients than in those without PTE. Receiver operating characteristic (ROC) analysis showed a 70.3% sensitivity and 70.1% specificity with a D-dimer value of 2.43 µg/ml (AUC = 0.714, p = 0.002) as the best cut-off point; and a 70.3% sensitivity and 61.6% specificity with a DDFR value of 0.417 × 10-(3) (AUC = 0.710, p = 0.004) as the best cut-off point. In backward stepwise regression analysis, DDRF (OR = 0.72, p = 0.025), gender (OR = 0.76, p = 0.049) and white blood cell count (OR = 1.11, p = 0.373) were modelled (p = 0.029, R(2) = 0.577).
CONCLUSION - For diagnosis of PTE, DDFR can be considered to have almost the same importance as D-dimer level. Moreover, it was possible to rule out PTE with only a D-dimer cut-off value < 0.43 mg/dl, without the use of DDFR. However, these values cannot be used as a replacement for angiography or CT angiography.
BACKGROUND - D-Dimer elevations have been associated with a striking increase in mortality in HIV-infected patients. However, D-Dimer has not been directly linked to endothelial dysfunction in HIV.
METHODS - In this cross-sectional study, we used flow-mediated dilation (FMD) of the brachial artery to measure endothelial function and several biomarkers to measure systemic inflammation and coagulation activation in HIV-infected adults on stable antiretroviral therapy with HIV-1 RNA levels <400 copies/ml. Multivariable linear regression was used to model FMD by these markers, traditional cardiovascular risk factors and HIV-related characteristics.
RESULTS - Analysis included 98 subjects (88% male, median age 47.5 years, CD4(+) T-cells 578.5 cells/mm(3)); all on ART (52% on protease inhibitors). The only factors independently associated with FMD were D-Dimer and body mass index.
CONCLUSIONS - We show for the first time an independent association between D-Dimer and endothelial dysfunction in virologically suppressed, HIV-infected adults on stable antiretroviral therapy, potentially explaining the link between D-Dimer and mortality in HIV.
Peptide-based mass spectrometry approaches, such as multiple reaction monitoring, provide a powerful means to measure candidate protein biomarkers in plasma. A potential confounding problem is the effect of preanalytical variables, which may affect the integrity of proteins and peptides. Although some blood proteins undergo rapid physiological proteolysis ex vivo, the stability of most plasma proteins to preanalytical variables remains largely unexplored. We applied liquid chromatography-tandem mass spectrometry shotgun proteomics and multiple reaction monitoring analyses to characterize the stability of proteins at the peptide level in plasma. We systematically evaluated the effects of delay in plasma preparation at different temperatures, multiple freeze-thaw cycles and erythocyte hemolysis on peptide and protein inventories in prospectively collected human plasma. Time course studies indicated few significant changes in peptide and protein identifications, semitryptic peptides and methionine-oxidized peptides in plasma from blood collected in EDTA plasma tubes and stored for up to a week at 4 °C or room temperature prior to plasma isolation. Similarly, few significant changes were observed in similar analyses of plasma subjected to up to 25 freeze-thaw cycles. Hemolyzed samples produced no significant differences beyond the presence of hemoglobin proteins. Finally, paired comparisons of plasma and serum samples prepared from the same patients also yielded few significant differences, except for the depletion of fibrinogen in serum. Blood proteins thus are broadly stable to preanalytical variables when analyzed at the peptide level. Collection protocols to generate plasma for multiple reaction monitoring-based analyses may have different requirements than for other analyses directed at intact proteins.
Previous genetic association studies of the fibrinogen gene cluster have identified associations with plasma fibrinogen levels. These studies are typically limited to plasma fibrinogen measured among European-descent populations. We sought to replicate previous well-known associations with fibrinogen variants and plasma fibrinogen. We then sought to identify and characterise novel associations with fibrinogen variants with plasma fibrinogen and several haematological traits in three racial/ethnic populations. We genotyped 25 single nucleotide polymorphisms (SNPs) in the fibrinogen gene cluster in 2,631 non-Hispanic whites, 2,108 non-Hispanic blacks, and 2,073 Mexican-Americans from the Third National Health and Nutrition Examination Survey (NHANES). We performed single SNP tests of association for plasma fibrinogen, mean platelet volume, platelet distribution width, platelet count, white blood cell count, and serum triglycerides. Five previously identified associations with plasma fibrinogen replicated in our study in non-Hispanic whites and blacks. We identified two novel associations between genetic variants and decreased plasma fibrinogen: rs2227395 (p=0.0007; non-Hispanic whites) and rs2070022 (p=0.001; Mexican-Americans). Several fibrinogen SNPs were also associated with haematological traits: rs6050 with decreased platelet distribution width in non-Hispanic whites; rs6050 and rs2066879 with decreased and increased platelet distribution width, respectively, in non-Hispanic whites;rs2227409 with increased mean platelet volume, rs2070017 with decreased platelet count, and rs6063 with increased platelet distribution width in non-Hispanic blacks; and rs4220 and rs2227395 with decreased white blood cell count, rs2227409 with increased platelet distribution width, rs2066860 and rs1800792 with increased and decreased triclyceride levels, respectively, and rs1800792 with decreased platelet counts in Mexican-Americans. We successfully replicated and identified novel associations with fibrinogen variants and plasma fibrinogen. These data confirm the importance of the fibrinogen gene cluster for plasma fibrinogen levels as well as suggest this gene cluster may have pleiotropic effects on haematological traits.
Silicon nanopore membranes (SNM) with monodisperse pore size distributions have potential applications in bioartificial kidneys. A protein resistant thin film coating on the SNM is required to minimize biofouling and, hence, enhance the performance efficiency of SNM. In this work, a zwitterionic polymer, poly(sulfobetaine methacrylate) (polySBMA), was used to coat silicon and SNM substrates via a surface initiated atom transfer radical polymerization method. The polySBMA-coated surfaces were characterized using contact angle goniometry, X-ray photoelectron spectroscopy (XPS), ellipsometry and scanning electron microscopy (SEM). Resistance of the coatings to protein fouling was examined by measurement of fibrinogen adsorption from fibrinogen solution and human plasma on coated silicon surfaces. Results showed that the polySBMA coating suppresses non-specific adsorption of fibrinogen. The protein-repellent property of polySBMA thin film coating is comparable to that of PEG-based coatings. Analysis of the surfaces by XPS indicated that the films remained stable when stored under physiologic conditions over a 4-week period.