Baseline Fibrinogen Levels Research Articles

Evaluation of local carotid stiffness and inflammatory biomarkers in stable angina pectoris.

IntroductionArterial stiffness (AS) is a well-accepted and reliable predictor of atherosclerotic diseases. Inflammation plays an important role in the development of AS.AimTo evaluate local carotid stiffness (CS) together with fibrinogen and high-sensitivity C-reactive protein (hsCRP) levels in stable angina pectoris (SAP) patients.Material and methodsThe study consisted of 353 consecutive patients with SAP. All underwent coronary angiography (CAG) after the evaluation of local CS parameters and carotid intima-media thickness (IMT) from both common carotid arteries by a real-time echo-tracking system. Baseline inflammatory biomarkers, serum hsCRP and fibrinogen levels were measured. Based on CAG findings, the patients were classified into 4 groups: control subjects with normal coronary arteries (group 1, n = 86), single-vessel disease (group 2, n = 104), double-vessel disease (group 3, n = 95) and triple-vessel disease (group 4, n = 68).ResultsThe mean carotid pulse wave velocity (PWV) in patients with angiographically confirmed coronary artery disease (CAD) was significantly higher than that in patients with normal coronary arteries (7.82 ±1.76 vs. 6.51 ±0.85 cm/s, p = 0.001). The mean carotid IMT was detected to be significantly higher in group 4 patients compared to those in group 1 (p < 0.001) and group 2 (p = 0.001). Significant correlations were observed between both inflammatory biomarkers and the number of diseased vessels and carotid PWV. Using multi-variate analysis, carotid stiffness, carotid IMT, hsCRP and fibrinogen were independently associated with the presence and extent of CAD.ConclusionsLocal CS, carotid IMT, hsCRP and fibrinogen levels are significant predictors of atherosclerotic burden and they may facilitate the identification of high-risk patients for the early diagnosis and prompt treatment of CAD.

Hemostasis biomarkers and risk of sepsis: the REGARDS cohort

Background Sepsis is a major public health concern, responsible for more than 750 000 hospitalizations and 200 000 annual deaths in the USA. Few studies have investigated the association between baseline measurements of hemostasis biomarkers and the future risk of sepsis. Objective To determine whether hemostasis biomarkers levels measured at baseline in a cohort of community-dwelling participants are associated with the risk of future sepsis events. Methods We performed a nested case-control study within the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. We identified sepsis hospitalizations occurring over a 10-year period. There were 50 incident sepsis cases with baseline measurements of hemostasis (fibrinogen, factor VIII, FIX, FXI, protein C, and D-dimer). Using incidence density sampling, we matched the 50 sepsis cases with 200 controls by age, sex, and race. We used conditional logistic regression to evaluate the association between baseline hemostasis biomarkers and future sepsis events. Results Comparison of 50 sepsis cases with 200 non-sepsis controls showed that sepsis cases had lower education and income, were more likely to live in the stroke belt, had chronic lung disease, and had higher albumin level/creatinine level ratios (ACRs). Individuals with higher baseline fibrinogen levels (adjusted odds ratio [OR] per standard deviation: 1.40, 95% confidence interval [CI] 1.01-1.94), FIX levels ([OR] 1.46, 95% [CI] 1.03-2.07) and FXI levels ([OR]1.52, 95% [CI] 1.04-2.23) were more likely to experience a sepsis event. Conclusion Baseline fibrinogen, FIX and FXI levels are associated with future episodes of sepsis. Hemostasis biomarkers may provide targets for sepsis mitigation or prevention.

Baseline and long-term fibrinogen levels and risk of sudden cardiac death: A new prospective study and meta-analysis

BackgroundInflammatory markers such as C-reactive protein (CRP) and interleukin-6 have been linked with an increased risk of sudden cardiac death (SCD), but the relationship between fibrinogen and SCD is uncertain. We aimed to assess the association between fibrinogen and SCD. MethodsPlasma fibrinogen was measured at baseline in a prospective cohort of 1773 men aged 42–61 years free of heart failure or cardiac arrhythmias, that recorded 131 SCDs during 22 years follow-up. Correction for within-person fibrinogen variability was made using data from repeat measurements taken several years apart. ResultsFibrinogen was strongly correlated with CRP, weakly correlated with several cardiovascular risk markers, and was log-linearly associated with SCD risk. In analyses adjusted for conventional risk factors, the hazard ratio (HR) (95% CIs) for SCD per 1 standard deviation (SD) higher baseline loge fibrinogen was 1.32 (1.11–1.57). The results remained consistent on further adjustment for alcohol consumption, resting heart rate, and circulating lipids 1.30 (1.09–1.56). The corresponding HRs were 1.80 (1.25–2.58) and 1.74 (1.20–2.52) after correction for within-person variability. HRs remained unchanged on further adjustment for CRP and accounting for incident coronary events. In a meta-analysis of three cohort studies, the fully-adjusted relative risks for SCD per 1 SD higher baseline and long-term fibrinogen levels were 1.42 (1.25–1.61) and 2.07 (1.59–2.69) respectively. The associations were similar for non-SCDs in both cohort analysis and the meta-analysis. Addition of plasma fibrinogen to a SCD risk prediction model containing established risk factors did not significantly improve risk discrimination, but improved the net reclassification. ConclusionsAvailable data suggest fibrinogen is positively, log-linearly, and independently associated with risk of SCD. Further research is needed to assess the potential relevance of plasma fibrinogen concentrations in SCD prevention.

Abstract 19224: Fibrinogen And Neopterin Predict Future Myocardial Infarction Events In Patients With Stable Coronary Heart Disease

Background: Fibrinogen is synthesized by hepatocytes. It is a precursor of fibrin and forms bridges between platelets during thrombus formation, but it is also a marker of ongoing inflammation. Neopterin is released by monocyte/ macrophage activation associated with atherosclerosis. Whether these markers interact or act independently among patients with suspected stable coronary heart disease has previously not been given much attention. Methods: We included 3526 patients undergoing elective coronary angiography at two university hospitals in Norway during 2000-2004, with a median follow-up of 7.3 years. Cox regression analysis was used to obtain hazard ratios (HR) and 95% confidence intervals (CI) for incident AMI of fibrinogen and neopterin levels in a crude model and a model adjusted for age, gender, diabetes, current smoking, hypertension and serum apoA1 and apoB. Potential effect modifications were investigated according to strata of fibrinogen or neopterin below or above the median, as well as across subgroups of age, gender, smoking status, diabetes, serum apoA1 and apoB. A p-value &lt;0.05 was considered significant. Results: During follow-up, 580 patients experienced an AMI. In the unadjusted model, both fibrinogen and neopterin predicted future AMI [HR = 1.32; 95% CI 1.22-1.43; p&lt;0.001 and HR = 1.31; 95% CI 1.23-1.40; p&lt;0.001, respectively]. The estimates were only slightly attenuated in the multivariate model, and still associated with incident AMI when both biomarkers were added simultaneously [HR = 1.15; 95% CI 1.05-1.25; p&lt;0.001 and HR = 1.20; 95% CI 1.12-1.28; p&lt;0.001, respectively]. Baseline fibrinogen and neopterin levels were modestly correlated (Spearman’s rho = 0.18, p-value &lt;0.001). There were no statistically significant interaction across subgroups (p for interaction fibrinogen and high/ low neopterin = 0.26, neopterin and high/low fibrinogen = 0.46, respectively). Conclusion: Patients with increased levels of fibrinogen or neopterin are at increased risk of future AMI. Neopterin levels did not significantly interact with the prognostic utility of fibrinogen. This suggests that circulating fibrinogen and neopterin may reflect different pathophysiological mechanisms.

Cushing`s disease: Fibrinogen and D-dimer levels fail to normalize despite early postoperative remission - a prospective, controlled study.

Effective transsphenoidal surgery (TSS) for Cushing`s disease (CD) normalizes cortisol levels and reduces complications of hypercortisolism. However, there is evidence of increased cardiovascular morbidity even after successful surgery. A prospective, controlled study on the dynamics of fibrinogen and D-dimer levels with a six-month follow-up after an effective TSS for CD. Forty patients with CD and forty healthy age- and sex-matched subjects were included. We assessed ACTH, urinary and serum cortisol, and fibrinogen and D-dimer levels before TSS and during follow-up. Baseline BMI (P < 0.001), fibrinogen (P = 0.002), and D-dimer (P = 0.001) levels in CD patients were significantly higher than those in healthy controls. High fibrinogen levels in the CD group were independent of BMI, and were positively associated with hsCRP (rS = 0.61, P < 0.001) and arterial hypertension (P = 0.029). After the six-month follow-up we confirmed a sustained difference between the remission group and controls in fibrinogen and D-dimer levels (P = 0.001 and P = 0.017, respectively). Despite early biochemical remission of CD the levels of fibrinogen and D-dimer failed to decrease. This probably contributes to the high risk of thrombotic events and indicates the need for a close follow-up for signs of thromboembolic and cardiovascular complications in patients with early CD remission. (Endokrynol Pol 2016; 67 (3): 283-291).

Use of human fibrinogen concentrate during proximal aortic reconstruction with deep hypothermic circulatory arrest

ObjectiveHuman fibrinogen concentrate (HFC) is approved by the Food and Drug Administration for use at 70 mg/kg to treat congenital afibrinogenemia. We sought to determine whether this dose of HFC increases fibrinogen levels in the setting of high-risk bleeding associated with aortic reconstruction and deep hypothermic circulatory arrest (DHCA). MethodsThis was a prospective, pilot, off-label study in which 22 patients undergoing elective proximal aortic reconstruction with DHCA were administered 70 mg/kg HFC upon separation from cardiopulmonary bypass (CPB). Fibrinogen levels were measured at baseline, just before, and 10 minutes after HFC administration, on skin closure, and the day after surgery. The primary study outcome was the difference in fibrinogen level immediately after separation from CPB, when HFC was administered, and the fibrinogen level 10 minutes following HFC administration. Additionally, postoperative thromboembolic events were assessed as a safety analysis. ResultsThe mean baseline fibrinogen level was 317 ± 49 mg/dL and fell to 235 ± 39 mg/dL just before separation from CPB. After HFC administration, the fibrinogen level rose to 331 ± 41 mg/dL (P < .001) and averaged 372 ± 45 mg/dL the next day. No postoperative thromboembolic complications occurred. ConclusionsAdministration of 70 mg/kg HFC upon separation from CPB raises fibrinogen levels by approximately 100 mg/dL without an apparent increase in thrombotic complications during proximal aortic reconstruction with DHCA. Further prospective study in a larger cohort of patients will be needed to definitively determine the safety and evaluate the efficacy of HFC as a hemostatic adjunct during these procedures.

Admission fibrinogen levels in severe trauma patients: A comparison of elderly and younger patients

IntroductionAcute coagulopathy of trauma has been much discussed recently. However, the changes in coagulation markers after trauma in the elderly are unknown. Furthermore, the baseline fibrinogen level is high in elderly patients, and the question remains as to whether fibrinogen levels also decrease early and the degree of decrease in elderly trauma patients. The purpose of this study was to compare coagulation markers including the fibrinogen level on admission in younger and elderly severe trauma patients. MethodsA cohort of severe trauma patients (Injury Severity Score (ISS) ≥16), admitted from January 2011 to June 2014, with coagulation markers including the fibrinogen level on admission available, was reviewed retrospectively. The patients were divided into a younger (16–64 years old) and an older (≥65 years old) group based upon their age at presentation. Activated partial thromboplastin time (aPTT), international normalized ratio (INR), fibrinogen, and D-dimer were compared between the younger and older groups. ResultsThere were 251 patients who met the inclusion criteria for this analysis. The younger group included 117 patients and the older group included 134 patients. The median aPTT (26.3 vs 27.5s, P=0.001) and median D-dimer levels (18.8 vs 40.2μg/dL, P=0.006) were significantly higher in the older group. However, the fibrinogen level (205 vs 248mg/dL, P<0.001) was significantly higher in the older group. The regression lines of fibrinogen and age in non-massive transfusion and massive transfusion cases are given by Y=1.03X+185 (r=0.24, r2=0.06, P<0.001) and Y=0.86X+134 (r=0.25, r2=0.06, P=0.09) respectively, and the fibrinogen levels tended to increase with older age in severe trauma patients. ConclusionsThe fibrinogen level did not show a low value as it can in younger patients in elderly patients. Therefore, the fibrinogen level is difficult to use as an early indicator of acute blood loss with haemorrhage in elderly severe trauma patients, as it can be used in younger patients. Thus, it is necessary to keep in mind that the fibrinogen level increases by approximately 1mg/dL when the age increases by 1 year and to carefully observe the fibrinogen level even if the admission level is not low.

Predictors of Occult Cancer in Acute Ischemic Stroke Patients

We investigated the prevalence of occult malignancy (OM) in acute ischemic stroke patients to evaluate if any biological marker could help to detect the presence of OM. We retrospectively reviewed all ischemic stroke patients during 48months. We did not perform any screening for OM. Demographic data, vascular risk factors, routine blood chemistry with fibrinogen and C-reactive protein (CRP), National Institutes of Health Stroke Scale (NIHSS), and etiological subtype of stroke according to Trial of Org 10172 in Acute Stroke Treatment criteria were analyzed. The patients were divided into 2 groups (Non-OM versus OM). We analyzed 631 patients with acute ischemic stroke. The mean age was 69.7±12.7years, and 59% were men. The distribution of vascular risk factors, etiological subgroups, and NIHSS was comparable between both groups. We detected 13 cases (2.1%) with OM, and this percentage was higher in patients with stroke of undetermined etiology (5.3%). We detected significant higher levels of fibrinogen and CRP in patients with stroke of undetermined cause with OM. Receiver operating characteristic curves showed a sensitivity of 75% and specificity of 96% for levels of CRP more than 20mg/L, and a sensitivity of 67% and specificity of 91% for fibrinogen levels greater than 600mg/dL. OM was present in 2.1 % of overall patients, and 5.3% of patients with stroke of undetermined cause. Baseline levels of fibrinogen more than 600mg/dL or CRP greater than 20mg/L in patients with undetermined stroke might be good predictors of OM.

The Sustained Increase of Plasma Fibrinogen During Ischemic Stroke Predicts Worse Outcome Independently of Baseline Fibrinogen Level

Hyperfibrinogenemia at the beginning of ischemic stroke is associated with poor outcome. We hypothesized that the sustained increase of plasma fibrinogen during stroke predicts outcome independently of baseline fibrinogen concentration. We included 266 patients with first-ever ischemic stroke in whom plasma fibrinogen level was measured on days 1, 7, and 14. The sustained fibrinogen’s increase was defined as the persistent elevation of fibrinogen’s concentration on days 7 and 14 by at least 20 % compared to the level on day 1. The functional outcome on day 30 was assessed using modified Rankin Scale (mRS). Favorable outcome was defined as mRS 0–1. The sustained increase of fibrinogen was found in 17 % of patients. On multivariate logistic regression analysis adjusted for age, NIHSS score, baseline fibrinogen >2.66 mmol/L, presence of infection, and hyperglycemia, the sustained fibrinogen’s level was associated with reduced chance of favorable outcome (OR: 0.17, 95 % CI: 0.06–0.48, P < 0.01).

Inflammatory markers and the risk of vascular complications and mortality in type 2 diabetes mellitus

Purpose: There are few data assessing the relationship between circulating levels of C-reactive protein (CRP), fibrinogen, and interleukin-6 (IL-6) and the risk of vascular complications in individuals with type 2 diabetes mellitus (T2DM). We studied the associations between these inflammatory markers and the risk of major CV events (CV death, myocardial infarction or stroke), microvascular complications and death in patients T2DM who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Methods: Baseline high sensitivity CRP, fibrinogen and IL-6 levels were determined in a case-cohort study (n=3,865), nested within the ADVANCE trial. Results: During 5 years of follow-up, 709 patients suffered a major CV event, 439 a microvascular complication and 706 died. All 3 markers were associated with an increased risk of CV events and death in analyses adjusting for age, sex and treatment groups. After further adjustment, for other potential confounders and for each other, only IL-6 was an independent predictor of these outcomes (hazard ratio [HR] for CV events 1.37 per 1 standard deviation [SD] increase in log IL-6, 95% confidence interval [CI] 1.24-1.51; HR for death 1.35, 95% CI 1.23-1.49). This increased hazard was seen in patients with and without prior CV disease (figure, HR per 1 SD increase in log IL-6). IL-6 significantly improved the prediction of CV events and death using reclassification statistics (net reclassification improvement in continuous models 23% for CV events and 30% for death). After adjustment, none of the markers predicted microvascular complications. ![Figure][1] Death stratified by prior CV disease Conclusions: IL-6, but not CRP or fibrinogen, levels add significantly to the prediction of CV events and mortality in individuals with T2DM. [1]: pending:yes

Delayed resolution of inflammatory response compared with clinical recovery in patients with acute exacerbations of chronic obstructive pulmonary disease

The temporal profile of inflammatory markers during acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and their relationship to clinical response are not well characterized. The aim was to assess the changes in levels of inflammatory markers in AECOPD and correlate these with clinical and laboratory indices of recovery. Serum levels of C-reactive protein (CRP), interleukin (IL)-6 and fibrinogen were measured in patients with AECOPD within 24 h of hospitalization and pre-discharge (stable state). Ninety-seven patients were evaluated (79 males; mean (SD) age, 61.4 (10.3) years). Eighty eight (90.7%) were current or former smokers, with a median consumption of 15 (0-75) packs/year. The median duration of COPD was 8 (2-25) years. Forty-six patients (56.9%) required mechanical ventilation for a median of 5 days (1-34) while in hospital. The median duration of hospital stay was 13 days (1-77). At reassessment before planned discharge, the levels of dyspnoea, leucocyte counts, erythrocyte sedimentation rate, creatinine, partial pressure of oxygen, and albumin normalized. The levels of CRP, IL-6 and fibrinogen reduced significantly but did not reach the normal range. Changes in IL-6 and fibrinogen levels correlated significantly with the acute physiologic assessment and chronic health evaluation II score, smoking history, blood pressure and leucocyte counts. Baseline IL-6 and fibrinogen levels significantly predicted a prolonged duration of mechanical ventilation. During AECOPD, the inflammatory response lags behind clinical and biochemical improvement. Fibrinogen and IL-6 are potentially useful markers for monitoring clinical response following an acute episode.

Effect of Statins on C-reactive Protein, Lipoprotein(a) and Fibrinogen in Hypercholesterolemic Patients

Objective: C-reactive protein (CRP), lipoprotein (a)[Lp(a)], and fibrinogen are associated with systemic inflammatory reactions. Statins have anti-inflammatory effects. However, the effect of statins on these parameters is inconsistent. We evaluated the effect of statins on inflammatory markers and variables related to changes in these markers. Methods: A total of 390 hypercholesterolemic patients were enrolled. Atorvastatin (n=112), lovastatin (n=25), pitavastatin (n=49), rosuvastatin (n=20), and simvastatin (n=184) were administered. Lipids, CRP, Lp(a), and fibrinogen levels were measured before and after 2 months of the therapy. Results: Statins reduced cholesterol, low density lipoprotein (LDL) cholesterol, and triglyceride levels by -28.9±9.1% (P=0.000), -41.4±12.4% (P=0.000), and -11.6±39.4% (P=0.000), respectively and increased high density lipoprotein (HDL) cholesterol level by 2.56±13.2% (P=0.014). CRP levels decreased from 1.23±1.30 to 1.14±1.29 mg/L (P=0.000). Lp(a) levels were not changed (P=0.91) and fibrinogen levels increased from 277.8±54.4 to 282.6±56.9 mg/dL (P=0.042). Changes in CRP levels were associated with baseline CRP levels (r=-0.56, P=0.000) and changes in HDL cholesterol levels (r=-0.14, P=0.005). Changes in Lp(a) levels were associated with changes in triglyceride (r=-0.24, P=0.000) and baseline aspartate aminotransferase level (r=0.12, P=0.015). Changes in fibrinogen levels were associated with baseline fibrinogen levels (r=-0.40, P=0.000), sex (r=0.18, P=0.001), and changes in HDL cholesterol levels (r=-0.15, P=0.003). Conclusion: Inflammatory markers showed different responses to statins and changes in these markers were associated with different parameters. This finding suggests that anti-inflammatory effect of statin is confined to a specific pathway of inflammation.

Pathogen Reduction Treatment of Whole Blood Inhibits Clot Lysis and Thrombin Generation Is Preserved to 14 Days by Storage At 4°C

Abstract 2272 Introduction:Fresh whole blood (WB) collected from a “walking blood bank” is used by the U.S. military to supplement component therapy when blood component supplies are exhausted. Currently, WB is used for emergency transfusion within 24 hours of collection, before results of pathogen testing are available. A pathogen reduction technology (PRT), which uses riboflavin and ultraviolet light to damage nucleic acids in pathogens, is being considered as a transfusion-transmitted disease (TTD) risk mitigation measure. The effect of this technology on the hemostatic properties of whole blood, particularly on clotting capacity and clot lysis, are poorly understood, and optimal storage conditions are not defined. We previously reported that activated partial thrombin time (aPTT) and prothrombin time (PT) are prolonged by treatment; however, these tests do not always correlate with clinical findings. Thromboelastography is a more robust measure of clot formation and stability over time; we previously found that maximum amplitude (MA), which represents clot strength, did not decrease with PRT treatment and was preserved by storage at 4°C. Here we explore the effects of PRT on other parameters important to clotting capacity and clot lysis, and present the effects of WB storage at 4°C compared to 22°C. Hypothesis:WB treated with PRT demonstrates similar hemostatic function to non-treated WB, and storage at 4°C reduces degradation of blood components essential to clotting capacity and clot lysis compared to 22°C. Methods:Under an IRB-approved protocol, 8 units per treatment group of WB were collected in CPD anticoagulant from healthy donors of normal hemostatic status according to standard blood donor guidelines. Pathogen reduction was performed using riboflavin and ultraviolet light (265–400nm phosphor; Mirasol® System, CaridianBCT) dosed at 80 J/mLRBC. Treatment groups included: control WB stored at 4° C (CON-04); control WB stored at 22° C (CON-22); PRT-treated WB stored at 4° C (PRT-04); and PRT-treated WB stored at 22° C (PRT-22). The hemostatic function of the blood was assessed at baseline, days 1–7, 10, 14, and 21. Factor VIII and fibrinogen were measured from assayed samples (BCS® XP system, Siemens). Thromboelastography (TEG®, Haemoscope Corp.) estimated total thrombin generation by calculating the first derivative of the TEG tracing, the Total Thrombus Generation variable (TTG). TEG was also used to measured lysis (LY30). Data were analyzed as repeated measures, followed by analysis of variance to assess interactions. Significance was set at p<0.05. Results:Treatment with PRT caused an initial drop in fibrinogen (baseline: 244 ± 77.5 mg/dL versus post-treatment: 185 ± 63.2 mg/dL, p≤0.04) and factor VIII (baseline: 96 ± 39% versus day post-treatment: 46 ± 23%, p≤0.001); however, levels stabilized thereafter (p≥0.987 and p≥0.871, respectively; see Fig. 1–2). Baseline fibrinogen levels were similar between groups p≥0.386). PRT-04 was the only group in which both fibrinogen and Factor VIII levels fell below clinical reference ranges (fibrinogen: p’0.039; factor VIII: p≤0.016). TTG was unaffected by PRT and was preserved through day 14 by storage at 4° C (p≥0.979, see Fig. 3), but only through day 10 when stored at 22°C (p≤0.290 at day 10). PRT treatment inhibited clot lysis (LY30) compared to storage at 22°C (p≤0.001), and variability was the lowest in the PRT-04 group (p≤0.001, see Fig. 4). [Display omitted] [Display omitted] Conclusions:Our data demonstrate that pathogen reduction inhibited clot lysis. Decreased clot formation could conceivably account for the smaller degree of lysis; however, we previously found that MA is unaffected, and now demonstrated that thrombin generation was preserved despite a treatment-related decrease in factor VIII levels. While fibrinogen levels were diminished in the PRT-04 group, they were preserved in the PRT-22 group, which also demonstrated the diminished lysis. Cold storage preserved WB clotting capacity compared to storage at room temperature. The clinical significance of these findings has yet to be established; a coagulopathic animal hemorrhage model could determine whether the effects of PRT-induced lysis inhibition and cold storage are beneficial. Disclosures:Mora:CaridianBCT: Research Funding. Pidcoke:CaridianBCT: Research Funding. Valdez-Delgado:CaridianBCT: Research Funding. Fedyk:CaridianBCT: Research Funding. Reddy:CaridianBCT: Employment, Research Funding. Goodrich:CaridianBCT: Employment, Research Funding. Cap:CaridianBCT: Research Funding.

Early stroke-related deep venous thrombosis: risk factors and influence on outcome.

Deep venous thrombosis (DVT) is a serious complication of various medical conditions including acute stroke. Our aim was to identify the occurrence of early stroke-related DVT, risk factors for its development and the influence on outcome. The study involved consecutive patients admitted to our center due to acute ischaemic (n = 278) or haemorrhagic (n = 12) stroke during a 16-month period. We collected data on their pre-stroke health status, neurological deficit on admission and baseline serum CRP and fibrinogen level. Ultrasonographic imaging was performed at the 3rd (IQR: 2–4) and 9th (IQR: 8–9) day after stroke. Patients thrombosis occurring between the first and second examination comprised the newly developed early stroke-related DVT group. We found DVT in 8.0% (24/299) of patients at initial evaluation. Newly developed DVT was present in 3.0% (9/299) of patients, and was predominantly distal (7 of 9 cases). It was associated with elevated serum CRP level (OR 8.75; 95%CI: 1.61–47.6), which was verified in a model adjusted for stroke severity and pre-stroke dependency (3–5 pts. in mRS). In a multivariate model, newly developed DVT significantly increased the risk of 3-month mortality (OR 12.4; 95%CI: 1.72–89.4), without affecting the combined risk of dependency and death (OR 2.57; 95%CI: 0.39–17.0). Early stroke-related DVT is an infrequent complication. However, it may be an independent risk factor for 3-month mortality. Increased serum CRP level combined with normal fibrinogen level seems predictive for development of DVT. It may be reasonable to provide those patients with additional DVT prophylaxis.

A cross-shift study of lung function, exhaled nitric oxide and inflammatory markers in blood in Norwegian cement production workers

ObjectivesTo study possible effects of aerosol exposure on lung function, fractional exhaled nitric oxide (FeNO) and inflammatory markers in blood from Norwegian cement production workers across one work shift (0...

Prolonged Prothrombin Time After Recombinant Activated Factor VII Therapy in Critically Bleeding Trauma Patients Is Associated With Adverse Outcomes

In trauma patients with significant hemorrhage, it is hypothesized that failure to normalize prothrombin time (PT) after recombinant activated factor VII (rFVIIa) treatment predicts poor clinical outcomes and potentially indicates a need for additional therapeutic interventions. To assess the value of PT to predict outcomes after rFVIIa or placebo therapy, we performed a post hoc analysis of data from 169 severely injured, critically bleeding trauma patients who had 1-hour postdose PT measurements from two randomized clinical trials. Baseline characteristics and outcome parameters were compared between subjects with 1-hour postdose PT >or=18 seconds and PT <18 seconds. In rFVIIa-treated subjects, prolonged postdose PT values >or=18 seconds were associated with significantly higher 24-hour mortality (60% vs. 3%; p < 0.001) and 30-day mortality, increased incidence of massive transfusion, and fewer intensive care unit-free days compared with postdose PT values <18 seconds. Recombinant rFVIIa-treated subjects with postdose PT >or=18 seconds had significantly lower baseline hemoglobin levels, fibrinogen levels, and platelet counts than subjects with postdose PT values <18 seconds even though they received similar amounts of blood products before rFVIIa dosing. Placebo-treated subjects with postdose PT >or=18 seconds had significantly increased incidence of massive transfusion, significantly decreased intensive care unit-free days, and significantly lower levels of fibrinogen and platelets at baseline compared with subjects with postdose PT values <18 seconds. The presence of prolonged PT after rFVIIa or placebo therapy was associated with poor clinical outcomes. Because subjects with postdosing PT >or=18 seconds had low levels of hemoglobin, fibrinogen, and platelets, this group may benefit from additional blood component therapy.

C-reactive protein and all-cause mortality--the Copenhagen City Heart Study

We tested whether elevated levels of C-reactive protein is robustly and causally associated with all-cause mortality. We studied 10 388 white persons from the general population. During 16 years 3124 persons died. We measured baseline high-sensitivity C-reactive protein and fibrinogen levels and genotyped for four C-reactive protein polymorphisms and two apolipoprotein E polymorphisms. Levels of C-reactive protein >3 mg/L vs. <1 mg/L associated with a multi-factorially adjusted two-fold increased risk of all-cause mortality. Stratifying C-reactive protein into tertiles, quintiles, or octiles resulted in step-by-step increased risk of all-cause mortality, even after fibrinogen adjustment. Finally, genetically elevated C-reactive protein levels associated with a causal hazard ratio of 0.94 (95% CI: 0.64-1.39) for all-cause mortality per doubling of C-reactive protein levels on instrumental variable analysis, for which the corresponding hazard ratio on Cox regression for a doubling in measured plasma C-reactive protein levels was 1.25 (1.21-1.29). As a positive control, a doubling in genetically elevated cholesterol levels via apolipoprotein E associated with a hazard ratio of 6.3 (1.8-22) for all-cause mortality. A single C-reactive protein measurement robustly associates with increased risk of all-cause mortality; however, this does not appear to be a causal association. Therefore, elevated C-reactive protein levels more likely are a marker of hidden, potentially fatal inflammatory disease.

Impact of Fibrinogen Levels on Angiographic Progression and 12-Year Survival in the Armed Forces Regression Study

We assessed the role of fibrinogen levels on angiographic progression and long-term survival among 111 patients with coronary disease enrolled in the Armed Forces Regression Study (AFREGS). Baseline fibrinogen levels and quantitative coronary angiography were performed initially and at 30 months. Progression or nonregression of coronary disease was more prevalent in patients with high fibrinogen than patients with normal fibrinogen (66.1% vs 45.5%; P = .022). Twelve-year cardiovascular (CV) mortality was substantially higher if fibrinogen was elevated (17.9% vs 3.6%, P = .016). Among patients with elevated fibrinogen and angiographic progression or nonregression, there were 10 deaths and all were CV. Elevated levels of fibrinogen predict the angiographic progression of existing coronary disease and likelihood of CV death. Among patients with elevated levels of fibrinogen, angiographic progression identifies a significantly increased likelihood of a fatal CV event.

Association between longitudinal changes in depressive symptoms and plasma fibrinogen levels in school teachers

Depression and anxiety previously predicted coronary artery disease (CAD) risk. Inflammation contributes to CAD and shows an association with depression. We followed 57 teachers (mean 49+/-8 years) over 21 months and investigated whether changes in depressive and anxiety symptoms relate to those in the CAD risk and inflammation marker fibrinogen and vice versa. Increase in depressive symptoms and in fibrinogen levels were significantly correlated. While controlling for baseline depression rendered the association between changes in depression and fibrinogen nonsignificant, taking into account baseline fibrinogen levels maintained the predictive value of fibrinogen change for depression change. Anxiety and fibrinogen changes were not significantly correlated. This dynamic relationship between depression and the inflammatory biomarker fibrinogen might advance our knowledge about psychobiological mechanisms underlying both CAD and sickness behavior.

Impact of ATRA Duration during the Induction Treatment of Newly Diagnosed APL

Background: ATRA combined to anthracycline based chemotherapy (CT) is the reference treatment of newly diagnosed APL. ATRA has also demonstrated a role during maintenance treatment in randomized studies (Fenaux, Blood 99; Talmann, NEJM 1997), and may even be useful during consolidation courses (Sanz, Blood, 2008, although this was not a randomized study). During induction treatment, the optimal duration of ATRA treatment, however, is unknown. We tried to assess this point using long-term results of APL 93 and APL 2000 trials, conducted by the European APL group in newly diagnosed APL between 1993 and 2004.Methods: APL 93 and 2000 trials combined ATRA plus 3 courses of daunorubicin (DNR) based CT and included a total of 902 pts with different randomizations (for date of introduction of CT, use or not of AraC and of maintenance treatment). Only treatment arms that proved “optimal” (ie with early addition of the first course of CT to ATRA, AraC in combination to DNR for the 3 CT courses, and combined maintenance with intermittent ATRA and low dose continuous CT) (Fenaux, Leukemia 2000;Ades JCO 2006) and adult pts who had achieved CR in those arms, ie 414 pts, were considered for this analysis of the influence of duration of ATRA during induction treatment on the cumulative incidence of relapse (CIR) and survival. Per protocol, ATRA (45 mg/m2/d, rounded to a daily dose of 8 pills of 10 mg per day, ie 80 mg/day in most pts) was to be administered “until CR”, and to be transiently discontinued only in case of severe ATRA syndrome. No dose reduction was allowed except in children, who were therefore excluded from this analysis.Results: In the 414 pts, who Included 263 (64%) pts with WBC < 10G/L and 151(36%) pts with WBC >10G/L, the median cumulative dose of ATRA administered during Induction treatment was 2160 mg (corresponding to 27 days at 80 mg/d) Early ATRA Interruptions, Ie before recovery from aplasia and patient discharge, were made almost exclusively for ATRA syndrome or unexplained fever, and were followed or not by restart of the drug. Final discontinuation of ATRA for induction treatment was made a median of 27 days after onset of ATRA treatment. Although both trials stated that ATRA should be continued “until CR”, ATRA discontinuation was more often made at the end of the period of aplasia and patient discharge, than at the time of documented CR on bone marrow examination, especially as marrow abnormal promyelocytes are known to disappear slowly in APL. No difference in 5 y CIR or survival were found in pts who had received more or less than 2160 mg of ATRA during induction in the whole population and in pts with baseline WBC less or greater than 10 G/L. 89/414 (21%) pts had received less than 1500 mg of ATRA during Induction (corresponding to less than 19 days at 80 mg/day), their 5 y CIR and survival were similar to those of pts who had received more than 1500 mg of ATRA during induction in the whole population, and in pts with baseline WBC > 10 G/L. However, in pts with baseline WBC <10G/L (263 pts), the 5 year CIR, and survival were 31.3% and 12.5% (p = 0.04) and 81.1% and 95.3% (p = 0.022), in patients who had received less and more than 1500 mg of ATRA during induction treatment, respectively. Differences persisted after adjustment on other prognostic factors of relapse Identified in our previous studies, including gender, baseline platelet count, circulating blasts and fibrinogen level and on the clinical trial (APL 93 vs APL 2000).Conclusion: Although ATRA duration for induction treatment was not randomized in APL 93 and 2000 trials, our results suggest that, in newly diagnosed APL pts with WBC < 10 G/L, short duration of ATRA during induction treatment may be associated with a higher risk of relapse. This, along with Spanish PETHEMA results supporting a possible role for ATRA during consolidation courses, suggests that sufficiently prolonged exposure to ATRA during the first months of treatment (and not only during maintenance) may be important for disease cure in APL.