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Background:  Haemostatic balance represented by low protein C (PC) and elevated factor VIII (FVIII) has been inconsistently associated with stroke and coronary heart disease (CHD) risk., Objective:  This article assesses whether an elevated FVIII and a low PC would increase cardiovascular risk more than either individually., Patients and Methods:  REGARDS recruited 30,239 black and white U.S. participants aged ≥ 45 years between 2003 and 2007. FVIII and PC were measured in a case-cohort sample of 646 stroke, 654 CHD, and a 1,104-person random sample with follow-up for approximately 4.5 years. Hazard ratios (HRs) were estimated using Cox models adjusted for demographic and cardiovascular risk factors., Results:  Elevated FVIII (per standard deviation [SD] increase) was associated with increased risk of both stroke (HR, 1.26; 95% confidence interval [CI], 1.08, 1.46) and CHD (HR, 1.52; 95% CI, 1.29, 1.79), while there was no association of PC per SD decrease. For PC, there was a trend towards increased cardiovascular disease risk in the lowest values (bottom 5%). For stroke, there was no interaction between FVIII and low PC ( p interaction  = 0.55). For CHD, the adjusted HR of FVIII per SD increase was significantly greater with PC in the bottom 5% (HR, 3.59; 95% CI, 1.39, 8.29) than PC in the upper 95% (HR, 1.45; 95% CI, 1.23, 1.71; p interaction  = 0.07)., Conclusion:  Higher FVIII was associated with both CHD and stroke risk and the risk potentiated by low PC for CHD. Findings demonstrate that risks for cardiovascular diseases conferred by adverse levels of haemostasis biomarkers may be augmented by levels of other biomarkers., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: The aim of this study was to examine treatments of septic shock in a sample of US hospitals and to assess whether patient and hospital characteristics are associated with use of sepsis therapies., Materials and Methods: We studied 192 hospitals that treated 50 or more adults with septic shock between 2004 and 2006. We examined hospital-level variation in commonly used therapies including mechanical ventilation, activated protein C (APC), hydrocortisone, central venous pressure (CVP) monitoring, albumin/colloid, and pulmonary artery catheters. We calculated interquartile range to assess the hospital-level variation in treatment. We developed hierarchical mixed-effects logistic regression models to examine the association between patient and hospital characteristics and selected treatments., Results: A total of 22702 patients met the inclusion criteria. When compared with patients younger than 45 years, patients 75 years or older were as likely to receive mechanical ventilation but less likely to receive APC (odds ratio [OR], 0.35 [95% confidence interval, 0.27-0.45]), hydrocortisone (OR, 0.65 [0.56-0.75]), or CVP monitoring (OR, 0.73 [0.63-0.84]). Compared with whites, black patients were more likely to be mechanically ventilated (OR, 1.15 [1.05-1.25]) but less likely to receive hydrocortisone (OR, 0.86 [0.78-0.95]) or APC (0.70 [0.58-0.86])., Conclusion: Treatment of septic shock varies across hospitals. In contrast to mechanical ventilation, treatments with weaker supporting evidence showed greater variation, especially among black and older patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Context: Hereditary and acquired deficiencies of antithrombin (AT), protein C (PC), and protein S (PS) are risk factors for venous thromboembolism. Proper diagnosis requires high-quality assays for these proteins., Objective: To determine the accuracy and interlaboratory precision of AT, PC, and PS assays used by laboratories participating in the United States College of American Pathologists proficiency testing program in thrombophilia and to grade the performance of laboratories., Design: Standardized normal plasma with assigned analyte values was sent in 2 separate challenges to participating laboratories. Participants measured AT, PC, and PS levels using local methods., Results: When compared with the assigned values for the international standard, the order of assay accuracy from highest to lowest was AT activity, PC antigen, AT antigen, total PS antigen, PC activity, PS activity, and free PS antigen (range of assay bias, 2.6%-8.8%). The order of assay precision from highest to lowest was PC activity, AT activity, AT antigen, total PS antigen, PS activity, free PS antigen, and PC antigen (range of assay coefficient of variation, 6.1%-20.0%). Most testing events (87.8%) could be graded as pass or fail using a target range of ±3 standard deviations from the method-specific mean. The pass rate was 98.2% for all AT, PC, and PS testing events combined., Conclusions: Accuracy and precision were higher for AT assays and lower for PC and PS assays. It was feasible to grade individual laboratory performance.

Thrombomodulin, an endothelial membrane glycoprotein, is an essential part of the protein C anti-coagulant pathway. It may also have a role in the regulation of fibrinolysis. We carried out a cross-sectional study to assess the association of soluble thrombomodulin (sTM) with peripheral artery disease (PAD) in a stratified random sample (n=863) of otherwise healthy black and white participants of the Atherosclerosis Risk in Communities (ARIC) Study. PAD was more common in black than in white participants and associated with classical risk factors in an expected manner; positively with age, smoking, hypertension, diabetes (P=0.05), and LDL-cholesterol, and inversely with HDL-cholesterol. Significant positive associations were observed also with fibrinogen and white blood cell count. Overall, the sTM concentration was not a significant predictor of PAD. The association was, however, modified by the level of factor VIII:C in whites (P=0.002 for the interaction), but not in blacks. Protein C was inversely associated with PAD prevalence (odds ratio 0.33, 95% CI 0.18--0.61, P=0.0004). sTM was inversely associated with plasminogen, but no associations with t-PA, PAI-1, or D-dimer were seen. In conclusion, the present results provide some additional evidence on the role of thrombomodulin-protein C pathway in atherosclerotic disease and support our earlier observation on interaction between sTM and factor VIII:C.

To evaluate the association of plasma protein C levels with constitutional, socioeconomic, life-style and biochemical factors important in cardiovascular diseases, we measured protein C levels in 12,290 middle aged (45-64 years) subjects participating in the ARIC study. Protein C levels had a normal distribution with a mean value of 3.17 micrograms/ml. They were higher in women than men and in whites than blacks; higher in postmenopausal women and further increased by hormonal supplements. The age influence was inconsistent and was considered to be inconsequential. Protein C levels were positively correlated with body mass index, LDL-cholesterol, HDL-cholesterol, and triglycerides and negatively associated with cigarette smoking. These factors should be taken into consideration when establishing normal protein C levels and when analyzing the relation between protein C and arterial and venous thrombotic disorders.

Mortality rates of coronary heart disease are much lower in Japan than in the United States. The authors' previous report on coagulation factors showed that population levels of plasma fibrinogen and factor VII activity parallel this mortality difference. To investigate other hemostatic variables, the authors assessed indicators of fibrinolytic activity (tissue plasminogen activator antigen) and coagulation inhibition (antithrombin III activity and protein C) in 136 men aged 34-55 years in four different samples: rural Japanese, urban Japanese, Japanese Americans, and Caucasian Americans. Mean tissue plasminogen activator antigen was higher in Caucasians and Japanese Americans than in rural and urban Japanese (p less than 0.01), while a contrasting trend in mean antithrombin III activity was suggested (p = 0.10). No significant differences were observed in mean levels of protein C. After controlling for known coronary risk factors, mean levels of tissue plasminogen activator antigen remained significantly different across the four samples (p less than 0.01); mean antithrombin III activity was not different (p = 0.23). Population differences in tissue plasminogen activator antigen parallel the coronary heart disease mortality difference between Japan and the United States. Although no definite evidence is available showing that tissue plasminogen activator antigen is a risk factor for coronary heart disease, the present study suggests a positive ecologic association between this hemostatic factor and coronary heart disease mortality.