Abstract: Background: Overt proteinuria is a strong risk factor for thromboembolism due to changes in levels of various coagulation proteins and urinary antithrombin loss. The described coagulation disturbances in these patients are based on outdated studies conducted primarily in the 1970's and 80's. Whether these coagulation disturbances resolve with antiproteinuric therapy has yet to be studied. Methods: A total of 32 patients with overt proteinuria (median 3.7 g/d; interquartile range 1.5-5.6) were enrolled in this intervention crossover trial designed to assess optimal antiproteinuric therapy with sodium restriction, losartan and diuretics. Levels of various pro- and anticoagulant proteins, and two thrombin generation assays (i.e., Calibrated Automated Thrombogram [CAT] and prothrombin fragment 1+2) of placebo period were compared to maximum anti-proteinuric therapy period. As secondary analysis, coagulation measurements of the placebo period in these patients were compared to 32 age and sex matched healthy controls. Results: During maximum treatment median proteinuria was significantly lower (median, 0.9 g/d; interquartile range, 0.6-1.4; P<0.001) as compared to placebo period. Similarly, levels of various liver-synthesized pro- and anticoagulant proteins, activated protein C resistance, as well as prothrombin fragment 1+2 levels were significantly lower during maximum treatment versus placebo period. However, Von Willebrand and factor VIII levels were similar. Based on the higher levels of procoagulant proteins (i.e., fibrinogen, factor V, VIII and Von Willebrand) and both thrombin generation assays, patients were substantially more prothrombotic than healthy controls (P<0.004). Conclusions: Antiproteinuric therapy ameliorates the protrombotic state. Proteinuric patients are in a more prothrombotic state, as compared to healthy controls.
Abstract: Cytomegalovirus is associated with hypercoagulability, and is reported to increase the risk of venous thrombosis in human immunodeficiency virus (HIV)-infected patients. Progression to AIDS, however, is also associated with hypercoagulability and venous thrombosis, and may result in more comorbidities, such as reactivation of cytomegalovirus. It is therefore unknown whether active cytomegalovirus in HIV infection results in a procoagulant state or whether hypercoagulability is the result of HIV infection itself. In this cross-sectional study of 104 consecutive HIV-infected patients, active cytomegalovirus infection was associated with hypercoagulability independently of stage of HIV disease. This finding may deserve attention in preventative recommendations for use of thromboprophylaxis in HIV-infected patients.
Abstract: Conflicting data have been reported on the accuracy of protein S (PS) assays for detection of hereditary PS deficiency. In this study we assessed the diagnostic performance of two total PS antigen assays, four free PS assays and three PS activity assays in a group of 28 heterozygous carriers of mutations in PROS1 and 165 control subjects. Several control groups were formed, one of healthy volunteers and - because PS levels are influenced by oral contraception and pregnancy, and assays measuring PS activity may be influenced by the presence of the factor V Leiden mutation -, we also investigated the influences of these factors. All nine PS assays detected significantly reduced PS levels in subjects with a PROS1 mutation. Eight out of nine PS assays showed a 100% sensitivity and 100% specificity to detect heterozygous carriers of mutations in PROS1 with values far below the lower limit of the reference values obtained from healthy volunteers. Low specificities were found in subjects with a factor V Leiden mutation and in pregnant women. At lower cut-off levels, equal to the highest PS value found in heterozygous carriers of mutations in PROS1, the specificity considerably increased in these subjects. When using low cut-off levels equal to the highest PS value found in heterozygous carriers of mutations in PROS1, ensuring 100% sensitivity, the specificity in all study groups increases considerably, by which misclassification can be maximally avoided.
Abstract: INTRODUCTION: Whether high factor (F)VIII and low free protein S levels are risk factors for arterial thrombosis is unclarified. MATERIAL AND METHODS: In a post-hoc analysis of a single-centre retrospective family cohort, we determined if these two proteins could increase the risk of arterial thrombosis. In total, 1399 relatives were analysed. RESULTS: Annual incidence in relatives with high FVIII levels was 0.29% (95%CI, 0.22-0.38) compared to 0.13% (95%CI, 0.09-0.19) in relatives with normal FVIII levels. In relatives with low free protein S levels, this risk was 0.26% (95%CI, 0.16-0.40), compared to 0.14% (95%CI, 0.10-0.20) in relatives with normal free protein S levels. Mean FVIII levels adjusted for age and sex were 11 IU/dL, 18 IU/dL, and 21 IU/dL higher in relatives with hypertension, diabetes mellitus, and obesity as compared to relatives without these arterial thrombotic risk factors. Moreover, a dose response relation between increasing FVIII and body mass index was found. None of these associations were shown for free protein S. CONCLUSIONS: High FVIII and low free protein S levels seemed to be mild risk factors for arterial thrombosis. High FVIII levels were particularly observed in relatives with traditional arterial thrombotic risk factors. Free protein S levels were not influenced by these thrombotic risk factors. This assumes that low free protein S levels were genetically determined.
Abstract: Conflicting data have been reported on the risk for venous thrombosis in subjects with low free protein S levels. We performed a post-hoc analysis in a single-center retrospective thrombophilic family cohort, to define the optimal free protein S level that can identify subjects at risk for venous thrombosis. Relatives (1143) were analyzed. Relatives with venous thrombosis (mean age 39 years) had lower free protein S levels than relatives without venous thrombosis (P < .001), which was most pronounced in the lowest quartile. Only relatives with free protein S levels less than the 5th percentile (< 41 IU/dL) or less than the 2.5th percentile (< 33 IU/dL) were at higher risk of first venous thrombosis compared with the upper quartile (> 91 IU/dL); annual incidence 1.20% (95% confidence interval [CI], 0.72-1.87) and 1.81% (95% CI, 1.01-2.99), respectively; adjusted hazard ratios 5.6, (95% CI, 2.7-11.5) and 11.3 (95% CI, 5.4-23.6). Recurrence rates were 12.12% (95 CI, 5.23-23.88) and 12.73% (95% CI, 5.12-26.22) per year; adjusted hazard ratios were 3.0 (95% CI, 1.03-8.5) and 3.4 (95% CI, 1.1-10.3). In conclusion, free protein S level can identify young subjects at risk for venous thrombosis in thrombophilic families, although the cutoff level lies far below the normal range in healthy volunteers.
Abstract: Hereditary protein S (PS) deficiency predisposes to venous thrombosis. Previously, we demonstrated a difference in risk of venous thrombosis between PS deficiency type I and type III. We used direct sequencing, multiplex ligation-dependent probe amplification (MLPA), and linkage analysis to study whether this difference could be explained by molecular heterogeneity. The study contained two sets of families with PS deficiency type I (cohort 1; 35 probands, 155 relatives) or type III (cohort 2; 52 probands, 241 relatives). In cohort 1, a mixed type I/type III PS-deficient phenotype was observed in 66% of the pedigrees. A total of 34 probands carried a mutant PROS1 allele, compared to one proband in cohort 2 (P<10(-10)). The proband's mutation was identified in all type I, but only in 57% of type III PS deficient relatives. MLPA-analysis in the mutation negative families did not reveal PROS1 deletions or insertions. Linkage analysis in 16 families showed cosegregation of PROS1 markers in the family with type I deficiency, but not in the 15 families with type III deficiency. The genotype-phenotype associations point to differences in genetic architecture. Whereas PS deficiency type I is a monogenic disease due to PROS1 allelic heterozygosity, PS deficiency type III is most likely a more complex or heterogeneous disorder.
Abstract: We report a family with type I and type III protein S (PS) deficiency, which showed to be phenotypic variants of the same genetic disease. Direct sequencing analysis of the PROS1 gene was performed to establish the genotype. The ratio of protein C antigen and total PS antigen levels (protein C/S ratio) was used to classify subjects at risk of venous thromboembolism. All PS deficient subjects had increased protein C/S ratios as well as a novel PROS1 c.1113T-->GG frameshift mutation.
