Social effects of current hemophilia treatment

The influence of modern substitution therapy on social functioning of haemophiliacs was studied by means of surveys of education and employment in 1972, 1978 and 1985. In addition we studied the physical mobility of the patients. Non-attendance at school and educational delay decreased substantially over thirteen years and the educational level of adult patients is the same as that of the general male population. Sick leave decreased also but the number of disabled did not. Considering the general rise in the number of disabled, the general unemployment situation may be partly blamed for this. Younger patients have a better physical mobility than the older ones who did not have appropriate treatment of bleedings when they were young. Trends in reduction of joint impairment and increase of physical mobility are expected to continue in the coming decades, with a positive effect on social functioning.     

The relation between Helicobacter pylori and atherosclerosis cannot be explained by a high homocysteine concentration

BACKGROUND: Recent studies have suggested that a chronic infection with Helicobacter pylori might be an independent risk factor for atherosclerosis. However, a direct role in atherogenesis is not plausible, since the bacterium has not been isolated from atherosclerotic lesions. An indirect mechanism that could link H. pylori with atherosclerosis might be through an increase in plasma homocysteine concentration caused by deficiencies of vitamin B12 and folate in plasma. MATERIALS AND METHODS: In 150 female patients with peripheral arterial disease (PAD) and in 412 healthy control women from a nation-wide population-based case-control study, blood samples were collected to determine the antibody titre against H. pylori and to measure plasma homocysteine, folate and vitamin B12 levels. First, the odds ratio for PAD in women with a positive antibody titre against H. pylori was calculated and adjusted for homocysteine level. Secondly, mean concentrations of vitamin B12, folate and homocysteine were compared in healthy controls with a positive or negative antibody titre against H. pylori. Thirdly, the relation between H. pylori and PAD in individuals with a normal or high homocysteine level was investigated. RESULTS: A positive immunoglobulin G antibody titre against H. pylori was found in 42% of the PAD patients and in 27% of the controls. The age- and socio-economic-status (SES) adjusted odds ratio for PAD was 1.5 (95%CI; 1.0-2.2). Additional adjustment for homocysteine plasma concentration did not essentially change the odds ratio. Secondly, among the healthy controls, the homocysteine plasma concentration did not depend on the immunoglobulin G titre, neither did the folate plasma concentration. The concentration of vitamin B12 was slightly higher in women with a positive titre. Thirdly, H. pylori infection was a risk factor for PAD in subjects with a normal homocysteine concentration [OR 2.0 (95%CI 1.3-3.1)]. CONCLUSIONS: This study shows a relationship between a positive immunoglobulin G antibody titre against H. pylori and PAD in young women. Moreover, this study does not support the hypothesis that H. pylori infection is related to atherosclerosis via an increase in plasma homocysteine concentration.     

Inter-relation of coagulation factors and d-dimer levels in healthy individuals

Summary.  Recently, high levels of coagulation factor (F)VIII, FIX and FXI have been associated with an increased risk of venous thrombosis. For several coagulation factors a substantial hereditary component was found. If regulatory genes are located outside the clotting factor genes, they may regulate the levels of several proteins in the coagulation system. Thus levels would then cluster in individuals. The aim of the present study was to assess the inter-relation among levels of the pro- and anticoagulant proteins in the coagulation cascade. We also investigated the relation between the coagulation factors and d -dimer levels (marker of coagulation activity). All analyses were performed in healthy subjects, the control population of the Leiden Thrombophilia Study (LETS), to eliminate the influence of a prior thrombosis on the interpretation of the results ( n  = 466). Using principal-components analysis, a method intended to explain relationships among several correlated variables, we found a clustering between the vitamin K-dependent factors (prothrombin, VII, IX, X) and FXI and FXII. FV and FVIII clustered with fibrinogen and d -dimer. FXIII remained relatively independent of the other factors. Adding the anticoagulant factors to the analysis resulted in minor changes in the clustering pattern. The anticoagulant factors clustered together. We found relatively independent clusters within the group of pro- and anticoagulant factors, which may suggest that the genetic basis for high or low levels of factors in the coagulation system may, at least partly, lie outside the genes coding for these factors.     

Estrogens, progestogens and thrombosis

Summary.  Hundreds of millions of women worldwide use either oral contraceptives or postmenopausal hormone replacement. The use of oral contraceptives leads to an increased risk of venous thrombosis, of myocardial infarction, of stroke and of peripheral artery disease, the risks of which are highest during the first year of use. Women with coagulation abnormalities have a higher risk of venous thrombosis when they use oral contraceptives (or postmenopausal hormones) than women without these abnormalities. The risk of venous thrombosis is also higher for preparations containing desogestrel or gestodene (third-generation progestogens) than for those containing levonorgestrel (second-generation progestogens). A previous thrombosis as well as obesity also increase the risk of oral contraceptive-related thrombosis. Hormone replacement therapy increases the risk of venous thrombosis, and has no beneficial, and possibly even a detrimental, effect on the risk of arterial disease. The risk of arterial disease in oral contraceptive users and users of hormone replacement therapy is at most weakly affected by the presence of prothrombotic abnormalities.     

Effect of oral contraceptives on thrombin generation measured via calibrated automated thrombography

In a study population consisting of healthy men (n = 8), women not using oral contraceptives (OC) (n = 28) and women using different kinds of OC (n = 187) we used calibrated automated thrombography (CAT) in the absence and presence of added activated protein C (APC) to compare parameters that can be obtained from thrombin generation curves, i.e. lag time, time to peak, peak height and endogenous thrombin potential (ETP). Both with and without APC, plasmas of OC users exhibited the shortest lag time and time to peak, and the highest peak height and ETP. In the absence of APC none of these parameters differed between users of OC containing different progestogens. In contrast, in the presence of APC shorter lag times and time to peak, and higher peak height and ETP were observed in plasma of users of gestodene-, desogestrel-, drospirenone- and cyproterone acetate-containing OC than in plasma of users of levonorgestrel- containing OC. The ETP determined in the absence of APC (ETP(-APC)) had no predictive value for the APCsr (r = 0.11; slope 0.9 x 10(-3); 95% CI: -0.1 x 10(-3) to 2.0 x 10(-3)) whereas the ETP measured in the presence of APC (ETP+APC) showed an excellent correlation with the APCsr (r = 0.95; slope 6.6 x 10(-3); 95% CI: 6.3 x 10(-3) to 6.9 x 10(-3)) indicating that the APCsr is entirely determined by the ETP+APC. In conclusion, OC use increases thrombin generation, but differential effects of second and third generation OCs on the protein C system likely determine the differences in the risk of venous thrombosis between these kinds of OC.     

The relationship between maintenance dosages of three vitamin K antagonists: acenocoumarol, warfarin and phenprocoumon

Introduction

Vitamin K antagonists of the coumarin type are widely used oral anticoagulants.

Objective

We developed a transition algorithm for the maintenance dosages of three frequently used coumarins: warfarin, phenprocoumon and acenocoumarol.

Methods

The study was conducted at the Leiden Anticoagulation Clinic. Patients were participants in a trial of which the main objective was to compare the quality of an oral anticoagulant therapy with phenprocoumon to warfarin. We included patients who initiated oral anticoagulant therapy and patients who were already using acenocoumarol. Patients were randomized to a treatment with warfarin or phenprocoumon. Patients who were randomized to warfarin switched to phenprocoumon at the end of follow-up. We analysed the switch from acenocoumarol to warfarin or phenprocoumon at the start of follow-up and the switch of warfarin to phenprocoumon at the end of follow-up and calculated the transition factors for stable anticoagulation between these three vitamin K antagonists.

Results

Fifty-eight patients switched from warfarin to phenprocoumon, 39 from acenocoumarol to phenprocoumon and 44 from acenocoumarol to warfarin. The maintenance dose of warfarin was 0.41 (95%CI 0.39-0.43) times the maintenance dose of phenprocoumon. The transition factor between acenocoumarol and phenprocoumon was 0.84 (95%CI 0.79-0.89) and between acenocoumarol and warfarin 1.85 (95%CI 1.78-1.92).

Conclusions

We determined the transition factors between warfarin, phenprocoumon and acenocoumarol. With these transition factors physicians are able to estimate the maintenance dose when it is necessary for a patient to switch from one coumarin to the other.     

Serum epidermal growth factor receptor and HER2 expression in primary and metastatic breast cancer patients

Background  

Breast tissue expression of the ERBB proto-oncogene family has been extensively studied. It was recently shown that expression of epidermal growth factor receptor (EGFR; c-erbB-1) and epidermal growth factor receptor (HER)2 (c-erbB-2) can be detected in the serum of breast cancer patients. The clinical relevance of this has not been fully established.