Rivaroxaban limits complement activation compared with warfarin in antiphospholipid syndrome patients with venous thromboembolism

Background: Complement activation may play a major role in the pathogenesis of thrombotic antiphospholipid syndrome (APS). Coagulation proteases such as factor Xa can activate complement proteins. Aims: To establish whether rivaroxaban, a direct factor Xa inhibitor, limits complement activation compared to warfarin in APS patients with previous venous thromboembolism (VTE). Methods: 111 APS patients with previous VTE, on warfarin target INR 2.5, had blood samples taken at baseline and at day 42 after randomisation in the RAPS (Rivaroxaban in Antiphospholipid Syndrome) trial. Fifty-six patients remained on warfarin and 55 switched to rivaroxaban. Fifty-five normal controls (NC) were also studied. Markers of complement activation (C3a, C5a, terminal complement complex (SC5b-9) and Bb fragment), were assessed. Results APS patients had significantly higher complement activation markers compared to NC at both time points irrespective of the anticoagulant. There were no differences between the two patient groups at baseline, or patients remaining on warfarin at day 42. In 55 patients randomised to rivaroxaban, C3a, C5a and SC5b-9 were significantly lower at day 42; median (ng/mL) [confidence interval] 64 [29-125] vs 83 [35-147], 9 [2–15] vs 12 [4 -18] and 171 [56-245] vs 201 [66-350] respectively, but levels of Bb were unchanged. There were no correlations between rivaroxaban levels and complement activation markers. Conclusions: APS patients with previous VTE on warfarin exhibit significantly increased complement activation, which is likely to occur via the classical pathway, and is decreased by rivaroxaban administration. Rivaroxaban may therefore potentially provide benefit additional to its anticoagulant effect in this patient group by limiting complement activation

Associations of plasma fibrinogen assays, C-reactive protein and interleukin-6 with previous myocardial infarction

Background: The association of plasma fibrinogen with myocardial infarction (MI) may (like that of C-reactive protein, CRP) be a marker of subclinical inflammation, mediated by cytokines such as interleukin-6 (IL-6). There are well- recognized discrepancies between commonly performed fibrinogen assays. Increased ratio of clottable fibrinogen to intact fibrinogen (measured by a recently developed immunoassay) has been proposed as a measure of hyperfunctional fibrinogen, and is elevated in acute MI.<br/> Objective: To compare the associations of intact fibrinogen and four routine fibrinogen assays (two von Clauss assays; one prothrombin-time derived; and one immunonephelometric) in a case-control study of previous MI. Patients/methods: Cases (n = 399) were recruited 3-9 months after their event; 413 controls were age- and sex-matched from the case-control study local population. Intact fibrinogen was measured in 50% of subjects. Results: All routine fibrinogen assays showed high intercorrelations (r = 0.82-0.93) and significant (P lt 0.0001) increased mean levels in cases vs. controls. These four routine assays correlated only moderately with intact fibrinogen (r = 0.45-0.62), while intact fibrinogen showed only a small, nonsignificant increase in cases vs. controls. Consequently, the ratio of each of the four routine assays to the intact fibrinogen assay was significantly higher (P lt 0.0003) in cases vs. controls. Each fibrinogen assay correlated with plasma levels of CRP and IL-6 (which were also elevated in cases vs. controls). Each routine fibrinogen assay remained significantly elevated in cases vs. controls after further adjustment for C-reactive protein and interleukin-6. Conclusions: These data provide evidence for acquired, increased hyperfunctional plasma fibrinogen in MI survivors, which is not associated with markers of inflammatory reactions. The causes and significance of these results remain to be established in prospective studies

The absolute abundance calibration project: the <i>Lycopodium</i> marker-grain method put to the test

Traditionally, dinoflagellate cyst concentrations are calculated by adding an exotic marker or “spike” (such as Lycopodium clavatum) to each sample following the method of Stockmarr (1971). According to Maher (1981), the total error is controlled mainly by the error on the count of Lycopodium clavatum spores. In general, the more L. clavatum spores counted, the lower the error. A dinocyst / L. clavatum spore ratio of ~2 will give optimal results in terms of precision and time spent on a sample. It has also been proven that the use of the aliquot method yields comparable results to the marker-grain method (de Vernal et al., 1987). Critical evaluation of the effect of different laboratory procedures on the marker grain concentration in each sample has never been executed. Although, it has been reported that different processing methods (e.g. ultrasonication, oxidizing, etc.) are to a certain extent damaging to microfossils (e.g. Hodgkinson, 1991), it is not clear how this is translated into concentration calculations. It is wellknown from the literature that concentration calculations of dinoflagellate cysts from different laboratories are hard to resolve into a consistent picture. The aim of this study is to remove these inconsistencies and to make recommendations for the use of a standardized methodology. Sediment surface samples from four different localities (North Sea, Celtic Sea, NW Africa and Benguela) were macerated in different laboratories each using its own palynological maceration technique. A fixed amount of Lycopodium clavatum tablets was added to each sample. The uses of different preparation methodologies (sieving, ultrasonicating, oxidizing …) are compared using both concentrations – calculated from Lycopodium tablets - and relative abundances (more destructive methods will increase the amount of resistant taxa). Additionally, this study focuses on some important taxonomic issues, since obvious interlaboratorial differences in nomenclature are recorded

The prevalence of thrombophilia in patients with symptomatic peripheral vascular disease.

Background The aim of this prospective study was to establish the prevalence of thrombophilia and hyperhomocysteinaemia using a comprehensive screen in patients with peripheral vascular disease. Methods A total of 150 patients with peripheral vascular disease (with an ankle brachial pressure index of less than 0·8) underwent thrombophilia screening (protein C and protein S, antithrombin, lupus anticoagulant, activated protein C resistance and factor V Leiden and prothrombin mutations). Fasting homocysteine assays were also performed. Results A thrombophilia defect was found in 41 patients (27·3 per cent). The commonest was protein S deficiency, found in 17 patients (11·3 per cent). Others included factor V Leiden mutation, found in 10 (6·7 per cent) and protein C deficiency, found in six (4·0 per cent). Lupus anticoagulant and prothrombin mutation were both found in six (4·0 per cent). One patient had an antithrombin deficiency. Only the presence of critical ischaemia was associated with a positive thrombophilia screen on single variable analysis (P=0·03). Hyperhomocysteinaemia was present in over a third of the study group (37·3 per cent): 45 defined as moderate and 11 as intermediate. Conclusion A quarter of patients with peripheral vascular disease had evidence of thrombophilia, and a third had hyperhomocysteinaemia.</p

Prevalence and risk of thrombophilia defects in vascular patients.

This paper reviews the available data on the prevalence of thrombophilia defects in patients with peripheral vascular disease (PVD) and attempts to delineate the risk of failure of vascular intervention in these patients. The prevalence of thrombophilia in stable claudicants is 25% and increases to 40% in those requiring revascularisation, compared to only 11% in the control group. The overall prevalence of thrombophilia defects in patients with premature atherosclerosis appears to be between 15 and 30%. The prevalence in the typical cohort of patients with PVD appears to be similar. All these studies have recruited patients with symptoms significant enough to warrant intervention. The overall prevalence of thrombophilia calculated from these trials, therefore, may not be truly indicative of the general vascular population who may not even present primary or secondary healthcare. The risk of thrombotic occlusion following arterial revascularisation in patients with an identified thrombophilia defect appears to be almost three times that of patients with no evidence of a thrombophilia defect. The best management of these patients has not been determined and needs to be evaluated by prospective randomized trials