Ewa Wypasek

The use of rivaroxaban in patients with antiphospholipid syndrome: A series of 12 cases

Vitamin K antagonists (VKAs) remain the mainstay treatment for antiphospholipid syndrome (APS), a common acquired thrombophilic disorder that presents as arterial or venous thromboembolism (VTE), or recurrent pregnancy loss. Non-vitamin K oral anticoagulants (NOACs) offer several advantages over VKAs such as a predictable dose response, fewer drug and food interactions, and no need for laboratory monitoring of the international normalized ratio (INR) – a frequent challenge in patientswithAPS [1]. NOACs are already being used in patientswith atrial fibrillation, which is the most common indication for a long-term anticoagulation therapy, as well as in those with VTE [1,2]. Owing to the paucity of clinical data, the use of NOACs in managing APS remains controversial. There have been a few reports suggesting that NOACs compared with VKAs are less beneficial in VTE patients with APS [3,4]. On the other hand, some experts have recommended NOACs as an alternative to VKAs in the prevention of VTE in APS [5]. We present 12 consecutive white patients with APS (two positive results obtained 3-5 months apart as recommended [6]) and previous single VTE episode and/or ischemic stroke (7 women and 5 men; mean age 42 ± 10 years) who were switched from VKAs (warfarin or acenocoumarol) to rivaroxaban for at least 2 months at our institution. Prior to the switch, the target INR range was between 2.0 and 3.0, with the value on the day of the first dose of rivaroxaban between 1.9 to 2.5. Patientswith a history of stroke and/ormultiple risk factors for thrombotic events additionally received low-dose acetylsalicylic acid (ASA). The duration of treatment with rivaroxaban (20 mg daily) in secondary prevention of VTE ranged from 2 to 16 months (Table 1). In all cases the change of anticoagulation therapy was due to logistic problems with INR monitoring that interfered with the professional activities of the patients and/or unstable INR values resulting in time in the therapeutic range below 50%. Inherited thrombophilia screening was negative in this group. All patients had normal creatinine clearance, liver function and plasma D-dimer below 500 ng/ml on the first day of the use of rivaroxaban. The patients declared regular rivaroxaban intake during follow-up. Peak rivaroxaban concentration (2-4 hours since the drug intake) was measured by the anti-Xa chromogenic assay, Biophen DiXaI (Hyphen Biomed, Neuilly-sur-Oise, France) at the time of symptoms of VTE recurrence or after 1-3months since the therapy onset in the remaining subjects to check adherence to the drug [7]. Two of the 12 patients developed a recurrent deep vein thrombosis (DVT) within the first few months of starting rivaroxaban (Table 1).

Increased levels of bone remodeling biomarkers (osteoprotegerin and osteopontin) in hypertensive individuals

OBJECTIVES Osteoprotegerin (OPG) and osteopontin (OPN) are bone metabolism biomarkers which are involved in the regulation of vascular calcification processes and prediction of future adverse cardiac events. DESIGN AND METHODS OPG, OPN levels and classic risk factors were determined in 130 asymptomatic and hypertensive subjects. Receiver operator characteristic (ROC) analysis was performed and the area under the curve (AUC) was calculated. RESULTS The hypertensive subjects had elevated OPG, OPN, fibrinogen, CRP and fasting glucose levels in comparison to the normotensive ones. There were significant correlations between age, CRP and OPG. Multiple regression analysis showed that as well as inflammation (CRP), age and hypertension were predictors of increased OPG levels. OPN increase was correlated with CRP and glucose levels. The AUCs were similar for OPG and OPG biomarkers. CONCLUSIONS Plasma OPG and OPN levels were significantly associated with inflammation and arterial hypertension. They might be useful as additional biomarkers for monitoring endothelial dysfunction and prognosis of cardiovascular diseases.

The increased plasma C-reactive protein and interleukin-6 levels in patients undergoing coronary artery bypass grafting surgery are associated with the interleukin-6−174G > C gene polymorphism

Background The interleukin-6 (IL-6) promoter −174G/C polymorphism (rs1800795) is associated with enhanced systemic inflammatory response to injury. However, data on the effect of this polymorphism on inflammatory markers in patients undergoing coronary artery bypass grafting surgery (CABG) are inconsistent. The aim of our study was to investigate whether −174G/C IL-6 polymorphism affects plasma IL-6 and C-reactive protein (CRP) concentrations in patients undergoing CABG. Methods A total of 179 consecutive white patients (77% men, aged 65 ± 8.6 standard deviation [SD] y) scheduled for elective isolated CABG were studied. Pre- and postoperative CRP and IL-6 levels were analysed in relation to the 174G/C IL-6 polymorphism determined by using TaqMan single-nucleotide polymorphism genotyping technique. Results The genotype distribution was as follows: GG –46 (26%), GC –93 (52%) and CC –40 (22%). The C allele carriers had higher baseline CRP (4.1 ± 0.35 versus 2.4 ± 0.59 mg/L, P = 0.02) and IL-6 levels (3.0 ± 0.17 versus 2.2 ± 0.3 pg/mL, P = 0.02) than GG patients. Five to seven days after CABG, CRP levels rose by 54% (P = 0.03), and IL-6 levels tended to be higher (P = 0.07) in −174C allele carriers than the non-carriers. There were no associations between −174G/C IL-6 polymorphism and any demographic-, clinical- or procedure-related variables as well as major adverse cardiovascular events. Multivariate regression analysis, including sex, age, body mass index, hypercholesterolaemia, smoking, hypertension diabetes, identified CG + CC genotype as the only independent predictor of preoperative CRP and IL-6 levels. Conclusions The presence of the −174C allele determines to some extent higher plasma CRP and IL-6 concentrations pre- and postoperatively in CABG patients.

False-positive lupus anticoagulant in patients receiving rivaroxaban: 24 h since the last dose are needed to exclude antiphospholipid syndrome.

Rivaroxaban, a direct factor Xa inhibitor, affects laboratory clotting tests. We report here 10 venous thromboembolism patients with false-positive lupus anticoagulant during rivaroxaban therapy. Two dilute Russell Viper Venom time (dRVVT)-based integrated assays, HemosIL dRVVT Screen/HemosIL dRVVT Confirm (Instrumentation Laboratory, LA1/LA2 (Siemens, Germany) and LA1/LA2 (Siemens, Marburg, Germany), showed that the patients were lupus anticoagulant-positive. Antiphospholipid antibodies were negative except for one patient. Screening activated partial thromboplastin time-based assay PTT lupus anticoagulant was lupus anticoagulant-positive, whereas the confirmatory Staclot lupus anticoagulant (both Diagnostica Stago, France) was lupus anticoagulant-negative. Re-examination after discontinuation of rivaroxaban (>24 h) ruled out the presence of lupus anticoagulant. Our data indicate that to reliably evaluate lupus anticoagulant in patients on rivaroxaban, blood should be drawn 24 h after the last dose.

Ezetimibe combined with simvastatin compared with simvastatin alone results in a greater suppression of oxidative stress and enhanced fibrinolysis in patients after acute coronary events.

We compared the effect of simvastatin versus simvastatin combined with ezetimibe on hemostasis and inflammation after acute coronary events [acute coronary syndromes (ACS)]. In an investigator-initiated, double-blind, placebo-controlled, randomized study, patients with ACS were assigned to 40 mg/d of simvastatin + 10 mg/d of ezetimibe (n = 26) or 40 mg/d of simvastatin + placebo (n = 28) administered for 2 months. Markers of coagulation (prothrombin fragments 1.2, thrombin-antithrombin complexes, free tissue factor pathway inhibitor), fibrinolysis [plasminogen activator inhibitor-1, clot lysis time (CLT)], platelet activation (soluble CD40 ligand, β-thromboglobulin, thromboxane B2), oxidative stress [8-iso-prostaglandin F2α (8-iso-PGF2α)], and inflammation (interleukin-6, interleukin-18, and interleukin-1β) were measured within the first 12 hours of ACS and at 1 and 2 months of therapy. A final analysis comprised 20 patients in the simvastatin + ezetimibe group and 26 patients in the simvastatin + placebo group. Both groups were similar with regard to demographics, risk factors, medications, and routine laboratory results. Inflammatory, coagulation, and platelet markers did not differ between both treatment groups at all time points. Reductions in low-density lipoprotein cholesterol, CLT, plasminogen activator inhibitor-1, and 8-iso-PGF2α were significantly greater (by 10%, 8.7%, 17.5%, and 22.4%) in the simvastatin + ezetimibe group after 1 month, with further decreases in CLT and 8-iso-PGF2α at 2 months (all P < 0.05). These changes were not associated with lipid and inflammatory parameters. In conclusion, compared with simvastatin alone, simvastatin + ezetimibe results in a greater suppression of oxidative stress and enhanced fibrinolysis in patients with ACS, indicating that ezetimibe might exert cholesterol-independent actions in humans (NCT00725829).

Reduced plasma fibrin clot permeability and susceptibility to lysis are associated with increased risk of postthrombotic syndrome.

Essentials The postthrombotic syndrome (PTS) is a common complication of deep vein thrombosis (DVT). Plasma fibrin clot properties were assessed in patients followed for 1 year after DVT. Lower fibrin clot permeability and impaired lysability can predispose patients to PTS. Severe PTS is associated with more unfavorable clot variables.

Impaired fibrinolysis is associated with the severity of aortic stenosis in humans

A role of fibrinolysis in the pathogenesis of aortic valve stenosis (AS) is unknown, although fibrinolytic proteins have been detected in aortic stenotic valves.

Mast cells are responsible for the lack of anti-inflammatory effects of morphine in CBA mice

BACKGROUND AND AIM Morphine co-injection has anti-inflammatory effects on zymosan-induced peritonitis in several strains of mice except that of CBA. As peritoneal mast cells (pMCs) are much more numerous in CBA mice than in SWISS mice, therole of pMCs in morphine-modulated zymosan peritonitis is compared in CBA and SWISS males. METHODS pMCs were treated in vitro with morphine or C48/80 for comparison of histamine release. In vivo accumulation of leukocytes and histamine in peritoneal exudate were recorded after intraperitoneal injection with morphine, zymosan, or zymosan plus morphine. RESULTS AND CONCLUSION Morphine induces histamine release by pMCs from CBA mice but not SWISS mice. In vivo morphine-induced peritonitis is stronger in CBA mice than SWISS mice. Corollary, morphine anti-inflammatory effects on zymosan peritonitis are reversed in CBA mice by its pro-inflammatory action through CBA pMCs.

Hypoglycosylation is a common finding in antithrombin deficiency in the absence of a SERPINC1 gene defect

Essentials We investigated the molecular base of antithrombin deficiency in cases without SERPINC1 defects. 27% of cases presented hypoglycosylation, transient in 62% and not restricted to antithrombin. Variations in genes involved in N‐glycosylation underline this phenotype. These results support a new form of thrombophilia.

Iron deficiency: a novel risk factor of recurrence in patients after unprovoked venous thromboembolism.

INTRODUCTION Patients with unprovoked venous thromboembolism (VTE) are at high risk of recurrence; however, its predictors remain largely unknown. There is evidence that iron is implicated in the pathophysiology of thrombosis. OBJECTIVES We aimed to investigate whether iron deficiency (ID) affects the risk of recurrence in patients after unprovoked VTE. PATIENTS AND METHODS In this prospective cohort study, we examined 229 consecutive patients aged 65 years or younger with the first-ever episode of unprovoked VTE within 6 to 12 months prior to enrollment. The exclusion criteria were as follows: hemoglobin levels of less than 11 g/dl, heart failure, diabetes, cancer, serum creatinine levels exceeding 120 μM, and previous or current use of iron or erythropoiesisstimulating agents, or both. ID was defined as serum ferritin levels below 30 μg/l. Recurrent VTE was recorded during a 24-month follow-up. RESULTS ID was observed in 47 patients (21%). In a multivariate regression model, the presence of ID was associated with female sex, elevated C-reactive protein (CRP), anemia and reduced hemoglobin levels (all P <0.05). In a multivariate model, the presence of ID (or low serum ferritin levels) and elevated CRP levels, but not anemia, predicted VTE recurrence during 24 months. The hazard ratio adjusted for CRP and the presence of anemia was 3.17 for ID (95% confidence interval [CI], 1.20-8.38; P = 0.02) and 0.64 for serum ferritin levels (95% CI, 0.43-0.94; P = 0.02). CONCLUSIONS ID may represent a novel risk factor for VTE recurrence in young and middle-aged patients following an unprovoked episode.