Teresa Iwaniec

Early antithrombotic and anti-inflammatory effects of simvastatin versus fenofibrate in patients with hypercholesterolemia

The aim of the study was to determine whether a short-term treatment with simvastatin or fenofibrate may result in beneficial anti-inflammatory and antithrombotic effects in patients with high risk of coronary artery disease. In a randomized, double-blind study, we compared markers of inflammation, thrombin formation and platelet activation in patients with LDL cholesterol >130 mg/dl assigned to receive simvastatin (40 mg/d; n=20) or micronised fenofibrate (160 mg/d; n=22) for 28 days. Simvastatin, but not fenofibrate, lowered C-reactive protein (CRP) by 32% on day 3 (p<0.001), while both drugs reduced CRP significantly on day 28. Interleukin-6, soluble CD40 ligand, and monocyte chemoattractant protein-1 levels decreased significantly (by 20 to 50%) in both treatment groups on days 3 and 28. Soluble cell adhesion molecules remained unchanged in both groups. Simvastatin and fenofibrate significantly lowered plasma concentrations of thrombin-antithrombin complexes on days 3 and 28, but not platelet beta-thromboglobulin (betaTG) levels. Soluble P-selectin was lowered only in the simvastatin group. The total amount of thrombin generated at the site of microvascular injury also declined (by about 30%) as early as after 3 days of fenofibrate or simvastatin therapy, whereas beta TG release was reduced only in the simvastatin group on days 3 and 28. All the effects were independent of the changes in lipid profiles. Our results suggest that statins and fibrates can exert antithrombotic and anti-inflammatory effects as early as after 3 days of therapy. However, in contrast to statins, fibrates have no influence on platelet function within one month of therapy.

Increased level of tumor necrosis factor-α in patients with antiphospholipid syndrome: marker not only of inflammation but also of the prothrombotic state.

Connections between inflammation and thrombosis are intriguing, especially in a condition such as an antiphospholipid syndrome (APS), a disease characterized by immune-mediated thrombosis. Tumor necrosis factor alpha (TNF-α) is a cytokine which shares proinflammatory and prothrombotic actions, while a soluble form of interlukin-2 receptor (sIL-2R) is considered a typical marker of (auto)immune inflammation with not known direct links to thrombosis. The differences in the pathogenesis of APS as compared to other autoimmune diseases might be connected with different serum levels of both mediators. To answer this question, we studied 147 patients with systemic lupus erythematosus (SLE), 21 with SLE-like syndrome (SLE-LS), 20 with isolated APS (primary antiphospholipid syndrome, PAPS), and 32 healthy controls. Thirty-six patients from the SLE group fulfilled the updated APS criteria (secondary APS, SAPS). In comparison to healthy subjects, TNF-α concentration was increased in all patients, while sIL-2R rose significantly in the SLE group only. APS (both SAPS and PAPS) was characterized by the highest levels of TNF-α. Moreover, patients with lupus anticoagulant or elevated levels of IgG anticardiolipin or IgG anti-β2-glycoprotein I antibodies had higher TNF-α levels than patients without the presence of any type of antiphospholipid antibodies (aPL). In conclusion, the presence of aPL is associated with higher TNF-α level, whereas increased level of sIL-2R is rather connected with definite SLE where inflammatory processes prevail. It might be hypothesized that TNF-α plays a major role in pathogenesis of APS thrombotic phenomena.

Risk factors for arterial thrombosis in antiphospholipid syndrome

INTRODUCTION Antiphospholipid syndrome (APS) is associated with the risk of both arterial and venous thrombosis. However, it is not known which factors might determine the location of thrombosis. MATERIALS AND METHODS To retrospectively characterize factors associated with the risk of arterial thrombosis in a cohort of APS patients. Analysis included laboratory and clinical criteria of APS, together with classical cardiovascular risk factors and the possible role of platelet integrin α₂β₁ (807 C/T) and α(IIb)β₃ (PI A1/2) genetic polymorphisms. We enrolled 163 APS patients (123 women and 40 men aged 21-75; mean age 43 years); 78 suffered from arterial thrombosis. RESULTS There were no significant differences in the frequency or titers of different antiphospholipid antibodies with the exception of slightly increased frequency of IgG anticardiolipin antibodies (ACL) in the arterial thrombosis group. Livedo reticularis was observed significantly more often in the arterial thrombosis group, particularly in stroke patients. In univariate analysis arterial thrombosis was associated with male gender (OR-2,201; p=0,033), arterial hypertension (OR-2,81; p=0,002) and hypercholesterolemia (OR-3,69; p=0,001). On multivariate analysis arterial hypertension (OR=1,78; p=0,008) and hypercholesterolemia (OR=2,001; p=0,002) remained as independent risk factors for arterial thrombosis. Platelet glycoprotein polymorphisms studied did not show any significant associations with arterial thrombosis in APS patients. CONCLUSIONS Among APS patients those with ACL IgG antibodies, having livedo reticularis, and suffering from hypertension an hypercholesterolemia are at the increased risk of arterial thrombosis.

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.

Valine/Leucine247 polymorphism of β2-glycoprotein I in patients with antiphospholipid syndrome: lack of association with anti-β2-glycoprotein I antibodies

In antiphospholipid syndrome (APS) the presence of anti-β2-glycoprotein I (β2GPI) antibodies is strongly associated with thromboembolic complications. It has been suggested that the common β2GPI Valine/Leucine247 (Val/Leu247)polymorphism could be found more commonly in APS and might influence the generation of anti-β2GPI antibodies. Therefore we studied β2GPI Val/Leu247single-nucleotide polymorphism (SNP) by PCR in 338 patients with various autoimmune diseases (46 with secondary and 84 with primary APS) and 147 sex and age-matched healthy controls. In all patients lupus anticoagulant, anticardiolipin and anti-β2GPI antibodies (both IgG and IgM) were also determined. All patients and controls were Caucasians. Frequencies of the SNP genotypes in patients did not depart from genetic equilibrum and did not differ from those found in controls. There was also no association between the presence of β2GPI Val/Leu247genotypes and the presence or absence of lupus anticoagulant, anticardiolipin antibodies, anti-β2GPI antibodies or clinical APS symptoms in all patients studied. In conclusion, among the exclusively Caucasian, Polish population of autoimmune patients β2GPI Val/Leu247SNP has the same distribution as in healthy subjects and does not influence the production of anti-β2GPI antibodies.

Asthma is associated with enhanced thrombin formation and impaired fibrinolysis

There is evidence that altered blood coagulation and fibrinolysis are involved in the pathogenesis of asthma. Increased thromboembolic risk has been reported in asthmatics.

Arterial and venous thrombosis and prothrombotic fibrin clot phenotype in a Polish family with type 1 antithrombin deficiency (antithrombin Krakow)

Arterial and venous thrombosis and prothrombotic fibrin clot phenotype in a Polish family with type 1 antithrombin deficiency (antithrombin Krakow) -

Clinical significance of anti-domain 1 β2-glycoprotein I antibodies in antiphospholipid syndrome

BACKGROUND Antiphospholipid syndrome (APS) is characterized by the presence of circulating antiphospholipid antibodies (aPL) in patients with thrombosis and/or pregnancy morbidity. In APS patients anti-domain 1 β2-glycoprotein I (anti-D1 β2GPI) IgG antibodies correlate strongly with thrombosis and to the lesser extent, with pregnancy complications. The aim of this study was to assess clinical utility of the anti-D1 β2GPI antibodies in the diagnosis and risk stratification of antiphospholipid syndrome. PATIENTS/METHODS In this retrospective study 202 autoimmune patients were studied (primary APS - 58, secondary - 45 SLE - 99). Anticardiolipin (aCL) and anti-β2GPI (aβ2GPI antibodies) (IgG and IgM class) together with anti-D1 IgG were tested with QUANTA Flash chemiluminescent immunoassay and lupus anticoagulant (LA) with coagulometric methods. RESULTS The highest anti-D1 values were observed in triple positive patients as compared to patients with other antiphospholipid antibody profiles. A strong correlation was found between levels of anti-D1 IgG and a β2GPI IgG antibodies for all patients analyzed (Spearmans ρ=0.87; p<0.0001). Anti-D1 IgG antibodies increase specificity resulting from classic aPL positivity but at the expense of sensitivity. Anti-D1 test does not add accuracy in predicting APS thrombotic complications on the top of accuracy offered by classic aPL tests and their profiles. CONCLUSIONS Anti-D1 IgG antibodies did not add diagnostic power to the standard laboratory aPL tests as assessed by this retrospective study. A true clinical significance of anti-D1 antibodies in thrombotic risk stratification of aPL positive patients will require a properly designed clinical prospective trials.

Clinical utility of automated chemiluminescent antiphospholipid antibody assay

BACKGROUND The threshold for clinically relevant levels of antiphospholipid (aPL) antibodies for the diagnosis of antiphospholipid syndrome (APS) remains a matter of debate. As new technologies for antibody detection are introduced, their performance characteristics must be clearly understood and compared to traditional assays. OBJECTIVES To assess the analytical performance and clinical utility of fully automated anticardiolipin (aCL) and anti-β2 glycoprotein I (aβ2GPI) chemiluminescent immunoassays (CIA) in comparison to the traditional ELISA tests. PATIENTS/METHODS Samples from 220 autoimmune patients were studied (primary APS - 74; secondary APS - 47, systemic lupus erythematosus (SLE) without APS - 99). All samples were tested for IgG and IgM aCL and β2GPI antibodies using both CIA and ELISA, and for lupus anticoagulant (LAC). RESULTS Good qualitative agreement and quantitative correlation were found between methods in regard to individual antibodies and their categories (profiles). All assays showed good clinical performance in APS, and strong correlation with APS-related clinical symptoms. Importance of determining individual laboratory 99 percentile values for a healthy population as normal cut-off values was shown. Additionally, based on a clinical approach, this study has established the low/medium threshold for QUANTA Flash aCL IgG and IgM assays. CONCLUSIONS This study showed good clinical performance and strong correlation of the new automated CIA aPL assays with APS clinical symptoms. It also enabled us to determine the corresponding low/medium antibody threshold for the aCL antibody methods with different unit types.

Two different fibrinogen gene mutations associated with bleeding in the same family (A αGly13Glu and γGly16Ser) and their impact on fibrin clot properties: Fibrinogen Krakow II and Krakow III

Two different fibrinogen gene mutations associated with bleeding in the same family (A αGly13Glu and γGly16Ser) and their impact on fibrin clot properties: Fibrinogen Krakow II and Krakow III -