Magdalena Celińska-Löwenhoff

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.

New nonlipid effects of statins and their clinical relevance in cardiovascular disease.

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, statins, have been demonstrated to reduce cardiovascular morbidity and mortality in patients with a wide range of cholesterol levels. Numerous cholesterol-independent effects of statins that may limit atherosclerosis are probably related to inhibition of the geranylgeranylation of GTP-binding intracellular signaling proteins and involve: improved vasoreactivity, mostly through increased NO bioavailability; decreased expression of proinflammatory cytokines (interleukin-6, interleukin-1 beta, tumor necrosis factor alpha), C-reactive protein, chemokines, matrix metalloproteinases, and tissue factor with the subsequent inhibition of thrombin generation; reduced platelet activity; increased thrombomodulin expression; enhanced fibrinolysis, regulation of angiogenesis and immunomodulation. However, the clinical relevance of multiple protective effects induced by statins has not been clarified yet.

Simvastatin Given for 3 Days Can Inhibit Thrombin Generation and Activation of Factor V and Enhance Factor Va Inactivation in Hypercholesterolemic Patients

To the Editor:nnThe 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have been reported to exert multiple cholesterol-independent actions, including inhibition of blood coagulation, most likely attributable to downregulation of tissue factor (TF) expression.1 Previously, we have demonstrated that simvastatin inhibits blood clotting after a 3-month simvastatin therapy.2 It is unknown how rapidly statin administration can influence thrombin formation, factor (F)V activation, and the proteolytic degradation of FVa. The aim of the current study was to assess early effects of statins on coagulant reactions.nnFourteen men (mean age, 54.6 years) with LDL cholesterol levels >3.4 mmol/L (130 mg/dL), who were treated with low-dose aspirin (75 mg/d), participated in the study after giving informed written consent. At baseline and after 3 days of simvastatin administration (40 mg/d), coagulant reactions were assessed in blood collected every 30 seconds at the site of microvascular injury, as previously described. …

Effects of simvastatin on angiogenic growth factors released at the site of microvascular injury

Effects of simvastatin on angiogenic growth factors released at the site of microvascular injury -

Altered fibrin clot structure/function in patients with antiphospholipid syndrome: association with thrombotic manifestation

We tested the hypothesis that plasma fibrin clot structure/function is unfavourably altered in patients with antiphospholipid syndrome (APS). Ex vivo plasma clot permeability, turbidity and susceptibility to lysis were determined in 126 consecutive patients with APS enrolled five months or more since thrombotic event vs 105 controls. Patients with both primary and secondary APS were characterised by 11% lower clot permeability (p<0.001), 4.8% shorter lag phase (p<0.001), 10% longer clot lysis time (p<0.001), and 4.7% higher maximum level of D-dimer released from clots (p=0.02) as compared to the controls. Scanning electron microscopy images confirmed denser fibrin networks composed of thinner fibres in APS. Clots from patients with triple-antibody positivity were formed after shorter lag phase (p=0.019) and were lysed at a slower rate (p=0.004) than in the remainder. Clots from APS patients who experienced stroke and/or myocardial infarction were 8% less permeable (p=0.01) and susceptible to lysis (10.4% longer clot lysis time [p=0.006] and 4.5% slower release of D-dimer from clots [p=0.01]) compared with those following venous thromboembolism alone. Multivariate analysis adjusted for potential confounders showed that in APS patients, lupus anticoagulant and triple-positivity were the independent predictors of clot permeability, while triple-positivity predicted lysis time. We conclude that APS is associated with prothrombotic plasma fibrin clot phenotype, with more pronounced abnormalities in arterial thrombosis. Molecular background for this novel prothrombotic mechanism in APS remains to be established.

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) -

Effects of hypolipemic drugs on the osteoprotegerin – sRANKL system in patients with coronary artery disease

Effects of hypolipemic drugs on the osteoprotegerin – sRANKL system in patients with coronary artery disease -

Antithrombin Krakow II (c.624+1 G > T): a novel mutation leading to type 1 antithrombin deficiency.

Hereditary antithrombin (AT) deficiency is a rare autosomal disease. More than 200 mutations have been described in the AT gene leading to its deficiency. We describe here a case of type I AT deficiency in a 26-year-old Polish man who experienced proximal deep vein thrombosis and pulmonary embolism associated with a transient thrombotic risk factor, the right ankle trauma, despite the use of low-molecular-weight heparin prophylaxis. The family history was negative for venous thromboembolism. The AT activity was initially 47% and on repeated analysis 53%, and the antigen level, 0.15 g/l. The analysis of AT gene revealed the presence at the heterozygous state of a substitution G more than T located at the first nucleotide 3 of exon 3a (c.624 + 1 G > T, Human Genome Variation Society numbering system). The substitution might be detrimental taking account for its position in a donor splice site. To the best of our knowledge this mutation has not been previously described, so it was named antithrombin Krakow II.

Interleukin-6 -174 G/C promoter polymorphism and effects of fenofibrate and simvastatin on inflammatory markers in hypercholesterolemic patients.

To evaluate whether the interleukin-6 (IL-6) −174 G/C polymorphism might alter the effects of micronized fenofibrate or simvastatin therapy on inflammatory markers, we measured IL-6, C-reactive protein, CD40 ligand, adhesion molecules, P-selectin and monocyte chemoattractant protein-1 in hypercholesterolemic patients both before and after a 30-day treatment. Serum IL-6 levels were significantly higher in patients with the GC or CC genotypes (P = 0.04). The presence of the C allele was associated with greater absolute reduction of IL-6 levels (P = 0.04) following fenofibrate treatment. There was no significant association between the −174 G/C IL-6 polymorphism and the effects of simvastatin treatment. A relationship between the −174 G/C IL-6 polymorphism and the anti-inflammatory action of fenofibrate reported might be useful in the optimization of the treatment regimen in patients receiving this class of drugs.

Genetic characterization of antithrombin, protein C and protein S deficiencies in Polish patients

INTRODUCTIONxa0xa0 xa0Inherited deficiencies of natural anticoagulants such as antithrombin (AT; gene: SERPINC1), protein C (PC; PROC), and protein S (PS; PROS1), with the prevalence in the general European population of 0.02% to 0.17%, 0.2% to 0.3%, and 0.5%, respectively, are associated with increased risk of thromboembolic events. Only a few case reports of Polish deficient patients with known causal mutations have been published so far. OBJECTIVESxa0xa0 xa0The aim of the study was to characterize the frequency of SERPINC1, PROC, and PROS1 mutations and their thromboembolic manifestations in patients with AT, PC, or PS deficiencies, inhabiting southern Poland. PATIENTS AND METHODSxa0xa0 xa0 Ninety unrelated patients (mean [SD] age, 40.1 [13.2] years) with AT (n = 35), PC (n = 28), or PS (n = 27) deficiencies, with a history of venous 73 (81%) or arterial 17 (19%) thromboembolism, were screened for mutations using the Sanger sequencing or multiplex ligation‑dependent probe amplification. RESULTSxa0xa0 xa0Twenty mutations (29%) described here were new, mostly in the SERPINC1 and PROC genes. Missense mutations accounted for 84% of all mutations in the PROC gene and approximately 50% of those in the SERPINC1 and PROS1 genes. In all 3 genes, the ratio of nonsense and splice-site mutations was 8% to 31% and 8% to 23%, respectively. The mutation detection rate was 90% for AT or PC when anticoagulant activity was below 70%, while for the PROS1 gene, the rate reached 80% at the free PS levels below 40%. CONCLUSIONSxa0xa0 xa0To our knowledge, this is the largest cohort of Polish patients deficient in natural anticoagulants and evaluated for the causal genetic background. Several new Polish detrimental mutations were detected, mostly in AT- and PC‑deficient patients.