Amotosalen and ultraviolet A (UVA) photochemical-based pathogen reduction using the Intercept™ Blood System (IBS) is an effective and established technology for platelet and plasma components, which is adopted in more than 40 countries worldwide. Several reports point towards a reduced platelet function after Amotosalen/UVA exposure. The study herein was undertaken to identify the mechanisms responsible for the early impairment of platelet function by the IBS. Twenty-five platelet apheresis units were collected from healthy volunteers following standard procedures and split into 2 components, 1 untreated and the other treated with Amotosalen/UVA. Platelet impedance aggregation in response to collagen and thrombin was reduced by 80% and 60%, respectively, in IBS-treated units at day 1 of storage. Glycoprotein Ib (GpIb) levels were significantly lower in IBS samples and soluble glycocalicin correspondingly augmented; furthermore, GpIbα was significantly more desialylated as shown by Erythrina Cristagalli Lectin (ECL) binding. The pro-apoptotic Bak protein was significantly increased, as well as the MAPK p38 phosphorylation and caspase-3 cleavage. Stored IBS-treated platelets injected into immune-deficient nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice showed a faster clearance. We conclude that the IBS induces platelet p38 activation, GpIb shedding and platelet apoptosis through a caspase-dependent mechanism, thus reducing platelet function and survival. These mechanisms are of relevance in transfusion medicine, where the IBS increases patient safety at the expense of platelet function and survival.

Background:Omega-3 fatty acids (n − 3 FA) may have blood pressure (BP)-lowering effects in untreated hypertensive and elderly patients. The effect of n − 3 FA on BP in young, healthy adults remains unknown. The Omega-3 Index reliably reflects an individuals’ omega-3 status. We hypothesized that the Omega-3 Index is inversely associated with BP levels in young healthy adults.Methods:The current study (n = 2036) is a cross-sectional study investigating the baseline characteristics of a cohort, which includes healthy adults, age 25–41 years. Individuals with cardiovascular disease, known diabetes or a BMI higher than 35 kg/m2 were excluded. The Omega-3 Index was determined in whole blood using gas chromatography. Association with office and 24-h BP was assessed using multivariable linear regression models adjusted for potential confounders.Results:Median Omega-3 Index was 4.58% (interquartile range 4.08; 5.25). Compared with individuals in the lowest Omega-3 Index quartile, individuals in the highest had a SBP and DBP that was 4 and 2 mmHg lower, respectively (P < 0.01). A significant linear inverse relationship of the Omega-3 Index with 24-h and office BP was observed. Per 1-U increase in log-transformed Omega-3 Index the lowering in BP (given as multivariable adjusted β coefficients; 95% confidence interval) was −2.67 mmHg (−4.83; −0.51; P = 0.02) and −2.30 mmHg (−3.92; −0.68; P = 0.005) for 24-h SBP and DBP, respectively.Conclusion:A higher Omega-3 Index is associated with statistically significant, clinically relevant lower SBP and DBP levels in normotensive young and healthy individuals. Diets rich in n − 3 FA may be a strategy for primary prevention of hypertension.

Rheumatoid Arthritis (RA) is a chronic inflammatory disorder where incidence and severity of myocardial infarction are increased. Data on the incidence and outcome of stroke are conflicting. Thus, we investigated outcome after Ischemia/Reperfusion (I/R) brain injury in a mouse model of RA and assessed for the role of the tumour necrosis factor-α (TNF-α) inhibitor Infliximab herein. We used a TNF-α reliant mouse model of RA. RA and wildtype (WT) animals were treated with vehicle (RA/WT) or Infliximab (RA Infliximab) for 4 weeks, before undergoing I/R brain injury. RA-animals displayed larger strokes and poorer neurological performance. Immunohistochemistry on brain sections revealed increased numbers of resident and peripheral innate immune cells (microglia and macrophages); increased Blood-Brain-Barrier (BBB)-disruption; decreased levels of the tight junction proteins (TJPs) claudin-5 and occludin; increased expression of matrix-metalloproteinases (MMP)-3 and -9 and enhanced lipid peroxidation. Treatment with Infliximab corrected these alterations. We show that RA associates to worse stroke-outcome via exacerbated BBB degradation by decrease of the TJPs claudin-5 and occludin. We identified MMPs-3 and -9 and increased oxidative stress as potential mediators thereof. Increased numbers of resident and peripheral innate immune cells (microglia and macrophages) may in turn contribute to all these effects. Infliximab-treatment restored the phenotype of RA-mice to baseline. Our data provide evidence clearly linking RA to adverse stroke-outcome in mice and indicate an approved TNF-α inhibitor as a potential strategy to reduce stroke-burden in this setting.

Introduction: Gut microbiota-dependent trimethylamine-N-oxide (TMAO) correlates with arterial thrombotic events including myocardial infarction and stroke, and mortality. However, the association of TMAO with recurrent venous thromboembolism (VTE) and mortality remains unknown. Methods: TMAO plasma levels were assessed by high performance liquid chromatography in 859 patients aged ≥65 years with acute VTE and categorized into low (<2.28µmol/L), medium (2.28-6.57µmol/L), and high levels (>6.57µmol/L) based on the 25 th and 75 th percentile. Associations of TMAO with recurrent VTE, major or non-major bleeding, and mortality were investigated. Results: During a mean follow-up of 28 months, 106 patients developed recurrent VTE, 259 had major or non-major bleeding events, and 179 patients died. The risk of recurrent VTE did not differ significantly between patients with low, medium (adjusted subhazard ratio [SHR], 1.38; 95% confidence interval [CI], 0.81 to 2.36; p=0.232) and high TMAO levels (SHR, 1.44; 95% CI, 0.80 to 2.58, p=0.221). Compared with low TMAO levels, the adjusted hazard ratio [HR] for mortality was 0.68 (95% CI, 0.47 to 0.98, p=0.039) in patients with medium TMAO levels and 1.02 (95% CI, 0.68 to 1.52, p=0.922) in patients with high TMAO levels. Fractional polynomial Cox-regression confirmed a U-shaped association (adjusted p=0.045), with the lowest mortality risk in patients with TMAO around 4 µmol/L. TMAO was not associated with major or non-major bleeding. Conclusion: TMAO showed a U-shaped association with mortality in elderly patients with acute VTE and was not associated with recurrent VTE and major or non-major bleeding.