Lombardy diagnostic and therapeutic network of thrombotic microangiopathy.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy (TMA) requiring urgent treatment. Standardization of its diagnosis and optimal management is challenging. This study aimed to evaluate the role of centralized, rapid testing of ADAMTS13 in patients experiencing acute TMAs requiring plasma-exchange (PEX) and to estimate the incidence of TTP in a large Italian Region. METHODS: We perfomed a cohort study in the frame of the project "Set-up of a Lombardy network for the study and treatment of patients undergoing apheresis", including 11 transfusion centers in the Region. Consecutive patients referred from 2014 to 2016 with acute TMAs requiring PEX were enrolled. Centralized ADAMTS13 activity testing was performed at the Milan Hemophilia and Thrombosis Center within 24 h. RESULTS: Forty-three TMA patients (44 events) were enrolled, of whom 35 (81%) had severe ADAMTS13 deficiency. Patients with severe ADAMTS13 deficiency were younger, mainly women, with a higher prevalence of autoimmune disorders and a lower prevalence of cancer. Clinical and laboratory characteristics of patients with and without severe ADAMTS13 deficiency largely overlapped, with a lower platelet count being the only baseline marker that significantly differed between the two patient groups (ADAMTS13 activity < 10% vs ≥ 10%: median difference of -27 × 109/l, 95% CI - 37 to - 3). PEX treatment was initiated in all patients, but soon discontinued in cases without severe ADAMTS13 deficiency. In this group, the mortality rate was higher and no episode exacerbations or relapses within 6 months occured. The estimated average annual incidence of acute acquired TTP events was 1.17 [0.78-1.55] per million people. CONCLUSIONS: Severe ADAMTS13 deficiency distinguished two groups of patients with largely overlapping clinical features but different treatment and disease course. This study provides a feasible model implemented in a large Italian region for the practical clinical approach to TMAs and underlines the importance of urgent ADAMTS13 activity testing for an accurate differential diagnosis and therapeutic approach.

Prevention of relapse in patients with acquired thrombotic thrombocytopenic purpura undergoing elective surgery: a case series.

Essentials Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease. Surgery is a possible trigger of acute TTP episodes and no guidelines are available. Six patients with severe ADAMTS-13 deficiency during remission underwent elective surgery. Patients were prophylactically treated to restore ADAMTS-13 activity and no relapses occurred. SUMMARY: Background Severe ADAMTS-13 deficiency has been recognized as the main risk factor for recurrence of thrombotic thrombocytopenic purpura (TTP). Several conditions, including surgery, may influence the levels of ultra-large von Willebrand factor and ADAMTS-13, acting as a trigger for an acute TTP event. Objectives To report our experience of management of six patients with acquired TTP who underwent elective surgery after prophylactic treatment to restore ADAMTS-13 activity levels. Patients Six patients followed for acquired TTP with severe ADAMTS-13 deficiency during remission were candidates for seven elective surgeries (inguinal hernioplasty, cholecystectomy, laparoscopic hysterectomy, oophorectomy, parotidectomy and two total hip arthroplasties). Results Four patients were treated with prophylactic plasma exchange (PEX) therapy immediately before surgery. One patient was treated with PEX therapy before her first surgery and with preemptive rituximab once her second surgery was scheduled. Because rituximab increased ADAMTS-13 levels only partially, she required one PEX procedure the day before her second surgery. One patient was treated with azathioprine after rituximab failure, obtaining a progressive increase of ADAMTS-13 activity to more than 40%. This level allowed her to undergo total hip arthroplasty without additional treatment. All surgeries were successful and no complications or relapses occurred. Conclusions Six patients with acquired TTP underwent seven successful surgical procedures using prophylaxis to restore ADAMTS-13 activity. Further observational studies or randomized clinical trials are needed to confirm whether prophylactic PEX could be the key factor in preventing relapse.

Particulate matter phagocytosis induces tissue factor in differentiating macrophages.

Airborne exposure to particulate matter with diameter < 10 mcM (PM10) has been linked to an increased risk of thromboembolic events, but the mechanisms are not completely understood. The aim of this study was to evaluate the effect of PM10 phagocytosis on the release of procoagulant molecules in human differentiating macrophages, and that of PM10 inhalation in an experimental model in rats. Human monocytes were separated from the peripheral blood by the lymphoprep method, differentiated in vitro and treated with standard PM10 or vehicle. Sprague-Dawley rats were instilled intratracheally with PM10 or vehicle alone. The outcome was expression of proinflammatory genes and of tissue factor (TF). In human differentiating macrophages, PM10 exposure upregulated inflammatory genes, but most consistently induced TF mRNA and protein levels, but not TF protein inhibitor, resulting in increased TF membrane expression and a procoagulant phenotype. Differentiation towards the anti-inflammatory M2 phenotype inhibited PM10 -mediated TF expression. TF induction required phagocytosis of PM10 , whereas phagocytosis of inert particles was less effective. PM10 phagocytosis was associated with a gene expression profile consistent with intracellular retention of iron, inducing oxidative stress. Both PM10 and iron activated the stress kinases ERK1/2 pathway, involved in the induction of TF expression. In rats, alveolar exposure to PM10 was associated with pulmonary recruitment of inflammatory cells and resulted in local, but not systemic, induction of TF expression, which was sufficient to increase circulating TF levels. In conclusion, TF induction by differentiating lung macrophages, activated following phagocytosis, contributes to the increased risk of thromboembolic complications associated with PM10 exposure.

The relationship between sex hormones, sex hormone binding globulin and peripheral artery disease in older persons.

OBJECTIVE: The prevalence of peripheral artery disease (PAD) increases with aging and is higher in persons with metabolic syndrome and diabetes. PAD is associated with adverse outcomes, including frailty and disability. The protective effect of testosterone and sex hormone binding globulin (SHBG) for diabetes in men suggests that the biological activity of sex hormones may affect PAD, especially in older populations. METHODS: Nine hundred and twenty-one elderly subjects with data on SHBG, testosterone (T), estradiol (E2) were selected from InCHIANTI study. PAD was defined as an Ankle-Brachial Index (ABI) < 0.90. Logistic regression models adjusted for age (Model 1), age, BMI, insulin, interleukin-6, physical activity, smoking, chronic diseases including metabolic syndrome (Model 2), and a final model including also sex hormones (Model 3) were performed to test the relationship between SHBG, sex hormones and PAD. RESULTS: The mean age (±SD) of the 419 men and 502 women was 75.0 ± 6.8 years. Sixty two participants (41 men, 21 women) had ABI < 0.90. Men with PAD had SHBG levels lower than men without PAD (p = 0.03). SHBG was negatively and independently associated with PAD in men (p = 0.028) but not in women. The relationship was however attenuated after adjusting for sex hormones (p = 0.07). The E2 was not significantly associated with PAD in both men and women. In women, but not in men, T was positively associated with PAD, even after adjusting for multiple confounders, including E2 (p = 0.01). CONCLUSIONS: Low SHBG and high T levels are significantly and independently associated with the presence of PAD in older men and women, respectively.

The impact of omega-3 fatty acids on osteoporosis.

The essential polyunsaturated fatty acids (PUFAs) comprise 2 main classes: n-6 and n-3 fatty acids. The most common source of n-6 fatty acids is linoleic acid (LA) which is found in high concentrations in various vegetable oils. Arachidonic acid (AA), the 20-carbon n-6 fatty acid, is obtained largely by synthesis from LA in the body. The n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic (DHA) are found in fish and fish oils. Long-Chain polyunsaturated fatty acids (LCPUFAs) and lipid mediators derived from LCPUFAs have critical roles in the regulation of a variety of biological processes including bone metabolism. There are different mechanisms by which dietary fatty acids affect bone: effect on calcium balance, effect on osteoblastogenesis and osteoblast activity, change of membrane function, decrease in inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha), modulation of peroxisome proliferators-activated receptor gamma (PPARgamma). Animal studies have shown that a higher dietary omega-3/omega-6 fatty acids ratio is associated with beneficial effects on bone health. In spite of increasing evidence of the positive effects of dietary fats on bone metabolism from animal and in vitro studies, the few studies conducted in humans do not allow us to draw a definitive conclusion on their usefulness in clinical practice.