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Monoclonal Gammopathy of Renal Significance (MGRS) encompasses a wide spectrum of histopathology. Characterizing rare forms of MGRS-related renal pathology remains work in progress. Light chain crystalline podocytopathy in the context of MGRS, either in isolation or combined with proximal tubulopathy (LCPT) has rarely been described. Unravelling MGRS pathologies is critical for patient management and often requires ancillary techniques for antigen retrieval to demonstrate light chain (LC) restriction on immunofluorescence (IF).

Management of symptoms and prevention of life-threatening haemorrhage in Immune thrombocytopenia (ITP) must be balanced against adverse effects of available therapies. Since current treatment guidelines based on platelet count are confounded by variable bleeding phenotypes, there is a need to identify new objective markers of disease severity for improved treatment stratification. In this cross-sectional, prospective study of 49 patients with ITP and lowest recorded (nadir) platelet counts below 30 x 109/L, we used Susceptibility-Weighted Magnetic Resonance Imaging (SWI) to detect cerebral microbleeds (CMBs) as a marker of occult haemorrhage. CMBs were detected using a semi-automated method and correlated with clinical metadata using multivariate Poisson regression analysis. Lobar CMBs were identified in 43% (21/49); prevalence increased with decreasing nadir platelet count (15/25 15x109/L), and was associated with longer disease duration (p=7x10-6), lower nadir platelet count (p=0.005), lower platelet count at time of MRI (p=0.029), and higher organ bleeding scores (p=0.028). Mucosal and skin bleeding scores, number of previous treatments, age and sex were not associated with CMBs. Occult cerebral microhaemorrhage is common in patients with moderate to severe ITP. Strong associations with ITP duration may reflect CMB accrual over time or more refractory disease. Although associated, neither low platelet count or bleeding scores predict CMBs. SWI could therefore provide an additional non-invasive biomarker of haemorrhagic phenotype, and potential adjunct for treatment stratification. Further longitudinal studies in children and adults will allow greater understanding of the natural history, and clinical and prognostic significance of CMBs.

The purpose of the study is to evaluate the incidence, association with serum cytokine profile, and prognostic value of thrombocytopenia, in critically ill patients with severe sepsis/septic shock.A cohort of 105 consecutive patients admitted in intensive care unit was included in our analysis. Serum levels of intercellular adhesion molecule, vascular cell adhesion molecule, interferon γ, interleukin 8, and soluble form of the urokinase-type plasminogen activator receptor (suPAR) were measured.Thrombocytopenia was observed in 53% of patients at the time of admission. Platelet counts showed a statistically significant negative correlation with serum levels of intercellular adhesion molecule, suPAR, and interleukin 8 (P.0001). In multivariate analysis, high Acute Physiological and Chronic Health Evaluation II score, high serum suPAR, and low platelet counts were associated with increased mortality, and receiver operating characteristic curve analysis was used to determine the best cutoff value for mortality prediction. Each variable with a value above or below the predefined cutoff levels were given 1 point. Patients were categorized in risk groups based on total point score. High-risk (2-3), intermediate-risk (1), and low-risk (0 points) groups consisted of 43%, 22%, and 35% and 28-day mortality was observed in 69%, 26%, and 3% of the patients in each group, respectively.Thrombocytopenia is associated with poor prognosis and a distinct serum cytokine profile.

Background: The anti-CD52 monoclonal antibody alemtuzumab (Alem) induces a rapid-onset, profound and long-lasting depletion of lymphocytes: B cells recover within 12 months, while T cell recovery is still incomplete after 30 months. Alem is used as induction therapy for solid organ transplantations, including renal. Autoimmune complications following Alem include thyroid disorders (20-30%), immune thrombocytopenia (ITP) (2-3%), and autoimmune hemolytic anemia (AIHA) and autoimmune nephropathies (< 1%). Methods: we retrospectively analyzed 41 patients (pts) attending the Haematology Clinic at Hammersmith Hospital (HH), who developed autoimmune cytopenias (ITP or AIHA) after an Alem-induced renal transplant. The autoimmune cytopenia was defined as a rapid onset of isolated thrombocytopenia and/or anemia without other explanation. For ITP, complete response (CR) and response (R) were defined according to IWG standard criteria (Rodeghiero,Blood,2009). For AIHA, CR was defined as a stable Hb level >120 g/L, no transfusion requirement and no signs of hemolysis; partial response (PR) as a rise in Hb levels >20 g/L, without transfusion requirement. The study aim is to report clinical features and treatment outcomes of these 41 pts. Results: Between 1/11/05 and 14/12/16, 1431 pts received an Alem-induced renal transplant at HH. 34 (2.3%) developed ITP and 7 (0.48%) AIHA; 28 (68%) pts were males. Median age at renal transplant was 48 (range 20-69) years. The cytopenia developed a median of 35 months (range 6-161) after Alem administration. Median lowest platelet count was 5.5x109/L (range 0-41) and median nadir of hemoglobin (Hb) was 58 g/L (range 35-65). ITP pts: 2 pts achieved spontaneous CR. Of the remaining 32, 91% received steroids, IVIG or both as first line therapy, with an overall response rate (ORR) of 62%. 10 pts (31%) maintained the response without any further treatment. 22 pts required second line therapy, 11 required ≥ 3 lines of treatment. Treatments included: thrombopoietin receptor agonists (TPO-RA), rituximab (RTX), MMF and/or a combination. TPO-RA were used 15 times, with an ORR of 80%, a relapse rate of 33% and a median duration of response (DOR) of 22 months (range 3-48); 10/12 pts (83%) who responded to TPO-RA, discontinued treatment after a median of 64 days (range 7 - 528): 6 maintained the response after discontinuation. RTX was used 10 times, with an ORR of 90%, a relapse rate of 22% and a median DOR of 27 months (range 3 - 83). A combination of RTX and TPO-RA was used 7 times, with an ORR of 71%, a relapse rate of 40% and a median duration of response (DOR) of 5 months (range 2-44); the 5 responders discontinued treatment after a median of 49 days (range 14-462): 3/5 maintained their response. After a median follow-up of 38 months (range 3-96), all ITP pts maintained a response (91% CR and 9% R); 4 were still on treatment (2 TPO-RA and 2 MMF). AIHA pts: 6 of 7 (86%) pts with AIHA received first line steroids +/- IVIG with an ORR of 67%. 4 pts needed second line therapy: all received RTX with an ORR of 50%. 2 pts needed ≥ 3 lines of therapy. After a median follow-up of 68 months (range 27-102) all AIHA pts maintained a response (57% CR and 43% PR), without any ongoing treatment. Adverse events: 33 pts (80%) experienced 1 or more adverse events (AEs): 25 cardiovascular (including 14 thrombosis), 21 infections (16 grade ≥3), 5 steroid-induced diabetes, 3 graft failures, 10 malignancies (6 solid tumors and 4 PTLD). 6 of the ITP pts also developed AIHA (Evans syndrome). 3 ITP pts died. Conclusions: ITP and AIHA represent important complications of Alem-induced renal transplant. Response rates after first-line therapy for ITP were comparable to primary ITP (30%). However, long-term response rate, sustained response to RTX and the proportion of pts able to continue in remission after discontinuing TPO-RA are higher than seen with primary ITP. Recovery from cytopenias may occur in conjunction with T cell reconstitution post Alem (this is under investigation). The large majority of AEs were related to multifactorial heavy immunosuppression and increased thrombotic risk distinguishing this group of pts. Hence for ITP and AIHA, steroids should be limited, as they are curative in only a few pts and burdened by many side effects. Both RTX and a short course of TPO-RA appear valid options, but the choice should be driven by the individual balance between thrombotic and infectious risks versus persistence of cytopenias. Disclosures Cooper: Amgen, Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

We sought to evaluate the potential enhanced fibrinolytic and antiplatelet activity of dabigatran etexilate (DE) due to decreased thrombin levels in patients with stroke or transient ischemic attack and non-valvular atrial fibrillation (NVAF).Consecutive patients with cerebrovascular diseases and NVAF that were treated with DE in a tertiary university hospital. Fibrinolysis and platelet function were assessed by thromboelastometry (ROTEM) and platelet function analyzer (PFA)-100, respectively, before and after treatment with DE. Conventional coagulation tests, endogenous thrombin potential (ETP) and hemoclot thrombin inhibitors (HTI), were also performed in order to detect any possible correlation between dabigatran plasma levels, its anticoagulant activity and the intensity of platelet dysfunction or fibrinolysis.A total of nineteen patients fulfilled our inclusion criteria (mean age 62.3±7.2years; 47% males; median CHADS2-score: 3; interquartile range: 2-4). DE treatment was associated with a significant reduction of the lysis index (LI60) at 60min (p=0.036), and prolongation of the PFA-100 CEPI closure time (p=0.024). After dabigatran treatment, abnormal PFA-100 results were obtained in two patients (11%, 95% CI: 2%-33%). DE levels (determined by HTI) were strongly inversely correlated (rho=-0.85; p0.001) with the area under the curve (AUC) values in ETP assay. Νo association was found between HTI and PFA-100 CEPI CT (p=0.64), or LI60 measurements (p=0.60).Our findings indicate that DE might affect platelet function and fibrinolysis and highlight the potential role of ETP as an alternative option in DE monitoring. The intensity and clinical relevance of DE antiplatelet and fibrinolytic effects require further investigation.

Introduction Sepsis is the result of an uncontrolled inflammatory response to various stimuli such as bacterial infections. Sepsis can be complicated by hemodynamic instability, multi-organ dysfunction and hematological abnormalities. Patients with severe sepsis usually develop thrombocytopenia due to various reasons, and the presence of thrombocytopenia is considered as a negative prognostic marker. The aim of the present study was to determine the cytokine profile in serum of patients with severe sepsis and thrombocytopenia. Patients and Methods Serum cytokine profile was analyzed in a cohort of 112 consecutive patients with severe sepsis and/or septic shock treated in the intensive care unit (ICU) of our institute from October/2009 to September/2012. Patients were divided in two groups (A and B). Group A consisted of 43 patients with severe sepsis and thrombocytopenia (platelet count below 70X103/ìl), while group B consisted of 69 patients without thrombocytopenia. Patients with thrombocytopenia due to disseminated intravascular coagulation (DIC), suspected drug etiology, or due to any obvious etiology such as hematologic malignancy were excluded from our analysis. A cohort of 10 healthy volunteers served as control group. Serum levels of IFNã, IL-8, ICAM, VCAM, and SUPAR (soluble urokinase plasminogen activation receptor) were estimated by using Luminex xMAP technology. Statistical analyses were performed using NCSS software. The following variables were entered in a multiple logistic regression model: 1) age and sex, 2) active malignancy vs. not, 3) septic shock vs. severe sepsis, 4) APACHEII score, 5) SOFA score, 6) serum IFNã, ICAM, VCAM, IL-8, and SUPAR levels, and 7) platelet number. All parameters were estimated on day of admission. Results Hospital Mortality: Overall 65 out of 112 patients died during their hospital stay. The overall hospital mortality was 58%. In multivariate analysis non-survivors had higher APACHE score (p=0.01) and had lower platelet counts (p Plasma cytokine levels in patients with and without thrombocytopenia: Patients in group A had a different cytokine profile as compared with patients in group B. Serum levels of VCAM and IFNã were not different between group A and B. However, patients with sepsis and thrombocytopenia had statistically significantly higher serum levels of ICAM, IL-8 and SUPAR (p Predictive value of serum cytokine for thrombocytopenia: Serum levels of ICAM, IL-8, and SUPAR were good predictors of the presence of thrombocytopenia in patients with sepsis. The ROC curves of ICAM, IL-8, and SUPAR serum levels in predicting thrombocytopenia in patients with sepsis are shown in Figure 1. The AUCs were 0.785 (95% CI, 0.696 – 0.857, p Conclusion Thrombocytopenia is not an uncommon finding in patients with severe sepsis. Although DIC or drug reactions are well known causes of low PLT counts, the pathogenesis of thrombocytopenia in patients with sepsis remains poorly understood. High levels of ICAM, IL-8 and SUPAR are usually associated with severe endothelial dysfunction. In our study, we showed that patients with thrombocytopenia have a specific serum cytokine profile expression consistent with the presence of endothelial damage. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.