Haemostatic profile of riboflavin-treated apheresis platelet concentrates

BackgroundThe haemostatic activity of platelet concentrates (PCs) treated with pathogen reduction technology (PRT) remains a subject of debate. Our aim was to investigate the effect of Mirasol PRT on the haemostatic properties of PCs stored in plasma.Material and methodsUntreated and Mirasol-treated platelets stored in plasma and derived from ten split double-dose apheresis PCs were evaluated in vitro on days 1, 3 and 5 post collection for functionality, microparticle procoagulation activity (MPA), endogenous thrombin potential (ETP), and haemostatic profile using rotational thromboelastometry (ROTEM).ResultsP-selectin expression was significantly higher in Mirasol-treated platelets compared with untreated counterparts on days 3 and 5 (p=0.003 and p=0.002, respectively). Clot strength, as shown by EXTEM maximum clot firmness (MCF), was significantly lower in the Mirasol-treated platelets at all time points (days 1, 3, 5) than in untreated platelets (p=0.009, p<0.001, p<0.001, respectively). There was a considerable increase in MPA over time (p<0.001) and this was significantly higher in the Mirasol-treated platelets on day 5 (p=0.015). A notable acceleration of decrease in ETP values was observed for Mirasol-treated PCs over time (p<0.001), with significant differences between PRT-treated and untreated PCs on days 3 and 5 (p=0.038 and p=0.019, respectively). Clot strength attenuation was significantly associated with pH reduction (p<0.001, Spearman’s rho: 0.84), increased microparticle procoagulant activity (p<0.001, Spearman’s rho: −0.75), and with decreased ETP (p<0.032, Spearman’s rho: 0.41).DiscussionIncreased platelet activation induced by PRT treatment leads to a decrease in in vitro haemostatic capacity as seen by reduced clot strength and thrombin generation capacity over time. The clinical relevance of this needs to be investigated.     

Primary gastric non-Hodgkin lymphomas: Recent advances regarding disease pathogenesis and treatment

Primary gastric lymphomas (PGLs) are distinct lymphoproliferative neoplasms described as heterogeneous entities clinically and molecularly. Their main histological types are diffuse large B-cell lymphoma (DLBCL) or mucosa-associated lymphoma tissue. PGL has been one of the main fields of clinical research of our group in recent years. Although gastric DLBCLs are frequent, sufficient data to guide optimal care are scarce. Until today, a multidisciplinary approach has been applied, including chemotherapy, surgery, radiotherapy or a combination of these treatments. In this minireview article, we provide an overview of the clinical manifestations, diagnosis and staging of these diseases, along with their molecular pathogenesis and the most important related clinical published series. We then discuss the scientific gaps, perils and pitfalls that exist regarding the aforementioned studies, in parallel with the unmet need for future research and comment on the proper methodology for such retrospective studies. Aiming to fill this gap, we retrospectively evaluated the trends in clinical presentation, management and outcome among 165 patients with DLBCL PGL who were seen in our institutions in 1980-2014. The study cohort was divided into two subgroups, comparing the main 2 therapeutic options [cyclophosphamide doxorubicin vincristine prednisone (CHOP) vs rituximab-CHOP (R-CHOP)]. A better outcome with immunochemotherapy (R-CHOP) was observed. In the next 2 mo, we will present the update of our study with the same basic conclusion.     

Pharmacological management of sepsis in adults with a focus on the current gold standard treatments and promising adjunctive strategies: evidence from the last five years

Introduction: The last five years, there have been considerable changes in our perception on the pathogenesis of sepsis. This review aims to summarize the current progress of the last five years in the management and research fields of sepsis in a holistic approach. To achieve this, accumulated evidence over the last five years coming from randomized clinical trials (RCTs) and observational studies in adults for the management of sepsis is provided.

Areas covered: In this review, the authors discuss available strategies in sepsis, divided into standard-of-care and adjunctive therapies. Standard-of-care approaches comprise antimicrobials, fluids, vasoactive agents, steroids. Antimicrobials remain the mainstay of treatment. However, key-point of management is early recognition of the patient that guides early start of antimicrobials. Patients with suspected infection and any two of: an altered mental state, more than 22 breaths per minute and systolic blood pressure below 100 mmHg should receive early intervention with broad-spectrum antimicrobials and fluids.

Expert opinion: Low dose hydrocortisone replacement and fludrocortisone seem promising for the patient at septic shock. Adjunctive macrolide treatment of severe CAP is also associated with survival benefit. Future studies will help to provide additional insight into the field.     

Mitochondrial dysfunction in cardiovascular disease: Current status of translational research/clinical and therapeutic implications

Mitochondria provide energy to the cell during aerobic respiration by supplying ~95% of the adenosine triphosphate (ATP) molecules via oxidative phosphorylation. These organelles have various other functions, all carried out by numerous proteins, with the majority of them being encoded by nuclear DNA (nDNA). Mitochondria occupy ~1/3 of the volume of myocardial cells in adults, and function at levels of high‐efficiency to promptly meet the energy requirements of the myocardial contractile units. Mitochondria have their own DNA (mtDNA), which contains 37 genes and is maternally inherited. Over the last several years, a variety of functions of these organelles have been discovered and this has led to a growing interest in their involvement in various diseases, including cardiovascular (CV) diseases. Mitochondrial dysfunction relates to the status where mitochondria cannot meet the demands of a cell for ATP and there is an enhanced formation of reactive‐oxygen species. This dysfunction may occur as a result of mtDNA and/or nDNA mutations, but also as a response to aging and various disease and environmental stresses, leading to the development of cardiomyopathies and other CV diseases. Designing mitochondria‐targeted therapeutic strategies aiming to maintain or restore mitochondrial function has been a great challenge as a result of variable responses according to the etiology of the disorder. There have been several preclinical data on such therapies, but clinical studies are scarce. A major challenge relates to the techniques needed to eclectically deliver the therapeutic agents to cardiac tissues and to damaged mitochondria for successful clinical outcomes. All these issues and progress made over the last several years are herein reviewed.     

The HMG-CoA inhibitor, simvastatin, triggers in vitro anti-tumour effect and decreases IgM secretion in Waldenstrom macroglobulinaemia

Waldenstrom macroglobulinaemia (WM) is an incurable lymphoplasmacytic lymphoma with secretion of serum monoclonal immunoglobulin M (IgM). We previously showed that patients receiving cholesterol-lowering statins, had the lowest IgM value in a large cohort of patients with WM. Simvastatin, a 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor, induced inhibition of proliferation, cytotoxic effect and apoptosis in IgM secreting cell lines as well as in primary CD19⁺ WM cells. Interestingly, those effects were reversed by addition of mevalonate and geranylgeranylpyrophosphate, demonstrating that simvastatin inhibited cell growth, survival and IgM secretion on BCWM.1 WM cells by inhibition of geranylgeranylated proteins. Furthermore, simvastatin overcame tumour cell growth induced by co-culture of WM cells with bone-marrow stromal cells. Simvastatin also decreased IgM secretion by BCWM.1 cells at an early time-point that had not affected cell survival. Simvastatin-induced cytotoxicity was preceded by a decrease in Akt (protein kinase B, PKB) and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathways at 18 h. In addition, simvastatin induced an increase in stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) MAPK followed by caspase-8, -9, -3 and poly(ADP-ribose) polymerase (PARP) cleavages at 18 h, leading to apoptosis. Furthermore, simvastatin enhanced the cytotoxicity induced by bortezomib, fludarabine and dexamethasone. Our studies therefore support our earlier observation of statin-mediated anti-WM activity and provide the framework for future clinical trials testing simvastatin in WM.     

Monitoring aspirin treatment in patients with thrombocytosis: comparison of the platelet function analyzer (PFA)-100 with optical aggregometry

Aspirin provides satisfactory protection against thrombotic episodes in essential thrombocythemia (ET), but at higher platelet counts has been less effective. Our aim was to compare the platelet function analyzer (PFA)-100 with optical aggregometry in order to determine a reliable method in monitoring aspirin's influence on platelet function in patients with thrombocytosis.We studied 36 patients with thrombocytosis. Sixteen of them, receiving aspirin, composed group A, while group B consisted of 20 patients not taking aspirin. In all patients, we compared the platelet function measured by classic optical aggregation tests with closure times (CT) obtained by the PFA-100.The definition of platelet responses as normal or pathological showed that PFA-100 collagen and/or epinephrine (CEPI) CTs and epinephrine-induced aggregometry is the pair of methods with the higher agreement in monitoring of platelet dysfunction due to ASA treatment (a = 94%). Satisfactory results were also obtained for group B (a = 81%). The comparison between PFA-100 CEPI CTs and arachidonic acid-induced aggregometry exhibited moderate agreement both in the total number of patients and in group A (a = 79% and 94%, respectively). PFA-100 collagen and/or ADP (CADP) CTs and ADP-induced aggregometry were not concordant.The PFA-100 system appears to be a reliable and rapid method in the assessment of aspirin's antiplatelet effect in patients with thrombocytosis. Regarding aggregometry, the selection of the inducer, its concentration and cut-off points is crucial in defining the response to antiaggregating agents. It still remains to determine whether there is any relevance between the measurements obtained by these methods and clinical outcome in thrombocythemic patients.     

Impact of low‐level BK polyomavirus viremia on intermediate‐term renal allograft function

Background

BK polyomavirus (BKPyV)‐associated nephropathy (PyVAN) is a significant cause of premature renal transplant failure. High‐level BKPyV viremia is predictive for PyVAN; however, low‐level BKPyV viremia does not necessarily exclude the presence of PyVAN. As data are limited regarding whether or not low‐level BKPyV viremia has an effect on intermediate‐term graft outcome, this study analyzes the impact of low‐level BKPyV viremia on intermediate‐term graft function and outcome compared with high‐level viremia and non‐viremic patients.

Methods

All renal transplant patients received follow‐up examinations at the Department of Nephrology, University Hospital Essen. Patients were screened for BKPyV viremia and stratified into three groups according to their maximum BKPyV load in serum (low‐level viremia, high‐level viremia, and no viremia).

Results

In 142 of 213 (67%) patients, BKPyV was never detected in serum; 42 of 213 (20%) patients were found positive for low‐level viremia (≤10⁴ copies/mL); and 29 of 213 (13%) patients showed high‐level viremia (>10⁴ copies/mL). No significant differences regarding transplant function and graft failure were observed between patients without BKPyV viremia (delta estimated glomerular filtration rate [eGFR] +0.1 mL/min [month 1 vs last visit at month 44]) and patients with low‐level BKPyV viremia (delta eGFR ?1.7 mL/min). In patients with high‐level viremia, transplant function was significantly restricted (delta eGFR ?6.5 mL/min) compared with low‐level viremia until the last visit at 44 ± 9.7 months after transplantation. Although the graft function and graft loss were worse in the high‐level viremia group compared with no viremia (eGFR 37 vs 45 mL/min), the difference was not significant.

Conclusions

High‐level viremia was associated with impaired graft function. In contrast, low‐level BKPyV viremia had no significant impact on intermediate‐term graft function.