BackgroundIn patients with chronic kidney disease studies focusing on platelet function and properties often are non-conclusive whereas only few studies use functional platelet tests. In this study we evaluated a recently developed functional flow cytometry based assay for the analysis of platelet function in chronic kidney disease.MethodsPlatelet reactivity was measured using flow cytometric analysis. Platelets in whole blood were triggered with different concentrations of agonists (TRAP, ADP, CRP). Platelet activation was quantified with staining for P-selectin, measuring the mean fluorescence intensity. Area under the curve and the concentration of half-maximal response were determined.ResultsWe studied 23 patients with chronic kidney disease (9 patients with cardiorenal failure and 14 patients with end stage renal disease) and 19 healthy controls. Expression of P-selectin on the platelet surface measured as mean fluorescence intensity was significantly less in chronic kidney disease patients compared to controls after maximal stimulation with TRAP (9.7 (7.9-10.8) vs. 11.4 (9.2-12.2), P = 0.032), ADP (1.6 (1.2-2.1) vs. 2.6 (1.9-3.5), P = 0.002) and CRP (9.2 (8.5-10.8) vs. 11.5 (9.5-12.9), P = 0.004). Also the area under the curve was significantly different. There was no significant difference in half-maximal response between both groups.ConclusionIn this study we found that patients with chronic kidney disease show reduced platelet reactivity in response of ADP, TRAP and CRP compared to controls. These results contribute to our understanding of the aberrant platelet function observed in patients with chronic kidney disease and emphasize the significance of using functional whole blood platelet activation assays.
Objectives There is scarce evidence about the effectiveness of anti‐bleeding measures in hematological outpatients experiencing persistent severe thrombocytopenia. We aim to describe clinical practice and clinicians' considerations on the administration of prophylactic platelet transfusions and tranexamic acid (TXA) to outpatients with acute leukemia, myelodysplastic syndrome (MDS), or aplastic anemia (AA) in the Netherlands. Methods We conducted an online survey among members of the Dutch Society for Hematology. Results The survey was filled out by 73 respondents. Prophylactic platelet transfusions are widely used in acute leukemia and MDS outpatients receiving disease‐modifying treatments (87%‐98% of respondents). TXA is predominantly prescribed in case of bleeding (tendency) (71%‐88% of respondents). Conditions potentially increasing bleeding risks highly variably influence clinicians' decision making on anti‐bleeding regimens, which includes a wide range in adhered platelet thresholds. Conclusion Considering that both the contribution of prophylactic platelet transfusions as well as TXA to limiting bleeding is insufficiently evidence‐based, there is an urgent need for trials on optimal anti‐bleeding strategies in this outpatient population, which should encompass efficacy, logistic, financial, and quality‐of‐life aspects.
We designed a study to describe the incidence of intracranial hemorrhage according to severity and duration of thrombocytopenia and to quantify the associations of platelet transfusions with intracranial hemorrhage in patients with acute leukemia. In this case-control study nested in a cohort of 859 leukemia patients, cases (n = 17) were patients diagnosed with intracranial hemorrhage who were matched with control patients (n = 55). We documented platelet counts and transfusions for seven days before the intracranial hemorrhage in cases and in a “matched” week for control patients. Three measures of platelet count exposure were assessed in four potentially important time periods before hemorrhage. Among these leukemia patients, we observed the cumulative incidence of intracranial hemorrhage of 3.5%. Low platelet counts were, especially in the three to seven days preceding intracranial hemorrhage, associated with the incidence of intracranial hemorrhage, although with wide confidence intervals. Platelet transfusions during the week preceding the hemorrhage were associated with higher incidences of intracranial hemorrhage; rate ratios (95% confidence interval) for one or two platelet transfusions and for more than two transfusions compared with none were 4.04 (0.73 to 22.27) and 8.91 (1.53 to 51.73) respectively. Thus, among acute leukemia patients, the risk of intracranial hemorrhage was higher among patients with low platelet counts and after receiving more platelet transfusions. Especially, the latter is likely due to clinical factors leading to increased transfusion needs.
IntroductionHaemato-oncological patients often receive platelet count driven prophylactic platelet transfusions to prevent bleeding. However, many prophylactically transfused patients still bleed. More knowledge on risk factors for bleeding is therefore needed. This will enable identification of bleeding risk profiles on which future transfusion policy can be optimised. The present BITE study (Bleeding In Thrombocytopenia Explained) aims to identify clinical conditions and biomarkers that are associated with clinically relevant bleeding events.Methods and analysisA matched case–control study nested in a cohort of haemato-oncological patients in the Netherlands. We collect a limited number of variables from all eligible patients, who together form the source population. These patients are followed for the occurrence of clinically relevant bleeding. Consenting patients of the source population form the cohort. Cases from the cohort are frequency matched to selected control patients for the nested case–control study. Of both case and control patients more detailed clinical data is collected.Study populationAdult haemato-oncological patients, who are admitted for intensive chemotherapeutic treatment or stem cell transplantation, or who received such treatments in the past and are readmitted for disease or treatment-related adverse events.Statistical analysisBleeding incidences will be calculated for the total source population, as well as for different subgroups. The association between potential risk factors and the occurrence of bleeding will be analysed using conditional logistic regression, to account for matching of case and control patients.Ethics and disseminationThe study was approved by the Medical Research Ethics Committee Leiden Den Haag and Delft, and the Radboudumc Committee on Research Involving Human Subjects. Approval in seven other centres is foreseen. Patients will be asked for written informed consent and data is coded before analyses, according to Dutch privacy law. Results will be published in peer-reviewed journals.Trial registration numberNL62499.058.17. NCT03505086; Pre-results.
Background: Prophylactic platelet transfusions prevent bleeding in hematooncology patients, but it is unclear how any benefit varies between patients. Our aim was to assess if patients with different baseline risks for bleeding benefit differently from a prophylactic platelet transfusion strategy. Study design and methods: Using the data from the randomized controlled TOPPS trial (Trial of Platelet Prophylaxis), we developed a prediction model for World Health Organization grades 2, 3, and 4 bleeding risk (defined as at least one bleeding episode in a 30 days period) and grouped patients in four risk-quartiles based on this predicted baseline risk. Predictors in the model were baseline platelet count, age, diagnosis, disease modifying treatment, disease status, previous stem cell transplantation, and the randomization arm. Results:The model had a c-statistic of 0.58 (95% confidence interval [CI] 0.54-0.64). There was little variation in predicted risks (quartiles 46%, 47%, and 51%), but prophylactic platelet transfusions gave a risk reduction in all risk quartiles. The absolute risk difference (ARD) was 3.4% (CI À12.2 to 18.9
Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an "N-of-1" study of milasen within 1 year after first contact with the patient. There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting). This study offers a possible template for the rapid development of patient-customized treatments. (Funded by Mila's Miracle Foundation and others.) R are diseases in aggregate affect approximately 30 million persons in the United States alone. 1 Although next-generation sequencing is revolutionizing their diagnosis, the sheer number of distinct conditions (more than 7000 [https://globalgenes . org/ rare -list]) and the limited number of patients affected by each rare disease present major challenges for drug development.This report shows a path to personalized treatment for patients with orphan diseases. It describes the identification of a novel mutation in a child with neuronal ceroid lipofuscinosis 7 (CLN7, a form of Batten's disease), a rare and fatal neurodegenerative disease. 2,3 Identification of the mutation was followed by the development and clinical deployment, within 1 year, of a tailored drug to treat the patient (Fig. 1A). Clinic a l Pr esentationA 6-year-old girl presented with the insidious onset of blindness, ataxia, seizures, and developmental regression. The parents' first concerns dated back to when the girl was 3 years of age, when her right foot began to turn inward. When she was 4 years of age, her family noticed her pulling books close to her face at bedtime. At 5 years of age, she came to medical attention because of modest language and social regression, as well as increased clumsiness and stumbling. In the months before she turned 6 years of age, the progression of symptoms accelerated, and she wasThe authors' full names, academic degrees, and affiliations are listed in the Appendix.
Background Intracranial hemorrhage is seen more frequently in acute leukemia patients compared to the general population. Besides leukemia‐related risk factors, also risk factors that are present in the general population might contribute to hemorrhagic complications in leukemia patients. Of those, cardiovascular risk factors leading to chronic vascular damage could modulate the occurrence of intracranial hemorrhage in these patients, as during their disease and treatment acute endothelial damage occurs due to factors like thrombocytopenia and inflammation. Objectives Our aim was to explore if cardiovascular risk factors can predict intracranial hemorrhage in acute leukemia patients. Methods In a case‐control study nested in a cohort of acute leukemia patients, including 17 cases with intracranial hemorrhage and 55 matched control patients without intracranial hemorrhage, data on cardiovascular risk factors were collected for all patients. Analyses were performed via conditional logistic regression. Results Pre‐existing hypertension and ischemic heart disease in the medical history were associated with intracranial hemorrhage, with an incidence rate ratio of 12.9 (95% confidence interval [CI] 1.5 to 109.2) and 12.1 (95% CI 1.3 to110.7), respectively. Conclusion Both pre‐existing hypertension and ischemic heart disease seem to be strong predictors of an increased risk for intracranial hemorrhage in leukemia patients.
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