Derek Norfolk

A no-prophylaxis platelet-transfusion strategy for hematologic cancers.

BACKGROUNDnThe effectiveness of platelet transfusions to prevent bleeding in patients with hematologic cancers remains unclear. This trial assessed whether a policy of not giving prophylactic platelet transfusions was as effective and safe as a policy of providing prophylaxis.nnnMETHODSnWe conducted this randomized, open-label, noninferiority trial at 14 centers in the United Kingdom and Australia. Patients were randomly assigned to receive, or not to receive, prophylactic platelet transfusions when morning platelet counts were less than 10×10(9) per liter. Eligible patients were persons 16 years of age or older who were receiving chemotherapy or undergoing stem-cell transplantation and who had or were expected to have thrombocytopenia. The primary end point was bleeding of World Health Organization (WHO) grade 2, 3, or 4 up to 30 days after randomization.nnnRESULTSnA total of 600 patients (301 in the no-prophylaxis group and 299 in the prophylaxis group) underwent randomization between 2006 and 2011. Bleeding of WHO grade 2, 3, or 4 occurred in 151 of 300 patients (50%) in the no-prophylaxis group, as compared with 128 of 298 (43%) in the prophylaxis group (adjusted difference in proportions, 8.4 percentage points; 90% confidence interval, 1.7 to 15.2; P=0.06 for noninferiority). Patients in the no-prophylaxis group had more days with bleeding and a shorter time to the first bleeding episode than did patients in the prophylaxis group. Platelet use was markedly reduced in the no-prophylaxis group. A prespecified subgroup analysis identified similar rates of bleeding in the two study groups among patients undergoing autologous stem-cell transplantation.nnnCONCLUSIONSnThe results of our study support the need for the continued use of prophylaxis with platelet transfusion and show the benefit of such prophylaxis for reducing bleeding, as compared with no prophylaxis. A significant number of patients had bleeding despite prophylaxis. (Funded by the National Health Service Blood and Transplant Research and Development Committee and the Australian Red Cross Blood Service; TOPPS Controlled-Trials.com number, ISRCTN08758735.).

Guidelines on the use of irradiated blood components prepared by the British Committee for Standards in Haematology blood transfusion task force

Search terms included: Transfusion-associated graft-versus-host disease, Transfusion-associated graft-versus-host, TA-GvHD. The last guideline covering this topic was published in 1996 (British Committee for Standards in Haematology (BCSH) Blood Transfusion Task Force, 1996. The writing group produced the new draft guideline, which was subsequently revised by consensus by members of the Haemato-oncology and Blood Transfusion Task Forces of the BCSH. The guideline was then reviewed by a sounding board of approximately 100 UK haematologists, the BCSH and the committee of the British Society for Haematology and amended, again by consensus. Criteria used to quote levels and grades of evidence are according to the GRADE system (Guyatt et al, 2006). Strong recommendations (grade 1, ‘recommended’) are made when there is confidence that the benefits either do or do not outweigh the harm and burden and costs of treatment. Where the magnitude of benefit or not is less certain a weaker grade 2 recommendation (‘suggested’) is made. Grade 1 recommendations can be applied uniformly to most patients whereas grade 2 recommendations require judicious application. The quality of evidence is graded as A (high quality randomized clinical trials), moderate (B) or low (C). This publication reports the key recommendations of the Writing Group. It is also accessible at http://www.bcshguide lines.com.

The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab

In Paroxysmal nocturnal haemoglobinuria (PNH), pregnancy is associated with increased maternal and foetal complications to such an extent that the condition has been considered relatively contra‐indicated in PNH. Eculizumab has revolutionized the treatment of PNH. We evaluate its use in pregnancy to date. We report on seven patients exposed to eculizumab at different stages of pregnancy including the first two patients to receive the drug from conception to delivery. There was no evidence of complement blockade from cord blood samples taken at delivery. Eculizumab appears safe to use in this setting and is likely to prevent many of the complications usually observed.

A practical guideline for the haematological management of major haemorrhage.

The aim of this guideline is to provide recommendations for the haematological management of major haemorrhage in any clinical situation, with practical guidance for Clinical Haematologists and laboratory staff on the content and delivery of major bleeding protocols, including the use of blood components and transfusion alternatives. Management of major haemorrhage in any setting requires a multidisciplinary approach. There have been advances in techniques for resuscitation as well as surgical, radiological and endoscopy interventions, to control bleeding alongside critical care support, but these are beyond the scope of this document. These updated guidelines are based on new studies, which have provoked reassessment of the principles of managing major haemorrhage in all clinical situations, and which mandate much closer working between hospital blood banks and emergency departments to provide timely transfusion support for patients with major bleeding. Alongside changes in the use of blood component therapy, the importance of antifibrinolytics has been demonstrated in the study by the Clinical Randomization of Antifibrinolytics in Significant Haemorrhage (CRASH-2) collaborators (2010). The recognition that tranexamic acid (TA) benefited not only those with massive haemorrhage but also the larger number of patients with, or at risk of, significant haemorrhage (i.e. not only those fulfilling the criteria for massive bleeding) has led to an expansion of our guidelines from massive to major haemorrhage so that we can include this group. Methods

Guideline on the investigation and management of acute transfusion reactions Prepared by the BCSH Blood Transfusion Task Force

Although acute non‐haemolytic febrile or allergic reactions (ATRs) are a common complication of transfusion and often result in little or no morbidity, prompt recognition and management are essential. The serious hazards of transfusion haemovigilance organisation (SHOT) receives 30–40 reports of anaphylactic reactions each year. Other serious complications of transfusion, such as acute haemolysis, bacterial contamination, transfusion‐related acute lung injury (TRALI) or transfusion‐associated circulatory overload (TACO) may present with similar clinical features to ATR.

Do All Patients With Hematologic Malignancies and Severe Thrombocytopenia Need Prophylactic Platelet Transfusions?: Background, Rationale, and Design of a Clinical Trial (Trial of Platelet Prophylaxis) to Assess the Effectiveness of Prophylactic Platelet Transfusions

Although considerable advances have been made in many aspects of platelet transfusion therapy in the last 30 years, some areas continue to provoke debate, including the use of prophylactic platelet transfusions for the prevention of thrombocytopenic bleeding in patients with bone marrow failure. We have designed a randomized controlled trial to compare prophylactic platelet use with a threshold of a platelet count of 10 x 10(9)/L with no prophylaxis in adult thrombocytopenic patients with hematologic malignancies. The trial question is whether a no-prophylactic policy for the use of platelet transfusions in patients with hematologic malignancies is not inferior to a threshold prophylactic policy at 10 x 10(9)/L, for bleeding at World Health Organization (WHO) grade 2, 3, or 4, up to 30 days from randomization. The primary outcome measure is the proportion of patients who have a significant clinical bleed, defined as WHO grade 2 or higher up to 30 days from randomization. Subsidiary clinical outcome measures include time to first bleed and a descriptive analysis of all severe bleeds. A bleeding assessment form is completed daily for all study subjects until day 30 from randomization. Minor modifications were made to the definitions at WHO grades 1 and 2 for petechiae and duration of nose bleeds, after piloting of the bleeding assessment forms. This study has been designed as a 2-stage randomized trial with an interim analysis planned after a minimum of 100 patients had been randomized and had completed their period of observation. Patients have initially been enrolled through 3 United Kingdom hematology centers. The interim analysis has been completed, and the results have confirmed a final sample size of 600 patients. Recruitment is now being extended to other centers in United Kingdom and Australia. Local research nurses are not blinded to treatment allocation, but a number of measures to reduce risk of assessment bias include repeated education around standard operating procedures, common definitions, and duplication of assessments. The expected completion date for the 5-year study is December 2011.

Quality of life and use of red cell transfusion in patients with myelodysplastic syndromes. A systematic review

The main treatment for many patients with Myelodysplastic Syndromes (MDS) remains red cell transfusion to attenuate the symptoms of chronic anemia. Fatigue can reduce a patients health related quality of life (HRQoL), but there is little understanding of the optimal use of transfusions to improve this. A systematic review was performed to identify and appraise publications reporting the use of HRQoL instruments in patients with MDS. A total of 17 separate studies were identified that used 14 HRQoL instruments, but only one MDS disease specific HRQoL instrument (QOL‐E) was reported. Two well established HRQoL instruments were most often used in MDS research (variants of the Functional Assessment of Cancer Therapy (FACT) and the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ‐C30)). Several common problems were identified in the published literature including a lack of power calculations to detect clinically relevant changes, small sample sizes and significant attrition rates for completion of HRQoL assessments, all of which limit the strength of any conclusions. There is no consensus on the optimal transfusion regimen to improve HRQoL in transfusion‐dependent MDS. Future research into HRQoL within MDS is a pressing requirement. Studies should focus on the domains that are of most clinical importance to the patient as well as traditional quantitative changes of hemoglobin concentration. Am. J. Hematol., 2009.

A distinct large granular lymphocyte (LGL)/NK-associated (NKa) abnormality characterized by membrane CD4 and CD8 coexpression

Summary. In a study of 870 individual patients with either lymphocytosis (excluding known lymphoproliferative disease), increased proportions of blood lymphocytes with granular morphology (LGL), or neutropenia, 14 cases were found with abnormally increased CD3+CD4+CD8+ components. Eleven of these were further investigated and 10 shown in follow‐up studies to be persistent in nature. Morphological assessments revealed increased LGL in 9/11 cases, and in seven of these > 50% lymphocytes had discernable cytoplasmic granulation. Immunophenotypic studies indicated that CD8 expression by CD4+ lymphocytes in these patients was of low density (CD8dim+), and that both the CD4+CD8− and CD4+CD8dim+ fractions in each patient was characterized by a CD11b+ CD16−CD56+CD57+ composite NK‐associated (NKa) phenotype (in contrast to normal CD4+ CD8− blood lymphocytes and CD4+CD8+ thymocytes which were consistently CD11b−CD16−CD56−CD57−). TCR genotypic studies revealed rearranged components (β plus 7. or β alone) in 5/11 cases, but there were no obvious relationships between TCR configuration (including rearranged band densities) and immunophenotypes, absolute lymphocyte or neutrophil numbers, the proportions of blood LGL, or the proportions of CD4+ cells coexpressing CD8. The occurrence of identical NKa phenotypic profiles in both germline and rearranged TCR cases does, however, suggest the possiblity of an evolutionary process from a non‐clonal expansion to a clonal state. Serum studies, including soluble CD4. CD8 and IL2‐R concentrations and autoantibody investigations, of representative germline and rearranged TCR cases failed to indicate any consistent abnormalities, but there was some suggestion for the existence of a chronic reactive process in some of the patients with germline TCR. These findings suggest that expanded LGL/NKa+ components with phenotypic evidence of CD4/CD8 coexpression should be regarded as a distinct diagnostic category and that persistent CD4+CD8+ abnormalities with germline TCR should be monitored for possible clonal transition.

76 Are complications during pregnancy in women with mechanical heart valves influenced by their choice of anticoagulation

Introduction Anticoagulation during pregnancy in women with mechanical valves is complex. Strategies include warfarin or low-molecular weight heparin (LMWH) throughout or LWMH during first trimester then warfarin until delivery. Warfarin poses risks of teratogenicity and fetal haemorrhage. However, LMWH poses increased thrombotic risk and frequent difficulties maintaining therapeutic peak and trough anti-Xa levels. We aimed to assess the complication rate in pregnant women with mechanical valves and whether anti-Xa levels were maintained within the recommended range with LMWH Methods All pregnant women with mechanical valves under the ACHD team at Leeds General Infirmary were identified 2001- 2016. Medical records and blood results were analysed, identifying thrombotic and haemorrhagic complications, pregnancies leading to delivery of a healthy child and efficacy of anti-factor Xa monitoring. Results The 12 patients identified had 25 pregnancies; 12 ultimately delivered a healthy child, 2 of which had no complications. Thrombotic events complicated 6 pregnancies, haemorrhage complicated 5 pregnancies and 1 pregnancy was complicated by both (including all pregnancies/miscarriages). Three pregnancies underwent planned termination, 7 miscarried pre-8 weeks gestation with 3 intra-uterine deaths. Ten patients used LMWH in the first trimester only and 5 used LMWH throughout pregnancy. The graph shows peak anti-factor Xa levels measured closest to complication development or average peak level if there were no complications (where measurements were available). The peak target was 1.0–1.2. Conclusions Pregnancy in women with ACHD and mechanical valves carried significant risk of haemorrhage and thrombosis, regardless of anti-coagulation strategy. Anti-Xa levels were generally not maintained within target range.Abstract 76 Figure 1 Graph shows patients rarely have anti factor xa levels in range.