Lise J Estcourt

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

BACKGROUND The 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. METHODS We 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. RESULTS A 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. CONCLUSIONS The 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 for the use of platelet transfusions.

NHSBT and Radcliffe Department of Medicine, University of Oxford, Oxford, NHSBT and Department of Haematology, North Bristol NHS Trust, Bristol, NHSBT and Department of Haematology, Royal London Hospital, London, Department of Haematology, Royal Cornwall Hospital Trust, Cornwall, Department of Critical Care Medicine & Anaesthesia, City Hospitals Sunderland NHS Foundation Trust, Sunderland, Department of Haematology, Royal Devon & Exeter NHS Foundation Trust, Exeter, School of Cellular and Molecular Medicine, University of Bristol, Bristol, NHSBT and Department of Haematology, John Radcliffe Hospital, Oxford and NHSBT, Newcastle upon Tyne, UK

Platelet transfusions in haematology patients: are we using them appropriately?

Background and Objectives  A large proportion of all platelet components are given to haematology patients. As there are risks associated with their transfusion, costs associated with production, and shortages may occur, it is important that their use is appropriate.

Platelet refractoriness – practical approaches and ongoing dilemmas in patient management

Platelet refractoriness can represent a significant clinical problem that complicates the provision of platelet transfusions, is associated with adverse clinical outcomes and increases health care costs. Although it is most frequently due to non‐immune platelet consumption, immunological factors are also often involved. Human leucocyte antigen (HLA) alloimmunization is the most important immune cause. Despite the fact that systematic reviews of the clinical studies evaluating different techniques for selecting HLA compatible platelets have not been powered to demonstrate improved clinical outcomes, platelet refractoriness is currently managed by the provision of HLA‐matched or cross matched platelets. This review will address a practical approach to the diagnosis and management of platelet refractoriness while highlighting on‐going dilemmas and knowledge gaps.

Platelet transfusions for patients with haematological malignancies: who needs them?

The goal of platelet transfusions is to prevent severe and life‐threatening bleeding in patients with thrombocytopenia. This aim needs to be balanced against the risks associated with platelet transfusions as well as the challenge of maintaining an adequate supply. This review summarizes the recent evidence regarding the clinical use of platelet transfusions in haematology patients, concentrating on the topics that still continue to provoke debate. These include the optimal dose for platelet transfusions and the relative safety of a ‘therapeutic only’ platelet transfusion strategy compared to the use of prophylactic platelet transfusions. The type of platelet product has been the subject of two recent systematic reviews. The results of these reviews will be discussed as well as their implications for current practice.

Impact of prophylactic platelet transfusions on bleeding events in patients with hematologic malignancies: a subgroup analysis of a randomized trial

A recent randomized trial compared a policy of no prophylaxis with a policy of prophylactic platelet (PLT) transfusions at counts of fewer than 10 × 109/L in patients with hematologic malignancies. The results suggested the effectiveness of prophylactic PLT transfusions may vary according to patient diagnosis and treatment plan.

Risk of bleeding and use of platelet transfusions in patients with hematologic malignancies: recurrent event analysis

A recent randomized trial (TOPPS) compared prophylactic platelet transfusions (for counts <10×109/L) with a strategy of no-prophylaxis in adults with hematologic malignancies. Seventy percent of enrolled patients received an autologous hematopoietic stem cell transplant. Statistical models were developed to explore which patient factors or clinical characteristics are important prognostic factors for bleeding. These models were presented for baseline characteristics and for recurrent analysis of bleeding to assess the risks of World Health Organization grade 2–4 bleeding on any given day. Additional analyses explored the importance of fever. Treatment plan (chemotherapy/allogeneic hematopoietic stem cell transplant), female sex, and treatment arm (no-prophylaxis) were significantly associated with an increased number of days of bleeding. The number of days with a platelet count <10×109/L was significantly associated with a grade 2–4 bleed (P<0.0001). Patients with a temperature of at least 38°C had the highest hazard of a grade 2–4 bleed (hazard ratio: 1.7, 95% confidence interval: 1.3 to 2.4, compared with the risk in patients with a temperature <37.5°C). There was no evidence that minor bleeding predicted a grade 2–4 bleed. The results highlighted the limited role of correction of thrombocytopenia by platelet transfusion in reducing the risk of bleeding. Clinically stable patients undergoing autologous hematopoietic stem cell transplantation had the lowest risk of bleeding and benefited least from prophylactic platelet transfusions. Prospective studies are required to address the usefulness of risk factors to support better targeted platelet transfusions. TOPPS Controlled-Trials.com number ISRCTN08758735.

Desmopressin for treatment of platelet dysfunction and reversal of antiplatelet agents: a systematic review and meta-analysis of randomized controlled trials

Essentials The optimal management of patients with platelet dysfunction undergoing surgery is unclear. This meta‐analysis compared perioperative administration of desmopressin to placebo. Desmopressin reduced red cell transfusions, blood loss and risk of re‐operation due to bleeding. There were too few events to determine if there was a change in the risk of thrombotic events.

Alternatives to allogeneic platelet transfusion.

Allogeneic platelet transfusions are widely used for the prevention and treatment of bleeding in thrombocytopenia. Recent evidence suggests platelet transfusions have limited efficacy and are associated with uncertain immunomodulatory risks and concerns about viral or bacterial transmission. Alternatives to transfusion are a well‐recognised tenet of Patient Blood Management, but there has been less focus on different strategies to reduce bleeding risk by comparison to platelet transfusion. Direct alternatives to platelet transfusion include agents to stimulate endogenous platelet production (thrombopoietin mimetics), optimising platelet adhesion to endothelium by treating anaemia or increasing von Willebrand factor levels (desmopressin), increasing formation of cross‐linked fibrinogen (activated recombinant factor VII, fibrinogen concentrate or recombinant factor XIII), decreasing fibrinolysis (tranexamic acid or epsilon aminocaproic acid) or using artificial or modified platelets (cryopreserved platelets, lyophilised platelets, haemostatic particles, liposomes, engineered nanoparticles or infusible platelet membranes). The evidence base to support the use of these alternatives is variable, but an area of active research. Much of the current randomised controlled trial focus is on evaluation of the use of thrombopoietin mimetics and anti‐fibrinolytics. It is also recognised that one alternative strategy to platelet transfusion is choosing not to transfuse at all.

Prospective observational cohort study of the association between thromboelastometry, coagulation and platelet parameters and bleeding in patients with haematological malignancies- the ATHENA study.

Previous studies have shown that total platelet count (TPC) inadequately predicts bleeding in thrombocytopenic patients with haematological malignancies. This prospective cohort study evaluated whether rotational thromboelastometry (ROTEM), coagulation or other platelet parameters were more strongly associated with bleeding than TPC. Adults treated at two UK haematology centres for haematological malignancy were enrolled if they had thrombocytopenia (TPC ≤ 50 × 109/l) at beginning of, or during treatment (International Standard Randomized Controlled Trial Number 81226121). TPC and bleeding symptoms were recorded daily for up to 30 d or until platelet count recovery, hospital discharge or death. Blood samples were tested thrice weekly using ROTEM, Platelet Function Analyser (PFA)‐100®, coagulation and platelet cytometry assays. Bleeding symptoms and TPC from 49/50 enrolled participants who completed the study were recorded on 754/760 study days. Mean platelet volume and PFA‐100® closure times were frequently inestimatable because of thrombocytopenia. TPC, absolute immature platelet number (AIPN) and ROTEM maximum clot firmness were significantly associated with bleeding on the day after blood sampling. Only AIPN was associated with bleeding after adjustment of test results for TPC (Odds Ratio 0·52, 95% confidence interval 0·28–0·97; P = 0·038). In a predictive model, AIPN was superior to TPC for predicting bleeding. This study indicates that AIPN may be more clinically useful than TPC at predicting bleeding.