Coronavirus disease 2019 subphenotypes and differential treatment response to convalescent plasma in critically ill adults: secondary analyses of a randomized clinical trial.

PURPOSE: Benefit from convalescent plasma therapy for coronavirus disease 2019 (COVID-19) has been inconsistent in randomized clinical trials (RCTs) involving critically ill patients. As COVID-19 patients are immunologically heterogeneous, we hypothesized that immunologically similar COVID-19 subphenotypes may differ in their treatment responses to convalescent plasma and explain inconsistent findings between RCTs . METHODS: We tested this hypothesis in a substudy involving 1239 patients, by measuring 26 biomarkers (cytokines, chemokines, endothelial biomarkers) within the randomized, embedded, multifactorial, adaptive platform trial for community-acquired pneumonia (REMAP-CAP) that assigned 2097 critically ill COVID-19 patients to either high-titer convalescent plasma or usual care. Primary outcome was organ support free days at 21 days (OSFD-21) . RESULTS: Unsupervised analyses identified three subphenotypes/endotypes. In contrast to the more homogeneous subphenotype-2 (N = 128 patients, 10.3%; with elevated type i and type ii effector immune responses) and subphenotype-3 (N = 241, 19.5%; with exaggerated inflammation), the subphenotype-1 had variable biomarker patterns (N = 870 patients, 70.2%). Subphenotypes-2, and -3 had worse outcomes, and subphenotype-1 had better outcomes with convalescent plasma therapy compared with usual care (median (IQR). OSFD-21 in convalescent plasma vs usual care was 0 (- 1, 21) vs 10 (- 1, to 21) in subphenotype-2; 1.5 (- 1, 21) vs 12 (- 1, to 21) in suphenotype-3, and 0 (- 1, 21) vs 0 (- 1, to 21) in subphenotype-1 (test for between-subphenotype differences in treatment effects p = 0.008). CONCLUSIONS: We reported three COVID-19 subphenotypes, among critically ill adults, with differential treatment effects to ABO-compatible convalescent plasma therapy. Differences in subphenotype prevalence between RCT populations probably explain inconsistent results with COVID-19 immunotherapies.

Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura (HERCULES trial).

CLINICAL QUESTION: In people with acquired thrombotic thrombocytopenic purpura (TTP), does caplacizumab decrease the time to normalisation of the platelet count and the risk of death and complications caused by thrombotic events and organ damage? EVIDENCE FROM TRIAL: In adults with acquired TTP, caplacizumab decreased the time to normalisation of the platelet count and decreased the risk of TTP-related death and recurrence of TTP.

Six-month outcomes after restrictive or liberal transfusion for cardiac surgery (TRICS III trial).

CLINICAL QUESTION: Is transfusing red cell components using a restrictive transfusion threshold (Hb < 75 g L-1 ) as safe as a liberal transfusion threshold (Hb < 95 g L-1 in intensive care and < 85 g L-1 outside intensive care) during and after cardiac surgery for adults at moderate to high risk of death? EVIDENCE FROM TRIAL: In adults undergoing cardiac surgery who were at moderate to high risk for death, using a restrictive red-cell transfusion threshold was as safe as a liberal red cell transfusion threshold (composite outcome of death from any cause, myocardial infarction, stroke or new-onset renal failure with dialysis at 6 months after surgery).

Platelet transfusion thresholds in premature neonates (PlaNeT-2 trial).

CLINICAL QUESTION: Does transfusing platelets to preterm infants (< 34 weeks) at a higher platelet count threshold count (< 50 x 109 /L) reduce the risk of major bleeding or death compared to only transfusing platelets when the platelet count drops below 25 x 109 /L. EVIDENCE FROM TRIAL: Preterm infants with a low platelet count who were transfused platelets at the higher platelet count threshold had a higher risk of dying or having a major bleed than those who were not. The reasons why this occurred are currently unclear.

A multicentred study to validate a consensus bleeding assessment tool developed by the biomedical excellence for safer transfusion collaborative for use in patients with haematological malignancy.

BACKGROUND: There continues to be uncertainty about the optimal approach to documenting bleeding data in platelet transfusion trials, with a desire to apply a common assessment tool across all trials. With this in mind, a consensus bleeding assessment tool (BAT) has been developed by the Biomedical Excellence for Safer Transfusion (BEST) collaborative, based on review of data collection forms used in published randomized trials and following content validation with a range of healthcare professionals at seven haematology centres through BEST members. This study aimed to evaluate reliability and reproducibility of the consensus BAT. METHODS: Replicated clinical assessments of bleeding were undertaken by participants with haematological malignancies recruited at four haematology centres in an international, multicentred, observational study. Concordance of repeat assessments was calculated for agreement in site and grade of bleeding observed. RESULTS: Forty patients consented to participate, and 13 trained bleeding assessors collected these data. Bleeding assessments were carried out on 113 separate days. Of all 225 bleeding assessments, 204 were compared for grade concordance, and 160 were compared for site concordance. There was very good grade concordance (83%, 95% confidence interval 74-93%) and good bleeding site concordance (69%, 95% confidence interval 57-79%) in observations of bleeding. Discordance was primarily in relation to assessing skin bleeding. CONCLUSIONS: Alongside a structured training programme, levels of concordance for a consensus BAT were high. Researchers using assessment tools for bleeding need to balance comprehensive data collection against potential loss of accuracy for some types of bleeding, such as skin findings.

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. SUMMARY: Background Platelet dysfunction, including that caused by antiplatelet agents, increases the risk of perioperative bleeding. The optimal management of patients with platelet dysfunction undergoing surgery is unclear. Objectives To assess whether desmopressin reduces perioperative allogeneic red cell transfusion and bleeding in patients with platelet dysfunction. Patients/Methods We searched for randomized controlled trials in The Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, the Transfusion Evidence Library and the ISI Web of Science to 7th July 2016. Data were pooled using mean difference (MD), relative risks or Peto odds ratios (pOR) using a random-effects model. Results Ten trials with 596 participants were identified, all in the setting of cardiac surgery. Platelet dysfunction was due to antiplatelet agents in six trials and cardiopulmonary bypass in four trials. Patients treated with desmopressin were transfused with fewer red cells (MD, -0.65 units; 95% Confidence Interval [CI], -1.16 to -0.13 units), lost less blood (MD, -253.93 mL; 95% CI, -408.01 to -99.85 mL) and had a lower risk of re-operation due to bleeding (pOR, 0.39; 95% CI, 0.18-0.84). The GRADE quality of evidence was very low to moderate, suggesting considerable uncertainty over the results Conclusions Desmopressin may be a useful agent to reduce bleeding and transfusion requirements for people with platelet dysfunction or with a history of recent antiplatelet drug administration undergoing cardiac surgery.

Why has demand for platelet components increased? A review.

Platelet transfusions are used in clinical practice to prevent and treat haemorrhage in thrombocytopenic patients or patients with severe platelet dysfunction. In the UK, and abroad there has been a recent rise in platelet component demand. The three largest patient groups that use platelet components are patients with haematological malignancies (up to 67%), patients receiving cardiac surgery (up to 10%) and patients receiving intensive care (up to 8%). This review has explored some of the factors that may explain this recent trend within these three main groups. These factors include a rise in the general population, an ageing population, an increase in the incidence and prevalence of haematological malignancies, and changes in the management of patients with haematological malignancies. However, the only data available that can be correlated directly with national component data are the size of the total population. There is no evidence to support the premise that use of platelet components in patients receiving cardiac surgery or intensive care treatment is rising over and above the general rise in the population, but the data are sparse.

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. STUDY DESIGN AND METHODS: The study was split into two parts, a survey to assess local practice guidelines and an assessment of platelet usage. A total of 123 hospitals completed the survey and 168 hospitals submitted data of 40 haematology patients over a 3-month period. RESULTS: The organizational survey found that 36% of hospitals routinely give prophylactic platelet transfusions to patients with long-term bone-marrow failure. Also, a significant minority of hospitals administer platelet transfusions if the platelet count is below a certain threshold prior to performing a bone-marrow aspirate (11%) or a bone-marrow aspirate and trephine (23%); both of these are contrary to UK platelet transfusion guidelines. Data were collected on a total of 3402 patients, of which 3296 cases were eligible for analysis. They received approximately 46% of all platelet components issued to participating hospitals in England during the study period. The majority (69%) of platelet transfusions were prophylactic; of these only 33% were given when the platelet count was ≤10×10(9)/l. Using an algorithm, based on current UK guidelines, 60% of prophylactic transfusions were appropriate, 6% could not be assessed and 34% were inappropriate. A total of 10% of all prophylactic transfusions were double the standard adult dose. CONCLUSIONS: There is considerable potential for decreased use of platelet transfusions with a consequent improvement in their appropriate use and cost reduction.

Recurrent thrombo-embolic episodes: the association of cholangiocarcinoma with antiphospholipid syndrome.

Antiphospholipid syndrome is a disorder of recurrent vascular thrombosis, pregnancy loss and thrombocytopenia associated with persistently elevated levels of antiphospholipid antibodies. It was first described in a group of patients with systemic lupus erythematosus but has since been associated with a wide range of conditions, including other autoimmune disorders and malignancy. It can also occur in isolation, the so-called primary antiphospholipid syndrome. We describe an elderly woman with the antiphospholipid syndrome thought to be associated with a cholangiocarcinoma.