Harnessing the potential of data-driven strategies to optimise transfusion practice.

No one doubts the significant variation in the practice of transfusion medicine. Common examples are the variability in transfusion thresholds and the use of tranexamic acid for surgery with likely high blood loss despite evidence-based standards. There is a long history of applying different strategies to address this variation, including education, clinical guidelines, audit and feedback, but the effectiveness and cost-effectiveness of these initiatives remains unclear. Advances in computerised decision support systems and the application of novel electronic capabilities offer alternative approaches to improving transfusion practice. In England, the National Institute for Health and Care Research funded a Blood and Transplant Research Unit (BTRU) programme focussing on 'A data-enabled programme of research to improve transfusion practices'. The overarching aim of the BTRU is to accelerate the development of data-driven methods to optimise the use of blood and transfusion alternatives, and to integrate them within routine practice to improve patient outcomes. One particular area of focus is implementation science to address variation in practice.

Older females have increased mortality after trauma as compared to younger females and males, associated with increased fibrinolysis.

INTRODUCTION: Female sex may provide a survival benefit after trauma, possibly attributable to protective effects of estrogen. This study aims to compare markers of coagulation between male and female trauma patients across different ages. METHODS: Secondary analysis of a prospective cohort study at six trauma centers. Trauma patients presenting with full trauma team activation were eligible for inclusion. Patients with a penetrating trauma or traumatic brain injury were excluded. Upon hospital arrival, blood was drawn for measurement of endothelial and coagulation markers and for rotational thromboelastometry (ROTEM) measurement.Trauma patients were divided into four categories: males <45 years, males ≥45 years, females <45 years and females ≥45 years. In a sensitivity analysis, patients between 45 - 55 years were excluded to control for menopausal transitioning. Groups were compared with a Kruskall-Wallis test with Bonferroni correction. A logistic regression was performed to assess whether the independent effect of sex and age on mortality. RESULTS: 1345 patients were available for analysis. Compared to the other groups, mortality was highest in females ≥45, albeit not independent from injury severity and shock. In the group of females ≥45 there was increased fibrinolysis, demonstrated by increased levels of plasmin-antiplasmin complexes with a concomitant decrease in α2-antiplasmin. Also, a modest decrease in coagulation factors II and X was observed. Fibrinogen levels were comparable between groups. The sensitivity analysis in 1104 patients demonstrated an independent relationship between female sex and age ≥ 55 years and mortality. ROTEM profiles did not reflect the changes in coagulation tests. CONCLUSION: Female trauma patients past their reproductive age have an increased risk of mortality compared to younger females and males, associated with augmented fibrinolysis and clotting factor consumption. ROTEM parameters did not reflect coagulation differences between groups. LEVEL OF EVIDENCE: Level III prognostic and epidemiological data.

Major haemorrhage: past, present and future.

Major haemorrhage is a leading cause of morbidity and mortality worldwide. Successful treatment requires early recognition, planned responses, readily available resources (such as blood products) and rapid access to surgery or interventional radiology. Major haemorrhage is often accompanied by volume loss, haemodilution, acidaemia, hypothermia and coagulopathy (factor consumption and fibrinolysis). Management of major haemorrhage over the past decade has evolved to now deliver a 'package' of haemostatic resuscitation including: surgical or radiological control of bleeding; regular monitoring of haemostasis; advanced critical care support; and avoidance of the lethal triad of hypothermia, acidaemia and coagulopathy. Recent trial data advocate for a more personalised approach depending on the clinical scenario. Fresh frozen plasma should be given as early as possible in major trauma in a 1:1 ratio with red blood cells until the results of coagulation tests are available. Tranexamic acid is a cheap, life-saving drug and is advocated in major trauma, postpartum haemorrhage and surgery, but not in patients with gastrointestinal bleeding. Fibrinogen levels should be maintained > 2 g.l-1 in postpartum haemorrhage and > 1.5 g.l-1 in other haemorrhage. Improving outcomes after major traumatic haemorrhage is now driving research to include extending blood-product resuscitation into prehospital care.

The effect of iron deficiency and anaemia on women's health.

Iron deficiency and anaemia are global health problems and major causes of morbidity in women. Current definitions of anaemia in women are historic and have been challenged by recent data from observational studies. Menstrual loss, abnormal uterine bleeding and pregnancy put women at risk of developing iron deficiency which can result in severe fatigue, reduced exercise capacity and poor work performance. Iron deficiency and anaemia during pregnancy are associated with adverse maternal and fetal outcomes, including neurocognitive deficits in children born to iron-deficient mothers. Both iron deficiency and anaemia are common in women undergoing surgery but their association with poor outcomes remains uncertain. The enduring burden of iron deficiency and anaemia in women suggests that current strategies for recognition, prevention and treatment are limited in their utility. Improvements in our understanding of iron homeostasis and the development of new iron preparations, which are better absorbed with fewer side-effects, may improve therapeutic effectiveness of oral iron. Intravenous iron is efficacious for correcting anaemia rapidly but high-quality data on patient-centred outcomes and cost-effectiveness are currently lacking. Many recommendations for the treatment of iron deficiency and anaemia in national guidelines are not supported by high-quality evidence. There is a need for robust epidemiological data and well-designed clinical trials. The latter will require collaborative working between researchers and patients to design studies in ways that incorporate patients' perspectives on the research process and target outcomes that matter to them.

Prothrombin complex concentrate vs. fresh frozen plasma in adult patients undergoing heart surgery - a pilot randomised controlled trial (PROPHESY trial).

There is equipoise regarding the use of prothrombin complex concentrate vs. fresh frozen plasma in bleeding patients undergoing cardiac surgery. We performed a pilot randomised controlled trial to determine the recruitment rate for a large trial, comparing the impact of prothrombin complex concentrate vs. fresh frozen plasma on haemostasis (1 h and 24 h post-intervention), and assessing safety. Adult patients who developed bleeding within 24 h of cardiac surgery that required coagulation factor replacement were randomly allocated to receive prothrombin complex concentrate (15 IU.kg-1 based on factor IX) or fresh frozen plasma (15 ml.kg-1 ). If bleeding continued after the first administration of prothrombin complex concentrate or fresh frozen plasma administration, standard care was administered. From February 2019 to October 2019, 180 patients were screened, of which 134 (74.4% (95%CI 67-81%)) consented, 59 bled excessively and 50 were randomly allocated; 25 in each arm, recruitment rate 35% (95%CI 27-44%). There were 23 trial protocol deviations, 137 adverse events (75 prothrombin complex concentrate vs. 62 fresh frozen plasma) and 18 serious adverse events (5 prothrombin complex concentrate vs. 13 fresh frozen plasma). There was no increase in thromboembolic events with prothrombin complex concentrate. No patient withdrew from the study, four were lost to follow-up and two died. At 1 h after administration of the intervention there was a significant increase in fibrinogen, Factor V, Factor XII, Factor XIII, α2 -antiplasmin and antithrombin levels in the fresh frozen plasma arm, while Factor II and Factor X were significantly higher in the prothrombin complex concentrate group. At 24 h, there were no significant differences in clotting factor levels. We conclude that recruitment to a larger study is feasible. Haemostatic tests have provided useful insight into the haemostatic changes following prothrombin complex concentrate or fresh frozen plasma administration. A definitive trial is needed to ascertain the benefits and safety for each.

Viscoelastic haemostatic assay augmented protocols for major trauma haemorrhage (ITACTIC): a randomized, controlled trial.

PURPOSE: Contemporary trauma resuscitation prioritizes control of bleeding and uses major haemorrhage protocols (MHPs) to prevent and treat coagulopathy. We aimed to determine whether augmenting MHPs with Viscoelastic Haemostatic Assays (VHA) would improve outcomes compared to Conventional Coagulation Tests (CCTs). METHODS: This was a multi-centre, randomized controlled trial comparing outcomes in trauma patients who received empiric MHPs, augmented by either VHA or CCT-guided interventions. Primary outcome was the proportion of subjects who, at 24 h after injury, were alive and free of massive transfusion (10 or more red cell transfusions). Secondary outcomes included 28-day mortality. Pre-specified subgroups included patients with severe traumatic brain injury (TBI). RESULTS: Of 396 patients in the intention to treat analysis, 201 were allocated to VHA and 195 to CCT-guided therapy. At 24 h, there was no difference in the proportion of patients who were alive and free of massive transfusion (VHA: 67%, CCT: 64%, OR 1.15, 95% CI 0.76-1.73). 28-day mortality was not different overall (VHA: 25%, CCT: 28%, OR 0.84, 95% CI 0.54-1.31), nor were there differences in other secondary outcomes or serious adverse events. In pre-specified subgroups, there were no differences in primary outcomes. In the pre-specified subgroup of 74 patients with TBI, 64% were alive and free of massive transfusion at 24 h compared to 46% in the CCT arm (OR 2.12, 95% CI 0.84-5.34). CONCLUSION: There was no difference in overall outcomes between VHA- and CCT-augmented-major haemorrhage protocols.

The association of pre-operative anaemia with morbidity and mortality after emergency laparotomy.

Pre-operative anaemia is associated with poor outcomes after elective surgery but its relationship with outcomes after emergency surgery is unclear. We analysed National Emergency Laparotomy Audit data from 1 December 2013 to 30 November 2017, excluding laparotomy for haemorrhage. Anaemia was classified as 'mild' 129-110 g.l-1; 'moderate' 109-80 g.l-1; or 'severe' ≤ 79 g.l-1. The primary outcome was 90-day mortality. Secondary outcomes were 30-day mortality, return to theatre and postoperative hospital stay. The primary outcome was available for 86,763 patients, of whom 45,306 (52%) were anaemic. There were 12,667 (15%) deaths at 90 postoperative days and 9246 (11%) deaths at 30 postoperative days. Anaemia was associated with increased 90-day and 30-day mortality, odds ratio (95%CI): mild, 1.15 (1.09-1.21); moderate, 1.44 (1.36-1.52); and severe, 1.42 (1.24-1.63), p < 0.001 for all; mild, 1.07 (1.00-1.12), p = 0.030; moderate, 1.30 (1.21-1.38), p < 0.001; and severe, 1.22 (1.05-1.43), p = 0.010, respectively. All categories of anaemia were associated with prolonged hospital stay, adjusted coefficient (95%CI): mild, 1.31 (1.01-1.62); moderate, 3.41 (3.04-3.77); severe, 2.80 (1.83-3.77), p < 0.001 for all. Moderate and severe anaemia were associated with increased risk of return to the operating theatre, odds ratio (95%CI): moderate 1.13 (1.06-1.21), p < 0.001; and severe 1.23 (1.06-1.43), p = 0.006. Pre-operative anaemia is common in patients undergoing emergency laparotomy and is associated with increased postoperative mortality and morbidity.

The application of a haemorrhage assessment tool in evaluating control of bleeding in a pilot trauma haemorrhage trial.

OBJECTIVES: To determine whether it was feasible to use a haemorrhage assessment tool (HAT) within a trauma trial and whether the data obtained could differentiate patients who had achieved haemostasis. BACKGROUND: Major haemorrhage is one of the leading causes of death worldwide, affecting 40% of trauma patients. Clinical trials evaluating haemostatic interventions often use transfusion outcomes as a primary endpoint. Transfusion is highly dependent on local practice, limiting its reliability as a robust, transferable endpoint. METHODS: A five-point HAT questionnaire was applied to participants enrolled into the EFIT-1 trial. This RCT evaluated the feasibility of administering a 6 g fibrinogen concentrate to patients with severe trauma haemorrhage. RESULTS: Of participants, 98% completed a HAT; 75% participants had 'achieved haemostasis' at the time of tool completion, as determined by clinical acumen alone. HAT scores were able to differentiate which participants required transfusion after 3 h. Of participants, 56% were transfused red blood cells when they scored 0-2, compared to 17% with HAT scores between 3 and 5. CONCLUSION: This study has confirmed the feasibility of using a HAT during the emergency care of patients suffering trauma haemorrhage, and future studies should be conducted to determine its value as an endpoint in haemostasis studies.

Protocolised thromboelastometric-guided haemostatic management in patients with traumatic brain injury: a pilot study.

Coagulopathy in patients with traumatic brain injury is associated with an increase in morbidity and mortality. Although timely and aggressive treatment of coagulopathy is of paramount importance, excessive transfusion of blood products has been linked with poor long-term outcomes in patients with traumatic brain injury. A point-of-care thromboelastometric-guided algorithm could assist in creating a more individually tailored approach to each patient. The aim of this study was to evaluate the feasibility of implementing a thromboelastometric-guided algorithm in centres that were formerly naïve to thromboelastometry. Hence, we developed such an algorithm and provided training to four centres across Europe to direct the haemostatic management of patients with severe traumatic brain injury. The primary outcome was adherence to the algorithm and timing of the availability of relevant results. Thirty-two patients were included in the study. Complete adherence to the algorithm was observed in 20 out of 32 cases. The availability of thromboelastometric results after hospital admission was reported significantly earlier than conventional coagulation tests (median (IQR [range]) 33 (20-40 [14-250]) min vs. 71 (51-101 [32-290]) min; p = 0.037). Although only 5 out of 32 patients had abnormalities of conventional coagulation tests, 21 out of 32 patients had a coagulopathic baseline thromboelastometric trace. Implementing a thromboelastometric-guided algorithm for the haemostatic therapy of traumatic brain injury is feasible in centres formerly naïve to this technology and may lead to more rapid and precise coagulation management. Further large-scale studies are warranted to confirm the results of this pilot trial and evaluate clinical outcomes.

Approaches to understanding and interpreting the risks of red blood cell transfusion in neonates.

In this review, we explore how to assess potential harm related to neonatal transfusion practice. We consider different sources of information, including passive or active surveillance systems such as registries, observational studies, randomised trials and systematic reviews. Future research directions are discussed.

Patient blood management, what does this actually mean for neonates and infants?

Patient blood management (PBM) refers to an evidence-based package of care that aims to improve patient outcomes by optimal use of transfusion therapy, including managing anaemia, preventing blood loss and improving anaemia tolerance in surgical and other patients who may need transfusion. In adults, PBM programmes are well established, yet the definition and implementation of PBM in neonates and children lags behind. Neonates and infants are frequently transfused, yet they are often under-represented in transfusion trials. Adult PBM programmes may not be directly applicable to these populations. We review the literature in neonatal (and applicable paediatric) transfusion medicine and propose specific neonatal PBM definitions and elements.

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.

Use of granulocyte transfusions among haematology units in England and North Wales.

OBJECTIVES: To establish the current use of granulocyte transfusions in haematology patients and explore interest in further research. BACKGROUND: Granulocytes may be used for the treatment of severe infection in neutropenic patients or for primary or secondary prophylaxis. Clinical utility of granulocyte transfusions is unclear, and recent studies have demonstrated equivocal outcomes. Pooled granulocytes are the main granulocyte product used in England and Wales, but there are no data on the patterns of use and little consensus on accepted indications. METHODS: A survey was distributed to UK hospitals delivering intensive chemotherapy. Clinical scenarios were posed, with further questions on clinician experience of using granulocytes, availability of the product, barriers to use and interest in further research. RESULTS: The response rate was 57%; 34·9% of all responses were from allogeneic stem cell transplant centres. Paediatric centres comprised 9·5% respondents, and 19% centres had access to apheresis granulocytes. Of respondents, 58·7% had used granulocytes in the last 3 years, 89·2% of whom used granulocytes to treat refractory infection. There was little consensus on use of granulocytes in the given clinical scenarios even when patients clearly met national guideline criteria. Paediatric centres were overall more likely to recommend granulocyte use. The most frequently identified barrier to use of granulocytes was lack of evidence of effect. Of the respondents, 75% indicated a willingness to participate in further research. CONCLUSION: There remains a lack of consistency about use of granulocytes, which is unsurprising given the lack of clinical data to support their efficacy. We did, however, demonstrate a willingness to participate in further research.