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The loss of 50% blood volume is one accepted definition of massive haemorrhage, which ordinarily would trigger the massive transfusion protocol, involving the administration of high ratios of fresh frozen plasma and platelets to allogeneic red cells. We investigated 53 patients who experienced50% blood loss during open elective abdominal aortic aneurysm surgery to assess allogeneic blood component usage and coagulopathy. Specialist patient blood management practitioners used a tailored cell salvage technique including swab wash to maximise blood return. We assessed the proportion of patients who did not require allogeneic blood components and develop evidence of coagulopathy by thromboelastography (TEG) parameters. Blood loss was 50%-174% (mean [SD] 68% [27%]) of blood volume. The mean (SD) intraoperative decrease in haemoglobin concentration, assessed by arterial blood gas analysis, was 5 (13) g/l. No patient received allogeneic red cells intraoperatively. Four of the 53 (8%) patients received blood components in the first 24 h postoperatively at the anaesthetists' discretion. No patient had intraoperative TEG changes indicative of fibrinolysis or coagulopathy. The 30-day mortality was 2% (one of 53). Reduction of allogeneic transfusion is one aim of patient blood management techniques. We have demonstrated virtual avoidance of allogeneic blood product transfusion despite massive blood loss. These data show possible alternatives to the current massive transfusion protocols to the management of elective vascular surgical patients.

This CIRSE Standards of Practice document is aimed at interventional radiologists and provides best practices for peri-operative anticoagulation management during interventional radiology procedures.

Pregnancy-associated haemophilia A is an uncommon, acquired bleeding disorder which usually presents post-partum; very rarely it may present during pregnancy. No consensus guidelines exist on the management of this condition in pregnancy and very few cases have been reported in the literature. Here we describe the case of a woman presenting with acquired haemophilia A during pregnancy and outline the management of her bleeding disorder. We contrast her case with that of two other women, presenting to the same tertiary referral centre, with acquired haemophilia A presenting post-partum. These cases highlight the heterogeneous management of this condition and how it may be successfully managed in pregnancy.

Bleeding of unknown cause (BUC), also known as unclassified bleeding disorders (UBD), has been defined as a clear bleeding tendency in the presence of normal haemostatic tests. There are challenges in the diagnosis and management of these patients. BUC/UBD encompasses a heterogenous group of disorders which may include undiagnosed rare monogenic diseases, polygenic reasons for bleeding; and patients without a clear bleeding disorder but with a previous bleeding event. Nevertheless, these patients may have heavy menstrual bleeding or be at risk of bleeding when undergoing surgical procedures, or childbirth; optimizing haemostasis and establishing a mode of inheritance is important to minimize morbidity. The bleeding score has been used to clinically assess and describe these patients, but its value remains uncertain. In addition, accurate distinction between normal and pathological bleeding remains difficult. Several studies have investigated cohorts of these patients using research haemostasis tests, including thrombin generation and fibrinolytic assays, yet no clear characteristics have consistently emerged. Thus far, detailed genetic analysis of these patients has not been fruitful in unravelling the cause of bleeding. There is a need for standardization of diagnosis and management guidelines for these patients. This review gives an overview of this field with some suggestions for future research.

Direct oral anticoagulants have become the mainstay of the management of venous thromboembolism and atrial fibrillation, and long-term anticoagulation is indicated for those at high risk of further thrombotic events. This includes patients diagnosed with antiphospholipid syndrome, for whom the ‘triple positive’ laboratory combination of lupus anticoagulant, β2-glycoprotein-1 and anti-cardiolipin antibodies signify those at greatest risk. Data from meta-analysis and randomised control trials have raised the concern that direct oral anticoagulants may be less effective than vitamin K antagonists for the prevention of thrombosis in patients with thrombotic antiphospholipid syndrome, particularly those with the triple positive profile. This article reviews the diagnosis of thrombotic antiphospholipid syndrome, strategies for testing without interruption of anticoagulation, evidence concerning the safety of direct oral anticoagulants in this setting, and the implications for current investigation and management of unprovoked venous thromboembolism.

Introduction Extended half-life factor IX concentrates (EHL-FIX) can be administered weekly to prevent bleeding for persons with severe haemophilia B. We report the experience of a large UK haemophilia comprehensive care centre using low dose EHL-FIX for persons with severe haemophilia B. Aim The low doses used in real world are approximately half of the doses used in clinical trials. We aim to assess the efficacy and safety of low dose EHL-FIX. Methods Data from a cohort of 13 patients who were switched from standard half-life factor IX (SHL-FIX) to Alprolix® (mean dose 31.5 IU/kg) and seven patients who switched from standard half-life factor IX to Idelvion® (mean dose 20.2 IU/kg) were included. Results The median annualized bleeding rate was similar for SHL-FIX (median 3, interquartile range [IQR] 1-5) and EHL-FIX (median 3, IQR 1-5.25). Quality of life scores, measured using the European Quality of Life 5 Dimensions assessment were similar for SHL-FIX (median 0.76, IQR: 0.63-0.84) and EHL-FIX (median 0.79, IQR: 0.58-0.88). Conclusion This study shows that EHL-FIX given at low doses can be effective for prevention of bleeding for persons with severe haemophilia B.

BACKGROUND Bleeding of unknown cause (BUC) and unclassified bleeding disorders (UBD) are increasingly recognized. There is no guidance on diagnosis and management. OBJECTIVES To examine UK haemophilia centre registration patterns and current practice for UBD patients. METHODS In a two-step process, the UK National Haemophilia Database (NHD) was reviewed for registration patterns of UBD patients and a survey of UK haemophilia centers was conducted (January/February 2021) to capture current practice for diagnosis and management of patients with UBD. RESULTS/DISCUSSION Overall, registrations with the NHD for UBD patients has sharply risen from 2012 to 2020 and in 2019 accounted for 2.65% of registered patients. For the survey, the response rate was 52/67 (78%). Practice was widely variable; 35/52 (67%) centers register UBD; among these 35 centers, terminology included UBD (28 centers), undiagnosed bleeding disorder (four centers), and BUC (three centers); 34/52 (65%) centers use a formal bleeding assessment tool. For management of dental extraction and high bleeding risk surgery in a fictional UBD patient we found that tranexamic acid was widely used; however, beyond this a variety of hemostatic products were advised including blood products, recombinant factor VIIa/prothrombin complex concentrate, and desmopressin. There was general consensus (≈90%) on avoiding regional anesthesia in pregnancy, but no agreement on the need for fetal precautions to avoid bleeding at delivery (50% would advise these). There was a disparity of opinion on chemical thromboprophylaxis, and management of patients without prior hemostatic challenges and offspring of these patients. CONCLUSION This study provides a snapshot of current practice and real-world data in this area. Future studies need to address the gaps in evidence.

Unclassified bleeding disorders account for 2.6% of all new bleeding disorder registrations in the UK. The management of the bleeding phenotype associated with these disorders is poorly described. Systematic review and meta-analysis to determine the bleeding rates associated with tranexamic acid, desmopressin, platelet transfusion, plasma transfusion and recombinant activated factor VII, for patients with unclassified bleeding disorders undergoing surgery, childbirth or with menorrhagia. We searched for randomized controlled trials in MEDLINE, Embase, The Cochrane Central Register of Controlled Trials, PubMed, ISI Web of Science and the Transfusion Evidence Library from inception to 24 February 2020. Wherever appropriate, data were pooled using the metaprop function of STATA. Two studies with 157 participants with unclassified bleeding disorders were identified. The pooled risk of minor bleeding for patients undergoing surgery treated with peri-operative tranexamic acid was 11% (95% confidence interval 3--20%; n = 52; I2 = 0%); the risk for desmopressin and tranexamic acid in combination was 3% (95% confidence interval 0--7%; n = 71; I2 = 0%). There were no instances of major bleeding. In one procedure, 1 of 71 (1.4%), treated with a combination of desmopressin and tranexamic acid, the patient had a line-related deep vein thrombosis. There were too few patients treated to prevent postpartum haemorrhage or for menorrhagia to draw conclusions. The GRADE quality of evidence was very low suggesting considerable uncertainty over the results. However, both tranexamic acid, and the combination of tranexamic and desmopressin have high rates of haemostatic efficacy and have few adverse events. Protocol registration PROSPERO CRD42020169727.

Background Antiplatelet therapy increases the risk of hematoma expansion in intracerebral hemorrhage (ICH) while the effect on functional outcome is uncertain. Methods and Results This is an exploratory analysis of the TICH‐2 (Tranexamic Acid in Intracerebral Hemorrhage‐2) double‐blind, randomized, placebo‐controlled trial, which studied the efficacy of tranexamic acid in patients with spontaneous ICH within 8 hours of onset. Multivariable logistic regression and ordinal regression were performed to explore the relationship between pre‐ICH antiplatelet therapy, and 24‐hour hematoma expansion and day 90 modified Rankin Scale score, as well as the effect of tranexamic acid. Of 2325 patients, 611 (26.3%) had pre‐ICH antiplatelet therapy. They were older (mean age, 75.7 versus 66.5 years), more likely to have ischemic heart disease (25.4% versus 2.7%), ischemic stroke (36.2% versus 6.3%), intraventricular hemorrhage (40.2% versus 27.5%), and larger baseline hematoma volume (mean, 28.1 versus 22.6 mL) than the no‐antiplatelet group. Pre‐ICH antiplatelet therapy was associated with a significantly increased risk of hematoma expansion (adjusted odds ratio [OR], 1.28; 95% CI, 1.01–1.63), a shift toward unfavorable outcome in modified Rankin Scale (adjusted common OR, 1.58; 95% CI, 1.32–1.91) and a higher risk of death at day 90 (adjusted OR, 1.63; 95% CI, 1.25–2.11). Tranexamic acid reduced the risk of hematoma expansion in the overall patients with ICH (adjusted OR, 0.76; 95% CI, 0.62–0.93) and antiplatelet subgroup (adjusted OR, 0.61; 95% CI, 0.41–0.91) with no significant interaction between pre‐ICH antiplatelet therapy and tranexamic acid (P interaction=0.248). Conclusions Antiplatelet therapy is independently associated with hematoma expansion and unfavorable functional outcome. Tranexamic acid reduced hematoma expansion regardless of prior antiplatelet therapy use. Registration URL: https://www.isrctn.com ; Unique identifier: ISRCTN93732214.

This is a case of an unexpected and dramatic bleeding complication in a patient post-bone marrow biopsy performed for investigation of an IgA paraprotein with the results confirming multiple myeloma. Subsequent investigations were suggestive of an acquired platelet disorder indicated by abnormal platelet light aggregometry readings. It was observed that the impaired platelet aggregation corrected on reduction of the paraprotein load following commencement of antimyeloma treatment and plasma exchange. This case is of significant clinical relevance as it highlights a risk factor for serious complication in patients undergoing procedures in those with untreated plasma cell dyscrasias.

IntroductionIntracerebral haemorrhage (ICH) can be devastating and is a common cause of death and disability worldwide. Pre-ICH antiplatelet drug use is associated with a 27% relative increase in 1 month case fatality compared with patients not using antithrombotic drugs. We aim to assess the feasibility of conducting a randomised controlled testing the safety and efficacy of desmopressin for patients with antiplatelet-associated ICH.Methods and analysisWe aim to include 50 patients within 24 hours of spontaneous ICH onset, associated with oral antiplatelet drug(s) use in at least the preceding 7 days. Patients will be randomised (1:1) to receive intravenous desmopressin 20 µg in 50 mL sodium chloride 0.9% infused over 20 min or matching placebo. We will mask participants, relatives and outcome assessors to treatment allocation. Feasibility outcomes include proportion of patients approached being randomised, number of patients receiving allocated treatment, rate of recruitment and adherence to treatment and follow-up. Secondary outcomes include change in ICH volume at 24 hours; hyponatraemia at 24 hours, length of hospital stay, discharge destination, early death less than 28 days, death or dependency at day 90, death up to day 90, serious adverse events (including thromboembolic events) up to day 90; disability (Barthel index, day 90), quality of life (EuroQol 5D (EQ-5D), day 90), cognition (telephone mini-mental state examination day 90) and health economic assessment (EQ-5D).Ethics and disseminationThe Desmopressin for reversal of Antiplatelet drugs in Stroke due to Haemorrhage (DASH) trial received ethical approval from the East Midlands—Nottingham 2 research ethics committee (18/EM/0184). The DASH trial is funded by National Institute for Health and Care Research RfPB grant: PB-PG-0816-20011. Trial results will be published in a peer reviewed academic journal and disseminated through academic conferences and through patient stroke support groups. Reporting will be in compliance with Consolidated Standards of Reporting Trials recommendations.Trial registration numbersNCT03696121;NCT67038373; EudraCT 2018-001904-12.

Highlights • Venous thrombosis is common in patients with severe COVID-19 pneumonia. • Many of these thromboses may be immunothromboses due to local inflammation, rather than thromboembolic disease. • Anticoagulated patients with COVID-19 pneumonia have a risk of major bleeding.

The cornerstone of life-saving therapy in immune-mediated thrombotic thrombocytopenic purpura (iTTP) has been plasma exchange (PEX) combined with immunomodulatory strategies. Caplacizumab, a novel anti–von Willebrand factor nanobody trialed in 2 multicenter randomized controlled trials (RCTs) leading to European Union and US Food and Drug Administration approval, has been available in the United Kingdom (UK) through a patient access scheme. Data were collected retrospectively from 2018 to 2020 for 85 patients (4 children) receiving caplacizumab from 22 UK hospitals. Patient characteristics and outcomes in the real-world clinical setting were compared with caplacizumab trial end points and historical outcomes in the precaplacizumab era. Eighty-four of 85 patients received steroid and rituximab alongside PEX; 26% required intubation. Median time to platelet count normalization (3 days), duration of PEX (7 days), and hospital stay (12 days) were comparable with RCT data. Median duration of PEX and time from PEX initiation to platelet count normalization were favorable compared with historical outcomes (P < .05). Thrombotic thrombocytopenic purpura (TTP) recurred in 5 of 85 patients; all had persistent ADAMTS13 activity < 5 IU/dL. Of 31 adverse events in 26 patients, 17 of 31 (55%) were bleeding episodes, and 5 of 31 (16%) were thrombotic events (2 unrelated to caplacizumab); mortality was 6% (5/85), with no deaths attributed to caplacizumab. In 4 of 5 deaths, caplacizumab was introduced >48 hours after PEX initiation (3-21 days). This real-world evidence represents the first and largest series of TTP patients, including pediatric patients, receiving caplacizumab outside of clinical trials. Representative of true clinical practice, the findings provide valuable information for clinicians treating TTP globally.

This retrospective cohort study investigated the association between factor 8 (F8) genotype severity and factor VIII (FVIII) levels during pregnancy for 52 women (64 pregnancies) who were heterozygous carriers of mild, moderate or severe haemophilia A. There were no significant differences in FVIII levels for carriers of mild, moderate or severe haemophilia A at baseline [mean (SD) level: mild, 0·78 (0·22); moderate, 0·83 (0·33); severe, 0·70 (0·25) iu/ml; P = 0·81] or in the third trimester [mean (SD) level: mild, 1·42 (0·28); moderate, 1·47 (0·41); severe, 1·37 (0·49) iu/ml; P = 0·80). Post-partum haemorrhage rates were higher for carriers of severe haemophilia A (13/24; 54·2%) compared to carriers of mild haemophilia A (four of 14; 28·6%).

BACKGROUND: Prolongation of prothrombin time (PT) is often recorded in critical illness, but has limited ability to predict risk of bleeding. This exploratory study was aimed at assessing a role for thrombin generation (TG) to predict bleeding. STUDY DESIGN AND METHODS: TG was measured by Calibrated Automated Thrombography in admissions to intensive care with prolonged PT. Bleeding events were recorded up to day 5 after enrolment and correlated with results of PT ratio (PTR) and parameters of TG. RESULTS: 306 patients were recruited. 101 bleeding events developed in 46 patients during the period of observation. Many patients with prolonged PT had endogenous thrombin potential (ETP) which was within the normal range (120/251 patients, 47.8%) or even elevated (8%). Although some patients had a reduction in ETP or peak thrombin these were present over a wide range of PTR. There was no suggestion by Receiver operating characteristic (ROC) analysis that parameters of conventional TG were sensitive at predicting bleeding. No bleeding events were documented in patients defined as ETP-high, despite elevated PTR. CONCLUSION: Future studies need to explore a role for alternatives tests of coagulation in critical illness. Development of TG assays is required to positively identify more patients at increased bleeding risk or to exclude a larger number at low risk and how this relates to subgroups, such as patients with liver disease, and the need for prophylactic plasma transfusion. Trial registration-ISRCTN50516147Keywords: critical illness, coagulopathy, prothrombin time, thrombin generation, plasma transfusion

An understanding of how to counteract the anticoagulant effect of direct oral anticoagulants is essential in the event of haemorrhage, emergency surgery and overdose. This review summarizes strategies for the reversal of direct oral anticoagulants, including the use of novel agents.

SummaryRed cells play a key role in normal haemostasis in vitro but their importance clinically is less clear. The objective of this meta-analysis was to assess if correction of anaemia by transfusing red cells at a high haemoglobin threshold (liberal transfusion) is superior to transfusion at a lower haemoglobin threshold (restrictive transfusion) for reducing the risk of bleeding or thrombotic events. We searched for randomised controlled trials in any clinical setting that compared two red cell transfusion thresholds and investigated the risk of bleeding. We searched for studies published up to October 19, 2016 in The Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, and the Transfusion Evidence Library and ISI Web of Science. Relative risks (RR) or Peto Odds Ratios (pOR) were pooled using a random-effect model. Nineteen randomised trials with 9852 participants were eligible for inclusion in this review. Overall there was no difference in the risk of any bleeding between transfusion strategies (RR 0.91, 95 % confidence interval [CI] 0.74 to 1.12). The risk of severe or life-threatening bleeding was lower with a restrictive strategy (RR 0.75, 95 % CI 0.57 to 0.99). There was no difference in the risk of thrombotic events (RR 0.83, 95 % CI 0.61 to 1.13). The risk of any bleeding was not reduced with liberal transfusion and there was no overall difference in the risk of thrombotic events. Data from the included trials do not support aiming for a high haemoglobin threshold to improve haemostasis. PROSPERO registration number CRD42016035519.Supplementary Material to this article is available online at www.thrombosis-online.com.

Intravenous immunoglobulin (IVIg) is a common therapy for patients with immune thrombocytopenia (ITP). The initial response rate for IVIg is 80%[1][1] and is typically rapid, with some patients responding in 24 hours, although usually in 2–4 days.[2][2] When IVIg is used alone, the response is

To promote trainee-led clinical research and audit in non-malignant haematology. Haematology Specialty Trainee Audit and Research (HaemSTAR) is a national network of haematology trainees. HaemSTAR is a new initiative, conceived in 2016 and supported by the National Institution for Health Research (

Acute upper gastrointestinal haemorrhage (AUGIH) is a common medical emergency and can present with life threatening haemorrhage. In the U.K., there are 70,000 hospital admissions per year. In the majority of cases, the aetiology is non-variceal in origin, but in other cases it is due to variceal bleeding in patients with cirrhosis. It is also a leading indication for transfusion of blood components. This review explores recent randomised data on the efficacy and safety of red blood cell transfusion for AUGIH. In addition, the evidence base for use of other blood components and pro-haemostatic pharmacological agents is discussed, including acid suppression, antifibrinolytics and fibrinogen.

Lumbar puncture (LP) is an important and frequently performed invasive procedure for the diagnosis and management of neurological conditions. There is little in the neurological literature on the topic of periprocedural management of antithrombotics in patients undergoing LP. Current practice is therefore largely extrapolated from guidelines produced by anaesthetic bodies on neuraxial anaesthesia, haematology groups advising on periprocedural management of antiplatelet agents and anticoagulants, and by neuroradiology on imaging-guided spinal procedures. This paper summarises the existing literature on the topic and offers recommendations to guide periprocedural antithrombotic management for LP, based on the consolidation of the best available evidence. ​. [Abstract copyright: © Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.]

Severe haemophilia A is associated with a severe bleeding phenotype (Richards et al, 2010). The factor VIII (FVIII) level is the mainstay of investigation and monitoring for these patients. However, there are often inconsistencies between the FVIII level and bleeding phenotype in haemophilia A (Franchini et al, 2009). Consequently, other tests have been under investigation to determine if they might have superior predictive value for assessing the bleeding risk for patients with haemophilia A.

There is an associated link between clinical research engagement and improved patient outcomes.[1][1] Not only does this apply to the subjects of research but also to those patients who are not active participants but are treated at sites where research is conducted.[2][2] Unfortunately, clinical

Background & Aims Patients who develop lower gastrointestinal bleeding (LGIB) while receiving anti-coagulants or anti-platelets have increased severity of bleeding and risk of re-bleeding. We compared outcomes of patients receiving anti-platelets, anti-coagulants, or direct oral anti-coagulants (DOACs) who develop LGIB, as well as the effects of withholding these drugs on their course of bleeding. Methods We performed a retrospective study of 2528 consecutive adult patients with LGIB at 143 hospitals in the United Kingdom, from September through December 2015; 917 were taking anti-coagulant or anti-platelet drugs and 1218 were taking neither (unexposed). We collected data on demographic features of patients, interventions or medications, outcomes, laboratory test results, and patient readmission until patient death, discharge, or 28 days after admission (whichever came first). Re-bleeding was defined as additional transfusion requirements and/or a decrease in hematocrit ≥20% after 24 hrs of clinical stability. Multivariate regression was used to examine the relationship between drug class on presentation with LGIB and re-bleeding, mortality, and cardiovascular events. Rates of re-bleeding and cardiovascular complications in patients who had these drugs withheld were also analyzed. Results Patients receiving anti-platelets, but not those receiving warfarin (n = 232) or DOACs (n = 102), had a higher risk of in-hospital re-bleeding (monotherapy hazard ratio [HR], 3.57; 95% CI, 1.13–11.28; n = 504 and dual anti-platelet therapy hazard ratio, 5.3; 95% CI, 1.56–18.54; n = 79) compared with the unexposed group. This risk was not lower in patients who received anti-platelets and had the drug withheld for fewer than 5 days, compared to those who continued the drug throughout admission (HR, 0.98; 95% CI, 0.45–2.17) No differences were observed in risk-adjusted mortality or re-admission with further bleeding for patients receiving anti-platelets, DOACs, or warfarin. Cardiovascular events were too few to allow meaningful comparison. Conclusions In patients with LGIB, antiplatelet drugs, but not warfarin or DOACs, are associated with an increased risk of re-bleeding. Withholding anti-platelets during admission does not lead to reduction in re-bleeding.

Background & Aims Cirrhosis is a complex acquired disorder of coagulation and frequent indication for transfusion of blood components. We characterised blood component use in patients with cirrhosis and compared this to transfusion guidelines. Methods All National Health Service trusts with representation on the British Society of Gastroenterology membership list were invited to take part. Data were collected prospectively on consecutive, unselected, hospitalised admissions with cirrhosis over 28 days. Detailed information was recorded for patients receiving blood components including indication (for bleeding or prophylaxis), type of component, laboratory indices triggering transfusion, complications, thromboembolic events and clinical outcome to day 28. Results Data on 1313 consecutive patients with cirrhosis were collected from 85 hospitals. A total of 391/1313 (30%) were transfused a blood component; in 238/391 (61%), this was for treatment of bleeding and in 153/391 (39%) for prophylaxis of bleeding. In 48/185 (26%) cases with bleeding, the haemoglobin threshold was >80 g/L prior to red blood cell transfusion. In the prophylaxis group, 238/391 (61%) received transfusion in response to an abnormal haematological value in the absence of any planned procedure. In patients transfused for procedural prophylaxis, 10/34 (29%) received fresh frozen plasma at an International Normalised Ratio lower than the threshold where a benefit would be anticipated. An in-patient thromboembolic event was recorded in 3% (35/1313) and 10% (138/1313) died by day 28. Conclusions One-third of hospitalised patients with cirrhosis were transfused. Strategies for Patient Blood Management should include ensuring transfusion practice is consistent with guidelines and greater emphasis on alternatives to transfusion.

BackgroundThe insertion of a lumbar puncture needle or epidural catheter may be associated with peri- and post-procedural bleeding. People who require this procedure may have disorders of coagulation as a result of their underlying illness, co-morbidities or the effects of treatment. Clinical practice in some institutions is to mitigate the risk of bleeding in these patients by prophylactically transfusing plasma in order to correct clotting factor deficiencies prior to the procedure. However, plasma transfusion is not without risk, and it remains unclear whether this intervention is associated with reduced rates of bleeding or other clinically-meaningful outcomes. ObjectivesTo assess the effect of different prophylactic plasma transfusion regimens prior to insertion of a lumbar puncture needle or epidural catheter in people with abnormal coagulation. Search methodsWe searched for randomised controlled trials (RCTs), non-randomised controlled trials (non-RCT) and controlled before-after studies (CBAs) in CENTRAL (the Cochrane Library 2016, Issue 11), MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), the Transfusion Evidence Library (from 1950), and five other electronic databases as well as ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform (ICTRP) for ongoing trials to 9 January 2017. Selection criteriaWe planned to include RCTs, non-RCTs, and CBAs involving transfusions of plasma given to prevent bleeding in people of any age with a coagulopathy requiring insertion of a lumbar puncture needle or epidural catheter. If identified, we would have excluded uncontrolled studies, cross-sectional studies and case-control studies. We would only have included cluster-RCTs, non-randomised cluster trials, and CBAs with at least two intervention sites and two control sites. In studies with only one intervention or control site, the intervention (or comparison) is completely confounded by study site making it difficult to attribute any observed differences to the intervention rather than to other site-specific variables.We planned to exclude people with haemophilia as they should be treated with the appropriate factor concentrate. We also planned to exclude people on warfarin as guidelines recommend the use of prothrombin complex concentrate for emergency reversal of warfarin. Data collection and analysisWe used standard methodological procedures expected by Cochrane. Main resultsWe identified no completed or ongoing RCTs, non-RCTs, or CBAs. Authors' conclusionsThere is no evidence from RCTs, non-RCTs, and CBAs to determine whether plasma transfusions are required prior to insertion of a lumbar puncture needle or epidural catheter, and, if plasma transfusions are required, what is the degree of coagulopathy at which they should be given. We would need to design a study with at least 47,030 participants to be able to detect an increase in the number of people who had bleeding after lumbar puncture or epidural anaesthetic from 1 in 1000 to 2 in 1000.

Background and study aims Investigations for lower gastrointestinal bleeding (LGIB) include flexible sigmoidoscopy, colonoscopy, computed tomographic angiography (CTA), and angiography. All may be used to direct endoscopic, radiological or surgical treatment, although their optimal use is unknown. The aims of this study were to determine the diagnostic and therapeutic yields of endoscopy, CTA, and angiography for managing LGIB, and their influence on rebleeding, transfusion, and hospital stay. Patients and methods A systematic search of MEDLINE, PubMed, EMBASE, and CENTRAL was undertaken to identify randomized controlled trials (RCTs) and nonrandomized studies of intervention (NRSIs) published between 2000 and 12 November 2015 in patients hospitalized with LGIB. Separate meta-analyses were conducted, presented as pooled odds (ORs) or risk ratios (RR) with 95 % confidence intervals (CIs). Results Two RCTs and 13 NRSIs were included, none of which examined flexible sigmoidoscopy, or compared endotherapy with embolization, or investigated the timing of CTA or angiography. Two NRSIs (57 – 223 participants) comparing colonoscopy and CTA were of insufficient quality for synthesis but showed no difference in diagnostic yields between the two interventions. One RCT and 4 NRSIs (779 participants) compared early colonoscopy ( Conclusions In LGIB there is a paucity of high-quality evidence, although the limited studies on the timing of colonoscopy suggest increased rates of diagnosis and therapy with early colonoscopy.

The Bruton tyrosine kinase (Btk) inhibitor ibrutinib induces platelet dysfunction and causes increased risk of bleeding. Off-target inhibition of Tec is believed to contribute to platelet dysfunction and other side effects of ibrutinib. The second-generation Btk inhibitor acalabrutinib was developed with improved specificity for Btk over Tec. We investigated platelet function in patients with non-Hodgkin lymphoma (NHL) receiving ibrutinib or acalabrutinib by aggregometry and by measuring thrombus formation on collagen under arterial shear. Both patient groups had similarly dysfunctional aggregation responses to collagen and collagen-related peptide, and comparison with mechanistic experiments in which platelets from healthy donors were treated with the Btk inhibitors suggested that both drugs inhibit platelet Btk and Tec at physiological concentrations. Only ibrutinib caused dysfunctional thrombus formation, whereas size and morphology of thrombi following acalabrutinib treatment were of normal size and morphology. We found that ibrutinib but not acalabrutinib inhibited Src family kinases, which have a critical role in platelet adhesion to collagen that is likely to underpin unstable thrombus formation observed in ibrutinib patients. We found that platelet function was enhanced by increasing levels of von Willebrand factor (VWF) and factor VIII (FVIII) ex vivo by addition of intermediate purity FVIII (Haemate P) to blood from patients, resulting in consistently larger thrombi. We conclude that acalabrutinib avoids major platelet dysfunction associated with ibrutinib therapy, and platelet function may be enhanced in patients with B-cell NHL by increasing plasma VWF and FVIII.

Background Blood transfusion is administered during many types of surgery, but its efficacy and safety are increasingly questioned. Evaluation of the efficacy of agents, such as desmopressin (DDAVP; 1-deamino-8-D-arginine-vasopressin), that may reduce perioperative blood loss is needed. Objectives To examine the evidence for the efficacy of DDAVP in reducing perioperative blood loss and the need for red cell transfusion in people who do not have inherited bleeding disorders. Search methods We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (2017, issue 3) in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (from 1937), the Transfusion Evidence Library (from 1980), and ongoing trial databases (all searches to 3 April 2017). Selection criteria We included randomised controlled trials comparing DDAVP to placebo or an active comparator (e.g. tranexamic acid, aprotinin) before, during, or immediately after surgery or after invasive procedures in adults or children. Data collection and analysis We used the standard methodological procedures expected by Cochrane. Main results We identified 65 completed trials (3874 participants) and four ongoing trials. Of the 65 completed trials, 39 focused on adult cardiac surgery, three on paediatric cardiac surgery, 12 on orthopaedic surgery, two on plastic surgery, and two on vascular surgery; seven studies were conducted in surgery for other conditions. These trials were conducted between 1986 and 2016, and 11 were funded by pharmaceutical companies or by a party with a commercial interest in the outcome of the trial. The GRADE quality of evidence was very low to moderate across all outcomes. No trial reported quality of life. DDAVP versus placebo or no treatment Trial results showed considerable heterogeneity between surgical settings for total volume of red cells transfused (low-quality evidence) and for total blood loss (very low-quality evidence) due to large differences in baseline blood loss. Consequently, these outcomes were not pooled and were reported in subgroups. Compared with placebo, DDAVP may slightly decrease the total volume of red cells transfused in adult cardiac surgery (mean difference (MD) -0.52 units, 95% confidence interval (CI) -0.96 to -0.08 units; 14 trials, 957 participants), but may lead to little or no difference in orthopaedic surgery (MD -0.02, 95% CI -0.67 to 0.64 units; 6 trials, 303 participants), vascular surgery (MD 0.06, 95% CI -0.60 to 0.73 units; 2 trials, 135 participants), or hepatic surgery (MD -0.47, 95% CI -1.27 to 0.33 units; 1 trial, 59 participants). DDAVP probably leads to little or no difference in the total number of participants transfused with blood (risk ratio (RR) 0.96, 95% CI 0.86 to 1.06; 25 trials; 1806 participants) (moderate-quality evidence). Whether DDAVP decreases total blood loss in adult cardiac surgery (MD -135.24 mL, 95% CI -210.80 mL to -59.68 mL; 22 trials, 1358 participants), orthopaedic surgery (MD -285.76 mL, 95% CI -514.99 mL to -56.53 mL; 5 trials, 241 participants), or vascular surgery (MD -582.00 mL, 95% CI -1264.07 mL to 100.07 mL; 1 trial, 44 participants) is uncertain because the quality of evidence is very low. DDAVP probably leads to little or no difference in all-cause mortality (Peto odds ratio (pOR) 1.09, 95% CI 0.51 to 2.34; 22 trials, 1631 participants) or in thrombotic events (pOR 1.36, 95% CI, 0.85 to 2.16; 29 trials, 1984 participants) (both low-quality evidence). DDAVP versus placebo or no treatment for people with platelet dysfunction Compared with placebo, DDAVP may lead to a reduction in the total volume of red cells transfused (MD -0.65 units, 95% CI -1.16 to -0.13 units; 6 trials, 388 participants) (low-quality evidence) and in total blood loss (MD -253.93 mL, 95% CI -408.01 mL to -99.85 mL; 7 trials, 422 participants) (low-quality evidence). DDAVP probably leads to little or no difference in the total number of participants receiving a red cell transfusion (RR 0.83, 95% CI 0.66 to 1.04; 5 trials, 258 participants) (moderate-quality evidence). Whether DDAVP leads to a difference in all-cause mortality (pOR 0.72, 95% CI 0.12 to 4.22; 7 trials; 422 participants) or in thrombotic events (pOR 1.58, 95% CI 0.60 to 4.17; 7 trials, 422 participants) is uncertain because the quality of evidence is very low. DDAVP versus tranexamic acid Compared with tranexamic acid, DDAVP may increase the volume of blood transfused (MD 0.6 units, 95% CI 0.09 to 1.11 units; 1 trial, 40 participants) and total blood loss (MD 142.81 mL, 95% CI 79.78 mL to 205.84 mL; 2 trials, 115 participants) (both low-quality evidence). Whether DDAVP increases or decreases the total number of participants transfused with blood is uncertain because the quality of evidence is very low (RR 2.42, 95% CI 1.04 to 5.64; 3 trials, 135 participants). No trial reported all-cause mortality. Whether DDAVP leads to a difference in thrombotic events is uncertain because the quality of evidence is very low (pOR 2.92, 95% CI 0.32 to 26.83; 2 trials, 115 participants). DDAVP versus aprotinin Compared with aprotinin, DDAVP probably increases the total number of participants transfused with blood (RR 2.41, 95% CI 1.45 to 4.02; 1 trial, 99 participants) (moderate-quality evidence). No trials reported volume of blood transfused or total blood loss and the single trial that included mortality as an outcome reported no deaths. Whether DDAVP leads to a difference in thrombotic events is uncertain because the quality of evidence is very low (pOR 0.98, 95% CI 0.06 to 15.89; 2 trials, 152 participants). Authors' conclusions Most of the evidence derived by comparing DDAVP versus placebo was obtained in cardiac surgery, where DDAVP was administered after cardiopulmonary bypass. In adults undergoing cardiac surgery, the reduction in volume of red cells transfused and total blood loss was small and was unlikely to be clinically important. It is less clear whether DDAVP may be of benefit for children and for those undergoing non-cardiac surgery. A key area for researchers is examining the effects of DDAVP for people with platelet dysfunction. Few trials have compared DDAVP versus tranexamic acid or aprotinin; consequently, we are uncertain of the relative efficacy of these interventions.

Supplemental Digital Content is available in the text., Objectives— The liver X receptors (LXRs) and farnesoid X receptor (FXR) have been identified in human platelets. Ligands of these receptors have been shown to have nongenomic inhibitory effects on platelet activation by platelet agonists. This, however, seems contradictory with the platelet hyper-reactivity that is associated with several pathological conditions that are associated with increased circulating levels of molecules that are LXR and FXR ligands, such as hyperlipidemia, type 2 diabetes mellitus, and obesity. Approach and Results— We, therefore, investigated whether ligands for the LXR and FXR receptors were capable of priming platelets to the activated state without stimulation by platelet agonists. Treatment of platelets with ligands for LXR and FXR converted platelets to the procoagulant state, with increases in phosphatidylserine exposure, platelet swelling, reduced membrane integrity, depolarization of the mitochondrial membrane, and microparticle release observed. Additionally, platelets also displayed features associated with coated platelets such as P-selectin exposure, fibrinogen binding, fibrin generation that is supported by increased serine protease activity, and inhibition of integrin αIIbβ3. LXR and FXR ligand-induced formation of coated platelets was found to be dependent on both reactive oxygen species and intracellular calcium mobilization, and for FXR ligands, this process was found to be dependent on cyclophilin D. Conclusions— We conclude that treatment with LXR and FXR ligands initiates coated platelet formation, which is thought to support coagulation but results in desensitization to platelet stimuli through inhibition of αIIbβ3 consistent with their ability to inhibit platelet function and stable thrombus formation in vivo.

Summary The story of the discovery of aspirin stretches back more than 3500 years to when bark from the willow tree was used as a pain reliever and antipyretic. It involves an Oxfordshire clergyman, scientists at a German dye manufacturer, a Nobel Prize-winning discovery and a series of pivotal clinical trials. Aspirin is now the most commonly used drug in the world. Its role in preventing cardiovascular and cerebrovascular disease has been revolutionary and one of the biggest pharmaceutical success stories of the last century.

L. Lieberman, D. V. Devine, H. W. Reesink, S. Panzer, J. Wong, T. Raison, S. Benson, J. Pink, G. C. Leitner, M. Horvath, V. Compernolle, P. S. Prado Scuracchio, S. Wendel, G. Delage, S. Nahirniak, X. Dongfu, T. Krusius, E. Juvonen, S. Sainio, J.-P. Cazenave, P. Guntz, D. Kientz, G. Andreu, P. Morel, E. Seifried, K. Hourfar, C. K. Lin, J. O’Riordan, E. Raspollini, S. Villa, P. Rebulla, P. Flanagan, D. Teo, S. Lam, A. L. Ang, M. Lozano, S. Sauleda, J. Cid, A. Pereira, B. Ekermo, C. Niederhauser, S. Waldvogel, S. Fontana, M. J. Desborough, R. Pawson, M. Li, H. Kamel, M. Busch, L. Qu & D. Triulzi

BACKGROUND: Acute upper gastrointestinal bleeding is a leading indication for red blood cell (RBC) transfusion worldwide, although optimal thresholds for transfusion are debated. METHODS: We searched MEDLINE, Embase, CENTRAL, CINAHL, and the Transfusion Evidence Library from inception to Oct 20, 2016, for randomised controlled trials comparing restrictive and liberal RBC transfusion strategies for acute upper gastrointestinal bleeding. Main outcomes were mortality, rebleeding, ischaemic events, and mean RBC transfusion. We computed pooled estimates for each outcome by random effects meta-analysis, and individual participant data for a cluster randomised trial were re-analysed to facilitate meta-analysis. We compared treatment effects between patient subgroups, including patients with liver cirrhosis, patients with non-variceal upper gastrointestinal bleeding, and patients with ischaemic heart disease at baseline. FINDINGS: We included four published and one unpublished randomised controlled trial, totalling 1965 participants. The number of RBC units transfused was lower in the restrictive transfusion group than in the liberal transfusion group (mean difference -1·73 units, 95% CI -2·36 to -1·11, p INTERPRETATION: These results support more widespread implementation of restrictive transfusion policies for adults with acute upper gastrointestinal bleeding. FUNDING: None.

Background People with thrombocytopenia due to bone marrow failure are vulnerable to bleeding. Platelet transfusions have limited efficacy in this setting and alternative agents that could replace, or reduce platelet transfusion, and are effective at reducing bleeding are needed. Objectives To compare the relative efficacy of different interventions for patients with thrombocytopenia due to chronic bone marrow failure and to derive a hierarchy of potential alternative treatments to platelet transfusions. Search methods We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (the Cochrane Library 2016, Issue 3), MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), the Transfusion Evidence Library (from 1980) and ongoing trial databases to 27 April 2016. Selection criteria We included randomised controlled trials in people with thrombocytopenia due to chronic bone marrow failure who were allocated to either an alternative to platelet transfusion (artificial platelet substitutes, platelet-poor plasma, fibrinogen concentrate, recombinant activated factor VII (rFVIIa), desmopressin (DDAVP), recombinant factor XIII (rFXIII), recombinant interleukin (rIL)6 or rIL11, or thrombopoietin (TPO) mimetics) or a comparator (placebo, standard of care or platelet transfusion). We excluded people undergoing intensive chemotherapy or stem cell transfusion. Data collection and analysis Two review authors independently screened search results, extracted data and assessed trial quality. We estimated summary risk ratios (RR) for dichotomous outcomes. We planned to use summary mean differences (MD) for continuous outcomes. All summary measures are presented with 95% confidence intervals (CI). We could not perform a network meta-analysis because the included studies had important differences in the baseline severity of disease for the participants and in the number of participants undergoing chemotherapy. This raised important concerns about the plausibility of the transitivity assumption in the final dataset and we could not evaluate transitivity statistically because of the small number of trials per comparison. Therefore, we could only perform direct pairwise meta-analyses of included interventions. We employed a random-effects model for all analyses. We assessed statistical heterogeneity using the I2 statistic and its 95% CI. The risk of bias of each study included was assessed using the Cochrane 'Risk of bias' tool. The quality of the evidence was assessed using GRADE methods. Main results We identified seven completed trials (472 participants), and four ongoing trials (recruiting 837 participants) which are due to be completed by December 2020. Of the seven completed trials, five trials (456 participants) compared a TPO mimetic versus placebo (four romiplostim trials, and one eltrombopag trial), one trial (eight participants) compared DDAVP with placebo and one trial (eight participants) compared tranexamic acid with placebo. In the DDAVP trial, the only outcome reported was the bleeding time. In the tranexamic acid trial there were methodological flaws and bleeding definitions were subject to significant bias. Consequently, these trials could not be incorporated into the quantitative synthesis. No randomised trial of artificial platelet substitutes, platelet-poor plasma, fibrinogen concentrate, rFVIIa, rFXIII, rIL6 or rIL11 was identified. We assessed all five trials of TPO mimetics included in this review to be at high risk of bias because the trials were funded by the manufacturers of the TPO mimetics and the authors had financial stakes in the sponsoring companies. The GRADE quality of the evidence was very low to moderate across the different outcomes. There was insufficient evidence to detect a difference in the number of participants with at least one bleeding episode between TPO mimetics and placebo (RR 0.86, 95% CI 0.56 to 1.31, four trials, 206 participants, low-quality evidence). There was insufficient evidence to detect a difference in the risk of a life-threatening bleed between those treated with a TPO mimetic and placebo (RR 0.31, 95% CI 0.04 to 2.26, one trial, 39 participants, low-quality evidence). There was insufficient evidence to detect a difference in the risk of all-cause mortality between those treated with a TPO mimetic and placebo (RR 0.74, 95%CI 0.52 to 1.05, five trials, 456 participants, very low-quality evidence). There was a significant reduction in the number of participants receiving any platelet transfusion between those treated with TPO mimetics and placebo (RR 0.76, 95% CI 0.61 to 0.95, four trials, 206 participants, moderate-quality evidence). There was no evidence for a difference in the incidence of transfusion reactions between those treated with TPO mimetics and placebo (pOR 0.06, 95% CI 0.00 to 3.44, one trial, 98 participants, very low-quality evidence). There was no evidence for a difference in thromboembolic events between TPO mimetics and placebo (RR 1.41, 95%CI 0.39 to 5.01, five trials, 456 participants, very-low quality evidence). There was no evidence for a difference in drug reactions between TPO mimetics and placebo (RR 1.12, 95% CI 0.83 to 1.51, five trials, 455 participants, low-quality evidence). No trial reported the number of days of bleeding per participant, platelet transfusion episodes, mean red cell transfusions per participant, red cell transfusion episodes, transfusion-transmitted infections, formation of antiplatelet antibodies or platelet refractoriness. In order to demonstrate a reduction in bleeding events from 26 in 100 to 16 in 100 participants, a study would need to recruit 514 participants (80% power, 5% significance). Authors' conclusions There is insufficient evidence at present for thrombopoietin (TPO) mimetics for the prevention of bleeding for people with thrombocytopenia due to chronic bone marrow failure. There is no randomised controlled trial evidence for artificial platelet substitutes, platelet-poor plasma, fibrinogen concentrate, rFVIIa, rFXIII or rIL6 or rIL11, antifibrinolytics or DDAVP in this setting.

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.

Frozen plasma (FP) is commonly used in an attempt to correct coagulation defects before performing bedside, radiologically guided, or operating room procedures. Use of FP prophylactically is closely linked to results for standard coagulation tests in the laboratory, including prothrombin time, but there is a general lack of evidence supporting the predictive value of abnormalities of these tests for bleeding. Use of FP has little effect on correcting abnormal coagulation tests when mild and moderate results are recorded. There is no support for evidence of effectiveness for the prophylactic use of FP when reviewing the wider randomized controlled trial literature. When the lack of clinical effectiveness is combined with the risks of FP transfusion, such as transfusion-related acute lung injury and transfusion-associated circulatory overload, the need to challenge continued preprocedure prophylactic use of FP becomes pressing. In clinical practice, abnormalities of standard coagulation tests should not be interpreted in isolation, but alongside review of clinical bleeding history and other hemostatic markers such as platelet count. A more appropriate transfusion strategy may be one that emphasizes the therapeutic use of FP.

Reovirus is a naturally occurring oncolytic virus that has shown preclinical efficacy in the treatment of a wide range of tumor types and has now reached phase III testing in clinical trials. The anti-cancer activity of reovirus has been attributed to both its direct oncolytic activity and the enhancement of anti-tumor immune responses. In this study, we have investigated the direct effect of reovirus on acute myeloid leukemia (AML) cells and its potential to enhance innate immune responses against AML, including the testing of primary samples from patients. Reovirus was found to replicate in and kill AML cell lines, and to reduce cell viability in primary AML samples. The pro-inflammatory cytokine interferon alpha (IFNα) and the chemokine (C-C motif) ligand 5 (known as RANTES [regulated upon activation, normal T-cell expressed, and secreted]) were also secreted from AML cells in response to virus treatment. In addition, reovirus-mediated activation of natural killer (NK) cells, within the context of peripheral blood mononuclear cells, stimulated their anti-leukemia response, with increased NK degranulation and IFNγ production and enhanced killing of AML targets. These data suggest that reovirus has the potential as both a direct cytotoxic and an immunotherapeutic agent for the treatment of AML.

We welcome the recent guidelines from the Women's Health Issues SSC of the ISTH which provide much needed guidance on the management of direct oral anticoagulants (DOACs) in women of childbearing potential [1]. We agree with the guidance except for one area and feel there would be benefit in reconsidering one of the recommendations: “Should pregnancy be desired, we recommend that the DOAC is switched to an alternative anticoagulant preconceptually, with the main alternative anticoagulant options vitamin K antagonists (VKAs) (to be switched to low molecular weight heparin (LMWH) as soon as possible when pregnant and before 6 weeks of gestation), or LMWH, with cognizance that the latter may result in prolonged subcutaneous injections until pregnancy is achieved.” This article is protected by copyright. All rights reserved.

Background Fresh frozen plasma (FFP) is a blood component containing procoagulant factors, which is sometimes used in cardiovascular surgery with the aim of reducing the risk of bleeding. The purpose of this review is to assess the risk of mortality for patients undergoing cardiovascular surgery who receive FFP. Objectives To evaluate the risk to benefit ratio of FFP transfusion in cardiovascular surgery for the treatment of bleeding patients or for prophylaxis against bleeding. Search methods We searched 11 bibliographic databases and four ongoing trials databases including the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 3, 2015), MEDLINE (OvidSP, 1946 to 21 April 2015), EMBASE (OvidSP, 1974 to 21 April 2015), PubMed (e-publications only: searched 21 April 2015), ClinicalTrials.gov, World Health Organization (WHO) ICTRP and the ISRCTN Register (searched 21 April 2015). We also searched the references of all identified trials and relevant review articles. We did not limit the searches by language or publication status. Selection criteria We included randomised controlled trials in patients undergoing major cardiac or vascular surgery who were allocated to a FFP group or a comparator (no plasma or an active comparator, either clinical plasma (any type) or a plasma-derived blood product). We included participants of any age (neonates, children and adults). We excluded studies of plasmapheresis and plasma exchange. Data collection and analysis Two authors screened all electronically derived citations and abstracts of papers identified by the review search strategy. Two authors assessed risk of bias in the included studies and extracted data independently. We took care to note whether FFP was used therapeutically or prophylactically within each trial. Main results We included 15 trials, with a total of 755 participants for analysis in the review. Fourteen trials compared prophylactic use of FFP against no FFP. One study compared therapeutic use of two types of plasma. The timing of intervention varied, including FFP transfusion at the time of heparin neutralisation and stopping cardiopulmonary bypass (CPB) (seven trials), with CPB priming (four trials), after anaesthesia induction (one trial) and postoperatively (two trials). Twelve trials excluded patients having emergency surgery and nine excluded patients with coagulopathies. Overall the trials were small, with only four reporting an a priori sample size calculation. No trial was powered to determine changes in mortality as a primary outcome. There was either high risk of bias, or unclear risk, in the majority of trials included in this review. There was no difference in the number of deaths between the intervention arms in the six trials (with 287 patients) reporting mortality (very low quality evidence). There was also no difference in blood loss in the first 24 hours for neonatal/paediatric patients (four trials with 138 patients; low quality evidence): mean difference (MD) -1.46 ml/kg (95% confidence interval (CI) -4.7 to 1.78 ml/kg); or adult patients (one trial with 120 patients): MD -12.00 ml (95% CI -101.16 to 77.16 ml). Transfusion with FFP was inferior to control for preventing patients receiving any red cell transfusion: Peto odds ratio (OR) 2.57 (95% CI 1.30 to 5.08; moderate quality evidence). There was a difference in prothrombin time within two hours of FFP transfusion in eight trials (with 210 patients; moderate quality evidence) favouring the FFP arm: MD -0.71 seconds (95% CI -1.28 to -0.13 seconds). There was no difference in the risk of returning to theatre for reoperation (eight trials with 398 patients; moderate quality evidence): Peto OR 0.81 (95% CI 0.26 to 2.57). Only one included study reported adverse events as an outcome and reported no significant adverse events following FFP transfusion. Authors' conclusions This review has found no evidence to support the prophylactic administration of FFP to patients without coagulopathy undergoing elective cardiac surgery. There was insufficient evidence about treatment of patients with coagulopathies or those who are undergoing emergency surgery. There were no reported adverse events attributable to FFP transfusion, although there was a significant increase in the number of patients requiring red cell transfusion who were randomised to FFP. Variability in outcome reporting between trials precluded meta-analysis for many outcomes across all trials, and there was evidence of a high risk of bias in most of the studies. Further adequately powered studies of FFP, or comparable pro-haemostatic agents, are required to assess whether larger reductions in prothrombin time translate into clinical benefits. Overall the evidence from randomised controlled trials for the safety and efficacy of prophylactic transfusion of FFP for cardiac surgery is insufficient.

Recurrence following initial treatment for venous thromboembolism is a significant cause of morbidity and mortality. Balancing the risks of recurrence against the risks of long-term anticoagulation is essential for optimizing patient outcomes.