How I approach the prevention and treatment of thrombotic complications in hospitalized patients.

This article uses case-based discussion to review prevention and management of thrombotic problems in hospitalized patients that involve a clinical hematologist. There is variation in the clinical hematologist's role in thrombosis practice throughout the world, and we discuss this where indicated. Hospital-associated venous thromboembolism (VTE), or hospital-associated thrombosis (HAT), is the term to cover VTE occurring during admission and for 90 days postdischarge and is a common patient safety problem. HATs are the most common cause of VTE accounting for 55% to 60% of all VTE, with an estimated 10 million occurring globally. VTE risk assessment alongside evidence-based thromboprophylaxis reduces this risk significantly. Many hospitalized patients, especially older patients, use direct oral anticoagulants (DOACs), mainly to prevent stroke in atrial fibrillation. DOACs require perioperative management and may need urgent reversal. Other complex interventions such as extracorporeal membrane oxygenation which require anticoagulation are also discussed. Lastly, those with uncommon high-risk thrombophilias, especially those with antithrombin deficiency, produce unique challenges when hospitalized.

Advances and current research in primary thromboprophylaxis to prevent hospital-associated venous thromboembolism.

Hospital-associated venous thromboembolism (VTE) is defined as any case of VTE occurring during hospital admission and for up to 90 days post discharge. It accounts for over 50% of all cases of VTE internationally; indeed, there are an estimated 10 million cases of hospital-associated VTE annually. Over the last decade, there has been increasing interest in improving VTE risk assessment and thromboprophylaxis. This review summarises all the recent and ongoing major research studies and future challenges in the different areas, including medical, surgical and obstetric patients, as well as special areas such as lower limb immobilisation. We include sections on both pharmacological and mechanical thromboprophylaxis.

Clinical Features of Vaccine-Induced Immune Thrombocytopenia and Thrombosis.

BACKGROUND: Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a new syndrome associated with the ChAdOx1 nCoV-19 adenoviral vector vaccine against severe acute respiratory syndrome coronavirus 2. Data are lacking on the clinical features of and the prognostic criteria for this disorder. METHODS: We conducted a prospective cohort study involving patients with suspected VITT who presented to hospitals in the United Kingdom between March 22 and June 6, 2021. Data were collected with the use of an anonymized electronic form, and cases were identified as definite or probable VITT according to prespecified criteria. Baseline characteristics and clinicopathological features of the patients, risk factors, treatment, and markers of poor prognosis were determined. RESULTS: Among 294 patients who were evaluated, we identified 170 definite and 50 probable cases of VITT. All the patients had received the first dose of ChAdOx1 nCoV-19 vaccine and presented 5 to 48 days (median, 14) after vaccination. The age range was 18 to 79 years (median, 48), with no sex preponderance and no identifiable medical risk factors. Overall mortality was 22%. The odds of death increased by a factor of 2.7 (95% confidence interval [CI], 1.4 to 5.2) among patients with cerebral venous sinus thrombosis, by a factor of 1.7 (95% CI, 1.3 to 2.3) for every 50% decrease in the baseline platelet count, by a factor of 1.2 (95% CI, 1.0 to 1.3) for every increase of 10,000 fibrinogen-equivalent units in the baseline d-dimer level, and by a factor of 1.7 (95% CI, 1.1 to 2.5) for every 50% decrease in the baseline fibrinogen level. Multivariate analysis identified the baseline platelet count and the presence of intracranial hemorrhage as being independently associated with death; the observed mortality was 73% among patients with platelet counts below 30,000 per cubic millimeter and intracranial hemorrhage. CONCLUSIONS: The high mortality associated with VITT was highest among patients with a low platelet count and intracranial hemorrhage. Treatment remains uncertain, but identification of prognostic markers may help guide effective management. (Funded by the Oxford University Hospitals NHS Foundation Trust.).

The History of Extracorporeal Membrane Oxygenation and the Development of Extracorporeal Membrane Oxygenation Anticoagulation.

Extracorporeal membrane oxygenation (ECMO) was first started for humans in early 1970s by Robert Bartlett. Since its inception, there have been numerous challenges with extracorporeal circulation, such as coagulation and platelet activation, followed by consumption of coagulation factors and platelets, and biocompatibility of tubing, pump, and oxygenator. Unfractionated heparin (heparin hereafter) has historically been the defacto anticoagulant until recently. Also, coagulation monitoring was mainly based on bedside activated clotting time and activated partial thromboplastin time. In the past 50 years, the technology of ECMO has advanced tremendously, and thus, the survival rate has improved significantly. The indication for ECMO has also expanded. Among these are clinical conditions such as postcardiopulmonary bypass, sepsis, ECMO cardiopulmonary resuscitation, and even severe coronavirus disease 2019 (COVID-19). Not surprisingly, the number of ECMO cases has increased according to the Extracorporeal Life Support Organization Registry and prolonged ECMO support has become more prevalent. It is not uncommon for patients with COVID-19 to be on ECMO support for more than 1 year until recovery or lung transplant. With that being said, complications of bleeding, thrombosis, clot formation in the circuit, and intravascular hemolysis still remain and continue to be major challenges. Here, several clinical ECMO experts, including the "Father of ECMO"-Dr. Robert Bartlett, describe the history and advances of ECMO.

Natural history of PF4 antibodies in vaccine-induced immune thrombocytopenia and thrombosis.

The COVID-19 pandemic has resulted in the rapid development of a range of vaccines against SARS-CoV-2. Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare but life-threatening complication of primarily adenoviral-based vaccines associated with the presence of antibodies to a PF4/polyanion neoepitope and measured by using enzyme-linked immunosorbent assays. Presented are serial anti-PF4/polyanion antibody, platelet, and D-dimer measurements in a large cohort of patients and their relation to relapse. Overall, 51% of patients using the Stago assay had persistently positive anti-PF4/polyanion levels 100 days' postdiagnosis, whereas 94% of patients monitored by using the Immucor assay remain positive. The median duration of positivity of the PF4 assay is 87 days, with 72% of patients remaining positive after a median follow-up of 105 days. The use of plasma exchange seemed to reduce anti-PF4/polyanion levels and increase platelet counts in the acute setting more rapidly than other therapies. The rate of relapse in this study was 12.6%, with all relapsed cases exhibiting persistently positive PF4 antibodies and falling platelet counts. Only one patient had extension of their thrombosis. Overall, despite the persistence of PF4 antibodies in 72% of patients, the rate of relapse was low and did not seem to result in recrudescence of the aggressive clinical picture seen at index presentation. Monitoring of these patients in the UK cohort is ongoing and will aid in definition of the natural history of this novel condition.

A comparison of computational algorithms for the Bayesian analysis of clinical trials.

BACKGROUND: Clinical trials are increasingly using Bayesian methods for their design and analysis. Inference in Bayesian trials typically uses simulation-based approaches such as Markov Chain Monte Carlo methods. Markov Chain Monte Carlo has high computational cost and can be complex to implement. The Integrated Nested Laplace Approximations algorithm provides approximate Bayesian inference without the need for computationally complex simulations, making it more efficient than Markov Chain Monte Carlo. The practical properties of Integrated Nested Laplace Approximations compared to Markov Chain Monte Carlo have not been considered for clinical trials. Using data from a published clinical trial, we aim to investigate whether Integrated Nested Laplace Approximations is a feasible and accurate alternative to Markov Chain Monte Carlo and provide practical guidance for trialists interested in Bayesian trial design. METHODS: Data from an international Bayesian multi-platform adaptive trial that compared therapeutic-dose anticoagulation with heparin to usual care in non-critically ill patients hospitalized for COVID-19 were used to fit Bayesian hierarchical generalized mixed models. Integrated Nested Laplace Approximations was compared to two Markov Chain Monte Carlo algorithms, implemented in the software JAGS and stan, using packages available in the statistical software R. Seven outcomes were analysed: organ-support free days (an ordinal outcome), five binary outcomes related to survival and length of hospital stay, and a time-to-event outcome. The posterior distributions for the treatment and sex effects and the variances for the hierarchical effects of age, site and time period were obtained. We summarized these posteriors by calculating the mean, standard deviations and the 95% equitailed credible intervals and presenting the results graphically. The computation time for each algorithm was recorded. RESULTS: The average overlap of the 95% credible interval for the treatment and sex effects estimated using Integrated Nested Laplace Approximations was 96% and 97.6% compared with stan, respectively. The graphical posterior densities for these effects overlapped for all three algorithms. The posterior mean for the variance of the hierarchical effects of age, site and time estimated using Integrated Nested Laplace Approximations are within the 95% credible interval estimated using Markov Chain Monte Carlo but the average overlap of the credible interval is lower, 77%, 85.6% and 91.3%, respectively, for Integrated Nested Laplace Approximations compared to stan. Integrated Nested Laplace Approximations and stan were easily implemented in clear, well-established packages in R, while JAGS required the direct specification of the model. Integrated Nested Laplace Approximations was between 85 and 269 times faster than stan and 26 and 1852 times faster than JAGS. CONCLUSION: Integrated Nested Laplace Approximations could reduce the computational complexity of Bayesian analysis in clinical trials as it is easy to implement in R, substantially faster than Markov Chain Monte Carlo methods implemented in JAGS and stan, and provides near identical approximations to the posterior distributions for the treatment effect. Integrated Nested Laplace Approximations was less accurate when estimating the posterior distribution for the variance of hierarchical effects, particularly for the proportional odds model, and future work should determine if the Integrated Nested Laplace Approximations algorithm can be adjusted to improve this estimation.

Temporal changes in markers of coagulation and fibrinolysis in adults during extracorporeal membrane oxygenation.

INTRODUCTION: Bleeding and thrombotic events (BTE) are frequent during extracorporeal membrane oxygenation (ECMO). They occur at varying timepoints and may be affected by temporal changes in coagulation and fibrinolysis. We aimed to assess various coagulation and fibrinolytic markers over time and their relationship with BTE. METHODS: A single-centre prospective study was performed in 17 patients with severe respiratory failure receiving veno-venous ECMO. Blood samples were collected before and during ECMO, and around circuit decannulation. RESULTS: Prior to ECMO, D-Dimer, Plasmin-Antiplasmin complexes (PAP), Plasminogen-Activator Inhibitor-1 (PAI-1) and fibrinogen were elevated. There was an increase in D-Dimer and Prothrombin Fragments 1+2 (PF1+2) (729 to 1305pmol/L, p = .034) by day 1 and PAP increased by day 2 from baseline levels (median 1022 to 1797 µg/L, p = .023). There was a strong positive correlation in PAP, PF1+2 and thrombin-antithrombin complexes (TAT) to D-Dimer. BTE were frequent - 18% had major extracranial haemorrhage and 24% had intracranial haemorrhage. Over time, there was a progressive elevation PAP in patients developing subsequent extracranial haemorrhage, whereas D-Dimer, PAP and PF1+2 increased after intracranial haemorrhage. CONCLUSIONS: There were early changes in coagulation activity during ECMO by PF1+2 followed by subsequent fibrinolysis by PAP. Changes in PAP, PF1+2 and TAT were associated with major haemorrhage.

Prevention of hospital-associated venous thromboembolism - Insight from the Getting It Right First Time thrombosis survey in England.

A national Venous Thromboembolism (VTE) Prevention Programme was introduced in England in 2010, with limited subsequent study of its impact. Whilst the National Outcomes Framework reports VTE deaths related to hospitalisation annually, there are little data regarding VTE prevention practice or non-fatal VTE associated with hospitalisation. We report the first national thrombosis survey undertaken in collaboration with Getting It Right First Time. 98 Trusts (103 sites, 67% of 144 invited) participated in at least one survey, contributing data regarding VTE prevention in 9553 patients. Anti-coagulant thromboprophylaxis was prescribed to 88% (when indicated), with 8.1% of patients missing doses. Written patient information was provided to 31%. Of 4595 episodes of hospital-associated VTE, 13% were considered potentially preventable. The survey highlights the success of the national programme and areas for improvement in delivery of thromboprophylaxis and patient information.

The European guideline on management of major bleeding and coagulopathy following trauma: sixth edition.

BACKGROUND: Severe trauma represents a major global public health burden and the management of post-traumatic bleeding continues to challenge healthcare systems around the world. Post-traumatic bleeding and associated traumatic coagulopathy remain leading causes of potentially preventable multiorgan failure and death if not diagnosed and managed in an appropriate and timely manner. This sixth edition of the European guideline on the management of major bleeding and coagulopathy following traumatic injury aims to advise clinicians who care for the bleeding trauma patient during the initial diagnostic and therapeutic phases of patient management. METHODS: The pan-European, multidisciplinary Task Force for Advanced Bleeding Care in Trauma included representatives from six European professional societies and convened to assess and update the previous version of this guideline using a structured, evidence-based consensus approach. Structured literature searches covered the period since the last edition of the guideline, but considered evidence cited previously. The format of this edition has been adjusted to reflect the trend towards concise guideline documents that cite only the highest-quality studies and most relevant literature rather than attempting to provide a comprehensive literature review to accompany each recommendation. RESULTS: This guideline comprises 39 clinical practice recommendations that follow an approximate temporal path for management of the bleeding trauma patient, with recommendations grouped behind key decision points. While approximately one-third of patients who have experienced severe trauma arrive in hospital in a coagulopathic state, a systematic diagnostic and therapeutic approach has been shown to reduce the number of preventable deaths attributable to traumatic injury. CONCLUSION: A multidisciplinary approach and adherence to evidence-based guidelines are pillars of best practice in the management of severely injured trauma patients. Further improvement in outcomes will be achieved by optimising and standardising trauma care in line with the available evidence across Europe and beyond.

Factor XIII levels, clot strength, and impact of fibrinogen concentrate in infants undergoing cardiopulmonary bypass: a mechanistic sub-study of the FIBCON trial.

BACKGROUND: Acquired factor XIII (FXIII) deficiency after major surgery can increase postoperative bleeding. We evaluated FXIII contribution to clot strength and the effect of fibrinogen concentrate administration on FXIII activity in infants undergoing cardiac surgery using cardiopulmonary bypass. METHODS: We conducted a prospectively planned, mechanistic sub-study, nested within the Fibrinogen Concentrate Supplementation in the Management of Bleeding During Paediatric Cardiopulmonary Bypass: A Phase 1B/2A, Open-Label Dose Escalation Study (FIBCON) trial, which investigated fibrinogen concentrate supplementation during cardiopulmonary bypass (ISRCTN: 50553029) in 111 infants (median age 6.4 months). The relationships between platelet number, fibrinogen concentration, and FXIII activity with rotational thromboelastometry clot strength (EXTEM-MCF) in blood taken immediately before cardiopulmonary bypass and after separation from bypass were estimated using multivariable linear regression. Changes in coagulation variables over time were quantified using a generalised linear model comparing three groups: fibrinogen concentrate-supplemented infants, placebo, and a third cohort with lower bleeding risk. RESULTS: Overall, 48% of the variability (multivariable R2) in EXTEM-MCF clot strength was explained by three factors: the largest contribution was from FXIII activity (partial R2=0.21), followed by platelet number (partial R2=0.14), and fibrinogen concentration (partial R2=0.095). During cardiopulmonary bypass, mean platelet count fell by a similar amount in the three groups (-36% to -41%; interaction P=0.98). Conversely, fibrinogen concentration increased in all three groups: 132% in the fibrinogen concentrate-supplemented group, 26% in the placebo group, and 51% in the low-risk group. A similar increase was observed for FXIII activity (61%, 23%, and 25%, respectively; interaction P<0.0001). CONCLUSIONS: FXIII contribution to clot strength is considerable in infants undergoing cardiac surgery. Fibrinogen concentrate supplementation also increased FXIII activity, and hence clot strength. CLINICAL TRIAL REGISTRATION: ISRCTN: 50553029.

Plasmapheresis to remove amyloid fibrin(ogen) particles for treating the post-COVID-19 condition.

BACKGROUND: The post-COVID-19 condition (PCC) consists of a wide array of symptoms including fatigue and impaired daily living. People seek a wide variety of approaches to help them recover. A new belief, arising from a few laboratory studies, is that 'microclots' cause the symptoms of PCC. This belief has been extended outside these studies, suggesting that to recover people need plasmapheresis (an expensive process where blood is filtered outside the body). We appraised the laboratory studies, and it was clear that the term 'microclots' is incorrect to describe the phenomenon being described. The particles are amyloid and include fibrin(ogen); amyloid is not a part of a thrombus which is a mix of fibrin mesh and platelets. Initial acute COVID-19 infection is associated with clotting abnormalities; this review concerns amyloid fibrin(ogen) particles in PCC only. We have reported here our appraisal of laboratory studies investigating the presence of amyloid fibrin(ogen) particles in PCC, and of evidence that plasmapheresis may be an effective therapy to remove amyloid fibrin(ogen) particles for treating PCC. OBJECTIVES: Laboratory studies review To summarize and appraise the research reports on amyloid fibrin(ogen) particles related to PCC. Randomized controlled trials review To assess the evidence of the safety and efficacy of plasmapheresis to remove amyloid fibrin(ogen) particles in individuals with PCC from randomized controlled trials. SEARCH METHODS: Laboratory studies review We searched for all relevant laboratory studies up to 27 October 2022 using a comprehensive search strategy which included the search terms 'COVID', 'amyloid', 'fibrin', 'fibrinogen'. Randomized controlled trials review We searched the following databases on 21 October 2022: Cochrane COVID-19 Study Register; MEDLINE (Ovid); Embase (Ovid); and BIOSIS Previews (Web of Science). We also searched the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov for trials in progress. SELECTION CRITERIA: Laboratory studies review Laboratory studies that investigate the presence of amyloid fibrin(ogen) particles in plasma samples from patients with PCC were eligible. This included studies with or without controls. Randomized controlled trials review Studies were eligible if they were of randomized controlled design and investigated the effectiveness or safety of plasmapheresis for removing amyloid fibrin(ogen) particles for treating PCC. DATA COLLECTION AND ANALYSIS: Two review authors applied study inclusion criteria to identify eligible studies and extracted data. Laboratory studies review We assessed the risk of bias of included studies using pre-developed methods for laboratory studies. We planned to perform synthesis without meta-analysis (SWiM) as described in our protocol. Randomized controlled trials review We planned that if we identified any eligible studies, we would assess risk of bias and report results with 95% confidence intervals. The primary outcome was recovery, measured using the Post-COVID-19 Functional Status Scale (absence of symptoms related to the illness, ability to do usual daily activities, and a return to a previous state of health and mind). MAIN RESULTS: Laboratory studies review We identified five laboratory studies. Amyloid fibrin(ogen) particles were identified in participants across all studies, including those with PCC, healthy individuals, and those with diabetes. The results of three studies were based on visual images of amyloid fibrin(ogen) particles, which did not quantify the amount or size of the particles identified. Formal risk of bias assessment showed concerns in how the studies were conducted and reported. This means the results were insufficient to support the belief that amyloid fibrin(ogen) particles are associated with PCC, or to determine whether there is a difference in the amount or size of amyloid fibrin(ogen) particles in the plasma of people with PCC compared to healthy controls. Randomized controlled trials review We identified no trials meeting our inclusion criteria. AUTHORS' CONCLUSIONS: In the absence of reliable research showing that amyloid fibrin(ogen) particles contribute to the pathophysiology of PCC, there is no rationale for plasmapheresis to remove amyloid fibrin(ogen) particles in PCC. Plasmapheresis for this indication should not be used outside the context of a well-conducted randomized controlled trial.

Antiphospholipid-related chorea.

Chorea can be associated with autoimmune diseases such as antiphospholipid syndrome and has been associated with the isolated presence of antiphospholipid antibodies (aPL). Chorea is a rare neurological manifestation of antiphospholipid syndrome. The pathophysiological mechanisms underlying aPL-related chorea are still debated. One postulated mechanism is aPL or other autoantibody binding to brain-blood vessel endothelium, resulting in endothelial dysfunction secondary to a proinflammatory cascade, with sequalae of inflammation and local microthrombosis. Another postulated mechanism considers immune-mediated attack (aPL or antibasal ganglia antibodies) against specific basal ganglia epitopes. Here, we report a patient with isolated aPL-related chorea that followed a relapsing-remitting course. We highlight the role of brain metabolic imaging with fluorodeoxy glucose positron-emission tomography in the diagnostic workup of chorea and the challenges in the practical management of aPL-related chorea with symptomatic treatments.

Tranexamic Acid in Gastrointestinal Bleeding: A Systematic Review and Meta-Analysis.

OBJECTIVES: Tranexamic acid is proposed as a treatment for gastrointestinal bleeding. The Haemorrhage Alleviation with Tranexamic Acid-Intestinal System trial evaluated extended-use (24 hr) high-dose tranexamic acid, prompting a reappraisal for tranexamic acid in gastrointestinal bleeding. DATA SOURCES: We conducted a systematic review and meta-analysis of randomized controlled trials comparing tranexamic acid with usual care or placebo in adults with gastrointestinal bleeding. We searched MEDLINE, EMBASE, and CENTRAL (inception to September 2019). DATA SELECTION: Two reviewers independently screened citations, extracted data, and assessed the risk of bias using the Cochrane risk of bias tool in duplicate. The main outcomes were mortality, bleeding, and adverse events. DATA EXTRACTION: Studies were analyzed as high-dose IV tranexamic acid versus all other dosing strategies for tranexamic acid using fixed-effects models. We assessed certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. DATA SYNTHESIS: Five randomized controlled trials evaluated extended-use high-dose IV tranexamic acid, seven evaluating low-dose IV or enteral tranexamic acid. Extended-use high-dose IV tranexamic acid did not reduce mortality (relative risk, 0.98%; 95% CI, 0.88-1.09; I2 = 63%; high certainty) or bleeding (relative risk, 0.92; 95% CI, 0.82-1.04; p = 0.17 and absolute risk differences, -0.7%; 95% CI, -1.5 to 0.3; high certainty) but resulted in a small increase in deep venous thrombosis (relative risk, 2.01; 95% CI, 1.08-3.72; I2 = 0%), pulmonary embolism (relative risk, 1.78; 95% CI, 1.06-3.0; I2 = 0%), and seizure (relative risk, 1.73; 95% CI, 1.03-2.93) with high certainty. Low-dose IV/enteral tranexamic acid did not reduce mortality (relative risk, 0.62; 95% CI, 0.36-1.09; I2 = 0%) but did reduce risk of rebleeding (relative risk, 0.5; 95% CI, 0.33-0.75; I2 = 9%) and need for surgery (relative risk, 0.58; 95% CI, 0.38-0.88; I2 = 11%), with moderate certainty. CONCLUSIONS: Extended-use high-dose IV tranexamic acid does not improve mortality or bleeding outcomes and increases adverse events. Low-dose/enteral tranexamic acid may be effective in reducing hemorrhage; more evidence is required to demonstrate its safety.

Antifibrinolytic Drugs for the Prevention of Bleeding in Pediatric Cardiac Surgery on Cardiopulmonary Bypass: A Systematic Review and Meta-analysis.

BACKGROUND: Bleeding is one of the commonest complications affecting children undergoing cardiac surgery on cardiopulmonary bypass. Antifibrinolytic drugs are part of a multifaceted approach aimed at reducing bleeding, though sufficiently sized pediatric studies are sparse, and dosing algorithms are heterogeneous. Our objective was to evaluate the efficacy and safety of antifibrinolytic agents as well as the effectiveness of different dosing regimens in pediatric cardiac surgery using cardiopulmonary bypass. METHODS: We performed a systematic review and meta-analysis evaluating randomized controlled trials published between 1980 and 2019, identified by searching the databases MEDLINE, EMBASE, PubMed, and CENTRAL. All studies investigating patients <18 years of age without underlying hematological disorders were included. The primary outcome was postoperative bleeding; secondary end points included blood product transfusion, mortality, and safety (thromboses, anaphylaxis, renal or neurological dysfunction, and seizures). Different dosing regimens were compared. Studies were dual appraised, outcomes were reported descriptively and, if appropriate, quantitatively using the Review Manager 5 (REVMAN 5) software (The Cochrane Collaboration). RESULTS: Thirty of 209 articles were included, evaluating the following drugs versus control: aprotinin n = 14, tranexamic acid (TXA) n = 12, and epsilon-aminocaproic acid (EACA) n = 4. The number of participants per intervention group ranged from 11 to 100 (median, 25; interquartile range [IQR], 20.5) with a wide age span (mean, 13 days to 5.8 years) and weight range (mean, 3.1-26.3 kg). Methodological quality was low to moderate.All agents reduced mean 24-hour blood loss compared to control: aprotinin by 6.0 mL/kg (95% confidence interval [CI], -9.1 to -3.0; P = .0001), TXA by 9.0 mL/kg (95% CI, -11.3 to -6.8; P < .00001), and EACA by 10.5 mL/kg (95% CI, -21.1 to 0.0; P = .05). Heterogeneity was low for TXA (I2 = 29%; P = .19), moderate for aprotinin (I2 = 41%; P = .11), and high for EACA (I2 = 95%; P < .00001). All agents also reduced 24-hour blood product transfusion. There was no clear dose-response effect for TXA nor aprotinin. Studies were underpowered to detect significant differences in mortality, thromboses, anaphylaxis, and renal or neurological dysfunction. CONCLUSIONS: The available data demonstrate efficacy for all 3 antifibrinolytic drugs. Therefore, the agent with the most favorable safety profile should be used. As sufficient data are lacking, large comparative trials are warranted to assess the relative safety and appropriate dosing regimens in pediatrics.

Effect of Antiplatelet Therapy on Survival and Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial.

Importance: The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. Objective: To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. Design, Setting, and Participants: In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). Interventions: Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from -1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. Results: The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years; 521 [33.6%] female). The median for organ support-free days was 7 (IQR, -1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23]; 95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62]; adjusted absolute difference, 5% [95% CrI, -0.2% to 9.5%]; 97% posterior probability of efficacy). Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28]; adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%]; 99.4% probability of harm). Conclusions and Relevance: Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support-free days within 21 days. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

The Safety of Continued Oral Anticoagulation Therapy in Joint Injections and Aspirations: A Qualitative Review of the Current Evidence.

ABSTRACT: Performing joint aspirations and injections on patients taking long-term oral anticoagulants poses a clinical conundrum. This review aimed to quantify the safety of performing joint procedures in these patients in terms of bleeding risk. In addition, it aimed to identify, in those receiving vitamin K antagonists, what level of international normalized ratio (INR) is the safest.A review of the medical literature was performed (electronic searches in Ovid [MEDLINE], EMBASE, and the Cochrane Library). English language original reports of patients undergoing joint injections or aspirations performed on anticoagulant therapy, published within the last 10 years, were included.Seven studies met the inclusion criteria. Patients were taking a variety of anticoagulants: warfarin, acenocoumarol, and direct oral anticoagulants. Four cases of hemorrhage were reported after 5427 procedures, over a pooled 32-year period, across 9 centers. The INR values were available for 3 cases with bleeding complications: values were 1.9, 2.3, and 3.4.Authors of all studies concluded that joint injection is safe in patients on anticoagulants. A variety of joints and approaches, reversal, or withholding of anticoagulation and bridging with low molecular weight heparin did not seem to alter bleeding risk. Bleeding complications remained low even in those with renal or hepatic impairment or those taking concomitant antiplatelets.In conclusion, joint aspiration and injection are safe in patients taking anticoagulants. Anticoagulation should not be routinely discontinued in these patients; decisions should be made on a case-by-case basis. Because of low event numbers, a recommended safe maximum INR value for joint procedures cannot be determined.

A Comparison of Thrombosis and Hemorrhage Rates in Patients With Severe Respiratory Failure Due to Coronavirus Disease 2019 and Influenza Requiring Extracorporeal Membrane Oxygenation.

OBJECTIVES: Extracorporeal membrane oxygenation is a lifesaving therapy for patients with severe acute respiratory distress syndrome refractory to conventional mechanical ventilation. It is frequently complicated by both thrombosis and hemorrhage. A markedly prothrombotic state associated with high rates of venous thromboembolism has been described in patients with severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019) infection. These rates have currently not been described during extracorporeal membrane oxygenation in comparison to other viral pneumonias. DESIGN: Retrospective observational study. SETTING: Single high-volume tertiary critical care department at a university hospital. PATIENTS: Patients 16 years old or greater receiving venovenous extracorporeal membrane oxygenation between March 1, 2020, and May 31, 2020, with coronavirus disease 2019 were compared with a cohort of patients with influenza pneumonia between June 1, 2012, and May 31, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The rates of venous thromboembolism and hemorrhage were compared in patients with coronavirus disease 2019 against a historic population of patients with influenza pneumonia who required extracorporeal membrane oxygenation. There were 51 patients who received extracorporeal membrane oxygenation due to coronavirus disease 2019 and 80 patients with influenza. At cannulation for extracorporeal membrane oxygenation, 37% of patients with coronavirus disease 2019 compared with 8% of patients with influenza had filling defects on CT pulmonary angiography (p = 0.0001). Catheter-associated deep vein thrombosis shown on ultrasound Doppler after decannulation was present in 53% with coronavirus disease 2019 versus 25% with influenza (p = 0.01). The rates of intracranial hemorrhage at the time of cannulation were 16% with coronavirus disease 2019 and 14% with influenza (p = 0.8). Elevated d-dimer levels were seen in both conditions and were significantly higher in those with pulmonary thromboembolism than those without in coronavirus disease 2019 (p = 0.02). Fibrinogen and C-reactive protein levels were significantly higher in those with coronavirus disease 2019 than influenza (p < 0.01). CONCLUSIONS: Significant rates of pulmonary thromboembolism and of catheter-associated deep vein thrombosis were seen in both viral infections but were greater in those requiring the use of extracorporeal membrane oxygenation in coronavirus disease 2019 than for influenza.

Degradation of the Endothelial Glycocalyx Contributes to Metabolic Acidosis in Children Following Cardiopulmonary Bypass Surgery.

OBJECTIVES: Cardiopulmonary bypass surgery is complicated by metabolic acidosis, microvascular dysfunction, and capillary leak. The glycocalyx-a layer of proteins and sugars lining the vascular endothelium-is degraded during cardiopulmonary bypass. We aimed to describe the kinetics of glycocalyx degradation during and following cardiopulmonary bypass. We hypothesized that cleavage of negatively charged fragments of the glycocalyx would directly induce metabolic acidosis through changes in the strong ion gap (defined using Stewart's physicochemical approach to acid-base chemistry). We also investigated whether glycocalyx degradation was associated with failure of endothelial function and cardiovascular dysfunction. DESIGN: Single-center prospective cohort study. SETTING: Twenty-two bed surgical/medical PICU. PATIENTS: Twenty-seven term infants and children requiring cardiopulmonary bypass surgery for the correction/palliation of congenital heart disease. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We recruited 27 patients, 5 days to 57 months old. We prospectively sampled plasma prior to, during, and following cardiopulmonary bypass at predefined time points. We measured plasma concentrations of interleukin-6 (inflammatory marker), heparan sulfate (negatively charged glycocalyx glycosaminoglycan), and syndecan-1 (neutrally charged glycocalyx protein). We defined the following outcome measures: metabolic acidosis (strong ion gap), renal dysfunction (fold change in creatinine), capillary leak (fluid bolus volume), cardiovascular dysfunction (Vasoactive Inotropic Score), and length of ventilation. In linear regression models, maximum measured heparan sulfate concentration (negatively charged) was associated with metabolic acidosis (p = 0.016), renal dysfunction (p = 0.009), and length of ventilation (p = 0.047). In contrast, maximum measured syndecan-1 concentration (neutrally charged) was not associated with these clinical endpoints (p > 0.30 for all). CONCLUSIONS: Our data show that metabolic acidosis (increased strong ion gap) is associated with plasma concentration of heparan sulfate, a negatively charged glycosaminoglycan cleaved from the endothelial glycocalyx during cardiopulmonary bypass. In addition, cleavage of heparan sulfate was associated with renal dysfunction, capillary leak, and global markers of cardiovascular dysfunction. These data highlight the importance of designing translational therapies to protect the glycocalyx in cardiopulmonary bypass.

Personal tales of venous thromboembolism in the UK the last 60 years: from no interest to clinical excellence.

Sixty years ago there was little interest in venous thromboembolism (VTE) in global medical circles, and the British were no different in this respect. And yet, from nowhere the clinical field has developed: now prevention and management of VTE accounts for a large part of many consultant haematologists' working life, while some nursing staff and pharmacists spend the majority of their clinical time in this area. Indeed the 'Brits' have developed enormous VTE expertise and arguably lead the world in prevention of 60% of all VTE, which is hospital-associated venous thromboembolism (HAT).

Managing venous thromboembolic risk in women undergoing spontaneous or induced early pregnancy loss: a consensus statement from the British Society of Haematology Obstetric Haematology Special Interest Group.

The level of venous thrombosis risk in women who experience spontaneous or induced pregnancy loss has previously been uncertain. However, recent data indicate that the risk of venous thrombosis in women undergoing pregnancy termination in the first trimester is increased two-fold compared to non-pregnant women but reduced five-fold compared to women in the 6 weeks following a term birth. The termination procedure itself appears not to influence thrombosis risk. In light of this data, this consensus statement provides recommendations for reducing the risk of venous thrombosis in women undergoing spontaneous or induced pregnancy loss based on Royal College of Obstetricians and Gynaecologists risk stratification guidelines.