Recombinant Activated Factor VII Significantly Reduces Transfusion Requirements in Cardiothoracic Surgery

Systemic Arterial and Venous Thrombotic Events Associated With Anti–Vascular Endothelial Growth Factor Injections: A Meta-Analysis

SummaryBackgroundMany international guidelines on the prevention of venous thromboembolism recommend targeting heparin treatment at patients with stroke who have a high risk of venous thrombotic events or a low risk of haemorrhagic events. We sought to identify reliable methods to target anticoagulant treatment and so improve the chance of avoiding death or dependence after stroke.MethodsWe obtained individual patient data from the five largest randomised controlled trials in acute ischaemic stroke that compared heparins (unfractionated heparin, heparinoids, or low-molecular-weight heparin) with aspirin or placebo. We developed and evaluated statistical models for the prediction of thrombotic events (myocardial infarction, stroke, deep vein thrombosis, or pulmonary embolism) and haemorrhagic events (symptomatic intracranial or significant extracranial) in the first 14 days after stroke. We calculated the absolute risk difference for the outcome “dead or dependent” in patients grouped by quartiles of predicted risk of thrombotic and haemorrhagic events with random effect meta-analysis.FindingsPatients with ischaemic stroke who were of advanced age, had increased neurological impairment, or had atrial fibrillation had a high risk of both thrombotic and haemorrhagic events after stroke. Additionally, patients with CT-visible evidence of recent cerebral ischaemia were at increased risk of thrombotic events. In evaluation datasets, the area under a receiver operating curve for prediction models for thrombotic events was 0·63 (95% CI 0·59–0·67) and for haemorrhagic events was 0·60 (0·55–0·64). We found no evidence that the net benefit from heparins increased with either increasing risk of thrombotic events or decreasing risk of haemorrhagic events.InterpretationThere was no evidence that patients with ischaemic stroke who were at higher risk of thrombotic events or lower risk of haemorrhagic events benefited from heparins. We were therefore unable to define a targeted approach to select the patients who would benefit from treatment with early anticoagulant therapy. We recommend that guidelines for routine or selective use of heparin in stroke should be revised.FundingMRC.

Introduction: Aneurysmal subarachnoid hemorrhage (aSAH) carries a high risk of morbidity and mortality. Endovascular coiling is an effective treatment option for ruptured aneurysms and offers certain advantages over microsurgical clipping. Thromboembolism is a known complication of endovascular therapy, but little has been reported regarding its causes. We hypothesized that platelet transfusion (PT) is a risk factor for thrombotic events (TE) during endovascular therapy. Methods: We retrospectively evaluated 84 patients presenting with aSAH to a Comprehensive Stroke Center in the United States between 2011 and 2015 who underwent endovascular treatment. In addition to TE related to endovascular aneurysm repair, charts were reviewed for variables including length of hospitalization, 3-month modified Rankin Scale (mRS), and smoking. Intergroup differences were evaluated with a Chi-squared and Student’s t-test. Logistic regression models were also fitted to the outcome of TE. Results: Patient demographics and clinical variables are seen in Table 1. 23% of patients incurred TE. Platelet transfusion was more common in patients with TE, but this association was not statistically significant in the logistic regression models (Table 2). In the adjusted model, active smoking and procedure length remained significantly associated with TE. Conclusion: To our knowledge, risk factors for thrombotic events in the setting of endovascular cerebral aneurysm treatment have not been previously reported. Procedure length and active smoking are associated with TE, and PT has a trend towards significance. After adjusting for potential confounders, active smoking remains the best predictor of TE (p=0.004), conferring an 11-fold risk.

Red Blood Transfusion Does Not Increase Risk for Venous or Arterial Thrombosis

Haemorrhage and blood product usage are common in venoarterial extracorporeal membrane oxygenation (VA ECMO) and associated with increased mortality. A prospective, investigator-initiated, longitudinal observational cohort study on major haemorrhagic events in 12 ECMO centres from 3 continents for three predefined subgroups (VA ECMO initiated during cardio-pulmonary resuscitation (ECPR), after cardiothoracic surgery (CTS), for cardiogenic shock (CS)). The aim was to describe haemorrhagic complications as well as transfusion practice and anticoagulation for the whole population as well as the subgroups. In addition, independent baseline predictors for red blood cell (RBC) transfusions were evaluated. 545 prospective patients were included between 2019 and 2022 (ECPR 149, CTS 169, CS 227). Hospital mortality was 46%. Over 2796 days 406 major haemorrhage events in 286 (52%) patients were recorded. CTS and ECPR patients had more frequent events occurring earlier in their course. 88% received RBC transfusions (1.27 (95%CI 1.22 – 1.31) units/day) with significantly more transfusions for CTS and ECPR patients. Platelet transfusion rates were highest in the CTS group (0.58 (95%CI 0.53–0.64) units/day). Haemoglobin and platelet count prior to transfusion were independent of subgroups and averaged (78 g/L (IQR 73, 84), 58 × 10^9/L (IQR 37, 85), respectively). However, platelet count prior transfusion was only marginally higher on days with major haemorrhage (74 × 10^9/L (IQR 50, 104). Systemic anticoagulation was started within the first 24 h in 83% (95% CI 80–87%) of patients, most frequently in CS patients (90%, CI 85–95%). Independent baseline predictors for RBC transfusion were ECPR (IRR 1.50, 95%CI 1.19–1.89) and prior use of antiplatelets (IRR: 1.43, 95%CI 1.13–1.80). Myocarditis and pulmonary embolism were associated with a lower rate of transfusion when compared to myocardial infarct (IRR: 0.57 (0.37–0.89), IRR: 0.67 (0.45–1.00, respectively). Haemorrhagic complications differ in clinical subgroups and RBC transfusion exposure is by far higher than in other critically unwell populations. We identified ECPR and antiplatelet therapy as additional predictors. Transfusion practice for RBC and platelets is variable and does not always follow international guidelines.

SummaryBackgroundPatients undergoing major surgery frequently experience major uncontrolled bleeding. The aim of this systematic review and meta‐analysis was to evaluate the clinical efficacy of using viscoelastic haemostatic assays to manage peri‐operative bleeding in elective surgery.MethodsWe searched PubMed/MEDLINE and Embase databases for randomised controlled trials according to pre‐determined criteria. The primary outcomes were blood product requirements; duration of stay in the operating theatre or ICU; and surgical reintervention rate.ResultsWe included 20 randomised controlled trials. The overall risk of bias was low to moderate. Twelve studies used thromboelastography‐based transfusion algorithms, while eight used thromboelastometry. Viscoelastic haemostatic assay‐guided therapy was associated with a statistically significant reduction in transfusion of red blood cells (standardised mean difference (95%CI) 0.16 (‐0.29 to 0.02)), platelets (standardised mean difference (95%CI) ‐0.33 (‐0.56 to ‐0.10)) and fresh frozen plasma (standardised mean difference (95%CI) ‐0.64 (‐1.01 to ‐0.28)). There was no evidence of an effect of viscoelastic haemostatic assay‐guided therapy on surgical reintervention (relative risk (95%CI) 1.09 (0.70–1.69)). Viscoelastic haemostatic assay‐guided therapy was associated with lower blood loss and shorter ICU duration of stay. There was no evidence of any effect on total duration of stay and all‐cause mortality.ConclusionsViscoelastic haemostatic assay‐guided therapy may reduce peri‐operative blood product transfusion requirements and blood loss during major elective surgery, with no discernible effect on patient‐centred outcomes. The overall quality of evidence was modest.

Impact of Iron Supplementation on Patient Outcomes in Women Undergoing Gynecological Procedures: Systematic Review and Meta-Analysis of Randomized Trials

Critically ill, extremely premature infants develop anemia because of intensive laboratory blood testing and undergo multiple red blood cell (RBC) transfusions in the early weeks of life. To date, researchers have had only limited success in finding ways to reduce transfusions significantly in this patient population. To reduce RBC transfusions for these infants by using a point-of-care bedside monitor that returns analyzed blood to the patient. This was a prospective, 2-center, randomized, open, controlled, clinical trial with a 1:1 assignment of extremely low birth weight infants (weighing 500-1000 g at birth) to control or monitor groups and analysis with the intention-to-treat approach. Predefined RBC transfusion criteria were applied uniformly in the 2 groups. Clinical treatment of study subjects with an in-line, ex vivo, bedside monitor that withdraws blood through an umbilical artery catheter, analyzes blood gases and sodium, potassium, and hematocrit levels, and returns the sample to the patient. The total volume and number of RBC transfusions during the first 2 weeks of life and the total volume of blood removed for laboratory testing. The trial was terminated prematurely when one center's NICU changed its standard method of laboratory testing. In the first 2 weeks of life, there was a nonsignificant 17% lower cumulative RBC transfusion volume in the monitor group (n = 46), compared with the control group (n = 47). However, data from the first week only (the period of greater catheter use) demonstrated a significant 33% lower cumulative RBC transfusion volume in the monitor group. Cumulative phlebotomy loss was approximately 25% less in the monitor group throughout the 2-week study period. There was no difference between groups in neonatal mortality, morbidity, and neurodevelopmental outcome rates at 18 to 24 months. This is the first randomized trial documenting that RBC transfusions administered to neonates can by reduced by decreasing laboratory phlebotomy loss. As long as an umbilical artery catheter is available for blood sampling with an in-line blood gas and chemistry monitor, significant reductions in neonatal RBC transfusions can be achieved. The patients most likely to benefit from monitor use are the smallest, most critically ill newborns.

BackgroundThe postpartum state is associated with a substantially increased risk of thrombosis. It is uncertain to what extent this heightened risk persists beyond the conventionally defined 6-week postpartum period.MethodsUsing claims data on all discharges from nonfederal emergency departments and acute care hospitals in California, we identified women who were hospitalized for labor and delivery between January 1, 2005, and June 30, 2010. We used validated diagnosis codes to identify a composite primary outcome of ischemic stroke, acute myocardial infarction, or venous thromboembolism. We then used conditional logistic regression to assess each patient's likelihood of a first thrombotic event during sequential 6-week periods after delivery, as compared with the corresponding 6-week period 1 year later.ResultsAmong the 1,687,930 women with a first recorded delivery, 1015 had a thrombotic event (248 cases of stroke, 47 cases of myocardial infarction, and 720 cases of venous thromboembolism) in the period of 1 year plus up to 24 weeks after delivery. The risk of primary thrombotic events was markedly higher within 6 weeks after delivery than in the same period 1 year later, with 411 events versus 38 events, for an absolute risk difference of 22.1 events (95% confidence interval [CI], 19.6 to 24.6) per 100,000 deliveries and an odds ratio of 10.8 (95% CI, 7.8 to 15.1). There was also a modest but significant increase in risk during the period of 7 to 12 weeks after delivery as compared with the same period 1 year later, with 95 versus 44 events, for an absolute risk difference of 3.0 events (95% CI, 1.6 to 4.5) per 100,000 deliveries and an odds ratio of 2.2 (95% CI, 1.5 to 3.1). Risks of thrombotic events were not significantly increased beyond the first 12 weeks after delivery.ConclusionsAmong patients in our study, an elevated risk of thrombosis persisted until at least 12 weeks after delivery. However, the absolute increase in risk beyond 6 weeks after delivery was low. (Funded by the National Institute of Neurological Disorders and Stroke.)

Clinicians are increasingly confronted with elderly patients across nearly all surgical disciplines. Advanced age is an independent risk factor for complications, prolonged hospitalization, and particularly for red blood cell (RBC) transfusion. The elderly suffer more frequently from anemia, which is associated with higher perioperative transfusion requirements, increased complication rates, and mortality Surgical disciplines differ not only in primary diagnoses but also in the demographics of their typical patient population. Hospitalized surgical patients in Germany between January 1st, 2013, and December 31st 2022, were analyzed. Age ≥65 years, surgical disciplines: General surgery, Gynecology, Cardiac surgery, Thoracic surgery, Oral and Maxillofacial surgery, Neurosurgery, Trauma and Orthopedic surgery, Urology or Vascular surgery. Exclusion criteria included unknown or overlapping surgical procedures. Risk factors, comorbidities, transfusion rates, bleeding, complications, and blood product use were assessed using ICD and OPS (the German national procedure coding system) codes. The primary endpoint was RBC transfusion rate; the secondary endpoint was preoperative transfusion rate. A total of No.=21,143,317 patients were analyzed of which No.=2,640,608 (12%) received RBC transfusion. The highest transfusion rate was seen in Trauma and Orthopedic surgery (17.2% - No.=1,116,082). Trauma and Orthopedic surgery also had the highest risk (Odds Ratio [OR]) for RBC Transfusion (1.36 [1.35-1.36]). The highest preoperative transfusion rate was noted in general surgery, where 48.2% (No.=384,553) of the transfused patients received at least one RBC transfusion prior to surgery. Our study revealed that the highest transfusion rate in elderly patients is in Trauma and Orthopedic surgery, while the highest rate of preoperative transfusion was seen in General surgery. It would seem worthwhile to reduce these rates wherever possible, and these are the disciplines which offer the most room for improvement and would thus benefit most from consistent establishment of PBM programs.

Recombinant activated Factor VII (rFVIIa) is a prohemostatic agent used for treatment of hemophilia patients with inhibiting antibodies. It has also been used in the context of massive uncontrolled blood loss, but the efficacy has not been proven. The aim of this study was to evaluate the effectiveness of rFVIIa in massive uncontrolled blood loss. In this retrospective observational analysis patients were included that had received rFVIIa between April 2004 and January 2008 in the context of bleeding that could not be controlled by conventional transfusion therapy. Data were retrieved from patient files, anesthesia reports, the electronic hospital information system, and the computer files of the hospital blood transfusion service. Baseline demographics, medication data, laboratory data, transfusion data, and surgical data were analyzed. In 32 patients with massive uncontrolled blood loss, a significant reduction in transfusion requirements was observed after infusion of rFVIIa, when comparing the transfusions before and up to 48 hours after infusion of rFVIIa. Mean red blood cell (RBC) transfusions showed a reduction of 20.1 units before rFVIIa to 8.7 after rFVIIa (mean difference, 11.4 units; 95% confidence interval [CI], 6.4-16.5) and fresh-frozen plasma (FFP) transfusions showed a reduction of 19.3 units before rFVIIa to 9.3 after rFVIIa (mean difference, 9.9 units; 95% CI, 4.2-15.6). Fifty-six percent of patients receiving rFVIIa for uncontrolled life-threatening bleeding were alive at discharge from the hospital. This study suggests that rFVIIa may play a role in patients with massive uncontrolled blood loss by reducing the amount of RBC and FFP transfusions and by improving the coagulation variables.

BackgroundCoagulation abnormalities in COVID-19 patients accompanied with poor prognosis. This study aimed to determine the prevalence and risk factors of thrombotic events on COVID-19 patients.Methods.We systematically reviewed all the studies about thrombotic events on COVID-19 patients in PubMed, Embase, Web of Science, MedRxiv, bioRxiv, from Dec 1, 2019 to July 5, 2020. The weighted mean difference (MD) or odds ratio (OR) or relative risk (RR) with 95 % confidence intervals (CI) for clinical data in COVID-19 patients with or without thrombotic events was calculated.Results12 articles contained 1083 patients were included for meta-analysis. The prevalence of thrombosis was 22 % (95 % CI 0.08–0.40) in COVID-19 patients and increased to 43 % (95 % CI 0.29–0.65) after admission to the intensive care unit (ICU). Compared with non-thrombotic patients, thrombotic patients had higher levels of D-dimer (MD = 2.79 μg/ml, 95 % CI 2.27–3.31 μg/ml), lactate dehydrogenase (LDH) (MD = 112.71 U/L, 95 % CI 62.40–163.02 U/L), and white blood cells (WBC) (MD = 1.14 *109/L, 95 % CI 0.47–1.81*109/L) while decreased lymphocytes (MD= -0.20*109/L, 95 % CI -0.38 – -0.02*109/L). Age, platelet counts, and male sex tended to be risks while diabetes tended to be a protection for thrombosis for COVID-19 patients, although no statistical difference was achieved. Finally, patients with thrombosis were at a higher risk of death (OR = 2.39, 95 % CI 1.36–4.20).ConclusionsPrevalence of thrombosis in COVID-19 patients was high, especially in ICU, though pharmacologic thromboembolism prophylaxis was applied. Therefore, higher levels of D-dimer, LDH, WBC, and decreased lymphocytes needed to be paid close attention to in patients with COVID-19.

Acute promyelocytic leukemia (APL) stands out as a distinctive form of acute leukemia, exhibiting a higher occurrence of thrombotic events when contrasted with other leukemia subtypes. Since thrombosis is a relatively rare but unfavorable condition with poor prognostic implications, it is crucial to determine the risk factors for thrombotic events in APL(thrombosis in large venous or arterial from onset to differentiation therapy in 30d). We performed a retrospective study involving 950 APL patients between January 2000 and October 2022, from which 123 were excluded by younger than 16years of age, 95 were excluded by incomplete data, and 6 were excluded by thrombosis related to CVC or PICC. A total of 23 APL patients with thrombosis for inclusion in our analysis were performed a 1:5 ratio matching based on sex (perfect match) and age (within 5years) to patients without thrombosis. These patients were continuously monitored in the outpatient department over a period of 5years. We meticulously examined clinical and laboratory data to pinpoint the risk factors related to thrombotic events in APL. Our primary clinical endpoints were all-cause mortality and achieving complete remission, while secondary clinical outcomes included APL relapse. Thrombotic events were observed in 2.4% (23/950) of APL patients. Compared to patients without thrombosis, patients with thrombosis had higher lactate dehydrogenase (LDH) [313 (223, 486) vs. 233 (188, 367) U/L, p = 0.020], higher indirect bilirubin [11.2 (7.4, 18.6) vs.8.3 (6.0, 10.7) umol/L, p = 0.004], higher creatinine [72 (62, 85) vs. 63 (54, 74) umol/L, p = 0.026], higher CD2 expression (65.2 vs. 15.2%, p < 0.001), higher CD15 expression (60.9 vs. 24.3%, p = 0.001), and PML/RARαisoforms (p < 0.001). Multivariate-logistic-regression analysis revealed several factors that were markedly related to thrombosis, including LDH (OR≈1.003, CIs≈1.000-1.006, p = 0.021), indirect bilirubin (OR≈1.084, CIs≈1.000-1.188, p = 0.043), CD2 expression positive (OR≈16.629, CIs≈4.001-62.832, p < 0.001), and CD15 expression positive (OR≈7.747, CIs≈2.005-29.941, p = 0.003). The S-type (OR≈0.012, CIs≈0.000-0.310, p = 0.008) and L-type (OR≈0.033, CIs≈0.002-0.609, p = 0.022) PML/RARα isoforms were negatively associated with thrombosis. Kaplan-Meier curves indicated that the survival rates were remarkably varied between APL patients with and without thrombosis (HR:21.34, p < 0.001). LDH and indirect bilirubin are variables significantly associated with thrombosis in APL, S-type and L-type PML/RARαisoforms exhibit a negative association with thrombotic events. The thrombotic events of APL can predict the subsequent survival of thrombosis. The findings of our study have the potential to facilitate early detection of thrombosis and enhance the prognosis for individuals with APL who develop thrombosis. Further validation of our findings will be essential through future prospective or multicenter studies.

We aimed to evaluate the usefulness of palliative radiotherapy in reducing the frequency of red blood cell (RBC) transfusions in patients with malignant tumor bleeding as a quantitative value to evaluate the hemostatic effect. In this study, we conducted a retrospective review of patients visiting our department between June 2013 and April 2021. All patients underwent RBC transfusions for 30 days before the initiation of radiotherapy. We determined the overall survival (OS) time and RBC transfusion-free (RBCTF) time using statistical tests. In total, 21 patients were enrolled in our study, including 13 women and 8 men; the median patient age was 63 years (range: 32-82 years). After radiotherapy, 19 of the 21 patients had a decreased frequency of requirement for RBC transfusion compared to that before radiotherapy. Fourteen patients had achieved an RBCTF state 1 month after radiotherapy. The estimated 1-year OS and RBCTF rates were 36.3% (95% confidence interval [CI]: 14.2%) and 66.7% (95% CI: 42.5%-42.5%), respectively. The present study revealed a reduction in RBC transfusion after palliative radiotherapy in patients with malignant tumor bleeding. We believe that reducing the frequency of blood transfusions in patients with terminal conditions would have significant clinical benefits.

Elevated White Blood Cell Levels and Thrombotic Events in Patients with Polycythemia Vera: A Real-World Analysis of Veterans Health Administration Data