Units Of Packed Red Blood Cells Research Articles

Developing a veno-venous extracorporeal membrane oxygenation program during the COVID-19 pandemic: don’t forget to notify the blood bank

ObjectivesDuring the SARS-CoV-2 pandemic, there has been significant increased use of vvECMO as rescue therapy. Patients with COVID-19 as anticoagulation is needed for vvECMO support, may develop bleeding complications requiring an increased number of RBC transfusions. We would like to report the RBC transfusion needs following the implementation of an ECMO program. Data on blood usage in this population is important in view of the decline in donations due to the pandemic.Study Design and Methods: We analyzed data on RBC transfusions in patients who required vvECMO for COVID-19 related ARDS in a Belgian ICU from March 2020 to March 2022. The primary end point was RBC transfusion requirements. and the relationship to outcome. We also analyzed the evolution of this requirement during the four waves. ResultsWe admitted 538 patients for hypoxemic ARDS due to COVID-19. Sixty patients (11%) required vvECMO, of whom 27 (45%) died. Forty-seven (78 %) of the vvECMO patients were transfused a total of 403 packed RBC units.. Sites of hemorrhagic complications were ECMO cannulation sites and lungs. RBC transfusion per patient per day on vvECMO was 0.50 [0.30-0.67] units. There were no differences in hemorrhagic complications in vvECMO survivors and non-survivors.The percentage of vvECMO patients receiving a RBC transfusion increased slightly during the last COVID-19 wave, with 92 % of patients transfused. ConclusionsvvECMO program is associated with a major need for RBC transfusions. These data are important when blood availability is decreased due to a pandemic and illustrates the need for studies on optimizing blood management including therapeutic anticoagulation target, threshold for RBC transfusion or alternatives to RBC transfusion.

Effectiveness of the Intrauterine Balloon Tamponade Compared With an Intrauterine, Vacuum-Induced, Hemorrhage-Control Device for Postpartum Hemorrhage

OBJECTIVE: To compare intrauterine balloon tamponade and vacuum-induced hemorrhage-control devices in a multicenter hospital system using a standardized three-stage postpartum hemorrhage response algorithm. METHODS: As part of a quality improvement project, data were prospectively collected through ongoing detailed hemorrhage case audits from 65 facilities from August 2022 to February 2024. Postpartum hemorrhage-control devices are recommended for stage 2 or 3 of the postpartum hemorrhage algorithm. The primary outcomes were 1) quantitative blood loss after device placement, 2) rate of packed red blood cell (RBC) transfusion, 3) use of 3 units of packed RBCs or more, and 4) device failure. RESULTS: During the 17-month observation period, there were 123,292 deliveries, and postpartum hemorrhage occurred in 5,931 (4.8%). Postpartum hemorrhage-control devices were used in 11.2% of cases (666 total, intrauterine balloon tamponade n=300, and vacuum-induced hemorrhage control n=366). For intrauterine balloon tamponade and vacuum-induced hemorrhage-control devices, quantitative blood loss (median and interquartile range) after device placement was similar at 194 (67–440) mL and 240 (113–528) mL (P=.40), respectively, as was the rate of any packed RBC transfusion (59.7% vs 50.0%, P=.08), transfusion of 3 packed RBC units or more (27.0% vs 24.9%, P=.53), and device failure (7.7% vs 8.5%, P=.70). Placement of either device at a quantitative blood loss between 1,000 and 1,499 mL compared with 1,500 mL or more resulted in significantly lower rates of packed RBC transfusion (39.1% vs 70.3%, P<.001), transfusion of 3 or more packed RBC units (13.7 vs 38.1%, P<.001), and device failure (3.4% vs 12.9%, P<.001). CONCLUSION: Transfusion and blood loss after device placement were similar with both hemorrhage-control devices. Earlier hemorrhage-control device placement reduced device failure and the need for transfusion.

Assessment of amino acids and metabolites in the supernatant of stored concentrates blood from sickle cell trait (SCT) and reference (non-SCT) donors.

Sickle cell trait (SCT) persons are significant donors, and discarding these blood units reduces their supplies, mainly in the third-world countries. This work focused on 12 metabolites associated with the red blood cell (RBC) storage lesion and 23 amino acids in the supernatants of packed RBC units from SCT and reference (non-SCT) donors stored in the same conditions. All samples of RBC concentrates were collected and separated from the storage of Colsan (Beneficient Association of Blood Collection), where they were routinely processed and separated as packed RBC units and stored in the refrigerator (2°-6°C). The supernatant samples of each packed RBC bag were separated by centrifugation at days 1, 7, 14, 21, 28 and 35 of storage and kept at -80°C till the metabolite analysis together. The quantitation of metabolites and amino acids examined in the supernatant of SCT and reference donors showed no statistical differences along the cold storage. Lactic acid and malic acid releases occur in three phases during RBC storage. Basic and acid amino acids and corresponding amides have low and stable values during the first 14 days of storage, followed by a steep increase. Our metabolomic results give elements that seem not to contraindicate the transfusion of RBC with SCT, besides its more structural fragility.

The effect of tranexamic acid on blood transfusion in lower gastrointestinal bleeding-A double blind prospective randomised controlled trial.

Acute gastrointestinal bleeding is a common emergency. Tranexamic acid (TXA) reduces clot breakdown by inhibiting the action of plasmin and has been shown to reduce the need for blood transfusion in trauma, surgical procedures, and upper gastrointestinal bleeding. This study examined the efficiency of intravenous TXA in patients with acute lower gastrointestinal bleeding. Eighty-one patients aged >18years with lower GI hemorrhage, presenting as active rectal bleeding and anemia (hemoglobin lower than 11g/dL or a decrease of 2 gr/dl from the patient's base level), were enrolled in this single center, double blind prospective research. Patients were randomly assigned to receive intravenous TXA or placebo from admission until colonoscopy took place. The need for transfusion of packed red blood cells (PRBC) and number of units was recorded and compared between the two groups. Eighty-one patients were randomized in this study, thirty-nine in the TXA arm, and forty-two in the placebo arm. Patient characteristics did not differ between the groups. Forty-three out of the 81 patients received blood transfusion; twenty-two were on the placebo arm and twenty-one on the TXA arm (p=0.89). Twenty-nine patients required 2 or more units, 14 in the TXA arm and 15 in the placebo arm (p=0.98). Intravenous TXA has no significant effect on blood requirement in patients with lower GI bleeding. There was no difference in the consumption of PRBC units among the patients in the placebo and TXA groups. It seems that tranexamic acid has no significant effect on transfusion of PRBC units in lower GI bleeding.

Extravasated Pudendal Artery Pseudoaneurysm Presenting as a Large Vaginal Hematoma Following Uncomplicated Delivery

Body of Abstract: (1) To report a case of an extravasated pudendal pseudoaneurysm presenting as vaginal hematoma following an uncomplicated delivery. (2) To discuss alternatives of management of vulvar hematomas. Introduction: Postpartum hemorrhage is a leading cause of maternal mortality and can infrequently (1/300-1/1500 deliveries) be caused by vulvar hematomas. Vulvar hematomas are typically small and resolve with conservative treatment. Rarely, they can develop rapidly, posing a significant risk to the patient. Risks for vulvar hematomas include a prolonged second stage of labor, multiple gestation, operative vaginal delivery, episiotomy, and vaginal laceration. Extravasation from a pseudoaneurysm in the pelvic arteries is a rare cause of vulvar hematomas (< 5% of cases) with >75% involving the uterine artery. Pseudoaneurysms typically result from damage to vasculature during a traumatic delivery. Spread into the retroperitoneal space can lead to shock and eventual demise if improperly managed. This case illustrates the exceptionally rare occurrence of a pudendal artery pseudoaneurysm with rapidly expanding potentially catastrophic hematoma formation. Case Summary: Presented is a 21-year-old G2P1011 patient at 39w5d with a large vaginal hematoma diagnosed shortly following spontaneous vaginal delivery. The case initially presented to the hospital one hour after spontaneous rupture of membranes with an unremarkable pregnancy. Normal labor ensued and stage II of labor lasted one hour with an uncomplicated nonoperative vaginal delivery. Postpartum a significant increase in fundal height was noted. Cytotec was given and bladder catheterization removed 800 ml urine. Abdominal pain increased. Vital signs were normal. Exam revealed a large posterior vaginal wall swelling extending upward, but without active bleeding. A computerized tomography (CT) scan of the abdomen/pelvis revealed a 9.7 X 10.5 X 13.2 cm pelvic hematoma arising from the posterior vaginal wall with extension cephalad into the perirectal space and right adnexa. Evidence of active bleeding and bilateral hydronephrosis were reported. Hemoglobin was 10.1, down from admission 12.5. Symptoms included worsening abdominal pain and dizziness. Based on the active bleeding noted on CT scan and the progressive symptoms, the patient was transferred to a tertiary care center. Upon tertiary center admission the patient was tachycardic and hypotensive (P 153 and BP 101/61). Hemoglobin was 9.3. Physical exam was unchanged. Interventional radiology recommended and patient underwent embolization of bilateral uterine arteries for treatment of a diagnosed pseudoaneurysm with extravasation of the right pudendal artery. Postpartum day 1, mild right lower quadrant pain was felt to be consistent with the embolization. Hemoglobin decreased to 6.5, and the patient received one unit of packed red blood cells (PRBCs). Clinically, ambulation was tolerated, but tachycardia and hypotension remained and there was decreased swelling. Hemoglobin remained low at 6.8, and another unit of PRBCs was given. Hospital course thereafter was uneventful and discharge was on day 3. Discussion: This case describes a vaginal hematoma and pudendal artery pseudoaneurysm as a very rare but potentially life-threatening postpartum hemorrhage following vaginal delivery. Association with an uncomplicated pregnancy and delivery, involvement of the pudendal artery with an expanding large hematoma dissecting the retroperitoneal space creating a hemodynamically unstable situation are only rarely seen concurrently. Hematoma treatment starts conservatively, utilizing ice, rest, and pain control if patient is hemodynamically stable and the hematoma is small. When large, rapidly expanding, or the patient is hemodynamically unstable, surgical intervention or artery embolization should be considered when imaging identifies the source of bleeding. Imaging may include ultrasound, CT, CT angiography, and magnetic resonance imaging as options for localization of hematoma. No superior mode of evaluation is identified. Pseudoaneurysms following delivery have most commonly been described in the uterine arteries with only a handful of case reports documenting other sources including the obturator, labial, vaginal, and internal pudendal arteries. Our case demonstrates that extravasated pelvic artery pseudoaneurysms can present in benign appearing nonoperative deliveries and should be considered in the differential diagnosis as a source of post-partum hemorrhage. Recently, pseudo-aneurysms have more commonly been treated with IR artery embolization as it is a less invasive and better tolerated procedure by patients. Tsumagari et al suggested an algorithm proposing vulvovaginal hematomas should be observed versus surgically evacuated, whereas upper vaginal hematomas should undergo CT angiography for assessment for selective arterial embolization. Conclusion: Pseudoaneurysms of the pudendal artery with hematoma formation occurring in an uncomplicated delivery are an extremely rare cause of potentially life-threatening hemorrhage as reported in only a handful of cases. Because of their potential for catastrophic sequelae, they should be considered in the differential diagnosis of expanding upper vaginal hematomas. This case depicts the importance and success of rapid identification and embolization of pudendal artery pseudoaneurysm to prevent mortality.

Procoagulant activity of red blood cell microparticles in stored packed red blood cell units and its relation to ABO blood grouping

BackgroundThroughout the storage of blood, the red cells undergo alterations known as “storage lesions,” which involve shape changes and the formation of microparticles (MPs). Studies of the formation of red cell microparticles (RMPs) emphasize the prospective application of RMPs as a quality control measure in the preparation and storage of blood components in the future. In the present study, twenty packed RBC units in citrate phosphate dextrose adenine-1 (CPDA1) were collected from volunteers and stored for 35 days. Over 35 days of storage, samples were collected at six distinct time points weekly and evaluated for the presence of RMPs. MPs were separated by the ultracentrifugation method. Electron microscopy was used to characterize the morphology and size of the isolated microparticles, and flow cytometry was performed to determine the percentage of RMPs that expressed glycophorin A (CD235a) and Annexin V antigens. RMPs' procoagulant activity (PCA) was assessed using a plasma recalcification test. RMP concentration in accordance with ABO blood grouping was assessed by using various types of donated blood groups.ResultsRMPs progressively increased over storage. The procoagulant activity (PCA) exhibited a significant increase during storage, as evidenced by a shorter plasma recalcification time (P value = 0.001). A significant negative correlation (P value = 0.001) between plasma recalcification time and Annexin V-positive microparticles, as well as a dual-positive Annexin V/CD235a population, was identified, indicating a strong correlation between the direct quantitative assay by flowcytometry and the functional assay through the PCA.ConclusionRMPs increase on storage with increased PCA. Finding ways to reduce these microparticles in packed RBC units is crucial for reducing the risk of transfusion-related coagulopathy.

Donor/recipient Rh-mismatched allogeneic hematopoietic stem cell transplantation: transfusion strategy and allo-immunization to red blood cell antigens.

In the case of donor/recipient rhesus (Rh)-incompatibility after allogeneic hematopoietic stem cell transplantation (alloHSCT), the transfusion policy in France is to transfuse red blood cells (RBC) in the donor's Rh phenotype from the day of transplantation, leading to a risk of allo-immunization, either of donor or recipient origin. In this single-center retrospective study, the incidence of donor/recipient Rh incompatibility was 7.1% over an 8-year period including 1012 alloHSCT. Six of 58 evaluable patients (10.3%) developed alloantibodies to RBC antigens within one year of alloHSCT. None of these allo-immunizations were directed against the donor-mismatched Rh antigens and none could have been prevented by the transfusion of recipient and donor Rh-compatible RBC units. None of these allo-immunizations led to immune-mediated hemolytic anemia. We observed a statistically significant higher incidence of chronic GVHD among patients with anti-RBC allo-immunization. In the context of donor/recipient Rh incompatibility, the transfusion of packed RBC units in the donor's Rh phenotype from the day of alloHSCT is feasible and not associated with a high risk of allo-immunization. The generalization of this strategy could be discussed even when donor and recipient Rh phenotypes could be respected, to allow the preservation of units of infrequent phenotypes for other indications.

PREBOA vs ER-REBOA impact on blood utilization and resuscitation requirements: A pilot analysis.

Partial occlusion of the aorta is a resuscitation technique designed to maximize proximal perfusion while allowing a graduated amount of distal flow to reduce the ischemic sequelae associated with complete aortic occlusion. The pREBOA catheter affords the ability to titrate perfusion as hemodynamics allows, however, the impact of this new technology for REBOA on blood use and other resuscitative requirements is currently unknown. We hypothesize pREBOA's ability to provide partial occlusion, when appropriate, decreases overall resuscitative requirements when compared to ER-REBOA. The entire AAST AORTA Registry was used to compare resuscitation requirements between all ER-REBOA and pREBOA. Unpaired t-tests were used to compare resuscitation strategies including packed red blood cells (PRBCs), fresh frozen plasma (FFP), platelets, cryoprecipitate, crystalloids, and need for pressors. When comparing ER-REBOA (n=800) use to pREBOA (n=155), initial patient presentations were similar except for age (44 vs 40 p=0.026) and rates of blunt injury (78.4% vs 78.7% p<0.010). Zone-1 occlusion was used less often in ER-REBOA (65.8 vs 71.7 p=0.046). Partial occlusion was performed in 85% of pREBOA compared to 11% in ER-REBOA (p<0.050). Vitals at the time of REBOA were worse in ER-REBOA, and received significantly more units of PRBCs, FFP, platelets, and liters of crystalloids than pREBOA (p<0.05). Rates of ARDS and septic shock were lower in pREBOA (p<0.05). When comparing pREBOA to ER-REBOA, there has been a rise in Zone-1 and partial occlusion. In our pilot analysis of the AORTA Registry, there was a reduction in administration of pRBC, FFP, platelets, and crystalloids. Though further prospective studies are required, this is the first to demonstrate an association between pREBOA, partial occlusion, and reduced blood use and resuscitative requirements.

Is there a need for fresh frozen plasma and platelet transfusion in trauma patients receiving submassive transfusion?

BackgroundBlood transfusions have become a vital intervention in trauma care. There are limited data on the safety and effectiveness of submassive transfusion (SMT), that is defined as receiving less than...

Effect of leukoreduction on the omics phenotypes of canine packed red blood cells during refrigerated storage.

Red blood cell (RBC) storage promotes biochemical and morphological alterations, collectively referred to as storage lesions (SLs). Studies in humans have identified leukoreduction (LR) as a critical processing step that mitigates SLs. To date no study has evaluated the impact of LR on metabolic SLs in canine blood units using omics technologies. Compare the lipid and metabolic profiles of canine packed RBC (pRBC) units as a function of LR in fresh and stored refrigerated (up to 42 days) units. Packed RBC units were obtained from 8 donor dogs enrolled at 2 different Italian veterinary blood banks. Observational study. A volume of 450 mL of whole blood was collected using Citrate-Phosphate-Dextrose-Saline-Adenine-Glucose-Mannitol (CPD-SAGM) transfusion bags with a LR filter to produce 2 pRBC units for each donor, without (nLR-pRBC) and with (LR-pRBC) LR. Units were stored in the blood bank at 4 ± 2°C. Sterile weekly samples were obtained from each unit for omics analyses. A significant effect of LR on fresh and stored RBC metabolic phenotypes was observed. The nLR-pRBC were characterized by higher concentrations of free short and medium-chain fatty acids, carboxylic acids (pyruvate, lactate), and amino acids (arginine, cystine). The LR-pRBC had higher concentrations of glycolytic metabolites, high energy phosphate compounds (adenosine triphosphate [ATP]), and antioxidant metabolites (pentose phosphate, total glutathione). Leukoreduction decreases the metabolic SLs of canine pRBC by preserving energy metabolism and preventing oxidative lesions.

Genetic regulation of carnitine metabolism controls lipid damage repair and aging RBC hemolysis in vivo and in vitro

AbstractRecent large-scale multiomics studies suggest that genetic factors influence the chemical individuality of donated blood. To examine this concept, we performed metabolomics analyses of 643 blood units from volunteers who donated units of packed red blood cells (RBCs) on 2 separate occasions. These analyses identified carnitine metabolism as the most reproducible pathway across multiple donations from the same donor. We also measured l-carnitine and acyl-carnitines in 13 091 packed RBC units from donors in the Recipient Epidemiology and Donor Evaluation study. Genome-wide association studies against 879 000 polymorphisms identified critical genetic factors contributing to interdonor heterogeneity in end-of-storage carnitine levels, including common nonsynonymous polymorphisms in genes encoding carnitine transporters (SLC22A16, SLC22A5, and SLC16A9); carnitine synthesis (FLVCR1 and MTDH) and metabolism (CPT1A, CPT2, CRAT, and ACSS2), and carnitine-dependent repair of lipids oxidized by ALOX5. Significant associations between genetic polymorphisms on SLC22 transporters and carnitine pools in stored RBCs were validated in 525 Diversity Outbred mice. Donors carrying 2 alleles of the rs12210538 SLC22A16 single-nucleotide polymorphism exhibited the lowest l-carnitine levels, significant elevations of in vitro hemolysis, and the highest degree of vesiculation, accompanied by increases in lipid peroxidation markers. Separation of RBCs by age, via in vivo biotinylation in mice, and Percoll density gradients of human RBCs, showed age-dependent depletions of l-carnitine and acyl-carnitine pools, accompanied by progressive failure of the reacylation process after chemically induced membrane lipid damage. Supplementation of stored murine RBCs with l-carnitine boosted posttransfusion recovery, suggesting this could represent a viable strategy to improve RBC storage quality.

The effect of transfusion on survival in head and neck cancer after free tissue reconstruction.

To examine if perioperative blood transfusion affects overall survival (OS) and recurrence-free survival (RFS) in head and neck cancer patients who undergo free tissue reconstruction. Retrospective cohort study. The medical records of free tissue flaps between 2007 and 2010 were reviewed. Differences in demographics and clinical factors based on the level of transfused packed red blood cells (PRBC) were examined using chi-squared tests, Kruskal-Wallis tests, and/or ANOVA tests. Survival time was compared using a Cox proportional hazard model. Data were available for 183 patients. Patients who had PRBC transfusion significantly differed from the non-transfused group by flap type, flap with bone, Charlson Comorbidity Index (CCI), and hemoglobin and hematocrit. When stratified into three groups based on units of PRBC; flap type, flap with bone, CCI, preoperative hemoglobin, and hematocrit were found to differ significantly. The 2-year Kaplan-Meier plot demonstrated improved OS for those who did not receive any PRBC transfusion. The use of more than 3 units of blood decreased 2-year OS significantly when compared to the non-transfused group. Finally, after adjusting for CCI using a Cox proportional hazard model, survival was significantly affected by CCI. After controlling for patient age, oncologic stage, cancer subsite, histology, type of free flap, vascularized bone-containing flap, recurrence type, CCI, and preoperative hemoglobin and hematocrit, patients who received 3 or more units of PRBC in the perioperative period had significantly decreased OS. RFS did not differ between the transfused versus non-transfused groups. Level 4.

Transfusion practice in Central Norway – a regional cohort study in patients suffering from major haemorrhage

BackgroundIn patients with major hemorrhage, balanced transfusions and limited crystalloid use is recommended in both civilian and military guidelines. This transfusion strategy is often applied in the non-trauma patient despite lack of supporting data. The aim of this study was to describe the current transfusion practice in patients with major hemorrhage of both traumatic and non-traumatic etiology in Central Norway, and discuss if transfusions are in accordance with appropriate massive transfusion protocols.MethodsIn this retrospective observational cohort study, data from four hospitals in Central Norway was collected from 01.01.2017 to 31.12.2018. All adults (≥18 years) receiving massive transfusion (MT) and alive on admission were included. MT was defined as transfusion of ≥10 units of packed red blood cells (PRBC) within 24 hours, or ≥ 5 units of PRBC during the first 3 hours after admission to hospital. Clinical data was collected from the hospital blood bank registry (ProSang) and electronic patient charts (CareSuite PICIS). Patients undergoing cardiothoracic surgery or extracorporeal membrane oxygenation treatment were excluded.ResultsA total of 174 patients were included in the study, of which 85.1% were non-trauma patients. Seventy-six per cent of all patients received plasma:PRBC in a ratio ≥ 1:2 (high ratio) and 59.2% of patients received platelets:PRBC in a ratio ≥ 1:2 (high ratio). 32.2% received a plasma:PRBC-ratio ≥ 1:1, and 23.6% platelet:PRBC-ratio ≥ 1:1. Median fluid infusion of crystalloids in all patients was 5750 mL. Thirty-seven per cent of all patients received tranexamic acid, 53.4% received calcium and fibrinogen concentrate was administered in 9.2%.ConclusionsMost patients had a non-traumatic etiology. The majority was transfused with high ratios of plasma:PRBC and platelet:PRBC, but not in accordance with the aim of the local protocol (1:1:1). Crystalloids were administered liberally for both trauma and non-trauma patients. There was a lower use of hemostatic adjuvants than recommended in the local transfusion protocol. Awareness to local protocol should be increased.

Placenta Accreta Spectrum Disorders - The Impact of the Creation of a Multidisciplinary Team on Maternal Outcomes in Portugal.

To describe a cohort of placenta accreta spectrum (PAS) cases from a tertiary care institution and compare the maternal outcomes before and after the creation of a multidisciplinary team (MDT). Retrospective study using hospital databases. Identification of PAS cases with pathological confirmation between 2010 and 2021. Division in two groups: standard care (SC) group - 2010-2014; and MDT group - 2015-2021. Descriptive analysis of their characteristics and maternal outcomes. During the study period, there were 53 cases of PAS (24 - SC group; 29 - MDT group). Standard care group: 1 placenta increta and 3 percreta; 12.5% (3/24) had antenatal suspicion; 4 cases had a peripartum hysterectomy - one planned due to antenatal suspicion of PAS; 3 due to postpartum hemorrhage. Mean estimated blood loss (EBL) was 2,469 mL; transfusion of packed red blood cells (PRBC) in 25% (6/24) - median 7.5 units. Multidisciplinary team group: 4 cases of placenta increta and 3 percreta. The rate of antenatal suspicion was 24.1% (7/29); 9 hysterectomies were performed, 7 planned due to antenatal suspicion of PAS, 1 after intrapartum diagnosis of PAS and 1 after uterine rupture following a second trimester termination of pregnancy. The mean EBL was 1,250 mL, with transfusion of PRBC in 37.9% (11/29) - median 2 units. After the creation of the MDT, there was a reduction in the mean EBL and in the median number of PRBC units transfused, despite the higher number of invasive PAS disorders.

A Phase II Study to Evaluate the Safety and Efficacy of Defibrotide and Changes in Plasma Biomarkers in Sickle Cell Disease-Related Acute Chest Syndrome (IND 127812)

Background: Acute Chest Syndrome (ACS) is the greatest contributor to the morbidity and mortality of Sickle Cell Disease (SCD) patients with a rate of 12.8 cases per 100 patient-years. The mortality rates of ACS are 4 times higher in adults than in children (Vichinsky et al, Blood, 1997). The root cause of ACS in SCD is related to endothelial dysfunction (Paul et al, European Journal of Hematology 2011). While existing therapies target infection, inflammation, and alveolar hypoxia, they do not address endothelial dysfunction, a major contributor to SCD associated ACS. Defibrotide is a polydisperse mixture of predominantly single stranded oligonucleotides derived from porcine intestinal mucosa. Several pre-clinical studies indicate that defibrotide primarily protects endothelium, particularly in small vessels, and reduces endothelial cell injury (Falanga et al, Leukemia, 2003) (Cairo/Cooke et al, British Journal of Haematology 2020). In a randomized phase III study, a decrease in incidence of SOS/VOD was observed in pediatric hematopoietic stem cell transplantation patients who received prophylactic defibrotide (Corbacioglu et al, Lancet, 2012). We hypothesized that Defibrotide would be safe and well tolerated in children and adolescents with SCD-associated ACS. Primary Aims: To determine the safety and efficacy of defibrotide in the treatment of patients with SCD-associated ACS. Design/Methods: Patients with SCD- (Homozygous Hemoglobin S disease, Hemoglobin SC Disease or Hemoglobin Sβ 0/+ Thalassemia) associated ACS 2 to 40 years of age were enrolled. Defibrotide, generously supplied by Jazz Pharmaceuticals, was administered at 6.25 mg/kg IV Q6H (total daily dose 25 mg/kg/day) within 24 hours of consent and continued for 7 days or until the patient was discharged from hospital (IND 127812) (NCT 03805581). All patients were treated with current standard of care, including antibiotics, analgesics, oxygen, intravenous fluids, and packed red blood cells (PRBC)/exchange transfusion. Complete blood counts and coagulation studies were performed at baseline, day 7 and day 30, while chest radiograph (CXR), CT chest angiogram (CTA), pulmonary function test, and transthoracic echocardiogram were performed at baseline and 30 days after defibrotide was first given. Blood plasma was collected from patients at baseline, day 7, day 30, and age matched SCD patients without ACS and analyzed for biomarkers of inflammation through ELISA and Luminex multiplex assays and significance was calculated using two-tailed T tests. Results: We have enrolled 20 patients (median age 9.5 years) with a gender ratio of M/F 8/12. Patients had hemoglobin SS (n=14), hemoglobin Sβ 0/+ (n=2), or hemoglobin SC (n=4). The median doses of defibrotide per patient was 18.5 (range 6-28) and the average hospital admission length was 6.1 days (range 3-13 days). There were no serious adverse events possibly, probably, or directly related to defibrotide, as judged by investigators. Two patients had a grade I/II epistaxis that did not disrupt defibrotide's course. Pulmonary infiltrate on CXR and/or CTA was the most common finding at diagnosis, detected in 18/20 study participants. Thirteen patients had fever as a presenting symptom, with an average fever duration of 2.8 days (range 1-6 days). Nine patients required O 2 supplementation, with an average duration of 4.1 days (range 2-7 days). Thirteen patients were treated with blood transfusions with a median of 1.9 units (PRBC unit was defined as 15ml/kg) transfused per patient (range, 1-5 units) and 1 patient underwent an exchange transfusion (Table 1). Soluble Intercellular Adhesion Molecule-1 (sICAM-1) was significantly elevated at the onset of ACS (p &amp;lt; 0.01) compared to control SCD plasma and was reduced by Day 30 after defibrotide treatment. Other markers of inflammation, including Angiopoetin-2 (Ang2), Interleukin-6 (IL-6), and Phospholipase A2-IIA (PLA2G2A) were elevated at baseline in patient plasma samples but were significantly decreased following defibrotide treatment (p &amp;lt; 0.05, 0.01, 0.01, respectively) (Figure 1). Conclusion: Our data suggests that defibrotide is safe and well tolerated in SCD patients with ACS. sICAM-1, Ang2, IL-6, and PLA2G2A may serve as important biomarkers in SCD associated ACS. A randomized phase II/III multi-center clinical trial will need to be conducted to further investigate efficacy of defibrotide in patients with SCD-associated ACS.

Red Blood Cell Transfusion Dependence Is Associated with Greater Healthcare Resource Utilization, Higher Medical Cost, and Poorer Prognosis in Patients with Lower-Risk Myelodysplastic Syndromes: A 28-Year Retrospective Observation Study Result

Myelodysplastic syndromes (MDS) encompass a heterogeneous group of myeloid neoplasms characterized by cytopenia due to inefficient hematopoiesis, with a considerable risk of progression to acute myeloid leukemia (AML) or early mortality. In lower-risk MDS (LR-MDS) patients, anemia and its associated complications have been the focus of clinical attention. A significant portion of these patients eventually develop red blood cell transfusion dependence (RBC TD), which has been linked to a poorer prognosis. Given the limited efficacy of available treatments in reducing RBC TD, most patients face increased risks of chronic anemia and various complications. Moreover, RBC TD is known to be associated with reduced overall survival (OS) and leukemia-free survival (LFS). This study aimed to assess the impact of RBC TD on the socioeconomic burden and clinical prognosis of LR-MDS patients, utilizing an electronic medical records (EMR) database spanning nearly 30 years of MDS patient data. This retrospective observational study examined adult MDS patients (≥ 18 years of age) treated at Samsung Medical Center in the Republic of Korea. Eligible patients were diagnosed with MDS between Sep 1, 1994, to Apr 1, 2022 (index period), with the observation period spanning from Sep 1, 1994, to Sep 1, 2022. Baseline assessments included estimation of revised international prognostic scoring system (IPSS-R) scores, categorizing patients with very low, low or intermediate risks as lower-risk MDS (LR-MDS). TD was defined as the occurrence of any 16-week period with RBC transfusion of ≥ 2 units per 8 weeks, without consecutive 56-day period without transfusion. Healthcare resource utilization (HCRU), medical costs, and prognosis indicators including overall survival (OS) and AML-free survival (AFS) were analyzed and compared between patients who experiencing TD and those not (non-TD). Out of 831 MDS patients, 349 (42.0%) were classified as lower-risk at baseline. Among LR-MDS patients, 29.5% (103/349) experienced TD while 23.3% (194/831) experienced TD in the entire study population. The median age at diagnosis of MDS was 63 (ranging from 18 to 89), and 65.3% (543/831) were male. In LR-MDS patients, there were no significant differences in either baseline age (61 vs 63, P=0.16) or gender (71.8% vs 61.0% males, P=0.053) between TD and non-TD groups. However, TD group exhibited significantly higher median erythropoietin (EPO) level than non-TD group (290.5U/L vs. 112U/L, P&amp;lt;0.001) among LR-MDS patients with available baseline serum EPO levels (76 TD and 178 non-TD). Among the 76 TD LR-MDS patients with baseline serum EPO levels, 51 (67.1%) exhibited &amp;gt; 200U/L, which is considered a clinical threshold for erythropoiesis-stimulating agent (ESA) treatment. As shown in Table 1, RBC TD was consistently associated with greater HCRU and higher medical costs, especially in LR-MDS patients. TD LR-MDS patients had higher rates of outpatient department and emergency room visits (15676 vs. 8303 visits and 587 vs. 328 visits per 1000 person-years [PY], respectively), and increased hospitalizations (709 vs. 456 per 1000 PY), with longer hospital stays (13343 vs. 8272 days per 1000 PY). Furthermore, TD LR-MDS patients required over four-times of packed RBC units than non-TD patients (31107 vs. 7073 units per 1000 PY). Consequently, TD LR-MDS patients incurred higher total medical cost than their non-TD counterpart (13.5 million vs. 6.1 million USD per 1000 PY). Median OS (58.4 months vs. 103.1 months) and AFS (52.7 months vs. 102.7 months) were both significantly shorter in the TD group compared to the non-TD group among LR-MDS patients, while the differences in OS and AFS did not reach the level of significance in the entire study population (Table 1 and Figure 1). Notably, median OS after the first documented RBC TD event was 33.8 months (95% confidence interval: 24.7-58.5 months) in LR-MDS patients. The findings of this study indicate that RBC TD can be a strong predictor of increased HCRU and medical costs, as well as decreased OS and AFS over a 20-year period following the initial diagnosis of LR-MDS. Given that a majority of LR-MDS patients experiencing TD may not be eligible for ESA treatment due to elevated EPO levels exceeding 200U/L, and the use of cytotoxic agents is not usually recommended for these patients, these results highlight a substantial unmet need for alternative treatment options to address RBC TD in LR-MDS patients.

Genetic Regulation of Carnitine Metabolism Controls Lipid Damage Repair Mechanisms and Hemolytic Propensity of Human Red Blood Cells during Aging In Vivo and in Vitro

Large scale genomics studies and vein-to-vein databases have started to reveal that donor biology and genetics influence red blood cell (RBC) storability and transfusion outcomes. To further delve into this concept, here we performed metabolomics analyses of 13,091 packed RBC units from donors enrolled in the Recipient Epidemiology and Donor Evaluation (REDS) RBC Omics study. End of storage (day 42) units were tested for metabolomics and hemolytic propensity. Donors ranking in the 5 th and 95 th percentile were contacted again and invited to donate a second unit of blood, which was stored again for 42 days (n=643). Correlation of end of storage metabolomics measurements for the first (index) and second (recalled) donation identified a core of metabolites involved in carnitine synthesis and acyl-carnitine metabolism as the most reproducible within the same donor across multiple donations ( Figure 1.A). Carnitine and its precursors, methyl- and trimethyl-lysine were the most significantly reproducible of all the metabolites tested in this study ( Figure 1.A). Association of L-carnitine measurements to genomics data (i.e., 879,000 single nucleotide polymorphisms that were assayed via a precision transfusion medicine array developed for this study - Figure 1.B) identified non-synonymous coding polymorphisms in the carnitine transporter SLC22A16 as a critical genetic factor contributing to inter-donor heterogeneity in end of storage carnitine levels ( Figure 1.B). Donors carrying two alleles of this SNP were characterized by the lowest L-carnitine levels, and associated depletion of the whole carnitine pool. Functionally, stored RBCs with the lowest levels of carnitine pools were characterized by significant elevation in in vitro hemolysis and the highest degree of vesiculation, in parallel to increases in lipid peroxidation markers (hydroxy-eicosatetraenoic - HETEs and hydroxy-octadecadienoic acids - HODEs). We leveraged a novel CFDA-SE staining protocol, which allows flow cytometry sorting of end of storage RBCs in two highly enriched preparations: a morphologically-altered subpopulation (CFDA-SE high) and a morphologically-normal RBC subpopulation (CFDA-SE low). The morphologically-altered subpopulations contains mostly storage-induced micro-erythrocytes (SMEs), i.e., RBCs with decreased surface/volume ratio upon storage-induced vesiculation. This RBC sub-population has increased susceptibility to extravascular hemolysis via splenic sequestration upon transfusion in vivo. Metabolic characterization of SMEs (i.e., CFDA-SE low) vs morphologically-normal end of storage RBCs (i.e., CFDA-SE low) showed that the former are characterized by a complete depletion of acyl-carnitine pools compared to the latter or to fresh RBCs. We thus propose a model where storage promotes lipid peroxidation, which is in turn counteracted by activation of the Lands cycle, a pathway that relies on acyl-carnitine pools to repair lysophospholipids secondary to oxidation of fatty acids in membrane lipids. To determine the translational relevance of this mechanism to RBCs as they age in the bloodstream in vivo, we separated packed RBCs via Percoll density gradients and determined total carnitine pools in each fraction. Our results indicate that the oldest circulating RBCs are not only the smallest, but are also characterized by the lowest levels of carnitine pools. Incubation of the youngest, oldest and intermediate RBC populations with radio-labeled palmitate showed that incorporation of labeled hexadecenoic acid into phosphatidylethanolamines is constrained by carnitine pools in old and average age RBCs, compared to the youngest population. Altogether, our results suggest an important role for L-carnitine levels during RBC aging in vivo and in vitro. As such, carnitine supplementation may represent a viable strategy to boost RBC storage quality and modulate hemolytic propensity, especially in RBCs from donors harboring genetic polymorphism associated with partial ablation of the carnitine transport system. Figure 1 - Levels of carnitine metabolites are reproducible across multiple donations from the 643 REDS RBC Omics donors across two consecutive donations (index and recalled in A), a phenomenon in part explained by genetic polymorphisms to the carnitine transporter SLC22A16 as gleaned by L-carnitine measurements in end of storage units from 13,091 blood donors ( B).

Association of blood donor characteristics with hemoglobin content in leukoreduced packed red blood cells.

A complex relationship exists between donor characteristics and red blood cell quality which remains partly explored. The present study aimed to determine the correlation of donor characteristics with the hemoglobin (Hb) content of leukoreduced packed red blood cells (PRBC). This prospective cross-sectional study was conducted on 100 blood donors. A pre-donation sample was collected for hemoglobin and hematocrit estimation. Whole blood was collected in quintuple blood bags and packed red cells were prepared. Sample from each packed red cell unit was estimated for hemoglobin and hematocrit. The volume, total Hb, actual total Hb, volume and Hb lost during processing, mathematical total Hb and hematocrit of each PRBC unit was calculated using formulas. The donor characteristics were analysed for correlation with Hb content of PRBC. The mean age of the 100 donors enrolled in the study was 36.3±9.9years. Majority of the donors were vegetarian, non-alcoholic, non-smokers, and had a pre-donation hemoglobin level of more than 14g/dl. The mean pre-donation Hb of the donors was 14.8±1.5g/dl. There was a strong positive correlation of donor pre-donation hemoglobin with total Hb (r=1.000, p=0.000), actual Hb (r=0.518, p=0.000) and mathematical hemoglobin (r=0.951, p=0.000) using the Pearson correlation test. A strong positive correlation was observed between the total and actual hemoglobin (r=0.518, p=0.000) of the units. There was no association of other donor characteristics with Hb content of leukoreduced PRBC. Donor pre-donation hemoglobin showed a strong positive correlation with the actual hemoglobin content of leukoreduced packed red blood cells.

Outcomes of drain versus no drain in total knee arthroplasty: a retrospective cohort study

PurposeThe use of suction drains in total knee arthroplasty (TKA) remains controversial. The aim of this study is to compare the outcomes of patients who received suction drains versus those who did not, focusing on blood loss, blood transfusion need, and length of hospital stay.MethodsA retrospective observational cohort study was conducted at a tertiary hospital between January 1, 2015, and December 30, 2019, and included 262 patients who underwent unilateral non-traumatic primary TKA and were over 18 years old. The Institutional Review Board (IRB) approved the study (MRC-02–20-278).ResultsA total of 262 patients were included, with an age range of 47 to 91 years. Most of the included patients were females, 74.4% (195). Hypertension was the most frequent risk factor, 67.6%, followed by diabetes. Of 262 patients, 156 (59.5%) received a drain. The drain group had significantly longer hospital stay, 30% longer tourniquet time, greater haemoglobin and haematocrit drops, higher count of transfused packed RBC units, and lower use of anticoagulants. Moreover, tranexamic acid (TXA) use (n = 106) in surgery reduced hospital stays, tourniquet time, drain output, and increased pre- and postoperative haemoglobin and hematocrit levels compared to no TXA group (n = 156) (p < 0.05, z-score reported).ConclusionsThis study found that patients who received a drain had longer hospital stays and greater blood loss and transfusion rates compared to those who did not. The use of TXA in surgery was associated with improved outcomes and reduced overall complications.

Red cell extracellular vesicles and coagulation activation pathways.

Packed red blood cells (PRBCs) are the most commonly transfused blood products. Preparation of PRBCs requires blood collection from donors, processing, and storage prior to transfusion to recipients. Stored red blood cells (RBCs) undergo structural and metabolic changes collectively known as the storage lesion. RBC extracellular vesicles (sREVs) are released in PRBC units during storage, and are transfused along with intact RBCs into recipients. For several decades, extracellular vesicles have been the focus of intense research, leading to the discovery of a wide variety of endogenous biological properties that may impact numerous physiologic and/or pathologic pathways. This study reviews the characteristics of extracellular vesicles present in PRBC units and the impact of prestorage and pretransfusion processing, as well as storage conditions, on their generation. Importantly, we discuss recently described interactions of sREVs with coagulation pathways and related interplay with inflammatory pathways in vitro and in vivo using animal models. Extracellular vesicles present in stored PRBC units are capable of activating coagulation pathways. However, it remains unclear whether this affects clinical outcomes in recipients of PRBC units. Further understanding of these pathways and their relationship to any adverse outcomes may yield novel strategies to mitigate complications of blood transfusion.