Red Blood Cell Transfusion Requirements Research Articles

Red Cell Alloimmunisation Is Associated with Development of Autoantibodies and Increased Red Cell Transfusion Requirements in Myelodysplastic Syndromes (MDS)

Introduction: Up to 90% of MDS patients require red blood cell (RBC) transfusions and 30-45% become RBC transfusion dependent (RBC-TD). However, literature addressing RBC alloimmunisation in MDS is limited. This study evaluates the incidence and clinical impact of RBC alloimmunisation in 817 adult MDS (or related disorders) patients enrolled in the South Australian-MDS registry.Methods: Demographic, clinical, laboratory and treatment (including transfusions) details of patients with at least 6-month follow up were analysed. RBC-TD was defined as >1unit of RBC transfusion every 8 weeks over a period of 4 months. Azacitidine, intensive chemotherapy or allogeneic stem cell transplantation were denoted as disease modifying therapies (DMT).Results: Median age at diagnosis was 73 years and 66% were male. During the study, 695 (85%) patients received >1 RBC unit, and 98 developed 175 alloantibodies. Of these, 11 patients developed alloantibodies following MDS-unrelated RBC transfusion well before the MDS diagnosis, and seven developed antibodies before their first documented RBC transfusion. Remaining 80 patients developed alloantibodies following MDS-related RBC transfusion. The cumulative incidence of RBC alloimmunisation with death as competing risk was 11% at 50 months following the first MDS-related RBC transfusion (Fig. 1A). Importantly, 73% and 50% of allo-immunised patients developed alloantibodies during first 20 RBC transfusions and within 6 months of commencement of RBC transfusion, respectively. Of the 98 allo-immunised patients, 50 (51%) developed one alloantibody, while 48 (49%) developed multiple alloantibodies. Rh (93/175; 54%) and Kell (41; 24%) alloantibodies were most frequent followed by Kidd (13, 7.5%) and Lutheran (10, 5.7%). Within Rh system anti-E, anti-C and anti-D were the most frequent.Autoantibodies were detected in significantly more alloimmunised than in non-alloimmunised patients (65% vs. 18%, p<0.0001; Fig 1B) and >85% autoantibodies occurred within 5 months of alloimmunisation. Though 73% of alloimmunised patients developed alloantibody during their first 20 RBC units, total RBC units transfused were significantly higher in alloimmunised compared to non-alloimmunised patients (90±100 vs. 30±52; p<0.0001) (Fig. 1C). In alloimmunised patients, total RBC transfused after alloimmunisation were significantly higher than before alloimmunisation (p<0.0001, Fig. 1D). In MDS patients, multiple other factors such as disease progression, infection, bleeding and treatment can influence RBC-transfusion intensity. Hence, we evaluated RBC-transfusion intensity in 33 patients meeting strict inclusion criteria (Fig. 2A). In these patients, RBC-transfusion intensity substantially increased after alloimmunisation (p=0.002; Fig. 2B-C).We then evaluated risk factors for alloimmunisation using RSF and R-PART analysis. RBC units transfused before alloantibody formation was the most important predictor of alloimmunisation, followed by RBC-TD status, treatment type and age. A classification tree using RPART suggested that 46% patients who were RBC-TD developed an alloantibody within first 20 units of RBC transfused. Landmark analyses using CRR model both at baseline (using age, sex, WHO subtype, IPSS-R risk groups and type of treatment) and at six months (baseline factors plus number of RBCs transfused within 6 months and RBC-TD status at 6 months) following the start of RBC transfusions were performed. At both time-points, alloimmunisation risk was significantly lower in DMT treated patients (HR -3.04; p=0.0023) and appears unrelated to number of RBC transfusions as patients managed with DMT received significantly more RBC units than patients treated with supportive care (p<0.0001).Conclusion: This study characterises alloimmunisation in a large statewide cohort of MDS patients and demonstrates a significant increase in RBC transfusion requirements following alloimmunisation, most probably due to development of additional alloantibodies and autoantibodies, resulting in subclinical/clinical haemolysis. Use of DMT is associated with lower alloimmunisation risk. Strategies mitigating alloimmunisation risk are critical for optimising RBC-transfusion management. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Effect of Erythropoiesis-Stimulating Agent on the Management of Chemotherapy-Induced Anemia and Tumor Growth in Diffuse Large B-Cell Lymphoma Patients

Bacground : Erythropoiesis stimulating agents (ESA) increase hemoglobin levels, reduce red blood cell (RBC) transfusion requirements and improve the quality of life (QoL) in patients with chemotherapy-associated anemia (CAA). The purpose of this study is to investigate the efficacy and safety of ESA for management of anemia caused by chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL). And this study estimated quality of life as measured by Functional Assessment of Cancer Therapy Scales for anemia (FACT-An) additionally. Until now, several studies suggested that ESA can affect the progression of tumors. This study conducted experiments to confirm whether the results of previous studies were also applied to lymphoma cells.Patients and Methods : This prospective, multicenter, phase II study enrolled 50 Histologically confirmed DLBCL patients who were treated with rituximab, cyclophosphamide, doxorubicin, vincristin, and prednisolone (R-CHOP) chemotherapy. This study enrolled patients who were shown hemoglobin < 10.0 g/dL at least 3 cycles after starting R-CHOP, were planning to receive at least 4 times of darbepoetin, could read Quality of life as measured by FACT-An and agreed with informed consent. However, this study excluded patients who combined iron deficiency anemia, received erythropoietin at least one months before starting darbepoetin, serious pre-existing medical condition, and untreated primary or metastatic CNS(central nervous system) malignancy. This study was registered in clinicaltrial.gov, and more information can be found at NCT02890602. All patients received darbepoietin alfa at fixed dose of 360 mg once every 3 weeks and if the hemoglobin level exceeds 12 g/dL, administration of darbepoietin was stopped temporarily. In addition, DLBCL cell lines or primary DLBCL cells were tested in vitro to investigate if there were any adverse effects of ESAs on the cancer cell growth.Results : Fifty patients were enrolled between Sep 2012 and Oct 2016. The median age was 64.5 years (range: 34-79 years). The baseline clinical features were as follows: female sex, 68.0%; ECOG >1, 75.5%; stage III/IV, 80.0% and International Prognostic Index score (IPI) > 2, 53.3%, and mean serum ferritin level, 648.13±982.52. The baseline mean hemoglobin level was 9.24 g/dL and overall mean change in hemoglobin level was 1.54±1.3 g/dL at 16 weeks. 46% of total enrolled patients achieved an increase in Hb levels of at least 2 g/dL after 16 weeks of darbepoietin administration and median time to response was 8 weeks. The change of OoL was not significant from baseline to finish of ESA. Most adverse events were hematologic complications which were attributed to the primary disease or received chemotherapy. Only one patient had a thrombotic event which was Common Terminology Criteria for Adverse Events (CTCAE) grade I. Transfusion necessity was determined by clinical judgment and the transfusion rates were 18%. In in vitro study using DLBCL cells, erythropoietin or darbepoietin did not alter cancer cell viability nor rituximab-mediated cytotoxicity under the conditions we have tested.Conclusions : Our study has demonstrated that ESA is effective and safe for patients suffering from anemia after RCHOP chemotherapy. The use of ESA in patients with DLBCL did not deteriorate the quality of life of the patients during chemotherapy. Finally, our research have also shown that the use of ESA does not affect the growth of lymphoma cells. (EPOMA ClinicalTrials.gov number, NCT02890602) DisclosuresNo relevant conflicts of interest to declare.

Clinical Outcomes up to 3 Years Following Lentiglobin Gene Therapy for Transfusion-Dependent β-Thalassemia in the Northstar Hgb-204 Study

BACKGROUNDAutologous hematopoietic stem cell (HSC) gene therapy could be an effective treatment for transfusion-dependent β-thalassemia (TDT) without some of the limitations and risks associated with allogeneic HSC transplantation. LentiGlobin Drug Product (DP) contains autologous HSC (CD34+ cells) transduced ex vivo with the betibeglogene darolentivec (BB305) lentiviral vector encoding a human β-globin gene with the anti-sickling T87Q mutation (HbAT87Q). The Northstar Study(HGB-204; NCT01745120) is an international, multi-center phase 1/2 clinical trial examining the safety and efficacy of LentiGlobin investigational gene therapy in patients with TDT. As of the most recent data cut (June 2, 2017), all patients have 1 to 3 years of follow-up post DP infusion. METHODSPatients (12-35 years of age) with TDT were enrolled at participating sites in the U.S., Australia, and Thailand. Autologous CD34+ cells were collected by mobilization and apheresis and transduced with the BB305 vector in a centralized facility. Patients underwent myeloablative conditioning with intravenous busulfan prior to infusion of transduced cells. Patients were monitored for hematologic engraftment, vector copy number (VCN), levels of HbAT87Q, and red blood cell (RBC) transfusion requirements post-infusion. Safety data, including adverse events (AEs), vector integration site analysis, and surveillance for replication competent lentivirus (RCL), were evaluated post-infusion. The primary analysis period for the study is 24 months following infusion; patients then transition into a long-term study for an additional 13 years of follow-up. RESULTSEighteen patients with TDT (8 with β0/β0 and 10 with non-β0/β0 genotypes; aged 12-35 years) received LentiGlobin DP. The median DP VCN was 0.7 (range: 0.3-1.5) copies/diploid genome, the median cell dose was 8.1 x 106 (range: 5.2-18.1 x 106) CD34+ cells/kg, and the proportion of transduced CD34+ cells was 17-58%. The toxicity profile observed to date has been typical of myeloablative conditioning. During a follow-up period of up to 38.3 months post-infusion (median 25.5 months; range: 14.9-38.3 months), there have been no ≥ grade 3 DP-related AEs and no evidence of clonal dominance or RCL. Serious AEs occurring after DP infusion have been reported in 6/18 (33%) patients: venoocclusive liver disease (n=2) and 1 case each of cellulitis, diarrhea, gastroenteritis, Klebisella infection, cardiac ventricular thrombosis, device-related thrombosis, and hyperglycemia. No serious AEs were considered related to DP.Of the 10 patients with non-β0/β0 genotypes, 8 have been free of transfusions for a median of 27.1 (range 12.5-35.2) months. At their latest study visit (n=8: Months 15-36), their total Hb level ranged from 9.3-13.7 g/dL, and their HbAT87Q level was 3.6-9.6 g/dL. The peripheral VCN ranged from 0.1−1.0. Notably, of these 8 patients, 6 have achieved “transfusion independence” (TI), defined as ≥12 months without transfusions with a weighted average Hb ≥9 g/dL. The 2 patients with non-β0/β0 genotypes who still require intermittent transfusions had annual transfusion volumes reduced by 30% and 94%; both received DP with a VCN in the lower range (DP VCNs: 0.3 and 0.4).Two patients with β0/β0 genotypes have not received a transfusion in more than a year. At the patients' last study visit (Month 24/Month 12), total Hb levels were 9.0 and 10.2 g/dL, HbAT87Q levels were 8.4 and 6.8 g/dL, and peripheral VCNs were 0.9 and 0.6, respectively. Six patients with β0/β0 genotypes have continued transfusions. However, their annual transfusion volumes have decreased by a median of 63% (range: 19% to 81%), from an annualized volume of 124.4-261.3 ml/kg/year at baseline to an annualized volume of 31.4-212.6 ml/kg/year (from 6 months post-infusion to data cut). CONCLUSIONSWith up to 3 years of follow-up, the Northstar Study is the largest international gene therapy trial in TDT to date. All patients, 9 of whom have at least 2 years of follow-up, have demonstrated ongoing clinical benefit with a manageable safety profile. A total of 10 patients (8/10 with non-β0/β0, 2/10 with β0/β0 genotypes) have been able to discontinue RBC transfusions and remain clinically well. The 8/18 patients still receiving transfusions have significantly reduced annualized transfusion volumes (up to 81% and 94% in patients with β0/β0 and non-β0/β0 genotypes, respectively). DisclosuresKwiatkowski:Bluebird Bio: Research Funding; Apopharma: Research Funding; Novartis: Research Funding; Agios: Consultancy, Honoraria; Ionis: Consultancy, Honoraria. Thompson:Novartis: Consultancy, Research Funding; Baxalta: Research Funding; Celgene: Consultancy, Research Funding; bluebird bio: Consultancy, Research Funding. Rasko:Genea: Equity Ownership; IMAGO Biosciences: Consultancy, Equity Ownership; Rarecyte: Consultancy, Equity Ownership; Novartis: Other: Clinical trials, Speakers Bureau; Spark: Equity Ownership, Other: clinical trials, Speakers Bureau; President-Elect International Society for Cellular Therapy: Membership on an entity's Board of Directors or advisory committees. Schiller:bluebird bio: Research Funding; mateon therapeutics: Research Funding. von Kalle:bluebird bio: Consultancy; GeneWerk: Equity Ownership. Leboulch:bluebird bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Deary:bluebird bio: Employment, Equity Ownership. Asmal:bluebird bio: Employment, Equity Ownership. Walters:bluebird bio: Research Funding; AllCells, Inc: Other: Medical Director; Sangamo Therapeutics: Consultancy; ViaCord Processing Lab: Other: Medical Director.

A Cost-Effective Implementation of Pre-Operative Protocol with Sucrosomial® Iron Supplementation

Low peri-operative hemoglobin (Hb) values in orthopedic surgery patients are associated to a longer hospital stay, higher red blood cells transfusion (RBCT) rates and mortality. Compared to non-anaemic patients, anaemic patients have a 42% higher risk of mortality and a 35% higher risk of serious complications [1]. Timely prevention of peri-operative anemia and iron stores can improve patient outcome and reduce RBCT requirements, since pre-operative anaemia appears to be also related to poor prognosis. Sucrosomial® iron (Sideral® Forte, PharmaNutra) is a formulation where iron is covered by phospholipids plus sucrose esters of fatty acids matrix, allowing a higher absorption of iron compared to ferrous sulfate and avoiding typical gastrointestinal side effects. Sucrosomial® iron appears to have high tolerability and to be effective in improving the patient's anaemic condition in terms of serum iron, Hb and ferritin, which have been confirmed by several studies, even in comparison with IV iron treatment, showing similar results [2, 3, 4, 5]. Thus, for these reasons, the efficacy of sucrosomial® iron supplementation in prosthetic hip surgery patients was assessed in terms of Hb levels, length of hospital stay (LOS) and RBCT.The study was conducted between 2015 and February 2017 on patients undergoing prosthetic hip surgery. The period taken into consideration was a follow-up period after the implementation of the pre-operative protocol, which was gradually implemented from 2011 to 2014 with the introduction of sucrosomial® iron. The protocol includes a full blood count, including CRP and ferritin, 21-28 days prior to surgery during the pre-operative visit. In case of a ferritin level <100 mcg/L and/or Hb level <14 g/dL for male and 13 g/dL for female, sucrosomial® iron is prescribed at a dosage of 1 cps/day corresponding to 30mg of elemental iron, for 21-28 days before and 7-10 days after surgery.Between 2015 and January 2017, 5869 patients were evaluated, of these 551 patients were anemic and 1958 were iron deficient. Thus, these patients received iron supplementation with an adherence to the treatment of 87%. Since the introduction of Sucrosomial® iron supplementation there was a reduction in the RBCT rate of 67% and the amount of RBCT significantly decreased from 10% in 2015 to 0% units in 2017 in the population treated. Moreover, sucrosomial® iron led to a reduced in the LOS from an average of 15.19 days in 2014 and to an average of 10.36 days in 2017 (Figure 1), which can be associated to a faster Hb recovery after surgery. Indeed, in January 2017 median Hb level at discharge was 11.2 g/dL, 1.3 g/dL higher than in 2014. The estimated saving for the shorter LOS was calculated as 2000 euro/patient, plus additional saving gained from a more efficient use of hospital beds (Figure 1) in addition to the saving derived from a reduced use of RBCT allowing a better allocation of hospital resources. Indeed, it was estimated an overall saving of 385,000 euro for the period taken into consideration.Pre-operative sucrosomial® iron supplementation 3\\4 weeks prior to prosthetic hip surgery patients contained the fall in post-operative Hb levels and determined a faster recovery of Hb levels and functional recovery after surgery, corresponding to a shorter LOS and decreased surgery-related costs.Bibliography1. Musallam KM, et al. Lancet (London, England). 2011;378:1396-407.2. Capra AP, et al. Hematology. 2017:1-6.3. Mafodda A, et al. Supportive care in cancer. 2017.4. Parisi F, et al. The Journal of Maternal-Fetal & Neonatal Medicine. 2016:1-21.5. Pisani A, et al. NDT Journal 2015;30:645-52. [Display omitted] DisclosuresPera:Pharmanutra S.p.A.: Employment. Tarantino:Pharmanutra S.p.A.: Employment.

Optimal protamine dosing after cardiopulmonary bypass: The PRODOSE adaptive randomised controlled trial

The dose of protamine required following cardiopulmonary bypass (CPB) is often determined by the dose of heparin required pre-CPB, expressed as a fixed ratio. Dosing based on mathematical models of heparin clearance is postulated to improve protamine dosing precision and coagulation. We hypothesised that protamine dosing based on a 2-compartment model would improve thromboelastography (TEG) parameters and reduce the dose of protamine administered, relative to a fixed ratio. We undertook a 2-stage, adaptive randomised controlled trial, allocating 228 participants to receive protamine dosed according to a mathematical model of heparin clearance or a fixed ratio of 1 mg of protamine for every 100 IU of heparin required to establish anticoagulation pre-CPB. A planned, blinded interim analysis was undertaken after the recruitment of 50% of the study cohort. Following this, the randomisation ratio was adapted from 1:1 to 1:1.33 to increase recruitment to the superior arm while maintaining study power. At the conclusion of trial recruitment, we had randomised 121 patients to the intervention arm and 107 patients to the control arm. The primary endpoint was kaolin TEG r-time measured 3 minutes after protamine administration at the end of CPB. Secondary endpoints included ratio of kaolin TEG r-time pre-CPB to the same metric following protamine administration, requirement for allogeneic red cell transfusion, intercostal catheter drainage at 4 hours postoperatively, and the requirement for reoperation due to bleeding. The trial was listed on a clinical trial registry (ClinicalTrials.gov Identifier: NCT03532594). Participants were recruited between April 2018 and August 2019. Those in the intervention/model group had a shorter mean kaolin r-time (6.58 [SD 2.50] vs. 8.08 [SD 3.98] minutes; p = 0.0016) post-CPB. The post-protamine thromboelastogram of the model group was closer to pre-CPB parameters (median pre-CPB to post-protamine kaolin r-time ratio 0.96 [IQR 0.78-1.14] vs. 0.75 [IQR 0.57-0.99]; p < 0.001). We found no evidence of a difference in median mediastinal/pleural drainage at 4 hours postoperatively (140 [IQR 75-245] vs. 135 [IQR 94-222] mL; p = 0.85) or requirement (as a binary outcome) for packed red blood cell transfusion at 24 hours postoperatively (19 [15.8%] vs. 14 [13.1%] p = 0.69). Those in the model group had a lower median protamine dose (180 [IQR 160-210] vs. 280 [IQR 250-300] mg; p < 0.001). Important limitations of this study include an unblinded design and lack of generalisability to certain populations deliberately excluded from the study (specifically children, patients with a total body weight >120 kg, and patients requiring therapeutic hypothermia to <28°C). Using a mathematical model to guide protamine dosing in patients following CPB improved TEG r-time and reduced the dose administered relative to a fixed ratio. No differences were detected in postoperative mediastinal/pleural drainage or red blood cell transfusion requirement in our cohort of low-risk patients. ClinicalTrials.gov Unique identifier NCT03532594.

Pretransplantation Red Blood Cell and Platelet Transfusion Burden in De Novo Myelodysplastic Syndrome Undergoing Allogeneic Transplantation

Most patients of myelodysplastic syndrome (MDS) require red blood cell (RBC) or platelet transfusion during their disease courses, which could cause an increased risk of iron overload and alloimmunization. However, it remains less clear whether pretransplantation RBC or platelet transfusion burden affects transplant outcomes in patients with MDS. The objective was to examine the significance of pretransplantation RBC and platelet transfusion burden on transplant outcomes after allogeneic HCT for adults with de novo MDS. We retrospectively evaluated the effect of pretransplantation RBC or platelet transfusion burden on transplant outcomes in a cohort of 1007 adult patients with de novo MDS treated by upfront allogeneic hematopoietic cell transplantation (HCT) between 2006 and 2018. Both higher pretransplantation RBC and platelet transfusion burdens were significantly associated with higher overall mortality and relapse-related mortality, but not non-relapse mortality in the multivariate analysis. Higher pretransplantation RBC transfusion burden was also significantly associated with lower neutrophil, platelet, and reticulocyte recovery in the multivariate analysis. In summary, our study clearly demonstrated that a higher pretransplantation RBC and platelet transfusion burden was independently associated with higher overall mortality, relapse-related mortality, and lower hematopoietic recovery after allogeneic HCT for de novo MDS. Early allogeneic HCT should be considered for patients with de novo MDS who require RBC and platelet transfusion repeatedly.

Luspatercept: A Review in Transfusion-Dependent Anaemia due to Myelodysplastic Syndromes or β-Thalassaemia

Luspatercept (Reblozyl®), a first-in-class erythroid maturation agent, is approved in several countries worldwide for the treatment of adults with transfusion-dependent anaemia due to myelodysplastic syndromes (MDS), who have failed prior erythropoiesis-stimulating therapy, or β-thalassaemia. In pivotal, placebo-controlled, phase III trials, subcutaneous luspatercept significantly reduced red blood cell (RBC) transfusion requirements in patients with MDS or β-thalassaemia. Luspatercept had a generally manageable tolerability profile in clinical trials. Adverse events of special interest include thromboembolic events, hypertension and bone pain. Thus, luspatercept is an emerging treatment option in adults with transfusion-dependent anaemia due to MDS or β-thalassaemia.

Hematological Biomarkers, Mortality, Transfusion and Acute Heart Disease

BackgroundPatients hospitalized with acute heart disease [acute myocardial infarction (MI); heart disease exacerbation] may require red blood cell (RBC) transfusion. These patients are at increased risk for morbidity and mortality. Hematological biomarkers may help to identify increased mortality risk. The aim of the study was to evaluate the association between hematological biomarkers and survival in these patients. MethodsA historical cohort study of all patients admitted to an internal medicine department, who were diagnosed with acute heart disease and requiring RBC transfusion, was carried out in a tertiary medical center between 2009-2014. The association between hematological biomarkers and 30-, 90-day and 5-year mortality was studied. ResultsA total of 254 patients (median age 80 years, IQR 74-86.25; 40.9% females; acute MI 24.8%), were included. During the 5-year follow-up 212(83.5%) patients died. In a multivariate analysis the lower platelet to neutrophil ratio (PNR) was significantly associated with increased 30-, 90-day and 5-year mortality (p<0.001, 0.041, 0.003 respectively). A higher red cell distribution width (RDW) was significantly associated with 30- and 90-day mortality (p=0.003, 0.023 respectively), while higher neutrophil to lymphocyte ratio (NLR) was associated with increased 30-day and 5-year mortality (p= 0.036, 0.033 respectively). ConclusionsHematological biomarkers may help to identify increased mortality risk of acute heart disease patients, receiving RBC transfusions in an internal medicine department.

Antifibrinolytics reduces blood loss in thoracic surgery: a systematic review and meta-analysis.

The purpose of this systematic review is to evaluate the efficacy of antifibrinolytics in non-cardiac thoracic surgery. We searched for all randomized controlled trials on this topic. A set of strict inclusion and exclusion criteria was developed. Six studies were meta-analysed together then in subgroups of topical tranexamic acid and intravenous aprotinin. We compared postoperative chest drain output, transfusions requirements and duration of hospital stay where available to determine the efficacy of topical tranexamic acid or intravenous aprotinin in reducing blood loss. The use of antifibrinolytics reduces 24-h chest drain output (-290.21 mL [-524.75, -55.66], P= 0.02, I2 = 98%), red blood cell transfusion requirements (-1.27 units [-2.24, -0.30], P= 0.01, I2 = 100%) and shortened duration of hospital stay (-1.81 days [-3.25, -0.36], P= 0.01, I2 = 96%). The subgroup analysis also supported this trend. We conclude that the use of antifibrinolytics appears to reduce postoperative blood loss by reducing chest drain output, transfusion requirements and length of stay after thoracic surgery.

The incidence, aetiology, and coagulation management of massive postpartum haemorrhage: a two-year national prospective cohort study

IntroductionBetween 2017 and 2018 a national quality improvement initiative was introduced incorporating point-of-care viscoelastic haemostatic assays (VHA) to guide blood product transfusion. Laboratory coagulation profiles, use and results of VHA, and administration of blood products were investigated. MethodsA two-year prospective cohort study of maternal outcomes of women experiencing massive postpartum haemorrhage (PPH) >1000 mL in Wales. In this study, cases of massive PPH (≥2500 mL and/or ≥5 units red blood cell (RBC) transfusion) were identified. ResultsMassive PPH occurred in 349 of 60 914 maternities (rate 5.7 per 1000). There were no deaths from PPH. Intensive care unit admission and/or hysterectomy occurred in 34/311 (10.9%) and 16/347 (4.6%), respectively. The leading cause of massive PPH was genital tract trauma (107/349, 30.6%). Two hundred and seventy-nine (80.6%) required RBC transfusion and 79/345 (22.9%) received at least one blood coagulation product. Results of VHA were recorded in 245/349 (70.2%), with 44/98 (44.9%) women tested in the first six months vs 63/77 (81.8%) in the final six months. Hypofibrinogenaemia (Clauss fibrinogen <2 g/L or FIBTEM A5 <12 mm) was observed in 56/328 (17.1%) of women, thrombocytopaenia (count <75 × 109/L) in 17/334 (5.1%) and either PT or aPTT >1.5×reference range in 10/293 (3.4%). ConclusionIn Wales, the use of VHA in cases of massive PPH increased over time, enabling clinicians to adopt a targeted, patient-specific approach to blood product administration, with only 22.9% of women receiving blood coagulation products and 17.1% having a documented clotting abnormality.

Red blood cell transfusions and potentially related morbidities in neonates under 32 weeks' gestation.

Preterm neonates are likely to require red blood cell (RBC) transfusion, and extremely low birth weight infants almost invariably receive multiple transfusions. Transfusion-reduction strategies can reduce transfusion rates, and might diminish certain adverse outcomes associated with transfusions. In a single centre, we retrospectively evaluated RBC transfusion rates among preterm infants ≤32 weeks' gestational age (GA), over a 6-year period before and after adopting national transfusion-reduction strategies. We compared demographic data, adverse events, and outcomes between transfused vs not-transfused neonates. Univariate logistic regression was used to evaluate associations between dichotomous outcomes and number of transfusions, and day of first transfusion. Multivariate logistic regression evaluated the correlation between dichotomous outcomes and transfusion as an independent risk factor. During the 6 years studied, 181 infants born at ≤32 weeks' GA were admitted to our Neonatal Intensive Care Unit of whom 80 (44%) received at least one RBC transfusion. The transfusion rate tended downwards after adopting transfusion-reduction strategies, reaching 31% in 2018. The reduction was largely due to a marked fall in transfusions of neonates born at 29-32 weeks' GA (p<0.001). The number of transfusions received correlated with odds of having intraventricular haemorrhage (IVH) (OR=1.9; 95% CI: 1.3-2.7; p=0.0001) and the duration of oxygen supplementation (rho=0.51; 95% CI: 0.33-0.66; p≤0.0001). In multivariate logistic regression analysis, transfusion was an independent risk factor for IVH (adjusted OR=7.38; 95% CI: 2.24-24.30; p=0.0001). The application of national, standardised transfusion-reduction strategies was associated with a lower transfusion rate in neonates born at 29-32 weeks' GA, but was less effective among neonates ≤28 weeks, in whom transfusions appeared to be an independent risk factor for severe IVH.

The Correlation Between Timing of Surgery and the Need for RBC Transfusions in the Geriatric Intertrochanteric Fracture Population

Objective:To identify whether the timing of surgery affects red blood cell (RBC) transfusion requirements in the elderly with intertrochanteric fractures.Methods:We retrospectively studied all patients undergoing surgical fixation of their intertrochanteric fractures in our hospital between January 2009 and December 2018 and analyzed the relationship between the timing of surgery and RBC transfusion.Results:A total of 679 patients were included in this study. The need for RBC transfusion was lower in the patients who underwent surgery within 12 h after admission (timing of surgery <12 h, <12 h group) than those who underwent surgery over 12 h after admission (timing of surgery >12 h, >12 h group) (P = 0.046); lower in the the patients who underwent surgery within 24 h after admission (timing of surgery <24 h, <24 h group) than in those who underwent surgery over 24 h after admission (timing of surgery >24 h, >24 h group) (P = 0.008), and lower in the <24 h group compared to the patients who underwent surgery within 48 h after admission (timing of surgery <48 h, <48 h group) (P = 0.035). Moreover, the need for RBC transfusion was lower in the <24 h group (in the first 24 h from admission to surgery) than in the 24-48 h group (in the second 24 h from admission to surgery) (P = 0.016), and also lower in the <24 h group compared to the 48-72 h group (in the third 24 h from admission to surgery) (P = 0.047). However, there were no differences between the <12 h group and 12-24 h group, between the <12 h group and <24 h group, and between the 12-24 h group and <24 h group, respectively.Conclusion:Timing of surgery within 24 h contributes to the reduction of RBC transfusion in the elderly with intertrochanteric fractures.

Therapeutic Impact of Deep Balloon-assisted Small Bowel Enteroscopy on Red Blood Cell Transfusion

Abstract Objective Evaluate impact of balloon-assisted deep small bowel enteroscopy on red blood cell transfusion requirement in patients with obscure gastrointestinal (GI) bleeding. Methods Retrospective study of patients, who underwent balloon-assisted deep enteroscopy with double-balloon enteroscopy (DBE) at two tertiary care academic centers (University of Wisconsin and Aurora St. Luke’s Medical Center) over a 55-month consecutive period. Sixty-nine patients with reliable blood transfusion records were identified during this time period. DBE was preceded by small bowel capsule endoscopy (CE) within 1 year in 38 cases. Transfusion requirements 6 months prior and postintervention were measured to see if DBE had any impact on the need for blood transfusions. Results Sixty-nine patients (25 females and 44 males) were included. Mean age ± standard deviation (SD) was 63 ± 17 years. Wilcoxon signed rank test statistics were used to find the difference in the rate of blood transfusion. There was a statistically significant decrease in rate of packed red blood cell (pRBC) transfusion post DBE and endoscopic therapy with coagulation (p &lt; 0.001). Argon plasma coagulation was used to ablate all arteriovenous malformations (AVMs) except in one (subepithelial lesion). Those that required &gt; 5 units pRBC transfusions pre-DBE had the most benefit. Conclusions Our study demonstrates that transfusion requirements are significantly reduced in those undergoing therapy with DBE and coagulation for obscure GI bleed.

Efficacy of Intravenous Tranexamic Acid in Reducing Perioperative Blood Loss and Blood Product Transfusion Requirements in Patients Undergoing Multilevel Thoracic and Lumbar Spinal Surgeries: A Retrospective Study.

Introduction: Acute perioperative blood loss is a common and potentially major complication of multilevel spinal surgery, usually worsened by the number of levels fused and of osteotomies performed. Pharmacological approaches to blood conservation during spinal surgery include the use of intravenous tranexamic acid (TXA), an anti-fibrinolytic that has been widely used to reduce blood loss in cardiac and orthopedic surgery. The primary objective of this study was to assess the efficacy of intraoperative TXA in reducing estimated blood loss (EBL) and red blood cell (RBC) transfusion requirements in patients undergoing multilevel spinal fusion. Materials and Methods: This a single-center, retrospective study of subjects who underwent multilevel (≥7) spinal fusion surgery who received (TXA group) or did not receive (control group) IV TXA at The Ohio State University Wexner Medical Center between January 1st, 2016 and November 30th, 2018. Patient demographics, EBL, TXA doses, blood product requirements and postoperative complications were recorded. Results: A total of 76 adult subjects were included, of whom 34 received TXA during surgery (TXA group). The mean fusion length was 12 levels. The mean total loading, maintenance surgery and total dose of IV TXA was 1.5, 2.1 mg per kilo (mg/kg) per hour and 33.8 mg/kg, respectively. The mean EBL in the control was higher than the TXA group, 3,594.1 [2,689.7, 4,298.5] vs. 2,184.2 [1,290.2, 3,078.3] ml. Among all subjects, the mean number of intraoperative RBC and FFP units transfused was significantly higher in the control than in the TXA group. The total mean number of RBC and FFP units transfused in the control group was 8.1 [6.6, 9.7] and 7.7 [6.1, 9.4] compared with 5.1 [3.4, 6.8] and 4.6 [2.8, 6.4], respectively. There were no statistically significant differences in postoperative blood product transfusion rates between both groups. Additionally, there were no significant differences in the incidence of 30-days postoperative complications between both groups. Conclusion: Our results suggest that the prophylactic use of TXA may reduce intraoperative EBL and RBC unit transfusion requirements in patients undergoing multilevel spinal fusion procedures ≥7 levels.

The intraoperative use of recombinant activated factor VII in arterial switch operations.

The rate of bleeding complications following arterial switch operation is too low to independently justify a prospective randomised study for benefit from recombinant factor VIIa. We aimed to evaluate factor VIIa in a pilot study. We performed a retrospective cohort study of patients undergoing arterial switch operation from 2012 to 2017. Nearest-neighbour propensity score matching on age, gender, weight, and associated cardiac defects was used to match 27 controls not receiving recombinant factor VIIa to 30 patients receiving recombinant factor VIIa. Fisher's exact test was performed to compare categorical variables. Wilcoxon's rank-sum test was used to compare continuous variables between cohorts. Post-operative thrombotic complications were not associated with factor VIIa administration (Odds Ratio (OR) 0.28, 95% CI 0.005-3.77, p = 0.336), nor was factor VIIa administration associated with any re-explorations for bleeding. No intraoperative transfusion volumes were different between the recombinant factor VIIa cohort and controls. Post-operative prothrombin time (10.8 [10.3-12.3] versus 15.9 [15.1-17.2], p < 0.001) and international normalised ratio (0.8 [0.73-0.90] versus 1.3 [1.2-1.4], p < 0.001]) were lower in recombinant factor VIIa cohort relative to controls. In spite of a higher post-bypass packed red blood cell transfusion requirement, patients receiving recombinant factor VIIa had a similar incidence of bleeding post-operatively. With no difference in thrombotic complications, and with improved post-operative laboratory haemostasis, a prospective randomised study is warranted to evaluate recombinant factor VIIa.

Duration of Response to Luspatercept in Patients (Pts) Requiring Red Blood Cell (RBC) Transfusions with Myelofibrosis (MF) - Updated Data from the Phase 2 ACE-536-MF-001 Study

Duration of Response to Luspatercept in Patients (Pts) Requiring Red Blood Cell (RBC) Transfusions with Myelofibrosis (MF) - Updated Data from the Phase 2 ACE-536-MF-001 Study

Characterization of INCB00928, a Potent and Selective ALK2 Inhibitor for the Treatment of Anemia

A significant population of patients with myelofibrosis (MF) develop anemia and either require red blood cell (RBC) transfusions or have an inadequate response to the currently available therapies and become transfusion-dependent. In patients with MF, elevated levels of serum hepcidin, a key iron regulatory hormone, is associated with increased dependence on RBC transfusions and reduced overall survival. Elevated hepcidin expression has also been observed to cause severe functional iron deficiency anemia and is central to the pathophysiology of anemia of chronic disease. Thus, to ensure proper maintenance of iron homeostasis, hepcidin levels are tightly regulated. Specifically, the production of hepcidin is controlled by the bone morphogenetic protein (BMP) type I receptor ACVR1, a gene that encodes the serine/threonine kinase ALK2. In preclinical models, knockdown or complete loss of ALK2 decreases hepcidin production resulting in elevated serum iron levels. In this study, we report characterization of INCB00928, a novel small molecule inhibitor of ALK2 for the treatment of anemia. INCB00928 was observed to have subnanomolar activity against ALK2 and selectivity over ALK1 and ALK3 in biochemical enzyme assays. In cell-based profiling studies, INCB00928 inhibited ALK2 potently and selectively over ALK1 and ALK3 as determined by the inhibition of ligand-induced SMAD pathway signaling. Importantly, in both an immortalized human liver cell line as well as primary human hepatocytes, INCB00928 inhibited BMP-induced production of hepcidin with nanomolar activity. INCB00928 was also observed to have suitable absorption, distribution, metabolism, and excretion properties to be dosed in in vivo rodent studies. In tumor- and inflammation-induced mouse models of anemia, INCB00928 improved RBC count, hemoglobin, and hematocrit levels while decreasing hepcidin levels in a dose-dependent manner. Additionally, consistent with the improved symptoms of anemia, pSMAD1/5 inhibition was observed in a dose-dependent manner in liver tissues collected from INCB00928-treated mice. In summary, INCB00928 is a potent, selective, and orally available small molecule inhibitor of ALK2, which significantly reduces the production of hepcidin in human liver cells, primary hepatocytes, and in rodent models of anemia. For the majority of patients with MF, the management of anemia remains an unmet need. The preclinical findings from this study suggest ALK2 kinase inhibition with INCB00928 may be a promising novel treatment to reduce the production of hepcidin and improve MF-related anemia in humans, thus warranting further investigation. Disclosures Chen: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Stubbs:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Pusey:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Wen:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Collins:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Kapilashrami:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Rupar:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Thekkat:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Lin:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Bowman:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Yang:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Diamond:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Yeleswaram:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Kim:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Koblish:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Chen:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Wee:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company.

Effect of Luspatercept on Biomarkers of Erythropoiesis in Patients (Pts) with Lower-Risk Myelodysplastic Syndromes (LR-MDS) in the Medalist Trial

Effect of Luspatercept on Biomarkers of Erythropoiesis in Patients (Pts) with Lower-Risk Myelodysplastic Syndromes (LR-MDS) in the Medalist Trial

PBSC Mobilization for Auto-HSCT in Myeloma: Growth Factors Vs Growth Factors + Chemotherapy

PBSC Mobilization for Auto-HSCT in Myeloma: Growth Factors Vs Growth Factors + Chemotherapy

Blood Loss and Transfusion in Pediatric Craniofacial Surgery in the Antifibrinolytic Era

Background : Children undergoing complex cranial vault reconstruction (CCVR) for craniosynostosis experience high rates of bleeding and blood product transfusion, increasing the risk of perioperative complications. The most severe issues relate to the rate and extent of blood loss, which can be up to several times the patient's total blood volume and is often equated to controlled massive hemorrhage. ε-Aminocaproic acid (EACA) and tranexamic acid (TXA) are antifibrinolytic agents that have been shown to reduce intraoperative hemorrhage and transfusion requirements during CCVR. However, the relative efficacy of EACA vs. TXA in CCVR has not yet been evaluated. The aim of this study was to compare perioperative blood loss and need for transfusion in children receiving EACA and TXA. We hypothesized that TXA is associated with a greater decrease in blood loss and transfusion requirements when compared to EACA. Methods: All patients who underwent CCVR from September 2015 to December 2019 at our institution were retrospectively evaluated. The primary outcome measures included intraoperative estimated blood loss (EBL), red blood cell (RBC) transfusion volume (mL/kg), and calculated blood loss (CBL) (Kearney et al., Can J Anaesth 1989). Secondary outcome measures included hematologic and coagulation parameters. Study cohort demographic and outcome data were analyzed; Fisher's exact test was used for categorical data, student's t-test was used for continuous data. A p-value of &amp;lt; 0.05 was considered statistically significant. Results: 104 patients were included in the study with 48 patients in the EACA cohort and 56 patients in the TXA cohort. There were slightly more patients with syndromic craniosynostosis in the EACA group, but overall no significant differences in cohort characteristics (Table 1). Mean EBL (mL/kg) was slightly higher in the EACA group vs. the TXA group (21 ± 13 vs. 17 ± 10), but not statistically significant. Intraoperative mean CBL (34 ± 21mL/kg) and intraoperative percent blood volume lost (43 ± 26%) for the cohort were high, but these were equal between groups. Likewise, postoperative DO, CBL and percent blood volume lost were similar between groups. Overall, intraoperative RBC transfusion was required in 66 (64%) of patients and was similar between groups (69% of EACA patients vs. 59% of TXA patients). Intraoperative transfusion of other products was equal between groups. Postoperatively, 23 (22%) of patients required RBC transfusion. Postoperative blood product transfusions were equal between groups (Table 2). We compared routine hematologic and coagulation parameters peri-operatively and did not find any differences between the EACA and TXA group (Table 3). In the EACA group, there were 6 reported perioperative complications, including 2 suspected seizure events, as compared to 7 complications in the TXA group, which included 2 thromboembolic events. Discussion: Pediatric CCVR is a high blood loss surgery and this can lead to a consumptive coagulopathy for which intraoperative antifibrinolytic agents have been demonstrated to improve outcomes. We found no significant difference in blood loss, transfusion requirements, or hematologic parameters between patients who received EACA and TXA in our retrospective pediatric CCVR cohort. Overall there were 4 postoperative outcomes that could have been related to antifibrinolytic use (seizure, thromboembolism), but this was equal between groups and causality was not confirmed. Further research is needed to define optimal antifibrinolytic dosing and duration of therapy. While standard hematologic and coagulation parameters were similar between groups, the mechanisms of surgically induced coagulopathy in CCVR still need to be explored. Future studies investigating coagulation-based and inflammatory assays may be useful in defining surgical-induced coagulopathy. Disclosures No relevant conflicts of interest to declare.