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Results and discussion, acknowledgments, blood transfusion trends in the united states: national inpatient sample, 2015 to 2018.

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Ruchika Goel , Xianming Zhu , Eshan U. Patel , Elizabeth P. Crowe , Paul M. Ness , Louis M. Katz , Evan M. Bloch , Aaron A.R. Tobian; Blood transfusion trends in the United States: national inpatient sample, 2015 to 2018. Blood Adv 2021; 5 (20): 4179–4184. doi: https://doi.org/10.1182/bloodadvances.2021005361

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There is significant decline in RBC and plasma transfusions nationally among hospitalized patients in the United States through 2018.

Increased cryoprecipitate use suggests wider adoption of hypofibrinogenemia management and hemostasis testing for coagulopathic patients.

Blood transfusions are among the most common therapeutic procedures performed in hospitalized patients. This study evaluates contemporary national trends in red blood cell (RBC), plasma, platelet, and cryoprecipitate transfusions. National Inpatient Sample, the largest all-payer inpatient database representing 94% to 97% of the US population, was evaluated from the fourth quarter (Q4) of 2015 through 2018. Quarterly trends for the percentage of hospitalizations with a transfusion procedure were separately examined for each blood product using log binomial regression and reported as quarterly percent change (QPC). The percentage of hospitalizations with an RBC transfusion decreased from 4.22% (2015Q4) to 3.79% (2018Q4) (QPC = −0.72; 95% confidence interval [CI], −1.26 to −0.19; P trend = .008). Although plasma transfusions also decreased, QPC = −1.33 (95% CI, −2.00 to −0.65; P trend < .001), platelet transfusions remained stable QPC = −0.13 (95% CI, −0.99 to 0.73; P trend = .766). In contrast, hospitalizations with cryoprecipitate utilization significantly increased QPC = 2.01 (95% CI, 0.57 to 3.44; P trend = .006). Significant quarterly reductions in RBC transfusions were also seen among many, but not all, strata of sex, race/ethnicity, patient risk severity, and admission type (elective vs nonelective). Despite significant declines in RBC transfusions among older adults, there were no significant changes among pediatric age-group (<18 years) and those 18 to 49 years. The decline in RBC and plasma transfusions suggests steady incorporation of robust evidence base showing safety of restrictive transfusions. Increased cryoprecipitate use may be reflective of wider adoption of hypofibrinogenemia management and hemostasis testing for coagulopathic patients.

Blood transfusions are some of the most common therapeutic procedures performed in hospitalized patients. There are robust randomized clinical trial data that have guided transfusion practices, including trials demonstrating the safety and efficacy of restrictive red blood cell (RBC) transfusion strategies in diverse patient populations. 1-3 Implementation of blood management programs based on high-quality data over the past few decades has improved patient outcomes while conserving a scarce resource and reducing health care costs. 2   Organizations, such as the Joint Commission, American Board of Internal Medicine, American Society of Hematology, and AABB, have also advocated for reducing RBC transfusions. Nationally representative administrative studies and surveys in the United States have previously shown a decline in blood utilization, particularly RBCs, with a concomitant reduction in blood collection of selected components. 4-6 This study evaluated contemporary national trends in RBC, plasma, platelet, and cryoprecipitate transfusions among inpatient hospitalizations in the United States (2015-2018).

The National Inpatient Sample (NIS) is the largest all-payer inpatient database in the United States, developed by the Agency for Healthcare Research and Quality. NIS uses a multistaged clustering design to develop a stratified probability sample of 20% of all inpatient discharges, representing approximately 94% to 97% of the US population across the included years 2015 through 2018. Hospitals are stratified by location, teaching status, bed size, ownership/control, and US census divisions. The unit of this analysis was record-level hospitalization, and patients may be included more than once in the database. Starting from the fourth quarter (Q4) of 2015, International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) procedure codes were reported in the NIS, which were used to identify percent of hospitalizations with ≥1 RBC, plasma, platelet, and cryoprecipitate transfusions (separate outcomes). All hospitalizations in the NIS from 2015Q4 to the end of 2018 were included in this study.

Calendar time was divided into quarters (3 months), yielding 13 quarters over the study period. Quarterly trends for the proportion of transfusion among all hospitalizations of each blood product were separately examined using log binomial regression (2015Q4 to 2018Q4). Quarterly percent change (QPC) in transfusions were estimated using ( e β - 1 ) × 100 % ⁠ , where β was the coefficient for quarter in log binomial regression. P trend values were estimated using log binomial regression. For RBC transfusions, subgroup analyses were performed stratified by individual-level factors (sex, age, race, All Patient Refined Diagnosis Related Group severity, primary payer, and admission type) and hospital-level factors (control/ownership of hospital). Analyses were weighted to account for the sampling design and generate nationally representative estimates. Standard errors were estimated using Taylor series linearization. Analyses were performed using “svy” commands in Stata/MP, v15 (Statacorp, College Station, TX) and R, V4.0 (R-Core Team, Vienna, Austria).

Because the NIS is a deidentified, publicly available data set, this study was deemed exempt from review by the Johns Hopkins institutional review board. It was conducted in accordance with the Declaration of Helsinki.

The proportion of hospitalizations with an RBC transfusion decreased from 4.22% in 2015Q4 to 3.79% in 2018Q4 (QPC = −0.72; 95% confidence interval [CI], −1.26 to −0.19; P trend = .008) ( Figure 1 ). Likewise, the proportion of hospitalizations with a plasma transfusion decreased from 0.57% in 2015Q4 to 0.48% in 2018Q4, QPC = −1.33 (95% CI, −2.00 to −0.65; P trend < .001). In contrast, hospitalizations with cryoprecipitate utilization increased from 0.07% in 2015Q4 to 0.08% in 2018Q4, QPC = 2.01 (95% CI, 0.57-3.44; P trend = .006) and those with platelet transfusions remained stable at 0.55% (2015Q4) and 0.52% (2018Q4); QPC = −0.13 (95% CI, −0.99 to 0.73; P trend = .766).

Temporal trends in transfusion among US hospitalizations between 2015Q4 and 2018Q4. The line graphs represent the proportion of discharges transfused with a given blood component per quarter year. The data represent weighted estimates for ∼10 million weighted discharges per quarter in the National Inpatient Sample (2015Q4-2018). The P trend values shown were calculated by log binomial regression. For 2015, only data from Q4 were included because of the transition to ICD-10 coding scheme from that time point.

In subgroup analyses, significant quarterly reductions in RBC transfusions were also seen among many, but not all, strata of sexes, race/ethnicity, patient risk severity, insurance payer types, admission type (elective vs nonelective), and hospital ownerships ( Table 1 ; supplemental Figures 1-7). For all quarters, pediatric hospitalizations with RBC transfusions were less common than adult hospitalizations ( P < .001 for all comparisons). Further, there were no significant changes in RBC transfusion for pediatric age group (<18 years) and 18 to 49 years, highlighting that the declines in utilization are largely restricted to older US adults ( Table 1 ; supplemental Figure 1). Although there was a significant declining trend in RBC transfusions among hospitalizations with Medicare as the primary payer (QPC = −1.09; 95% CI, −1.61 to −0.57); P trend < .001), there were no significant reductions in RBC transfusions for hospitalizations with Medicaid, self, or private insurance payments. In addition, although private investor-owned hospitals had a significant declining trend in RBC transfusions (QPC = −2.08; 95% CI, −3.29 to −0.88; P trend < .001), there were no significant trends for the government hospitals or private non-profit hospitalizations.

Quarterly percent changes in RBC transfusions between 2015Q4 and 2018Q4 stratified by patient- and hospital-level characteristics

The data represent weighted estimates for approximately 40 million weighted discharges per year in the National Inpatient Sample (2015Q4-2018).

APR-DRG, All Patient Refined Diagnosis Related Group.

QPC =   ( e β - 1 ) × 100 % ⁠ , where β is the coefficient for the quarter variable in log binomial regression.

P trend was calculated using log binomial regression.

The race categories were predefined by Healthcare Cost and Utilization Project (HCUP) and includes race and ethnicity in 1 data element (RACE). If the source supplied race and ethnicity in separate data elements, ethnicity takes precedence over race in setting the HCUP value for race.

APR-DRG: Severity of illness subclass: (0) no class specified, (1) minor loss of function (includes cases with no comorbidity or complications), (2) moderate loss of function, (3) major loss of function, (4) extreme loss of function. APR-DRG classes 1 and 2 are considered low risk and classes 3 and 4 are considered high risk.

No payment/charity care/free care for indigent population.

The hospital's ownership/control category is obtained from the American Hospital Association Annual Survey of Hospitals and includes categories for government nonfederal (public), private not-for-profit (voluntary), and private investor-owned (proprietary). These types of hospitals tend to have different missions and different responses to government regulations and policies.

The overall continued decline in RBC and plasma transfusions through 2018 likely suggests an increased adherence to RBC transfusion guidelines and steady incorporation of the robust evidence base showing safety of restrictive transfusions into the routine transfusion practice.

Although RBC and plasma transfusions decreased, cryoprecipitate transfusions increased and platelet transfusions remained stable. RBCs are the most commonly transfused blood component in the United States, and RBC transfusion is the most common procedure among hospitalized patients. 7   The Joint Commission and American Society of Hematology have targeted RBC transfusions as one of the most overused procedures in the US hospitals. 8   Although data and guidelines pertaining to plasma utilization are limited, plasma use historically follows RBC transfusion trends. 4,9,10   By contrast, this study demonstrated a national increase in cryoprecipitate utilization. This could stem from the increasing recognition that acquired hypofibrinogenemia contributes to hemorrhage, 11   fibrinogen concentrates, and cryoprecipitate, garnering increased attention 12   and wider adoption of hemostasis testing that leads to increased usage of cryoprecipitate. 13-15 Although clinical practice guidelines recommend prophylactic platelet transfusions, 3   the evidence supporting platelet transfusions in specific clinical indications has been rated as low/very-low quality by GRADE methodology and there are inconsistent recommendations across various guidelines. 16,17   Although Patient Blood Management (PBM) initiatives appear to be effective in restricting RBC and plasma transfusions nationwide, targeted interventions are needed for platelets.

Although RBC transfusions decreased in most strata, they were unchanged among hospitalizations of younger individuals, non-Medicare payers, and government and private nonprofit hospitalizations. In general, the declines in transfusions followed those groups with the highest prevalence of transfusions in 2015. The pediatric age spectrum is broad with changing physiology and there are vastly different parameters to be considered for transfusion. 18,19   A paucity of comparable data pertaining to transfusion thresholds in this vulnerable age group has precluded establishment of evidence-based guidelines or pediatric PBM programs. 2,20  

This study has limitations including reliance on ICD-10 billing codes, which may lead to measurement error. Reassuringly, the NIS has previously been extensively validated against the National Hospital Discharge Survey and Medicare Provider Analysis and Review File, and also been shown to be applicable to transfusion practices. 21,22   The laboratory data supporting indication for transfusion and the number of units transfused were unknown. This study being limited to the inpatient setting does not capture changes in outpatient utilization. Specifically for platelet utilization, a major component of the utilization is in the outpatient setting for cancer patients. Thus, this analysis could miss the overall platelet utilization trends. Notably, the 2019 National Blood Collection Utilization Survey (NBCUS) showed an overall 15% increase in transfusion between 2017 and 2019 for apheresis and whole blood-derived platelet units combined. 23  

Data by the AABB and Centers for Disease Control and Prevention that focused on number of units of blood collected suggested a decline in the total number of RBC units transfused may have begun as early as 2008. 5,24   The current study demonstrates the trend has continued through at least 2018. Other published data such as the NBCUS also support an overall decline in red cell transfusion, at least through 2017. The more recent NBCUS shows that there may be no further decrease in utilization between 2017 to 2019 and that utilization of RBC in the United States might have reached a nadir. 6   Although single-center studies assessing the effect of COVID-19 on blood transfusion utilization are emerging, national transfusion trend data assessing the impact of COVID-19 on blood utilization will be important but not available for a few years and likely not reflective of long-term trends. 25  

The overall national decrease of transfusions implies lower overall cost burden on hospitals and increased adoption of an evidence-based and patient-centric approach to transfusion medicine. However, decreased collections and distributions may also suggest potential worsening of financial stressors for blood collection centers that have long been under economic pressure. It is reassuring, nevertheless, to observe improved patient care based on sound medical evidence.

This study was supported in part by grants from the National Institutes of Health (R01AI120938 and R01AI128779 to A.A.R.T, K23HL151826 to E.M.B., T32AI102623 to E.U.P.).

The funder/sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Contribution: X.Z., R.G., A.A.R.T., and E.U.P. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis; all authors contributed to drafting the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Aaron Tobian, Department of Pathology, Johns Hopkins University, Carnegie 437, 600 N. Wolfe St., Baltimore, MD 21287; e-mail: [email protected] .

Author notes

R.G. and X.Z. are joint first authors.

Original data are available by e-mail request to the corresponding author.

The full-text version of this article contains a data supplement.

Supplemental data

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Current advances in transfusion medicine 2020: A critical review of selected topics by the AABB Clinical Transfusion Medicine Committee

Affiliations.

• 1 Department of Pathology, University of California San Diego, La Jolla, California, USA.
• 2 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.
• 3 Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA.
• 4 Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA.
• 5 Department of Pathology, NorthShore University Health System, Chicago, Illinois, USA.
• 6 Vitalant, Scottsdale, Arizona, USA.
• 7 Department of Pathology, New York University Grossman School of Medicine, New York, New York, USA.
• 8 American Red Cross, Biomedical Services, Baltimore, Maryland, USA.
• 9 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
• 10 Clinical Pathology Division, Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
• 11 Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
• 12 Department of Medicine, University of Chicago, Chicago, Illinois, USA.
• 13 Department of Pathology, University of New Mexico, Albuquerque, New Mexico, USA.
• 14 Department of Pathology, Stanford University, Stanford, California, USA.
• 15 Office of Blood Research and Review, Food and Drug Administration, Silver Spring, Maryland, USA.
• 16 Transfusion Medicine Division, Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.
• PMID: 34423446
• PMCID: PMC8630708
• DOI: 10.1111/trf.16625

Background: The AABB Clinical Transfusion Medicine Committee (CTMC) compiles an annual synopsis of the published literature covering important developments in the field of transfusion medicine (TM), which has been made available as a manuscript published in Transfusion since 2018.

Methods: CTMC committee members reviewed original manuscripts including TM-related topics published electronically (ahead) or in print from December 2019 to December 2020. The selection of topics and manuscripts was discussed at committee meetings and chosen based on relevance and originality. Next, committee members worked in pairs to create a synopsis of each topic, which was then reviewed by two additional committee members. The first and senior authors of this manuscript assembled the final manuscript. Although this synopsis is extensive, it is not exhaustive, and some papers may have been excluded or missed.

Results: The following topics are included: COVID-19 effects on the blood supply and regulatory landscape, COVID convalescent plasma, adult transfusion practices, whole blood, molecular immunohematology, pediatric TM, cellular therapy, and apheresis medicine.

Conclusions: This synopsis provides easy access to relevant topics and may be useful as an educational tool.

Keywords: cellular therapy; therapeutic apheresis; transfusion practices (adult).

© 2021 AABB.

Publication types

• Research Support, Non-U.S. Gov't
• Transfusion Medicine / trends*

Grants and funding

• K23 HL140132/HL/NHLBI NIH HHS/United States
• L30 HL143548/HL/NHLBI NIH HHS/United States

• Frontiers in Anesthesiology
• Perioperative Medicine
• Research Topics

Patient Blood Management and Transfusion Strategies in Perioperative Settings

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About this Research Topic

Recent years have witnessed an outstanding and impressive contribution of patient blood management strategies to global perioperative patient care, particularly with the implementation of pre-, per-, and post-operative strategies. The Management of blood transfusion in the perioperative period is of particular importance due to several reasons, including possible complications related to the use of blood products, not limited to immunizations, the risk of infection, Transfusion Acute Lung Injury (TRALI), electrolyte disturbances, and coagulopathy. Several years ago, the three pillars matrix for patient perioperative blood management was defined and included optimizing red cell mass, minimizing blood loss, and mobilizing and optimizing the physiological reserve of anaemia. (Isbister). Thus, different techniques and strategies were proposed in each pillar to be implemented either in the pre-, per, or postoperative period, aiming either to reduce blood loss, avoid the use of blood products, or use alternatives to allogeneic blood transfusion. These techniques include (and are not limited to) normovolemic haemodilution, autologous blood transfusion, pre-operative optimization using Iron with or without erythropoietin, the use of cell saver, and many more. In these management strategies, drugs such as Tranexamic acid are also useful tools. Among the remaining questions in the process were: to define the right product needed for the replacement therapy, the specific lab test needed to help such determination, and the ideal timing and protocol to decide on this replacement therapy. Whenever surgery would result in significant blood loss (typically 500-1000 ml or more), a discussion involving the surgical team and haemostasis expert is needed to design a targeted patient blood management strategy. Major surgeries have been associated with higher blood loss. Depending on the pathophysiology of the patient's disease and comorbidities, the surgery type, the risk of significant blood loss, and the case complexity, many techniques have been proposed in different settings including all pediatric populations’ surgeries, cardiac, trauma-based, orthopedic, digestive surgeries, and obstetrics. The previous works have also led to the diversification of techniques and strategies, using techniques such as thromboelastography (TEG) and rotational thromboelastography (ROTEM). advantages of this latter technique include a shorter turnaround time, rapid decision-making, and guidance on the specific blood product, factor concentrate, or adjuvant needed. These techniques could be used alone or with specific decision algorithms targeting patient needs, procedures, hemostatic objectives, and possible alternatives to allogeneic blood transfusion. These technics and strategies can be implemented for all ages and might be used in various applications. An example of these management strategies was recently published in a review article on the advantages of Prothrombin complex concentrate (PCC) in the pediatric population in the failure of blood transfusion to achieve hemostasis and coagulation based on experiences in cardiac, trauma, and other coagulopathy scenarios, emphasizing particularly on Pediatric patients with congenital heart disease. At this time, researchers are studying various algorithms and bundle strategies adapted to specific patients, and postoperative coagulopathy management strategies that could be used to optimize patient care. Others research areas are in perioperative blood transfusion management. In this research topic, we are seeking original papers from authors with articles focusing on the domain of perioperative blood management strategies and associated domains such as hemostasis and perioperative coagulation.

Keywords : Patient Blood Management, Blood Transfusion, Perioperative, Blood Sparing Strategies, Transfusion Medicine, Bleeding

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On Medicine

Topics in blood transfusion

Today marks World Blood Donor Day and so we asked Deputy Editor for Journal of Intensive Care , Hiroshi Morisaki, to explain more about the importance of blood transfusion, and how research in this area is progressing.

Hiroshi Morisaki 14 Jun 2016

To date, humans have uncovered a number of natural principles and issues such as the origin and mysteries of the universe, the earth and even life. We have simultaneously developed innumerable non-natural products for human use.

However, we have not yet succeeded in creating a man-made, cost-effective alternative to red blood cells (RBCs) despite the performance of extensive research and numerous clinical trials.

A life-saving intervention

The cellular health of the host requires an oxygen (O 2 ) supply that matches the O 2 requirements of its tissue. An insufficient O 2 supply results in ischemia, subsequently inducing tissue and/or organ injury, frequently observed in critically ill patients.

RBC transfusion, first performed over 300 years ago, remains a fundamental life-saving intervention in medicine.

Hemoglobin, which is enclosed in RBCs as an O 2 carrier, plays the most important role in supplying O 2 to the tissues. Accordingly, RBC transfusion, first performed over 300 years ago, remains a fundamental life-saving intervention in medicine.

Until the early 1980s, RBC transfusion was considered to be practically risk-free and a truly effective intervention in patients with active bleeding or anemia due to a variety of reasons in the intensive care field.

However, the threat of potentially-fatal transfusion-related infections, i.e., human immunodeficiency virus, has led physicians throughout the world to obviate this conventional intervention to the extent that is possible.

Research in the literature

In 1999, Canadian investigators examined the effects of a restrictive RBC transfusion strategy in comparison to a liberal strategy in critically ill patients. They indicated that a restrictive strategy was at least as effective as and possibly superior to a liberal transfusion strategy in critically ill patients with some exceptions.

Although several debates are currently ongoing, most physicians now agree that a restrictive strategy to limit RBC transfusion is a valuable approach in the treatment of stable patients with anemia.

However, we need to be cautious when interpreting the results of the Canadian study as it indicated some exceptions.

Even though we have seen extraordinary advances in medical science and related technology over the last several decades, clinical practices have been determined based on the balance between the benefits and related risks of intervention.

They found that a restrictive transfusion strategy was significantly associated with reduced mortality in younger patients and in those with less severe conditions. In other words, a liberal RBC transfusion strategy might be more effective for older patients and patients with more severe conditions.

RBC transfusion by itself is not an exception. The level of hemoglobin that works in some patients may not work in others. Indeed, a previous cohort study of intensive care unit patients suggests that restrictive RBC transfusion policies may not be uniformly applicable in the clinical setting.

World Blood Donor Day

In 2012, the World Health Organization (WHO) released a document entitled, “ Blood donor selection – Guideline on assessing donor suitability for blood donation ”. In this guideline, the authors noted that a careful process to assess the suitability of donors is essential for protecting the safety and sufficiency of the blood supply, and safeguarding the health of both ‘recipients’ and ‘donors’. We should therefore understand that blood transfusion not only improves the recipients’ conditions but also affects the donors’ health.

Away from the discussion of whether restrictive or liberal RBC transfusion strategies should be applied, natural human blood is needed to save the lives in emergency and long-term treatment settings, even in the 21 st century.

If you believe yourself to be in good health, you should donate your blood to prove it and to save lives at the same time.

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• Topics in blood transfusion - 14th June 2016

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Clinical Trials

Blood transfusion.

Displaying 8 studies

This is a Phase 2, multicenter, open-label study to evaluate the efficacy and safety of luspatercept in subjects with MPN-associated myelofibrosis and anemia with and without RBC-transfusion dependence. The study is divided into a Screening Period, a Treatment Period (consisting of a Primary Phase, a Day 169 Disease Response Assessment, and an Extension Phase), followed by a Posttreatment Follow-up Period.

Do ambulatory RBC transfusions improve home functional status?

The objective of the study is to identify a population of healthy blood donors that would be willing to donate blood within short notice (less than 6 hours) and to identify perceived barriers to donation.

The purpose of this study is to evaluate pomalidomide vs. placebo in patients with hereditary hemorrhagic telangiectasia (HHT) with moderate-to-severe epistaxis who require parenteral iron infusions or blood transfusions. A total of 159 patients will be randomized 2:1 to treatment with oral pomalidomide or matching placebo for 24 weeks. Mean change from baseline to 24 weeks in the Epistaxis Severity Score (ESS) will be compared between treatment groups to determine pomalidomide efficacy.

The purpose of this study is to compare a restrictive versus a more liberal transfusion strategy in high risk patients having cardiac surgery.

The purpose of this study is to evaluate the impact of tranexamic acid (TXA) on perioperative blood transfusion in patients undergoing liver resection. The rationale for this study includes: (1) experimental evidence supporting the use of TXA in other surgical populations; (2) lack of evidence in patients undergoing liver resection; (3) clinical uncertainty and extensive support amongst hepatobiliary surgeons, anaesthesiologists, and hematologists for this proposed trial; (4) a feasible and efficient study design; and (5) the importance of the question: incidence of blood transfusion in patients undergoing liver resection is high, and the consequences serious. Participants enrolled in the prior Vanguard ...

The purpose of this study is to compare two red blood cell transfusion strategies (liberal and restrictive) for patients who have had an acute myocardial infarction and are anemic.

The purpose of this study is to better understand the role of HIV and/or HCV infection and/or SARS-CoV-2 on the immune system and potential ways to eliminate the virus(es).

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Silberstein LE , Toy P. Research Opportunities in Transfusion Medicine. JAMA. 2001;285(5):577–580. doi:10.1001/jama.285.5.577

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Research Opportunities in Transfusion Medicine

Author Affiliations: Harvard Medical School, Boston, Mass (Dr Silberstein), and the Department of Laboratory Medicine, University of California, San Francisco (Dr Toy).

In recent years, the translation of basic research in transfusion medicine has led to development of novel cellular therapies using well-characterized cell populations isolated from either bone marrow or blood (eg, hematopoietic stem and progenitor cells, T lymphocytes, dendritic cells). Refinements in cell therapies will make possible optimal stem cell engraftment, gene therapy, immunotherapy of cancer and infectious disease, and even solid organ regeneration. Moreover, the immune consequences of transfusion therapy are better appreciated and opportunities are at hand to prevent or blunt unwanted immune responses, such as platelet refractoriness and graft-vs-host disease. Transfusion medicine has become a broad, multidisciplinary field that has evolved beyond issues related to blood procurement and storage. The next series of advances in transfusion medicine will complement the current approaches of donor blood screening and viral/bacterial inactivation steps to ensure a safe and adequate blood supply.

The field of transfusion medicine began 100 years ago, in 1900, with the discovery by Landsteiner 1 of the ABO blood group system. This discovery demonstrated that plasma proteins have defined specificities. These plasma proteins, later termed antibodies, recognize epitopes on red blood cells. These discoveries constituted a starting point for blood banking—collection and storage of blood—and for immunohematology, the serological investigation of blood group antigens ( Figure 1 ). During the past 3 to 4 decades, significant advances have been achieved in improving the blood supply with respect to availability, safety, and fractionation into components, such as red blood cells, platelet concentrates, and plasma proteins.

Donors currently donate approximately 12 million units of blood annually in the United States. 2 Without these donations, many procedures and treatments, such as hematopoietic stem cell transplantation, complex cardiac and orthopedic surgery, and organ transplantation, would not be possible. A safe and adequate blood supply is a fundamental necessity to support state-of-the-art medical and surgical therapies. However, resources are now needed to translate advances in the biology of hematopoietic cells into newer cellular therapies and to investigate the unique immunological effects that result from transfusion of blood cells. This article discusses current status and progress in several aspects of transfusion medicine, including adequacy and safety of the blood supply, appropriate use of transfusion therapy, development of novel cellular therapies, and manipulation and prevention of immune responses.

Advances in transfusion medicine that have occurred during the past 25 years include reduction in risk of virally transmitted disease, pharmaceutical production of recombinant clotting factors, isolation and storage of stem and progenitor cell populations for transplantation, and genetic characterization of blood group antigens.

Reduction in transfusion-transmitted viral disease was achieved by a conversion from paid to volunteer donors, by improvement in donor screening, and by improvement of assays that detect viruses in donor blood. Since implementation of nucleic acid testing of donor blood, the estimated risks of hepatitis B (1 per 63 000 units), hepatitis C (1-3 per 1 million units), and human immunodeficiency virus (HIV) (1-2 per 1 million units), are now minuscule ( Figure 2 ). 3 At the same time, pasteurization and solvent-detergent treatment have virtually eliminated risk of HIV and hepatitis transmission through clotting factor concentrates and other plasma derivatives.

Advances have also been made in hematopoietic stem and progenitor cell transplantation for both hematologic and nonhematologic malignancies. The realization that stem and progenitor cells circulate in peripheral blood and that these cells can be mobilized from bone marrow using cytokines has led to outpatient cytapheresis procedures. 4 Transfusion medicine specialists are now involved in collection, in vitro manipulation, and storage of hematopoietic stem and progenitor cells for both allotransplantation and autologous transplantation.

Historically, blood group antigens were defined only by serological means, and their expression was thought to be limited to red blood cells. During the past 2 decades, establishment of the molecular basis for the majority of these blood group antigens has led to the realization that many of these antigens are expressed on other tissue cells. In addition, the biological functions of some of these antigens have been defined (eg, as receptors for pathogens or as ion transporters in the cell membrane 5 ). It is now possible to develop blood group antigen testing by genetic approaches. 6 Genotyping may lend itself to screening larger numbers of units in the blood supply and may be more amenable to laboratory automation. 7 This development could therefore enhance compatibility testing by selecting donor red blood cell units, which genetically match the red blood cells of the recipient. As a result, alloimmunization would be less likely.

The indications for transfusion of blood products continue to evolve. The hemoglobin concentration alone is an inadequate indication for red blood cell transfusion but improved clinical guidelines have not yet been defined. The importance of this issue is underscored by evidence that suggests that more liberal use of red blood cell transfusion may possibly harm younger, less severely ill patients in the intensive care unit. 8 Similar questions pertain to the indications for platelet concentrates, plasma, and specialized blood products (eg, leukoreduced cellular products, cytomegalovirus seronegative blood, washed red blood cells, fresh blood).

Alloimmunization is a major clinical problem in transfusion medicine, particularly in the setting of patients with multiple transfusions who become refractory to both red blood cells and platelet concentrates. For example, patients with hemoglobinopathies, such as sickle cell disease, rely heavily on transfusions for prevention and treatment of stroke, treatment for acute pulmonary disease, and preparation for surgery. 9 Unfortunately, a large percentage of sickle cell disease patients (25%-30%) develop multiple alloantibodies and autoantibody syndromes and become refractory to transfusion. Similarly, patients undergoing stem cell transplantation and aggressive chemotherapy often require frequent and sustained platelet transfusion support. A significant proportion of patients (30%) develop anti-HLA antibodies, resulting in platelet refractoriness. 10 A different aspect of alloimmunization pertains to graft-vs-host disease, in which transfused allogeneic T cells react with antigens on host tissues. These allogeneic T cells are transfused via traditional blood components (eg, packed red blood cells and platelet concentrates) or via stem cell products for hematopoietic stem cell transplantation.

There is also a deliberate use of alloimmunity in transfusion medicine, which involves the transfusion of allogeneic T cells to induce a graft vs leukemia/tumor effect for treatment of residual or recurrent tumor. 11 In addition, transfusion of viable donor leukocytes may induce ill-defined immunosuppression, referred to as the immunomodulatory effect, leading to tumor recurrence and postoperative infections. 12 It has been argued that more research is needed to understand the biology and clinical implications of the immunomodulatory effect before expensive strategies, such as universal leukoreduction of blood products, are instituted. 13

Current research is aimed at reducing viral transmission of blood products. Several viral/bacterial inactivation methods are being investigated for cellular products that are not amenable to solvent-detergent treatment or pasteurization. 14 Also, artificial blood substitutes (now in phase 3 trials) ultimately may have clinical utility, but they are unlikely to replace the volunteer donor blood supply. 15

With respect to cell therapies, attempts are under way to define hematopoietic stem cells and to understand stem and progenitor cell replication and differentiation. 16 These studies may lead to better approaches for ex vivo stem and progenitor cell expansion. Also, stem cell homing (eg, chemokines) and engraftment (eg, facilitator cells) are critical for hematopoietic stem cell transplantation. 17 Other cell therapies in development include T-cell therapies, for their graft vs tumor effect (ie, residual/recurrent chronic myelogenous leukemia), and the ex vivo generation of dendritic cells, for use in tumor vaccines. 18 , 19 Progress also is being made in differentiating the cells (and surface molecules) of the immune system that generate immune responses to foreign and host antigens. 20 , 21 As a result, experimental research and clinical trials are ongoing to find ways to either prevent or blunt autoimmune or alloimmune responses by costimulatory molecules (eg, using anti-CD40, CTLA4-Ig). 22 - 24

Basic principles of quality and risk management support establishment of evidence-based guidelines. A network of clinical research centers in transfusion medicine is essential to improve the effectiveness of the research that this discipline requires. Basic research analyzing the control of hematopoiesis is critical to expansion of hematopoietic cells and important to development of novel cellular therapies. Several issues must be resolved to advance hematopoietic stem cell transplantation. For example, which cells or factors are necessary for long-term engraftment? Which cells exist in the bone marrow environment and how do they influence hematopoietic growth and differentiation? Which factors influence the retention and trafficking of hematopoietic progenitor cells to and from the bone marrow environment?

Alloimmunity is a common consequence of blood cell transfusion. Further studies are needed to elucidate the mechanisms involved in generation of these immune responses. Such studies may focus on definition of target antigens (eg, tumor antigens, antigens in graft-vs-host disease, immune cell types, and the membrane molecules involved), cell origin (eg, host vs donor), the role of cytokines in establishing and perpetuating an alloimmune response, and the role of chemokines and chemokine receptors in homing immune cells. To date, few animal models exist that can be used to study alloimmune responses to blood cell elements. A special need exists to develop murine models to take advantage of existing reagents; the ability to inactivate murine background genes and knock-in human genes may be useful to study the induction, prevention, and modulation of immune-hematological responses. Such models may help define the role of specific immune cells (eg, T cells, dendritic cells), the role of donor vs host antigen-presenting cells, and the role of certain receptors (eg, Fcγ).

Current problems with blood shortages can be solved by finding ways to increase blood donations, by establishing donor criteria that maintain a safe blood supply without turning away safe donors, and by more accurately defining the indications for transfusions. Blood group genotyping will improve compatibility testing and selection of appropriate donor blood. In addition, genotyping will more precisely define fetal risk for neonatal hemolytic disease. Transfusion safety will be further enhanced by improved genetic testing of donated blood for known pathogens and by use of viral/bacterial inactivation steps suitable for cellular products. While reduction in the transmission risk of hepatitis B, hepatitis C, and HIV infection during the past 15 years is a major advantage, it is important to continue surveillance for newly emerging viruses and other pathogens (eg, prions, associated with variant mad cow disease) ( Figure 2 ). 25

Advances in cell and molecular biology of immune and hematopoietic cells will make it possible to isolate and grow cells in vitro for specific cell therapies. 26 Such therapies will include hematopoietic stem and progenitor cell populations with optimal engraftment and minimal graft-vs-host disease, 27 dendritic cells for tumor vaccines, T-cell populations defined for their antitumor/antiviral effects, 28 and stem and progenitor cells that are rendered resistant to infectious disease or genetically modified to correct genetic disorders. Since hematopoietic stem cells are capable of differentiating into cells of different lineage (eg, liver cells), it may possible to generate human tissue and blood cells in vitro for therapeutic applications. 29 ( Figure 3 )

Further understanding of alloimmune responses after transfusion may lead to ways to mitigate or prevent unwanted consequences of transfusion, such as graft-vs-host disease and refractoriness to platelet transfusion. Collectively, this interdisciplinary research effort will translate into safer and more effective transfusion therapy with a wide range of applications.

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Could Alzheimer’s Spread Through Blood Transfusions? New Research Suggests A Worrying Link.

by Trisha Leigh

Alzheimer’s has one of the biggest research funds of any disease out there, and for good reason.

It affects many, and is devastating not only for the people suffering from it, but those who love them.

Now, scientists are finding evidence that it could be spread through a simple blood transfusion.

Researchers have suspected for a long time that more than genetic factors are at play. Environmental factors like exposure to pollution and eating a lot of meat and processed food seem to also lead to a Alzheimer’s diagnosis, or at least contribute to one.

Now, they’re thinking blood could go on that growing list as well.

This new study , published in  Stem Cell Reports, suggests that transfusions of blood, bone marrow, organs and other matter from one person who has hereditary Alzheimer’s Disease can cause the disease to show up in the recipient.

They came to this conclusion after performing extensive experiments on mice and their stem cells.

They bred mice to be carriers of human inheritable Alzheimer’s, as well as a gene that synthesizes amyloid plaques. Then they extracted stem cells from their bone marrow and injected that tissue into healthy mice.

Within 9 months, the healthy mice were showing signs of cognitive decline, as well as changes to their brain chemistry. They showed an accumulation of amyloid plaques that are the classic hallmarks of Alzheimer’s.

Scientists conclude that first of all, Alzheimer’s seems to be able to arise from stem cells outside the nervous system.

“One of the potential outcomes of this study is to spur the field to move away from the conventional central dogma of AD pathology, which states that the accumulation of brain-derived amyloid, specifically produced by neurons, is the cause of the disease. This study demonstrates the contribution of amyloid, generated outside the brain, in establishing the disease.”

They also took away that this pathway to developing AD could be similar to how prion brain diseases are transmitted.

ie: people eating cows with Mad Cow Disease developing Creutzfeldt-Jakob disease.

This would, of course, mean that blood donations would have to be much more extensively screened, says immunologist and study author Wilfred Jeffries.

“This supports the idea that Alzheimer’s is a systemic disease where amyloids that are expressed outside of the brain contribute to central nervous system pathology. As we continue to explore this mechanism, Alzheimer’s disease may be the tip of the iceberg and we need to have far better controls and screening of the donors used in blood, organ, and tissue transplants we well as in the transfers of human-derived stem cells or blood products.

It’s all very daunting.

But, if it’s possible to stop people from getting the disease to begin with, that’s obviously the best possible scenario.

If you found that story interesting, learn more about why people often wake up around 3 AM and keep doing it for life.

Categories: SCI/TECH Tags: · Alzheimer's Disease , amyloid , blood transfusions , hereditary , research , science , single topic , top

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Tsetse fly protein provides anticoagulant with its own on-off switch

Discovery a potential game-changer in surgery and suppressing blood clots.

Researchers at the University of Sydney and University of Geneva have developed a new anticoagulant, whose anticlotting action can be rapidly stopped 'on demand'. The result could lead to new surgical and post-operative drugs that minimise the risk of serious bleeding.

The research team applied a completely new method to discover the molecule. The anticoagulant combines a short protein molecule (a peptide) from a tsetse fly -- a blood-feeding insect -- with a second, synthesised peptide. The bonds holding the two peptides together can be broken on demand, providing the anticoagulant ingredient with its own on-off switch.

This new drug-discovery approach is a potential game-changer in surgery and for suppressing blood clots. It could also be applied in other fields such as immunotherapy.

The results are published today in Nature Biotechnology .

In addition to surgical applications, anticoagulant therapies are essential for managing a wide range of conditions, such as heart disease, stroke and venous thrombosis. However, current treatment options, such as heparin and warfarin, have major drawbacks, including the need for regular monitoring of blood coagulation and the risk of serious bleeding in the event of overdose.

About 15 percent of emergency hospital admissions due to adverse drug reactions are attributable to complications from anticoagulant treatments, emphasising the importance of developing new, safer and more effective therapeutic options.

Professor Rich Payne from the School of Chemistry is an NHMRC Investigator Leadership Fellow and Deputy Director of the ARC Centre of Excellence for Innovations in Peptide and Protein Science (CIPPS) and is a coauthor of the research.

He said: "What's exciting here is that we have applied a completely novel approach to drug discovery. The anticoagulant we have developed uses what we call supramolecular chemistry. This allows the two active molecules needed to suppress coagulation to self-assemble.

"The architecture also means we can apply an antidote that can quickly disassemble the joined molecules, triggering a rapid cessation of the active combination and the anticoagulant effect.

"This has never been done before in drug discovery."

Research lead, Professor Nicolas Winssinger from the Department of Organic Chemistry at the University of Geneva, said: "This result goes beyond the development of a new anticoagulant and its associated antidote. The supramolecular approach proposed is remarkably flexible and can be easily adapted to other therapeutic targets. It is particularly promising in the field of immunotherapy."

Revolution for surgery

The new anticoagulant could offer a more reliable and easier-to-use option for surgical procedures. Heparin, commonly used in this field, is a mixture of polymers of different lengths extracted from pig intestine. The use of heparin in the clinic is problematic due to the risk of serious bleeding side effects and requires coagulation tests during surgery. The new synthetic anticoagulant developed by the Geneva and Sydney team could help solve the problems of purity and availability associated with heparin.

One of the breakthroughs in this work lies in the use of a peptide nucleic acid (PNA) to link the two molecules that bind and block the action of thrombin, the enzyme that produces fibrin that makes up our blood clots.

In this case, the tsetse-fly-derived peptide molecule and a synthetic ketobenzothiazole containing peptide bind to two distinct sites on thrombin as a 'supramolecule' connected by a PNA double helical linker, similar in shape to DNA.

These two strands of PNA that make up the double helix can come together via relatively weak -- non-covalent -- bonds that can be broken when needed. The research team has shown that by introducing correctly matched strands of free PNA, it is possible to dissociate the two thrombin-binding molecules. The two free PNA strands are no longer active as anticoagulants. This is a major innovation in the field.

The tsetse fly peptide was developed in laboratories at the University of Sydney. Tests for the efficacy of the supramolecular anticoagulant were also tested at Sydney in human and mouse blood samples and also in vivo in mice.

Useful for immunotherapy

Beyond the problem of anticoagulation, this supramolecular concept of activating and deactivating the active principle could be of significant interest in the field of immunotherapy, particularly for CAR-T therapies.

Although CAR-T therapies are one of the major advances in the treatment of certain cancers in recent years, their use is associated with a significant risk of immune system storm, which can be fatal. The ability to rapidly deactivate treatment with an accessible antidote could be a crucial advance in improving the safety and efficacy of CART-T therapies.

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Story Source:

Materials provided by University of Sydney . Note: Content may be edited for style and length.

Journal Reference :

• Millicent Dockerill, Daniel J. Ford, Simona Angerani, Imala Alwis, Luke J. Dowman, Jorge Ripoll-Rozada, Rhyll E. Smythe, Joanna S. T. Liu, Pedro José Barbosa Pereira, Shaun P. Jackson, Richard J. Payne, Nicolas Winssinger. Development of supramolecular anticoagulants with on-demand reversibility . Nature Biotechnology , 2024; DOI: 10.1038/s41587-024-02209-z

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Researchers identify over 2,000 genetic signals linked to blood pressure in study of over 1 million people

by Queen Mary, University of London

Researchers led by Queen Mary University of London have discovered over a hundred new regions of the human genome, also known as genomic loci, that appear to influence a person's blood pressure. In total, over 2,000 independent genetic signals for blood pressure are now reported, demonstrating that blood pressure is a highly complex trait influenced by thousands of different genetic variants.

The study, published in Nature Genetics, is one of the largest such genomic studies of blood pressure to date, including data from over 1 million individuals and laying the groundwork for researchers to better understand how blood pressure is regulated.

To understand the genetics of blood pressure, the researchers combined four large datasets from genome-wide association studies (GWAS) of blood pressure and hypertension. After analyzing the data, they found over 2,000 genomic loci linked to blood pressure, including 113 new regions.

The analyses also implicated hundreds of previously unreported genes that affect blood pressure. Such insights could point to potential new drug targets, and help to advance precision medicine in the early detection and prevention of hypertension ( high blood pressure ).

From these analyses, the researchers were able to calculate polygenic risk scores, which combine the effects of all genetic variants together to predict blood pressure and risk for hypertension. For example, these risk scores show that individuals with highest genetic risk have mean systolic blood pressure levels which are ~17 mmHg higher than those with lowest genetic risk, and a 7-fold increased risk of hypertension. Therefore, these polygenic risk scores can discriminate between patients according to their hypertension risk, and reveal clinically meaningful differences in blood pressure.

"We have now revealed a much larger proportion of the genetic contribution of blood pressure than was previously known," says Helen Warren, Senior Lecturer in Statistical Genetics at Queen Mary University of London and senior last author of the study.

"We are making our polygenic risk scores data publicly available. There are many different potential applications of genetic risk scores, so it will be exciting to see how our blood pressure scores can be used to address more clinically relevant questions in the future."

"This large study builds on over 18 years of blood pressure GWAS research. Our results provide new resources for understanding biological mechanisms and importantly new polygenic risk scores for early identification and stratification of people at risk for cardiovascular diseases," says Patricia Munroe, Professor of Molecular Medicine at Queen Mary University of London, also a senior author of the paper.

Polygenic risk scores have potential to serve as a useful tool in precision medicine, but more diverse genomic data is needed for them to be applicable broadly in routine health care. While the collected data was mostly from people of European ancestry (due to limited availability of diverse datasets when the study was started), the researchers found that the polygenic risk scores were also applicable to people of African ancestry, who have previously been underrepresented in genetic studies.

This African ancestry result was confirmed through analyzing data from the National Institute of Health's (NIH) "All of Us" Research Program in the U.S., which aims to build one of the largest biomedical data resources and accelerate research to improve human health.

An estimated 30% of adults in the UK have high blood pressure, known as hypertension. High blood pressure often runs in families, meaning that there is a genetic component to developing the condition in addition to environmental contributions such as a high-salt diet, lack of exercise, smoking and stress.

When blood pressure is consistently too high, it can damage the heart and blood vessels throughout the body, increasing a person's risk for heart disease, kidney disease, stroke and other conditions.

The study combined previously published genetic data from the UK Biobank, a large-scale biomedical database and research resource containing genetic and health information from half a million UK participants (N~450,000 individuals); the International Consortium for Blood Pressure (N~300,000 individuals combined from 77 different cohort studies); and the U.S. Department of Veterans Affairs' Million Veteran Program (N~220,000 individuals), with new data from Vanderbilt University Medical Center's biorepository, BioVU (N~50,000 individuals).

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