PLUS Fall 2022

Over the past four decades, the occurrence of obesity has tripled in the United States with the prevalence of adult obesity and severe obesity estimated at 42.4% and 9.2%, respectively, with projections to 48.9% and 24.2% by 2030. ^1,2,3 Obesity is defined by a body mass index (BMI) between 30 to 39.9 kg/m2 with severe obesity (SO) defined by a BMI of greater than 40 kg/m2. With the patient population demonstrating increased tendency towards obesity, it is necessary to adapt medical procedures to provide accurate care for patient with SO. One such procedure that requires weight consideration in transfusion medicine is therapeutic plasma exchange (TPE).

In therapeutic plasma exchange (TPE), apheresis devices use Nadler’s formula using inputs of the patient’s height, weight, and gender to calculate total blood volume (TBV) and derive plasma volume (PV). Because adipose tissue is not as vascular as many of the other organs of the body, using the actual weight of SO patients can lead to an overcalculation of TBV and PV. This overcalculation can result in longer procedure times and use of excessive volume, increasing the risk of transfusion reactions when donor plasma is transfused.

There is a lack of literature providing guidelines for calculating plasma volume for TPE in patients with SO. To understand the practices of institutions performing TPE in SO patients, a nationwide survey was conducted at Thomas Jefferson University Hospital with findings recently published in the Journal of Clinical Apheresis [Babariya et.al.]. The survey asked questions about institutional practices for performing TPE on patients with obesity and used two hypothetical cases to evaluate how institutions determine PV for TPE. Out of the 144 academic institutions that were contacted, 45 (31%) responded. Nine (20%) out of 45 institutions had a policy to calculate PV for SO patients differently than nonobese patients. Seven (16%) institutions reported a specific BMI above which PV is altered for TPE. Seven (16%) respondents reported having a maximum PV limit when performing TPE on SO patients.⁴

Though approximately 80-85% of the respondents did not have a procedure for performing TPE on patients with SO, there was variability in how institutions chose to treat the hypothetical cases. In the first case, an AB-positive male with TTP and BMI of 49.5 was described. Only 36% of respondents chose to calculate PV using actual body weight, while 20% chose to use ideal body weight (IBW) and 44% selected “other”. In the second case, a female with myasthenia gravis and BMI of 49 was described, in which 56.5% of respondents chose to calculate PV using actual body weight, 15.5% using IBW, and 29% selected “other”. Of those that selected “other”, many of respondents had reported having an institutional policy while 30-40% of respondents selecting “other” did not.⁴

Weight modifications are used in other fields of medicine to determine TBV in patients with obesity. One such modification is the use of Lemmens-Bernstein-Brodsky formula which determines TBV in relation to IBW. Due to overprediction of TBV, this formula was developed to estimate fluid replacement in patients with obesity undergoing surgical procedures.⁵ In pharmacology and nutrition, it is common practice to use IBW and adjusted body weight to determine nutritional needs and dosing of medications because lean tissue is metabolically more active when compared to adipose tissue.^6,7

In conclusion, there was a great deal of variability in the answers provided by institutions responding to the survey mentioned above. Only a small minority of the institutions have set procedures for altering PV when treating SO patients with TPE. There is a need for further study to determine accurate PV for TPE in different weight classes to establish evidence-based recommendations.

By Shraddha Babariya, MD

American Red Cross Resources:

• A Compendium of Transfusion Practice Guidelines: an American Red Cross publication, with a chapter focused on the hospital transfusion committee. https://www.redcrossblood.org/content/dam/redcrossblood/hospital-page-documents/CompendiumofTransfusionPracticeGuidelines.pdf

• Therapeutic Apheresis: redcrossblood.org site that discusses American Red Cross clinical apheresis service offerings. https://www.redcrossblood.org/biomedical-services/specialty-services/therapeutic-apheresis.html

• Therapeutic Apheresis Fundamentals: SUCCESS educational offering, presented by Dr. Erin Goodhue. https://successeducationna134.force.com/s/learning-plan-detail-standard?ltui__urlRecordId=a2v4R000003uFeIQAU&ltui__urlRedirect=learning-plan-detail-standard

References:

• Fryar CD, et al. Prevalence of Overweight, Obesity, and Severe Obesity Among Adults Aged 20 and Over: United States, 1960–1962 Through 2015–2016. National Center for Health Statistics. Health E-Stats; 2018.

• Hales CM, et al. Prevalence of obesity and severe obesity among adults: United States, 2017–2018. NCHS Data Brief. 2020;360:1-8.

• Ward ZJ, et al. Projected U.S. state level prevalence of adult obesity and severe obesity. N Engl J Med. 2019;381(25):2440-2450. https://doi.org/10.1056/NEJMsa1909301

• Babariya SP, et al. Therapeutic plasma exchange in patients with severe obesity (BMI >40): A survey of practices in the United States. J Clin Apher. 2021;36(6):802-807. https://doi.org/10.1002/jca.21931

• Lemmens HJ, Bernstein DP. Brod sky JB. Estimating blood volume in obese and morbidly obese patients. Obes Surg. 2006;16:773-776.

Although blood transfusions can be lifesaving, unnecessary blood transfusions may cause adverse events and increase healthcare costs. Patient blood management (PBM) is an evidence-based approach for patient care that is focused on improving patient safety by treating anemia, minimizing blood loss during medical procedures, and avoiding unnecessary blood transfusions. In addition to improving patient outcomes and reducing costs, PBM programs may also help to reduce blood product wastage and conserve the blood supply to ensure that blood products will be available for patients who need them most.

Hospitals in Europe and Canada have employed Transfusion safety officers (TSO) to support their PBM programs for many years, and studies have found that having a TSO is associated with reduced red blood cell utilization, improved patient safety, and reduced blood product wastage. The TSO role has only more recently been adopted in the United States, and most hospitals have still not assigned personnel to this position. A 2017 survey published by Sapiano et al found that only 19.3% of U.S. hospitals employed a TSO.

The background, skills, and responsibilities of the TSO position may vary between PBM programs. A more recent survey of 104 hospitals in the United States, published by Jacobs et al, was performed to better understand the characteristics, background, and responsibilities of TSOs in hospitals that currently support this role. Most of the hospitals that were included in the survey were large academic centers connected with PBM-associated resource groups; 77% reported that their hospital had an active PBM program.

The survey found that 63% of responding hospitals have at least one TSO. This rate was much higher than reported in previous surveys, but it was expected since this survey was specifically targeted towards hospitals likely to have active PBM programs. In hospitals that currently employ a TSO, the educational background of the person in the role was most commonly nursing (61%), but several other backgrounds were also noted including business administration, specialist in blood banking, medical laboratory technology, perfusionist, and informatics.

Although TSO responsibilities may differ between among hospitals, there were several duties that were found to be common on this survey. TSOs are often involved with the hospital Transfusion Committee, and they are responsible for creating reports related to PBM goals, turn-around time, blood product expiration rates, and cost savings. They review orders that don’t meet hospital transfusion guidelines, monitor transfusion reactions and safety events, and collaborate with clinical teams to manage patients who are found to be anemic before a planned surgery. Educational responsibilities are also an important part of the TSO role, including developing and presenting educational programs and training for hospital staff on transfusion safety, blood administration, and informed consent.

Communication skills, collaboration ability, and persistence were identified as the most important skills of a TSO. Leadership skills and teaching ability were also recognized as valuable skills for TSOs given the importance of their educational responsibilities. Prior clinical or laboratory experience was considered to be less important when bringing on a new TSO, since that knowledge can be learned on the job.

Despite studies supporting the benefits of TSOs, hospitals reported several barriers to implementing a new TSO position as well as sustaining the TSO role. The most common challenges included budget constraints, lack of support and understanding of the value of the TSO position by hospital leadership and frontline clinical staff, and attrition since TSOs have specific training and expertise. Outcome data must be shared with hospital leadership to demonstrate the benefits of the TSO role.

TSOs serve an important role in supporting PBM programs and contributing to transfusion safety. The results of this survey may serve as a helpful resource for hospitals that are planning to implement a new TSO position.

American Red Cross Resources:

• A Compendium of Transfusion Practice Guidelines:  an American Red Cross publication, with a chapter focused on the hospital transfusion committee.  https://www.redcrossblood.org/content/dam/redcrossblood/hospital-page-documents/CompendiumofTransfusionPracticeGuidelines.pdf  

• Patient Blood Management: SUCCESS educational offering presented by Dr. Corinne Goldberg. https://successeducationna134.force.com/s/learning-plan-detail-standard?ltui__urlRecordId=a2v4R000003uFMHQA2&ltui__urlRedirect=learning-plan-detail-standard

• Transfusion Management and Blood Utilization: SUCCESS educational offering. https://successeducationna134.force.com/s/learning-plan-detail-standard?ltui__urlRecordId=a2v4R000000E4aaQAC&ltui__urlRedirect=learning-plan-detail-standard

References:

• Sapiano MRP, et al. Supplemental findings of the 2017 national blood collection and utilization survey. Transfusion 2020;60(Suppl. 2):S17–37.

• Jacobs J, et al. Transfusion safety officers in the United States: Survey of characteristics and approaches to implementation. Transfusion and Apheresis Science. 2021;60.

• Gammon RR, et al. Patient blood management—it is about transfusing blood appropriately. Ann Blood. 2022;7:21.

• Shander A, et al. A global definition of patient blood management. Anesth Analg. 2022 Feb 10.

• Levine RL, et al. The transfusion safety officer: an effective tool in patient blood management. Blood. 2015;126(23):4742.

• Dunbar NM, Szczepiorkowski ZM. How do we utilize a transfusion safety officer? Transfusion. 2015;55(9):2064-8.

Patients with SCD (Sickle Cell Disease) are more likely to have a severe COVID-19 disease course and a higher case-fatality rate in contrast to the general population. RBC (Red Blood Cell) transfusions are commonly given to patients with SCD and COVID-19. Hyperhemolysis syndrome (HHS) is an infrequent, severe hemolytic transfusion reaction primarily been described in patients with SCD (HbSS disease). HHS is characterized by rapid destruction of RBCs (red blood cells) from both donor and recipient, resulting in severe anemia to below pre-transfusion levels of hemoglobin and commonly reticulocytopenia. HHS can progress to multi-organ failure and death. The pathophysiology of HHS is not fully understood.

There are limited data to guide treatment of HHS, with avoidance of further transfusions and supportive care being the main therapies. Immunosuppressive therapy should be initiated promptly in patients with life-threatening hemolysis. More recent case reports have reported effective treatment outcomes with monoclonal antibodies such as rituximab, eculizumab, and tocilizumab. Tocilizumab, which blocks the interleukin-6 (IL-6) receptor and prevents macrophage response, has been used to treat various autoimmune conditions including macrophage activation syndrome (MAS), cytokine release syndrome (CRS), and most recently, patients with severe COVID-19 pneumonia. In June of 2021, the U.S. Food and Drug Administration (FDA) issued an Emergency Use Authorization for the use of tocilizumab in the treatment of COVID-19 in hospitalized patients.

The ARC (American Red Cross) National Reference Lab for Blood Group Serology (NRLBGS) recently encountered a patient with a history of sickle cell disease complicated by prior vaso-occlusive crises and acute chest syndrome coupled with recent SARS-CoV-2 infection, leading to pneumonia. The patient's antibody history included anti-Fy^a and a warm autoantibody. RBC antigen genotyping revealed the presence of the canonical mutation in the GATA binding site of the FY gene, resulting in loss of Fy^b expression on RBCs. Per SCD matching policy, the blood bank provided this patient with multiple RBC units appropriate for transfusion. Fourteen days after the last transfusion, the patient was readmitted due to chest and back pain with a significant drop in hemoglobin. Anti-N was identified by the regional IRL (Immunohematology Reference Lab), and additional units were transfused with no improvement in the patient’s hemoglobin. NRLBGS later identified additional anti-FY3/5, anti-Le^a and anti-Le^b as well as an antibody to a KN system antigen. The patient developed multi-organ failure and was successfully treated with a single dose of tocilizumab.

Several case reports that have shown success in treating HHS with tocilizumab; our patient showed dramatic improvement after initiation of tocilizumab. Additionally, serology showed a decrease in reactivity after starting tocilizumab, declining two grades in the repeat antibody screen. While there have been no clinical trials on tocilizumab’s efficacy in the treatment of COVID-19 pneumonia specifically in SCD patients, several recent publications suggest tocilizumab is helpful in this population.

In conclusion, the relationship between SARS-CoV-2 infection and HHS is not well understood, however, it is likely that COVID-19 can augment risk factors associated with the onset of HHS. The anti-IL-6R agent tocilizumab also shows potential to be an effective treatment for patients with SCD that develop HHS, including patients with recent SARS-CoV-2 infection.

By Paul M. Mansfield, MLS(ASCP)SBBCM 

References:

• Fuja C, Kothary V, Carll TC, Singh S, Mansfield P, Woo GD. Hyperhemolysis in a patient with sickle cell disease and recent SARS-CoV-2 infection, with complex auto- and alloantibody work-up, successfully treated with tocilizumab. Transfusion. 2022;62:1446 – 1471.

• De Luna G, Habibi A, Deux JF, et al. Rapid and severe Covid-19 pneumonia with severe acute chest syndrome in a sickle cell patient successfully treated with tocilizumab. Am J Hematol. 2020;95(7):876-878.

In the United States, and globally, the “REDS” moniker is well-known and widely regarded in the transfusion medicine community. Funded by the US National Heart, Lung and Blood Institute of NIH, the original REDS program (initiated in 1989 and renewed through 2001) stood for Retrovirus Epidemiology Donor Study and was introduced to address concerns for HIV and other infectious risks in the blood supply. Successive iterations have broadened the scope of the program, combining systematic data collection, laboratory and survey research, judicious use of stored repository samples, and rapid response capacity for newly emerging agents such as Zika or SARS-CoV-2 viruses. The REDS-II program from 2004-2012 continued its focus on blood donors and infectious disease, but enlarged the research portfolio to include non-infectious blood safety issues such as HLA antibodies in blood donors and risk for transfusion related acute lung injury (TRALI) and donation safety issues such as risk for iron depletion in blood donors. REDS-III was a 7-year program (2011-2018) that expanded the number of partners and investigator expertise by adding 12 hospitals that sourced blood from the 4 participating blood centers. Inclusion of data from blood recipients supported analyses of the epidemiology of plasma transfusion, functional improvement following red cell transfusion in elderly patients, and correlates adverse events following transfusion.

The latest and ongoing incarnation of REDS, called REDS-IV-P, reflects the natural progression of NHLBI’s interest in improving donation and transfusion safety as well as outcomes. Maintaining the same acronym while adjusting the name to capture its emphasis on non-adult patients who receive blood components (Recipient Epidemiology and Donor Evaluation Study), REDS-IV-P continues many activities of REDS-III but expands the patient base beyond adults to neonatal and pediatric patient populations. Begun in 2019 and funded for 7 years, REDS-IV-P will include as a key resource a vein-to-vein database allowing for statistical evaluation of donor-, manufacturing-, and patient-related factors that influence donation outcomes. While the importance of donor and patient characteristics is expected, examples of the manufacturing process that might alter component quality or potency include pathogen inactivation and gamma irradiation, especially if followed by prolonged storage.

The data are sourced from the program’s four domestic “hubs,” which like REDS-III consists of one or more blood centers partnered with at least one tertiary care hospital and one community hospital. The hubs are located in the Connecticut (Red Cross region), New York, Wisconsin, and California; as well as an international collaboration with Brazilian investigators, who had participated in REDS-III. Altogether, the REDS-IV-P program represents 22 hospitals (which includes 6 children’s hospitals). In addition, the program is to be supported by a central laboratory and a data coordinating center.

Aside from multiple data analyses leveraging linked donor-recipient variables, REDS-IV-P will also conduct stand-alone projects that are patient- and/or donor-facing. The TIPI Study (Transfusion in Preterm Infants), which is already underway, is designed to identify the donor, manufacturing, and patient factors that affect outcomes for very low birthweight (<1500 g) infants, about 50% of whom receive a blood transfusion.

The RBC Impact Study (RBC IMProving TrAnsfusions for Chronically Transfused Pediatric and Adult Recipients) focuses primarily on patients with sickle cell disease and thalassemia, populations that frequently receive red cell products as supportive therapy. The study will evaluate transfusion efficacy as a function of defined factors of both donor and recipient, as well as storage characteristics. These and several other epidemiological and laboratory studies are described in more detail in a recent Transfusion paper authored by Cassandra Josephson, et al.

Following the end of the REDS-IV-P program in 2026, much of the data from the database and from other studies will be deposited as public use datasets, in de-identified form, in the BioLincc database (https://www.biolincc.nhlbi.nih.gov/) for ongoing curation and availability as a resource to the transfusion medicine investigator community.

REDS-IV-P follows a strong legacy of contributions by REDS to blood safety and transfusion medicine, and the program is poised to continue this success with attention to understudied and underserved populations and to further the advancement of personalized medicine research. The REDS-IV-P program welcomes collaborations with outside investigators and interested parties should feel free to reach out to the author of this article or other co-authors of the Josephson paper.

By Bryan Spencer, PhD, MPH

Additional Resources:

• Red Cross Science Website: https://www.redcrossblood.org/biomedical-services/educational-resources/science.html

• REDS-IV-P Program Website: https://redsivp.com/

References:

• Josephson CD, et al. The Recipient Epidemiology and Donor Evaluation Study-IV-Pediatric (REDS-IV-P): A research program striving to improve blood donor safety and optimize transfusion outcomes across the lifespan. Transfusion. 2022 May;62(5):982-999.

• Kleinman S, et al. The National Heart, Lung, and Blood Institute Recipient Epidemiology and Donor Evaluation Study (REDS-III): a research program striving to improve blood donor and transfusion recipient outcomes. Transfusion. 2014 Mar;54(3 Pt 2):942-55.

• Kleinman S, et al. The National Heart, Lung, and Blood Institute retrovirus epidemiology donor studies (Retrovirus Epidemiology Donor Study and Retrovirus Epidemiology Donor Study-II): twenty years of research to advance blood product safety and availability. Transfus Med Rev. 2012 Oct;26(4):281-304, 304.e1-2.

Babesia is a red blood cell parasite and the agent of babesiosis. Ticks naturally transmit it to humans; however, the parasite can also be transmitted through blood transfusion. Healthy individuals can be infected without knowing it or may experience mild, flu-like symptoms; however, the disease can be severe and cause death in 5% of infected individuals with underlying conditions. The mortality rate for immunocompromised patients is 21%. In the past 50 years, hundreds of transfusion-transmitted Babesia (TTB) cases have occurred; from 2010 to 2020, the Red Cross investigated an average of 18 TTB cases per year and identified positive donors in about 60% of the cases.

Testing for Babesia is now part of routine blood screening in endemic areas of the United States. While this is a success story, the history of the implementation of Babesia screening is a long and complicated story. 

Several cases of transfusion-transmitted babesiosis (TTB) in highly endemic areas were reported in the literature between 1980 and 1986. The first published data concerning the antibody prevalence indicative of parasitic exposure in blood donors showed positive rates that were alarmingly high (3.7 to 4.7%) ^1,2 As this was still considered a relatively rare event, the only recommendation provided at this time to physicians was to include babesiosis in the differential diagnosis for a blood recipient experiencing a febrile response.

Babesia microti, the species responsible for most of the human infections in the US, has emerged as a public health issue, as did the recognition of TTB. A report published in 2011 described 159 US cases of TTB occurring between 1979 and 2009, 122 of which were reported between 2000 and 2009.³ At the same time, several publications reported on B. microti seroprevalence in blood donors residing in endemic areas of the Northeastern United States, with rates between 0.9% and 1.4% in Connecticut and on the offshore islands of Massachusetts. ^4,5

By 2010 it was clear that an intervention was needed to reduce transmission of B. microti to US blood recipients. So, why did it take so long for a screening test to be implemented? Several factors have contributed to this "perfect storm," starting with the geographically restricted distribution of the parasite. B. microti was primarily found in the Northeast and the upper Midwest. Testing blood donors residing in non-endemic states was deemed costly and unnecessary, and the prospect of developing a blood screening assay that would not be used nationwide seemed less than appealing for most test-manufacturers. However, shortly after 2010, various blood centers partnered with research companies to incorporate screening tests under FDA approved investigational new drug (IND) protocols. Although B. microti blood donation screening under IND had focused only on a limited geographic area, the impact was significant.⁶ The accompanying reduction of TTB cases in blood recipients from donors that live in endemic areas demonstrated that testing is a successful strategy. However, the initial investigational screening relied heavily, if not exclusively, on antibody testing, which can be positive years after the infection has resolved.

Without a donor re-entry policy in place, donors who tested positive by any single test (antibody or molecular) were permanently deferred, a costly price to pay for the blood establishments and patients. Some of the tests used under an Investigational New Drug protocol (IND) were abandoned along the way, but the combination of antibody and nucleic acid testing (NAT) performed by PCR tests developed by IMUGEN received FDA licensure in July 2018, and in the same year, the FDA released draft guidance with recommendations for reducing the risk of TTB by using the licensed two-test system. However, shortly after, and for financial reasons, IMUGEN discontinued B.microti blood donation screening.  By then, a new generation of NAT-only, more sensitive assays, were available and in use under IND protocols⁷ . Their better performance is due to their methodology which amplifies ribosomal RNA templates as well as DNA templates. These tests are used with today’s blood screening platforms, pooling several donor samples in a single test and therefore providing a significant financial advantages when screening a larger number of samples. Also, these new tests detect all four of the strains of Babesia known to infect humans. With implementation of these new testing strategies no case of TTB has been identified from a screened American Red Cross unit of blood.

As the new assays received FDA licensure in 2019, new recommendations for reducing the risk of TTB were released. The new guidance includes Babesia screening for all donation types collected in endemic areas and areas contiguous to endemic areas, which includes 14 states in the USA plus the District of Columbia. The exception is if pathogen inactivation is performed on a blood product, then Babesia testing is not required. The deferral for reactive donors was reduced to two years.

With the implementation of Babesia screening, the expectation is that the number of TTB cases will be reduced almost to zero. Travelers to endemic areas from non-endemic, non-screened states may still offer a risk, but these cases represent less than 2% of the total reported TTB cases. We are finally on the right path but should always remember to check for ticks!

By Laura Tonnetti, PhD and Sue Stramer, PhD

Links to Additional Resources/Information:

• ARC Infectious disease donor qualification information:  https://www.redcrossblood.org/biomedical-services/blood-diagnostic-testing/blood-testing.html

• AABB Babesiosis: https://www.aabb.org/regulatory-and-advocacy/regulatory-affairs/infectious-diseases/babesiosis

• Creative Testing Solutions Babesia: https://www.mycts.org/News/Videos

References:

• Tonnetti L et al. Babesia blood testing: the first-year experience Transfusion 2022. 62:135–142.

• Popovsky MA, et al.. Prevalence of Babesia antibody in a selected blood donor population. Transfusion 1988;28: 59-61.

• Linden JV, et al. Transfusion-associated transmission of babesiosis in New York State. Transfusion 2000;40: 285-9.

• Herwaldt BL, et al. Transfusion-associated babesiosis in the United States: a description of cases. Ann Intern Med 2011;155: 509-19.

• Leiby DA, et al. Demonstrable parasitemia among Connecticut blood donors with antibodies to Babesia microti. Transfusion 2005;45: 1804-10.

• Johnson ST, et al. Seroprevalence of Babesia microti in blood donors from Babesia-endemic areas of the northeastern United States: 2000 through 2007. Transfusion 2009;49: 2574-82.

• Tonnetti L, et al.The impact of Babesia microti blood donation screening. Transfusion 2019;59: 593-600.

• Tonnetti L et al. Detection of Babesia ribosomal RNA reveald a longer duration of parasitemia in infected blood donors. Transfusion 2019;59: 10A.