PLUS Current Issue

Is Sporadic Creutzfeldt-Jakob Disease Transfusion-Transmissible?

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of extremely rare and fatal neurodegenerative diseases. TSEs are caused by the buildup of prions (PrP^TSE), proteins that cause normal proteins(PrP^C) in the brain to fold improperly.¹ Creutzfeldt-Jakob disease (CJD) is the most common prion disease in humans and can be subclassified as sporadic (sCJD), familial (fCJD) which is an inherited form, or iatrogenic (iCJD) which is due to medical treatment. There is also a variant form of CJD (vCJD), linked to consuming beef contaminated causing TSE bovine spongiform encephalopathy (commonly known as Mad Cow’s Disease).^2,3

The normal PrP^C is expressed in all mammalian tissues, including humans. In blood, PrP^C is mostly found in plasma, but is also present in white blood cells and platelets^4,5. Based on the widespread expression of PrP^Cand infectivity of PrP^TSE in non-neuronal tissues, especially in patients with vCJD^6,7, investigators raised concerns about the potential transfusion transmissibility of prion diseases. While CJD is not known to be transfusion-transmitted, the same cannot be said of vCJD. To date of the 177 UK vCJD cases, only 18 individuals had donated blood components that were subsequently used and traced to identified recipients. Four recipients of components from three donors died of TT-vCJD ^8,9 and a probable fifth case in a hemophilia patient¹⁰ has been reported in the United Kingdom (UK).

While experimental evidence indicates that blood from some sCJD patients harbors infectivity, data from several case-control^11,12 and lookback studies show no evidence of transfusion-transmission of sCJD. The Red Cross, in collaboration with and funding from the US Centers for Disease Control and Prevention (CDC), is conducting a lookback study on the transmission risk of the non-variant forms of CJD through blood transfusion. The study has been active since 1995, and in 2017 the most recent results were published in Transfusion.¹³

Currently, through a study funded through a five year contract, the Red Cross study has enrolled 79 CJD diagnosed blood donors who gave 1,954 donations (median 18 donations per donor). From those donations, 1,056 traceable transfused recipients have been identified for the study. According to the most recent National Death Index search, 814 recipients are deceased and 242 are alive, with no reported CJD transfusion transmission. These results are comparable to those of UK’s Transfusion Medicine Epidemiology Review (TMER) and Denmark/Sweden’s SCANDAT2 study.^{14, 15} Collectively these three studies contributed 147 donors and more than 13,900 person-years of follow-up. The results of these studies strongly indicate that the transfusion-transmissibility of sCJD remains theoretical. If sCJD is transmissible via blood, it is undoubtedly less infectious than vCJD.

Because of these findings, in April 2020, the US Food and Drug Administration (FDA) released “Recommendations to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Components Guidance for Industry”.¹⁶ This document recommended the removal of deferral status to what was previously considered CJD exposure risks, including the consumption of UK-sourced beef on US military bases; clinical treatment with human-derived growth hormone; and self-identified donors who have a blood relative with CJD.

Altogether, the data summarized above, highlight the relevance of lookback studies to inform policy changes and the importance of continuing surveillance of human prion diseases to ensure the safety of the blood supply.

Link to abstract:

Is Sporadic Creutzfeldt-Jakob Disease Transfusion-Transmissible?

Paula Saá PhD & Whitney Steele, PhD, MPH

References

1. Prusiner SB. Prions. Proc Natl Acad Sci U S A 1998; 95: 13363-83.

2. Hill AF, Desbruslais M, et al. The same prion strain causes vCJD and BSE. Nature 1997;389: 448-50, 526.

3. Head MW. Human prion diseases: molecular, cellular and population biology. Neuropathology 2013; 33: 221-36.

4. Choi EM, Geschwind MD, et al. Prion proteins in subpopulations of white blood cells from patients with sporadic Creutzfeldt-Jakob disease. Lab Invest 2009; 89: 624-35.

5. Holada K, Vostal JG. Different levels of prion protein (PrPc) expression on hamster, mouse and human blood cells. Br J Haematol 2000; 110: 472-80.

6. Ramasamy I, Law M, et al. Organ distribution of prion proteins in variant Creutzfeldt-Jakob disease. Lancet Infect Dis 2003; 3: 214-22.

7. Wadsworth JD, Joiner S, et al. Tissue distribution of protease resistant prion protein in variant Creutzfeldt-Jakob disease using a highly sensitive immunoblotting assay. Lancet 2001;358: 171-80.

8. Hewitt PE, Llewelyn CA, et al. Three reported cases of variant Creutzfeldt-Jakob disease transmission following transfusion of labile blood components. Vox Sang 2006;91: 348.

9. Peden AH, Head MW, et al. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 2004;364: 527-9.

10. Peden A, McCardle L, et al. Variant CJD infection in the spleen of a neurologically asymptomatic UK adult patient with haemophilia. Haemophilia 2010;16: 296-304.

11. Collins S, Law MG, et al. Surgical treatment and risk of sporadic Creutzfeldt-Jakob disease: a case-control study. Lancet 1999;353: 693-7.

12. Zerr I, Brandel JP, et al. European surveillance on Creutzfeldt-Jakob disease: a case-control study for medical risk factors. J Clin Epidemiol 2000;53: 747-54.

13. Crowder LA, Schonberger LB, et al. Creutzfeldt-Jakob disease lookback study: 21 years of surveillance for transfusion transmission risk. Transfusion 2017;57: 1875-8.

14. Urwin PJ, Mackenzie JM, et al. Creutzfeldt-Jakob disease and blood transfusion: updated results of the UK Transfusion Medicine Epidemiology Review Study. Vox Sang 2016;110: 310-6.

15. Holmqvist J, Wikman A, et al. No evidence of transfusion transmitted sporadic Creutzfeldt-Jakob disease: results from a bi-national cohort study. Transfusion 2020;60: 694-7.

16. Food and Drug Administration USDHHS. Recommendations to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Components [monograph on the internet]. 2020. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/recommendations-reduce-possible-risk-transmission-creutzfeldt-jakob-disease-and-variant-creutzfeldt

Links to Additional Resources/Information

a. ARC, current donor eligibility: https://www.redcross.org/about-us/news-and-events/press-release/2020/red-cross-to-implement-fda-eligibility-changes.html

b. CDC, general information: https://www.cdc.gov/prions/cjd/index.html

c. FDA, recommendation to reduce transfusion transmission: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/recommendations-reduce-possible-risk-transmission-creutzfeldt-jakob-disease-and-variant-creutzfeldt

National Death Index: https://www.cdc.gov/nchs/ndi/index.htm

Iron Deficiency Status of Blood Donors – New Insights

Iron depletion (ID) occurs frequently in blood donors as each whole blood donation removes about 250 mg of iron from the body. This represents approximately one-fourth of the iron stores of the average male donor and close to 100% for many female donors. If the body’s iron, a key element in the production of new red blood cells and hemoglobin (the oxygen carrying protein in the red blood cells storage) is further reduced, the blood donors can develop a condition called iron deficiency anemia (IDA). Symptoms are more likely with IDA than with ID alone. IDA can have a direct impact on blood centers as it decreases blood collections due to placement of donor deferral from low donor hemoglobin counts.

The prevalence of iron depletion and its relationship with blood donation has been the focus of many recent studies. It is now clear that many blood donors experience this condition, with approximately 13 to 17% of US blood donors estimated to have fully depleted iron stores. ID is identified when the donor’s plasma is tested for ferritin, a protein that stores iron throughout the body. Recovery of iron loss from a single donation can take more than six months, far longer than the required minimum interval of 8 weeks between donations.

Industry consensus recommends iron supplementation (multivitamins containing iron or strictly iron supplements) to “frequent donors” who are at risk for iron deficiency, and who are generally defined as females who donate blood twice a year or males who donate three times annually. Use of supplemental iron is known to facilitate the recovery of both iron stores and therefore hemoglobin counts following donation, but few blood collectors in the US directly provide iron pills to their donors. One reason is an incomplete understanding of who would benefit from increasing iron intake.

A recent study involving the American Red Cross sought to better define which donor populations might benefit from oral iron consumption, by determining the recovery rate of iron storage and the manufacture of new red cells. Three groups of blood donors were studied with differing iron status (<12, 12 – 50 ≥ 50 ng/mL) before undergoing collection of a whole blood unit. Subjects were randomized to receive daily iron pills vs no pills; follow-up samples were drawn at 7 time points post-donation. Then the individuals were assessed to determine how iron altered the recovery efforts over 24 weeks.

The primary finding was that iron supplements helped recovery of many biomarkers of iron storage for when the pre-donation plasma ferritin was <50 ng/mL; whereas for subjects with initial ferritin ≥ 50 ng/mL, results were comparable to those not taking iron. Subjects in the defined iron deficient group, with ferritin <12 ng/mL, and who did not take iron were found to be in negative iron balance during the entire 24-week follow-up. In contrast, iron deficient donors taking iron pills reached positive iron balance at the 2-week mark. The intermediate group, with ferritin 12-50 ng/mL, recovered to baseline values by 8 weeks post-donation, if iron supplementation was accepted. For those above 50 ng/mL, the use of iron supplementation did not impact the tested biomarkers [storage iron, RBC iron, and TBI]. Similarly, recovery kinetics of erythropoietin, a hormone required for red cell manufacture, were virtually identical regardless of iron dosage taken if baseline ferritin ≥ 50 ng/mL; but recovery was greater for those with lower index iron status.

While the study contributes to the academic literature on iron metabolism, there is a take-home message for blood centers, too. We estimate that at least 25% of male donors and 50% of female donors have ferritin levels < 50 ng/mL; however, a separate Red Cross study shows only 20% of blood donors report taking iron. Though formidable obstacles exist to blood center distribution of iron pills, these findings point to the need for enhanced education to promote donor self-initiation of iron supplementation. The result should be better donor health, and stronger donor retention.

Link to abstract:

Iron Deficiency Status of Blood Donors – New Insights

Bryan Spencer, PhD

Links to Additional Resources/Information

a. ARC donor information: https://www.redcrossblood.org/donate-blood/blood-donation-process/before-during-after/iron-blood-donation.html

b. ARC donor information #2: https://www.redcrossblood.org/donate-blood/blood-donation-process/before-during-after/iron-blood-donation/donors-deferred-forlowhemoglobin.html

The long road to Babesia blood donation screening

Testing for Babesia, a parasite reportedly involved in over 200 cases of transfusion-transmission, 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 based on 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!

Link to abstract:

The long road to Babesia blood donation screening

Laura Tonnetti, PhD and Sue Stramer, PhD

References

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

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

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

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

5. Johnson ST, Cable RG, 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.

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

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

Links to Additional Resources/Information

a. Tracking of donor reactivity: https://www.redcrossblood.org/biomedical-services/educational-resources/science/tracking-of-donation-reactivity.html

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

c. AABB Babesiosis: http://www.aabb.org/advocacy/regulatorygovernment/donoreligibility/babesiosis/Pages/default.aspx

d. Creative Testing Solutions Babesia: https://www.mycts.org/Whats-New/Videos

Stop Bugging my Platelets

Bacterially contaminated platelets pose the greatest risk of transfusion-transmission infection (TTI) in comparison with other blood products. The rate of adverse reactions resulting from transfusion of contaminated platelets is extremely low with between 1 and5 reported instances from approximately 2 million platelet transfusions per year^1,2. However, this low rate is attributed to underreporting so that contaminated platelets remain a significant TTI risk. The FDA addressed this issue in September of 2019, in a final guidance with steps that blood centers must take in the 18 months following the release of the guidance. Bacterial risk control mitigations set forth by FDA in this guidance are secondary rapid testing, sampling and culture strategies, and pathogen reduction (PR). This brief discussion will only address platelets with a 5-day shelf-life, stored at room temperature.

Rapid (point of issue) tests such as the Verax Pan Genera Detection (PGD) test³may be part of a two-step safety strategy. This handheld immunoassay, which costs ~$30 per test, is designed to detect a broad spectrum of both aerobic and anaerobic bacteria with a sensitivity as low as 10³ to 10⁵ CFU/mL. Limitations and challenges of the PGD test include implementation, the need for additional testing to confirm an initial positive result, and a significant false positive rate (0.51%).

A recently published article investigated the number of PGD-positive test results between 2013 and 2018 using the Red Cross hemovigilance database; a total of 475 initially reactive PGD tests were identified of which only 1.5% turned out to be true positives. ⁴ Despite the increasing number of initially reactive PGD tests reported by hospitals to the Red Cross in five years’ time the total number of reports remains low (Chart 1). Notably, a disproportionate number of positives were reported when testing whole blood-derived platelets. The article stated that in 2018 alone, 93 presumed positive PGD tests were reported and the estimated cost to the Red Cross as calculated from the investigations of 64 hospital reports was $87,000. This figure includes the cost of the platelets, any non-platelet co-components, the labor involved in managing the positive cases, and the ‘loss’ of units not collected due to the resulting donor deferral that is applied while investigating for bacterial contamination. Based on their analysis the authors conclude that initially reactive PGD test results have an adverse impact both on platelet inventories and blood center costs. The authors note that the test may have been more widely adopted by hospitals not served by the Red Cross.

The strategy of large-volume delayed sampling (LVDS) involves taking larger volumes from each platelet unit and inoculating the sample into aerobic and anaerobic culture media 36-48 hours after collection, rather than 24-hour interval that is now widely used. The greatly increased sample volume of at least 16 mL per unit, and additional time prior to sampling may coax any bacteria present to grow. LVDS is a single-step strategy as no other steps need to be taken prior to transfusion.

In another option, if the first (primary) culture is taken and inoculated into aerobic and anerobic media no sooner than 24 hours, the product may be transfused up to three days (even though it is a 5-day product) after which time a secondary culture must be taken prior to transfusion. Please refer to the FDA guidance for additional details.

Chart 1. Reactive PGD Tests Reported to Red Cross 2013-2018

As an alternative to the measures discussed above, the FDA recognizes the use of pathogen inactivation technology to produce pathogen reduced (PR) platelets. This method, developed by Cerus Corporation, exposes an apheresis collected platelet to an amotosalen compound and UV light to virtually eliminate most infectious agents, which obviates the need for any additional bacterial testing. The safety of PR products

In summary, FDA considers LVDS (no sooner than 36 hours after collection) and PR to be single-step strategies as no other steps must be taken prior to release for transfusion. All work is performed by the blood center which simplifies the process for the blood bank or transfusion service. Two-step strategies involve a primary culture at the 24-hour mark followed by a rapid test prior to transfusion; or, a primary culture taken at the 24-hour mark followed by a secondary culture at the 3-day mark. Two-step strategies may need to be performed both at the blood center and at the blood bank or transfusion service.

Link to abstract:

Stop Bugging my Platelets

Liz Marcus, BSc, PMP

References

1. Ramirez-Arcos S, DiFranco C, McIntyre T, et al. Residual risk of bacterial contamination of platelets: six years of experience with sterility testing. Transfusion 2017; 57:2174-81.

2. Katus MC, Szczepiorkowski ZM, Dumont LJ, et al. Safety of platelet transfusion: past, present and future. Vox Sang. 2014; 107:103-13

3. Bacterial risk control strategies for blood collection establishments and transfusion services to enhance the safety and availability of platelets for transfusion: guidance for industry. 2019.Available from: https://www.fda.gov/media/123448/download.

4. Rios J, Westra J, Dy B et al. Adoption trends of point of issue Verax PGD rapid test for bacterial screening of platelets between 2013 and 2018 among hospitals supplied by the American Red Cross and impact on platelet availability. Transfusion 2020; 60: 1364-72.

Links to Additional Resources/Information

a. FDA Bacterial Risk Control Strategies, 2019 Guidance: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/bacterial-risk-control-strategies-blood-collection-establishments-and-transfusion-services-enhance

Convalescent Plasma Collections for the Treatment of COVID-19: the American Red Cross Experience

The World Health Organization declared COVID-19 a global pandemic on March 11, 2020, and as case numbers rose, COVID-19 began to change the shape of our world: how we conduct business, how we travel, how we educate our children, and how we visit family and friends. With the ever-increasing number of people dying and with no proven cure or treatment in sight, the medical community quickly turned its attention to convalescent plasma, a blood product with historical potential in the support of clinical intervention of past viral pandemics.

Convalescent plasma is the straw-colored liquid portion of blood, rich with antibodies which may provide a passive form of immunological defense against an offending pathogen. Its use as a therapy against infectious disease dates to the 1800s in the treatment of diphtheria. Though many people are unaware, history records convalescent plasma resurgences in various infectious disease pandemics and outbreaks including the 1918 Spanish influenza pandemic, 1920’s scarlet fever and, most recently in the past two decades, during the Ebola outbreaks, as well as the SARS and H1N1 influenza virus pandemics.

As the nation’s largest blood supplier, hospitals large and small look to the American Red Cross for support to meet their transfusion needs, of which our newest available product line is the COVID-19 Convalescent Plasma (CCP). In the weeks that followed the WHO declaration of the COVID-19 pandemic, interest for CCP grew and the American Red Cross evaluated the feasibility of mass production of the product. The organization rapidly mobilized their operations to develop work flows, procedures, and to train numerous staff. The phrase often heard was that this endeavor felt like trying to build a plane already in flight.

The FDA invited the American Red Cross to be the clearinghouse for this new product and began permitting physicians to transfuse CCP to individuals with severe-to-life-threatening disease as an emergency Investigational New Drug (eIND). Mayo University broadened access to CCP by inviting hospitals to register under their Expanded Access Protocol (EAP) and the Biomedical Advanced Research and Development Authority (BARDA) joined the endeavor by funding its production. Individuals with severe disease, often in the ICU and requiring mechanical ventilatory support, were among the first to receive the standard dose of one unit of CCP, with the hope that the influx of antibodies would supplement the patient’s own immune system, target the virus to help clear it from the body, thus expediting recovery.

The American Red Cross collected its first unit of CCP on April 1^st in Pennsauken, New Jersey, a region hit particularly hard by the first wave of the virus. Unlike a standard blood donation, CCP is collected on an apheresis machine, an instrument that withdraws blood from the donor and separates the plasma from the cellular components, which are returned to the donor. One collection can yield up to four units of CCP. Initially identification of donors was dependent on hospitals directing patients who had recovered from the viral infection, that is until ARC launched a web-based registration process that screened any individual with confirmed COVID-19 diagnoses and who were recovered for at least 14 days. Donors must meet standard eligibility requirements and CCP undergoes all the usual rigorous tests for infectious disease. On April 27^th, COVID-19 antibody screening was implemented on all CCP collections, widening the pool of eligible donors and allowing reliable testing for the presence of the therapeutic antibodies.

By the end of July, the American Red Cross had distributed close to 20,000 units of COVID Convalescent Plasma and the efforts continue as the virus rages on. The support of donors, volunteers, organizations, hospitals, and an extraordinarily committed staff have demonstrated how the stalwart resolve of the component parts of a community can help a nation navigate the unchartered waters of a global pandemic, exemplifying the American Red Cross’ mission to prevent and alleviate human suffering.

Baia Lasky, MD

Links to Additional Resources/Information

a. ARC donor schedule: https://www.redcrossblood.org/donate-blood/dlp/plasma-donations-from-recovered-covid-19-patients.html

b. ARC clinician information: https://www.redcrossblood.org/donate-blood/dlp/plasma-donations-from-recovered-covid-19-patients/clinician-registration.html

c. ARC tracking of COVID-19 donation reactivity: https://www.redcrossblood.org/biomedical-services/educational-resources/science/tracking-of-donation-reactivity.html

d. ARC video by Dr. Erin Goodhue: https://www.redcross.org/about-us/news-and-events/news/2020/how-you-can-help-patients-battling-covid-19-by-donating-convalescent-plasma.html

e. FDA Preparedness & Response COVID-19: https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/donate-covid-19-plasma

f. Creative Testing Solutions COVID-19: https://www.mycts.org/Resources/COVID-19