Historic and emerging trends in transfusion medicine: Maintaining relevance as a specialty

Progressive scientific advances continue to impact the field of transfusion medicine (TM). In this commentary, we present historical and emerging trends highlighting the evolving nature of this specialty. To remain relevant, TM practitioners must continuously adapt as alternatives to traditional modalities emerge. Developments such as red cell genotyping as an adjunct to traditional serologic phenotyping, the addition of nucleic acid amplification testing to successive refinements in serologic infectious disease marker testing, and the impact of evidence-based medicine on transfusion practice and patient blood management are a part of this tapestry—but these and many more are too numerous to cover in a single commentary. To support our premise, we will therefore focus on the development of alternatives and modifications to plasma and the evolving landscape of therapeutic apheresis and cellular therapy. Fresh frozen plasma (FFP—i.e., plasma frozen within 8 hours of collection to preserve thermolabile factors V and VIII) and its related product, cryoprecipitate, had been mainstays in the treatment of congenital bleeding disorders, namely hemophilia and von Willebrand Disease (VWD).1 Recognition of transfusion transmitted infections and development of more effective alternatives for the treatment of congenital bleeding disorders and factor deficiencies (see Table 1) demonstrates a key example of change in the TM specialty. To increase potency and efficacy, factor concentrates2 and methods for preparation of cryoprecipitate3, 4 were developed. The infectious complications of these non-pathogen reduced products5-8 led to improved manufacturing technologies9-11 and finally the emergence of recombinant clotting factors.12 With these scientific advances, FFP and cryoprecipitate have largely lost their historic indications for the treatment of hemophilia A and VWD (save for emergency settings where concentrates or recombinant factor products are unavailable). Cryoprecipitate was in use for the treatment of bleeding in VWD as late as 1995.13 Humate-P (CSL Behring GmBH, Marburg, Germany), first licensed in Germany in 1981 and in the United States in 1986 for the treatment of hemophilia A-related bleeding, became the gold standard for prophylaxis and treatment of bleeding in VWD.14 Since 1981, additional von Willebrand factor (VWF) concentrates, including Wilate (Octapharma USA, Inc, Paramus NJ, USA), Alphanate (Grifols Biologicals LLC, Los Angeles CA, USA), Biostate (CSL Behring, Broadmeadows VIC, Australia), and others have become available.15 Two high-purity VWF preparations are now available, including Wilfactin (LFB, Letchworth Garden City, UK)—a plasma derived VWF concentrate nearly devoid of FVIII, and VONVENDI (Baxalta, Lexington MA, USA)—a recombinant VWF that received US Food and Drug Administration (FDA) approval in 2015. The use of FFP, it could be argued, has also lost its indication for reversal of vitamin K antagonist effect. In 1942 Dicumarol emerged as a treatment for thrombosis and in 1948 its successor, warfarin, reached the marketplace.16 Rapid reversal of warfarin effect was carried out predominantly with FFP and vitamin K. In the early 2000s, numerous studies suggested superiority of prothrombin complex concentrates (PCCs) over plasma for rapid reversal of warfarin effect.17 Furthermore, between 2010 and 2012, approvals of the first three Direct Oral Anticoagulants (DOACs) heralded a coming change in the anticoagulation landscape—away from warfarin. In 2013, Kcentra (CSL Behring, Kankakee IL, USA), a 4 Factor PCC (4F-PCC), received FDA approval for warfarin reversal18 and subsequently, in 2014, the AABB chose to include “Don't routinely use plasma to reverse warfarin” as part of its American Board of Internal Medicine (ABIM) Choosing Wisely recommendations.19 Indeed, between 2013 and 2018, warfarin prescription volume decreased from 85.9% to 42.7% of all anticoagulant prescriptions among Medicare beneficiaries.20 In this context—as well as increased adoption over the last two decades of patient blood management principles—a nationwide reduction in distribution of plasma by 16.5% occurred between 2017 and 2019.21 Even prior to US market approval of Kcentra, alternatives to plasma and cryoprecipitate for single factor deficiencies had become established. By the late 1960s and early 1970s, clotting factor concentrates had become the predominant treatment modality in some areas for hemophilia A and B. Factor Eight Inhibitor Bypassing Activity (FEIBA—Takeda Pharmaceuticals, Lexington MA, USA), a PCC containing activated clotting factors, became available in 1976, with initial US approval in 1986.2, 22, 23 By the early 1990s, the first factor VIII (1992), IX (1997), and VII (1996—European Union; 1999—the United States) recombinant replacement products had become available.12 A bispecific factor IXa- and X directed antibody—emicizumab (Hemlibra—Genentech, South San Francisco, CA)—received FDA approval in 2017 for routine prophylaxis against bleeding in hemophilia,24 representing a novel departure from factor-based therapy in hemophilia management. For antithrombin deficiency, a plasma derived antithrombin concentrate, Thrombate III (Grifols Biologics LLC, Research Triangle Park, NC), received initial US approval in 1991. For factor XIII deficiency, a commercial FXIII concentrate became available in Europe in 1993.25 An FDA approved plasma-derived FXIII concentrate is available in the United States—Corifact (ex-US as Fibrogammin P, CSL-Behring, Kankakee IL, USA; US approval 2011)—that can be used for individuals with either subunit A or B deficiencies. A recombinant product is available for FXIII-subunit A deficiency (Tretten, NovoNordisk, Bagsvaerd, Denmark).26 Fibrinogen concentrates are also now available as alternatives to cryoprecipitate—including Riastap (approved 2009, CSL Behring, Kankakee IL, USA) and Fibryga (approved in 2017; Octapharma AB, Lars Forsells gata 23, Sweden). In 2014, recombinant porcine FVIII (Obizur—Takeda Pharmaceuticals, Lexington, MA) became available for management of on-demand treatment and control of bleeding episodes in patients with acquired hemophilia A,27 an indication for which off-label use of emicizumab has been reported.28 These trends have translated to worldwide growth in plasma-derived medicinal products (PDMPs), which include not just coagulation factors but also albumin, intravenous and subcutaneous immunoglobulins, and others. As a testament to this growth, the FDA since 2020 has provided biologic device application approvals for at least four new plasma collection systems29, 30 and the number of plasma donation centers in the United States grew from 300 to over 900 between 2005 and 2020 in support of a growth industry worth $4 billion in 2008, $21 billion in 2016, and forecast to reach $48 billion by 2025.31 For the TM specialist, therefore, it is important to understand alternatives to plasma as it pertains to growth in the source plasma market and future implications for plasmapheresis collections. Over the last decade, convalescent plasma has received attention in the wake of Ebola Virus Disease (EVD) outbreaks and the COVID-19 pandemic. In both instances convalescent plasma served a short-term role based upon lack of available treatments and was eventually surpassed due to lack of benefit and evolution of alternatives to plasma-based therapy. In 2014, the World Health Organization issued an interval guidance for use of convalescent whole blood or plasma as empiric treatments during EVD outbreaks.32 A subsequent non-randomized study infusing up to 500 mL of non-titered convalescent plasma to 99 patients showed no difference in mortality between the primary analysis group (n = 84) and that of a historical control group (n = 418).33 In a later EVD outbreak, four different non-plasma therapeutics were studied in randomized fashion: ZMapp (a triple monoclonal antibody agent), remdesivir (a nucleotide analog RNA polymerase inhibitor), MAb114 (a single human monoclonal antibody derived from an Ebola survivor), and REGN-EB3 (a mixture of three human IgG1 monoclonal antibodies). An interim analysis led to continuation only of the latter two treatment arms, which proved superiority to ZMapp in reducing mortality from EVD.34 The COVID-19 pandemic spurned issuance by FDA in August 2020 of an Emergency Use Authorization (EUA) for use of COVID-19 Convalescent Plasma (CCP) for treatment of hospitalized patients with COVID-19.35 Based upon data from clinical trials reported or analyzed since the original EUA was issued, in February of 2021, FDA revised the EUA to limit use to only high-titer CCP and among hospitalized patients. In March of 2021, the clinical trial of COVID-19 Plasma in Outpatients (C3PO) study was halted prematurely for absence of benefit36 and subsequently, the National Institutes of Health issued treatment guidelines recommending against the use of CCP in immunocompetent individuals and declaring insufficient evidence to recommend for or against its use among most immunocompromised individuals.37 Briefly, however, two monoclonal agents were available under EUA as alternatives to plasma-based therapy—sotrovimab (GlaxoSmithKline LLC, Philadelphia, PA) and bebtelovimab (Eli Lilly and Company, Indianapolis, IN)—until the emergence of high-frequency circulating SARS-COV-2 variants not susceptible to these formulations and subsequent declaration of an end to the pandemic on May 11, 2023.38-41 Variations of plasma, including FFP, plasma frozen within 24 hours of phlebotomy (FP24), and thawed plasma, do remain key components of trauma resuscitation and massive transfusion protocols, and remain alternatives to Kcentra if this agent is not immediately available. For single factor deficiencies, however, a wide range of factor concentrates and recombinant factors now offer alternatives to plasma and cryoprecipitate as replacement options. Transfusion medicine specialists need to be aware not only of indications for standard blood components, but of the alternatives as well. This is especially important in the setting of patient blood management and management of patients with bleeding disorders or religious restrictions to transfusion. Amid these changes, advances in blood safety progressed with entry into the US market of solvent/detergent-treated, pooled plasma—Octaplas (Octapharma, Paramus, NJ) in 2013 and market approval of the Cerus Intercept system for pathogen reduction of plasma and platelets in 2014. In November of 2020, Cerus gained approval of the Intercept Blood System for Cryoprecipitation. This system is used for the production of Pathogen Reduced Cryoprecipitated Fibrinogen Complex for the treatment and control of bleeding, including massive hemorrhage, associated with fibrinogen deficiency; simultaneously, approval was received for Pathogen Reduced Plasma, Cryoprecipitate Reduced for transfusion or TPE in patients with thrombotic thrombocytopenic purpura (TTP).42 Pathogen reduction technologies represent a paradigm shift away from the reactive nature of donor screening and testing to a proactive strategy that introduces an additional layer of protection against both known and emerging infectious diseases.43 The evolution of regulatory aspects of blood safety and availability also deserves mention. In 2014, the FDA launched the Transfusion Transmissible Infections Monitoring System (TTIMS) in the United States to monitor rates of relevant transfusion transmissible infections detected among blood donors before and after policy changes.44 In December of 2015, the FDA reduced the lifetime deferral period for male-sex-with-male (MSM) to 12 months. After careful evaluation of available data, including surveillance information and experience with 3-month deferral periods in other countries, and to improve blood availability during the COVID-19 pandemic, the deferral period for a number of risk factors—including MSM, tattoo or piercing, commercial sex work, transfusion or accidental needle stick, and injection drug use—was reduced in April of 2020 from 12 months to 3 months.45 In May of 2023, the FDA finalized recommendations for assessing donor eligibility using individual risk-based questions.46 Together, these regulatory changes, which were influenced both by data-driven decisions and a response to pandemic-related illness and blood shortages, contribute to the theme of continuous adaptation and emerging trends that contribute to the evolving nature of the TM specialty. In the mid-1970s, therapeutic plasma exchange (TPE), which can rapidly reduce titers of pathologic antibodies, became a therapeutic modality for the treatment of immune-mediated diseases.47 The literature in this area is extensively reviewed in the American Society for Apheresis (ASFA) evidenced based guidelines, most recently published in 2023.48 Over time, however, the emergence of newer immunosuppressive treatments such as rituximab, eculizumab, and now the Neonatal Fc Receptor (FcRN) blockers offer an alternative to TPE for lowering of pathologic antibody titers or their effects. A key disease process for which donor plasma is considered a first-line therapy is thrombotic thrombocytopenic purpura (TTP), a disorder in which deficiency of ADAMTS13 (A Disintegrin and Metalloproteinase with a thrombospondin type 1 motif, member 13) is a central feature. TTP can either result from a congenital absence of ADAMTS13—aka Upshaw Schulman Syndrome (congenital TTP or cTTP)—or through autoimmune depletion of ADAMTS13 through development of an inhibitor (idiopathic TTP, or iTTP). For cTTP, regular plasma infusions have been utilized but associated with allergic and other transfusion reactions. A monoclonal ADAMTS13 replacement product is under development which could replace donor plasma among cTTP patients.49, 50 For iTTP, TPE is a standard first-line modality. With each exchange, a volume to a volume-and-a half of plasma containing the inhibitor is removed, thus reducing its titer. Donor plasma, which contains ADAMTS13, is then used to replace the volume removed thus supplementing deficient ADAMTS13. However, donor plasma may not always be an option—for example, devout members of the Jehovah's Witness faith refuse on religious grounds transfusion of white blood cells, red blood cells, platelets, or plasma, but may accept fractions thereof.51 Instead, TPE can be conducted with an accepted media, such as albumin, and supplementation of deficient ADAMTS13 accomplished using ADAMTS13-enriched plasma fractions, provided they are acceptable to the individual patient. Reported fractions utilized in this circumstance include cryoprecipitate, cryo-poor plasma, Koate-DVI, and Alphanate.52 To reduce inhibitor levels, hasten remission, and prevent relapse, rituximab (Genentech, South San Francisco, CA) has entered standard practice for management of TTP.52 More recently, caplacizumab (Genzyme, Cambridge MA, USA), an anti-VWF humanized single-variable-domain immunoglobulin available for management of iTTP,53-55 received FDA approval in December of 2019 for the treatment of iTTP in conjunction with TPE. This approval was followed shortly thereafter by reports of iTTP managed without TPE and instead relying solely upon caplacizumab and medical immunosuppression.56, 57 These two options are acceptable in populations who might otherwise refuse standard blood products. Even the role of TPE itself is being reenvisioned with advancements in modern therapeutics. Its central mechanism in myasthenia gravis (MG), the lowering of pathologic Immunoglobulin G (IgG) autoantibody directed against acetylcholine receptor (AChR), is now possible with a recombinant intravenous product: Efgartigimod (Argenx Inc, Boston MA, USA), approved in December 2021 with a subcutaneous formulation approved in 2023. This IgG1 Fc fragment is a homodimer consisting of two identical peptide chains with affinity for FcRN.58 FcRN participates in the recycling of IgG thus extending its half-life by fourfold compared to those immunoglobulins (i.e., IgM or IgA) not recycled by FcRN.59 Inhibition of FcRN by efgartigimod produces reductions in IgG levels of similar magnitude to TPE.60 However, efgartigimod was not studied for acute MG crisis, which remains an ASFA Category I (Grade 1B evidentiary support) indication for TPE.48 For long-term treatment, TPE remains a Category II indication. In addition, the C5 blocker, eculizumab (Alexion Pharmaceuticals Inc, Boston, MA—purchased by AstraZeneca in 2021), received FDA approval for use in MG in 2017. Ravulizumab (Alexion Pharmaceuticals Inc, Boston, MA—purchased by AstraZeneca in 2021), a long-acting C5 blocker, gained FDA approval for treatment of MG in 2022. While MG patients in the pivotal phase III study of efgartigimod were ineligible if receiving long-term TPE management,61 such patients—particularly those with limited intravenous access options—could be converted to this agent as a TPE alternative. For MG as an immunologic side effect of immune checkpoint inhibitor therapy, international consensus guidelines for management of MG regard TPE as a therapeutic option.62 While efgartigimod is currently the only FcRN blocker on the market, others are in the pipeline and under study for such disorders as chronic inflammatory demyelinating polyneuropathy (CIDP—a Category I indication for TPE48), immune thrombocytopenic purpura (ITP), warm autoimmune hemolytic anemia (WAIHA), and hemolytic disease of the fetus and newborn (HDFN).63-65 In Neuromyelitis Optica Spectrum Disorder (NMOSD), the implicated autoantibody is directed against aquaporin 4 (AQP4) and acute attacks or relapses bear an ASFA 2023 Category II indication for TPE, whereas maintenance therapy bears a Category III indication for TPE.48 Eculizumab received FDA approval in 2019 for use in anti-AQP4 positive NMOSD. In addition, Satralizumab (Genentech, South San Francisco, CA), a recombinant, humanized anti-human IL-6 receptor monoclonal antibody, was approved in 2020 for treatment of anti-AQP4 positive NMOSD. For NMOSD patients on maintenance TPE, these agents represent additional treatment options which in some circumstances might displace TPE. Autoimmune diseases, in fact, are now under study as a target for chimeric antigen receptor-T cell (CAR-T) therapy.66 The prospect of cellular therapy in this arena may therefore reduce the need for TPE albeit with a concomitant rise in leukapheresis collections. The evidentiary support for use of TPE is evolving, and this will impact its utilization. In the latest edition of the ASFA guidelines, several indication categories have been modified, as summarized in Table 2.48 These changes include the addition of seven new fact sheets and three diseases/conditions newly incorporated into existing fact sheets. In one market analysis, compound annual growth rate (CAGR) in the global TPE market was estimated at 7.5% from 2018–2026 with valuation of $1 billion in 2017 and estimated to reach $2 billion by 2026.67 This was in general agreement with another analysis assessing CAGR at 6.3% with market valuation of $1.2 billion in 2022 and estimated to reach $1.9 billion by 2030.68 To remain relevant in apheresis medicine, therefore, TM specialists must stay abreast not only of the evolving indications for TPE, but also of TPE alternatives and adjunctive agents. The growth in TPE is being surpassed by expansion in the cellular therapy arena. In a 2019 letter by then FDA commissioner Scott Gottlieb and Center for Biologics Evaluation and Research (CBER) director Peter Marks anticipated that by 2020 FDA would be receiving more than 200 Investigational New Drug (IND) applications per year, building upon a total of more than 800 active cell-based or directly administered gene therapy INDs already on file with FDA. Based upon assessment of current pipeline and clinical success rates for these products, FDA predicted that by 2025, it will be approving 10–20 cell and gene therapies per year.69 The current list of FDA-approved cellular and gene therapy products is already 28 items long as of this writing.70 Indeed, the global cellular therapy market size was valued at $15 billion in 2021 (with a research use segment accounting for 62% of revenue share) and projected growth at a CAGR of 14.9% from 2022 to 2030.71 The proliferation of cellular therapy trials has led to the reorganization of CBER's Office of Tissues and Advanced Therapies (OTAT) into the Office of Therapeutic Products (OTP), and elevation of OTP to a Super Office that oversees an expansion of review capabilities with enhanced expertise in new cell and gene therapies, for which the majority involve leukapheresis collected source material.72-74 Even the primary accrediting body for the TM specialty has been impacted by expansion of the cellular therapies arena. In October of 2021, the AABB announced a logo and name change to the Association for the Advancement of Blood and Biotherapies.75 In recognition of these trends, the AABB and other organizations have increased their cellular therapy-related educational offerings. Examples of online options include the AABB Cellular Therapies Certificate Program,76 AABB Foundations in Cellular Therapy Course,77 and Massachusetts Institute of Technology Exchange (MITx) Making a Cell Therapy: Principles and Practice of Manufacturing.78 University of California, Davis offers a cellular therapy course with option for hands-on training79 and examples of dedicated Cellular Therapy fellowship training programs include those at the Mayo Clinic80 and the University of Pennsylvania.81 The continual evolution of transfusion medicine and growth of cellular therapies may not, however, be matched by a commensurate increase in TM physicians. Pathology is the only residency that has a minimal requirement for apheresis training and blood banking/transfusion medicine (BB/TM), the only fellowship to include apheresis training in their milestones to achieve the highest level of expectations.82 For the 2017–2018 training year, the total number of anatomic and clinical pathology residents was 2258 with only 50 (2.2%) listed as active trainees of BB/TM programs. For the same year, nephrology and hematology/oncology trainees—comprising other specialties who might receive apheresis training—represented only 3.3% and 6.5% of internal medicine trainees, respectively.83 For the 2020–2021 training year, numbers were similar—with BB/TM fellows numbering 45/2281 (2.0%), pathology trainees and hematology/oncology and nephrology representing 2.9% and 6.6% of internal medicine trainees.84 While BB/TM fellowship training programs have witnessed a small increase in number—from 49 in 2016 to 52 in 2020—the annual fill rates of 66.2% (or about 54 trainees per year) has remained relatively static.85 The importance of dedicated apheresis medicine training as it pertains to patient safety should also be a key consideration for physician credentialing.86 Furthermore, a survey of BB/TM program directors found that while training in progenitor/mononuclear cell collection was deemed adequate, there exists a need to bolster cellular therapy laboratory training.87 It is also important to note, that a workforce shortage is evident in terms of cellular therapy laboratory technologists—an additional area where expansion of education, training, and certification options is needed.88, 89 Given the landscape of apheresis medicine and projected demand, an increased emphasis in apheresis training, as well as training in cellular therapy laboratory management and operations, is needed. The BB/TM fellowship remains a key contributor to these endeavors and board certification provides evidence of competence. In addition, a Qualification in Apheresis (QIA) certification became available as of January 2016 as a means of further establishing specialist credentials in all areas of apheresis.90, 91 Also, an examination-based Certified Advanced Biotherapies Professional (CABP) credential administered by the AABB92 became available in 2022. Maintenance of this credential requires evidence of continuing education in CABP examination domains. Specialists in transfusion medicine have seen FFP and cryoprecipitate overtaken by safer, more potent factor concentrates and recombinant products for the treatment of hereditary bleeding disorders. A 4F-PCC has been available since 2013 as an alternative to plasma for reversal of warfarin—the use of which is declining owing to the rise of DOACs. To be good stewards of blood products, knowledge of alternatives to blood products is needed. In addition, the growth in PDMPs has fueled significant expansion and projected growth in source plasma collections—thus prompting an increase in number of approved apheresis-based collection instruments and number of plasma donation centers. Advances in immunotherapy offer potential alternatives to plasma exchange in certain areas, whereas therapeutic apheresis indications are expanding in other areas. The field of cellular therapy is experiencing especially rapid growth. This growth has not, however, been matched by an expansion of TM and cellular therapy specialists. While TM fellowships are available, they do not consistently fill even though current TM opportunities are abundant. There exists a need, therefore, to address the pipeline problem for the TM specialty—increasing awareness of this specialty among non-pathologist primary trainees may be one strategy. Development of formal training in cell therapy and engineering should be further developed, promulgated, and perhaps recognized by accreditation organizations such as the American Council for Graduate Medical Education (ACGME). Also, expansion of training opportunities and certification pathways for cellular therapy laboratory technologists is also of key importance. This study was conducted without external funding. MHT–No conflicts to disclose. GM–Relationship to AABB (authorship, editorial board, committees, etc.): Team leader, Annual Meeting Education Committee (2020-Present). Member, Perioperative Accreditation Committee (2021-Present). Member, Pediatric Transfusion Safety Subsection (2021-Present). Member, Hospital-Based Blood Collectors Forum (2021-Present). Member, Annual Meeting Education Committee (2019-2020). SB–No conflicts to disclose. JS–Relationship to AABB (authorship, editorial board, committees, etc.): Chair, Publications committee.