Demand forecast for plasma collections

Introduction: global demand for plasma-derived (pd) products is driving collection growth

Over the past 5 years, demand for pd products increased globally by a compound annual growth rate (CAGR) of about 7% across all product types [a retrospective meta-analysis of public sources (1-6) was performed and combined with proprietary data from Adivo’s electronic medical record (EMR) derived patient data (data not shown)]. The main value driver of pd product demand continues to be the immunoglobulin (Ig) fraction (derived from fractions II + III) with a 5-year CAGR of about 10% and a total global market size of nearly $19 billion [United States dollar (USD)] in 2023 [proprietary Adivo EMR-derived data—data not shown]. Following Ig, Albumin holds the second-largest share of the global market at 18–20% (valued at $6 billion, with a ~6% 5-year CAGR), while Coagulation products rank third (proprietary Adivo EMR-derived data—data not shown). Other pd-products [pdC1-inhibitors, alpha-1 antitrypsin (AAT), etc.] each contribute a smaller revenue contribution.

In addition to representing the primary value driver of plasma products, Ig also sets the pace for the growing demand for plasma collections. As manufacturers optimize plasma utilization for Ig purification, they base their plasma collection infrastructure and volume growth strategies on the rising demand for Ig. Therefore, to fully understand and forecast the need for future plasma collections, it is essential to understand the dynamics of Ig therapy demand.

Ig—the major driver of pd-product use globally

Ig products drive value globally due to their broad range of clinical applications, particularly in immunodeficiency treatment. Most notably, their primary use is as an Ig replacement therapy (IgRT) for primary immune deficiencies (PID), where Ig is the only available treatment option. They are also widely used in managing secondary immune deficiencies (SID), which are acquired during a patient’s life through conditions such as chronic lymphocytic leukemia (CLL), lymphoma, and myeloma, or as a result of therapeutic agents targeting the immune system, such as anti-CD20 monoclonal antibodies (aCD20 mAbs). Typically, immunodeficient patients are dosed at 0.4–0.5 g/kg/month to maintain sufficient IgG levels to combat infections (7,8). However, Ig is also frequently used at higher doses (1 g/kg every 3–4 weeks) to achieve an immunomodulatory effect in autoimmune conditions characterized by the production of autoantibodies against otherwise “healthy” tissues or cells (9). Generalized myasthenia gravis (gMG), Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN) and several other autoimmune motor neurological diseases are recognized indications for Ig therapy, with varying frequency of use. Additionally, Ig is used in the treatment of other autoimmune conditions such as immune thrombocytopenic purpura (ITP), depending on disease severity and clinical guidelines.

While Ig therapy modulates immune function via several mechanisms, its primary impact involves increasing and potentially overloading plasma IgG levels, which can trigger a regulatory response via the neonatal Fc receptor (FcRn). This receptor-mediated process facilitates the clearance of IgG from the patient’s plasma, thereby degrading all Ig (both autoantibodies and therapeutically beneficial antibodies) to bring total plasma IgG levels back down to a normal range (9-11).

So far, this therapeutic approach has been shown to be useful in the above-mentioned indications. The idea that Ig should be effective across a broad spectrum of antibody-mediated autoimmune diseases, combined with an acceptable risk profile and limited treatment alternatives, has contributed to its widespread application despite insufficient clinical validation (12-15). Prominent therapeutic failures in multiple sclerosis (MS), Parkinson’s disease (PD), and Alzheimer’s disease (AZ) demonstrate some of the inadequacies and limitations of Ig therapy in these indications, which can be explained by the underlying pathophysiology of each disease (16,17). Such limitations are often multifactorial, encompassing complex interactions across several cell signaling pathways, diverse cell and tissue types, and overall disease responses. In many cases, pathology extends beyond autoantibody production to include inflammation, dysregulated immune signaling, and other systemic responses that may not be adequately addressed by Ig therapy alone (18-20).

While Ig therapy has been used and tested, both successfully and unsuccessfully, in numerous conditions, manufacturers and clinicians continue to assess and establish Ig therapy usage in an ever-expanding set of indications. Recent label extensions for indications like dermatomyositis (DM) as well as ongoing efforts by clinicians to explore Ig therapy in more areas, including autoimmune encephalitis, continue to demonstrate the utility of Ig for new indications (21,22). Furthermore, the use of Ig therapy is expanding within established indications like SID, particularly in response to new immune-targeted therapeutics for CLL, lymphomas and myeloma. Novel therapies, such as chimeric antigen receptor (CAR) T-cell therapies, are associated with high rates of SID, thereby expanding the size of the indication (23). In response, manufacturers are moving to strengthen and expand product labels for SID to better address the growing need for IgRT in these patient populations.

New competition is expanding but not replacing Ig

As Ig use spans multiple indications, therapeutic areas, and medical specialties, competitive threats from other therapeutic classes have manifested at an individual indication level without significantly limiting Ig growth at an aggregated level. A notable example is the increasing use of thrombopoietin receptor agonists (TPO-RAs) in ITP to manage chronic ITP patients. These agents have outcompeted Ig (and other treatment modalities) in this indication, reducing Ig growth. However, the impact at the aggregate level has been limited, as ITP represents less than 10% of total Ig volume used (24).

Competition for Ig therapies is expected to increase with the recent advancement of new mechanisms of action (MOAs) like anti-neonatal Fc receptor (aFcRn) therapies, which directly compete with Ig due to its similar mechanism of immune modulation. These products are antibody fragments that bind to the FcRn receptor and drive degradation of circulating IgG leading to a similar reduction in circulating IgG autoantibodies as immunomodulatory doses of Ig (Figure 1) (9,25). Due to the similar therapeutic mechanisms, it is predicted that aFcRn therapies will be effective in several autoimmune conditions where Ig is used (26). Collectively, aFcRn products hold labeled indications for gMG, CIDP and ITP (though the ITP indication is not currently approved by the FDA or EMA), with ongoing clinical trials in additional indications where Ig is approved or used, such as DM, antibody-mediated rejection, and several other rare autoimmune indications (27-29). In addition, therapeutics targeting the complement cascade are approved in indications where Ig is used (gMG) or are in development (e.g., MMN, GBS, CIDP). These therapies will also compete more broadly with Ig treatment (30-34).

Figure 1 Overview of therapeutic interventions targeting FcRn recycling. Overview of IgG recycling mechanisms by the FcRn under normal circumstances as well as mechanisms of degrading pathologic IgG by therapeutic interventions of treatment with exogenous IgG or FcRn-targeted therapies (aFcRn) (3). This figure is reprinted from Berger et al. (9) with permission. FcRn, neonatal Fc receptor; IgG, immunoglobin G.

Clinical trial data and early market data suggest that while there is overlap between patients who benefit from Ig and aFcRn therapies, aFcRn products are not an exact one-to-one replacement for Ig, and both treatments will hold distinct positions in various treatment paradigms (27,29,31). In addition, aFcRn and complement-targeted therapies experienced hurdles in local approvals and usage due to cost, including the notable rejection of aFcRn and complement-targeted therapies for gMG treatment by NICE in the UK. Such hurdles may limit use of these products in cost-conscious markets, favoring greater use of other therapeutic options including Ig. These decisions further show that clinical and health-economic benefit still require more evaluation and that efficacy versus side-effect trade-offs require more clinical evidence creation (35,36).

Notably, these new therapeutics all compete in the immune-modulation segments of Ig use, accounting for roughly half of Ig volume in the US [Adivo’s EMR-derived patient data (data not shown)] (3-5,37). Conversely, no new therapies have launched or are in late-stage clinical development to directly compete with IgRT segments, i.e., PID and SID. However, there is early-stage development for recombinant polyclonal Ig for preventing infections (38). Overall, the limited competition in these segments allowed growth of Ig to match that of the broader PID and SID indications historically and it is predicted that future growth in these indications will experience limited competition for at least the coming 5 years.

Growing demand for Ig in PID, SID and CIDP drives use globally

Ig product volume has experienced steady growth globally, primarily driven by growing diagnosis of new patients in PID, SID and CIDP. While growth is observed across several other indications where Ig is used (e.g., DM and autoimmune encephalitis), PID, SID, and CIDP represent the top three indications in terms of total Ig grams consumed as well as in contribution to global growth. In fact, in most markets, these three indications represent the top indications in both size and growth, though the relative position and growth rates vary due to local market factors. While trends and driver commonalities are observed at a global and regional level, they are not representative of all markets, as highlighted below.

Historically, PID represents the initial indication for Ig therapy. PID continues to grow as patient diagnoses increase and awareness of immunodeficiencies expands, particularly amongst general practitioners who refer suspected immunodeficiency patients to immunologists for diagnosis. Global and local patient advocacy groups (e.g., Jeffrey Modell Foundation, Immunodeficiency Foundation, International Patient Organization for Primary Immunodeficiencies, Latin American Society for Immunodeficiencies) play an important role in supporting disease awareness. In addition, ongoing medical education, conferences, and seminars, as well as efforts from immunologists and PID experts to educate local physicians, all support continued PID awareness efforts and new diagnosis growth. Even in markets with a comparatively small diagnosed PID patient population, such as multiple markets in the Asia-Pacific (APAC) region, awareness and new PID diagnoses continue to expand and increase Ig demand.

CIDP also represents a major global growth driver of Ig use, though regional dynamics vary widely. Growth in new diagnoses continues to be the largest individual growth driver across regions. However, there are concerns of misdiagnosis of CIDP in patients with other neurological conditions, leading to inappropriate initiation of Ig therapy and potentially inflating the apparent CIDP population (39). CIDP claims data reviews estimated the misdiagnosis rates to range from 10–50% (40). Nonetheless, new CIDP diagnoses continue to occur in the US and globally, supporting growth in Ig use.

Ig is the primary first-line treatment for CIDP across North American and European markets, and Ig growth generally mirrors growth of new diagnoses. However, with the launch of aFcRn products for CIDP in the U.S. in 2024 and with anticipated launches in European markets, Ig usage has been impacted. Ig use in CIDP has slowed significantly within the US market as aFcRn usage has increased. This therapy is expected to continue to limit growth moving forward, while the impact in European markets may be muted if local markets more tightly control aFcRn usage due to its comparatively higher price. Outside of North American and European markets, corticosteroids are either a common or the primary treatment line for CIDP patients due to the lower product price compared to Ig. However, Ig is increasingly being established as an important treatment leading to strong Ig growth in CIDP in these markets as Ig is increasingly used over corticosteroids.

SID is also a major contributor to Ig growth globally, though growth is strongest in the United States. SID is associated with numerous underlying causes, but the largest groups of affected patients are those with specific hematologic malignancies, such as CLL, lymphoma, and multiple myeloma (MM). SID prevalence continues to rise as the rates of these cancers increase with the aging population and more B-cell targeted therapies are used (i.e., targeted therapies depleting B-cells drive high rates of SID). Ig use for SID has been strongest in North America as new B-cell depleting therapies for these cancers have picked up most, followed by European markets. However, cost concerns for new B-cell targeted therapies (e.g., CAR T-cell therapies) and Ig use for SID by European markets as well as localized Ig supply shortages have curbed greater growth of Ig in the segment. SID growth is also expanding in Asian markets as new B-cell depleting agents are adopted further; however, outside of North America, Europe and Asia, SID growth has been limited as cost concerns for Ig use in these patients have driven greater preference for lower cost alternatives for infection prevention and management, primarily prophylactic antibiotic therapy.

Collectively, there has been robust Ig growth globally across the top three indications for PID, SID and CIDP despite headwinds from competition like aFcRn. While competition is expected to persist and expand in the coming years, it is projected that the continued growth momentum, particularly in PID and SID, as well as the broader climbing global demand for Ig will continue to drive demand growth in the coming years.

Albumin—the second largest global pd-plasma protein market

Albumin is made in the liver and helps maintain the body’s oncotic pressure and fluid balance as it keeps fluids in the bloodstream, preventing leakage into tissues. Albumin also carries various molecules like hormones, fatty acids, and calcium throughout the body. Additionally, it contributes to maintaining acid-base balance and acts as an antioxidant (41). Therapeutically, the two largest indications utilizing albumin treatment are hypoalbuminemia (decreased production or increased loss of albumin) and liver disease [patients with impaired albumin liver synthesis due to underlying liver diseases such as liver cirrhosis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and hepatitis] (42). The prevalence of hypoalbuminemia is higher in patients presenting with chronic/acute inflammation, enteropathy, hypovolemic shock, and malnutrition. Other indications for albumin use include during or after cardiac surgery to preserve renal function, expanding intravascular volume during sepsis or septic shock, general volume replacement to correct severe volume losses during acute hemorrhages or general surgery, and treatment of burn victims (42).

However, many other uses are known, such as refractory or tense ascites (following total paracentesis treatment), cerebral pathologies (including craniocerebral diseases, intracranial pressure, edema, and ischemia), hyperbilirubinemia, hemolytic disease in newborns, pancreatitis, preeclampsia, ovarian hyperstimulation, acute respiratory distress syndrome, plasmapheresis and many others (43). In Chinese Alternative Medicine, albumin infusions are at times perceived to contribute to overall health, rejuvenation of the body, and prevention of aging, which has led to a separate consumer-driven market segment in China (44).

Due to its many applications and the return of general and specialized surgeries post- coronavirus disease (COVID) but also the increase in global with larger number of trauma incidences (45,46) the demand for albumin has increased globally over the past few years to generate approximately $5.9 billion (2023) in revenue.

Going forward, liver disease and hypoalbuminemia are anticipated to create further demand for albumin utilization. The pandemic contributed to an increase in liver cirrhosis due to higher alcohol consumption (47). A general increase of infectious liver diseases, including COVID infections, but also hepatitis, human immunodeficiency virus (HIV) and other viruses infecting liver cells, will drive demand for albumin-augmentation (48).

Unlike in many other therapeutic areas, the albumin market is mostly driven by the APAC region, which generates 2/3 of global revenue and was growing faster than any other geography as of 2023. Within APAC, China creates the largest demand and is also globally the largest and fastest growing market overall (44). In contrast, the North American market contributes only ~10% of all revenue to the global albumin market, matched by all of Europe.

Demand for albumin as a plasma expander was further fostered over the last 15 years as safe alternatives were lacking after hydroxyethyl starch (HES) products received a black-box warning for increased mortality risk, renal injury, and bleeding in critically ill patients (49). Meanwhile, dextran use is associated with several adverse effects such as allergic reactions, kidney damage, and blood clotting disorders (50). These pressures drove consumption of high-concentration albumin presentations (i.e., 20% and 25%) over 5% presentations.

With little product differentiation, some companies such as Takeda and Grifols started offering plastic bag product presentations to contrast from the standard glass bottle finishes. Bag presentations provide easier handling and storage and reduce glass waste. However, premium pricing for bag presentations hindered uptake in emerging and price-sensitive (tender) markets but drove revenue generation in established markets with higher buying power. It will remain to be seen if the albumin market will transition to become a 100% bag presentation market, as we have seen in the saline and colloid markets.

In 2025, the first recombinant albumin (recAlb) products received approval in Russia and China after similar recAlb initiatives failed to produce tangible products over the past 20 years (51-54). The historical failures have resulted in skepticism from the physician community regarding whether recAlb can replace human albumin for all use cases. Although clinical trial results seem promising at first sight, it remains to be seen if the new recAlb products can overcome issues of post-translational modification introduced by the producing host expression systems (i.e., rice expression system), causing efficacy limitations and/or triggering SEs/AEs (52,54).

From clinical trials it seems that recAlb might be able to fulfill the plasma-expanding volumetric functions that the protein provides to keep blood pressure and fluid-balance in check but there is no evidence that it can address albumin’s Ca²⁺ and hormone as well as fatty acid transporter functions, and the other physiological capabilities that human albumin fulfills (52).

Additionally, it remains to be seen if recAlb production costs can really be lowered through rec production systems when large amounts of albumin will need to be manufactured and aspects such as large-scale production facility upkeep, energy and transportation costs as well as down-stream purification costs are factored into the product cost of goods sold (COGS).

Overall, demand for albumin use is likely to grow in the next few years due to an aging global population, improving buying power and access, as well as all downstream incidences that correlate with a global population and resulting geopolitical conflicts.

However, constant cost focus by most global healthcare systems already shows a push for cheaper colloid solutions to reserve albumin for uses without proper alternatives. All ahead China, as albumin’s biggest consumer, is pushing for utilization constraints and policies to curb the financial impact of what is perceived to be “albumin over-use” within this unique marketplace.

pd coagulation product market—complex and challenging

The global coagulation product market is comprised of various product types that range from pd factor VIII and FIX products to treat hemophilia A and B, respectively, to so-called bypassing agents [factor FVII and activated prothrombin complex concentrates (aPCC)], and fibrinogen and prothrombin complex concentrates (PCC) containing multiple clotting factors (II, VII, IX, and X) as well as von Willebrand factor (vWF) amongst others. Historically, the FVIII and FIX pd-markets experienced recombinant entries first, with subsequent second- and third-generation recombinant replacement factor variants following, with long-acting FVIII and FIX products addressing the high treatment burden that hemophiliacs were exposed to at the time (55,56). However, shortly after long-acting products reached the market, the first bi-specific antibody bridging FVIII function entirely became the first subcutaneous and bi-weekly or monthly injection (rather than a more time-consuming infusion), depending on bleed phenotype. This therapy drastically changed FVIII patient’s quality of life. More recently, two prominent gene therapies have been launched (FVIII and FIX respectively), and other mimetic-FVIII products are currently entering the FVIII and FIX market to complete an already complex and highly competitive market space (Figure 2) (57-60). It is the high patient value that drives competition in these markets since one single severe patient can exceed $1M in revenue for a manufacturer. However, the FVIII and FIX markets are also good case studies on how rec-product and gene therapy competition can disrupt an established pd-product market over time. In the FVIII and FIX space, innovation through new product launches in established markets such as the United States, Europe and parts of APAC, may replace pd-products, which has created an evasion strategy for pdFVIII and pdFIX products into emerging markets. In emerging markets, cost-containment and buying power (often regulated through public and private tender programs) incentivize the lowest bidder. Hence, price competition is the biggest driver in emerging markets, which is further intensified by self-sufficiency mandates from local governments, putting larger multinational manufacturers with higher cost structures under pressure. Going forward pd-FVIII and pd-FIX products are likely to address price-sensitive and price-regulated emerging markets until newer product types are released into these markets at competitive prices or buying power in these markets increases.

Figure 2 Overview of the coagulation cascade and new therapeutics mimicking or bypassing factor activity. In addition to recombinant factors for FVIII and FIX, additional treatments have been developed competing with both plasma derived and recombinant factor products (43). This figure is created in BioRender and reused with permission. aPCC, activated prothrombin complex concentrate; AT, antithrombin; FVIII, coagulation factor VIII; PL, phospholipid; RISC, RNA-induced silencing complex; TF, tissue factor; TFPI, tissue factor pathway inhibitor.

For other coagulation products, such as PCC and fibrinogen products, market dynamics are vastly different, as those products do not address rare bleeding disorders but find use in surgeries and trauma cases with massive bleeding events to stop patients from hemorrhaging, including patients on anticoagulants (anti-coagulant reversal patients). These coagulation products can theoretically address many patients but compete with other blood products that contain the same coagulation factors in less concentrated form such as whole blood, fresh frozen plasma (FFP), and cryo-preservatives. These products are collected through general blood donations and are made available to hospitals via their associated blood banks. However, highly concentrated PCC and fibrinogen products bear certain advantages over the mentioned blood products which also result in a higher product cost. Hence, most hospitals in developed countries need to balance use with clinical need and cost to the patient and hospital, which makes them frequently second-line products after lower cost options have failed or reserve products for critical patients where other product types are likely to fail. Despite the higher product cost, it is anticipated that the PCC and fibrinogen markets will grow due to their efficacy in bleeding control but also since an earlier use of these products in the treatment paradigm might save cost and consumption of lower concentrated alternatives that at times can be supply constrained. This trend is likely to lag in emerging markets due to the lower buying power and lower availability of PCC and fibrinogen products on the global market. These products are at times supply-constrained within the global marketplace. Demand is likely to increase due to an aging population requiring cardiac surgery more than once in their lifetime (61), an increase in trauma cases in global conflict areas, which are also increasing in number (62), as well as global industrialization and automation resulting in access to trauma-inducing equipment (i.e., more cars, trucks, industrial machines) (63).

The remaining coagulation products, such as the so-called bypassing agents and others, address smaller patient populations, rare bleeding disorders with diagnosis rates varying between established and emerging markets, and buying power within the local healthcare markets. The relatively small size of these markets offers some unique opportunities for innovators but has little impact overall on the global coagulation market.

Impact of the COVID-19 pandemic on pd-product supply

We mainly focus on the clinical use cases in this article as pd-product supply is heavily influenced by blood and plasma donation which in turn are regulated and managed differently in each country (64). However, the global COVID-19 pandemic and its resulting lock down response affected blood and plasma donations heavily as donors did not attend donation centers at the same frequency and volume (65). Consequently, pd-product supply dropped during the pandemic which forced clinicians to ration pd-treatments or use alternative treatment options where available. The pandemic was a stark reminder of the supply vulnerability in this product category which pd-supply limitations affect valuable treatment options for select patient groups in indications that have no, or very limited, alternatives such as PID and others (65).

Conclusions—Igs will continue to drive the ever-increasing demand for plasma

Innovation for pd products is focused on incremental expansion for Igs, albumin, clotting factor, HAE, and AAT markets and is not projected to radically shift the demand dynamics of each class. Thus, for at least the next few years, broader pd product market growth will be primarily driven by the market trends described above in Igs and albumin, as well as in segments such as AAT and clotting factors for acute hemorrhage.

In the Ig market, the contribution of IgRT to growth will increase due to increasing demand in patients with hematologic malignancies (i.e., SID), at least partially offsetting the impact from competing MOAs like aFcRn therapies in the immune-modulation segment. However, demonstration of health-economic advantages for competing MOAs like aFcRn and future pricing reductions might impact growth rates for Ig further. Albumin demand is also anticipated to increase in the coming years, though demand growth is more concentrated when compared with Igs. This is because albumin growth is driven by APAC markets (especially China), whereas Ig growth is observed globally (though the US is the single largest market).

The remaining plasma product classes have mixed performance. Products such as pd factor for Hemophilia A and B as well as other pd products (not discussed here) are facing significant headwinds from recombinant versions (particularly rFVIII and rFIX) and from other MOAs, limiting growth. However, products like fibrinogen for massive hemorrhage management and AAT are experiencing growth from expanding indications and geographic expansion.

Together, Igs and albumin account for more than half of pd product revenue and are expected to continue to drive revenue and demand growth in the coming years (proprietary Adivo data—data not shown) (1-6). Therefore, in-market, global dynamics of these two products (though almost exclusively Igs) are the primary forces influencing the current and future need for plasma collection. It is therefore paramount to closely monitor these trends to accurately gauge future needs and ensure there is sufficient capacity and action to collect and fractionate enough plasma to meet these growing and shifting demands.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Jan Hartmann) for the series “Source Plasma” published in Annals of Blood. The article has undergone external peer review.

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-2025-1-41/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-2025-1-41/coif). The series “Source Plasma” was commissioned by the editorial office without any funding or sponsorship. M.K. and J.B. are employees of Adivo Associates, a Herspiegel company. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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