Therapeutic Plasma Exchange: Current and Emerging Applications to Mitigate Cellular Signaling in Disease

Abstract

Therapeutic plasma exchange (TPE) is a blood purification technique which functions to remove pathological plasma constituents such as autoantibodies, inflammatory cytokines, immune complexes, and extracellular vesicles (EVs) that contribute to a range of disease states. In this review, we examine current and emerging indications for TPE across cardiovascular, metabolic, neurological, inflammatory, and oncological diseases. We cover emerging preclinical animal models and new applications, emphasizing the roles of cellular signaling and EV biology in mediating plasma functions, and discuss unique therapeutic "windows of opportunity" offered by TPE. We conclude that TPE is underutilized in both preventative and precision medicine, and that next generation TPE therapies will involve personalized plasma biomarker and modulation feedback, with synergistic plasma infusion therapies to mitigate age associated disease and promote tissue rejuvenation.

Keywords: apheresis; blood exchange; cancer; diabetes; extracellular vesicles; inflammation; metabolic disease; neurological disease; plasmapheresis; therapeutic plasma exchange.

Figure 4

Automated murine TPEs and associated improvements in hind limb ischemia (HLI) recovery. Automated triple plasma exchanges (TPE) in aged diabetic mice improve ischemic vascular injury recovery and blood. (A) Overview of automated murine TPE. Briefly, mice with jugular catheters and vascular access buttons are anesthetized and their blood exchanged with saline washed donor blood cells within glass syringes containing magnetic stirrers. Using an equivalent donor fluid volume to that of the recipient mouse and through a series of automated infusion and withdrawal cycles, blood exchanges effectively dilute recipient mouse plasma by ~50% over 2 h. (B) Experimental timeline. 80-week-old male mice fed high fat high sucrose (HF/HS) for 3 months underwent HLI on the right limb (femoral artery ligation). TPE or control mice (all surgeries, sham exchange) were performed on day 1, 3, and 5 post ligation. (C) Representative images of perfusion on day 12 post-ligation in control and triple-exchange group. Perfusion was measured by LAser Speckle Contrast Analysis (LASCA), left and right legs noted by L and R, respectively. Red coloration indicates increased perfusion. (D) Quantification of fold change in perfusion pre- vs. post-TPE/sham exchange. (N = 5, *** p = 0.0006, Student’s t-test).

Figure 1

An overview of TPE strategies for clinical implications. Centrifugation TPE involves blood removal, anticoagulant addition typically favoring sodium citrate, and centrifuge-based plasma separation. Replacement albumin and fresh frozen donor plasma is infused upon fluid return to the patient, along with calcium supplementation prior to plasma return to avoid hypocalcemia. In membrane TPE patient blood (anticoagulated with heparin) is filtered over a hollow fiber filter, and fluids are returned as described for centrifugal TPE. Alternatively, in double-filtration plasmapheresis (DFPP), plasma separation is followed by a second membrane filter (plasma fractionator) to remove specific circulating components (e.g., autoantibodies) based predominately on size. Component depleted plasma is returned to patients. In general, membrane TPE utilizes a higher flow rate and is thus completed more quickly than centrifugal TPE. On the other hand, overall plasma removal is greater in centrifugal TPE per unit of time, with ~65–85% removal depending on donor exchange volume used for centrifugal, and ~30% for membrane filtration [2,3]. The use of either approach is typically indication specific. Common and rare complications are provided, of which most are due to either access (IV site pain) or rapid changes in blood volume, and easily treatable. Plasma components are highlighted, including those often implicated in human disease. Common and future replacement or adjuvant therapies are also emphasized and discussed further in subsequent sections. Created in BioRender. Tompkins, J. (2025) https://BioRender.com/5r1lysi, accessed on 6 June 2025.

Figure 2

Current disease-specific indications and applications of TPE in clinical practice. Two example indications are shown for each disease category, followed by category ranking from ASFA guidelines [9]. I = Disorders for which apheresis is accepted as first-line therapy. II = Disorders for which apheresis is accepted as second-line therapy. III = Optimum role of apheresis therapy is not established. ECP = extracorporeal photopheresis. Created in BioRender. Tompkins, J. (2025) https://BioRender.com/7d5zyiz, accessed on 6 June 2025.

Figure 3

An overview of TPE applications in oncology. TPE roles in supportive involve removal of damaging associated immune complexes, reducing hyperviscosity syndrome, cancer-associated autoimmunity, and aiding in renal protection. As an adjuvant, evidence points to synergistic applications for TPE in combating adverse immune related events to checkpoint inhibitor treatments with radiation [87]. TPE effectively removes many excess chemotherapies, which may enable increasing doses in future trials. As a cancer intervention, the depletion of tumor driving PD-L1 may reduce tumor recurrence. Underexplored areas of research involve systemic immune system and metabolic augmentation to those less favorable for cancer development.

Figure 5

Signaling pathways, EVs, and inflammatory signaling potentially altered by TPE. An overview of key signaling categories contributing to chronic systemic inflammation: (1) transcription factor pathways (NF-κB, STAT3, MAPK/JNK/ERK) that regulate inflammatory gene expression and immune evasion; (2) innate immune sensors (TLRs, NLRP3 inflammasome) driving release of cytokines and chemokines (e.g., IL-1, IL-6, TNF-α); (3) extracellular vesicles (EVs) produced by immune, cancer, or stressed cells that carry pro-inflammatory cargo (e.g., PD-L1, p-tau, autoantigens, miRNAs). Therapeutic plasma exchange (TPE) reduces inflammatory burden by depleting cytokines, immune complexes, and EVs, promoting immune modulation (e.g., increased Tregs, Th2 shift) and resulting in a more regenerative systemic environment. Created in BioRender. Hussey, D, Tompkins J. https://BioRender.com/tqvmd79, accessed on 6 June 2025.