Mechanism of Action of Therapeutic Plasma Exchange: Beyond Antibody Removal - A Systematic Review

Therapeutic plasma exchange (TPE) is widely used across dozens of conditions, but the standard explanation — "we remove pathogenic substances from the blood" — doesn't hold up. In 2014, Reeves & Winters published a landmark paper posing 6 unanswered questions about how TPE actually works. Over a decade later, nobody has systematically attempted to answer them. This review aims to do that, while also integrating a large body of new evidence that has emerged since 2014. The 7 Research Questions: 1. Q1 — Antibody paradox: Why does TPE work when antibody titers don't correlate with disease severity (e.g., in myasthenia gravis, GBS, CIDP)? 2. Q2 — Extravascular paradox: How does TPE help when the pathological antibodies aren't even in the bloodstream (e.g., MS, NMO — targets behind the blood-brain barrier)? 3. Q3 — Immunomodulation existence: Does TPE genuinely alter the immune system beyond simple removal? 4. Q4 — Immunomodulation mechanism: If yes, what drives it — cytokine removal, antibody removal, direct blood-device contact, or replacement fluid effects? 5. Q5 — Cytokine debate: Is cytokine removal meaningful given their short half-lives and large volumes of distribution? 6. Q6 — Device-specific mechanisms: Are the mechanisms different for centrifugal TPE (cTPE) vs membrane-based TPE (mTPE)? 7. Q7 — Emerging frontiers: How do extracellular vesicles, intracellular signaling pathways (NF-κB, JAK/STAT, MAPK, NLRP3), and biological aging/parabiosis research inform the mechanistic framework? Review Structure (11 sections) 1. Introduction 2. Classical mechanism: removal of pathogenic substances 3. The antibody paradox (Q1) 4. The extravascular paradox (Q2) 5. Immunomodulatory effects of TPE (Q3/Q4) 6. Cytokine removal debate (Q5) 7. Complement modulation 8. Emerging frontiers — EVs, signaling, aging (Q7) 9. Device-specific mechanisms: cTPE vs mTPE (Q6) 10. Replacement fluid as a mechanistic variable 11. Synthesis and future directions Methodology - Full PRISMA 2020 compliance — pre-registered protocol on OSF, structured search, documented screening, PRISMA flow diagram - Search: 24 search lines across 5 databases (PubMed, MEDLINE, Embase, Web of Science, Scopus, Cochrane), plus forward/backward citation chaining and hand-searching of 3 key apheresis journals - Screening: Single reviewer (Hugo Fabre) with LLM-assisted triage - Quality assessment: Newcastle-Ottawa Scale, JBI, RoB 2 as appropriate per study design - Synthesis: Narrative (qualitative) — no meta-analysis due to heterogeneity of endpoints across studies Expected Outcomes / Novelty 1. First synthesis bridging classical and frontier evidence — connecting the Reeves & Winters 2014 framework with the Rony et al. 2025 EV/signaling/aging evidence 2. First systematic attempt to answer all 6 questions with a decade of accumulated new data 3. First focused review of cTPE vs mTPE mechanistic differences — an area with almost no dedicated literature, directly relevant to Terumo BCT's product portfolio 4. Integration of COVID-19 and CAR-T cytokine storm data as natural experiments illuminating the cytokine removal debate 5. Incorporation of biological aging literature — parabiosis and epigenetic clock studies as a new lens on TPE mechanisms Team - Hugo Fabre First author, sole reviewer, project lead (Terumo Blood and Cell Technologies, Global Medical Affairs) - Mickael Beraud Author, internal review - Melissa Kovac Medical librarian, search execution Current Status (as of March 2026) - Phase 1 (Protocol & Preparation): Complete — OSF registered, all search tools ready - Phase 2 (Search Execution): In progress — Q1 returned 1,858 records across 4 databases; all 21 priority papers obtained as full-text PDFs; Q2-Q10 pending from Melissa - Phase 6 (Data Extraction): Started early — extracting data from the 21 priority papers while waiting for remaining searches