The Physiology Behind Therapeutic Plasma Exchange

November 30, 2020

Therapeutic plasma exchange (TPE) is the procedure in which a patient’s blood plasma is removed, purified, and returned.1 In most uses of TPE, blood is circulated through a centrifuge, which separates blood into its constituent parts. Blood can also be separated using filtration-based devices, which allows only plasma, but not cellular components, to pass through. The plasma, which may contain pathological substances such as autoantibodies, is discarded, and a replacement fluid mixed with the other blood components is returned to the patient.2 One round of treatment can typically remove 65 to 70% of pathological plasma proteins.1 

TPE, then referred to as “plasmapheresis,” was first successfully completed in 1914, when Russian scientists substituted the plasma in the blood of uremic dogs with a replacement fluid.3 The first use of TPE in humans occurred in the 1950s, as a way of treating the blood serum viscosity that results from Waldenström macroglobulinemia.4 It has since been used for a variety of hematological diseases, many of which require different mechanisms of removal and replacement. The mechanism used for macroglobulinemia, for example, is the removal of monoclonal IgM antibodies, which, even after just one treatment, results in a dramatic decrease in blood viscosity.5 When combined with immunosuppression, removing antibodies via TPE can enable the successful transplantation of organs originally incompatible with the recipient’s blood type.6 

An additional mechanism of TPE with proven versatility is the removal of cytokines, the cell signaling peptides that trigger inflammation in response to infection.7 This mechanism has emerged as a potential treatment for patients critically ill with COVID-19, who may experience a proliferation of helper T cells and, consequently, an overproduction of cytokines.8 In an attempt to mitigate the potentially fatal effects of uncontrolled fluctuations in cytokine levels, such as severe inflammation and organ failure, physicians have used TPE to remove cytokines from the plasma of COVID patients for whom the treatment is indicated. Fernandez et al. report four cases of severely ill patients infected with coronavirus that received two to six treatments of TPE, with 5% albumin as the replacement fluid and a dose of immunoglobulin to prevent hypogammaglobulinemia.9 All four patients showed a rapid and considerable decrease in plasma levels of most cytokines and were discharged within weeks of beginning treatment.  

Using TPE to treat COVID-19, despite its efficacy, has setbacks. Khamis et al. note that TPE could also remove the COVID-19 antibodies that may be critical to long-term immunity, and that TPE may induce allergic reactions, hypotension, and hypocalcemia.10 Owing to the novelty and urgency of COVID-19, large, controlled trials that could more firmly establish the physiology behind and benefits of TPE have not been conducted. Additionally, the efficacy of TPE in reversing the cytokine storm must be weighed against other existing methods, such as convalescent plasma therapy, in which plasma from a person who has recovered from a coronavirus infection is donated in the hopes that their antibodies can help block the patient’s inflammatory cytokines. 11 Regardless, TPE on the whole is a safe and effective treatment for a variety of immune- and blood-related disorders. 


  1. Therapeutic Plasma Exchange: Conditions & Treatments: UT Southwestern Medical Center.” Conditions & Treatments | UT Southwestern Medical Center,  
  1. Reeves, Hollie M., and Jeffrey L. Winters. “The Mechanisms of Action of Plasma Exchange.” British Journal of Haematology, vol. 164, no. 3, 2013, pp. 342–351., doi:10.1111/bjh.12629.  
  1. Khamis, Faryal, et al. “Therapeutic Plasma Exchange in Adults with Severe COVID-19 Infection.” International Journal of Infectious Diseases, vol. 99, 2020, pp. 214–218., doi:10.1016/j.ijid.2020.06.064
  1. Skoog, W.A. & Adams, W.S. “Plasmapheresis in a case of Waldenström’s macroglobulinemia.” Clinical Research, vol. 7, 1959, p. 96. 
  1. Treon, S.P. “How I treat Waldenstrom macroglobulinemia.” Blood, vol. 114, 2009, pp. 2375–2385. 
  1. Schwartz, Joseph, et al. “Guidelines on the Use of Therapeutic Apheresis in Clinical Practice-Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Sixth Special Issue.” Journal of Clinical Apheresis, vol. 28, no. 3, 2013, pp. 145–284., doi:10.1002/jca.21276
  1. Tisoncik, J. R., et al. “Into the Eye of the Cytokine Storm.” Microbiology and Molecular Biology Reviews, vol. 76, no. 1, Mar. 2012, pp. 16–32.  doi:10.1128/MMBR.05015-11
  1. Chousterman, Benjamin G., et al. “Cytokine Storm and Sepsis Disease Pathogenesis.” Seminars in Immunopathology, vol. 39, no. 5, July 2017, pp. 517–28. doi:10.1007/s00281-0170639-8
  1. Fernandez, Javier, et al. “Plasma Exchange: An Effective Rescue Therapy in Critically Ill Patients With Coronavirus Disease 2019 Infection.” Critical Care Medicine, Publish Ahead of Print, 2020, doi:10.1097/ccm.0000000000004613.  
  1. Khamis, Faryal, et al. “Therapeutic Plasma Exchange in Adults with Severe COVID-19 Infection.” International Journal of Infectious Diseases, vol. 99, 2020, pp. 214–218., doi:10.1016/j.ijid.2020.06.064
  1. “Convalescent Plasma and Immune Globulins.” National Institutes of Health, U.S. Department of Health and Human Services, 9 Oct. 2020,