Plasma Exchange: New Uses for a Therapeutic Workhorse

THE IDEA OF removing harmful substances in the blood by apheresis — from the Greek aphairesis meaning “taking away” — originated nearly a century ago in Baltimore. In 1914, Dr. John Abel and his team at Johns Hopkins Medical School repeatedly removed quantities of blood from dogs, discarded the liquid plasma portion and reinfused the cellular blood elements with an isotonic salt solution. The dogs tolerated the procedure well.¹

Dr. Abel coined the term “plasmapheresis” for this experimental procedure, and suggested that “if this method can be employed without harmful consequences, it is probable that it could be applied in a bolder manner in a greater variety of morbid states” than the old and now-discredited practice of simple bloodletting. Decades later in 1951, Dr. José A. Grifols Lucas — a member of the family that founded Grifols, a leading multinational plasma fractionator — published landmark research demonstrating the feasibility of plasmapheresis as a potential means to routinely collect donor plasma for purification into products such as albumin, clotting factors and immunoglobulins.

It would not be until the 1960s, however, that major engineering advances made it safe and practical to separate, remove and replace the plasma portion of blood in humans. These advances suddenly made it possible to collect plasma from donors on a regular basis, just in time to meet the growing needs of manufacturers that fractionate human plasma into critical therapeutic proteins. But for the medical community, which had long struggled to help patients with serious blood hyperviscosity syndromes and drug-resistant autoimmune disorders, plasmapheresis offered a powerful new treatment tool. Today plasmapheresis — more accurately therapeutic plasma exchange (TPE) — is an established treatment modality for an impressive range of renal, hematologic and neurological disorders (Table 1).

TPE Basics

In the U.S., plasma separation from whole blood is most commonly accomplished by centrifugation, and involves the use of sophisticated, software-controlled equipment, disposable kits and other supplies. Alternatively, membrane separation technology may be used in conjunction with dialysis equipment (Figure 1). Plasma containing the toxic antibodies or other macromolecules is removed, discarded and replaced with 5% human albumin or, for certain rare hematological disorders, with donor fresh frozen plasma.

The therapeutic principle behind TPE is simple: to acutely reduce circulating blood levels of the toxic substance — most commonly harmful IgG or IgM antibodies — to allow for recovery and healing. To achieve this, five to six TPE procedures, each removing around one to one-and-ahalf “plasma volumes,” are usually required.

Multiple repetitions of the procedure are needed because less than half of the IgG antibody in the body actually circulates in the blood. The rest can be found in the extravascular compartment, including the lymphatic system. So while a single TPE procedure removes roughly 60 percent to 75 percent of the intravascular IgG, the circulating IgG level partly recovers due to re-equilibration of extravascular IgG that enters the bloodstream. Generally, the goal of a series of TPE procedures is to reduce the circulating IgG level by at least 70 percent to 85 percent.²

Plasma exchange has now been in clinical use for nearly five decades. One would think that by now every disease for which TPE might potentially provide a benefit has been evaluated and proved or disproved. But that is not at all the case. Thanks to an evolving understanding of mechanisms and variations in certain immune-mediated diseases and carefully focused clinical research, several important therapeutic applications for TPE have recently been identified and incorporated into standard clinical practice.

TPE for Exacerbations in Demyelinating CNS Disease

Either in instances where a patient inadequately responds to intravenous immunoglobulin (IVIG) therapy or as first-line therapy, TPE is established as effective for treatment of two relatively rare demyelinating autoimmune neuropathies: chronic inflammatory demyelinating polyneuropathy (CIDP) and a closely related disorder, GuillainBarré syndrome. 3 But in multiple sclerosis (MS), a far more common demyelinating disease of the central nervous system affecting about 400,000 Americans, the question of whether TPE offered therapeutic benefit remained unanswered for many years.

The problem was due in part to the fact that MS has differing clinical presentations, which likely reflect different underlying disease variants. More than four in five patients start out with a relapsingremitting course with exacerbation of symptoms, followed by partial resolution. Others start and remain on a chronic progressive course. To complicate things further, many patients with relapsingremitting disease advance to a secondary progressive phase.In a number of studies, TPE has failed to show evidence of benefit against progressive forms of MS.¹

Then, in 1999, a randomized, doubleblind trial showed that TPE therapy achieved a dramatically higher response rate (42.11 percent vs. 5.9 percent) than sham TPE treatments in patients with a mix of MS and other central nervous system (CNS) demyelinating disorders suffering acute, severe attacks that failed to respond to high-dose steroids. More than a decade later — in its first revised guidelines for the use of TPE in 15 years — the American Academy of Neurology (AAN) concluded that TPE as adjunctive therapy is “probably effective” and “should be considered for adjunctive treatment of exacerbations in relapsing forms of [steroid-resistant] MS.”

The new AAN guidelines also encourage neurologists to consider TPE for treatment of other fulminant CNS demyelinating diseases that fail to respond to high-dose corticosteroid treatment. These include neuromyelitis optica (NMO), associated with vision loss and eye pain, and transverse myelitis, which can cause weakness, numbness and paralysis of the arms and legs.

TPE for ABO-Incompatible Kidney Transplantation

Kidney transplantation is the ideal treatment for end-stage renal disease. Unfortunately, a severe shortage of donor kidneys has created a waiting list that has grown to well over 80,000 patients. Between 4,000 and 5,000 patients on that waiting list will die this year before a human leukocyte antigen (HLA)-matched kidney becomes available.

Living donor kidneys have helped to fill the gap; more than four in 10 transplanted kidneys now come from a living donor. But even here, another barrier has often stood in the way of finding a suitable donor: ABO incompatibility.

Consider a transplant candidate with an O blood type. She has neither A nor B antigens on her own red blood cells, kidneys or other body tissues. But she does have naturally occurring antibodies in her bloodstream against both the A and B antigens. If she is transplanted with a kidney from a donor with the B blood type, her circulating anti-B antibodies will instantly target the “B” antigens all over those donor kidney cells, triggering within minutes or hours an acute or “hyperacute” rejection of that kidney.

There is at least a 35 percent chance that any two individuals are ABOincompatible (ABO-I).⁴ For years, surgeons could not transplant an otherwise well-matched kidney from an ABO-I living donor — typically a relative — leaving patients on the waiting list to deteriorate further or die before a suitable organ could be found.

Enter plasma exchange and the ABO-I “desensitization protocol.” Typically used in conjunction with immunosuppressive drugs and IVIG, a short series of TPE procedures before and after transplantation physically removes most of the harmful anti-A or anti-B antibody that would otherwise cause rejection of the kidney graft.

Recently, specialists at The Johns Hopkins Hospital in Baltimore reported 100 percent one-year graft kidney survival in 53 consecutive ABO-I kidney transplants using their TPE and drug conditioning protocol.⁵ “The current literature and our results indicate a critical role for TPE in ABO-I renal transplantation,” they concluded.

What’s Next for TPE?

Much like other immunomodulatory treatments whose effects are incompletely understood — think IVIG and tumor necrosis factor (TNF) inhibitors, for example — ongoing investigations promise to generate new future clinical applications for TPE. But if you’d like to pick just one to follow, consider work now being sponsored by Grifols. Six decades after Dr. Grifols Lucas’ pioneering work in plasmapheresis, the company’s Spanish and U.S. investigators are conducting clinical trials to determine whether TPE with 5% human albumin replacement can slow or reverse the progression of Alzheimer’s disease.

Encouraged by laboratory and clinical findings in a small pilot study, Grifols is now completing a Phase II study randomizing 42 Alzheimer’s patients with mild to moderate disease to receive either a series of 18 TPE treatments or an equal number of sham procedures.⁷ The primary endpoint of this study is clearance of beta-amyloid peptide from the cerebrospinal fluid (CSF). Intensive TPE therapy removes circulating albumin-bound beta amyloid, creating a gradient that draws the toxic peptide from the CSF into the bloodstream, where some of it binds to endogenous and freshly infused albumin and in turn is removed in the next TPE procedure. A larger trial, set to start this year, will try to answer whether TPE in combination with IVIG at different doses and frequencies can slow cognitive decline or actually improve cognitive function.

Modern medicine remains helpless against this devastating neurodegenerative condition, which now affects some five million Americans. The Grifols Alzheimer’s initiative is nothing if not a bold application of Dr. Abel’s century-old plasmapheresis concept. If he were here today, he would certainly be pleased.