Toward a Restrictive Use of Plasma Exchanges in Thrombotic Microangiopathies

For decades, plasma exchanges have been used in the management of various medical conditions, including several kidney diseases, on the basis of a level of proof of variable quality. One of the best illustrations of the clinical use of plasma exchanges is thrombotic microangiopathies (TMAs), a group of disorders that share common biological (thrombocytopenia, mechanical hemolytic anemia) and pathological (thrombi in the microvasculature) features, and a propensity for kidney and brain involvement.¹ TMAs are heterogeneous in terms of mechanisms of endothelial cell injury, thrombosis, and prognosis.

The benefit of plasma exchanges in TMAs was first established in a prospective Canadian trial conducted in the 1990s that included mainly patients with thrombotic thrombocytopenic purpura (TTP). In this study, plasma exchanges proved superior to plasma infusion in terms of disease remission and survival.² Noteworthy, this study was conducted before the major shift in the perspective of TMAs, the delineation of the underlying pathogenic mechanisms of two prototypic, but rare, forms of TMAs: A disintegrin and metalloprotease with thrombospondin type 1 repeats (ADAMTS13) deficiency in TTP and complement alternative pathway dysregulation in atypical hemolytic uremic syndrome (HUS) (Figure 1A).

Figure 1.

Several breakthroughs in the understanding of the pathogenesis of TMA paved the way for a plasma exchange–free treatment of TMAs. (A) Main milestones in the delineation of the underlying mechanisms and treatment breakthroughs of two main forms of TMAs: TTP and atypical HUS. (B) Proposed algorithm for a plasma exchange–free management of an adult patient with a first episode of TMA. ADAMTS13, A disintegrin and metalloprotease with thrombospondin type 1 repeats; CAP, complement alternative pathway; HUS, hemolytic uremic syndrome; TMAs, thrombotic microangiopathies; TTP, thrombotic thrombocytopenic purpura.

Nevertheless, except for some other relatively rare forms of TMAs (cobalamin-C deficiency, diacyl-glycerol kinase epsilon-HUS), and to some extent Shiga-toxin–associated HUS, the exact mechanisms of endothelial cell injury in most TMAs remain poorly understood, including in secondary TMAs associated mainly with malignancy and drugs.¹

The demonstration of the pivotal role of ADAMTS13 acquired deficiency in TTP has also comforted the use of plasma exchanges in this type of TMA to remove pathogenic inhibitory autoantibodies targeting ADAMTS13 and to restore a significant activity of this enzyme. By contrast, the reconsideration of the clinical picture of atypical HUS in view of the newly recognized risk factor (dysregulation of the complement alternative pathway) did not provide evidence that plasma exchanges are a disease-changing treatment of this form of TMA.

With or without plasma exchanges, 50%–80% of patients with atypical HUS, with or without complement gene variants, reached kidney failure at 1 year of disease onset.³ Furthermore, to the best of our knowledge, there is no evidence that plasma exchanges restore normal regulation of the complement alternative pathway by providing normal circulating complement inhibitory factors, such as Factor H or Factor I, or by removing hyperfunctional complement proteins, such as C3 and Factor B. No prospective randomized trial has assessed the benefit of plasma exchanges in atypical HUS—this is also the case for C5 blockers. The absence of a clear effect of plasma exchanges on the prognosis of atypical HUS led to the development of C5 inhibitors that dramatically changed the management and outcome of this disease.

For all the remaining TMAs, including those with clearly identified mechanisms, there are no published data substantiating the benefit of plasma exchanges. So, why are we still using plasma exchanges in the management of TMA? First, it is noteworthy that plasma exchanges have almost disappeared from the treatment of TMAs in children (except for some patients with anti-Factor H antibody–associated atypical HUS), at least in countries where anti-C5 drugs are available.⁴ The more limited differential diagnosis and high morbidity of plasma exchanges in children are two explanations for this shift in the management algorithm. Noteworthy, plasma exchanges in adults also carry a significant burden of morbidity⁵ and impair quality of life.

Plasma exchanges are still used in adults with TMA for three main reasons. The most important is the urgent need, in an adult patient presenting with a first episode of TMA, to start the treatment of a potential TTP because of high mortality and morbidity of the latter. The (modified) French⁶ and Platelet count; combined hemoLysis variable; absence of Active cancer; absence of Stem-cell transplant or solid-organ transplant; Mean corpuscular volume; International normalized ratio; and Creatinine (PLASMIC) scores are used in clinical practice to distinguish TTP from other forms of TMAs, but they are not fully reliable on an individual basis, especially in some settings, such as pregnancy, and in patients older than 55 years. The implementation of commercially available rapid tests for ADAMTS13 activity has, however, dramatically reduced the time for the diagnosis or exclusion of TTP, but these tests are not yet universally available.

The second reason is that the costly C5 inhibitors are not available and funded in several countries, including high-income ones. In this setting, plasma exchanges are the only remaining alternative that may provide some limited effect, at least on hematological features of atypical HUS. The third reason is that plasma exchanges are still considered by some clinicians as the ultimate salvage treatment of several severe disorders.

The first reason pleading for the use of plasma exchanges in adults with a first episode of TMA has been recently challenged by two major breakthroughs in the management of TTP: the introduction in clinical practice of (1) caplacizumab, an anti–vWf humanized Ig fragment that inhibits the interaction between vWf multimers and platelets,⁷ and (2) recombinant ADAMTS13⁸ (Figure 1A). This was an addition to the now widely used anti–B-cell therapies introduced more than 20 years ago⁹ that have become part of the standard of care of acquired TTP.

In prospective studies and in real-life use, capalcizumab alleviates the need for plasma exchanges and reduces time to platelet normalization as well as refractoriness and mortality in patients with TTP.^7,10 Plasma exchange–free management of TTP, using caplacizumab and immunosuppression, is implemented in an increasing number of centers,¹⁰ including in patients with neurological and cardiac involvement. One may even argue that life-threatening features of TTP should urge the use of capalcizumab (Figure 1B). However, more prospective data are needed to validate such a plasma exchange–free treatment strategy for TTP. Finally, recombinant ADAMTS13 that changed the management of congenital TTP will probably prove an additional potent therapeutic tool in acquired TTP.

If a plasma exchanges–free alternative is efficacious in the urgent treatment of TTP, no rationale for the use of plasma exchanges in the management of TMAs still holds. Furthermore, the use of plasma exchanges delays the start of C5 blockers in patients with atypical HUS and thus compromises an optimal kidney recovery. Thus, similarly to TTP, a plasma exchange–free approach to HUS with first-line C5 blockers seems to be a reasonable approach, especially in patients with severe AKI (Figure 1B). The potential main limitation for such an approach is that atypical HUS remains to date a diagnosis by exclusion. However, if another cause of HUS is ultimately diagnosed, C5 blockers can be rapidly stopped, with no negative effect on the patient's kidney outcome. Besides, retrospective series even suggest that C5 blockers may have a beneficial effect in some forms of severe secondary HUS.

Then, are we ready for a plasma exchange–free management of TMAs? Not quite yet. The major limitation remains the wide implementation of rapid (<24 hours), reliable ADAMTS13 tests in TMA centers. This is a crucial step in the algorithm of the management of patients with TMA (Figure 1B) because available predictive scores are not fully accurate. Moreover, the cost of all innovative drugs implemented in potential plasma exchange–free approaches to TMAs is a major obstacle for worldwide implementation. The cost-effectiveness of some of these therapies, such as caplacizumab, remains debated.¹¹ However, the individualization of treatment duration in patients with atypical HUS and the commercialization of the first-line C5 blocker biosimilars have already led to a significant decrease in the total economic burden of C5 blockade in TMAs. We believe that the development of cheaper forms of potent drugs will ultimately provide a plasma exchanges–free strategy for patients with TMA worldwide. In the meantime, the use of plasma exchanges should be restricted to patients with suspected and/or severe TTP. It is not yet the end for plasma exchanges in TMA, but it is probably the beginning of the end.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/E921.

Funding

None.

Author Contributions

Writing – original draft: Fadi Fakhouri.

Writing – review & editing: Marie Frimat, François Provôt, Nora Schwotzer.