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Current Opinion in Hematology:
Transfusion medicine

New directions in plasma exchange

Winters, J. L.; Pineda, A. A.

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Department of Laboratory Medicine and Pathology, Mayo Medical School and Division of Transfusion Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA

Correspondence to Alvaro A. Pineda, MD, Mayo Foundation, Division of Transfusion Medicine, 200 1st Street SW, Rochester, MN 55905, USA


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Purpose of review: This review examines the literature published on therapeutic plasma exchange during 2002. The review was performed by searching Medline for pertinent articles.

Recent findings: One hundred thirty articles were identified, of which 11 are reviewed. During the period, reviews of the use of therapeutic plasma exchange for managing Guillain-Barré syndrome and myasthenia gravis were published. A large randomized trial of the use of plasma exchange to treat sepsis also appeared. Finally, a large case series of the use of plasma exchange in Wegener granulomatosis was published.

Summary: The literature confirms the use of plasma exchange for Guillain-Barré syndrome but suggests that inadequate evidence exists to support its use for long-term improvement in myasthenia gravis. The study of patients with severe sepsis suggests that plasma exchange may benefit a subset of patients, those with abdominal infections. Finally, plasma exchange for Wegener granulomatosis with severe renal dysfunction appears not to offer any benefit over immunosuppressive therapy.

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Abbreviations:AIDP acute demyelinating polyneuropathy, ANCA anti-neutrophil cytoplasmic antibodies, ASFA American Society for Apheresis, DFPP double filtration plasmapheresis, HUS hemolytic uremic syndrome, MFS Miller Fisher syndrome, MG myasthenia gravis, RPGN rapidly progressive glomerulonephritis, TTP thrombotic thrombocytopenic purpura, vWFCPase von Willebrand factor cleaving protease

The development of medical technologies can be thought of as following four phases: “idea,” “adoption,” “acceptance,” and “decay” [1]. These can be used to describe the development of plasmapheresis as a therapeutic modality. In the 1970s, with the development of blood cell separators, plasma exchange became possible as a treatment for disease. Plasma exchange was applied initially to treat antiglomerular basement membrane disease with the intent of lowering circulating antibody by bulk extraction of plasma. This represented the “idea” phase of development of TPE. This was followed by widespread adoption of TPE as a treatment modality during the “adoption” phase when evidence in support of its use consisted of case reports and case series. With the design and performance of randomized controlled trials for TPE, the treatment modality entered the “acceptance” phase of growth. Currently, this is the phase that describes most uses of TPE. It can be anticipated that TPE will begin to be replaced by other technologies as it enters into the “decay” phase. Evidence of this can already be seen with the replacement of some indications, such as hypercholesterolemia, by selective extraction methods and others by immunotherapy, such as the use of intravenous immunoglobulin in the treatment of acute demyelinating polyneuropathy (AIDP) or Guillain-Barré syndrome.

This review examines the literature published between May 1, 2002 and April 30, 2003 to identify indications that fit into the “acceptance” phase of growth of TPE. To this end, Medline was searched using the terms “plasma exchange” and “plasmapheresis” to identify all articles published during the period of interest. A total of 130 articles were identified, of which 11 are summarized. These English-language articles were selected by the authors because they represented randomized prospective trials, large case series, reviews of the Cochrane Database, or small case series believed by the authors to be of particular interest.

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Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are disorders characterized by fever, microangiopathic hemolytic anemia, variable neurologic symptoms, and variable renal dysfunction. These disorders may represent a spectrum of a single disease process or, given differences in recently identified biochemical markers seen in the two, may represent discrete disease entities [2,3]. In the case of TTP, plasma exchange is a primary treatment modality the application of which has resulted in the reduction of mortality from 85% per episode to 15%. Because the use of TPE to treat TTP is evidence based, TTP is categorized as a category I indication for plasma exchange by the American Society for Apheresis (ASFA) [2]. During the period of review, three articles of interest appeared that examined the use of TPE in TTP [4•,5•,6].

Coppo et al. [4•] performed a retrospective review comparing two groups of TTP/HUS patients at the same institution who underwent either TPE or large-volume plasma infusion as treatment. Previous studies looking at TPE versus plasma infusion have found a significant benefit of TPE over plasma infusion or no difference in outcome [2]. In both of these studies, patients randomized to plasma infusion received smaller volumes of plasma than did those undergoing TPE. Because of the recent discovery of the presence of a von Willebrand factor cleaving protease involved in the pathogenesis of TTP/HUS, Coppo et al. sought to determine whether infusion of plasma in larger volumes was beneficial [4•]. Nineteen patients in the “high-dose” plasma infusion group and 18 patients in the TPE group were compared. The two groups were comparable with regard to clinical and laboratory features. The plasma infusion group received an average daily plasma volume of 27.5 mL/Kg of solvent detergent-treated plasma while the TPE group received 32 mL/Kg. The difference between these was statistically significant but the volume of plasma infused in the “high-dose” plasma group was higher than that reported in the other trials [4•].

The outcome of the trial was that the remission rate, mortality rate, relapse rate, time-to-platelet recovery, time-to-LDH normalization, and duration of hemodialysis did not differ significantly between the two groups. A statistically significant difference in therapy-related complications was seen with more complications occurring in the “high-dose” plasma group. This was due to the occurrence of volume overload in eight of the nineteen patients in this group, including four who were switched to TPE because of this complication [4•]. While appearing to be as effective as TPE, large-volume plasma infusion resulted in severe and potentially fatal volume overload that limited its usefulness in the treatment of TTP/HUS. Because of this, the authors of the paper suggested that this therapy be used in the treatment of TTP/HUS when TPE is not available [4•].

In treating TTP/HUS with plasma exchange, it is currently not possible to identify those patients who will respond to therapy and those who will not. Papers by Haas et al. [5•] and Mori et al. [6] sought to identify factors that could be used to predict response to TPE and allow better treatment of these patients. Haas et al. [5•] retrospectively examined 30 TTP/HUS patients, 20 “responders” and 6 “nonresponders” with regard to clinical characteristics and laboratory values in an attempt to identify characteristics associated with response to TPE. Unfortunately, they could identify no measures or signs obtained before plasma exchange that predicted response. They did find that the ratio of the LDH level prior to the third daily TPE divided by the LDH level prior to the first TPE was the best predictor of response. A ratio of less than 0.6 predicted a favorable outcome with a sensitivity of 0.96 and a specificity of 0.83 [5•].

Mori et al. [6] prospectively examined von Willebrand factor cleaving protease (vWFCPase) activity and the presence of inhibitors of vWFCPase in 27 patients with nonfamilial TTP/HUS. The clinical characteristics of these patients were not given and it was not reported whether they represented sporadic TTP/HUS or secondary TTP/HUS. The authors found that those patients with severe deficiency of vWFCPase activity (< 3% of normal controls) and those with vWFCPase inhibitor responded to combination therapy of TPE and immunosuppression while those with moderate deficiency of vWFCPase activity (24–48% of normal controls) and no inhibitors did not [6].

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Guillain-Barré syndrome

Acute demyelinating polyneuropathy (AIDP) is an acute symmetric ascending paralyzing disorder resulting from the demyelination of peripheral nerves by autoantibodies [7]. While patients affected by the disorder may spontaneously recover, 75% of patients suffer persistent neurologic deficits and 1 in 20 patients may die from complications associated with the disorder. TPE has been shown in randomized clinical trials to improve the disability and result in faster recovery [7]. It is a category I indication for plasmapheresis according to ASFA [7].

Raphael et al. [8••], in a review of the Cochrane Neuromuscular Disease Group register, summarized the results of randomized and quasi-randomized trials of plasma exchange versus sham exchange or supportive therapy. A total of six trials involving 649 patients that fulfilled their strict criteria for evaluation were identified. The results of the review were that TPE is the “first and only treatment that has been proven to be superior to supportive treatment alone” [8••]. In addition the authors found that TPE was most effective if started within 7 days of disease onset, that two sessions of TPE are superior to none in mild AIDP, that four sessions are superior to two in moderate AIDP, and that six sessions are no better than four in severe AIDP [8••].

Lyu et al. [9] performed a retrospective review of 102 patients undergoing either TPE or double filtration plasmapheresis (DFPP) for Guillain-Barré syndrome at four hospitals in Taiwan. A total of 39 patients underwent TPE and 63 underwent DFPP. The two groups were equivalent with regard to clinical features as well as a number of outcome measures with two exceptions. The TPE group demonstrated significantly better changes in disability scores and a shorter time to onset of these changes [9]. DFPP is more selective than TPE with regard to the removal of plasma substances, especially large molecular substances. The authors of the paper postulated that some substances that are removed by the nonselective TPE might remain after DFPP resulting in continued injury [9].

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Miller Fisher syndrome

Miller Fisher syndrome (MFS) is a rare neurologic disorder that is thought to be a variant of AIDP. It is characterized by the triad of ataxia, ophthalmoplegia, and areflexia [10••]. An antibody to GQ1b is present in the serum of affected individuals and is thought to play a role in the pathogenesis of the disorder. The prognosis of MFS is generally good, without residual neurologic deficit [10••]. Because of the possible relation of MFS to AIDP and the presence of an antibody, it has been postulated that TPE may be effective in managing the disorder. ASFA has not determined a category for this disease. Two papers evaluating the role of TPE in MFS appeared during the period of study [10••,11].

Kambara et al. [11] retrospectively analyzed four patients with MFS who had undergone TPE. They found that the four MFS patients had a shifted Th1/Th2 ratio favoring a Th2-dominant status. The performance of TPE was associated with a shift in this ratio to a Th1-dominant status. The neurologic deficits in the four treated patients resolved up to 50 days after the onset of symptoms [11].

Mori et al. [10••] retrospectively examined 50 patients with MFS. Of these patients, 22 underwent plasmapheresis every other day for 2 to 6 treatments using filtration methods [10••]. The remaining patients did not undergo TPE or intravenous immunoglobulin infusion. There was no statistically significant difference between the two groups with regard to age, gender, clinical characteristics, or severity of the disease [10••]. The time to resolution of the symptoms of MFS, ataxia, ophthalmoplegia, and areflexia, did not differ between those who received plasmapheresis and those who did not with almost all of the patients being free of symptoms 6 months after onset [10••]. Because of this, the authors believed that plasmapheresis in MFS should be limited to those cases that overlap with AIDP [10••].

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Myasthenia gravis

Myasthenia gravis (MG) is an autoimmune disorder characterized by variable weakness of voluntary muscle groups, which worsens with repeated activity and improves with rest [7]. The disorder is caused by autoantibodies toward acetylcholine receptors located at the neuromuscular junction. These autoantibodies result in blockade of the receptors, increased turnover of the receptors, and complement fixation on the postsynaptic membrane [7]. Because of the noncontroversial observational studies suggesting improvement of patients with MG following TPE, it is categorized by ASFA as a category I indication for TPE [7].

Gajdos et al. [12••], in a review of the Cochrane Neuromuscular Disease Group register, summarized the evidence available indicating the effectiveness of TPE in the management of MG. Studies were selected if they were randomized or quasi-randomized and evaluated TPE either alone or in combination with steroids or other immunosuppressive drugs. The authors identified only a single randomized trial. This trial found no significant difference in the muscle scores of those treated with TPE and prednisone when compared with prednisone alone [12••]. The authors believed that TPE was useful prior to thymectomy, during the postoperative period, to lessen the symptoms during the initiation of drug therapy, and to treat acute crisis. This was based upon uncontrolled clinical trials and anecdotal reports. Based upon the lack of randomized controlled trials for MG, however, the authors recommended that further research be performed to determine the benefit of TPE in the long-term outcome of MG [12••].

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Sepsis is common disease process among severely ill patients with high mortality among those with septic shock. TPE has been used as a treatment for sepsis with the results appearing in a number of case reports and series. The use of TPE for sepsis is currently not categorized by ASFA. Two papers, including a randomized controlled trial, were published examining the use of TPE to treat severe sepsis and septic shock [13,14••].

Ataman et al. [13] retrospectively examined the physiologic effects of TPE in seven patients suffering from norepinephrine refractory septic shock. They noted only a transient decrease in central venous pressure with no changes in the other physiologic parameters examined [13].

Busund et al. [14••] performed a randomized prospective trial examining the use of TPE to treat patients with severe sepsis or septic shock admitted to a university hospital ICU in Archangels, Russia. A total of 106 patients were enrolled with 54 randomized to TPE and 52 randomized to standard therapy. The two groups were identical with regard to a number of clinical factors except mean age, site of infection, mechanical ventilation, and use of fresh frozen plasma with the latter being greater in the TPE group due to the experimental treatment. The patients in the control group were older (48 ± 16 years vs. 41 ± 15 years, P = 0.03), were less likely to have an abdominal source of their sepsis (33 vs. 16), and were more likely to receive mechanical ventilation (67 vs. 46%P = 0.03) [14••]. The authors saw a statistically significant greater change in APACHEIII score in the TPE group in the first 24 hours than in the control group. The 28 day all-cause mortality was less in the TPE group (33.3 vs. 53.8%, P = 0.050) with a relative risk of fatal outcome in the TPE group of 0.61, an absolute risk reduction of 20.5% [14••]. Correcting for the variables that were different between the two groups (age and site of infection) using multiple logistic regression, however, reduced the significance of the effect of treatment on mortality to P = 0.07. The authors also examined the subgroup of patients with abdominal infections and found a statistically significant difference in mortality (33% in TPE group vs. 69% in the control group with P < 0.05). Again, age was significantly different between the two groups [14••]. Finally, the authors also acknowledge that the differences in mechanical ventilation with a higher rate in the control group may have also biased the results of the study [14••]. While the results of the study are intriguing, differences between the treatment and control groups make interpretation of the paper difficult.

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Wegener granulomatosis

Wegener granulomatosis is a small vessel vasculitis associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). It presents as a rapidly progressive glomerulonephritis (RPGN) as well as upper respiratory granulomatous inflammation. Because of the presence of a removable substance in the blood (ANCA) and the response of another RPGN, anti-basement antibody syndrome or Goodpasture syndrome, to TPE, plasmapheresis has been used to treat Wegener granulomatosis [3]. While Wegener's granulomatosis has not been specifically classified by ASFA, RPGNs are considered a category II indication for TPE [3].

Aasarod et al. [15•] retrospectively compared 29 patients treated with TPE and 79 patients treated with immunosuppression during the same period. The two groups differed with regard to age, number of organs affected, dialysis dependence, serum creatinine, and urinary protein excretion, as well as the severity of findings on renal biopsy. With the exception of age, which was older in the control group, all of the other factors mentioned were worse in those patients treated with TPE [15•]. Total or partial remission was achieved in 89.9% of controls versus 82.8% of the TPE group. Two- and 5-year survival in the TPE group was worse than in the control group (75 vs. 92% for 2-year survival and 71 vs. 75% for the 5-year survival). The overall mortality was not significantly different between the two groups but the survival at 2 years was higher in the TPE group (P = 0.044) suggesting a short-term benefit of TPE in these patients [15•]. The development of end-stage renal disease was greater in those receiving TPE (P = 0.0016) but when this was adjusted for baseline serum creatinine and number of organs affected, no difference was seen between the two groups [15•]. The authors interpreted the results of the study to indicate poor prognosis of Wegener granulomatosis with extensive renal involvement regardless of the use of TPE as an adjuvant treatment [15•].

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Review of the literature demonstrates that for diseases such as Guillain-Barré syndrome and TTP, TPE continues to be in the “acceptance” phase of development with randomized controlled trials indicating utility and limited alternate therapies at this time. Other diseases such as sepsis are moving from the “idea” or “adoption” phase toward the “acceptance” phase through the publication of results of randomized controlled trials. While plasma exchange may no longer be used to manage some diseases in the future, as the pathophysiology of these diseases become understood and a selective approach becomes feasible, for other diseases, in the absence of knowing the pathophysiology, TPE will continue to be a viable therapy.

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References and recommended reading

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Papers of particular interest, published within the annual period of review, have been highlighted as:

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• Of special interest

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•• Of outstanding interest

1. Vamvakas EC, Pineda AA: Selective extraction of plasma constituents. In Apheresis Principles and Practice. 2nd ed. Edited by McLeod BC. Bethesda:AABB Press: publication pending.

2. Grima KM: Therapeutic apheresis in hematological and oncological diseases. J Clin Apheresis 2000, 15:28–52.

3. Winters JL, Pineda AA, McLeod BC, et al.: Therapeutic apheresis in renal and metabolic diseases. J Clin Apheresis 2000, 15:53–73.

4.• Coppo P, Bussel A, Charrier S, et al.: High-dose plasma infusion versus plasma exchange as early treatment of thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome. Medicine (Baltimore) 2003, 82:27–38. Paper compares the efficacy of plasma exchange to large-volume plasma infusion.

5.• Haas M, Leko-Mohr Z, Lang T, et al.: The LDH ratio as a marker for response to plasma exchange in HUS/TTP of the adult. Clin Nephrol 2002, 57:414–420. Describes a marker that may be useful in predicting response to plasma exchange in TTP.

6. Mori Y, Wada H, Gabazza EC, et al.: Predicting response to plasma exchange in patients with thrombotic thrombocytopenic purpura with measurement of vWF-cleaving protease activity. Transfusion 2002, 42:572–580.

7. Weinstein R: Therapeutic apheresis in neurological disorders. J Clin Apheresis 2000, 15:74–128.

8.•• Raphael JC, Chevret S, Hughes RA, et al.: Plasma exchange for Guillain-Barré syndrome. Cochrane Database Syst Rev 2002, 2:CD001798. Comprehensive review of the randomized controlled trials of plasma exchange for Guillain-Barré syndrome. This article provides guidelines for treating patients based on these trials.

9.• Lyu RK, Chen WH, Hsieh ST: Plasma exchange versus double filtration plasmapheresis in the treatment of Guillain-Barré syndrome. Ther Apher 2002, 6:163–166. Study demonstrates an apparent inferiority of double-filtration plasmapheresis compared to plasma exchange.

10.•• Mori M, Kuwabara S, Fukutake T, et al.: Plasmapheresis and Miller Fisher syndrome: analysis of 50 consecutive cases. J Neurol Neurosurg Psych 2002, 72:680. The largest case series of Miller Fisher syndrome patients treated with plasmapheresis. The study demonstrates no benefit of plasmapheresis in the treatment of this disorder.

11. Kambara C, Matsuo H, Fukudome T, et al.: Miller Fisher syndrome and plasmapheresis. Ther Apher 2002, 6:450–453.

12.•• Gajdos P, Chevret S, Toyka K: Plasma exchange for myasthenia gravis. Cochrane Database Syst Rev 2002, 4:CD002275. Comprehensive review of the literature on plasma exchange as a treatment for Myasthenia gravis. This paper outlines clinical situations in which plasma exchange is supported by the literature and those where additional research is needed.

13. Ataman K, Jehmlich M, Kock S, et al.: Short-term cardiovascular effects of plasmapheresis in norepinephrine-refractory septic shock. Intensive Care Med 2002, 28:1164–1167.

14.•• Busund R, Koukline V, Utrobin U, et al.: Plasmapheresis in severe sepsis and septic shock: a prospective, randomised, controlled trial. Intensive Care Med 2002, 28:1434–1439. Large randomized trial of plasma exchange for severe sepsis and septic shock. This article suggests a possible benefit of plasma exchange in a subset of septic patients.

15.• Aasarod K, Iversen BM, Hammerstrom J, et al.: Clinical outcome of patients with Wegener's granulomatosis treated with plasma exchange. Blood Purif 2002, 20:167–173. Large case series comparing plasma exchange versus immunosuppressive therapy.

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Section Description

Edited by S Gerald Sandler

Cited By:

This article has been cited 7 time(s).

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plasma exchange; plasmapheresis; sepsis; Guillain-Barré syndrome; Wegener granulomatosis

© 2003 Lippincott Williams & Wilkins, Inc.


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