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Protein A Columns for Immune Thrombocytopenia

Health Technology Assessment Reports, 1990 Number 7

, D.O.

Created: .


The Office of Health Technology Assessment (OHTA) evaluates the risks, benefits, and clinical effectiveness of new or unestablished medical technologies that are being considered for coverage under Medicare. These assessments are performed at the request of the Health Care Financing Administration (HCFA). They are the basis for recommendations to HCFA regarding coverage policy decisions under Medicare.

Questions about Medicare coverage for certain health care technologies are directed to HCFA by such interested parties as insurers, manufacturers, Medicare contractors, and practitioners. Those questions of a medical, scientific, or technical nature are formally referred to OHTA for assessment.

OHTA's assessment process includes a comprehensive review of the medical literature and emphasizes broad and open participation from within and outside the Federal Government. A range of expert advice is obtained by widely publicizing the plans for conducting the assessment through publication of an announcement in the Federal Register and solicitation of input from Federal agencies, medical specialty societies, insurers, and manufacturers. The involvement of these experts helps assure inclusion of the experienced and varying viewpoints needed to round out the data derived from individual scientific studies in the medical literature.

After OHTA receives information from experts and the scientific literature, the results are analyzed and synthesized into an assessment report. Each report represents a detailed analysis of the risks, clinical effectiveness, and uses of new or unestablished medical technologies considered for Medicare coverage. These Health Technology Assessment Reports form the basis for the Public Health Service recommendations to HCFA and are disseminated widely. Individual reports are available to the public once HCFA has made a coverage decision regarding the subject technology.

OHTA is one component of the Agency for Health Care Policy and Research (AHCPR), Public Health Service, Department of Health and Human Services.

  • Thomas V. Holohan, M.D.
  • Director
  • Office of Health Technology Assessment
  • J. Jarrett Clinton, M.D.
  • Acting Administrator
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Extracorporeal immunoadsorption with protein A (ECI) has been developed for the purpose of selectively removing circulating immune complexes (CICs) and immunoglobulins (IgG) from the plasma of patients in whom these substances are associated with their disease.(1) The ECI technology commonly involves a continuous-flow immunoadsorption system consisting of an online cell separator, protein A columns, and a semiautomatic elution component which may be added.(2) During this process, the patient's venous whole blood is anticoagulated and pumped through a plasma-cell separator from which 1-3L of plasma are collected and then perfused over adsorbent columns containing Staphylococcus aureus protein A covalently bound to one of a variety of solid phase matrices (e.g., silica, collodion-charcoal or sepharose beads); the plasma then rejoins the separated, unprocessed cells and is retransfused.(3-6) An offline procedure using a fixed volume of plasma passed through an adsorbent column is an alternative technique in which separated blood cells are immediately reinfused after centrifugation, and plasma is reinfused after passing through the column.(7) Some IgG-or CICs-saturated columns may be eluted and reused, thereby offering efficient and unlimited adsorptive capacity. However, no such system is currently approved for marketing by the Food and Drug Administration (FDA). Although the complete removal of IgG complexes may not be possible, the extracorporeal perfusion of one plasma volume results in an acute decrease in IgG levels of approximately 50-60 using adsorption columns in series.(2,8,9) The clinically effective elimination of IgG and CICs may require processing of up to 20 L or more of plasma.(5) The procedure is commonly performed daily or every day until the desired results are achieved.(10) The mechanism for enhanced binding of immune complexes to protein A is unclear, and bound immune complexes, in contrast to bound IgG, cannot be eluted from columns by additional perfusion of the patient's plasma.(11,12)

Protein A is a major component of the cell wall of certains strains of Staphylococcus aureus, which has regions of selective high affinity for the Fc portion of the IgG molecule and also for aggregated or complexes IgG.(8,11) Protein A is highly specific for IgG subclasses 1, 2, and 4, but not for subclass 3, IgM, or complement.(2). IgG and IgG-containing CICs are removed from plasma by means of solid-phase immunoadsorption, which is the specific physiochemical binding of these substances to the receptor protein within the column.


Idiopathic thrombocytopenic purpura (ITP) is an acquired hemorrhagic disorder characterized by persistent thrombocytopenia, episodes of acute hemorrhage, and normal or increased numbers of megakaryocytes in an otherwise normal marrow. ITP is not a clearly defined condition. Rather, it is a diagnosis after exclusion of other diseases or agents known to induce or to be associated with thrombocytopenia.(13-15)

ITP may be acute, intermittent, or chronic, and patients classically exhibit easy bruisability, petechiae, epistaxis, and gingival, gastrointestinal, or central nervous system bleeding.(7,16) Acute ITP is usually seen in patients aged 2-15, often following a viral illness.(12) In children, the majority of acute cases of ITP spontaneously resolve within 6-12 months, but spontaneous resolution is not commonly seen in adults.(17). Classic chronic ITP, which may have a course of several years or more, is primarily a disease of females between the ages of 15 and 45, and responses to standard therapy (steroids or splenectomy) are initially seen in 60-80 of patients.(13) ITP in patients over the age of 45 is generally more refractory to therapy with responses seen in approximately 30 of patients. More recently, ITP has been seen in approximately 10 of individuals infected with the human immunodeficiency virus (HIV) (16) Mortality in ITP is approximately 1 in patients under the age of 20 and 6-10 in older patients.(9,13).

The humoral nature of the antiplatelet factor in ITP was first established by Harrington et al in 1957.(18) This antiplatelet substance was later identified as a combination of antiplatelet IgG antibody and CICs, which prompted some investigators to change the name of the disorder from idiopathic to autoimmune thrombocytopenic purpura.(7,19)

Autoantibodies and CICs have been implicated in the pathogenesis of several other autoimmune disease including Goodpasture's syndrome and myasthenia gravis.(20,21) CICs have the potential for inducing tissue injury and can also act as immunoregulators involving macrophages, T-cells, and B-cells.(22) Autoantibodies can induce immune-mediated tissue injury.(23) In ITP, the thrombocytopenia is generally regarded to be a consequence of the production of IgG antiplatelet antibodies that react with platelets, rendering them susceptible to oipsonization and accelerated clearance and destruction by macrophages in the reticuloendothelial system (RES) (7,16,17,24) It has also been hypothesized that in some patients the predominant cause of thrombocytopenia may be ineffective marrow production rather than accelerated clearance of platelets.(25) Platelet antibody levels do not predict response to therapy or directly correlate with disease state.(26) However, an inverse correlation exists between these levels and platelet counts and platelet survival, suggesting that increased levels of bound platelet-associated immunoglobulin are associated with greater severity of disease.(25,26) Elevated levels of platelet-associated IgG are not necessarily a specific disease finding and are seen in only 80-90 of patients with ITP.(27) Although ITP can resolve spontaneously, the untreated disease becomes chronic or recurrent in 95 of adult cases.(28)

Treatment for ITP is designed to suppress the clearance of antibody-bound platelets by the RES or reduce the level of antibody directed against platelets.(7,29) The alleviation of thrombocytopenia has been accomplished by blocking antibody production or its binding to platelets, interfering with phagocytosis of the antibody-platelet complexes, or removing the sites of sequestration. Additional and as yet underscribed mechanisms may be operative. In the absence of a permanent remission, the goal of therapy is the maintenance of hemostatic stability with platelet counts in the range of 40,000-100,000/mm(3) by means of increasing production, decreasing destruction, or pooling of platelets.(7,25). Corticosteroids, which are palliative rather than curative, are generally used as the initial treatment for chronic ITP. They block the removal of CICs by the RES by inhibiting its phagocytosis, blocking adherence of antibody-coated platelets to granulocytes, and preventing phagocytosis of the platelets.(12) In addition, steroids are associated with an increased production of platelets in the bone marrow.(25) This treatment is usually effective within 7-10 days in 40-75 of patients. If no response is seen within 3 weeks, other treatment, usually splenectomy, is considered.

Splenectomy, which removes the principle site of platelet destruction and the major site of antiplatelet antibody production, results in improvement in 70-80 of patients and normalization of platelet counts in 60 of patients.(23,30) However, the circumstances under which splenectomy is appropriate and its exact role in the treatment of chronic ITP are not well defined.(30) Splenectomy is not a benign procedure. Both the morbidity and mortality of the surgery itself is high, and there is a subsequent significantly higher lifelong risk of overwhelming infection and thromboembolism compared with the normal population.(31,32) The postsurgical morbidity and mortality of splenectomy (30 days) ranges from 3.3-50 and 1.4-6 respectively.(33-36) The selection of patients most likely to respond to splenectomy can be made by platelet kinetic studies using radiolabeled chromium to determine if the spleen is indeed the major site of platelet sequestration. A significantly percentage (from 5-20) of patients eventually become refractory to steroids or splenectomy.(23) The treatment of refractory ITP using immunosuppressives, high-dose gamma globulin, plasmapheresis, or a variety of other therapies has resulted in achieving satisfactory platelet counts, albeit transient, in less than 50 of patients.(12,30,37) Androgens and the antiestrogen, tamoxifen, have been used in patients with refractory ITP as single agents or combined with glucocorticoids to offset their antianabolic effects and have occasionally resulted in improved platelet counts for period of up to 13 months.(38,39) The mechanism of action of androgens for this indication is unknown. Since lifelong therapy is generally required for most patients with chronic ITP, the long-term side effects of therapies, other than splenectomy, limit their use.(28,39)

Several less common form of thrombocytopenia include the disease complex of thrombotic thrombocytopenic purpura (TTP) in conjunction with hemolytic-uremic syndrome (HUS), which is most commonly seen as a consequence of cancer chemotherapy (particularly mitomycin-C), or immunosuppression using cyclosporine.(40,41) This is a rapidly progressing and often fatal disease. By contrast, HUS unassociated with TTP is characterized by thrombocytopenia, hemolytic anemia, and renal failure. Conventional therapy for these syndromes consist of immunosuppressives, plasmapheresis, or antiplatelet drugs and has a reported 70-80 failure rate.


Extensive preclinical and clinical studies have suggested an immunomodulatory role for both lgG and CICs in a number of illnesses including red cell aplasia, HUS, ITP, cancer, and other autoimmune diseases.(8,22,42,43) It has been hypothesized that the removal of these circulating humoral factors may be clinically beneficial to such patients.(10,11)

In the past, the major approach to the removal of CICs and IgG has been plasmapheresis, which although non-specific, has been used with success with in a wide variety of immunologic disorders.(9) However, plasmapheresis is expensive, invasive, and requires large volumes of replacement fluids with its associated risk of adverse reactions, including hemodynamic instability and viral infections.(5,23,44)

Extracorporeal immunoadsorption is proposed as an alternative to plasmapheresis for the specific removal of IgG and CICs with no need for replacement fluids, therefore involving less cost, less risk, increased efficiency, and better hemodynamic control.(2,5,22,45).

Review of Available Literature

There no prospective, randomized, controlled clinical trials of the safety, effectiveness, or clinical utility of protein A columns in the treatment of any disease. In the following clinical reports, the patient groups are highly variable both within and between studies, generally contain relatively few patients, and include both untreated patients and prior treatment failures. In addition, response criteria are not well defined. In clinical studies of the safety and efficacy of ECI using protein A columns as initial therapy in 61 treatments at four institutions, Jones et al(23). observed a platelet count increase of 50 or more in 8 of 11 patients with chronic ITP and a 1.7-to 4.3-fold increased platelet count in 6 of 9 patients with HIV-associated ITP. Side effects noted included pain, fever, chills, rash, nausea, respiratory distress, vomiting, itching, hives, diarrhea, tachycardia, muscle spasm, and dizziness. The most frequent side effects during or after treatment were pain (26), fever (21), chills (16), and rash (11). These side effects were transient and manageable, and similar to those seen during routine hemodialysis and therapeutic apheresis procedures.

Mittelman et al(46). demonstrated control of the bleeding diathesis and an increased platelet count of more than 50 in 16 of 36 patients with HIV-associated ITP after ECI using protein A. Patients received no treatment for 4 weeks prior to entry into the study. The median duration of response was 8-12 months.

In a pilot study of the use of protein A columns in 10 patients with refractory ITP, including 5 who failed splenectomy, Guthrie and Oral(12). reported 1 complete response, 4 with partial responses, and 5 nonresponders. The response duration was 1-6+months. Adverse reactions included nausea, vomiting, headache, myalgia, fever, rash, and hypotension.

A recent report by Muroi et al, (47). involved the use of protein A columns once or twice weekly in patients with ITP. In two cases of acute ITP, platelets markedly increased and platelet-associated IgG and CICs were decreased. A transient increase in platelets was achieved in one patient with chronic ITP.

Messerchmidt et al(42,28). have reported the results of clinical trials using ECI with perfusion columns in the treatment of various malignancies. In the first study, using heat-inactivated, formalin-fixed Cowan I strain Staphylococcus aureus in the columns, no antitumor responses were noted in 16 patients with a variety of tumors.(42) The other study, a multicenter trial involving 1,113 perfusion procedures in 114 patients, demonstrated only partial tumor responses in 24 of 87 evaluable patients. This study used highly purified protein A columns.(48) Responses were observed in AIDS-related Kaposi's sarcoma (8/17), breast cancer (8/22), colon cancer (2/18), and lung cancer (2/7). The procedures were well tolerated and could be performed in an outpatient setting. Most patients did not experience adverse reactions. In the earlier study, reported in 1984, 8 of 16 patients exhibited cardiovascular and respiratory toxicity related to the volume and rate of the perfusion and 2 of 16 patients died from inadequate respiratory function. In the later study, reported in 1988, there were no study-related deaths, and the most common adverse reactions were pain and an influenza-like syndrome consisting of fever and chills. The difference in toxicities noted in the two studies was probably related to the differences in the adsorbent columns.

In a 1988 case report, Garley et al(49). reported a fatal pulmonary reaction in a 40-year-old patient with poor respiratory reserve following the fourth daily perfusion over protein A columns used to treat pure red cell aplasia. Cardiopulmonary toxicity during ECI has been postulated to be a consequence of the hemodynamic effects of differing plasma volumes and perfusion rates.(50)

Watson et al(43). reported the successful treatment using protein A of a patient with chemotheraphy-related HUS who failed to respond to plasmapheresis.

In a study involving 11 patients with HUS treatment using protein A columns an average of five times over 10 days, Korec et al(40). reported that 9 of 11 patients exhibited a significant rise in platelet and red cell counts and long-term control (over 9 months) in 7 to 11 patients. In addition, 8 of 11 patients exhibited decreased levels of CICs, 7 to 11 demonstrated normalization of previously depressed complement, and 6 to 11 patients had stabilization of their renal disease. These studies are summarized in the table.

Table. Clinical reports of extracorporeal immunoadsorption.


Table. Clinical reports of extracorporeal immunoadsorption.


The mechanism of action of ECI using protein A remains speculative but may involve the selective removal of both CICs and IgG that are exerting an adverse immunologic effect.(51) However, clinical responses to ECI cannot be attributed to the direct quantitative removal of CICs or IgG.(16) In some instances, improved platelet counts can be initiated by the removal of as little as 1 g of IgG, which may, in turn, trigger a series of positive immunomodulatory responses involving CICs and autoantibodies.(51-53)

Various clinical studies have used different adsorbent materials, varying volumes of treated plasma, differing procedures and treatment schedules, and variable patient selection, making any evaluation of clinical benefits and adverse reactions difficult. In addition, the existence of a large number of therapies suggests that none is particularly satisfactory.(17)

The standard treatment for ITP continues to be the use of steroids, followed by splenectomy for those patients failing to respond to the initial treatment. Splenectomy is ultimately indicated for most patients with ITP.(24) Exceptions are those patients with very mild disease or in whom surgery is contraindicated. Alternatively treatments are considered for those patients in whom a rapid rise in platelet counts is deemed essential, i.e., preoperatively or with life-threatening hemorrhage, or in refractory chronic patients.(38) For those patients, other treatments, such as high-dose intravenous gamma globulin or ECI, are reasonable considerations.(12,17,29,53-55)

In response to the Federal Register notice of this assessment(56). and the solicitation of information and opinions from Public Health Service agencies and the general medical community, the Office of Health Technology Assessment (OHTA) has received a number of communications concerning protein A immunoadsorption using the PROSORBA (R) column.

  • The Children's Hospital-San Francisco has had experience with more than 1,000 procedures using protein A immunoadsorption and demonstrated safety with minimal side effects. The indications were for patients with ITP failing steroid therapy or having contraindications for steriod, intravenous gamma globulin, or splenectomy. ECI for the treatment of malignancies or AIDS-related Kaposi's sarcoma requires further investigation. Chemotherapy-induced HUS also responds to ECI.
  • The University of Michigan Medical Center stated that Protein A immunoadsorption has proven to be effective in the treatment of breast cancer (20 partial response) and Kaposi's sarcoma (40 partial response) with less toxicity than chemotherapy, and is widely accepted as standard treatment for ITP and HUS.
  • The Medical College of Georgia has had experience using ECI in 50 patients with either ITP or TTP failing plasma exchange, chemotherapy-induced HUS, and various end-stage malignancies. They stated that ECI is the only effective treatment for HUS, and in classic ITP, ECI is equal to the effectiveness of other therapies and has less toxicity. ECI is also effective in patients with HIV-associated ITP and Kaposi's sarcoma. EECI is recommended as a substitute therapy for patients failing plasma exchange.
  • The Vancouver General Hospital stated that either suggestive evidence or a good rationale exists for the use of ECI in treating other diseases in addition to ITP, such as myasthenia gravis, relapsing demyelinating polyneuropathy, and hemolytic anemia. However, support for these indications requires confirmation by clinical trials.
  • The Central Blood Bank, Pittsburgh, states that experience with ECI suggests its consideration as second-or third-line treatment for chronic ITP in adults, and possibly first-line treatment for HIV-associated ITP. On the basis of limited experience, ECI is considered first-line treatment of HUS. ECI is potentially useful in all autoimmune-related diseases, especially where immune complex disease is not part of the underlying autoimmune process and there are no clinical inflammatory signs, such as florid systemic lupus erythematosus (SLE) and vasculitis. Testing the use of ECI in antitumor clinical trials is warranted.
  • New York Medical College has demonstrated responses to ECIA in a small number of patients with breast cancer and Kaposi's sarcoma and recommends ECI as a second-line treatment for ITP patients who fail to respond to steroids as a therapeutic trial prior to consideration of splenectomy.
  • Baystate Medical Center recommends ECI for ITP patients failing conventional therapy and as a treatment of last resort for patients with breast cancer.
  • Mayo Clinic Blood Bank and Transfusion Services states that ECI is indicated for adult patients with life-threatening ITP who are refractory to conventional therapy. ECI should not be first-line therapy for ITP and is regarded as investigational for patients having HUS, red cell aplasia, factor VIII inhibitors, breast cancer, Kaposi's sarcoma, and other diseases associated with circulating antibodies or immune complexes.
  • IMRE Corporation reported no differences in responses to ECI between HIV-associated ITP and classic refractory ITP. Responses were seen in approximately 50 of patients and were maintained for a mean of 8.1 months. Responses have also been observed in patients with breast cancer and Kaposi's sarcoma.
  • The National Institutes of Health (NIH) noted the existence of conflicting reports concerning the efficacy and relative safety of protein A columns used in the treatment of ITP and stated that its use as first-line therapy does not appear to be warranted. There has not been a clear demonstration of its usefulness in patients with HIV. The NIH concluded that ECI is of minor importance in the treatment of ITP and remains unproven as a treatment for patients with AIDS or cancer where only short-term clinical improvements have been seen; its use is regarded as a research tool without clear long-term efficacy.
  • FDA reports that only one device, the IMRE PROSORBA (R) column, utilizing protein A for immunoadsorption, is regarded as safe and effective for removing IgG and CICs from plasma and was approved for marketing in December 1987. The summary of safety and effectiveness data was based on in vitro and animal studies and a multicenter clinical study involving 142 cancer patients and 42 patients with either ITP or mitomycin-C-induced TTP/HUS. The FDA labeling states that the sole indication for its use is for patients with ITP having platelet counts less than 100,000/mm(3).


ECI using protein A columns has been designed to selectively remove circulating CICs and IgG from the plasma of patients in whom these substances are associated with their disease. The use of protein A columns appears to be a reasonable alternative to plasmapheresis in many autoimmune disorders for which plasma exchange is indicated. Although preliminary evidence suggests efficacy of plasma exchange, there is a paucity of data indicating that ECI would indeed provide comparable efficacious results.

Although the role of ECI using protein A columns for the treatment of ITP continues to be poorly defined, its use in urgent and life-threatening situations in both ITP and HUS appears reasonable. The results of any treatment for chronic refractory ITP continue to be unsatisfactory. However, favorable responses have been achieved using protein A columns, suggesting the need for further The role of ECI in the treatment of other disorders, including AIDS, TTP, and the treatment of malignancies, where clinical effects are transient, continues to be investigational.

The true clinical response rates and duration or responses to ECI using protein A in treating any disorder requires definition in studies involving a larger number of patients with longer followup. The demonstration of the ultimate clinical value of this therapy will require clinical trials comparing its efficacy to other therapies. Although more serious reactions have been reported, toxicities associated with the use of protein A columns are generally transient and mild.


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Garley DC, Peny E, Jackson B Fatal pulmonary reaction with staph protein A immune adsorption for pure red cell aplasia Transfusion 1988. 28 (suppl 1)–.
Young LB, Ayus JC, Miller LK, et al Cardiopulmonary toxicity in patients with breast carcinoma during plasma perfusion over immobilized protein A Am J Med 1983. 75:278–288. [PubMed: 6881180]
Snyder HW Jr, Balint JP Jr, Jones FR Modulation of immunity in patients with autoimmune disease and cancer treated by extracorporeal immunoadsorption with Prosorba columns Semin Hematol 1989. 26 (suppl 1)31–41. [PubMed: 2543085]
Pinsky CM Introduction to supplement Semin Hematol (suppl 1) 1989. 26:1–2.
Buchanan GR Childhood acute idiopathic thrombocytopenia purpura: How many tests and how much treatment required? Edit. J Pediatr 1984. 106:928–930. [PubMed: 4039754]
LeClerc JR, Sternbach M, Solymoss S, et al Intravenous immunoglobulin therapy for refractory chronic idiopathic thrombocytopenic purpura CMAJ 1987. 136:961–962. [PMC free article: PMC1491954] [PubMed: 3567813]
McMillen McMillan R Chronic idiopathic thrombocytopenic purpura N Engl J Med 1981. 304:1135–147. [PubMed: 7012619]
[no authors listed] Federal Register, October 6, 1988. 53:–.

AHCPR Pub. No. 91-0008


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