Plasmapheresis

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General Background
Plasmapheresis (PP), apheresis, plasma exchange (PE), or therapeutic plasma exchange (TPE) is a process by which plasma is removed via a cell separator and the red cells, white cells, platelets and a sterile plasma substitute (e.g., plasma protein fractions or albumin with sterile saline) are transfused back into the body. The goal of PP is to decrease the concentration of harmful plasma constituents, allowing a disease course to improve. The abnormal blood constituents implicated in diseases and removed by PP include toxins, metabolic substances and plasma components (e.g., complement antibodies). The procedure takes one to three hours, and the number of treatments needed (e.g., six to ten treatments over a two-to ten-week period) depends upon the patient's condition and underlying disease.
Plasmapheresis is a recognized treatment modality for multiple conditions. The American Society for Apheresis (ASFA) (Padmanabhan, et al., 2019) updated guidelines for PP include four categories that were developed based on the quality of the evidence and the strength of recommendations derived from the evidence. These categories rate the indications for PP by condition and include the following: • Category I -Disorders for which apheresis is accepted as first-line therapy, either as a primary standalone treatment or in conjunction with other modes of treatment. • Category II -Disorders for which apheresis is accepted as second-line therapy, either as a standalone treatment or in conjunction with other modes of treatment. • Category III -Optimum role of apheresis therapy is not established. Decision making should be individualized. • Category IV -Disorders in which published evidence demonstrates or suggests apheresis to be ineffective or harmful. IRB approval is desirable if apheresis treatment is undertaken in these circumstances.
In the ASFA guideline, the grade system was used to assign recommendation grades for therapeutic apheresis to enhance the clinical value of the ASFA categories: • In their 2011 guidelines (reaffirmed in 2016) for plasmapheresis for neurologic disorders, the American Academy of Neurology (AAN) reported that PP is an established, effective therapy and should be offered in the treatment of acute inflammatory demyelinating polyneuropathy (AIDP)/Guillain-Barré syndrome (GBS) that is "severe enough to impair independent walking or to require mechanical ventilation." AAN also stated that PP should be considered in the treatment of milder clinical presentations of AIDP/GBS (i.e., stand unaided or walk five meters without assistance).

Additional AAN recommendations included:
• PP is an established, short-term treatment option and recommends its use for CIDP.
• PP is probably effective for IgA and IgG-MGUS-associated polyneuropathy, but probably not effective for polyneuropathy with IgM-MGUS. • There is inadequate data in randomized controlled trials with masked outcomes to support or refute PP for the treatment of myasthenia gravis crisis or prethymectomy AAN noted that PP is used by many medical centers for the above indications.

Category II Indications
Evidence in the published peer-reviewed scientific literature and the Society for Apheresis, the American Academy of Neurology and other professional societies (e.g., National Cancer Institute), support PP as an acceptable adjunct therapy for the conditions listed below.

Cardiac Transplantation, Desensitization (Grade 1C):
The four types of cardiac allograft rejection include hyperacute in cases of ABO or major human leukocyte antigen (HLA) incompatibility, acute cellular (ACR), acute antibody-mediated (AMR) or chronic rejection (allograft vasculopathy). ACR is the most common form of rejection and is mediated by T cells. Rejection is treated by immunosuppression. Steroids are used for episodes of rejection. If AMR progresses, rituximab and TPE are considered. Many past studies focusing on desensitization were performed with older medical regimens. Newer agents, such as bortezomib, are now used for desensitization. Extracorporeal photopheresis (ECP) may be used to treat cellular rejection and allograft vasculopathy. PP has been proposed as a treatment modality during the acute rejection period to remove donorspecific antibodies and/or inflammatory mediators in AMR. However, the evidence is primarily in the form of case series, case reports and retrospective reviews.

Lambert-Eaton Myasthenic Syndrome (LEMS) (Grade 2C):
The primary goal of treatment for LEMS is to identify and treat any tumors or other underlying disorders. In some cases, prednisone or other medications that suppress the immune response may be used initially to improve symptoms. PP may be a useful adjunct for patients with severe or rapidly developing neurological deficit, in the case of patients who are too uncomfortable to wait for immunosuppressive or aminopyridine drugs to take effect, or who cannot tolerate treatment with IVIG (Padmanabhan, et  In their 2011 guidelines for plasmapheresis for neurologic disorders, the American Academy of Neurology (AAN) reported that there was insufficient evidence to support or refute PP for the treatment of PANDAS (AAN, 2011; reaffirmed 2016).

Phytanic Acid Storage Disease (Refsum's Disease) (Grade 2C):
The mainstay of therapy for Refsum's disease is to limit the daily intake of foods rich in phytanic acid. PP is indicated for acute attacks or exacerbations because of its ability to rapidly decrease the level of phytanic acid (Padmanabhan, et

Vasculitis (Hepatitis B Virus [HBV] Polyarteritis Nodosa [PAN]) (Grade 2C):
Polyarteritis nodosa (PAN) is a form of vasculitis that mainly affects medium-sized arteries, frequently presenting with peripheral neuropathy, skin, renal, and other organ and system manifestations, some of these are non-specific: weight loss, fever, rash, myalgia, neuropathy, or abdominal ischemia. It can be idiopathic, or associated with infection such as

Category III and Category IV Indications
For conditions rated as a category III or IV by the American Society for Apheresis, scientific studies have reported inconsistent outcomes, and/or lack of consistent efficacy, and/or no benefit from PP as a treatment modality. Therefore, in these conditions, PP is not recommended as a treatment modality (Padmanabhan, et

ABO Incompatible Solid Organ Transplantation -Liver; Deceased Donor; Humoral Rejection (III Grade 2C):
Major incompatibility refers to the presence of natural antibodies in the recipient against the donor's A or/and B blood group antigen. These antibodies may cause hyperacute/acute humoral rejection of the organ due to endothelial damage. There is a paucity of evidence that PP, in combination with enhanced immunosuppression may be effective in reversing humoral rejection in the liver allograft. In the deceased donor liver transplant setting. PP is typically instituted immediately before and sometimes both before and after transplantation in an attempt to prevent hyperacute rejection and acute antibody medicated rejection (AMR). In deceased donor liver transplant, PP procedures are often utilized in the urgent/emergent setting after a deceased ABO incompatible allograft has been identified, making a thorough analysis of PP efficacy challenging.

Amyloidosis, Systemic (IV Grade 2C):
Systemic amyloidosis is a metabolic storage disease in which protein is deposited throughout the body, resulting in an insoluble matrix in a variety of tissue. Treatment depends upon which organs are involved and is aimed at preventing overproduction of the precursor proteins, further tissue deposition and fibril formation. Chemotherapy and stem cell transplantation may be included in the treatment. PP has been proposed as a treatment for amyloidosis, but has not been proven to be an effective therapy (Padmanabhan, et

Coagulation Factor Inhibitors (CFI) (III Grade 2C):
Blood coagulation factor inhibitors interfere with the normal clotting mechanism of the blood as seen in conditions such as hemophilia. Treatment depends on the etiology and aims to accomplish cessation of bleeding and suppression of inhibitor production. This may be accomplished by replacing the factor or bypassing it. Inhibitor suppression may be accomplished by the administration of high dose corticosteroids and IVIG. It has been proposed that PP may be useful in the removal of inhibitors, but its effectiveness has not been proven (Padmanabhan, et al., 2019; Schwartz, et al., 2013, 2016).

Complex Regional Pain Syndrome (CRPS) (III Grade 2C):
The pathophysiological mechanisms of complex regional pain syndrome (CRPS) are not fully understood.

Erythropoietic Porphyria, Liver Disease (EPP) (III Grade 2C):
EPP is a rare autosomal recessive disorder characterized by partial deficiency of ferrochelatase. Defective activity of ferrochelatase mainly in erythropoietic cells leads to the accumulation of protoporphyrin in RBCs and secondarily in plasma, skin, hepatocytes, bile, and stool. Clinical manifestations in EPP include a nonblistering painful photosensitivity, commonly presenting in childhood. Cholestatic liver failure is uncommon in EPP and the optimal therapeutic approach remains unknown. The goal of TPE during acute liver failure is to decrease the protoporphyrin level in the plasma and to prevent further deposition in the liver. It has been proposed that TPE may also be advantageous in removal of bile acids with improvement in pruritus.

Henoch-Schonlein Purpura (III Grade 2C):
Henoch-Schonlein purpura (HSP) is the most common systemic vasculitis in childhood with 95% of cases occurring in this age group, but is less common in adults. Treatment is predominantly supportive care. In patients with severe kidney involvement (i.e., crescentic glomerulonephritis) or severe symptoms of vasculitis, treatment also includes pharmacotherapy. If end stage renal disease develops, kidney transplantation may be necessary. PP is proposed for removal of IgA-containing immune complexes or IgG autoantibodies. However, the evidence is primarily in the form of case series and case reports.

Inclusion Body Myositis (IV Grade 2C): Inclusion body myositis (IBM) is an inflammatory myopathy characterized by chronic muscle inflammation and muscle weakness.
There is no standard treatment or cure for the disease. Physical therapy and supportive care may be helpful. IVIG may produce short-term effects. Corticosteroids and immunosuppressive drugs are generally ineffective (Schwartz, et al., 2013) The American Society for Apheresis (Shaz, et al., 2007) reported on studies using PP for the treatment of inclusion body myositis. The studies included a single case report, an uncontrolled study of 35 patients with idiopathic inflammatory myopathy nonresponsive to treatment. Improvement following PP was reported, but the patients were treated in conjunction with either cyclophosphamide or chlorambucil. The diagnosis of IBM was not specified and the role of PP was undetermined.

Lung Allograft, Rejection; Desensitization (III Grade 2C):
Recent case reports and series suggest that antibody mediated rejection; (AMR) should be considered a potential cause of graft dysfunction, particularly when resistance to corticosteroid therapy is encountered. Formal criteria for the diagnosis of pulmonary AMR have now been put forth by the the International Society for Heart and Lung Transplantation. Both anti-HLA and antiendothelial antibodies have been proposed in mediating AMR. Recent reports suggest that PP may be efficacious in treating AMR, but the evidence is insufficient to support PP for this indication. In the area of desensitization of highly alloimmunized lung transplant waitlisted patients, use of a multimodal desensitization protocol including TPE, steroids, rituximab, and bortezomib in a small cohort of patients (n=8) did not appear to significantly reduce pretransplant HLA antibodies and survival among the treated group was comparable to untreated cohort. (Schwartz, et al., 2013(Schwartz, et al., , 2016Snyder, et al., 2014).

Neuromyelitis Optica Spectrum Disorders (NMSOD), Maintenance (III Grade 2C):
NMSOD is an inflammatory disease of the central nervous system with episodes of inflammation and damage to the myelin that most often affects the optic nerves causing temporary or permanent blindness. Approximately 80% of patients with NMO have relapsing course, which has a poor prognosis: 50% of patients become legally blind or wheelchair bound and 30% die with respiratory failure within 5 years. There is not a progressive phase like Multiple Sclerosis; the disease worsens by incomplete recovery with each acute attack. Prophylaxis to prevent further acute attacks includes immunosuppressive medications and immunomodulation. There is insufficient evidence supporting the efficacy of PP as maintenance therapy for NMO (Padmanabhan, et

Overdose, Envenomation, and Poisoning (Compounds Other than Mushroom Poisoning) (III Grade 2C):
Excessive exposure to drugs and poisoning by ingestion, inhalation, injection, or snake bites can lead to tissue injury and/or organ dysfunction. Initial treatment focuses on supportive care and removal of the toxic agent by antidotes, lavage, inducted vomiting and other methods of toxic desensitization. Dialysis may also be indicated.
To aid in the removal of protein-bound toxins, PP has been proposed as an alternate therapy to dialysis or hemoperfusion, but for PP to be effective, toxic agents must not be lipid soluble, bound to tissue, or be present in large volume outside of the bloodstream. There is insufficient evidence in the published clinical trials supporting the efficacy of PP for overdosing, envenomation and poisoning by compounds other than mushroom poisoning (Padmanabhan, et  According to the American Society of Apheresis (Shaz, et al., 2007), TPE was initially used as a treatment for POEMS because it was diagnosed as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) or monoclonal gammopathy of undetermined significance (MGUS). The number of scientific studies are limited and included small patient populations (n=1-30). There were no reported differences in the outcomes with the use of PP and corticosteroids compared to steroid therapy alone. PP is considered ineffective for this condition.

Progressive Multifocal Leukoenchephalopathy (PML) associated with Natalizumab (NTZ) (III Grade 1C):
PML is a rare central nervous system (CNS) demyelinating disorder typically seen in patients with impaired cellimmunity. Prevention of PML development with risk stratification approaches are warranted. Immune reconstitution is the only intervention with demonstrated efficacy for PML. For NTZ-PML, management includes discontinuation of the drug (temporary or permanent) and consideration for initiation of TPE to accelerate clearance, especially if the drug is recently infused. Both will increase number and function of leukocytes migration to the CNS. Rapid immune reconstitution may precipitate an extreme immune response called Immune Reconstitution Inflammatory Syndrome (IRIS), which associated with neurological status deterioration, often life threatening. IRIS usually develops 2-6 weeks after TPE (versus 3 months after drug discontinuation) in almost all patients. Retrospective studies had major limitations including containing small number of patients and potential differences in baseline characteristics between the groups received TPE and the group did not. Thus, the benefits of immune reconstitution in patients with severe NTZ-PML may outweigh the risk of IRIS and although the role of TPE is not yet optimized in this condition and that the benefits of TPE are conjectural, and have not been proven rigorously, it can be considered in selected group of patients (Padmanabhan, et al., 2019).  Red Cell Alloimmunization in Pregnancy, gestational age < 20 weeks (III Grade 2C): Management of red cell alloimmunization includes assessing the phenotype of the father and performing maternal antibody titers.

Pruritus due to Hepatobiliary Diseases (III
Depending upon the titer level, ultrasound and/or amniocentesis may be performed. Ongoing assessment of the status of the fetus may also be indicated. If the fetus is determined as being high risk for hydrops fetalis, intrauterine transfusion is the primary therapy. Treatment of the mother with IVIG and/or PP may be used as an adjunct therapy if there is a high risk of fetal demise or signs of hydrops at <20 weeks gestational age, especially in a mother with a previously affected pregnancy. PP of the mother removes the maternal red call alloantibody, reduces the maternal antibody titer, and protects the fetus from hemolytic disease (Padmanabhan, et al., 2019;Schwartz, et al., 2013Schwartz, et al., , 2016Ruma, et al., 2007).

Rheumatoid Arthritis (RA) (IV Grade 1B):
RA is a chronic inflammatory autoimmune disorder of unknown cause that can affect most joints and is characterized by symmetrical erosive synovitis that can progress to joint destruction and significant disability. Therapy may include the use of nonsteroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), and/or low doses of steroids. Physical and occupational therapy may also be helpful (Shaz, et al., 2007;Schwartz, et al., 2013;Seror, 2007;Szczepiorkowski, et al., 2007;Smith, et al., 2003).
PP has been proposed for the treatment of RA in an attempt to remove circulating immune complexes and rheumatoid factors. Two controlled trials reported no benefit from the use of PP (Shaz, et al., 2007). Seror et al. (2007) conducted a systematic review of the literature and reported on two studies that used PP for the treatment of RA. The patient populations were small (n=19 and 20), and improvement was shown in the control group, as well as the study group, but values returned to baseline within eight weeks.
Rheumatoid Vasculitis: Rheumatoid vasculitis is an inflammatory disease that occurs in small and mediumsized blood vessels and can involve the nerves in the hands and feet, as well as blood vessels in the heart, eyes, fingers, and toes. Treatment may include pharmacotherapy and surgical intervention for severely affected joints. PP has been proposed as a treatment option for renal vasculitis, but its effectiveness remains unproven. 1A): Schizophrenia is a chronic, disabling psychiatric disorder characterized by acute and chronic psychosis and deterioration in function. The mainstay of treatment is antipsychotic medication and adjunctive supportive psychosocial therapies targeted at both the effected individual and their families. Data is limited and, based upon one randomized trial, the American Society for Apheresis states PP offers no benefit in the treatment of schizophrenia (Schwartz, et al., 2010;Shaz, et al., 2007).

Scleroderma (Progressive Systemic Sclerosis) (III Grade 2C):
Scleroderma is a chronic multisystem disorder characterized by an accumulation of connective tissue and involvement of the gastrointestinal tract, lungs, heart and kidney. Scleroderma is not curable, and treatment is aimed at relieving symptoms and improving function. is now known to be mainly due to genetic mutations of complement and complement regulatory molecules leading to uncontrolled activation of the alternative complement pathway. Genetic mutations in proteins of the coagulation cascade appear to be implicated in the clinical syndrome of aHUS. This may be because underlying HUS pathophysiology is due to small vessel thrombosis; thus, genetic mutations of the coagulation proteins may increase the risk TMA. Thrombomodulin, THBD, is a thrombin cofactor that acts as an anticoagulant and also decreases factor I (CFI)-induced inactivation of C3b. The benefit for TPE is not consistent in these patient groupings (Schwartz, et al., 2016).

Thrombotic Microangiopathy (TMA), Complement-Associated (Except for Factor H Antibodies) (III Grade 2C):
Atypical hemolytic syndrome (aHUS) is caused by uncontrolled activation of the alternative complement system, now called complement-mediated thrombotic microangiopathy (TMA). Many affected patients are children. A growing list of genetic mutations and polymorphisms are now known to predispose to complementmediated TMA, primarily involving complement regulatory proteins, leading to complement-mediated endothelial injury. Empiric plasma therapy in all forms of complement-mediated TMA is recommended, pending testing. It has been reported that in contrast to TPE, the use of eculizumab not only can lead to recovery of hematological parameters, but can also lead to renal function recovery. Kidney transplantation may be considered but risks recurrence of the disease process in the allograft; graft loss are common. The availability of eculizumab may also reduce the need for kidney transplantation. The rationale for TPE use is that it has been reported to remove the autoantibody or mutated circulating complement regulators while replacing absent or defective complement regulators. With the current understanding of the pathological mechanism and extensive use of eculizumab in this condition, use of TPE becomes somewhat limited. Before a firm diagnosis can be made, it is still considered as standard care to initiate TPE when idiopathic thrombotic thrombocytopenic purpura is suspected. When eculizumab is not available, TPE remains an alternative treatment option, although the evidence suggests a more robust effect with eculizumab. TPE may not work for patients with membrane cofactor protein mutations, as the factor does not circulate and plasma therapy has in general not been shown to influence patient outcomes proposed as a treatment option for TMA to remove plasma protein bound drugs, therapeutic benefit has not been defined.
TMA following allogeneic hematopoietic stem cell transplantation, also known as transplant associated (TA)-TMA may be caused by endothelial cell injury due to chemotherapy, irradiation, graft-versus-host disease (GVHD), calcineurin inhibitor drugs and infections. Management of TA-TMA includes reduction or discontinuation of certain medications, as well as treatment of underlying graft-versus-host disease (GVHD), and infections. PP has been proposed as a treatment option for TA-TMA but available studies have reported no improvement following therapy (Padmanabhan, et  The most common TMA, hemolytic uremic syndrome (HUS), is a potentially life-threatening condition characterized by TMA that typically targets the kidney causing renal failure. In the majority (90%) of patients with HUS, the cause is due to the action of Shiga-like toxin (Stx) on the renovascular endothelium and is often referred to as STEC-HUS (D1HUS). Another infection-induced HUS that usually occurs in children <2 years is due to sepsis, pneumonia, or meningitis caused by Streptococcus pneumoniae (pHUS). Stx binds to multiple cells in the kidney and causes a spectrum of renal injury. Brain endothelial and neuronal cells are also targeted. The severity of acute illness, particularly central nervous system impairment and the need for dialysis is strongly associated with a worse longterm prognosis. replacement therapy. There is no robust evidence from the available literature that TPE benefits patients with STEC-HUS. TPE may reduce concentrations of various cytokines, von Willebrand factor multimers, and Stx that damage the endothelium however there is limited data to support this. Free Stx has not been detected in the serum, and how it transits from the GI tract to target organs remains unclear. For pHUS, TPE would remove antibodies directed against the exposed T-antigen, as well as circulating bacterial neuraminidase. There evidence for treating pHUS with PP is limited without reported adverse effects (Padmanabhan, et

Centers for Medicare & Medicaid Services (CMS)
• National Coverage Determinations (NCDs): This Medical Coverage Policy is broader in scope than the NCD for Apheresis (Therapeutic Pheresis) (110.14). Refer to the CMS NCD table of contents link in the reference section. • Local Coverage Determinations (LCDs): No LCDs found.

Use Outside of the US
In guidelines for the management of pemphigus vulgaris (PV) the British Society of Dermatologists (2003) stated, "plasma exchange cannot be recommended as a routine treatment option in newly presenting patients with PV." Although the evidence is poor, they suggest that PP "could be considered in difficult cases if combined with systemic corticosteroids (CS) and immunosuppressant drugs".

Coding/Billing Information
Note: 1) This list of codes may not be all-inclusive.
2) Deleted codes and codes which are not effective at the time the service is rendered may not be eligible for reimbursement.