Hemolytic anemia medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Shyam Patel [2]

Overview

Medical therapy focuses on immunosuppression. Typical treatment options include corticosteroids or non-steroidal immunosuppressants. Non-steroidal immunosuppressants include rituximab, azathioprine, mycophenolate mofetil, cyclophosphamide, and other agents. The advantage to the use of non-steroidal immunosuppressants is that patients can be spared of adverse effects of steroids like bone loss, cataracts, and glaucoma.

Medical Therapy

The goal of medical therapy for hemolytic anemia involves correction of the underlying pathophysiology. In most cases, the cause of hemolytic is due to abnormal immune activation, resulting in antibody production against red blood cells. Immunosuppression is a mainstay of treatment for hemolytic anemia that is caused by alloimmunization. For non-immune-related hemolytic anemia, elimination of the precipitant is the most important aspect of treatment. Supportive care, such as packed red blood cell transfusions, can serve as a temporizing measure but will not alter the disease course or address the underlying pathophysiology.

Medications

• Corticosteroids: The cornerstone of therapy for warm autoimmune hemolytic anemia is steroids. Steroids are the first-line therapy for induction of a response. The initial regimen of steroids is usually prednisone 1-1.5 mg/kg PO daily, to be continued for 1-3 weeks until the hemoglobin increases to 10 g/dl. Steroids are then rapidly tapered. If a patient has been on steroids for a prolonged period of time (such as more than 1 month), a gradual taper of steroids should be done to avoid the effects of adrenal insufficiency. Steroids are effective in approximately 70-85% of patients in the short term. In the long-term, however, only 15-20% of patients continue to benefit from steroids. The benefits of steroids are that they can induce a remission within a relatively quick timeframe, such as days to weeks. Furthermore, patients feel very well from a symptomatic standpoint after an initial bolus of high-dose steroids.
  • Adverse effects: The use of steroids is meant for short-term, as there can be many adverse effects from long-term systemic steroid use. These adverse effects include immunosuppression with risk for infections, bone loss, muscle loss, weight gain, cataracts, glaucoma, and Cushing's syndrome.
• Rituximab: This is a monoclonal antibody that targets the CD20 antigen on B cells. The basis for the use of rituximab in hemolytic anemia is that B cells are producing antibodies that bind to red blood cell membranes and cause hemolysis. Rituximab binds to B cells and eliminates the B cells by antibody-dependent cell-mediated cytotoxicity. This medication is considered a biologic agent, as it is derived from mice. It is used as second-line therapy for hemolytic anemia, if corticosteroids are ineffective. The effect of rituximab usually lasts for nearly 1 year, as B cells remain depleted for 1 year after administration of rituximab. The response rate is about 60-70%, and 5-year remission occurs inapproximately 20% of patients.
  • Adverse effects: Risks of rituximab include infusion reaction (during the initial administration of the agent), serum sickness, hepatitis B reactive, lymphoma, and opportunistic infections, such as progressive multifocal leukoencephalopathy. The benefits of rituximab are that there are no steroid-specific adverse effects, such as bone loss, cataracts, glaucoma, stress ulcers, muscle loss, and weight gain.
• Azathioprine: This is an alternative immunosuppressive agent. It is a purine antimetabolite that is converted to 6-mercaptopurine. It can inhibit the synthesis of DNA and RNA in lymphocytes, and thus it functions by inhibiting immune cell proliferation. Azathioprine is used in the third-line setting for hemolytic anemia. The dose is usually 3-4 mg/kg daily and can be given alone or alongside steroids. The response rate is about 70-80%.
  • Adverse effects: Risks of azathioprine include leukopenia and infections. Importantly, the other adverse effects of steroids are spared.
• Cyclophosphamide: This is an cytotoxic immunosuppressive agent that functions as an alkylating agent, which results in DNA damage to rapidly diving B cells and T cells. The response rate is usually 80-90% and the onset of effect is usually within 1 month. The dose for cyclophosphamide is usually 1-2mg/kg daily (compared to the far higher doses that are used for cancer chemotherapy).
  • Adverse effects: Risks of cyclophosphamide include hemorrhagic cystitis, neutropenia, thrombocytopenia, nausea, vomiting, hair loss, and worsening anemia.
• Mycophenolate mofetil: This is an alternative immunosuppressive agent. It is an inhibitor of inosine monophosphate dehydrogenase and thus inhibits rapidly dividing B cells and T cells, hindering the immune response. Mycophenolate mofetil is used in the third-line setting for hemolytic anemia. The dose is usually 1-2 g daily. The response rate is about 70-80%.
  • Adverse effects: Risks of mycophenolate mofetil include nausea, vomiting, abdominal pain, swelling, neuropathy, anxiety, and insomnia.

Supportive Interventions

• Transfusion support: Packed red blood cell transfusions can be administered to help treat hemolytic anemia in the short-term. This is the most rapid method that raises hemoglobin level. Transfusions were the mainstay of treatment greater than 50 years ago, prior to the develop of effective immunosuppressive therapies. However, it is important to note that transfusions are a temporizing measure until a more long-term or disease-modifying medication can be given.
  • Adverse effects: Transfusions are associated with the risks of volume overload, transfusion reactions, iron overload, and additional alloimmunization.
    • Volume overload includes conditions line transfusion-related acute lung injury (TRALI) or transfusion-related circulatory overload (TACO).
    • Transfusion reactions include conditions like hemolytic transfusion reactions (from ABO blood group incompatibility) and febrile non-hemolytic transfusion reactions (from non-leukoreduced blood).
    • Iron overload can result in conditions like cirrhosis (if iron deposition occurs in the liver), diabetes (if iron deposition occurs in the pancreas), hyperpigmentation (if iron deposition occurs in the skin), infertility (if iron deposition occurs in the gonads), and heart failure (if iron deposition occurs in the heart).
    • Alloimmunization involves the production of antibodies by the recipient against the donor red blood cells. The production of additional antibodies poses a significant challenge to future red blood cell transfusions, as it becomes more difficult to find a matched product.
• Cause-specific treatments: In some cases, the cause of hemolytic anemia is clearly identified, and treatment can focus on removing the underlying trigger. Examples include:
  • Withdrawal of the offending agent: If drug-induced hemolysis is the reason for hemolytic anemia, the offending agent should be discontinued.
  • Oxidative stress management: If a precipitant of oxidative stress is causing the hemolytic anemia, the precipitant should be avoided. For example fava beans can cause hemolysis in patients with G6PD deficiency. Persons with G6PD deficiency should avoid these precipitants.
  • Correction of faulty cardiac valves: If a mechanical heart valve or other intracardiac device is causing hemolytic anemia via shear stress, the device should be replaced or repaired. In some cases, a bypass circuit or ECMO circuit can cause shear stress. The use of these should be minimized if possible.
• Erythropoiesis-stimulating agents: These agents work by increasing hemoglobin production by binding to the erythropoietin receptor on red blood cell precursors. Examples include epogen-alfa and darbopoetin.
  • Adverse effects: Risks include thrombosis, polycythemia, and injection-site reaction.