Anemia Treatment & Management

The purpose of establishing the etiology of an anemia is to permit selection of a specific and effective therapy. For example, corticosteroids are useful in the treatment of autoimmune hemolytic anemia.

Therapy and medical care vary considerably in the group of hereditary disorders. Splenectomy has been advantageous in hereditary spherocytosis and hereditary elliptocytosis, in some of the unstable hemoglobinopathies, and in certain patients with pyruvic kinase deficiency. It has little value in most other hereditary hemolytic disorders.

Drugs and chemicals capable of producing aplasia or a maturation arrest of erythroid precursors should be discontinued or avoided. Similarly, diseases known to be associated with anemia should be appropriately treated. Guidelines for the treatment of chemotherapy-associated anemia are available.

Surgery is useful to control bleeding in patients who are anemic. Most commonly, bleeding is from the GI tract, uterus, or bladder. Patients should be hemodynamically stable before and during surgery. A blood transfusion may be needed.

Management of beta-thalassemia major and major hemoglobinopathies

Patients with beta-thalassemia major and the major hemoglobinopathies associated with sickle hemoglobin (Hb) usually require medical attention at frequent intervals for the treatment of anemia, infection, pain, and leg ulcers because of the serious nature of these illnesses. Conversely, many of the other hereditary abnormalities have minimal or no clinical manifestations; the patient requires only reassurance.

Luspatercept, an erythroid maturation agent, is approved for anemia in adults with beta thalassemia who require regular red blood cell transfusions. The drug is a recombinant fusion protein that diminishes Smad2/3 signaling by binding several endogenous TGF-beta superfamily ligands. In a model of beta thalassemia, luspatercept decreased abnormally elevated Smad2/3 signaling and improved hematology parameters associated with ineffective erythropoiesis. 

Approval of luspatercept was based on the BELIEVE phase 3 clinical trial that included adults with beta thalassemia who require regular RBC transfusions (defined as 6-20 RBC units per 24 weeks, with no transfusion-free period greater than 35 days during that period). Patients (n=336) were randomized 2:1 to receive luspatercept (n=224) or placebo (n=112) at a starting dose of 1 mg/kg SC every 21 days for up to 48 weeks. In the patients who received luspatercept, 21.4% achieved a 33% or greater reduction from baseline in RBC transfusion burden (with a reduction of at least 2 units) during weeks 13-24 after randomization, compared with 4.5% (n=5) in the placebo arm (risk difference [95% CI]: 17.0 [10.4, 23.6], P< 0.0001). ^[17]

Consultations

Surgical consultation is indicated to control bleeding, for splenectomy when necessary, and for biopsies to establish the presence of neoplasia. Consultation with gastroenterologists is frequently sought to identify a bleeding site in the gut. Urologic consultation may be needed to investigate hematuria.

Follow-up

Patients with chronic anemia can usually be cared for on an outpatient basis. Follow-up care is necessary to ensure that therapy is being continued and to assess the efficacy of treatment.

Transfusion of packed red blood cells (RBCs) should be reserved for patients who are actively bleeding and for patients with a severe and symptomatic anemia. ^[18] Transfusion is palliative and should not be used as a substitute for specific therapy. In chronic diseases associated with anemia of chronic disorders, erythropoietin may be helpful in averting or reducing transfusions of packed RBCs.

Hemolytic transfusion reactions and transmission of infectious disease are risks of blood product transfusions. Patients with autoimmune antibodies against RBCs are at greater risk of a hemolytic transfusion reaction because of difficulty in cross-matching the blood. Occasionally, the blood of patients with autoimmune hemolytic anemia cannot be cross-matched in vitro. In these cases, the patients require in vivo cross-matching, in which incompatible blood is transfused slowly and periodic determinations are made to ensure that the patient is not developing hemoglobinemia. This method should be used only in patients with either significant hypoxia from the anemia or evidence of coronary insufficiency.

The appropriate treatment of anemia due to blood loss is correction of the underlying condition and oral administration of ferrous sulfate until the anemia is corrected and for several months afterward to ensure that body stores are replete with iron. Relatively few indications exist for the use of parenteral iron therapy, and blood transfusions should be reserved for the treatment of shock or hypoxia.

Although the traditional dosage of ferrous sulfate is 325 mg (65 mg of elemental iron) orally three times a day, lower doses (eg, 15-20 mg of elemental iron daily) may be as effective and cause fewer side effects. To promote absorption, patients should avoid tea and coffee and may take vitamin C (500 units) with the iron pill once daily. If ferrous sulfate has unacceptable side effects, ferrous gluconate, 325 mg daily (35 mg of elemental iron) is a possible alternative for patients who cannot tolerate ferrous sulfate. ^[19]

A study in Iran demonstrated that once-weekly, low-dose iron supplementation can be effective in improving iron status and in treating iron deficiency anemia. ^[20] Mozaffari-Khosravi et al randomly selected and assigned 193 adolescent girls aged 14-16 years to receive either 150 mg ferrous sulfate once weekly for 16 weeks or no iron supplementation. Before and after intervention, the percentage of anemia, iron deficiency anemia, and iron deficiency were measured in both groups of girls.

Although the parameters measured before the intervention were not significantly different, at the end of 16 weeks, the group that received the ferrous sulfate had significant improvement in the same parameters. ^[20] In addition, all cases of iron deficiency anemia were resolved in the group receiving the low-dose iron supplementation.

Adults with iron deficiency anemia who cannot tolerate oral iron or who have an unsatisfactory response to it can be treated with ferric carboxymaltose injection (Injectafer). The agent is given in two intravenous infusions one week apart.

Nutritional therapy is used to treat deficiencies of iron, vitamin B12, and folic acid. Pyridoxine may be useful in the treatment of certain patients with sideroblastic anemia, even though this is not a deficiency disorder. A strict vegetarian diet requires iron and vitamin B12 supplementation.

Iron deficiency anemia is prevalent in geographic locations where little meat is in the diet. Many of these locations have sufficient dietary inorganic iron to equal the iron content in persons residing in countries in which meat is eaten. However, heme iron is more efficiently absorbed than inorganic food iron. Folic acid deficiency occurs among people who consume few leafy vegetables. Coexistence of iron and folic acid deficiency is common in developing nations.

Treatment of aplastic disorders includes removal of the offending agent whenever it can be identified, supportive therapy for the anemia and thrombocytopenia, and prompt treatment of infection. Avoid transfusion in patients with a potential bone marrow donor, because transfusion worsens the probability of cure from transplantation.

As part of supportive therapy, British Committee for Standards in Haematology guidelines recommend immunosuppression with antithymocyte globulin and cyclosporine as first-line therapy in the following adult patients ^[21] :

• Patients with severe or very severe aplastic anemia who lack a matched sibling donor (MSD)
• Patients with severe or very severe aplastic anemia aged >35-50 years

The British guidelines recommend up-front hematopoietic stem cell transplant (HSCT) for young and adult patients who have an MSD. Similarly, Italian guidelines for treatment of aplasti anemia in children recommend HSCT from an MSD as the treatment of choice, with immunosuppressive therapy or unrelated-donor HSCT as options if an MSD is not available. ^[22]

Splenectomy may provide sufficient improvement for patients with hypoplastic, but not totally aplastic, marrow so that transfusion is not necessary and platelet and granulocyte counts increase to less dangerous levels. (See Splenectomy.)

Splenectomy is useful in the treatment of autoimmune hemolytic anemias and in certain hereditary hemolytic disorders (ie, hereditary spherocytosis and elliptocytosis, certain unstable Hb disorders, pyruvic kinase deficiency). Improvement in survival rates has been reported in patients with aplastic anemia, but splenectomy is not the preferred therapy. Leg ulcers have shown improvement in some patients with thalassemia. Prior to splenectomy, patients should be immunized with polyvalent pneumococcal vaccine. Preferably, this should be administered more than 1 week prior to surgery.

Bone marrow and stem cell transplantation have been used in patients with leukemia, lymphoma, Hodgkin lymphoma, multiple myeloma, myelofibrosis, and aplastic disease. Survival rates in these patients improved, and hematologic abnormalities were corrected. Allogeneic bone marrow transplantation has successfully corrected phenotypic expression of sickle cell disease and thalassemia and provided enhanced survival in patients who survived transplantation.

However, incomplete immune recovery after hematopoietic stem cell transplantation (HSCT) may predispose to autoimmune cytopenias, including anemia. From 2-6% of pediatric patients develop new-onset autoimmune hemolytic anemia (AIHA) after HSCT. Schuetz et al report that treatment with the anti-CD38 antibody daratumumab, which is approved for use in multiple myeloma, was curative in two of three patients with life-threatening posttransplant AIHA, with the third patient showing a transient response before relapse of AIHA 8 months afterward. ^[23]  

Patients with severe anemia should curtail their activity until the anemia is partially corrected. Transfusion can often be avoided by ordering bed rest while therapy is initiated for a patient with correctable anemia (eg, pernicious anemia).

March hemoglobinuria is a rare hemolytic disorder usually observed in young males. Individuals develop hemoglobinuria after marching or running on hard surfaces. Curtailing the precipitating exercise (ie, running on grass rather than concrete) and using shoes with reinforced soles are helpful in preventing this form of hemoglobinuria.

Patients with a benign etiology for anemia usually do not require transfer to another institution. Occasionally, transfer is necessary to establish the etiology of the anemia or to provide a treatment that is not locally available.

If patients are being transferred for diagnostic reasons, transferring them before transfusion is helpful. If the transfusion is necessary before transfer to achieve hematopoietic stability, consult with the receiving physician to determine laboratory tests that should be performed before transfusion. Patients who are hemodynamically unstable should not be transported.