Occasionally, the anemia is so severe that support with transfusion is required. These patients usually do not respond to erythropoietin therapy. Some cases have been reported that the anemia is reversed or heme level is improved through use of moderate to high doses of pyrodoxine (vitamin B). In severe cases of SBA, bone marrow transplant is also an option with limited information about the success rate. Some cases are listed on MedLine and various other medical sites. In the case of isoniazid-induced sideroblastic anemia, the addition of B is sufficient to correct the anemia. Desferrioxamine, a chelating agent, is used to treat iron overload from transfusions.

Therapeutic phlebotomy can be used to manage iron overload.

In cases where oral iron has either proven ineffective, would be too slow (for example, pre-operatively) or where absorption is impeded (for example in cases of inflammation), parenteral iron can be used. The body can absorb up to 6 mg iron daily from the gastrointestinal tract. In many cases the patient has a deficit of over 1,000 mg of iron which would require several months to replace. This can be given concurrently with erythropoietin to ensure sufficient iron for increased rates of erythropoiesis.

Treating immune-mediated aplastic anemia involves suppression of the immune system, an effect achieved by daily medicine intake, or, in more severe cases, a bone marrow transplant, a potential cure. The transplanted bone marrow replaces the failing bone marrow cells with new ones from a matching donor. The multipotent stem cells in the bone marrow reconstitute all three blood cell lines, giving the patient a new immune system, red blood cells, and platelets. However, besides the risk of graft failure, there is also a risk that the newly created white blood cells may attack the rest of the body ("graft-versus-host disease"). In young patients with an HLA matched sibling donor, bone marrow transplant can be considered as first-line treatment, patients lacking a matched sibling donor typically pursue immunosuppression as a first-line treatment, and matched unrelated donor transplants are considered a second-line therapy.

Medical therapy of aplastic anemia often includes a course of antithymocyte globulin (ATG) and several months of treatment with ciclosporin to modulate the immune system. Chemotherapy with agents such as cyclophosphamide may also be effective but has more toxicity than ATG. Antibody therapy, such as ATG, targets T-cells, which are believed to attack the bone marrow. Corticosteroids are generally ineffective, though they are used to ameliorate serum sickness caused by ATG. Normally, success is judged by bone marrow biopsy 6 months after initial treatment with ATG.

One prospective study involving cyclophosphamide was terminated early due to a high incidence of mortality, due to severe infections as a result of prolonged neutropenia.

In the past, before the above treatments became available, patients with low leukocyte counts were often confined to a sterile room or bubble (to reduce risk of infections), as in the case of Ted DeVita.

Treatment consists of frequent blood transfusions and chelation therapy. Potential cures include bone marrow transplantation and gene therapy.

Treatments for anemia depend on cause and severity. Vitamin supplements given orally (folic acid or vitamin B) or intramuscularly (vitamin B) will replace specific deficiencies.

Iron overload is an unavoidable consequence of chronic transfusion therapy, necessary for patients with beta thalassemia. Iron chelation is a medical therapy that avoids the complications of iron overload. The iron overload can be removed by Deferasirox, an oral iron chelator, which has a dose- dependent effect on iron burden. Every unit of transfused blood contains 200–250 mg of iron and the body has no natural mechanism to remove excess iron. Deferasirox is a vital part in the patients health after blood transfusions. During normal iron homeostasis the circulating iron is bound to transferrin, but with an iron overload, the ability for transferrin to bind iron is exceeded and non-transferrin bound iron is formed. It represents a potentially toxic iron form due to its high propensity to induce oxygen species and is responsible for cellular damage. The prevention of iron overload protects patients from morbidity and mortality. The primary aim is to bind to and remove iron from the body and a rate equal to the rate of transfusional iron input or greater than iron input. During clinical trails patients that received Deferasirox experienced no drug-related neutropenia or agranulocytosis, which was present with other iron chelators. Its long half life requires it to be taken once daily and provides constant chelation. Cardiac failure is a main cause of illness from transfusional iron overload but deferasirox demonstrated the ability to remove iron from iron-loaded myocardial cells protecting beta thalassemia patients from effects of required blood transfusions.

Long-term transfusion therapy to maintain the patient’s hemoglobin level above 9-10 g/dL (normal levels are 13.8 for males, and 12.1 for females). Patients are transfused by meeting strict criteria ensuring their safety. They must have: confirmed laboratory diagnosis of thalassemia major, and hemoglobin levels less than 7g/dL, to be eligible for the transfusion. To ensure quality blood transfusions, the packed red blood cells should be leucoreduced with a minimum of 40g of hemoglobin content. By having leucoreduced blood packets, the patient is at a lower risk to develop adverse reactions by contaminated white cells and preventing platelet alloimmunisation. Pre-storage filtration of whole blood offers high efficiency for removal and low residual of leukocytes; It is the preferred method of leucoreduction compared to pre-transfusion and bedside filtration. Patients with allergic transfusion reactions or unusual red cell antibodies must received “washed red cells” or “cryopreserved red cells.” Washed red cells have been removed of plasma proteins that would have become a target of the patient’s antibodies allowing the transfusion to be carried out safely. Cryopreserved red cells are used to maintain a supply of rare donor units for patients with unusual red cell antibodies or missing common red cell antigens. The transfusion programs available involve lifelong regular blood transfusion to main the pre-transfusion hemoglobin level above 9-10 g/gL. The monthly transfusions promote normal growth, physical activities, suppress bone marrow activity, and minimize iron accumulation. It has been announced the starting of the first clinical trial with CRISPR/Cas9 in Europe in 2018.

Usually no treatment is needed. Folic acid supplementation may help produce normal red blood cells and improve the symptoms of anemia

Gene therapy, as well as, bone marrow transplant are also possible treatments for the disorder, but each have their own risks at this point in time. Bone marrow transplantation is the more used method between the two, whereas researchers are still trying to definitively establish the results of gene therapy treatment. It generally requires a 10/10 HLA matched donor, however, who is usually a sibling. As most patients do not have this, they must rely on gene therapy research to potentially provide them with an alternative. CDA at both clinical and genetic aspects are part of a heterogeneous group of genetic conditions. Gene therapy is still experimental and has largely only been tested in animal models until now. This type of therapy has promise, however, as it allows for the autologous transplantation of the patient's own healthy stem cells rather than requiring an outside donor, thereby bypassing any potential for graft vs. host disease (GVHD).

In the United States, the FDA approved clinical trials on Beta thalassemia patients in 2012. The first study, which took place in July 2012, recruited human subjects with thalassemia major, and ended in 2014.

Treatment of individuals with CDA usually consist of frequent blood transfusions, but this can vary depending on the type that the individual has. Patients report going every 2–3 weeks for blood transfusions. In addition, they must undertake chelation therapy to survive; either deferoxamine, deferasirox, or deferiprone to eliminate the excess iron that accumulates. Removal of the spleen and gallbladder are common. Hemoglobin levels can run anywhere between 8.0 g/dl and 11.0 g/dl in untransfused patients, the amount of blood received by the patient is not as important as their baseline pre-transfusion hemoglobin level. This is true for ferritin levels and iron levels in the organs as well, it is important for patients to go regularly for transfusions in order to maximize good health, normal ferritin levels run anywhere between 24 and 336 ng/ml, hematologists generally do not begin chelation therapy until ferritin levels reach at least 1000 ng/ml. It is more important to check iron levels in the organs through MRI scans, however, than to simply get regular blood tests to check ferritin levels, which only show a trend, and do not reflect actual organ iron content.

One exploratory, and potential alternative method for the treatment of pernicious anemia is the use of transdermal patches. In one such system, the patches are composed of cyanocobalamin, its stabilizers, and epidermal penetration enhancers. The transdermal route allows the cobalamin derivative to passively diffuse through the stratum corneum, epidermis, and dermis, and ultimately entering the bloodstream; hence, the cobalamin avoids the hepatic first pass effect, and so offers the potential for improved bioavailability and efficacy. Slow release increases cobalamin half-life, offering the potential of decreases in required dosage required relative to oral delivery methods. In one such system, a drug-loaded polycaprolactone fiber that is prepared as a electrospun nanofiber can release hundreds of micrograms of cobabalmin per day.

The most important measure is prevention – avoidance of the drugs and foods that cause hemolysis. Vaccination against some common pathogens (e.g. hepatitis A and hepatitis B) may prevent infection-induced attacks.

In the acute phase of hemolysis, blood transfusions might be necessary, or even dialysis in acute kidney failure. Blood transfusion is an important symptomatic measure, as the transfused red cells are generally not G6PD deficient and will live a normal lifespan in the recipient's circulation. Those affected should avoid drugs such as aspirin.

Some patients may benefit from removal of the spleen (splenectomy), as this is an important site of red cell destruction. Folic acid should be used in any disorder featuring a high red cell turnover. Although vitamin E and selenium have antioxidant properties, their use does not decrease the severity of G6PD deficiency.

Corticosteroids and immunoglobulins are two commonly used treatments for warm antibody AIHA. Initial medical treatment consists of prednisone. If ineffective, splenectomy should be considered.

If refractory to both these therapies, other options include rituximab, danazol, cyclosphosphamide, azathioprine, or ciclosporin.

High-dose intravenous immune globulin may be effective in controlling hemolysis, but the benefit is short lived (1–4 weeks), and the therapy is very expensive.

The ideal treatment for anemia of chronic disease is to treat the chronic disease successfully, but this is rarely possible.

Parenteral iron is increasingly used for anemia in chronic renal disease and inflammatory bowel disease.

Erythropoietin can be helpful, but this is costly and may be dangerous. Erythropoietin is advised either in conjunction with adequate iron replacement which in practice is intravenous, or when IV iron has proved ineffective.

Treatment with high-dose vitamin B by mouth also appears effective.

When treating iron-deficiency anemia, considerations of the proper treatment methods are done in light of the "cause and severity" of the condition. If the iron-deficiency anemia is a downstream effect of blood loss or another underlying cause, treatment is geared toward addressing the underlying cause when possible. In severe acute cases, treatment measures are taken for immediate management in the interim, such as blood transfusions or even intravenous iron.

Iron-deficiency anemia treatment for less severe cases includes dietary changes to incorporate iron-rich foods into regular oral intake. Foods rich in ascorbic acid (vitamin C) can also be beneficial, since ascorbic acid enhances iron absorption. Other oral options are iron supplements in the form of pills or drops for children.

As iron-deficiency anemia becomes more severe, or if the anemia does not respond to oral treatments, other measures may become necessary. In addition to the previously mentioned indication for intravenous iron or blood transfusions, intravenous iron may also be used when oral intake is not tolerated, as well as for other indications. Specifically, for those on dialysis, parenteral iron is commonly used. Individuals on dialysis who are taking forms of erythropoietin or some "erythropoiesis-stimulating agent" are given parenteral iron, which helps the body respond to the erythropoietin agents and produce red blood cells.

The various forms of treatment are not without possible adverse effects. Iron supplementation by mouth commonly causes negative gastrointestinal effects, including constipation. Intravenous iron can induce an allergic response that can be as serious as anaphylaxis, although different formulations have decreased the likelihood of this adverse effect.

Splenectomy is usually ineffective for the treatment of cold agglutinin disease, because the liver is the predominant site of sequestration. However, if the patient has splenomegaly, then the disease may respond to splenectomy. More importantly, a lymphoma localized to the spleen may only be found after splenectomy.

Most affected individuals with pyruvate kinase deficiency do not require treatment. Those individuals who are more severely affected may die in utero of anemia or may require intensive treatment. With these severe cases of pyruvate kinase deficiency in red blood cells, treatment is the only option, there is no cure. However, treatment is usually effective in reducing the severity of the symptoms.

The most common treatment is blood transfusions, especially in infants and young children. This is done if the red blood cell count has fallen to a critical level. The transplantation of bone marrow has also been conducted as a treatment option.

There is a natural way the body tries to treat this disease. It increases the erythrocyte production (reticulocytosis) because reticulocytes are immature red blood cells that still contain mitochondria and so can produce ATP via oxidative phosphorylation. Therefore, a treatment option in extremely severe cases is to perform a splenectomy. This does not stop the destruction of erythrocytes but it does help increase the amount of reticulocytes in the body since most of the hemolysis occurs when the reticulocytes are trapped in the hypoxic environment of the spleen. This reduces severe anemia and the need for blood transfusions.

Much literature exists regarding the treatment of AIHA. Efficacy of treatment depends on the correct diagnosis of either warm- or cold-type AIHA.

Warm-type AIHA is usually a more insidious disease, not treatable by simply removing the underlying cause. Corticosteroids are first-line therapy. For those who fail to respond or have recurrent disease, splenectomy may be considered. Other options for recurrent or relapsed disease include immunosuppressants such as rituximab, danazol, cyclophosphamide, azathioprine, or cyclosporine.

Cold agglutinin disease is treated with avoidance of cold exposure. Patients with more severe disease (symptomatic anemia, transfusion dependence) may be treated with rituximab. Steroids and splenectomy are less efficacious in cold agglutinin disease.

Paroxysmal cold hemoglobinuria is treated by removing the underlying cause, such as infection.

Definitive therapy depends on the cause:

- Symptomatic treatment can be given by blood transfusion, if there is marked anemia. A positive Coombs test is a relative contraindication to transfuse the patient. In cold hemolytic anemia there is advantage in transfuse warmed blood

- In severe immune-related hemolytic anemia, steroid therapy is sometimes necessary.

- In steroid resistant cases, consideration can be given to rituximab or addition of an immunosuppressant ( azathioprine, cyclophosphamide)

- Association of methylprednisolone and intravenous immunoglobulin can control hemolysis in acute severe cases

- Sometimes splenectomy can be helpful where extravascular hemolysis, or hereditary spherocytosis, is predominant (i.e., most of the red blood cells are being removed by the spleen).

The type of treatment depends on the severity of the patient’s bone marrow failure disease. Blood transfusion is one treatment. Blood is collected from volunteer donors who agree to let doctors draw blood stem cells from their blood or bone marrow for transplantation. Blood that is taken straight from collected blood stem cells is known as peripheral blood stem cell donation. A peripheral stem cell donor must have the same blood type as the patient receiving the blood cells. Once the stem cells are in the patient’s body through an IV, the cells mature and become blood cells. Before donation, a drug is injected into the donor, which increases the number of stem cells into their body. Feeling cold and lightheaded, having numbness around the mouth and cramping in the hands are common symptoms during the donation process. After the donation, the amount of time for recovery varies for every donor, “But most stem cell donors are able to return to their usual activities within a few days to a week after donation”.

Patients with cold agglutinin disease should include good sources of folic acid, such as fresh fruits and vegetables, in their diet. Activities for these individuals should be less strenuous than those for healthy people, particularly for patients with anemia. Jogging in the cold could be very hazardous because of the added windchill factor.

Sideroblastic anemias are often described as responsive or non-responsive in terms of increased hemoglobin levels to pharmacological doses of vitamin B.

1- Congenital: 80% are responsive, though the anemia does not completely resolve.

2- Acquired clonal: 40% are responsive, but the response may be minimal.

3- Acquired reversible: 60% are responsive, but course depends on treatment of the underlying cause.

Severe refractory sideroblastic anemias requiring regular transfusions and/or that undergo leukemic transformation (5-10%) significantly reduce life expectancy.

Blood transfusion is sometimes used to treat iron deficiency with hemodynamic instability. Sometimes transfusions are considered for people who have chronic iron deficiency or who will soon go to surgery, but even if such people have low hemoglobin, they should be given oral treatment or intravenous iron.

Untreated, severe aplastic anemia has a high risk of death. Modern treatment, by drugs or stem cell transplant, has a five-year survival rate that exceeds 85%, with younger age associated with higher survival.

Survival rates for stem cell transplant vary depending on age and availability of a well-matched donor. Five-year survival rates for patients who receive transplants have been shown to be 82% for patients under age 20, 72% for those 20–40 years old, and closer to 50% for patients over age 40. Success rates are better for patients who have donors that are matched siblings and worse for patients who receive their marrow from unrelated donors.

Older people (who are generally too frail to undergo bone marrow transplants), and people who are unable to find a good bone marrow match, undergoing immune suppression have five-year survival rates of up to 75%.

Relapses are common. Relapse following ATG/ciclosporin use can sometimes be treated with a repeated course of therapy. In addition, 10-15% of severe aplastic anemia cases evolve into MDS and leukemia. According to a study, for children who underwent immunosuppressive therapy, about 15.9% of children who responded to immunosuppressive therapy encountered relapse.

Milder disease can resolve on its own.