If the splenomegaly underlies hypersplenism, a splenectomy is indicated and will correct the hypersplenism. However, the underlying cause of the hypersplenism will most likely remain; consequently, a thorough diagnostic workup is still indicated, as, leukemia, lymphoma and other serious disorders can cause hypersplenism and splenomegaly. After splenectomy, however, patients have an increased risk for infectious diseases.

Patients undergoing splenectomy should be vaccinated against "Haemophilus influenzae", "Streptococcus pneumoniae", and "Meningococcus". They should also receive annual influenza vaccinations. Long-term prophylactic antibiotics may be given in certain cases.

In cases of infectious mononucleosis splenomegaly is a common symptom and health care providers may consider using abdominal ultrasonography to get insight into a person's condition. However, because spleen size varies greatly, ultrasonography is not a valid technique for assessing spleen enlargement and should not be used in typical circumstances or to make routine decisions about fitness for playing sports.

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.

Often, no treatment is required or necessary for reactive thrombocytosis. In cases of reactive thrombocytosis of more than 1,000x10/L, it may be considered to administer daily low dose aspirin (such as 65 mg) to minimize the risk of stroke or thrombosis.

However, in primary thrombocytosis, if platelet counts are over 750,000 or 1,000,000, and especially if there are other risk factors for thrombosis, treatment may be needed. Selective use of aspirin at low doses is thought to be protective. Extremely high platelet counts in primary thrombocytosis can be treated with hydroxyurea (a cytoreducing agent) or anagrelide (Agrylin).

In Jak-2 positive disorders, ruxolitinib (Jakafi) can be effective.

Although research is ongoing, at this point there is no cure for the genetic defect that causes hereditary spherocytosis. Current management focuses on interventions that limit the severity of the disease. Treatment options include:

- Splenectomy: As in non-hereditary spherocytosis, acute symptoms of anemia and hyperbilirubinemia indicate treatment with blood transfusions or exchanges and chronic symptoms of anemia and an enlarged spleen indicate dietary supplementation of folic acid and splenectomy, the surgical removal of the spleen. Splenectomy is indicated for moderate to severe cases, but not mild cases. To decrease the risk of sepsis, post-splenectomy spherocytosis patients require immunization against the influenza virus, encapsulated bacteria such as Streptococcus pneumoniae and meningococcus, and prophylactic antibiotic treatment. However, the use of prophylactic antibiotics, such as penicillin, remains controversial.

- Partial splenectomy: Since the spleen is important for protecting against encapsulated organisms, sepsis caused by encapsulated organisms is a possible complication of splenectomy. The option of partial splenectomy may be considered in the interest of preserving immune function. Research on outcomes is currently limited, but favorable.

- Surgical removal of the gallbladder may be necessary.

There is no real treatment for Felty's syndrome, rather the best method in management of the disease is to control the underlying rheumatoid arthritis. Immunosuppressive therapy for RA often improves granulocytopenia and splenomegaly; this finding reflects the fact that Felty's syndrome is an immune-mediated disease. A major challenge in treating FS is recurring infection caused by neutropenia. Therefore, in order to decide upon and begin treatment, the cause and relationship of neutropenia with the overall condition must be well understood. Most of the traditional medications used to treat RA have been used in the treatment of Felty's syndrome. No well-conducted, randomized, controlled trials support the use of any single agent. Most reports on treatment regimens involve small numbers of patients.

Splenectomy may improve neutropenia in severe disease.

Use of rituximab and leflunomide have been proposed.

Use of gold therapy has also been described.

Prognosis is dependent on the severity of symptoms and the patient's overall health.

There is increasing use of immunosuppressants such as mycophenolate mofetil and azathioprine because of their effectiveness. In chronic refractory cases, where immune pathogenesis has been confirmed, the off-label use of the "vinca" alkaloid and chemotherapy agent vincristine may be attempted. However, vincristine has significant side effects and its use in treating ITP must be approached with caution, especially in children.

Initial treatment usually consists of the administration of corticosteroids, a group of medications that suppress the immune system. The dose and mode of administration is determined by platelet count and whether there is active bleeding: in urgent situations, infusions of dexamethasone or methylprednisolone may be used, while oral prednisone or prednisolone may suffice in less severe cases. Once the platelet count has improved, the dose of steroid is gradually reduced while the possibility of relapse is monitored. 60–90 percent will experience a relapse during dose reduction or cessation. Long-term steroids are avoided if possible because of potential side-effects that include osteoporosis, diabetes and cataracts.

Because of the increased risk of infection, physicians administer oral antibiotics as a prophylaxis after a surgical splenectomy (or starting at birth, for congenital asplenia or functional asplenia).

Those with asplenia are also cautioned to start a full-dose course of antibiotics at the first onset of an upper or lower respiratory tract infection (for example, sore throat or cough), or at the onset of any fever.

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).

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.

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.

Asplenia is the absence of normal spleen function. It predisposes to some septicemia infections. Therefore, vaccination and antibiotic measures are essential in such cases. There are multiple causes:

- Some people congenitally completely lack a spleen, although this is rare.

- Sickle-cell disease can cause a functional asplenia (or autosplenectomy) by causing infarctions of the spleen during repeated sickle-cell crises.

- It may be removed surgically (known as a splenectomy), but this is rarely performed, as it carries a high risk of infection and other adverse effects. Indications include following abdominal injuries with rupture and hemorrhage of the spleen, or in the treatment of certain blood diseases (Idiopathic thrombocytopenic purpura, hereditary spherocytosis, etc.), certain forms of lymphoma or for the removal of splenic tumors or cysts.

In secondary cases, treatment of the cause, where possible, is indicated. Additionally, treatment for HLH itself is usually required.

While optimal treatment of HLH is still being debated, current treatment regimes usually involve high dose corticosteroids, etoposide and cyclosporin. Intravenous immunoglobulin is also used. Methotrexate and vincristine have also been used. Other medications include cytokine targeted therapy.

An experimental treatment, an anti IFN-gamma monoclonal antibody tentatively named NI-0501, is in clinical trials for treating primary HLH. The FDA awarded breakthrough drug status to NI-0501 in 2016.

It is suggested that splenectomized persons receive the following vaccinations, and ideally prior to planned splenectomy surgery:

- Pneumococcal polysaccharide vaccine (not before 2 years of age). Children may first need one or more boosters of pneumococcal conjugate vaccine if they did not complete the full childhood series.

- Haemophilus influenzae type b vaccine, especially if not received in childhood. For adults who have not been previously vaccinated, two doses given two months apart was advised in the new 2006 UK vaccination guidelines (in the UK may be given as a combined Hib/MenC vaccine).

- Meningococcal conjugate vaccine, especially if not received in adolescence. Previously vaccinated adults require a single booster and non-immunised adults advised, in UK since 2006, to have two doses given two months apart. Children too young for the conjugate vaccine should receive meningococcal polysaccharide vaccine in the interim.

- Influenza vaccine, every winter, to help prevent getting secondary bacterial infection.

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

The one known curative treatment is allogeneic stem cell transplantation, but this approach involves significant risks.

Other treatment options are largely supportive, and do not alter the course of the disorder (with the possible exception of ruxolitinib, as discussed below). These options may include regular folic acid, allopurinol or blood transfusions. Dexamethasone, alpha-interferon and hydroxyurea (also known as hydroxycarbamide) may play a role.

Lenalidomide and thalidomide may be used in its treatment, though peripheral neuropathy is a common troublesome side-effect.

Frequent blood transfusions may also be required. If the patient is diabetic and is taking a sulfonylurea, this should be stopped periodically to rule out drug-induced thrombocytopenia.

Splenectomy is sometimes considered as a treatment option for patients with myelofibrosis in whom massive splenomegaly is contributing to anaemia because of hypersplenism, particularly if they have a heavy requirement for blood transfusions. However, splenectomy in the presence of massive splenomegaly is a high-risk procedure, with a mortality risk as high as 3% in some studies.

In November 2011, the FDA approved ruxolitinib (Jakafi) as a treatment for intermediate or high-risk myelofibrosis. Ruxolitinib serves as an inhibitor of JAK 1 and 2.

The "New England Journal of Medicine" (NEJM) published results from two Phase III studies of ruxolitinib. These data showed that the treatment significantly reduced spleen volume, improved symptoms of myelofibrosis, and was associated with improved overall survival compared to placebo.

Pneumococcal septicemia, or whole-body infection caused by the "Streptococcus pneumoniae" bacteria, has been reported to cause autosplenectomy but is a very rare and poorly understood complication of the infection.

Splenic diseases include splenomegaly, where the spleen is enlarged for various reasons. On the other hand, a lack of normal spleen function is called asplenia.

Experimental gene therapy exists to treat hereditary spherocytosis in lab mice; however, this treatment has not yet been tried on humans due to all of the risks involved in human gene therapy.

Absence of effective splenic function or absence of the whole spleen (asplenia) is associated with increased risks of overwhelming post splenectomy infection, especially from polysaccharide encapsulated bacteria and organisms that invade erythrocytes. People without a spleen have a weakened immune system, although other immune organs compensate for the missing spleen. Vaccination against encapsulated bacteria and prophylactic antibiotics can be used to counteract lowered immunity in asplenic patients. Specifically, people without a spleen are recommended to be vaccinated against pneumonia, influenza, Haemophilus influenza type b and meningococci.

Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant (LUQ) of the human abdomen. Splenomegaly is one of the four cardinal signs of "hypersplenism" which include; some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any combination, a compensatory proliferative response in the bone marrow, and the potential for correction of these abnormalities by splenectomy. Splenomegaly is usually associated with increased workload (such as in hemolytic anemias), which suggests that it is a response to hyperfunction. It is therefore not surprising that splenomegaly is associated with any disease process that involves abnormal red blood cells being destroyed in the spleen. Other common causes include congestion due to portal hypertension and infiltration by leukemias and lymphomas. Thus, the finding of an enlarged spleen, along with caput medusa, is an important sign of portal hypertension.

The only known cure for CAEBV is allogenic haematopoietic stem cell transplant (HSCT), with all other treatment options (rituximab, cytotoxic chemotherapy and immunosuppressive therapy) being nothing more than stopgaps.

The prognosis is guarded with an overall mortality of 50%. Poor prognostic factors included HLH associated with malignancy, with half the patients dying by 1.4 months compared to 22.8 months for non-tumour associated HLH patients.

Secondary HLH in some individuals may be self-limited because patients are able to fully recover after having received only supportive medical treatment (i.e., IV immunoglobulin only). However, long-term remission without the use of cytotoxic and immune-suppressive therapies is unlikely in the majority of adults with HLH and in those with involvement of the central nervous system (brain and/or spinal cord).

Treatment with chemotherapy has been used with some success, particularly using lomustine, prednisone, doxorubicin, and cyclophosphamide. Because of the rapid progression of this aggressive disease, the prognosis is very poor.

Fulminant infection from meningococci bacteria in the bloodstream is a medical emergency and requires emergent treatment with adequate antibiotics. Benzylpenicillin was once the drug of choice with chloramphenicol as a good alternative in allergic patients. Ceftriaxone is an antibiotic commonly employed today. Hydrocortisone can sometimes reverse the adrenal insufficiency. Plastic surgery and tissue grafting are sometimes needed to treat tissue necrosis resulting from the infection.