This is a syndrome characterized by splenomegaly, a decrease in any or all blood cell lines with resultant marrow hyperplasia, and correction of the blood cytopenias postsplenectomy. Not all patients with splenomegaly manifest hypersplenism. The associated cytopenia or cytopenias are believed to result from splenic sequestration and increased splenic macrophage mediated cell lysis. The list of splenomegaly etiologies is extensive and includes infections, hepatic cirrhosis, right-sided cardiac failure, portal or splenic vein thrombosis, lymphomas, leukemias, multiple myeloma, systemic lupus erythematosus, amyloidosis, myeloproliferative disorders (PCV, ET, and primary myelofibrosis), thalassemia major, Felty's syndrome, Gaucher's disease, and infections (viseral leishmaniasis, hyperreactive malarial splenomegaly, and Mycobacterium avium complex).

If the resultant cytopenias are symptomatic, therapy may be offered via surgical removal of the spleen. Patients should be counseled about the complications postsplenectomy, which include a transient elevation of platelets and white blood cells (peak levels occur within 10 days postsplenectomy and then subside) and an increased risk of infection. The most common infecting organism is Streptococcus pneumoniae; however, there is a long list of other possible pathogens, which includes Haemophilus influenzae, Neisseria meningitidis, Escherichia coli, Pseudomonas aeruginosa, Capnocytophaga canimorsus, Enterococcus species, Bacteroides species, Salmonella species, and Bartonella.

Persons undergoing splenectomy should first be immunized with pneumococcal vaccine. The vaccination should be given 2 weeks prior to surgery and then repeated every 6 years thereafter. Other recommended vaccinations include hemophilus b conjugate vaccine (Hib TITER, PedvaxHIB, ProHIBiT), meningococcal polysaccharide vaccine (Menomune-A/C/Y/W-135), and yearly influenza virus vaccine (Fluogen, FluShield, Fluzone).