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.he most common causes of splenomegaly in developed countries are infectious mononucleosis, splenic infiltration with cancer cells from a hematological malignancy and portal hypertension (most commonly secondary to liver disease, and Sarcoidosis).