HUS is believed to result from an inflammatory reaction in the blood that causes platelets to sludge and form clots, leading to decreased platelets elsewhere in the body. The triggering event for HUS may be a bacterial infection, such as E. coli or Streptoccoccus pneumoniae; a rickettsial infection, such as Rocky Mountain spotted fever; a viral infection, such as human immunodeficiency virus or influenza virus; or a fungal infection, such as Aspergillus fumigatus. Other possible triggers include pregnancy, cancer (and chemotherapy), vaccinations, transplantation, and medications. The trigger for HUS may also be idiopathic. There is also an inherited form of HUS that affects the normal clotting mechanism.

D+HUS more frequently affects children younger than age 5 and is more common than D−HUS. However, mortality in patients with D−HUS is higher than that in patients with D+HUS.

Complications of HUS include renal failure, stroke, coma, seizures, and bleeding complications. Irreversible brain damage can occur, as can death. Complications associated with HUS caused by E. coli include dehydration and electrolyte imbalances. HUS has also been associated with prostatic, gastric, and pancreatic cancers. Cardiac dysfunction and fluid overload may occur. Death may occur if the patient is not treated and the disease has progressed.

HUS associated with E. coli infection initially presents with abdominal cramping and vomiting along with watery diarrhea, which becomes bloody after 1 to 2 days in 70% of cases, and decreased urine output. After resolution of these symptoms, signs of anemia may be present, including weakness, lethargy, and sleepiness. There may also be signs of a low platelet count, including purpura and bleeding. Other signs include hypertension, edema, pallor, and anuria. Seizures may also occur, along with irritability or altered mental status.