Thrombotic Microangiopathy

Key Features

Essentials of Diagnosis

• Microangiopathic hemolytic anemia and thrombocytopenia, in the absence of another plausible explanation, are sufficient for a presumptive diagnosis

• Fever, neurologic abnormalities, and kidney disease may occur but are not required for diagnosis

• Kidney dysfunction is more common and more severe in hemolytic-uremic syndrome (HUS)

General Considerations

• The thrombotic microangiopathies (TMAs) include but are not limited to

  • Thrombotic thrombocytopenic purpura (TTP)

  • HUS

• These disorders are characterized by

  • Thrombocytopenia, due to the incorporation of platelets into fibrin thrombi in the microvasculature

  • Microangiopathic hemolytic anemia, which results from shearing of erythrocytes in fibrin networks in the microcirculation

  • Mutations in complement genes (such as factor H, a complement regulator) account for the uncontrolled activation of complement

• In idiopathic TTP, autoantibodies against the ADAMTS-13 (A disintegrin and metalloproteinase with thrombospondin type 1 repeat, member 13), also known as the von Willebrand factor cleaving protease, leads to accumulation of ultra-large von Willebrand factor (vWF) multimers

  • These multimers bridge and aggregate platelets in the absence of hemostatic triggers

  • This bridging and aggregation in turn leads to the vessel obstruction and various organ dysfunctions seen in TTP

• In some cases of pregnancy-associated TMA, an antibody to ADAMTS-13 is present

• In contrast, the activity of the ADAMTS-13 in congenital TTP is decreased due to a mutation in the gene encoding for the molecule

• Classic HUS is thought to be due to damage to endothelial cells from ingestion of undercooked ground beef contaminated by Escherichia coli

• Patients with complement-mediated HUS have genetic defects in proteins that regulate complement activity

• Certain drugs are associated with the development of TMA

  • Cyclosporine

  • Quinine

  • Ticlopidine

  • Clopidogrel

  • Mitomycin C

  • Bleomycin

Clinical Findings

Symptoms and Signs

• Microangiopathic hemolytic anemia and thrombocytopenia are presenting signs in all patients with TTP and most patients with HUS

• In a subset of patients with HUS, the platelet count remains in the normal range

• Only about 25% of patients with TTP manifest all components of the original pentad of findings (Table 14–4)

  • Microangiopathic hemolytic anemia

  • Thrombocytopenia

  • Fever

  • Kidney disease

  • Neurologic system abnormalities

• Most patients (especially children) with HUS have a recent or current diarrheal illness, often bloody

• Neurologic manifestations may result from deposition of microthrombi in the cerebral vasculature

  • Headache

  • Somnolence

  • Delirium

  • Seizures

  • Paresis

  • Coma