Thrombotic microangiopathies

1. Define thrombotic microangiopathy.

Thrombotic microangiopathy (TMA) is a pathologic description characterized by arteriole and capillary endothelial vessel wall damage that results in platelet activation, thrombosis, and damaged erythrocytes (schistocytes) leading to ischemia and organ failure. Several different clinical syndromes can present with the characteristic features of TMA.

2. What are the clinical features associated with thrombotic microangiopathy?

The main clinical features of all TMA syndromes include microangiopathic hemolytic anemia (anemia with the presence of schistocytes), thrombocytopenia, and altering degrees of renal and neurologic dysfunction. Due to the hemolysis, patients will have an elevated lactate dehydrogenase (LDH) and a low haptoglobin. The direct antiglobulin test (Coombs test) is negative because the anemia is nonimmune in nature.

3. What are the most common clinical syndromes associated with thrombotic microangiopathy?

• Shiga toxin–associated hemolytic uremia syndrome (ST-HUS)

• Thrombotic thrombocytopenic purpura (TTP)

• Atypical hemolytic uremic syndrome (aHUS)

4. Are there clinical features that may help distinguish between these clinical syndromes?

Yes and no. HUS often presents with kidney injury, whereas TTP is associated with more neurologic dysfunction and less often kidney injury. Although these associations are “classic,” patients with TTP can have kidney injury and patients with HUS can have neurologic manifestations. The platelet count in aHUS as compared with TTP is rarely less than 80,000. The classic clinical pentad of TTP includes:

• microangiopathic hemolytic anemia

• thrombocytopenia

• acute kidney injury

• neurologic symptoms

• fever

5. What are the underlying pathophysiologic mechanisms of the major TMA syndromes?

• ST-HUS: This is caused by Shiga toxin secreted from strains of Escherichia coli (most common is E. coli O157:H7) or Shigella dysenteriae . Shiga toxin binds to vascular endothelial cells, renal mesangial cells, and renal epithelial cells, leading to cell damage.

• TTP: This is caused by a deficiency in von Willebrand factor–cleaving metalloprotease (A Disintegrin And Metalloproteinase with ThromboSpondin Motifs 13 [ADAMTS13]) that cleaves von Willebrand factor. The deficiency leads to large multimers of von Willebrand factor that increase the risk of platelet thrombi in small vessels.

• aHUS: This is caused by uncontrolled activation of the alternative complement pathway, leading to increased formation of the membrane attack complex injuring normal cells.

6. What is the incidence of the varying clinical syndromes of TMA?

• ST-HUS: 60 cases for 1,000,000/year in children <5 years of age; 10 to 20 cases for 1,000,000/year in overall population including adults >18 years of age.

• TTP: 0.1 case for 1,000,000/year in children; 3 cases for 1,000,000/year in adults.

• aHUS: 1 case for 1,000,000/year in the overall population

7. Does shiga toxin–associated HUS occur more often in children or adults?

ST-HUS occurs more frequently in children. When ST-HUS occurs in adults, the clinical manifestations are often more severe.