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.
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:
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microangiopathic hemolytic anemia
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thrombocytopenia
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acute kidney injury
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neurologic symptoms
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fever
5. What are the underlying pathophysiologic mechanisms of the major TMA syndromes?
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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.
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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.
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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?
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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.
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TTP: 0.1 case for 1,000,000/year in children; 3 cases for 1,000,000/year in adults.
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aHUS: 1 case for 1,000,000/year in the overall population
8. Describe the presentation and clinical course of patients with ST-HUS.
Patients often develop prodromal hemorrhagic diarrhea with associated abdominal pain after eating Shiga toxin–contaminated food. The kidney failure and other clinical manifestations (including thrombocytopenia and neurologic manifestations) develop after the diarrhea has begun to resolve. Among patients who develop Shiga toxin enteritis, 5% to 15% develop HUS. If neurologic abnormalities and hypertension occurred, they can persist even after the acute phase is over. End-stage kidney disease (ESKD) is rare.
9. What are the treatment options for patients with ST-HUS?
The mainstay of treatment for patients with ST-HUS is supportive care. This entails aggressive supportive care including hydration with intravenous fluids, supporting the anemia, and managing the renal failure with renal replacement therapy, if needed. There are no randomized clinical trial data to support plasmapheresis or eculizumab, but they have been used in severe ST-HUS with reported success, especially in Germany after the E. coli O157:H7 outbreak from contaminated bean sprouts in 2011 ( Fig. 41.1 ).
