A 57 year-old woman presented with five days of worsening confusion and drowsiness associated with headache, generalized abdominal pain, nausea, and new rash. She had a history of interstitial lung disease treated with prednisone and ritixumab. She was afebrile, oriented to person only, had coarse crackles at bilateral lung bases, diffuse abdominal tenderness, and a petechial rash on her inner thighs. Labs were significant for hemoglobin 10.7 and platelets 20,000 with schistocytes on the peripheral smear. In addition, BUN was 54, creatinine 5.4, and total bilirubin 2.5. The tetrad of altered mental status, hemolytic anemia, thrombocytopenia, and acute kidney injury raised concern for TTP/HUS, and empiric plasma exchange was initiated. Mental status improved; however, other symptoms did not. Further labs revealed normal ADAMTS13 activity, negative ADAMTS13 antibody, and negative stool Shiga toxin. HUS genetic panel demonstrated CFHR3-CFHR1 homozygosity, which correlates with an increased risk of antibodies to Factor H, a cause of atypical HUS. Plasma exchange was discontinued, and the patient began weekly treatment with Eculizumab. While anemia and thrombocytopenia improved, renal failure progressed and necessitated hemodialysis. Renal biopsy on day 19 demonstrated changes consistent with thrombotic microangiopathy, confirming the diagnosis. The patient’s clinical course was improving until she developed acute hypoxemic respiratory failure followed by asystole arrest on day 42; death was attributed to renal failure.
Both TTP and HUS are characterized by a classic pentad: fever, neurological symptoms, microangiopathic hemolytic anemia with schistocytosis, consumptive thrombocytopenia, and renal failure. TTP is caused by deficiency of or antibodies against ADAMTS13, yielding the enzyme unable to cleave long von Willebrand multimers that promote platelet aggregation in the vasculature. HUS is most commonly associated with abdominal pain and diarrheal illness caused by Shiga-toxin producing E. coli 0157:H7 and Shigella, which are thought to disrupt the complement pathway. Initial treatment of both conditions is plasma exchange until the potential diagnosis of TTP is eliminated or the schistocytes removed.
Similar to typical HUS, atypical HUS is caused by mutations in the complement pathway that allow unregulated activity on host cells, leading to activation of platelets, leukocytes, and endothelial cells that promotes thrombotic microangiopathy. The CFHR3-CFHR1 mutation decreases the activity of factor H, which regulates the alternative complement pathway by decreasing activity of C3b, thereby preventing the formation of the membrane attack complex (MAC) on host cells. Mutated factor H is unable to bind to C3b that is bound to the surface of host endothelial cells; thus, it is unable to regulate the formation of MAC on host cells. Eculizumab, a monoclonal antibody that inhibits the formation of C5a and MAC, has been shown in case series to improve renal function and quality of life in patients with atypical HUS. However, as seen in this patient, atypical HUS is still associated with a 50% progression to end stage renal disease and 25% mortality.
Distinguishing between TTP, typical HUS and atypical HUS is critical to determining which treatment is correct to decrease the thrombotic microangiopathy. Recognition of atypical HUS can help hospitalists prevent progression to end stage renal disease and death.