A 41 y.o. male presents with anemia and shortness of breath. His peripheral smear appears below.

 What is the differential?

What is the differential?

Our patient had atypical hemolytic uremic syndrome. This was called atypical because in most cases the syndrome is preceded by an episode of diarrhea which is caused by E Col, O157:H7,  other non -O157 E. coli, shigella and campylobacter.  It can also be preceded by a virus.  Another atypical feature of this case was that HUS most commonly occurs in children where it remains the most common cause of acquired renal failure.  5% of the cases result after infection by Strep pneumo. In atypical HUS, genetic defects cause uncontrolled complement activation.

HUS was first described in 1955. The toxin binds to GB3 receptors which are more common in children and in adults are concentrated in the kidneys.   The virus or bacteria cause endothelial damage, platelet activation , and widespread inflammation leading to  thromboses in small blood vessels. Stroke, MI , renal failure in 55-70%, liver necrosis, pancreatitis, and seizures may result .

rbc.JPG

The mechanism of action includes binding of the toxin to BG3 receptor on the surface of glomerular endothelium, and binding of leukocytes to endothelial cells.  The binding of toxin inactivates  a metalloproteinase call ADAMTS13 and multimers of von Willebrand Factore  form and initiate platelet activation, causing microthrombi.  These thrombi lodge in small vessels and break red blood cells as that try to squeeze through.  Lastly, the toxin activates the alternative complement pathway and interferes with complement factor 5, an inhibitor of complement activation.  In contrast to DIC where coagulation factors are consumed, in HUS fibrinogen and DDimers are normal.

 causes of hemolysis

causes of hemolysis

The country with the highest incidence of HUS is Argentina possibly because of the association between E coli and contaminated meat.  In the 1990’s Jack in the Box restaurants served contaminated meat causing an outbreak of HUS. Outbreaks have also been linked to cookie dough and spinach.

If you see schistocytes you may have a thrombotic microangiopathy.

HUS-  positive shiga-toxin confirms the diagnosis, plasmapheresis is contraindicated, use eculizumab

TTP  ADAMTS13 deficiency <5% of normal; plasmapheresis is indicated.

Our patient was treated with Eculizumab , a monoclonal Ab against CD5( blocks complement)  In one week,  his platelet count increased from 56,ooo to 122,000,  his hgb increased from 7.3 to 8.7 and he began making urine.   One year of treatment costs $500,000.

Benz K, AmannK. Thrombotic microangiopathy:new insights. Current Opinion in Nephrology and Hypertension. 2010 19(3) 242-247.

Shimizu M, Yokoyama T, et al. Thomsen-Friedereich antigen exposure aas a cause of Strep pyogenes-associated hemolytic-uremic syndrome.  Clinical Nephrology 78(4):328-31.

Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. 2009. NEJM 361(17):1676-1687.

thrombocy.JPG