How Does aHUS Differ from Other Thrombotic Microangiopathies?

Thrombotic microangiopathy (TMA) refers to the formation of blood clots in the small blood vessels of the body. Atypical hemolytic uremic syndrome (aHUS) is a form of TMA that is associated with such symptoms as hemolytic anemia (loss of red blood cells) and thrombocytopenia (low platelet count).

Severe forms of aHUS can lead to chronic kidney disease and kidney failure.

Diagnosing aHUS can be a complicated process, as its symptoms overlap with those of other forms of TMA, including Shiga-toxin producing E.coli HUS (STEC-HUS), thrombotic thrombocytopenic purpura (TTP), and disseminated intravascular coagulation (DIC).

Here are some important points in confirming an aHUS diagnosis or suspected case, and differentiating aHUS from other types of TMA.

Ruling out STEC-HUS

STEC-HUS can be diagnosed by evaluating whether blood is visibly present (gross blood) in the stool. However, around 30% of aHUS and TTP cases also involve bloody diarrhea.

Since STEC is also most often associated with E. coli infection as well as bloody stool, techniques such as polymerase chain reaction (PCR) and cultures for Shiga toxin-producing E.coli can be used to confirm the presence of this bacteria.

Organ system involvement

Understanding which organ system is severely affected can help identify the form of TMA a patient has. At least one organ system has to be involved to confirm a TMA diagnosis. Although any tissue may develop the small blood clots characteristic of TMA, about 20% of patients diagnosed with aHUS are not found to show involvement of the kidneys. In contrast, more than 50% of all TTP cases show kidney involvement, albeit to a lesser severity than is seen in aHUS.

Similarly, the lungs are never involved in TTP, whereas they are found to be frequently implicated in untreated aHUS.

Absolute platelet count and creatinine blood levels

The absolute platelet count in aHUS is greater than 30,000 per mm³ in the absence of factors such as other autoimmune diseases, infections, cancer, and certain medications. Such counts are rare in TTP.

Similarly, creatinine levels in the blood are usually greater than 2.3 mg/dL in aHUS. Serum creatinine levels greater than 2.3 mg/dL are likely to be indicative of aHUS.

ADAMTS13 activity

The ADAMTS13 gene produces an enzyme that is involved in blood clotting. The activity of the ADAMTS13 enzyme in the blood can help in differentiating types of TMA.

ADAMTS13 enzyme activity that is less than 5% (10% in some assays) rules out aHUS and STEC-HUS but confirms TTP. ADAMTS13 activity greater than 5% indicates aHUS.

Differential response to plasma exchange therapy

The normalization of platelet counts after plasma exchange (PEX) therapy in TTP results in normal platelet function and lower levels of markers such as P-selectin.

In people with aHUS, PEX can normalize platelet counts, but the platelets remain activated with high levels of P-selectin evident.

Complement activation

Even before antibodies are produced in response to an infection, the body’s immune system uses a “complementary” method of marking pathogens, such as bacteria, for targeting by immune cells. This is called the complement system. Mutations in genes that are involved in this system, such as those in the CFH gene, are known to be associated with aHUS.

Simply estimating the levels of complement system proteins in the blood is not a reliable way to confirm a diagnosis of aHUS. However, mutations in the CFH gene and the presence of autoantibodies against the CFH protein are highly indicative of aHUS.

Last updated: Feb. 24, 2020

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