AHUS Is A Disease Of Excessive Activation Of The Alternative Complement Pathway (ACP)

11 Mar, 2021

Dr. Rajesh Bollam

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aHUS is a disease of excessive activation of the alternative complement pathway (ACP).
ACP is always active at low levels and the "tick over" is regulated by proteins on cell surfaces and in the plasma. These proteins have mostly an inhibitory effect on the ACP
Some of the cell-surface proteins are:
- CD55 and CD59: if they are lost and/or mutated -> ACP is activated -> PNH develops.
- CD46: this binds to factor I and inactivates complement
- Thrombomodulin
Some of the soluble protiens are:
- Factor H: binds and disrupts complement
- Factor I: synthesized in the liver, also has an inhibitory role on complement
So how does aHUS develop?
Inherited mutations in ACP genes or acquired autoantibodies to ACP proteins. Most commonly leading to loss of function of regulatory proteins (factor H, factor I, CD46, or thrombomodulin) -> overly active ACP
Triggers of aHUS include inflammation, surgery, autoimmunity, and pregnancy. These are cases where a genetic panel is negative (approx. 50%), and the remaining are genetic mutations (most commonly in factor H).
When ACP is overly active, it leads to microthrombi in blood vessels due to inflammation.
This leads to the triad of:
1. Microangipathic hemolytic anemia (MAHA)
2. Thrmbocytopenia
3. Organ damage (usually kidneys)
The reason aHUS and TTP are clumped together is because the clinical presentation can be identical. Initially, all patients get plasmapheresis.
aHUs is a diagnosis of exclusion. A genetic panel looking for mutations in the complement system can be sent but takes a couple of weeks to come back, and is negative half the time.
So in the acute setting all patients get plasmapheresis, and if TTP is ruled out (ADAMTS13 >10%), then treatement for aHUS can be started.
You may have wondered why it's called "atypical" HUS?
Because "typical" HUS was described first as is a clinical syndrome caused by Shiga-toxin producing E. coli. It also has the same clinical presentation. The pathophysiology is different, but likely involves ACP activation.
Back to aHUS.
Treatment:
- Inhibiting complement activation
Eculizumab is a drug that binds to C5 and prevents formation of the membrane attack complex (MAC). It is used for PNH and for aHUS.
In the 2 prospective trials, eculizumab was associated with significant change in the platelet count (in trial 1) and absence of thrombotic microangiopathic events (in trial 2).
Plasmapheresis/infusion was discontinued in almost 100% of patients.
In both trials, kidney function improved during treatment with eculizumab.
Problems have been mentioned before and include:
- Long-term, indefinite, use
- Risk of infection with encapsulated organisms
- Cost high
So to summarize, aHUS is caused by genetic mutations and/or autoantibodies against ACP regulators -> overly active complement system -> thrombotic microangiopathy -> organ damage and hemolysis
Treat by blocking complement activation or dealing with the source (e.g. liver tx)

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