The question should be why do some triggers kick off a complement only TMA ( Primary aHUS ) and yet can also trigger its own TMA which turns into complement TMA secondly?
The same condition can injure the blood vessels in direct and indirect ways. and the order depends on which part of the immune system gets overwhelmed first.
Pathway A: Condition → complement system goes into overdrive → complement‑mediated TMA (including aHUS)
Pathway B: Condition → endothelial injury + clotting → “ordinary” TMA → complement becomes activated on top → complement‑mediated TMA (including aHUS) follows.
Both end up looking like a TMA, but the starting point and dominant driver of the condition are different.
Some conditions strongly activate the innate immune system, especially C3 and C5 in complement and the inflammatory cytokines.
If the person has an underlying complement “vulnerability” (known or unknown? genetic variants, autoantibodies, low regulatory proteins), then even a normal infection can cause runaway complement activation-endothelial damage-platelet consumption–TMA
This is primary complement‑mediated TMA which includes aHUS that is triggered by a condition in the blood through the alternative .pathway of complement.
Think of it like complement system is already “twitchy,” and the condition presses the accelerator in a car with faulty brakes.
Some infections damage blood vessels directly, without involving complement at the start. These include Shiga toxin (“classic” HUS). Severe viral endothelial injury (COVID,) adenovirus) or sepsis‑related clotting activation
This produces blood vessel inflammation- microclots- platelet consumption- TMAs
This is non‑complement TMA at first and maybe the only TMA to happen.
Except for the “danger signals” sent out by the immune system involved in such TMAs. These go out from the inflamed endothelial cells.
These microscopic molecules are powerful complement activators. This is normal it happens to everyone. A massive cytokine storm can activate complement even if complement genetics are normal.
But if someone is vulnerable with complement mutations ( known or unknown), poor controls, anti factor H anti bodies then the complement system becomes activated and creates its own TMA secondary ( after) the first the TMA.
So the sequence becomes: condition → endothelial injury → non‑complement TMA– endothelial injury signalling → complement activation– a MAC- compounds and perpetuates TMAs
This is secondary complement‑mediated TMA , which includes secondary aHUS.
Think of it like this the initial condition ignites the fire and complement pours petrol on it.
It cannot work the other way round and can only happen if someone is vulnerable. Complement is easily triggered so Pathway A is more likely.
This is going on unseen and unfelt when at a moment in time it begins and then grows.
A mild condition may cause slow endothelial injury from which complement joins later. A severe condition may activate complement almost immediately.
So unobserved there is moment when one or other begins and if its other TMA first there then is moment when complement begins to follow.
Some days later when the patient presents how does a doctor know what to think about a first,, secondary or primary situation. According to the diagnosis protocols secondary aHUS would thought of before primary aHUS and even then it disregards treatment of a possible complement situation which is going on in parallel until last to be assumed
WHY? WHY? WHY?
Both pathways are real, both are seen clinically, and both can end up looking identical unless you examine the timing and underlying complement biology. But do you need to ?
Complement doesn’t always need a virus to activate. It only needs “damage signals.” sometimes. Endothelial injury produces those signals instantly.
A virus can activate complement directly — but only if it interacts with complement‑recognition pathways. Not all viruses do this strongly.
So the difference comes down to what part the immune system “sees” first. And the time between first sight and the beginning of something determines the order.
So how fast can one pathway precede the other? This is the part most people don’t realise: The timing difference can be minutes to hours not days.
This is why any TMA, even non‑complement TMA, can quickly become complement‑amplified too. Conditions vary in the way that they interact with complement some strongly activate complement component C1q. Viruses like influenza and SARS-COV2. Complement activations can begin in minutes and endothelial damage follows as complement attacks the vessel walls. Complement-first TMAs begin 0–6 hours after infection triggers the innate immunity
These have surface proteins that bind C1q, activate lectin pathway, or trigger alternative pathway and others like rhinovirus activate complement directly. But these viruses also cause cell injury, inflammation, and cytokine release — but they don’t directly bind complement proteins strongly. So in those infections endothelial injury cause the first TMA: 6–48 hours after infection begins damaging cells and complement activation follows after within minutes.
So the difference is not days — it’s often a matter of which switch flips first.
Sometimes aHUS hits people who are well and extremely fit from training and exercise. Physical stress, heat exhaustion, dehydration, and extreme exertion can cause endothelial damage, and that damage can activate complement even without any infection. But the degree of damage and the person’s underlying complement biology determine whether this becomes clinically meaningful
Complement is designed to detect any abnormal surface — not just viruses or bacteria. When endothelial cells are stressed or injured, they express signals which are picked up by complement among others. These are universal complement triggers.
So anything that injures the endothelium like heat stress, dehydration, extreme exercise can in turn activate complement.
None of these require a virus. It can be for example as simple as in dehydration low plasma volume makes blood thicker. Thicker blood increases mechanical stress on vessel walls → micro‑injury → complement activation.
These apply to all people but again it is the aHUS vulnerable that can face runaway complement activity even with only small endothelial injury. But it is a very rare occurrence. There is little evidence that such stresses creae their own TMA which complement could be secondary to.
It is like aHUS is a normal complement trigger in an abnormal host. It can take seconds to hours to surge. .
The signals are “normal” but it is those those without complement controls are “abnormal” through no fault of their own. So is it a matter of if there are lots or a small number of signals?
Some are from small, transient stresses that create tiny patches of altered endothelial surface however started. And it can happen lots of times. These can activate complement and can be a challenge to those without complement controls.
There is also widespread, sustained injury across large areas of the vascular system. This overwhelms complement regulation even in people with normal complement biology.
This is why the same trigger can be harmless for one person and catastrophic for another. Complement’s amplification loop then multiplies the signals -complement activation → more endothelial injury.→ runaway TMA. This is why the amount of damage matters less than the ability to regulate complement.
Complement activation after endothelial injury is extremely fast:
Damage appears → seconds
C3 activation → minutes
C5 activation → minutes
MAC formation → minutes to hours
So “a little” damage can escalate quickly if regulation of complement fails.
But whether it’s primary or secondary does it matter when it comes to TMA treatment?
In diagnosis algorthIms TTP (another TMA) and STEC-HUS can be ruled out relatively quickly with specific clinical tests.
Eliminating them that leaves -other TMAs inly and complement TMAs – and complement TMAs secondary to other TMAs.
In the diagnosis algorithms the focus would move on from TTP and HUS to rule out all the the potential other TMAs first before getting to aHUS and treating them.
WHY!WHY! WHY!
Two of the above situations involve a complement TMA which would respond to a complement inhibitor treatment so the complement mediated damage would be stopped in those two cohorts. It would result in the best of health outcomes for both from rapid access to treatment even with an uncertain diagnosis.
Complement inhibition would of course not help other TMAs only patients that would be wasted but .only for a short duration and would do no harm.
The treatment for other TMAs although a waste would do no harm to complement only patients and would only be of short duration if the TMA condition is resolved. Those with secondary TMA would obviously benefit from both at the same time.
Given the small margin between an other TMA turning into a Secondary TMA from similar beginnings in a very short time who would know how many complement TMAs, including aHUS, and other TMA patients are actually experienced the secondary condition at a very early outset.
So other than some wasted treatments what does it matter if the best of heath outcomes are achieved for most after all it is not uusaul for treatment to be wasted in heath care when diagnosis is unclear when diagnosis involves a very fine line between options. But the heath outcomes benefits can be huge. There could be an advantageous “incremental cost per QALY”.
There must be data on the proportions of other TMA only, Secondary TMAs and complement TMAs somewhere. Research could fill in any knowledge gaps including a trial of a less sequential and more simultaneous treatment regime to determine the health outcome benefits that would ensue.
Consciously allowing harm to complement TMA patients ( including aHUS patients) should no longer be acceptable. It makes prognosis for treatment discontinuation clearer.
Surely that should be something the disease renaming could do towards this. TTP will not have a TMA name. STEC TMA could be ruled out quickly.
Presuming complement treatment needed further up the TMA diagnosis process rather than consciously deny it until diagnosis is certain. If the name is being rethought so that TMA binds us then that should be reflected in the diagnosis journey, then an earlier treatment could be one of the potential benefits to patients that the renaming plans can deliver.
Primary or Secondary TMA should it really matter for cTMA including aHUS. Those terms will go with renaming and may have been detrimental. But more TMA should be seen as involving complement and the earlier the treatment the better.
Article No: 813
