This question about difference in disease triggers and treatments from Jeff did not feature in the RDD2022 video but was given as example in the invitation to participate in the project.
It is a huge question which could, and has been, the subject of major published articles. So this is just the simple blog answer, Jeff.
The first difference is that Primary aHUS is a Primary TMA and Secondary aHUS is a Secondary TMA.
I know that all that does is say that both are thrombotic microangiopathies or TMAs. One is a Primary kind and the other is a Secondary version. Both involve impairment of the kidneys still, as is essential for aHUS, but now can be regarded as damaging other organs too.
Any thing which is not a primary version becomes a secondary TMA.
So what makes Primary TMAs, Primary TMAs. I guess it could be claimed that it is because they grew up together. Everything was once something called Thrombotic Thombocytopenic Purpura, or TTP . The someone noticed that TTPs were the result of TMA. Then a doctor in Zurich noticed that some of his young child patients had specific symptoms that were both hemolytic and uremic, and so called what they had died from “HUS”, or, as he claimed, HUSs ( i,e, Syndromes).
Now instead of everything being called TTP , the term TTP/HUS begun to be used. They became the primary TMAs and consisted of TTP , HUS and what was eventually to be called aHUS.
The three primary TMAs. There were other TMAs but they were not regarded as primary. Not because there were fewer of them. There are substantially more incidents of Secondary TMA than Primary TMAs. SUBSTANTIALLY more.
Other than the common factor of TMA in all , the three primary TMAs are different in the way that the damaging TMA comes about.
TTP is caused by a deficiency of a substance called “disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13”, or ADAMTS 13 for short, which performs a control function by cutting another part of the coagulation system called Von Willebrand Factor, which can ,if not controlled, lead to uncontrolled TMA.
In HUS its the toxins given out by viruses, usually E. coli O157:H7 infection, which invade the body that causes the damage to blood vessels.
And for aHUS it is loss of control of a part of the immune system called Complement. A damaging combination of Complement component attacks the lining of blood vessels themeslves .
The initial thrombotic responses is just intended to repair the damage as needed, but such an excessive response develops that it becomes part of the problem as a TMA. Blocking the blood vessels and causing blood cells to burst.
The same thing happens with Secondary TMAs but for different reasons. Blood vessels are inflamed and damaged. It could, for example, be an autoimmune disease like lupus/SLE where the disease acquired auto-antibodies provoke inflammation and damage to blood vessels and triggering repair clotting process which becomes a problematic TMA.
Or a particular drug, being used for another health condition, which has toxins that can inflame and damage blood vessels again calling for repair by the coagulation system and so on.
It could be triggered too by immune response in haempoeitic bone marrow transplant when the “graft” blood rejects and attacks the host, inflammation and damage to blood vessels result, the coagulation system wades in and a problematic TMA can follow.
Even the coagulation system can itself cause the damage to the blood vessels(as seen in TTP and Plasminogen TMA) and then calls on itself to repair it and then leads to a problematic TMA.
So Jeff , the difference is really down to what causes the inflammation and damage to the blood vessels in the first place and how the coagulation system responds to . In Primary aHUS it is down to complement but in Secondary aHUS such aHUS is secondary to the primary disease, or condition, which starts the blood vessel damage
aHUS is a complement mediated TMA. CM-TMA is Primary aHUS. Non complement mediated aHUS is a Secondary aHUS.
Being Primary does not mean that CM- aHUS is more common, it is far from that it is ultra rare. Nor does being Primary give it more priority in the TMA diagnosis process. In fact CM -aHUS is often the last to be considered . Secondary non -CM- aHUS diagnosis may have a higher priority.
And now, here is something to make your head spin , Jeff.
A Secondary TMA or aHUS can begin because of the underlying diseases or conditions which can inflame and damage blood vessels. But that can cause an excessive Complement response too. Causing more blood vessel inflammation and damage but this time it is Complement which is doing the damage.
To a greater or lesser extent it is possible therefore to have Primary aHUS and Secondary aHUS at the same time!.
TMA is common to both and what triggers and causes the blood vessel damage is down to each disease.
After a diagnosis of the cause of the TMA, treatment takes different courses.
Traditionally The best resolution of Secondary TMAs is treating the underlying illness.
For the Primary TTP, it is plasma exchange. It even has a ”mab” these days Capalcizumab.
No treatment for Primary TMA HUS as it is self limiting once the infection disappears.
For CM- aHUS, a complement inhibitor like eculizumab is needed, or plasma exchange if there is no access to an inhibitor.
For those Secondary aHUS patients whose TMA has developed into CM-aHUS too, in addition to the traditional treatment approach, a temporary course of eculizumab treatment could also be beneficial.
Reading this explanation it is obvious that there is a need to redefine the TMA classification and disease nomenclature to make clearer the differences to patients . Doctors may also struggle to understand it too.
Sadly this is happening without patients who have the illness having a say about their concerns and insights from an actual sufferer’s perception. For aHUS Global Action view on the subject click HERE
Article No 514