It is said that thrombomodulin, or TM(AKA THBD) or CD141 plays only an indirect part in TMA ( thrombotic microangiopathy) .
TM is something which is ubiquitously spread on the surface of the endothelial cells of the capillaries. Its job is to modulate coagulation. Influence its activation.
It is an important part of the coagulation system.
It is also said to modulate complement but it is not part of the complement system.
It is been found to act with the Classical and Lectin pathways of the complement system. TM helps control C3a and C5a to avoid an excessive inflammation response. C3a and C5a have no direct implication for aHUS.
It is important that it acts properly. Good TM can help suppress a TMA.
Is TM a cause of aHUS?
Technically not some would say. But it depends on what you are calling aHUS these days
If it is not part of the complement system which mediates aHUS, i.e. primary aHUS. then it is not a primary aHUS but that does not rule out it playing a role in complement activity.
It is therefore in that confusing terminology of aHUS which blurs its meaning that the problem lies.
Terminology is in need of revision because “aHUS” now embraces so many disparate diseases. Its name creates problems for understanding. For clinicians and patients alike.
But for those with TM mutations and TMAs there remains a dilemma.
If not calling it the aHUS of the complement mediated type, then the current marketing licence for complement inhibitors means that its treatment is not covered. Its use can only be “off label” if it works.
When you think about it at first any potential mutations would not be thought about at all on diagnosis and the patient would be treated with a complement inhibitor if aHUS was “suspected”.
Only after the results of genetic testing are known and TM mutation has been identified, with or without other genetic mutations, does it become a factor.
Meanwhile a complement inhibitor has been working for TM patients.
So those TM patients receiving complement inhibitor treatment believe it works for them in real life.
There are anecdotes which claim that stopping treatment is followed by an almost abrupt return of TMA activity in TM patients. Sparse information exists about long term remission.
So what is happening?
While on a complement inhibitor treatment, patients with defective TM, which is not part of the complement system, appear to not have a TMA.i
It is the same defective TM and coagulation system so it begs the question why is there no TMA independent of a complement mediate one when complement is blocked? Logically that must count for something in a prognosis.
After all the complement inhibitor had only been only inhibiting complement.
If TM patients did have a TMA when their complement is blocked then complement treatment could then be seen as useless and the TM patients would need a different diagnosis and treatment.
Maybe disseminated intravascular coagulation (DIC) , and a recombinant thrombomodulin therapy , rTM .
DIC and TMA are frequently confused with each other on first diagnosis. Though mostly wrongly called DIC when actually a TMA.
It is only when the complement inhibitor is withdrawn that another TMA episode begins in TM patients. The only difference is what is happening in complement and why is it happening?
Usually there has to be a trigger for complement to be activated . Too much to expect that such a trigger to complement over action arises immediately, unless there is a coincidental subclinical “bubbling” of activity already occurring. If so what could that be?
All that is known is that the patient has a genetic mutation in TM and not complement.
Whilst experts do not agree that a positive response to a complement inhibitor defines what aHUS is, so experts imply something not aHUS can still respond to a complement inhibitor.
Does anyone anywhere say that TM patients are right that their complement is impacted in some way by their TM?
Delvaeye et al said this back in 2009 “We recently established that TM is a physiologically important negative regulator of the alternative pathway (AP) of complement activation, defects of which increase the risk of the thrombotic microangiopathy, atypical hemolytic uremic syndrome. “
Important negative regulator” that is STOPS it!
“Defects of which” relate to complement component defects. But TM patients may not have identifiable complement genetic defects. Tests may be negative other than for a TM mutation.
Identifiable!
Some refute Delvaeye’s claim that a TM mutation can cause aHUS. But is Delvaeye saying that it causes aHUS? Is not the defects in the alternative pathway that do?
The refuters say the evidence supporting the relationship between TM and autosomal dominant aHUS has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role plays in this disease.
“Role plays in this disease”. “Support or entirely refute”. Juries out really so no verdict yet!
aHUS experts have now agreed that “the identification of a pathogenic complement gene variant or a high-titre FH autoantibody should not be the sole criterion for confirming the role of complement in disease”.
aHUS experts also agree that “the absence of a complement gene variant does not rule out complement-mediated HUS” .
(CM-HUS another new unofficial term for aHUS!)
aHUS experts now propose that aHUS should be called C-TMA, complement-mediated thrombotic microangiopathy and should have three categories with a common root i.e. based on C-TMA, complement-mediated thrombotic microangiopathy
- GC-TMA, genetic complement-mediated thrombotic microangiopathy (i.e., with a known pathogenic variant)
- NGC-TMA, complement-mediated thrombotic microangiopathy with no known pathogenic variant;
- CFHAb-TMA, thrombotic microangiopathy driven by anti–complement FH antibodies;
Setting aside the TM mutation for now and given what experts have said , would identified TM aHUS patients without an identified complement variant be categorised as NGC – TMA and if so would the TM only patients be entitled to complement inhibitor treatment just as other NGC-TMA patients would be?
But would some clinicians say that TM patients , without identifiable complement genetic variant involvement, but with only defective TM be categorised as GNC-TMA, non–complement-related known pathogenic variant in other genes (DGKE, TSEN, INF, EXOSC, etc.) thrombotic microangiopathy?
Is thrombomodulin one of the “etc”?
If so they would not be treated with a complement inhibitor?
Even though they could actually be a NGC-TMA patients, a cohort of the recategorized aHUS patients who will respond to a complement inhibitor. (The order of the “N” and “G” is so very vital)
Some experts say in contrast to TMA involving a TM mutation, TMAs due to DGKE and plasminogen mutations are not complement-mediated TMAs.
So TM mutations are involved in complement mediated HUS in the opinion of those experts.
Furthermore experts have said that TM is expressed on endothelial cell surfaces and serves as a cofactor for thrombin which enhances the activation of its anticoagulant substrate protein. In addition, TM assists in the factor H–mediated inactivation of C3b, as well as previously mentioned the inactivation of C3a and C5a.
“TM helps CFH inactivate C3b!” Mutated TM doesn’t.
So is defective TM not being able to help CFH control complement not as important in any complement overactivation, as anti factor H autoantibodies are when being an hinderance to CFH’s control function.
No one has said that anti factor H autoantibody aHUS should not be treated with a complement inhibitor.
So the answer to that question is of vital importance to the aHUS patients affected by TM mutations only.
One further point is that NGC-TMA patients, ie aHUS patients without an identifiable complement mutation are most likely to go into remission without a complement inhibitor.
Yet those with TM mutations appear to relapse. Should TM in fact be considered an additional risk risk factor in a discontinuation of complement treatment decision?
OK this was a tortuous route to get to a reasonable conclusion that TH only variant “aHUS” patients possibly have added risk of relapse if a complement inhibitor treatment is discontinued.
Think back to the “refuters” and what the jury is out over.
If evidence is found that TM is integral to loss of complement control causing TMA then treat it as an aHUS/C-TMA.
If it is an irrelevant factor and the patient also has no identifiable complement genetic mutation then treat the patient as having aHUS/C-TMA as no identifiable complement genetic predisposition factor has been found and TH is a distraction.
Integral or a distraction. Does it really matter?
Either way logic says what ever is found the result would be treatment with a complement inhibitor.
Obviously this is not definite and the logic of a patient advocate is not enough. Some clinician(s) will need to step up to the plate eventually to say “yay or nay!” for the sake of TH mutation aHUS patients.
But there are experts’ opinions in this blog, which if taken at their word, offers a reasonable doubt argument in a discontinuation decision if a doctor is of opinion that treatment should be withdrawn.
As experts say aHUS means different things to different doctors. The science must be definite so that no harm is done.
So those with TM mutations only can inform themselves to maybe advocate this reasonable concern based on expert evidence.
It would help further if TM patients out there who have faced or are facing treatment discontinuing decisions make themselves known to the community. There are likely to be a few hundred of them.
As far as Global Action’s discontinuation model is concerned a slight amendment is needed on the question about genetic mutation status by adding a proviso that no known genetic mutation patients might be at higher risk with a possible “TH variant only” relapse factor.
So to summarise :
- TM genetic mutation only and no complement ones;
- No separate and accurate DIC diagnosis;
- Complement inhibitors worked while awaiting genetic results;
- TMA relapse after complement inhibitor withdrawal;
- A NGC-TMA diagnosis is a reasonable “aHUS” diagnosis option;
- TM maybe a special risk factor in complement inhibitor discontinuation decisions.
On balance therefore TM only mutation aHUS patients , (TMC-TMA ?) benefit from continuous complement inhibitor treatment.
Article No: 752
Note: aHUS alliance Global Action are advocates and not medically qualified, so anyone affected by this should seek an rely on professional medical advice.
The following expert articles were used in the writing of this blog.
