My Autoimmune (AIHA) experience so far...and significance of a Coombs test showing positive DAT

Following my (currently) monthly haematology consultation, I am now beginning to understand the AHIA (autoimmune) complication...looks like 10% to 20% of us get this at sometime). Symptoms of AIHA include in isolated fall in haemoglobin, positive DAT (what's that? - I will explain), rise in reticulocytes (AIHA risk factors at at end of this post). AIHA can be caused by CLL (it can also be sometimes caused by other things). Mentally I am now considering it as a separate complication, with separate treatment regimes (which do NOT count as a CLL treatment): the key I have learned is that some of the symptoms of AIHA can be confused with progressing CLL.......the CLL might not be progressing after all.

In my case, when diagnosed in Jan, the CLL was clearly BINET stage A (only the spleen is currently effected) and RAI stage II (again spleen growth puts me here). What I did not know at the time was a Coombs test also showed a positive DAT. This means effectively my red blood cells are being coated and there is thus a risk that my body (spleen) is fooled into thinking they are a foreign body and starts disposing of them. This is the cause of increased risk of AIHA. My understanding is that the Coombs test is a standard test in CLL diagnosis process (in UK at least). So our DAT score (positive, or negative) is a bit of information we should be asking for! Should also the CLLSA blood test guidance mention it/explain it?

In the first half of this year, my spleen grew to over 8cm larger than it should have been, haemoglobin dropped (to where I was beginning to think the CLL had moved to Stage III on RAI...so were things getting worse?). The drop in haemoglobin was compensated by a large rise in reticulates. So my spleen had indeed decided the red blood cells were foreign and grew to cope with their mass destruction: but a healthy bone marrow increased red cell production to largely compensate. So actually, knowing my bone marrow is healthy is good news on the CLL front!

My drop in haemoglobin is ENTIRELY caused by the AIHA: there is no reason to believe that the CLL is contributing and so I remain Stage II. So the underlying CLL remains stable: again good news that I only really understood yesterday.

The treatment for AIHA has been a very high dose of steroids. I think this lowers immune response and the spleen thus no longer thinks the red blood cells are foreign (the spleen sets a tougher test to decide is a body is foreign: the coated red blood cells now get through the test as not-foreign). During high steroid doses, my haemoglobin increased and reticulates dropped to healthy levels (as in CLLSA blood test results guidance). The steroids also dramatically increased all white blood cell counts (lymphosite and neutrophil)...so the lymphocyte doubling time measure is currently meaningless and not relevant to understanding CLL progression - it is caused only by the steroids.

I am now in final stages of coming off the steroids and haemoglobin currently remains ok. My understanding is that as I have had a short-sharp bust of steroids (over 3 months), there should be no complications of coming off that people who are on long-term steroids get (where the body's natural production stops during steroid treatment and then fails to re-start after treatment).

If I am lucky (around 66% of people - next 6 to 12 months will tell), my spleen will somehow (no-one knows why) have been re-programmed to recognise my coated red blood cells at actually part of me (ie not a foreign body) and so not re-embark on a destruction policy. If I am unlucky, there might be a second treatment option (however, if steroids don't do it, I am in a 'difficult to treat' category, so the second option I don't think has huge success rates), then/or my spleen might be to be removed to stop the AHIA. Spleen removal is not without complications, but it might have to happen.

So what are the risk factors for AIHA. they are positive DAT (I only found out that is me yesterday), advanced CLL (not me), high white blood cell count (I was only just over normal counts, so not me), older age (not me), gender (me, as male), poor prognostic markers (unknown for me, as FISH test only done when looking at CLL treatments) and initiating (CLL) treatment. So looking at that list, I was thinking I only had one (male) with two unknowns (DAT and poor CLL prognostic markers).....which was obviously was worrying as had I got AIHA because of poor prognostic CLL markers? Well I don't yet know, but at least it is possibly that being male with a positive DAT is enough....so I can remain positive!

Overall I have learned:

1 - know your DAT...it has probably been measured. A positive means increased risk your red cells will be seen as foreign and thus get destoyed

2 - AIHA can give measurements that can be confused with CLL progression: however, they are caused by the AIHA, alone NOT the CLL so don't get concerned/mix it up with CLL progression!

Hope this helps others facing the AIHA complication!

Andy

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Thanks Andy. You've greatly improved my understanding of AutoImmune Haemolytic Anaemia (AIHA) with that interesting and informative post. Sorry the subject had to be you! At least you now know that your bone marrow is still healthy. I hope you've managed all right on the high dose steroids and that you go OK weaning yourself off them, as I've heard steroids can cause some very unpleasant side effects.

I found this great definition of AIHA for those that aren't familiar with the condition:

"Autoimmune haemolytic anaemia (AIHA) is an autoimmune condition in which the immune system produces antibodies that target and destroy red blood cells. In AIHA, the red blood cell’s outer surface membrane is destroyed or lysed, causing the protein haemoglobin to spill out into the plasma. This causes a condition known as haemolysis and a type of anaemia called autoimmune haemolytic anaemia."

As you mentioned, with CLL and the often associated swollen spleen and impacted bone marrow, how can we tell whether a drop in red blood cells is due to less being made in the bone marrow, more being removed in an enlarged spleen or due to our immune system getting confused and attacking our red blood cells? So now I know that a Coombs test or Direct Antiglobulin Test (DAT) is used to check if a patient’s red blood cells are coated with the red blood cell autoantibodies that lead to their destruction.

It must be encouraging to know you are being looked after by a knowledgeable team that correctly diagnosed what treatment you needed and that your CLL hasn't progressed.

I'll have to remember to ask my haematologist about the policy for Coombs testing in Australia as I'm pretty sure I haven't had that done. It may only be done when the red blood cell count begins to fall to concerning levels.

Thanks,

Neil

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Thanks - I think re reaction to steroids, I have been lucky: only minor reactions and I am not going to complain!

My understanding is the reticulocytes (baby red blood cells in marrow) is a measure of red cell production in the bone marrow. Mine went to well over 5 before steroids, but is now down to almost 1.6ish (0.5 to 2.5 being normal). I am given number as part of the standard blood test results.

So if haemoglobin/red cells reducing and reticulocytes not increasing to compensate, I guess that is a sign bone marrow is not in great shape.

However, as you say it is hard to distinguish red cell destruction/production causes, as a lot of variables. I guess that is why we have specialist doctors!

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I've noticed that as my red blood cell count has dropped with the progression of my CLL, my haemoglobin levels have climbed, compensating somewhat. This has finally caused my Mean Corpuscular Haemoglobin (MCH) reading to go out of the normal range in my last blood test. MCH measures the amount of haemoglobin in an average red blood cell and is a derived figure from dividing the haemoglobin reading by the red blood cell count.

I'll have to ask my haematologist if this MCH rise is typical with falling red blood cell counts.

It is pretty amazing what information they can garner from a few measurements and ratios.

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I have not heard of MCH before...ah....another thing to research.

How are your reticuloytes....if they are holding up, production is good. Hope it is

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I'm assuming you had a specific test for your reticulocyte levels due to your haematologist's concern at falling red blood cell levels? They aren't on the standard panel of tests I have done.

Anyway, thanks for your concern. I trust you are going well weaning yourself off the steroids. Thanks for sharing about the potential side effects - and thanks also for the tip on how to justify a Ferrari purchase for anyone prescribed steroids!!

PS I've edited down the tags - can't have MartyR complaining about unfair competition! ;)

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Reticulocytes are just amongst my standard blood test outputs. I always just thought it was thus standard, as no I understand what they are, it seems an obvious thing to measure/keep track of for CLL patients. I will ask at end of month when I next go.

Thinking about it, I have missed my opportunity to buy those very expensive golf clubs! Blast! School boy error.....etc

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Checked this with my haematologist today and it isn't unusual for those with CLL to see a higher MCH as the body compensates for a lower red blood cell count.

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is MCH the reticulocytes? The upside of higher reticuloytes is that the bone marrow is in good shape.....so any CLL has not got to is yet.

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Quarry,

Blood cells, which all have their origin from a pluripotent haemopoietic stem cell, are derived from either the lymphoid or myeloid line, with red blood cells (also called erythrocytes) coming from the latter.

Your body makes about 2 million red blood cells a second in a process called erythropoiesis in which the red blood cells go through a number of development states lasting a week, with the second to last stage being reticulocytes.

en.wikipedia.org/wiki/Eryth...

MCH (Mean Corpuscular Hemoglobin), measures the amount of hemoglobin in an average red blood cell - it's just a ratio.

To calculate it, you just divide the haemoglobin value by the red blood cell count.

Neil

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Asked my haematologist today about DAT testing and that is only done as part of an investigation into the cause of an abnormal haemoglobin result.

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Interesting. And looking back, I suspect my whole CLL diagnosis process was triggered by my AIHA (which manifested as low haemoglobin, so abnormal) which is why I was sent to GP in first place!

So I also had a DAT test during diagnosis because of the low haemoglobin (though I did not know at the time) - and one that came out positive, so showing high risk indicator of AIHA

Live and learn!

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Hey Andy & Neil,

Well you certainly smashed my record of "tags" ! I counted 33

But seriously, I enjoyed reading your explanation in clear and understandable words.

It like recently I had to evaluate the options for treatment - and Idelalisib was mentioned. On the interweb you can find the following:-

" Isoform-selective PI3K (phosphatidylinositol 3-kinase) inhibitor. CAL-101 inhibits class I isoform p110 delta (p110δ), which is one of the mediators of activation of the PI3K pathway and is expressed at high levels by hematopoietic cells, particularly leukocytes. Disruption of the various pathways regulated by PI3K is hypothesized to have therapeutic applications by affecting cellular metabolism, growth, oncogenesis, and survival."

BUT when my haematologist explained that Idelalisib "squeezed" the lymphocyte nodes and pushed the lymphocyte out in my blood stream for the B + R chemo to attack and destroy - I could relate this to my blood test results.

Nearly overnight my Lymphocyte level in my blood tripled and my nodes in neck, spleen and groin were much softer & smaller!

I guess too many patients accept their condition and don't really understand what the doctor is saying - just put their trust in him / her.

I have always maintained that it is "my body" and I want to know what is going on inside AND what the treatments will be doing.

IF you don't ask or question - most doctors won't volunteer the answers!

Have a great weekend,

Marty

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Thanks Guys for sharing in a clear and precise way that even I understand. Gradually accumulating knowledge, and agree as time goes on I will want to understand what is, or may happen to me. Organising all the information has me severely challenged, so many similar symptoms, so many different illnesses linked to CLL.

Good job this is a trek and not a sprint.

Thank you.

Bub

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Bub - I agree on trying to understand CLL......8 months in and I feel I might just have a grip of W&W issues/blood tests......I have not yet dared to enter into the realm of understanding CLL treatments!

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Good afternoon quarry

I have just read your report on AIHA very useful and informative. I would be interested to know what symptoms you have experienced with steroids and what level you have been taking them for what period. I have just finished three weeks starting with twenty per day and reducing to five in the last week which has pushed my level up to eleven, it was prescribed with folic acid and I have to say I did not experience any side effects. My AIHA was diagnosed when testing before treatment which starts on Monday, I have opted for an Ibrutinib trial in the UK. After eight years of W & W with my white count gradually increasing to 200 it was decided that it was time for treatment, I believe the trigger is 200 WBC, 10 haemoglobin, and 10 platelet. My only symptom has been a little fatigue in the last two months.I had a prognostic marker of 13q but tests for treatment ( bone marrow biopsy, ouch! ) showed that my bone marrow was beginning to fail.

At the end of the day we can all learn what we must about our conditions and from what I have read they vary considerably, but there comes a time when we must choose the best CLL specialist we can find and put our trust and lives in their hands.

Berrytog ( It still does not stop the worry!! )

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Good morning Berrytog - you obviously know more about your CLL than I do and I hope treatment goes well.

On AIHA, I appear to be following UK's BMJ guidelines (it is beyond me to put in a link/attach doc, but Neil, if you are reading this, you have succeeded before...), for which pp 554 and 555 are relevant (it does not start at p1!). The guidelines appear to say treat AIHA before undertaking any CLL treatment. If 20mg/day for 3 weeks is what you had, your dose feels lightweight unless you are a quarter of my body-mass (unlikely). However, no CLL path (disease and so treatment) is the same....one of our trials. However, worth asking why you had so little. Perhaps your CLL treatment is complementary.

I was pure AIHA treatment. Guidelines say 1mg/kg/day for 6 weeks. So I was on 80mg/day for the 6 weeks, then to wean off reducing by 10mg/day a week. So a week each on 70mg/day, 60mg/day.....10 mg/day and then 5 mg/day (where I currently am) and finally 5 mg every other day for a week. Overall 15 weeks or so in total.

As to side-effects - nothing compared to the horrors the accompany the tablets. I was buzzing for about 3 weeks and found sleep very difficult (I tried herbal sleep tablets, but don't think they did anything). Eventually my body adjusted and I slept ok even at the high doses.

I have got some spots, bizarrely I think getting worse as I come off them - however, I am sure temporary

I also think I am more easily irritated, so have to be careful not to snap at the kids. However, I think I have been ok at that. Occasional very short-term highs and lows.

So overall I am not complaining given what they have done - just hope it lasts!

Good luck in your treatment!

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Quarry,

I think the link below is what you are after; it is a stand alone extract so the numbering is different. Pages 13 to 15 cover AIHA and other autoimmune complications in CLL.

onlinelibrary.wiley.com/doi...

Neil

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Thanks Neil - that is the one.

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Just noticed your comment on folic acid (my haemoglobin was 11 at AIHA treatment: plateletes around 110 and lymphosite doubling time well over a year (until all white cells increased by steroids: doubling time was not much more than a month, but this is entirely due to steroids and I can now see lymphocytes dropping as I come off them) - so this is why my CLL currently stable and I am pure AIHA

My haematologist recommends folic acid (and green tea tablets) as standard. I have been taking these since diagnosed in Jan - there is some evidence the green tea inhibits CLL progression and I think the folic acid is a vitamin used in red cell production. Red cell production in my case needed to replace those destroyed by AIHA, but also good anyway for CLL. However, I have been taking both folic acid (prescribed) and green tea tables since CLL diagnosis

So the folic acid is nothing to do with stopping AIHA, but will help raise red cell production to compensate their destruction caused by the AIHA.

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Good evening Quarry

Just back from hospital, a long day,took my first dose of Ibrutinab at 4.30 pm this afternoon, so far so good. My WBc had dropped from 350 to 200 having stopped steroids on Friday, my other levels were acceptable for treatment to begin. Although my spleen was at four centimetres and lymph nodes normal my bone marrow, I think, is why they decided to treat and I did not want to miss the opportunity of the Ibrutinib trial that my CLL specialist thinks is the bee's knees as does Dr. Brian Koffman from Oregon whose blogs are well worth a read in understanding our condition, he has had various failed treatment including a bone marrow transplant and now he swears by Ibrutinib for it's successes and very low side effects. As a matter of interest talking to my trial doctor two things came out of our conversation that I was not aware of., steroids can produce aggression and irritability and many CLL patients complain of watering eyes.

I hope your AIHA remains under control and your CLL does not progress, there are other remedies for AIHA than spleen removal.

Berrytog

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good luck with your treatment - hope all continues well. I am lucky so far, in that my bone marrow appears to be v healthy, so don't yet need CLL treatment.

Yes on steroid side-effects. I was warned that you can get v depressed (even suicidal) or manic (go buy a Ferrari) or irritable/aggressive. Mercifully, I really had none of these. I am not sure percentage of people that get these side-effects.

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Hi Quarry,

Just read your post from four years ago.....I hope this stream is still active. Can you offer any suggestions to my case so that I can ask better questions at my next doctor`s appointment in February.

Quick history. Recommended for treatment December 2016. The erythrocytes failed first and I have been on two weekly blood transfusions since then. Began treatment on a six month trial with twinned Rituxamab and Venetoclax. The Rituxamab brought down the WBC to normal levels, but due to side-effects the Venetoclax was stopped. Bone Marrow Biopsy - 70% infiltrated, minimal reticulocyte recovery, but the blood red cells were healthy. Started Obrutinib in September, no change. Prednisone, 20mg, prescribed for anti-bodies. I also take Exjade to reduce ferritin from blood transfusions.

Questions!

Do I have AIHA or are the antibodies from the blood transfusions? After reading your post I note these differences: i) my haemoglobin drops consistently and, in the absence of my own erythrocyte production, is boosted by blood transfusions. ii) there is no discernible rise in reticulocytes, 0.1, not measurable, or highest 0.26. iii) WBC counts have risen to just above normal ranges. iv) I assume my steroid dose, 20mg, is not high.

After an initial success in the reduction of WBC count, my treatment has been stuck for about 8 months. I remain blood transfusion dependent because I do not produce erythrocytes and as far as I can work out this is likely to continue. Do you have any suggestions about what I can ask the CLL specialist about the next steps and options, if any?

I'm sorry that you have been through so much, but I appreciate that you may be able to offer the benefits of your experience.

Best wishes,

Peter

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Peter

Not sure I can be much help, as I am not sure you are looking at AIHA. Do you know why you HB is dropping?

In AIHA, the reds are taken out by the spleen (hence drop) and reticulocytes (baby reds) should go up, as you are manufacturing more to compensate for the mass destruction of the mature ones. I guess if your bone marrow full of CLL cells, you can't make more reds, so reticulocytes manufacture can't happen.

Steroid dose give depends upon weight, but your dose is not what I would expect - so yes low - I think for full AIHA treatment it is 1mg/kg for first 6 weeks...I doubt you weigh 20kg!!

So my suspicion is your HB is dropping for a non-AIHA-related reason. But key question to ask is why is it dropping?

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Hi Quarry,

Thanks for your helpful answer. I will ask the doctor where my antibodies come from. From what you say and have written, it is unlikely to be AIHA.

As I understand it, my dropping Haemoglobin is due to the inability of the reticulocytes and erythrocytes to reproduce in the infiltrated bone marrow.

Not only is my body stuck but I am stuck. In November the doctor unexpectedly gave me an appointment 3 months away in February, though I come in for two weekly blood tests and blood transfusions. The endless waiting and hoping for something to happen, makes me think that there are few options for my treatment.

Best wishes

Peter

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Hi Andy, "Yes" your reply is very helpful. I do understand that AIHA course is independent from my CLL course. I see two separate hem/onc MDs(one at a major medical center in Boston, MA/USA, the other at a Veterans Administration(VA) Hospital)(I am receiving full medical coverage from the VA as it is felt that my CLL may have been triggered by Agent Orange exposure in Vietnam) who both feel that my decreased Hgb is caused by the AIHA, not the CLL. Both feel that although the AIHA complicates care that my CLL prognosis will not be affected. I am DAT positive. I am Rai Stage 0. Despite my low Hgb I am able to exercise aggressively, which I do at a local rowing club. I will continue to W&W, see the two MDs alternating every three months, eat well, exercise often and hope for the best. Thank you for your quick reply. MARK

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Mark - it looks like you are following my track - low-level CLL (a long way short of needing treatment) has triggered the AIHA. It sounds like at moment the AIHA also not at level treatment needed and enjoy the exercising! If things do deteriorate, rest assured there are treatments, so keep peace of mind!

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