can someone help me out?

Hi friends, 

I'm becoming a little concerned about my son's antibody.  This warm autoantibody has persisted for over two years now - we had hoped that it would disappear by now.  He has been on prednisone for 2 years now - and this is only keeping it under control such that he is transfused every 3 weeks.  If there is an illness, his hg will drop quicker. 

Does this mean that this antibody has become chronic and will persist or that it will be associated with a more globalized problem?  He looks well, and is very healthy.  His spleen is not enlarged and he looks and acts great. 

However, I am very concerned due to this antibody.   Some of the new avenues of research for thalassemia also suggest that they can help with autoimmune issues - autoimmune hemolysis (which is what my son has).  Is it possible that if he is cured of thalassemia, that he may also be cured of the autoimmune issue? 

I am comfortable with the thalassemia, and hopeful that the treatment will get better soon - but this autoimmune issue has left me very much afraid.  Can someone please help!  Thank you.

Sharmin

Hi Sharmin,

There aren't many treatments for hemolytic anemia other than prednisone and splenectomy and I don't think your son's condition is bad enough to be talking about splenectomy at this stage. Usually that won't be considered unless the spleen is quite enlarged and transfusion frequency is one week or less. Two things I did find are use of folic acid (what dose is your son taking daily?) and slowing down the rate as which blood is taken.

http://www.emedicine.com/med/topic979.htm

Administer packed RBCs slowly to avoid cardiac stress.
In autoimmune hemolytic anemia (AIHA), type matching and crossmatching may be difficult. Use the least incompatible blood if transfusions are indicated. The risk of acute hemolysis of transfused blood is high, but the degree is dependent on the rate of infusion. Slowly transfuse by administering half units of packed red cells to prevent rapid destruction of transfused blood.

I don't know if this has been tried yet but it does seem to slow down the destruction of transfused red blood cells.

I would also suggest vitamin E and low dose of vitamin C daily (100mg), as both make for healthier circulatory systems. Do not exceed 100 mg C for a child his age. Thals often totally avoid vitamin C but if taken between meals, it will not add to iron absorption and thals are universally deficient in C. Low doses daily are no danger and will help the vitamin C starved body.

Thank you Andy, I have had some anxiety over this issue for a while. 

My son is not on a folic acid supplement - what dose would be appropriate for him (his current weight is 25.5kg). 
He is also not on vitamin E - can you also suggest a dose?  He is on vitamin C - he gets 100mg with his desferal nightly. 

The doctor has told us that the antibody seems to be slowing down over time, which gives me some hope, but it has not gone away yet.  Apparently, hitting the body with intermittent high doses of prednisone can sometimes shut the antibody right down as well. 

In the meantime, I will mention to his doctor that maybe we can try to slow his transfusion rate down.  Currently, he gets 20cc/kg - at a rate of 90/hr.  He gets 1 and 3/4 bags of blood.  Maybe we can split the transfusion between 2 days or something to make it last longer - 1 unit every two weeks may last longer than almost 2 units every 3 weeks.   So far your ideas have made a big differnce - maybe this will help out too Andy. 

Who would have thought that a child with thal major would also develop hemolytic autoimmune anemia??  The doctor says that the two are completely unrelated - and perhaps someone who makes their own blood may not notice the small amount of hemolysis - but in a thalassemic - the transfused blood cells are being broken down - meanwhile the body is unable to replace them - resulting in an increased transfusion requirement.   

No matter how strong we try to be, I think some days we can get shaken up.  Especially when unexpected issues arise.  Hopefully, with our prayers - and the prayers of all of our friends on this site - this pesky antibody will go away soon.

Sharmin

I am sure Sharmin, that God will answer all our prayers and your heart will rest. I am praying for him and please try Andy's suggestions, i am sure they will make a difference. Please keep us informed

Manal

Thank you Manal, you are a great friend 

Andy's advice has helped us avert so many crisis in the past - i am sure it will help us overcome this roadblock too. 

Hi Sharmin,

I would suggest 1 mg folic acid daily. Adult thals are known to take 5-10 mg daily. 100-200 iu Natural complex vitamin E daily.

Although the autoantibody response is not directly related to thalassemia, it may be related to the transfusions. It has become apparent in recent years that the incidence of this in transfusing thals has been underestimated because of lack of data on the subject. As more data has been collected, the relationship has become more apparent.

http://asheducationbook.hematologylibrary.org/cgi/content/full/2006/1/13#R8

Association with blood transfusion
While alloantibody formation is a recognized and reasonably common complication of blood transfusion, the possibility of autoantibody formation has not been well recognized. Young et al analyzed over 2600 patients with a positive direct antiglobulin test or indirect antiglobulin test, and identified 41 patients who had both an autoanti-body and an alloantibody. About a third of them developed their autoantibody in close temporal association with alloimmunization following recent transfusion.7 Therefore, AIHA (Autoimmune hemolytic anemia) developed either concurrently or shortly after alloimmunization from blood transfusion. The authors conclude that AIHA is a potential complication of allogeneic red blood cell transfusions, and recommended supportive treatment with iron and erythropoietin analogues, avoiding further transfusion whenever possible. This complication of red blood cell transfusion may be more common than previously appreciated.8 It has also been noted in patients with hemoglobinopathies who have received multiple transfusions.9–11

A study from Oakland Children's Hospital published in 2000 investigated the immune response among those of Asian descent who received blood transfusions with the blood of predominantly white donors.

http://bloodjournal.hematologylibrary.org/cgi/content/full/96/10/3369

Alloimmunization and autoimmunization are common, serious complications in Asian thalassemia patients, who are affected by donor-recipient RBC antigen mismatch and immunological factors.

World wide, thalassemia is most prevalent in Asians, and due to large population movements, people of Asian descent constitute the majority of patients in many thalassemia centers in Western countries. However, there is very limited data on the RBC phenotypes among Asians, the extent of alloimmunization, and the role of phenotype differences between blood donors and recipients in forming antibodies.

We studied the frequency of alloimmunization and erythrocyte autoimmunization among thalassemia patients who received regular transfusions and in particular looked at the RBC phenotypes of Asians. We investigated factors possibly affecting the antibody formation: RBC phenotypic differences between the local donor pool and Asian recipients; patient- and blood-related immune factors; and preliminary findings of conformational changes of the transfused RBCs, which perhaps trigger antibody response.

The association of thalassemia and erythrocyte autoantibodies has not been studied. The true frequency and the clinical spectrum are unknown.1 We found a high frequency (25%) of autoantibody formation, mostly IgG warm antibodies, of which 18% had a significant clinical hemolysis. The antibody development was associated with alloimmunization, exposure to nonleukoreduced blood, and absence of spleen

Our data show altered RBC deformability profiles, more so in patients without spleen than in patients with spleen (Figure 1). These findings are consistent with senescent erythrocytes and may expose new antigens and promote or enhance an immune reaction, as known to occur in aging and impaired RBCs.26,27 It is likely that the absence of an efficient filtering system for removal of damaged erythrocytes enhances the process. In accordance with this hypothesis, a previous study showed increased hemolytic autoantibody response in mice without spleen compared to mice with spleen and a spleen role in regulating this response.28

In summary, our data show that alloimmunization to minor erythrocyte antigens and erythrocyte autoimmunization, of variable clinical significance, are frequent findings in transfused thalassemia patients. The causes are not fully understood; however, data suggest that the recipient's immune status, along with the effects of multiple allogeneic blood transfusions, can induce antibody formation. We found an association with the absence of spleen and the presence of deformed ex-vivo RBCs that probably augments these mechanisms. The difference in the RBC antigen profile between the predominantly white donor population and the Asian recipients likely further contributes to the phenomena.

With the growing knowledge base of the immune effects of current blood transfusions23,24 and limited data on the immune status of thalassemia patients, a large study addressing the complex interaction of these factors is needed. Such information may enable understanding and prevention of this serious and common complication. In clinical and transfusion practice, when considering splenectomy, a potential higher risk for future RBC immunization should also be taken into account. We recommend obtaining a RBC antigen phenotype on all thalassemia patients, particularly of Asian ethnicity, who are started on transfusions, and if feasible, providing leukodepleted blood matched for antigens of the ABO-D and Kell systems. Recruitment of Asian blood bank donors, just like recruitment of black donors for SCD patients, can increase the availability of compatible blood for thalassemia patients, who have a life-long transfusion-dependent disease.

An important note from this discussion is that splenectomy may actually make the autoantibody problem more likely and worse.

Although your son's transfusion requirements increased, they are not in any way, out of control. I agree that this will probably pass with prednisone use and that a temporary higher dose may clear it up. I think it would be preferable to knock it out with a high dose and eventually withdraw the prednisone, than continue long term use of prednisone. There is a very high percentage of this reaction going into remission in patients using prednisone. If there is a later recurrence, prednisone therapy is resumed. A very positive note is the lack of any visible effects on your son's health. He looks really good in the pics. 

Wow Andy,
thank you so much - I am absolutely blown away by all of your research.  You are so resourceful! 

I have learned more from your message than I have been able to learn over the past two years!  This knowledge has the potential to change our approach to his treatment - once we discuss it with his doctor.  His doctor is absolutely wonderful, once he learns all of this I am sure he will be happy to take this approach. 
 

Sharmin

Sharmin,

This has been a real challenge and as you can see from the discussion, far more work needs to be done to study patients and these immune system responses. Dr Vichinsky has been at the forefront of putting this knowledge into practice with more specific blood matching and I wasn't surprised to see his name on this article. The doctors on the west coast have seen more of the new generation of Asian thals and are making every attempt to deal with the new problems that arise in treatment and awareness. I would suggest a consultation with Dr Vichinsky at some point, if at all possible.

Hi Sharmin,

I hope everything will become smooth and easy for you and your son,give my love to little mr handsome 

ZAINI.

Andy

I thought that the benefits of folic acid is only restricted to the formation of the blood ( it prolongs its life span and increase the red blood cells count ) , so how is it going to have the same effect on the ''already made blood'' i.e transfused blood?
By the way Ahmad takes 5mg folic acid daily

Manal

Thank you Zaini, Manal and Andy 

I actually have good news - my son was transfused last Tuesday - and the doctor did a post transfusion hg which was 118 (because he was very low to begin with). 

He had us do another one today because he wanted to see if the large drop last week was due to the fever and illness or if it was because of the antibody going crazy again.  The blood test today revealed that his hg is 117! So his transfusion tomorrow will probably be postponed.   

Even if there was a degree of error - in the post transfusion hg or this one - there does not appear to be a lot of antibody activity going on!  I hope that things continue to go well.  Look my friends, your prayers were heard over night!  I'll keep you all posted - when we we check again next week. 

Sharmin

Sharmin,

That is a big relief! If his Hb has maintained at the same level for a week after transfusion, slowing down the transfusion rate may not be needed. The effect of slowing the blood is to decrease the immediate breakdown of RBC's that can occur on autoimmune hemolytic anemia. This also has me thinking that his drop in Hb may not be related to the AIHA and more likely just a result of illness.

Thank you Andy,  it has been a great relief.  We will be testing his hg on Sunday and transfusing him on Monday.  I am glad that things are going well so far.  He does tend to drop rather quickly nearing the end of his 3 weeks - I am wondering whether it may be a good idea to spit his transfusion up so that he receives a unit every two weeks - using a slower rate - rather than getting the entire amount every 3 weeks.  It may maintain him better and he may be getting less blood over time. 

Hi Manal,

The answer about folic acid is in the same article at http://www.emedicine.com/med/topic979.htm

Administer folic acid because active hemolysis may consume folate and cause megaloblastosis (abnormally large nucleated red blood cells).

Almost all thal majors are deficient in folate because the excessive hemolysis needs more than is being supplied. This increases with the hemolysis, and increases the need for folic acid. One other thing I want to note is that I keeping seeing mention of masked vitamin B-12 deficiency in thals. B complex should really be considered to help counter the daily physical stresses of thalassemia.

Sharmin,

I have always wondered about this issue since some thals transfuse monthly and others twice monthly. Since the transfused blood begins to break down so quickly, it does seem that twice monthly would be more efficient and patients wouldn't tire so much when it's close to their transfusion date. Talk to your doctor and see what he says. I think one reason some take blood only once monthly is for time considerations; accommodating school or work schedules, etc.

Andy,

you are right, it would be easier on thals to transfuse twice a month.  I wonder if it is to avoid exposing the patient to fewer donors over time - 12 a year rather than 24. 

I know of some thals who transfuse biweekly - because it fits in with their work schedules better than taking a day off of work each month.  I think I may prefer this for my son - it should work especially well in his situation. 

Sharmin