Study On Why Nplate works on some and Promacta on others

www.haematologica.org/content/100/5/623


Immune thrombocytopenia: antiplatelet autoantibodies inhibit proplatelet formation by megakaryocytes and impair platelet production in vitro

Although most ITP samples tested responded similarly to both romiplostim and eltrombopag (either positively or negatively) (Figure 5) there was one, namely ITP7, which responded differently (responding to romiplostim but not to eltrombopag). This suggests that the response to TPO-R agonists may be determined by the nature/specificity of the autoantibody.

Nice find, Jay. This is an important article that, I think, we missed when it came out 1-1/2 years ago.

"After 5 days of treatment the number of proplatelet-bearing megakaryocytes was significantly decreased by 13 immune thrombocytopenia autoantibodies relative to the control group (P<0.0001) and this decrease was accompanied by a correspondin g reduction of platelet release."

This seems to contradict a recent study on an previous thread which seemed to state that there were two types of antiplatelet antibodies, one type of anti-TPO receptor antibody, and one type of anti-TPO antibody.

This study could be a good argument for some patients needing combination treatments using TPO-RAs along with immunosuppressant treatments, as certain antiplatelet antibodies appear to act on mega kartocytes to interfere with platelet formation.

I hope I will have more to say after I find time to get my teeth into the study.

Jay, that article looks like quite a challenge. Do you recall, does the author suggest a reason why some do not respond to (either) TPO agonist?

Hello HAl

To your question why they did not respond to both, I did not see any mention of this issue.

Main points out of this article-
1. Megakaryocyte numbers donot vary between persons with ITP and non ITP. BASICALLY BONE MARROW BIOPSY IS A USELESS PROCEDURE.

2. Pro Platlet Megakaryocytes (Megakaryocyte which produce platlets) are attacked by antibodies and lead to apoptosis.

3. Step 2 is actually prevented by TPO agonists (NPLATE or PROMACTA)

4. From the test results NPLATE is a better solution than Promacta because more antibodies respond to NPLATE.

5. Like you have pointed out there are some antibodies which donot respond to both.

6. Iam going to get into trouble with No Surgery crowd but except for 2 samples with very low platlets other samples with splenectomy have very decent platlet numbers.

Two main charts to ponder over-

Details of ITP Patients-
www.haematologica.org/highwire/markup/65480/expansion?width=1000&height=500&iframe=true&postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed

Nplate vs Promacta
dsas9a9gxtv2e.cloudfront.net/content/haematol/100/5/623/F5.large.jpg?width=800&height=600&carousel=1

Two quick comments.
1. Your #1 is an excellent observation. I've been trying to say this for years because many doctors keep insisting that patients do not have production problems if the BMB results are normal. The biopsies can be useful when a patient is over the age of 60 or when other labs are abnormal to rule out other causes (as written in the diagnostic protocol).
2. Your #6 (as you might have expected) could have flawed results. Did the patient try N-Plate prior to splenectomy? If not, the numbers may have been decent prior to surgery. Also, do they mention the patients who experienced thrombosis as a result of the combination? I have seen enough of that here to make my head spin, even in very young patients (20's).

jayinchicago wrote: BASICALLY BONE MARROW BIOPSY IS A USELESS PROCEDURE.

Diagnosis of ITP is a process of exclusion and the biopsy excludes the more serious condition of myelodysplastic syndrome. Some of the treatments for ITP can make this serious condition worse. Biopsy - generally only done on people over 60.

"MDS can affect people of any age, but is most common in people aged 65-70 years. Only one in five people with MDS are younger than 50."

Interesting about the Bone Marrow Biopsy! I've been to three top hematologists in the San Francisco area and all 3 told me that a Bone Marrow Biopsy was not needed. They said they could diagnose ITP from a CBC. So I've never had a BMB.
This is a quote from the American Cancer Society website that explains some of the problems seen in the CBC when a person has myelodysplastic syndrome. Its not just low platelets--
Patients with MDS often have too few red blood cells. They may have shortages of white blood cells and blood platelets as well. Patients with RAEB (refractory anemia with excess blasts) may have a small number of myeloblasts in the blood. Blasts are very early cells that are produced by bone marrow stem cells and are normally only found in bone marrow. When blasts are present in the blood it is always abnormal and often signals a bone marrow problem. Blood cells from MDS patients may also have certain abnormalities in size, shape, or other features that can be seen under the microscope.

Blood abnormalities may suggest MDS, but the doctor cannot make an exact diagnosis without examining a sample of bone marrow cells.

What you all are saying about MDS is consistent with my hema comments. She said usually you see abnormalities at least occasionally in CBCs when one has MDS. She had seen enough of my CBCs to say that she didn't think I had MDS - without ever doing a bone biopsy.

As I recall, one (black box) warning on Promacta is that it could make MDS worse - thus suggesting exclusion of that condition before taking.

Ok Jay, thanks for the response. Still working on digesting the study. I did come across this paragraph. I think it answers my question, LOL, but I'm not sure.
"
On examination of bone marrow from ITP patients, Barsam et al. found that both responders and non-responders to treatment with eltrombopag, a thrombopoietin receptor (TPO-R) agonist, showed a boost in MK proliferation without, however, the expected increase in platelet production in the non-responders.13 These observations may be explained by failure of eltrombopag to counter the antibody-induced defective proplatelet production in non-responding patients, suggesting that antiplatelet autoantibodies can have a direct, deleterious effect not only on MK production and maturation, but also on their crucial capacity to form proplatelets and consequently on platelet production.
"
What do you think Jay? I wonder if the author(s) didn't know about TPO Receptor antibodies (reference Rob's 4 antibody ITP cause earlier post). I think the existence of TPO Receptor antibodies alone would account for the author's 'observations' in the above paragraph.

If I've got things right so far, then back to your original post on this thread. Why did patient ITP7 happen? Can variants ('nature/specificity') in the TPO Receptor antibodies explain ITP7's response? I think the receptor is CD110.
en.wikipedia.org/wiki/Thrombopoietin_receptor

I dunno, can there be variants to CD110 ?
Is it possible that a polyclonal antibody, instead of a monoclonal antibody, would be a variant of CD110 ?

jayinchicago wrote

6. I am going to get into trouble with No Surgery crowd but except for 2 samples with very low platlets other samples with splenectomy have very decent platlet numbers.

This may be so but we know nothing about these patients i.e. age , previous treatments, length of time post splenectomy and, as Sandi rightly pointed out, post splenectomy complications.

There were 5 asplenic patients in the trial therefore for 40% of them the operation was a failure.

Hello Hal,
You are bringing up very good points.
Didnt the authors not know about TPO receptor antibodies?
One theory is if they include these antibodies is it possible that conclusions are totally wrong so they ignore them?

It looks like the ITP researchers are clumped into multiple camps-
1. Platelet Antibody Destruction Issue followers.
2.T Cell Cytotoxicity.
3. Production Issues (MK destruction with traditional antibodies)
4. Newly formed Theories (TPO Antibodies, TPO receptor Anti bodies ) etc.

There is no body who is forming a holistic view of everything because all these guys want to publish papers or sell drugs.

jayinchicago wrote: There is no body who is forming a holistic view of everything because all these guys want to publish papers or sell drugs.

You got that right. I have been researching the toxic affects of mercury and aluminum on the body. There is something to it. Watch "Trace Amounts" on Youtube. It is a fantastic documentary. I'm looking into mercury detox now...I have many fillings from years of steroids.

Must be reading a lot of published studies Jay to come up with those groups. Let me ask you something. Have you ever seen a published study revised years later - which cleaned up erroneous speculations? Seems it's left up to the reader to filter out failed notions. I wonder if we had studied this subject for years we would be better equipped to see the evolution of ideas - which failed and which succeeded. That study Rob had was published just last month.

Sandi, I watched the whole video. I know of the subject but don't keep current. Just off hand, I thought some of it had been debunked. Something like, if vaccinations are spread out over time the issue (some people are sensitive) vastly diminishes?

I think you will find that one way to (help) detox metals is to eat eggs. That was music to my ears when I heard that because I've been eating 3 eggs for breakfast a long time, and still do. I love ham and eggs. Are eggs still considered good for metals detox?

In the movie, they demonstrated that mercury can damage neurons in the brain. The damage cannot be reversed, so spreading them out wouldn't help if the damage is already done. Babies and young children are hit with many vaccines in a short period of time, so if they think sensitivities are diminished by spreading vaccines out, then why aren't they doing that?

I thought the movie discussed not only vaccines, but the constant onslaught of mercury exposure that people experience. When you take all of that into account, it adds up to a lot of exposure. I cannot attribute my health issues to vaccines. I only had three when I was little and one tetanus vaccine about six years ago. I do have a lot of fillings that are frequently replaced. I may have to start requesting the white fillings. They are expensive though! I have not read anything about eggs and mercury detox. Cilantro, Alpha Lipoic Acid, Selenium, etc....

Yes, they did show damage to (snail?) nerve cells. But wasn't that in a petri dish? Then there is the issue of crossing the blood-brain barrier. I have forgotten if they made mention of that issue or not. Can the (methyl?) mercury cross that barrier? If methyl mercury is anything like the tuna and mercury issue, as far as I know, the mercury ends up being deposited in body tissues.

As the video pointed out, not every child who receives vaccinations develops symptoms. The issue is that some are more sensitive to the mercury than others. The debunking that I heard was something like spreading the vaccines out over time is enough so that those with mercury sensitivity do not develop symptoms - like others. I dunno though. Don't keep up with it all. Just presumed that pediatricians are doing that now...

A quick Goo-Foo search of 'chelation therapy eggs' brought up this article - which talks about the amino acids in eggs are good for removing metals from the body.
naturalsociety.com/6-foods-natural-heavy-metal-chelation/

Do you take Alpha Lipoic Acid or Selenium supplements? Before ITP diagnoses, I had been taking one selenium tablet once a week - for many years.

They debunk everything that has to do with vaccines. I'm not going on a tirade about it now, but I will say that we cannot deny the rise in autism, ADD, neurological disorders, early onset dementia, Alzheimers, etc. We have become complacent and accept it as normal. It's not. Ingesting mercury and injecting it are two very different things. They will admit that eating it is harmful...hmmmm.
I took Alpha Lipoic Acid years ago, but stopped. I just ordered some of that and some Selenium which came in today, so I'm going to start it.

And oh, I forgot. There are studies that show that those with the MTHFR gene mutation tend to have more complications after vaccines. You asked why some people react and some do not. One possible reason:

www.ncbi.nlm.nih.gov/pmc/articles/PMC2746083/
www.jpands.org/vol9no4/boris.pdf

Two others since you appear to have interest:

livelovefruit.com/synergistic-toxicity-and-vaccine-safety/
info.cmsri.org/the-driven-researcher-blog/vaccine-molecular-mechanisms

I see from reading those links that methyl mercury does indeed cross the blood-brain barrier. Not good. I looked up methyl mercury on Wikipedia. This sentence was interesting.
"
Recent evidence suggests that the developmental and cardiovascular toxicity of methylmercury may be mitigated by co-exposures to omega-3 fatty acids and perhaps selenium, both found in fish and elsewhere [26][27][28][29][30]
"
Used to eat fish 5 days a week. If counts ever get back to normal will go back to that. Fish diet also was very good for lowering cholesterol levels too.

All this mercury and autism issues is more 'terrifying' to me than 'normal' these days. I do what I can with diet - selenium and fish. Ruled out taking Alpha Lipoic acid in the past. Don't remember why.

Let me guess. Your son having kids soon has got you wound up in regards to this subject. Yes?

Ha, actually it's my daughter. She is a nurse and is forced to get the flu vaccine every year. She has an autoimmune disorder and those shots bother me. She agrees about vaccine dangers but there isn't anything she can do other than change professions. My son also agrees, so I'm not that worried about their kids yet. However, I've heard stories about parents saying no to the Hep B after birth and the hospitals take the baby and do it anyway. That's scary.

You have to watch fish eating too; fish can contain mercury.

Would you know? Is it possible the drug companies can produce vaccinations without thimerosal preservative in them? Vaccines with limited shelf life? Offer them at additional cost for those that prefer that option?

Is it the amino acids in fish that seem to be able to transport mercury both to and from us? It's been a while since I've looked into this subject. As I recall bottom feeding fish, like catfish, should be avoided due to mercury. That the problem with Tuna is that they eat other smaller fish. I think some fish are ok to eat because of what the fish eats. I eat salmon but I think white fish and perch are good ones too.

LOL, tell your daughter she must eat eggs, selenium, and other metals detox stuff after a vaccine.