High Platelet Levels and Chronic Pain?

[calico]

I'm trying to determine if there may be a connection between high platelet levels and chronic pain. Chronic inflammation (among other things) activates the immune system response which causes the production of cytokines which causes the production of thrombopoietin which causes an abnormal elevation of platelets.

Anybody have any of their lab tests hanging around they could check?

Thanks!

Calico

[dejerine]

Dear Calico,

When a neuroscientist see the word, "cytokines' he or she thinks "acid" because cytokines are part of the group of acid causing cascades like bradykinin, prostaglandin, and of course, arachidonic acid. Of equal interest are the peculiar "heat shock proteins" which lurk around in the background and which may turn out to be the discovery of the century as relates to atherosclerosis. You can bet platelets get involved wherever cytokines are excited, and cytokines ARE upped in CP; however, the affect may be on a local level and may not be picked up in the lab study of blood circulating in the body. I am not aware of any CP patient who has increased platelet count, but remember the range of normal is huge and slight increases might have been overlooked. Good question. you might like to read "People of the Acid" at painonline.org, if you have not already done so.

[calico]

Dear Dejerene,

Thanks for your reminder about the "People of the Acid" article and your comments about cytokines being acids! I had read the article awhile back and really related to it, but hadn't put it together with the platelet issue.

A friend gave me a very good article about cytokine research from the July 2001, 54th Edition newsletter of the "Fibromalgia Network". I haven't been able to find a link to this article on-line, but this is an article link that gives good information about cytokines, too:

http://www.immunesupport.com/library/showarticle.cfm/ID/3748/e/1/T/CFIDS_FM/

The fibro newsletter article I have talks about the research of Linda Watkins, PhD and Dr. Daniel Wallace, MD in the context of documenting fibromyalgia, but it seemed like it could be just as applicable to spinal cord injury given that they list triggers/aggravants of cytokine production as being physical trauma (neck whiplash, back injury, nerve injury, and tissue inflammation specifically).

I have another article discussing the reactive increase in platelets caused by an increase in cytokines such as tumor necrosis factor (TNF), interleukin-1 and interleukin-6 (IL-1 and IL-6). This article says that "more than 80% of patients with (reactive platelet increase) have elevated serum levels of IL-6". This makes it sound like you can measure at least IL-6 in testing. However, the Fibro Network article says IL-1 and IL-6 aren't elevated in fibro patients and TNF can't be accurately measured once it mixes with the blood. It goes on to say, though, that the work of Dr. Wallace shows that the level of an IL-1 receptor agonist, IL-1ra, is twice as high in fibro patients as in controls. So maybe IL-1ra levels are an indicator of chronic inflammation/pain.

I'm really hopeful that further research in this area will do two things: 1) come up with tests that can be used as objective evidence of chronic pain; and 2) lead to the development of substances to calm the cytokine beast and result in significant pain decreases. The newsletter says there are two drugs in clinical trials which cross the blood-brain barrier, work to block the action of pro-inflammatory cytokines, and suppress all types of pain that one would expect with the release of cytokines. I'll drink to that!

Calico

[dejerine]

Calico.

You are thinking GOOD. You have even picked the right cytokine, interleukin. Maybe some fancy platelet test WILL measure pain. Great idea on your part.

The cytokine interleukin was the acid Tarek Samad, of Clifford Woolf's group at Harvard, first found in the thalamus in neuropathic pain, to show that acidification was occuring at all three synapses, in the skin, in the cord, and in the thalamus. This copycat acidification was not known until Samad detected the interleukins in the thalamus.

Pain exciters are proteins. Chromosomes are long chains of many genes. Gene protein factories are governed by little switches in the chromosomes, known as proto-oncogenes. The proto-oncogene can be burned out by overfiring, as in prolonged pain, so the pain exciter production starts running out of control, ie when the rest of the system fails, the default mode of genes is to pour the pain chemicals out. That is called Central Pain.

The theory is that genes which regulate production of mitogen activated protein kinase are upregulated (turned higher), ERK1 ERK2 are part of this cascade. Protein kinase C is also involved. The kinases attach high energy phosphate bonds to the pain exciters, like the form of aspartate in the Central nervous system, namely N-methyl-d-aspartate, which is abbreviated NMDA, which everyone knows mediates long acting pain in the CNS.

Aspartate and glutamate are the two ACIDIC amino acids. Most other amino acids aren't really acids. The cytokines and also leukotrienes and other acidifiers are part of this process. Acids deform the shape of organic molecules (protein is an organic molecule, ie they contain Carbon) which are VERY sensitive to changes in pH. Neurotransmission is designed to operate properly only in a very narrow range of pH. (pH means how acidic the environment is)

The protein world is about SHAPE, more than chemical composition. Did you know that shape determines whether something tastes sweet to you. It has nothing to do with the chemical composition.

One of the theories expressed by McHenry (of the Wall/McHenry CP component grouping) is that the acification distorts the shape of the ion channels, G-proteins, peptides, kinases, and carriers, and alters their function.

Approaching the study of this at Stanford's shape lab, in response to McHenry's request, have reported that the receptor which links to NMDA is too large for their computer to handle mathematically, so we won't know about McHenry's shape theories until the computers get more powerful.

The bonding angles of the many atoms which make up the proteins must be calculated before shape can be derived and the molecules go through many rapid changes, like in a millionth of a second each,and huge Coulomb forces at each little part must be instantaneously recalculated for each step in the deformation to know what the shape would have to be, and there are many intermediate shapes before the final protein shape is reached. The final shape may not even be the one of interest and usually is not. For example, in the sodium pump, which moves sodium out of the neuron to create a voltage potential, there are FOUR major configuration steps, each of which has its role.

Interacting substances may only have effect if a certain intermediate shape is passed through. Unusual final shapes may be caught forever in their receptors and be unable to escape, like the little wire puzzles kids play with. Acids alter shape at all stages.

Deformation defects are already known to cause mad cow disease). The receptor must act for NMDA to act, and also for it to quit acting. Parkinson's disease is now known to result from proteins that get into the dopamine 2 receptor and stay locked inside it, eliminating that D2 receptor. Use of amphetamines locks or destroys the D2 receptor. With time there aren't enough D2 receptors left and we have Parkinson's.

McHenry felt the hypersensitization of CP was similarly locking up receptors mediating inhibition, as well as locking on Nav 1.3 ion channel production. Coull likes to call these steps in neurotransmitter function, "switches". You can be sure acids will affect switching, as well.

Now back to your cytokines. The events are at a very small scale and you are correct that by the time it gets out into the peripheral blood, effects have been diluted, like dumping a little acid in a big pot.

"People of the acid" at painonline.org, is still the best analysis of this whole thing in print.

In the end, acidic alteration of pathways of inhibition may be equally or of greater importance, but we await the Stanford bending studies, which are very big now that we know proteins are like bunches of strings in shape which go through tremendously complicated shape alterations as they do their job.

The kinases mentioned above are proteins, as are the building blocks of ion channels. The shape changes act sort of like micromachines, moving ions which create voltage gradients at the neuronal membrane along, as the protein strings wiggle and stretch and contract. In other words, structural proteins like ion channels actually move, but they must have a certain shape before atoms, like Na or K can move selectively through the tubules formed by these structural proteins.

A protein is defined as something with MORE than 200 amino acids making it, while peptides are things with LESS than 200 amino acids making it up. Many of the neurotransmitters in the CNS are peptides.

Glutamate is the big amino acid in the cord, and most of the drugs we use are directed against Glutamate, including the new pregabalin. Glutamate is the big actor in short acting pain. What we are looking for is drugs against aspartate, or rather against NMDA. Lidocaine blocks the action potentials which reach the NMDA globs in the nerve but as Haines article shows (see painonline.com) rats with CP have SO MANY sodium channels going that safe amounts of lidocaine won't reach severe CP. One look at the pictures in the 1 Oct Journal of Neuroscience to see the voltage gated Nav 1.3 ion channels in CP in the dorsal horn of the cord and you will realize what is going on inside you.

The little "v" in Nav stands for voltage gated. Na stands for sodium. Voltage gated means the channel is opened by a change in voltage (created by ions like Na, K, Cl, and Ca2+ on either side of the cell membrane, see review of chloride by Coull at painonline.com)

However, other ion channels are opened by ligands, (tying G-proteins, ligands) which bring the pain neurotransmitter to the channel and combine them to open the channel. This latter kind of ion channel is often said to be metabotrophic, meaning its production is linked to local activity in the area.

Now you can read PubMed to your heart's content, but don't over-logon, we need to leave a little access available for those people from the Florida Rehab Center who think all we need is nonsupportive spouses. What are they smoking? Those conveyors of ancient prejudices and misunderstanding of pain need to realize they need to do some more reading. Maybe we could hire them to act as "advocates" for patients in labor to replace the epidural. I hate it when back pain is used as a model for CP. It guarantees you will be kicked to the curb and I have watched too many people lose it all in the face of such treatment. I knew them and now I miss them.

We watch movies where aliens appear but no one believes the witnesses, and we think how can they be so dumb. That is how I feel about pain docs who don't get it that people who march off for brain surgery must have something wrong with them a nonsupportive spouse won't cure.

This chemistry will give you a headache, but you seem to want answers, so "you want it, you got it, Toyota".

Of course, if you believe that article which gave Wise pause (as well it should), all we need is neglect from our spouses and we can avoid this hard science and get better just sitting there being independent. What a load of crock. Those pain experts need to go get degrees in neurochemistry and stop badmouthing US, because THEY aren't helping us.

I will trade one Wise for a hundred of those nutty professors. Back pain is a universal in America, CP is not. What is there about this calculation they don't understand. I know they don't like yet another back pain person walking in the door, but this would be like a world food bank that shuts down entirely because some non needy people were there among the starving children.

We badly need some technique to measure pain, because right now too many peoople think it is all equal. This is like saying all numbers are equal because they are all numbers. Give me a break.

People get lost in words sometimes and fail to realize words are just code for something. Do we really have to go back to high school logic where we learned "Chevrolets are cars. This is a car. But that does not make it a Chevrolet". Back pain is NOT code for CP. Back pain is mechanical, whereas CP is a disorder of the pain transmission apparatus inside the nervous system.

The eskimos have 400 words for snow because their survival depends on it. It is time we got rid of the word "pain" at these clinics and became more precise because survival depends on it.

Let the back pain cynics set up one little kiosk for back pain, where the entire nation can go, and then and form another center for neuoropathy, where few must go, and where talk of the benefits of a nonsupportive spouse would be laughed to scorn.

As a starter I don't know anyone with back pain who has gone to Kevorkian but I know some with CP who have. That should provide even the hardest head with a CLUE. However, the hard heads are still getting published, while the thinkers live quiet lives in their lonely labs, doing the hard work of real research. Guess which group I admire most.

[This message was edited by dejerine on 10-06-03 at 02:14 AM.]

[Skye83]

Brief but partly relevant to this discussion. High positive EBV titers since 1985, with attendant fibromyalgia, profound fatigue, sore throat, swollen glands...diagnosed as depression until 1991. Further tests confirmed high ANA and nucleolar anti-nuclear Ab pattern. T8-10 ependymoma (tumor composed of ependymal cells lining the central canal of cord) diagnosed 1997 with subsequent resection. I have long wondered why the majority of my ependymoma cohorts don't seem to be as functionally debilitated from pain post-resection. I have wondered about my upregulated immune system since 1985 and have piles of abstracts around here on cytokines. I'm sorry this isn't specifically addressing platelet levels, calico. I don't believe I've had any levels outside the reference range on that one. But as far as the subject of cytokines, BINGO! If my IQ level hadn't taken such a dive this past yr, I'd get more specific. I still get flu-like symptoms out of the blue-I feel flu-like ABOVE the level of injury and the twisting, pulling, crushing pressure in my legs is constant. I've even wondered if I might not have MS. I wish I could participate further in this thread, but I cannot type anymore. I just had to put this information "out there." good discussion..

[calico]

Dejerene, you may understand the nuances of how this research could or is being done to document the differences between neuropathic/CPS pain and the garden variety inflammation related to increases in cytokines. As you mentioned earlier, cytokines are found with arteriosclerosis, and also arthritis and other maladies. Heck, it even said they rise after menopause. So I'm kind of bummed that they appear with so many problems. How then to tie them directly to chronic pain? I presume lots of people have high cytokines and don't have chronic pain.

You may have already explained this in your prior post and it went over my head. Maybe the work being done by Dr. Watkins on cytokines and fibromyalgia will offer some distinctions between cytokines types/levels in pain versus other inflammatory conditions such as that linked to arteriosclerosis. I guess if these tests existed already we'd have docs sending their patients for the tests to document pain in an "objective" way for disability insurers.

I just read that the NIH has proposed a new "road map" for medical research in the US, and one of the many initiatives is to find better ways of measuring pain.

As an aside, given that cytokines are acids and are kicked off by activity in the immune system, perhaps it's more than coincidental that we with CPS often describe the chemical burning feeling as one of the worst. For me, I have long said things like "I feel like my arms are painted with acid" and "I feel like I have the flu in my arms". One tries and tries to think of ways to describe these feelings but doctors still don't get it.

Calico

[This message was edited by calico on 10-05-03 at 11:07 AM.]

[Wise Young]

calico, I just did a literature search on the subject. There is nothing that I can find. It would be very difficult to do because platelet counts can be affected by medication and it would be really hard to tell whether elevated counts are due to pain medications, are due to the cause of the pain, or are themselves the cause of the pain. Wise.

[calico]

Hi, Dr. Wise, the article I read on Medscape was a study of 777 Saudi Arabian patients. The conclusions about why platelet counts were elevated ranged from chemotherapy (ah, a medication) to chronic inflammation. The authors were James L. Chen and Khosrow Afsari, MD.

Perhaps a more definitive list of what medications are known to cause platelet elevation would help. Any idea where one might find this?

Then there's the question that if platelet counts rise with certain medications, is there also a corresponding increase in cytokines or specific cytokine markers that are associated with inflammation? It would be great if there wasn't because then maybe we could tie the platelet rise back to something like inflammation vs the medication. But I guess life would be far too easy, then.

Calico



[QUOTE]Originally posted by Wise Young:

calico, I just did a literature search on the subject. There is nothing that I can find. It would be very difficult to do because platelet counts can be affected by medication and it would be really hard to tell whether elevated counts are due to pain medications, are due to the cause of the pain, or are themselves the cause of the pain. Wise.[/QUOTE

[Wise Young]

Essential thrombocythaemia is the name of the condition where platelet precursors are abnormally proliferative in the bone marrow.

http://dspace.dial.pipex.com/lrf-/diseases/et_book.htm

Because cytokines stimulate hematopoeisis (increased blood cell production) and thrombopoiesis (increase platelet production), chronic infection, inflammation, and even stress can increase platelet counts. I presume that this would include pain. Of course thrombopoietin and erythropoietin are hormones that stimulate thrombopoiesis and erythropoiesis respectively.

Thrombocytosis means increased platelet count from any cause. Normal platelet count is in the range of 150,000 to 450,000 per microliter of blood. Leukemia is of course the condition where one has a cancer of blood cells and it can be associated with high platelet counts. A variety of conditions cause secondary thrombocytosis:

http://www.emedicine.com/med/topic2267.htm

Secondary thrombocytosis may develop as a result of:

* acute hemorrhage or infection
* anemia
* arthritis and other chronic inflammations
* cancer
* exercise
* iron deficiency
* medication
* csteoporosis
* removal of the spleen (splenectomy)
* polycythemia vera (a disorder affecting other red blood cells, as well as platelets)
* stress
* surgery
Source (http://www.ehendrick.org/healthy/001352.htm#Causesandsymptoms)

Relatively few drugs cause thrombocytosis but they include miconazole (an anti-fungal) and possibly beta lactam antibiotics:

J Clin Pharm Ther. 1993 Feb;18(1):45-8. Related Articles, Links

Drug-induced thrombocytosis.

Frye JL, Thompson DF.

College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City 73117.

Thrombocytosis is generally defined as platelet counts greater than 400,000/mm3. Thrombocytosis can be either primary or secondary. Adrenalin was one of the first drugs noticed to cause platelet elevations, probably due to demargination of platelets in the pulmonary vasculature. Vinca alkaloids have the most convincing data to show that they can induce thrombocytosis through their thrombocyte-stimulating properties. Miconazole has been implicated in causing thrombocytosis and has a documented case validated by drug rechallenge. Iron, predictably, can cause a transient thrombocytosis. The beta-lactam antibiotic data are very difficult to interpret due to the possibility of an acute-phase reaction in an infected patient being the cause of the thrombocytosis.
Abstract Source (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=93232088)

[calico]

Thanks, Dr. Wise, that was a good link at emedicine. Is it fair to say then that hypothesizing that a high platelet count could be the result of chronic inflammation/pain would be a diagnosis of exclusion? In other words, if a person is tested for and not found to have any of the known causative conditions EXCEPT osteoarthritis/well-documented chronic pain lasting over a period of years, would it be too much of a stretch for a doctor to say that the arthritis/chronic pain (and in this situation, history of spinal stenosis) MAY be the cause of the high platelet count?

The emedicine write-up says that "the presence of elevated IL-1, IL-6, C-reactive protein, granulocyte-macrophage colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) . . . suggests that these cytokines may be involved in reactive thrombocytosis". Are these common tests that any lab can run and something I could ask my GP to do?

Thank you!

Calic

[Wise Young]

calico,

Yes, it is possible for a clinician to order tests of cytokine levels. It will probably be expensive and will require a fair amount of research to get the right testing laboratory to do it. I am not sure that it is worth it. What all the discussion suggests is that stress from the pain itself, in addition to a multitude of other causes, can cause thrombocytosis. If you should find that the cytokine levels are elevated, it is still not certain what the cause is. If this is what you have, however, it is important to rule out some treatable cause of thrombocytosis and to make sure that it does not signify that something else is going on. I think that should be the goal of the diagnostic tests.

Oh, by the way, one strong argument against the role of thrombocytosis being the cause of pain is that most people with thrombocytosis do not have pain and may not even be aware that they have it until their doctor tells them that they have increased platelet counts.

Wise.

[This message was edited by Wise Young on 10-07-03 at 01:58 PM.]

[calico]

Thanks, Dr. Wise, I promise not to let my physicians overlook other possible causes of my high platelet levels.

I don't think high platelet levels cause pain. I'm postulating that high cytokine levels may result in chronic pain and perhaps high platelet levels, but I understand that there doesn't seem to be a good way for modern medicine to make this connection in any sort of a definitive way, at least at this time.

Calico