Red Blood Cell Shape and Function

[Merida]

in 1989 researcher Leslie O Simpson published research that ME patients exhibited marked morphological abnormalities in their red blood cells. ( Nondiscocytic erythrocytes in myalgic encephalomyelitis. N Z Med J 102( 864) : 126-127. 1989) ME patients had a significantly lower per cent of the 'ideal' disc-shaped red blood cells, and a higher per cent of cup-shaped ( and other shaped ) red cells. The non-disc shaped cells have a more difficult time traveling through capillary beds, as they are less flexible. Thus, the ability to deliver oxygen to cells and remove metabolic waste is compromised.

This research was referred to in a classic work, edited by I. Jon Russell, MD, PhD., The Fibromyalgia Syndrome: A Clinical Case Definition for Practitioners, 2003. There was also personal communication with Dr. Simpson.

Dr. Simpson comments that when ME patients felt better, they had a higher percent of disc shaped red cells. Also : the red blood shapes can vary from day to day, minute to minute. This phenomenon is affected by stress, exercise, and other issues.

His experience suggests that several things can influence red cell shape, and increase the preferred disc-shaped cells.
1. B12 injections- hydroxocabalamin, not cynidocabalamin.
2. Ginkgo Bilbao extract - tablets, not leaf capsules
3. Evening primrose oil - 8-12 500 mg capsules with meals
( Source: Melissa Kaplan's Chronic Neuroimmune Diseases. www.anapsid.org/cnd/diagnosis/redcells.html )

Sadly, Dr. Simpson died in 2015.

A few points:
1. Red blood cells do not have mitochondria. They produce energy by fermentation, via anaerobic breakdown of glucose followed by lactic acid production. Lactate dehydrogenase 1 is a critical enzyme in this process.
2. When red blood cells experience 'shear stress' inside arterial constrictions they release ATP as a vasodilatory signaling mechanism.
3. Recently a nitric oxide synthase-like enzyme has been found in red blood cells. The significance of this is still being researched. However, apparently, red bloods cells may be producing nitric oxide to help regulate oxygen delivery. Yes, more research states that Nitric oxide regulates normal vascular tone and modulates various homeostatic functions. There are indications that hemoglobin and red blood cells are critical in the regulation of nitric oxide in the vessels. This gets complex, but seems VERY important.
4. Again, back to the RhD negative folks : We lack a protein on the surface of our red blood cells. At one support group meeting ( About 15-17 women) 55 per cent were RhD negative. The highest percent in the world is with the Basques at 35 %.

So, seems really important to have some research on red blood cell morphology, oxygen delivery, CO 2 release, and red blood cell nitric oxide production.

Okay, Forum Folks, please add your info.

 

[Cort]

in 1989 researcher Leslie O Simpson published research that ME patients exhibited marked morphological abnormalities in their red blood cells. ( Nondiscocytic erythrocytes in myalgic encephalomyelitis. N Z Med J 102( 864) : 126-127. 1989) ME patients had a significantly lower per cent of the 'ideal' disc-shaped red blood cells, and a higher per cent of cup-shaped ( and other shaped ) red cells. The non-disc shaped cells have a more difficult time traveling through capillary beds, as they are less flexible. Thus, the ability to deliver oxygen to cells and remove metabolic waste is compromised.

This research was referred to in a classic work, edited by I. Jon Russell, MD, PhD., The Fibromyalgia Syndrome: A Clinical Case Definition for Practitioners, 2003. There was also personal communication with Dr. Simpson.

Dr. Simpson comments that when ME patients felt better, they had a higher percent of disc shaped red cells. Also : the red blood shapes can vary from day to day, minute to minute. This phenomenon is affected by stress, exercise, and other issues.

His experience suggests that several things can influence red cell shape, and increase the preferred disc-shaped cells.
1. B12 injections- hydroxocabalamin, not cynidocabalamin.
2. Ginkgo Bilbao extract - tablets, not leaf capsules
3. Evening primrose oil - 8-12 500 mg capsules with meals
( Source: Melissa Kaplan's Chronic Neuroimmune Diseases. www.anapsid.org/cnd/diagnosis/redcells.html )

Sadly, Dr. Simpson died in 2015.

A few points:
1. Red blood cells do not have mitochondria. They produce energy by fermentation, via anaerobic breakdown of glucose followed by lactic acid production. Lactate dehydrogenase 1 is a critical enzyme in this process.
2. When red blood cells experience 'shear stress' inside arterial constrictions they release ATP as a vasodilatory signaling mechanism.
3. Recently a nitric oxide synthase-like enzyme has been found in red blood cells. The significance of this is still being researched. However, apparently, red bloods cells may be producing nitric oxide to help regulate oxygen delivery. Yes, more research states that Nitric oxide regulates normal vascular tone and modulates various homeostatic functions. There are indications that hemoglobin and red blood cells are critical in the regulation of nitric oxide in the vessels. This gets complex, but seems VERY important.
4. Again, back to the RhD negative folks : We lack a protein on the surface of our red blood cells. At one support group meeting ( About 15-17 women) 55 per cent were RhD negative. The highest percent in the world is with the Basques at 35 %.

So, seems really important to have some research on red blood cell morphology, oxygen delivery, CO 2 release, and red blood cell nitric oxide production.

Okay, Forum Folks, please add your info.

This is very interesting. I have the feeling that Simpson's work was tested at some point and it did not work out....but I'm not sure

Here is his 1993 paper


N Z Med J. 1993 Mar 24;106(952):104-7.
Red cell shape changes following trigger finger fatigue in subjects with chronic tiredness and healthy controls.

Simpson LO1, Murdoch JC, Herbison GP.
Author information


Abstract

AIMS:

To investigate the possibility of a correlation between the percentage of nondiscocytic erythrocytes and muscle fatiguability in subjects with the symptom of chronic tiredness.
METHODS:

Sixty nine volunteers suffering from persisting or intermittent tiredness and 72 healthy controls provided 3-drop samples of venous blood for red cell shape analysis before and after inducing fatigue in the trigger finger muscles by repeatedly pulling the trigger of an antique revolver. Elapsed time and the number of pulls were recorded. A work index was calculated from the number of trigger pulls divided by the time in seconds then multiplied by the number of trigger pulls.
RESULTS:

Subjects with tiredness had fewer discoid cells (males 62.5% vs 69.2%, p = 0.029; females 65.8% vs 71.8%, p = 0.002) than controls. They also had fewer trigger pulls (males 62.3 vs 84.0, p = 0.003; females 29.5 vs 36.8, p = 0.042) and lower "work indices" (males 75.6 vs 104.7, p = 0.001; females 26.1 vs 39.6, p = 0.001) than controls at the first trigger pulling. After 5 minutes rest the number of trigger pulls for males was fewer than the controls (56.0 vs 64.2) but the difference was not significant, but the female values (24.3 vs 33.2) were significantly different (p = 0.008). Work indices for both sexes were significantly different from controls (males p = 0.020, females p = 0.001).
CONCLUSIONS:

The association of increased nondiscocytes and impaired muscle function could indicate a cause and effect relationship. This would be in agreement with the physiological concept of fatigue as a consequence of inadequate oxygen delivery.

 

[Cort]

I found this in 2010 from Marshall-Gradisnuk's group

J Transl Med. 2010 Jan 11;8:1. doi: 10.1186/1479-5876-8-1.Immune and hemorheological changes in chronic fatigue syndrome.
Brenu EW1, Staines DR, Baskurt OK, Ashton KJ, Ramos SB, Christy RM, Marshall-Gradisnik SM.
Author information
Abstract

BACKGROUND:

Chronic Fatigue Syndrome (CFS) is a multifactorial disorder that affects various physiological systems including immune and neurological systems. The immune system has been substantially examined in CFS with equivocal results, however, little is known about the role of neutrophils and natural killer (NK) phenotypes in the pathomechanism of this disorder. Additionally the role of erythrocyte rheological characteristics in CFS has not been fully expounded. The objective of this present study was to determine deficiencies in lymphocyte function and erythrocyte rheology in CFS patients.
METHODS:

Flow cytometric measurements were performed for neutrophil function, lymphocyte numbers, NK phenotypes (CD56(dim)CD16(+) and CD56(bright)CD16(-)) and NK cytotoxic activity. Erythrocyte aggregation, deformability and fibrinogen levels were also assessed.
RESULTS:

CFS patients (n = 10) had significant decreases in neutrophil respiratory burst, NK cytotoxic activity and CD56(bright)CD16(-) NK phenotypes in comparison to healthy controls (n = 10). However, hemorheological characteristic, aggregation, deformability, fibrinogen, lymphocyte numbers and CD56(dim)CD16(+) NK cells were similar between the two groups.
CONCLUSION:

These results indicate immune dysfunction as potential contributors to the mechanism of CFS, as indicated by decreases in neutrophil respiratory burst, NK cell activity and NK phenotypes. Thus, immune cell function and phenotypes may be important diagnostic markers for CFS. The absence of rheological changes may indicate no abnormalities in erythrocytes of CFS patients.

 

[Cort]

But then there was this tantalizing bit

Exp Biol Med (Maywood). 2007 Sep;232(8):1041-9.Hematologic and urinary excretion anomalies in patients with chronic fatigue syndrome.
Niblett SH1, King KE, Dunstan RH, Clifton-Bligh P, Hoskin LA, Roberts TK, Fulcher GR, McGregor NR, Dunsmore JC, Butt HL, Klineberg I, Rothkirch TB.
Author information
Abstract

Patients with chronic fatigue syndrome (CFS) have a broad and variable spectrum of signs and symptoms with variable onsets. This report outlines the results of a single-blind, cross-sectional research project that extensively investigated a large cohort of 100 CFS patients and 82 non fatigued control subjects with the aim of performing a case-control evaluation of alterations in standard blood parameters and urinary amino and organic acid excretion profiles. Blood biochemistry and full blood counts were unremarkable and fell within normal laboratory ranges.

However, the case-control comparison of the blood cell data revealed that CFS patients had a significant decrease in red cell distribution width and increases in mean platelet volume, neutrophil counts, and the neutrophil-lymphocyte ratio. Evaluation of the urine excretion parameters also revealed a number of anomalies.

The overnight urine output and rate of amino acid excretion were both reduced in the CFS group (P < 0.01). Significant decreases in the urinary excretion of asparagine (P < 0.0001), phenylalanine (P < 0.003), the branch chain amino acids (P < 0.005), and succinic acid (P < 0.0001), as well as increases in 3-methylhistidine (P < 0.05) and tyrosine (P < 0.05) were observed. It was concluded that the urinary excretion and blood parameters data supported the hypothesis that alterations in physiologic homeostasis exist in CFS patients.

 

[Cort]

This study didn't look at red blood cell shape but it did find problems - high levels of damage due to oxidative stress - that could impact red blood cell shape.


Arch Med Res. 2007 Jan;38(1):94-8. Epub 2006 Nov 3.Erythrocyte oxidative damage in chronic fatigue syndrome.
Richards RS1, Wang L, Jelinek H
Abstract

BACKGROUND:

It has been hypothesized that a link exists between erythrocyte metabolism (particularly redox metabolism) and erythrocyte shape and that both are related to erythrocyte deformability. The aim of this research is to confirm the results of earlier studies and to investigate a correlation between erythrocyte morphology and erythrocyte oxidative damage in chronic fatigue syndrome (CFS).
METHODS:

Reduced glutathione (GSH), malondialdehyde (MDA), methemoglobin (metHb) and 2,3-diphosphoglyceric acid (2,3-DPG) were measured in 31 patients suffering from CFS and 41 healthy control subjects. Scanning electron microscopic studies of the erythrocytes from both groups were also carried out.
RESULTS:

There was evidence of oxidative damage in CFS with statistically significant increases in 2,3-DPG (p < 0.05), metHb (p < 0.005) and MDA (p < 0.01). The CFS patients in this study also had significantly more stomatocytes in their blood than the normal subjects (p < 0.005).
CONCLUSIONS:

There is a strong likelihood that the increase in erythrocyte antioxidant activity is associated with the presence of stomatocytes. The results of this study provide further evidence for the role of free radicals in the pathogenesis of CFS and a link between erythrocyte metabolism and erythrocyte shape.

Apparently so did this study:


Oxidative stress might reduce essential fatty acids in erythrocyte membranes of chronic fatigue syndrome patients.
Nijs J, De Meirleir K.
Nutr Neurosci. 2004 Aug;7(4):251-3. No abstract available.
PMID:
15682653

 

[Cort]

There hasn't been much research on Simpson's interesting findings. What did Simpson attribute the red blood cell malformation's to? Did he believe the oxidative stress might be involved?

 

[weyland]

What did Simpson attribute the red blood cell malformation's to? Did he believe the oxidative stress might be involved?

It's been a while since I've looked at his stuff, but in his chapter in Hyde's 1992 ME book, he does not make any definite attribution. He notes that viral infection causes the same shape changes but he states that in ME it could either be due to the persistence of the infection or a failure of the red cells to return to normal shape after resolution of infection.

One of the interesting things he notes in that chapter is that once a certain threshold of these poorly shaped red blood cells is reached that it will impede normal blood flow, first in the smallest capillaries, causing an autoregulated vasodialation in order to restore normal blood flow. This is interesting since we do seem to have problems with vasodialation, making it difficult for us to tolerate things like heat, alcohol, and orthostasis. He also ties the poor blood flow to the increased lactic acid production that we have in muscles, which could be caused by inadequate oxidative metabolism rather than excessive glycolytic activity. It's all very plausible which makes it too bad that nobody really picked up on his work, though it seems like the Norwegians have kind of shown some interest in this area as well.

 

[Gijs]

For bloodflow issues and NK cel dysfunction you can try L-Arginine. It increases your NO and relax the bloodvessels etc...
Follow the discussion: http://forums.phoenixrising.me/inde...since-starting-nitric-oxide-supplement.43761/

 

[Merida]

Thanks, everyone. Interesting stuff. I posted, then fell off the CFS cliff. I have thought a lot about the delivery of oxygen across the blood brain barrier. Has anyone measured O2 in the spinal fluid?? It seems reasonable that for O2 to be transported and delivered across the blood brain barrier, the dura-meningeal system must be uninjured / not inflamed , and not excessively 'tight.'

It is interesting that neurosurgeon Shokei Yamada, who defined the pathophysiology of tethered cord syndrome, found ( through some non invasive spectrophotometric ? technique) that the mitochondria in the spinal cord nerve cells were dysfunctional - hence symptoms. The mito were not getting enough oxygen. Have notebooks of research on this tethered cord stuff.

Also, it is important to note that in spinal cord injury folks research has shown " Deficits in immune function and the presence of a chronic inflammatory state have been documented in the acute and chronic phases of spinal cord injury." This includes reduced NK cell counts and impaired neutrophil phagocytocsis. Much more. Too tired to add more now . Source: Spinal Cord Medicine: Principles and Practice. Vernon W. Lin, MD, PhD. A huge important 20 pound book.

We have such global problems, there must be a very basic process that is off.

 

[weyland]

Just another interesting note. The treatment for this that Les Simpson apparently described was 8x500mg a day of fish oil + evening primrose oil. This is the same exact treatment that was used by Behan in a RCT in ME patients.

Simpson notes that fish oil and evening primrose oil increase the fluidity of the lipid bilayer of the red blood cell membrane, improving the red cells ability to contort its shape when passing through the microcirculation. What's interesting is that part of Behan's RCT involved measuring EFA levels in the patients red blood cell membranes and they found that they were deficient. The trial showed that 8x500mg a day of Efamol Marine both improved symptoms and returned the red blood cell EFA levels to normal. This would seem to validate Simpson's theory, though it's odd that Behan makes no reference to Simpson in his paper. I'm not sure if they knew of each others work or not.

 

[lisaadele]

Just another interesting note. The treatment for this that Les Simpson apparently described was 8x500mg a day of fish oil + evening primrose oil. This is the same exact treatment that was used by Behan in a RCT in ME patients.

Simpson notes that fish oil and evening primrose oil increase the fluidity of the lipid bilayer of the red blood cell membrane, improving the red cells ability to contort its shape when passing through the microcirculation. What's interesting is that part of Behan's RCT involved measuring EFA levels in the patients red blood cell membranes and they found that they were deficient. The trial showed that 8x500mg a day of Efamol Marine both improved symptoms and returned the red blood cell EFA levels to normal. This would seem to validate Simpson's theory, though it's odd that Behan makes no reference to Simpson in his paper. I'm not sure if they knew of each others work or not.

That's interesting. I've noticed in my bloodwork results when my good cholesterol is higher that my MCV and MCH aren't as high. Seems to be an inverse thing happening. I'm going to increase my fish oil supplements and try taking evening primrose oil some more and see what happens.

 

[weyland]

That's interesting. I've noticed in my bloodwork results when my good cholesterol is higher that my MCV and MCH aren't as high. Seems to be an inverse thing happening. I'm going to increase my fish oil supplements and try taking evening primrose oil some more and see what happens.

Just to throw it out there, I have done the protocol as described above, 8 pills of Efamol Marine per day. While it's hard to say because I was trying other things at the same time, after several months I had almost a week of improved symptoms to a level that I had not yet reached since becoming ill two years ago. Unfortunately with the reduced symptoms I overexerted myself easily and crashed back roughly to where I was before. It also caused some symptoms of mast cell activation that took several months to go away after stopping the Efamol. I'm slightly weary of trying it again, but I may at some point in the near future.

 

[duckcove]

Probably early 90's, when Simpson came to the US, I attended his lecture. His findings indicated that on a global level CFS patients had a distinct, identifiable distribution of red blood cell shapes (cups, plates, discs, etc), as did Down's syndrome and several other medical groups. His recommendations for CFS were: for chronic CFS to take the high dose evening primrose oil (EPO), and for the acute CFS to get the B12 shots. Both should increase the flexibility of the cell membrane, allowing them to squish through the capillaries more easily. It takes about 8 weeks for your body to regenerate most of your RBC's.
I also have Reynauds, cold hands and feet. He collected blood samples and later returned reports to us. Since then I have taken EPO, starting with the 8 x 500mg/day. The results were dramatic. I could not stand still for more than a few minutes before my legs would start to severely ache. That went away. The Reynaud's greatly diminished. Before our family went to Vail for a ski vacation (8000' elevation +) even though I could no longer ski, he recommended upping the dose, starting a month earlier. Believe it or not I did better the first few days than the skiers did walking up hills and stairs.
That was over 20 years ago. Now I take 1300mg/day. Standing, like at a cocktail party, still exhausts me, but no achy legs. CFS is still a daily battle for me, 30 years later.
Now I am wondering about the various Omega 3, 6, 7's, DHA, EPA, GLA, LA, and taking fish oils, etc. exactly what I should be taking to optimize Omega 3's. Evening Primrose oil ( LA 949mg, GLA 117mg) I also take fish oil (EPA 1430, DHA 570mg) and had until recently taken a low dose aspirin. I have stopped the aspirin because I bleed too easily. Should I also stop either the EPO or the fish oil? Any thoughts?

 

[Issie]

Dejurgen discovered some interesting things with red blood cells and oxygen carrying capacity. He started a new thread here.

Potential linking RBC, glycolysis, air hunger, thyroid, ATP dumping, pregnancy improvement and... | Health Rising's Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia Forums
https://www.healthrising.org/forums...d-atp-dumping-pregnancy-improvement-and.6236/