A great surprise this morning: a comment from John. Yup, THE John. So taking a page out of Scott’s book, I thought it would be worth sharing with everyone as its own post, as opposed to just a comment. I think this is must-read material for everyone.
So without any further adue:
“I thought I might add some quirky ideas to your discussion.
We are now getting familiar with the concept of endothelial cells covered by a surface glycocalyx layer, that forms part of the barrier and mechano-sensing functions of the blood-tissue interface. We have discussed in some detail, the role of the glycocalyx in preserving endothelial integrity. I am gonna try and add a bit more spice into the whole transfusion drama.
In recent times, we have started talking a lot about a bioactive phospholipid called sphingosine-1-phosphate (S1P), as a crucial element in preserving vascular barrier integrity by ‘protecting’ the Glycolcalyx. (Most geeky papers on TRALI and other transfusion related complications do mention it).
Because albumin is one of the primary carriers of sphingosine-1-phosphate (S1P), it is possible that S1P, acting via S1P1 receptors, plays the primary role in stabilizing the endothelial glycocalyx. Infact, antagonism of S1P1 receptors have been shown to cause widespread shedding of the glycocalyx, as evidenced by increased serum concentrations of Heparan sulphate and Chondroitin sulphate. (This might probably be one of the mechanisms how albumin is glycocalyx friendly).
RBC transfusions are a double edged sword…..especially in situations of acute anemia as in post hemorrhagic situations ( major GI bleed or trauma.)….I totally agree with you in that the two are conceptually very similar.
Erythrocytes have been identified as an important buffer for sphingosine-1-phosphate . In mice, depletion of plasma S1P by genetic inactivation of S1P synthesizing enzymes (sphingosine kinases 1 and 2) elicits profound pulmonary vascular leak, which can be reversed by restoring circulating S1P via RBC transfusion.
In humans, hematocrit (Hct) predicts plasma S1P levels. There also seems to be a dynamic equlibrium between SIP levels of the plasma, and the circulating RBCs. It has been demonstrated that in anemic individuals, plasma S1P levels are not uniformly restored by RBC transfusion. Rather, the age of the RBC unit at the time of transfusion tended to negatively correlate with the ability of RBC transfusion to replenish plasma S1P. During storage, the S1P content of human RBC markedly declines, likely due to enzymatic degradation. Because erythrocytes serve as a buffer for circulating S1P, aged RBC with low S1P content may be incapable of restoring plasma S1P levels and may actually remove S1P from plasma, which in turn could contribute to increased endothelial permeability, capillary leak, and infiltration of inflammatory cells.
I hope this partly answers your question as to how the glycocalyx may be impacted by inappropriate and irresponsible transfusion triggers. I agree that these are all very novel ideas and as such, exist in the realm of experimental clinical physiology, but my gut tells me that the delicate Glycocalyx may hold the clue to a lot of answers to questions that have plagued us for a long long time!
John from India…”
So first of all, thank you very, very much for reading and taking the time to comment and enlighten us.
As John says, this is still in the realm of experimental physiology, but I think there are a lot of situations we are faced with, perhaps grey zone areas where we debate two potential therapeutic avenues, where we can use some of this data. We might debate giving that extra bit of fluid, or debate crystalloid vs albumin, or blood or no blood with an Hb of exactly 70, and I think we have to start weighing in some of this physiological data, even if it isn’t “evidence-based-by-RTC” to help guide these decisions.
The more I look into it the more it seems that our interventions – particularly fluid resuscitation, needs to be reassessed from the ground up both in nature, quantity and rate of infusion while measuring glycocalyx damage – e.g. biomarkers such as S1P, heparan or chondroitin sulfate, etc…
I’ve previously posted and podcasted about my general strategy for fluid resuscitation, and I am definitely in the process of revising it, still unsure what is best. I’d love to hear how John resuscitates his patients…
Mystery John has an uncanny ability to describe complex physiology in the simplest way possible. I am very interested in digging more into his predictions of the possibility of aged erythrocytes removing S1P from circulating plasma.
Dr. John, if you’re out there, could you point us all to some of these studies you’ve mentioned? Any good S1P review papers you’d recommend to those, like me, who are S1P novices?
Thanks for your input! It was a pleasure.
Thank you Derek, for the kind comments…. I think the concept of S1P is still in the process of evolving and assuming a definitive shape, so a good review might be hard to stumble across.
A good research article which cites some excellent references might be —
Synergistic Effect of Anemia and Red Blood Cells Transfusion on Inflammation and Lung Injury
— Anping Dong et al. (It is open access at http://dx.doi.org/10.1155/2012/924042).
Hope this helps……
Here is the article: