My research focus is on systemic sclerosis (SSc)s, in particular understanding the role of abnormal blood rheology in SSc pathogenesis. It is generally understood that all fibrosis and systemic organ damage in SSc starts with damage to the endothelial layer of the microvascular system. The mechanisms of fibrosis are fairly well understood at this point but the earlier endothelial damage stage is not well understood.
There is clear documentation that blood rheology is highly abnormal in SSc. There is increased overall whole blood viscosity and also red blood cell clumping. There appear to be two distinct types of RBC clumping going on in SSc. There are Rouleaux formations where RBCs are aggregated together in linear stacks. This is also seen in rheumatoid arthritis and lupus. A key characteristic of Rouleaux stacks is that they are not at all shear resistant - they break apart and reform quickly and easily.
However, two research studies have documented that there is also highly shear-resistant clumping in SSc. In one 1999 paper, researchers documented that there are non-linear clumps as well as Rouleaux formations. It appears that these are small clumps, but this was not specifically noted in the 1999 paper. (I am trying to contact the lead researcher to ask about this.)
In 1993, I formulated a disease pathogenesis model for SSc that suggests that highly shear-resistant small RBC clumps could theoretically lead to the endothelial damage seen in SSc. If these shear-resistant clumps are very small (just a few cells), this could lead to gradual damage over time, potentially explaining why the slower progressing variants of SSc often start with Raynaud's for a few years before other symptoms start to develop. However, if the clumps are larger, you would start to see microcapillary blockage. In the faster progressing variants of SSc, initial symptoms are frequently systemic pain and fatigue, even before Raynaud's and other symptoms like skin changes.
This leads me to sickle cell anemia (SCA) crisis. In SCA crisis, my (very limited) understanding is that you have clumps of RBCs that block blood flow and it is common to have severe pain and fatigue as part of the symptom cluster. Please correct me if this is incorrect.
Assuming that my understanding of SCA crisis is at least basically correct, this brings up a couple of important questions:
1) If you have shear-resistant clumps of RBCs blocking blood flow, whether the type that occurs in SSc, the clumping that you see in SCA crisis, or potentially in any other disease that includes shear-resistant RBC clumps large enough to block blood flow, would pain and fatigue be expected symptoms?
2) What is the nature of RBC clumping in SCA? Are there small (a few cells) shear-resistant clumps of RBCs or are they shear-resistant and capable of blocking blood flow only when in the large clumps seen in SCA crisis?
There is clearly endothelial damage in SCA as well as in SSc. There are a number of papers that note that sickled cells tend to adhere to the endothelium. I have not seen any suggestion that a similar phenomenon occurs in SSc. If RBCs in SCA do not exhibit the phenomenon of small shear-resistant clumping, this could potentially lead to the possibility that the nature of the endothelial damage may be different between these two diseases.
(While not directly germane to this question, you might find it interesting that a series of four weekly therapeutic plasma exchange (TPE) treatments completely eliminates the RBC clumping in SSc and that, somewhat surprisingly, it takes months for RBC clumping to return to pre-TPE levels. This also correlated with rapid improvement of Raynaud's symptoms and healing of digital ulcers. I presented a poster about this at ACR 2016 and co-authored a recently published comprehensive review of 46 published studies on the use of TPE as a treatment for SSc that mentions this as well.)
Why is understanding the differences between RBC clumping in SSc and SCA important? If my disease pathogenesis model is correct, then any treatment that can eliminate RBC clumping in SSc and then keep the RBCs from re-clumping should prevent further endothelial damage and potentially stop disease progression completely. If started early enough, you should theoretically never develop downstream fibrosis and organ damage. This would make SSc, which has the highest mortality rate of any major autoimmune disease, completely treatable. Long-term pulsed TPE appears to be one way to do this, but even though TPE has an excellent safety profile, it is invasive, moderately expensive (about the same cost as biologics used to treat RA), and is frequently unavailable for patients who do not live near a major population center with a large hospital that does TPE on a regular basis.
One of my colleagues has correctly noted that since RBCs clump together in both SSc and SCA, and both diseases exhibit endothelial damage, we need to be able to explain why fibrosis only develops in SSc and not in SCA? That is what prompted this (very long) question.
Happy to provide references to anything mentioned above if anyone is interested.