Some Medical Hypotheses

Many people in medical fields accumulate these points of curiosity that are outside their specialization or that they otherwise never have time to follow up on. Here are several. As always, nothing here should be taken as medical advice.

1. The decline in alveolar ventilation with age as measired by DLCO (about 1% a year) results partly from the gradual accumulation of small subclinical pulmonary emboli. This predicts that people on blood thinners should show a slower decline. Also, part of the increased all-cause mortality seen in people who sit a lot relative to those who don't is the result of such emboli, in the lungs and elsewhere, suggesting people who sit less should also show a decreased rate of lung function loss. (This second part of the hypothesis is appealing because you can't undo sitting mortality by adding exercise, just like you can't undo that PE from your flight to JFK by hitting the gym after you get off the plane. Also, frequent sitting is evolutionarily recent, and in fact our ancestors most likely had more exsanguinating traumas than we do, so even without sitting the balance in our current environment is still too tilted toward clotting.) Of note, capillary microthrombi do account for some of the dysfunction in COVID hypoxemia, though I am unaware to what extent this mechanism accounts for persistent hypoxemia in recovered COVID patients (Dhont et al 2020.)
   
   
2. One of the functions of a four-chambered heart is to prevent clots from reaching end organs. In the brains of animals with less dependence on complex behavior and/or without small capillaries, this is less of a problem. True cold blooded modern reptiles do not have small capillaries and have three chambered hearts. Dinosaurs, birds and mammals are all warm blooded or poikilothermic and have four- chambered hearts. A four chambered heart provides an additional aperture that thrombi have to pass through, and for developmental reasons may make it more likely that patent foramen ovale-type defects are less likely.
   
   
3. Mammalian red blood cells are enucleate. The prevailing theory is that mammals have the tiniest capillaries of all orders (even moreso than birds, consistent with being warm blooded). The new hypothesis here is that mammals' on average more communal living makes them more susceptible to viruses. (Yes birds live communally but in terms of physical contact mammals on average spend more time directly touching.) The majority of cells in blood are RBCs. A virus adapted for infecting nucleate RBCs could do quite a bit of damage in animals that had them. But in mammals, these viruses would only enter an empty shell. Note that the next most common type of blood cell, the neutrophil, is programmed to self-destruct in 24 hours, and indeed ejects its nucleus as its main defense, frustrating any pathogen that needs time to do its work and on top of that would have to be adapted to both intra and extracellular conditions. I am not aware of any virus which infects and reproduces using the translational machinery of avian red blood cells but the existence of such viruses would support this theory. In fact RBCs in non-mammalian vertebrates do have active adaptive immunity functions (Nombela and Ortega-Villaizan 2018). That the maturation of red blood cells is directly dependent on ejection of the nucleus suggests this is an important pathway (Testa 2004), which may also be an adaptation for cancer resistance in long-lived species that thusfar only mammals have taken advantage of. Of course many viruses interact with RBCs in mammals, but do not (cannot!) use them to reproduce.

REFERENCES
Dhont, S., Derom, E., Van Braeckel, E. et al. The pathophysiology of ‘happy’ hypoxemia in COVID-19. Respir Res 21, 198 (2020). https://doi.org/10.1186/s12931-020-01462-5

Nombela I. and Ortega-Villaizan MdM. Nucleated red blood cells: Immune cell mediators of the antiviral response. PLoS Pathog. 2018 Apr; 14(4): e1006910. Published online 2018 Apr 26. doi: 10.1371/journal.ppat.1006910

Testa, U. Apoptotic mechanisms in the control of erythropoiesis. Leukemia 18, 1176–1199 (2004). https://doi.org/10.1038/sj.leu.2403383