key: cord-0792158-k0j75m4w
authors: Hacking, Sean M.
title: Red blood cell exchange for SARS-CoV-2: a Gemini of therapeutic opportunities
date: 2020-09-02
journal: Med Hypotheses
DOI: 10.1016/j.mehy.2020.110227
sha: 9add1c47bd2dd22b8cc96253458b0978279e0a0e
doc_id: 792158
cord_uid: k0j75m4w

As of now, therapeutic strategies for the novel coronavirus (SARS-CoV-2) are limited; much focus has been placed on social distancing techniques to “flatten the curve”. While initial treatment efforts including ventilation and hydroxychloroquine garnered significant controversy. Today, SARS-CoV-2 outbreaks are still occurring throughout the world and new therapeutic strategies are needed to combat this unprecedented pandemic. Nature Reviews Immunology recently published an article hypothesizing the pathogenesis of TAM receptor signaling in COVID-19. In it they expressed that hypercoagulation and immune hyper-reaction could occur secondary to decreased Protein S (PROS1). And hypoxia has been recently discovered to significantly decrease expression of PROS1. Regarding the cause of hypoxia in COVID-19, NIH funded research utilizing state-of-the-art topologies has recently demonstrated significant metabolomic, proteomic, and lipidomic structural aberrations in hemoglobin (Hb), secondary to infection with SARS-CoV-2. In this setting, Hb may be incapacitated and unable to respond to environmental variations, compromising RBCs and oxygen delivery to tissues. The use of red blood cell exchange would target hypoxia at its source, representing a Gemini of therapeutic opportunities.

It has been 102 years since the outbreak of the 1918 Spanish flu; today, we face the everevolving lexicon of the coronavirus pandemic 1 . The outbreak of novel coronavirus (SARS-CoV-2) began in Wuhan, China and has spread rapidly throughout the world 2 . The pandemic has left health, economic, environmental and social consequences for the entire world 3 . Currently, treatment strategies are lacking and the use of ventilation therapy in COVID-19 also faces criticism 4 . For hydroxychloroquine, studies showing therapeutic efficacy are also lacking; while side effects from usage still occur 5 . Today, social distancing tactics as well as wide spread mask usage have been crucial for "flattening the curve" 6 . However, outbreaks are still occurring throughout the world and novel therapeutic strategies are needed to combat this unprecedented virus.

We hypothesize that Red Blood Cell (RBC) exchange could be used for the successful treatment of COVID-19. This hypothesis was sparked by a recent publication illustrating the effects of SARS-CoV-2 on the protenomic and lipid structure of hemoglobin (Hb). If such is the case for Hb, these patients would be unable to bind oxygen and ventilation may not be the answer to treating hypoxia in this setting. And perhaps this is why some COVID-19 patients are responding to High-flow oxygen 7 . This may also be the reason behind the COVID-19 clinical picture, reminiscent of methemoglobinemia with very low oxygen saturations (SpO2). This is seen in methemoglobinemia, where methodologic problems consistently hinder oximetry and elevated methemoglobin results in the underestimation of SpO2. In methemoglobinemia, RBC exchange has actually been demonstrated to be superior to methylene blue for therapeutic treatment 8, 9 . In addition, hypoxia has been most recently discovered to affect the production of Protein S (PROS1) 10 . And academics are beginning to believe that hypercoagulability and immune hyperreaction in COVID-19 is mechanistically linked to Protein S 11 .

COVID-19 disease is most commonly associated with shortness of breath, dry cough and fever 12 . Some experience symptoms most reminiscent of hypoxia and now, red blood cells (RBCs) have been found altered in patients infected with SARS-CoV-2. One of the most significant studies utilized state-of-the-art topologies to investigate the metabolomic, proteomic, and lipidomic effects of COVID-19 on RBCs 13 .

In this COVID-19 study, RBCs were collected from 23 healthy patients and 29 molecularlydiagnosed COVID-19 patients 13 . Differences in RBCs from COVID-19 patients were observed; increased levels of glycolytic intermediates resulted in oxidation and fragmentation of ankyrin, spectrin beta, in addition to the N-terminal cytosolic domain of band 3 (AE1) 13 . Aberrant lipid metabolism was also observed in the short and medium chain saturated fatty acids, acylcarnitines and sphingolipids 13 .

Similar to other studies, they did not notice as many significant aberrations in clinical hematological parameters including: RBC count, hematocrit, and mean corpuscular hemoglobin concentration 13 .

It has been long understood that enhancing the release of membrane-bound glycolytic enzymes to the cytosol, results in the induction of glycolysis which shifts to the production of 2,3bisphosphoglycerate (2,3-BPG) facilitating O2 release 14 . Although this would improve the capacity of hemoglobin to off-load oxygen, it would result in difficulty for Hb to bind oxygen in the lungs. At the same time, as the N-terminus of AE1 is also affected and is responsible for stabilizing deoxyhemoglobin for finely tunes oxygen off-loading 13 . In this setting, RBCs affected by SARS-CoV-2 may be incapacitated and unable to respond to environmental variations in Hb oxygen saturation, resulting in an inability to transport and deliver oxygen to tissues. This undoubtably would result in severe hypoxia despite normal hematological parameters, such as those seen in SARS-CoV-2 15 .

It has been long understood that hypoxia can cause thrombosis 16, 17 . Hypoxia is known to be caused by many factors including: high altitude, smoking, lung failure and sickle cell anemia 10, 18, 19 , Interesting, per se however, is that hypoxia has more recently been found to decrease the body's natural anticoagulant -Protein S, with an increased risk for blood clotting from thrombosis 10 . This is why deficiencies of protein S occur in diseases such as sickle cell anemia and at a high altitude. This suggests that hypoxia and PROS1 deficiency, in turn, elevate one's thrombotic risk.

More specifically, hypoxia drives the dimeric transcription factor hypoxia inducible factor 1 (HIF1), something expressed constitutively in many tissues. O 2 deficiency inhibits HIF1α destruction; thereby stabilizing HIF1α 20 . An analysis in one study revealed that hypoxia accelerated HIF1α transcription -from 100% to 340% 10 . At the same time, decreasing O 2 from 20% to 1%, in turn, decreased PROS1 transcription from 100% to 20% 10 .

This decrease in PROS1 in the setting of hypoxia could be responsible for significant disease related thrombosis now termed, Coronavirus-associated coagulopathy (CAC), by the International Society on Thrombosis and Haemostasis 21, 22 . Most interestingly, is that in a Spanish series of non-ICU hospitalized COVID-19 patients, pulmonary emboli were found in the absence of deep-vein thrombosis 23 . A finding which suggests the presence of small-vessel thrombosis in the setting of hyperinflammatory immune responses.

This has also been a common finding in our regional autopsy service based in the New York Metropolitan Area. An example being this 48-year-old patient, who developed a saddle pulmonary embolus secondary to COVID-19 disease (FIGURE. 1) .

TAM receptors including Tyro3, Axl, and Mer, are part of the larger receptor tyrosine kinases (RTK) family 24 . Today, some feel that excessive coagulation and immune modulation may be intrinsically linked to the TAM receptors and Protein S. Nature Reviews Immunology recently published an article hypothesizing the pathogenesis of TAM receptor signaling in SARS-CoV-2 11 . This hypothesis is based on the premise that PROS1 also functions as an activating ligand for TAM RTKs, in addition to functioning as an anticoagulant 24 .

In the human immune system, TAM RTKs are almost exclusively expressed by MER receptors found on the surface of all phagocytic tissue macrophages 11 . Its kinase signaling pathway is activated by Protein S, which binds to the extracellular domain of MER8 11 . The activation of MER in immune cells has a immunosuppressive function, which hinders immune response mechanisms including: TNF, cytokines and interferons released in response to SARS-CoV-2 25 .

We have also known that SARS-CoV-2 causes significant hypercoagulation. Hypercoagulation can weaken vessel walls resulting in tissue hemorrhage 11 . However, expanding clot work to consume many important clotting factors, including the anticoagulant PROS1, a crucial ligand responsible for the immunosuppressive through MER, a TAM RTK expressed on immune cells 11 (FIGURE. 2) . PROS1 depletion also decreased MER signaling, which ultimately results in immune cells secreting inflammatory cytokines, commonly referred to as a 'cytokine storm' 11, 25 .

Reprinted by permission from Springer Nature, Nature Reviews Immunology [ 11 

As mentioned previously, hypoxia is also an important contributor to deficiencies in Protein S and could be the initial event triggering Coronavirus-associated coagulopathy. However, the role of hypoxia as a possible initiator of fulminant blood clotting in SARS-CoV-2 is not currently well understood. In future, treatments targeting RBC based oxygenation could be the key to clinical heterogeneity in COVID-19. And patients expected to have poor outcomes could experience dramatic changes in clinical course 26 .

As previously mentioned, replenishing the oxygen carrying capacity of blood could be the key to addressing COVID-19 induced hypoxia and its downstream consequences. This is supported by a case report demonstrating a patient with cardiac arrest and multiple comorbidities including COPD, congestive heart failure, and anemia secondary gastrointestinal bleeding 26 . The patient subsequently tested positive for SARS-CoV-2 and this ultimately progressing to pulmonary disease with bilateral interstitial infiltrates on his chest X-ray. The patient was anemic and treatment with packed red blood cells was undertaken. Initially, the patient was intubated for ventilation of acute respiratory failure. To the surprise of attending clinicians, oxygen stats improved and the patient was later extubated.

Compared to regular transfusion and SARS-CoV-2, the use of RBC exchange could actually be a much more effective approach for improving oxygenation. And RBC exchange is commonly performed for many hemoglobin disorders including sickle cell disease 27 . RBC exchange also offers a lower risk of iron accumulation, while also replacing pathologically aberrant erythrocyte populations 27 . Disadvantages include higher operating costs, along with the requirement for apheresis devices and trained hospital staff 27 . In theory, RBC exchange could improve both symptomatology and laboratory abnormalities, without real significant adverse outcomes (FIGURE. 3).

RBC exchange has also been used in 'Blackwater fever', or severe falciparum malaria characterized by intravascular hemolysis 28, 29 . Where RBC exchange results in the clearance of peripheral parasitemia and prevents hemolysis of RBCs 28 . It is entirely possible that RBC exchange could also lower viral load through this same mechanism.

Finally, simple transfusion is traditionally recommended for the treatment of symptomatic anemia with a Hb level of less than 9 g/dL 27, 30 . On the other hand, red cell exchange is indicated to prevent or treat complications arising from the presence of abnormal hemoglobin proteins such as hemoglobin S (HbS) in sickle cell disease 30 . And the goal of exchange is to lower HbS level to less than 30% 30 . In the setting of such significant HB protein and lipid structural damages, the use of RBC exchange would likely be more beneficial than that of simple transfusion.

SARS-CoV-2 has likely been causing prolonged and progressive hypoxia secondary to downstream alterations in the Hb protein and lipid membrane structures 13 . This likely has been leading to a failure of the blood to carry oxygen, along with the multi-organ failure and mortality seen in COVID-19 disease.

Interestingly, many COVID-19 patients come to the hospital with low peripheral oxygen concentrations (SpO2) at presentation 31 . This is because initially, COVID-19 pneumonia causes oxygen deprivation without significant symptoms. Something termed "silent" hypoxia, a phenomena commonly seen in COVID-19 disease 32 . You wouldn't know this from talking to these patients though, as they don't seem starved of oxygen. This is something also seen with methemoglobinemia and many patients with methemoglobin levels of 30% or higher do not have symptoms of hypoxia despite very low SpO2 [33] [34] [35] . Methodologic problems consistently hinder oximetry in methemoglobinemia and elevated methemoglobin results in the underestimation of SpO2 36 . If this SARS-CoV-2 has the ability to adversely affect the structure of hemoglobin, this could also bias oximetry estimates of SpO2.

For the discussion of this hypothesis, it is important to understand that hypoxia can have downstream consequences; possibly result in increased HIF1α, decreased protein S with resultant hypercoagulation, along with impaired immune modulation through the TAM RTKs. The inverse relationship between HIF1α and PROS1 could represent the bodies normal adaptive compensation to O 2 concentration. And functionally, HIF1 may work to regulate PROS1. However, in the setting of COVID-19, pathological stabilization of HIF1α is likely responsible for significant complications and patient demise.

Pertaining to Protein S, deficiencies are probably also exacerbated by dysregulated blood coagulation and are not solely a consequence of hypoxia 11 . Future studies examining the effects of RBC exchange on hypoxia, admission status and overall patient outcomes, will be paramount for determining the efficacy of this therapeutic.

It is important to acknowledge that blood shortages could become a problem through the remaining duration of the COVID-19 pandemic. And RBC exchange does carry a somewhat high blood requirement, as some erythrocytes transfused ultimately become removed throughout the apheresis 37 . Currently however, it seems that reductions in donor blood products have largely been matched by a significant reduction in the demand for transfusion during this pandemic 38 .

In summary, from pathological findings and the silent hypoxia seen in COVID-19 clinical disease; along with extensive review of the literature, I hypothesize that hypoxia secondary to altered structural Hb may well be responsible for mortality in COVID-19 disease. The use of red blood cell exchange would target hypoxia at the source; this would be a Gemini of therapeutic opportunities.

The author has no conflicts of interest to report in this work.

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 Figures 1 and 3 were created with BioRender.com. Figure 2 was reprinted by permission from Springer Nature, Nature Reviews Immunology [ 11 ] (Blood clots and TAM receptor signalling in COVID-19 pathogenesis, Lemke G and Silverman GJ), (2020).

The publication was carried out in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.References