It is a curious thing how medical dogma settles in, simultaneously setting the foundation for future developments and discoveries while also closing the door to other more imaginative, less orthodox ways of treating a disease. 

A quick browse through medical history demonstrates this principle powerfully at work. In the past, before the widespread use of the microscope, people had no concept of disease-causing microscopic organisms we colloquially call germs. Hence, the prevailing theory at the time was that disease was spread by “bad air.” This scientific misconception handicapped infection control for a good half-century or so before germ theory was established, ending the decades-long dominance of a false doctrine and heralding the start of a brand new scientific age. 

The topic for this article today is far less dramatic in consequence, but no less important. It is a subtle rethink on the old dogma about how anemia should be treated, and the exciting possibilities awaiting us if we choose to approach the problem differently. 

Treatment Protocol for Anemia 

Sickle cell disease (SCD) is caused by the presence of abnormally sickle-shaped red blood cells, which have a reduced oxygen affinity. This often results in chronic hemolytic anemia and painful vaso-occlusive crises that require hospitalization and close monitoring. In addition, the tissues and organs of the body aren’t able to receive adequate amounts of oxygen, resulting in varying degrees of damage. 

Read more about SCD etiology 

“These multifactorial abnormalities have both acute and chronic clinical consequences across multiple organ systems, including acute pain episodes, chronic pain syndromes, acute chest syndrome, anemia, stroke and silent cerebral infarcts, cognitive dysfunction, pulmonary hypertension, and a wide range of other clinical consequences,” Neumayr and colleagues write in the American Journal of Managed Care. 

There are a number of established drugs for treating SCD, of which hydroxyurea is an example. However, regarding the anemia aspect of the disease (ie, the body does not receive enough oxygen due to deformed blood red cells), the traditional prescription has not changed: blood transfusions in proportion to the severity of the anemia. 

“Long-term red blood cell transfusion therapy is commonly given to patients with SCD for the management of both acute and chronic complications,” say Neumayr and colleagues. “Transfusion has a number of beneficial effects in SCD, including correcting anemia and suppressing endogenous red blood cell production.” 

Rethinking Blood Transfusions 

Instead of repetitive, lifelong red blood cell transfusion therapy, what if there was another way to deal with the low oxygen affinity of sickle-shaped red blood cells? What if there was a way to correct these problematic red blood cells and, by extension, treat the disease? 

This idea is explored in a study written by Henry and colleagues in an article in Blood. They understand that the root problem with SCD is the sickling of erythrocytes. With this in mind, they investigated the merits of voxelotor therapy, which can reduce the sickling of red blood cells, thereby increasing their oxygen affinity. 

Voxelotor is an antisickling drug that stabilizes the R quaternary structure of red blood cells and increases their oxygen affinity. In addition, it synergistically destabilizes the HbS polymer. According to experiments, voxelotor therapy can significantly reduce the sickling of erythrocytes, even to the point of eliminating them altogether.

However, the researchers also noticed that any increase in ability to deliver oxygen to the tissues made possible by voxelotor therapy is also easily offset by the left shift in the oxygen-hemoglobin dissociation curve (ODC). Henry et al explained, “Despite the markedly reduced sickling produced by voxelotor, which should increase oxygen delivery to the tissues, apart from the very lowest oxygen pressures, this increase is largely offset by the left shift in the ODC, even taking into account increased hemoglobin levels in drug-treated patients.”

Read more about SCD treatment 

In other words, much more research needs to be carried out to ensure that any therapy administered does not simply fix the shape of red blood cells, but also succeeds in delivering optimal oxygen levels to tissues and organs throughout the body. 

While Henry and colleagues do not believe that the reduction of erythrocyte sickling by voxelotor therapy can reduce the frequency of pain episodes, they concede that “the long-term effects of reduced hemolysis from less sickling should be beneficial.” 

The decrease in the sickling of red blood cells is an obvious place to start when it comes to treating SCD, but real-world evidence suggests that it is less valuable than we might be inclined to believe based on theoretical conjecture. However, administering red blood cell infusions every time a person is anemic is costly, painful, and burdensome to both patients and the health care system. Hence, continued investment in new ways of treating old problems should be cautiously welcomed, as future discoveries may vindicate early hopes. 


Neumayr LD, Hoppe CC, Brown C. Sickle cell disease: current treatment and emerging therapiesAm J Manag Care. 2019;25(18 Suppl):S335-S343.

Henry ER, Metaferia B, Li Q, et al. Treatment of sickle cell disease by increasing oxygen affinity of hemoglobinBlood. 2021;138(13):1172-1181. doi:10.1182/blood.2021012070