Key Points

  • Voxelotor therapy reduces sickling and increases hemoglobin, but oxygen delivery to tissues is offset by increased hemoglobin O2 affinity

  • Drugs that reduce sickling by increasing HbF or decreasing MCHC should be more effective than drugs that increase O2 affinity

The issue of treating sickle cell disease with drugs that increase hemoglobin oxygen affinity has come to the fore with the FDA approval in 2019 of voxelotor, the only anti-sickling drug approved since hydroxyurea in 1998. Voxelotor reduces sickling by increasing the concentration of the non-polymerizing, high oxygen affinity R (oxy) conformation of HbS. Treatment of sickle cell patients with voxelotor increases Hb levels and decreases indicators of hemolysis, but with no indication as yet that it reduces the frequency of pain episodes. Here we use the allosteric model of Monod, Wyman, and Changeux to simulate whole blood oxygen dissociation curves and red cell sickling in the absence and presence of voxelotor under the in vivo conditions of rapid oxygen pressure decreases. Our modeling agrees with experiments using a new robust assay, which shows the very large, expected decrease in sickling from the drug. The modeling indicates, however, that the increase in oxygen delivery from reduced sickling is largely offset by the increase in oxygen affinity. The net result is that the drug increases overall oxygen delivery only at the very lowest oxygen pressures. Reduction of sickling does, however, mitigate against red cell damage and explains the observed decrease in hemolysis. More importantly, our modeling of in vivo oxygen dissociation, sickling, and oxygen delivery suggests that drugs that increase fetal hemoglobin or decrease MCHC, should be more therapeutically effective than drugs that increase oxygen affinity.

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