Provided herein are methods of treating sickle
cell disease, methods of increasing
hemoglobin levels in a subject diagnosed with sickle
cell disease, and methods of reducing
hemolysis-associated complications in a subject diagnosed with sickle
cell disease, together with kits for such treatments, in a subject in need thereof, comprising administering a Gardos channel inhibitor such as 2,2-bis(4-fluorophenyl)-2-phenylacetamide and a
pyruvate kinase activator such as N-(4-((4-(Cyclopropylmethyl)-1-piperazinyl)carbonyl)phenyl)-8- quinolinesulfonamide to the subject. Subjects eligible for treatment include subjects as having
hemolysis dominant (HD) sickle cell disease on the basis of laboratory markers, clinical history, and / or sequelae.