1. By exposing hemoglobin solutions to an alkaline reagent at a pH of 12.7 it was found that normal pigment is completely denatured within one minute. Thus even small amounts of more resistant hemoglobins, which may also be present in the solution, can be readily detected. Fetal hemoglobin, which is alkali resistant, may remain demonstrable until the end of the second year of life.

2. Alkali resistant hemoglobins were regularly encountered in sickle cell anemia (but not in the trait), in the more fully developed Mediterranean syndromes, and in 1 out of 4 families with hereditary spherocytosis. In addition to these hereditary hemolytic disorders, abnormally denaturing hemoglobin fractions were observed in 3 instances of chronic aregenerative anemia, and, irregularly, in patients with untreated pernicious anemia, acute and chronic leukemia and myelophthisic anemia. All other kinds of anemias were found to have only normally denaturing pigments.

3. Three definite types of hemoglobin are identifiable at present by means of electrophoresis and denaturation. These have been designated as type N (normal adult), type F (fetal), and type S (sickle cell hemoglobin). The hypothesis is advanced that the resistant fraction in the hereditary hemolytic syndromes may represent a continued production of fetal pigment beyond the physiologic age limit and the appearance of the abnormal hemoglobins in the "acquired" disorders may indicate a reactivation of such a mechanism. The implications of such an assumption for the distribution of the various types of hemoglobin in sickling erythrocytes are discussed.

4. The diagnostic significance of the denaturation test and its limitations are outlined.

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