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CONFERENCE ON HEMOGLOBIN: 2-3 MAY 1957 (1958)

Chapter: CLINICAL CHARACTERISTICS ASSOCIATED WITH ABNORMAL HEMOGLOBINS

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Suggested Citation:"CLINICAL CHARACTERISTICS ASSOCIATED WITH ABNORMAL HEMOGLOBINS." National Research Council. 1958. CONFERENCE ON HEMOGLOBIN: 2-3 MAY 1957. Washington, DC: The National Academies Press. doi: 10.17226/9550.
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Suggested Citation:"CLINICAL CHARACTERISTICS ASSOCIATED WITH ABNORMAL HEMOGLOBINS." National Research Council. 1958. CONFERENCE ON HEMOGLOBIN: 2-3 MAY 1957. Washington, DC: The National Academies Press. doi: 10.17226/9550.
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Suggested Citation:"CLINICAL CHARACTERISTICS ASSOCIATED WITH ABNORMAL HEMOGLOBINS." National Research Council. 1958. CONFERENCE ON HEMOGLOBIN: 2-3 MAY 1957. Washington, DC: The National Academies Press. doi: 10.17226/9550.
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Suggested Citation:"CLINICAL CHARACTERISTICS ASSOCIATED WITH ABNORMAL HEMOGLOBINS." National Research Council. 1958. CONFERENCE ON HEMOGLOBIN: 2-3 MAY 1957. Washington, DC: The National Academies Press. doi: 10.17226/9550.
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Suggested Citation:"CLINICAL CHARACTERISTICS ASSOCIATED WITH ABNORMAL HEMOGLOBINS." National Research Council. 1958. CONFERENCE ON HEMOGLOBIN: 2-3 MAY 1957. Washington, DC: The National Academies Press. doi: 10.17226/9550.
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Suggested Citation:"CLINICAL CHARACTERISTICS ASSOCIATED WITH ABNORMAL HEMOGLOBINS." National Research Council. 1958. CONFERENCE ON HEMOGLOBIN: 2-3 MAY 1957. Washington, DC: The National Academies Press. doi: 10.17226/9550.
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Suggested Citation:"CLINICAL CHARACTERISTICS ASSOCIATED WITH ABNORMAL HEMOGLOBINS." National Research Council. 1958. CONFERENCE ON HEMOGLOBIN: 2-3 MAY 1957. Washington, DC: The National Academies Press. doi: 10.17226/9550.
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Suggested Citation:"CLINICAL CHARACTERISTICS ASSOCIATED WITH ABNORMAL HEMOGLOBINS." National Research Council. 1958. CONFERENCE ON HEMOGLOBIN: 2-3 MAY 1957. Washington, DC: The National Academies Press. doi: 10.17226/9550.
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Suggested Citation:"CLINICAL CHARACTERISTICS ASSOCIATED WITH ABNORMAL HEMOGLOBINS." National Research Council. 1958. CONFERENCE ON HEMOGLOBIN: 2-3 MAY 1957. Washington, DC: The National Academies Press. doi: 10.17226/9550.
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Suggested Citation:"CLINICAL CHARACTERISTICS ASSOCIATED WITH ABNORMAL HEMOGLOBINS." National Research Council. 1958. CONFERENCE ON HEMOGLOBIN: 2-3 MAY 1957. Washington, DC: The National Academies Press. doi: 10.17226/9550.
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Suggested Citation:"CLINICAL CHARACTERISTICS ASSOCIATED WITH ABNORMAL HEMOGLOBINS." National Research Council. 1958. CONFERENCE ON HEMOGLOBIN: 2-3 MAY 1957. Washington, DC: The National Academies Press. doi: 10.17226/9550.
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Suggested Citation:"CLINICAL CHARACTERISTICS ASSOCIATED WITH ABNORMAL HEMOGLOBINS." National Research Council. 1958. CONFERENCE ON HEMOGLOBIN: 2-3 MAY 1957. Washington, DC: The National Academies Press. doi: 10.17226/9550.
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Suggested Citation:"CLINICAL CHARACTERISTICS ASSOCIATED WITH ABNORMAL HEMOGLOBINS." National Research Council. 1958. CONFERENCE ON HEMOGLOBIN: 2-3 MAY 1957. Washington, DC: The National Academies Press. doi: 10.17226/9550.
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Suggested Citation:"CLINICAL CHARACTERISTICS ASSOCIATED WITH ABNORMAL HEMOGLOBINS." National Research Council. 1958. CONFERENCE ON HEMOGLOBIN: 2-3 MAY 1957. Washington, DC: The National Academies Press. doi: 10.17226/9550.
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Suggested Citation:"CLINICAL CHARACTERISTICS ASSOCIATED WITH ABNORMAL HEMOGLOBINS." National Research Council. 1958. CONFERENCE ON HEMOGLOBIN: 2-3 MAY 1957. Washington, DC: The National Academies Press. doi: 10.17226/9550.
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Suggested Citation:"CLINICAL CHARACTERISTICS ASSOCIATED WITH ABNORMAL HEMOGLOBINS." National Research Council. 1958. CONFERENCE ON HEMOGLOBIN: 2-3 MAY 1957. Washington, DC: The National Academies Press. doi: 10.17226/9550.
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Suggested Citation:"CLINICAL CHARACTERISTICS ASSOCIATED WITH ABNORMAL HEMOGLOBINS." National Research Council. 1958. CONFERENCE ON HEMOGLOBIN: 2-3 MAY 1957. Washington, DC: The National Academies Press. doi: 10.17226/9550.
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Suggested Citation:"CLINICAL CHARACTERISTICS ASSOCIATED WITH ABNORMAL HEMOGLOBINS." National Research Council. 1958. CONFERENCE ON HEMOGLOBIN: 2-3 MAY 1957. Washington, DC: The National Academies Press. doi: 10.17226/9550.
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Suggested Citation:"CLINICAL CHARACTERISTICS ASSOCIATED WITH ABNORMAL HEMOGLOBINS." National Research Council. 1958. CONFERENCE ON HEMOGLOBIN: 2-3 MAY 1957. Washington, DC: The National Academies Press. doi: 10.17226/9550.
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Suggested Citation:"CLINICAL CHARACTERISTICS ASSOCIATED WITH ABNORMAL HEMOGLOBINS." National Research Council. 1958. CONFERENCE ON HEMOGLOBIN: 2-3 MAY 1957. Washington, DC: The National Academies Press. doi: 10.17226/9550.
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PART V. CLINICAL CHARACTERISTICS ASSOCIATED WITH ABNORMAL HEMOGLOBINS CLINICAL MANIFESTATIONS OP SICKLE CELL DISEASES ERNEST W. SMITH AND C. L. CONLEY Erythrocytes which contain sickle hemoglobin can be made to sickle if the oxygen tension is reduced. Less reduction is necessary to produce sickling in erythrocytes containing a high percentage of sickle hemoglobin than in cells containing lesser percentages of sickle hemoglobin. Erythrocytes of individuals with sickle cell anemia (S - S) contain virtually one hundred per cent sickle hemoglobin and sickling is easily brought about at the oxygen tension of venous blood. Sickle trait erythrocytes contain less than fifty per cent sickle hemoglobin and under ordinary circumstances intravascular sickling is mimi- mal or absent; and the percentage of the sickle hemoglobin in the genetic variants of sicklemia, (S-C, S-D, S-Thal) most often lies between the high values for sickle cell anemia and the low values for sickle trait, with moderate amounts of intravascular sickling occurring. It seems clear that increased blood destruction and anemia are related to the sickling phenomenon. Sickling is accompanied by a marked increase in whole blood viscosity and an increase in the mechanical fragility of the er~rthrocytes. Increased viscosity and the mechanical entwining of the distorted red cells can produce vascular blockade, with more anoxia and more sickling, and the in- crease in mechanical fragility leads to premature removal of the erythrocytes from the circulation. Although other factors might be implicated, this provides a basic mechanism by which hemolytic anemia of sicklemia can be explained. Since Pauling and his associates) demonstrated that sicklemia is a molecular disease it is probable that most of the other manifestations of sicklemia are similarly related to the sickling phenomenon, or to other properties of the abnormal hemoglobin molecule. In general, the severity of the clinical manifestations of sicklemia parallels the percentage concentration of sickle hemoglobin within the erythrocyte. Thus in sickle cell anemia the hematocrit is almost invariably less than thirty per cent; in the genetic variants of sicklemia the degree of anemia is less often severe, and individuals with sickle trait do not ordinarily have anemia. Anemia might occur in individuals with sickle trait, however, if chronic oxygen deprivation results in sufficient reduction of the oxygen tension of the blood. The following case illustrates such an occurrence. E. B. (]HH No. A51753), an 11 year old Negro boy experienced art in- * This paper was presented by Dr. Smith. '' Medical Associate of the Howard lIughes Medical Institute. 276

SICKLI: CELL :l)ISEASlTS SMITH AND CONLEY so 4 51 _ 40 35 o/ /O 3O 25 20 15 10 5 277 it, O_0~ T X 10` Retic.t t 28% Retic. 2 %. MR8C 11 %.NRBC ~ f, O P E R AT-I ON E.B. 11 y, CM JOSH ~ A S1753 . 17 21 1 8 17 24 9 24 27 JUNE OCT JAN JULY N OV F E B MAR 4? 47 48 50 50 51 51 FIG. 1.—Sickle trait with anemia. JAN OCT FEB APR FFB FEB MAR 52 52 53 54 55 56 57 creasing cardiac failure, intermittent cyanosis and anemia during the first four years of life. On two occasions anemia became profound and nucleated red cells and increased numbers of reticulocytes were present in the blood (see fig. 1~. He was found to have tetralogy of Ballot which was associated with an arterial oxygen saturation of 64 per cent. A Blalock pulmonary-subclavian artery anastamosis was followed by marked improvement in the cardiac reserve, disappearance of cyanosis and disappearance of the anemia. Electro- phoresis of the hemoglobin revealed the sickle trait pattern. It is probable that the patient had a chronic hemolytic anemia which dis- appeared when the oxygen tension of the blood was returned toward normal by the operation. In the usual anemic varieties of sicklemia, however, the degree of anemia remains relatively constant over long periods of time. A fall in the hematocrit may follow a sudden increase in hemolytic activity, a happening designated as a hemolytic crisis. A precipitous fall in the hemato- crit following cessation of erythropoiesis, an aplastic crisis, is more to be feared because the suddenly produced anemia is a real threat to life. The cause for transient marrow aplasia is not clearly understood and aplastic crises occur in disorders other than sicklemia. The following case is illustra- tive of the clinical course of sickle cell anemia with an aplastic crisis. R. B. (JHH No. A 96466), a 4 year old Negro boy experienced repeated episodes of bone and abdominal pain and was repeatedly found to have severe hemolytic anemia. Over a two day period and in the absence of fever or of pain he became dyspneic, extremely pale and finally lethargic. On admission to the hospital he was in moderate shock and the hematocrit was less than 10 per cent. Bone marrow aspiration revealed absence of erythroid

278 30 25 20 15 10 s PART V. CLINICAL CH/NR.NCTERISTICS R.B. 4 yr CM MARROW MARROW MARROW JHH ~ A 96466 NO EARLY MANY LATE ER~HROID ERYTHROID ERYTHROID ACTIVITY ~ iCELLS iFORMS > T \~N / CRISIS— CRISIS— LEG PAIN ABO. P~N FEVER FEVER VOG i\ ^> v PALLOR SHOCK 9 12 19 F E B. 1956 1952 1953- 55 FIG. 2. Aplastic crisis in sickle cell anemia. ~ ,'18 NRBC ~ , a_ A, 26 28 29 2 6 MAR. 1956 activity. Whole blood transfusions were administered and during the ensuing five days repeated aspiration of bone marrow revealed a gradual resumption of erythroid activity, accompanied by reticulocytosis and entry of nucleated erythrocytes into the peripheral blood. The hematocrit subsequently re- mained at the level usual for the patient, approximately 22 per cent (see fig. 2~. It should be emphasized that hemolytic or aplastic crises are seldom ac- companied by severe pain, and that conversely, severe, painful crises and ever death occur in the absence of a fall in the hematocrit. In addition to predisposing to erythrocyte destruction, the vascular stasis which results from intravascular sickling undoubtedly is followed by tissue infarction. Many instances of infarction of various tissues are encountered in the sickle cell disorders. In general, infarctions are more common in sickle cell anemia than in other forms of sicklemia, but significant exceptions will be mentioned. Pulmonary infarction is extremely,- common among individuals with sickle cell anemia. Repeated episodes of infarction without other evidences of sickle crisis may occur.2 Pulmonary infarctions are less common in the genetic variants of sicklemia. Cerebral infarction occurs in sickle cell anemia and not infrequently results in a permanent neurological deficit. Infarction of the brain has been observed infrequently in sickle trait, but in some of the cases in which massive occlusion of vessels in the region of the infarction is due to sickled erythro- cytes the probability exists that sickle trait is causally related. In two in-

SICKLE CELL DISEASES SMITH AND CONLEY 279 stances the infarction occurred during an episode of anoxia due to pneumonitis. Infarction of the capital epiphysis of the femur or humerus occurs in various forms of sicklemia. However, it is encountered with far greater frequency among individuals with sickle-hemoglobin C disease or sickle- thalassemia than among those with sickle cell anemia. This departure from the generalization that intravascular stasis due to sickling should result in infarction more frequently in sickle cell anemia remains unexplained. Such- a generalization, however, does reflect the occurrence of splenic infarctions. The spleen of individuals with sickle cell diseases almost always shows evidences of infarction at autopsy or following surgical removal of the spleen. In individuals with sickle cell anemia the spleen may be reduced to a small mass of scar tissue. And presumably as a result of repeated infarction, a spleen which is enlarged during childhood may be observed to become smaller. Fibrous replacement of the spleen may occur in the sickle variants but more frequently splenomegaly with one or more old areas of infarction is en- countered in these disorders. Infarction of the spleen in sickle trait is not ordinarily encountered. However, the recent association of splenic infarc- tion in a few- individuals with sickle trait with airplane flight has yielded a considerable support to the belief that under circumstances of oxygen de- privation the erythrocytes of sickle trait individuals may sickle within the body and lead to infarction. The mechanism is, then, essentially like that which produced anemia in the patient with sickle trait and congential, cyanotic heart disease. Infarction of the spleen in individuals with genetic variants of sickle cell anemia, such as sickle-hemoglobin C disease or sickle-thalassemia, has occurred at lower altitudes than in individuals with sickle trait. Only gross infarction has been recognized in patients with sicklemia who were in airplane flight,3 ~ but few instances of gross splenic infarction with pain, fever, and shock have been observed in any form of sicklemia when not air- borne. The explanation for this discrepancy is not apparent. The mechanism by which severe pain of the bones, joints or of the viscera is produced in sicklemia is obscure. Engorgement of blood vessels with sickled cells and ~ resultant tissue anoxia has been implicated as a factor; but many severe crises with associated fever, leucocytosis, board-like rigidity of the abdominal wall have terminated in death and no vascular engorgement or infarction has been found. Following death during a crisis in other instances, however, extensive vascular engorgement has been found. Because of the extreme pairs and the not infrequently fatal outcome, the crisis is the most formidable part of the sickle syndrome. Although the entire list of manifestations of sicklemia will not be con-

280 PART V. CLINICAL CHARACTERISTICS ._ ._ ~ . ._ In ~ ._ o ~ U) 5 ~ ,~ . _ _= Cal o — _ O Cal =0 ,c~ Cal 1 ~ , 4 - 3 ·> ,`}

SICKLE CELL DISEASES SMITH AND CONLEY 281 sidered, four points deserve consideration. In figure 3a, a patient with sickle cell anemia exhibits the long, thin extremities which characterize the sickle cell habitue. The patient in figure 3b has painful crises and hemolytic anemia which are extremely severe, and has sickle-hemoglobin D disease. The con- trast between his normal body configuration and that of the individual with sickle cell anemia is apparent, but art explanation for the contrast is not ap- parent. Renal hemorrhage, which is most often unilateral and frequently massive, is encountered in patients with sickle cell Preemie, the genetic variants of sickle cell disease, and in sickle cell trait. Most of the reported cases have been in sickle trait. Infarction of the renal tissues has not been demonstrated. Finding of erosion of small veins and capillaries in some involved kidneys has supported ~ belief that hemorrhage resulted from leakage in a locally damaged vessel. A somewhat similar vascular accident may account for the intra-ocular hemor- rhage and vascular changes in the optic fundus which have been observed in sicklemia. Peculiar aneurysmal dilatations, twisted vascular loops and fine net-works of new vessel formation have been observed in the peripheral retinal fields of patients with different forms of sicklemia.5 (Figure 4, A & B.) In our ex- perience this vascular pattern has been encountered in only sickle-hemoglobin C diseased Obstruction of vessels with creation of a considerable back pressure and with ir~travascular sickling might be postulated as the damaging mech- anism for the vessels of the eye and of the kidney. ~ second form of renal lesion in sicklemia is represented by decreased water FIG. 4A and B.—Drawings of vascular anomalies visible in the peripheral retinal fields of patients with sickle-hemoglobin C disease. (Reproduced by permission from American Journal of Ophthalmology 42: 709, 1956.)

282 PART V. CLINICAL CHARACTERISTICS cc~centrating power.` Most marked in sickle cell anemia, the defect may be present in individuals with sickle trait. If erythrocytes containing sickle hemoglobin are replaced with normal erythrocytes the defect is abolished. These observations suggest that the loss of concentrating power is not due to anemia or to the sickling phenomenon, but is in some clay related to the presence of sickle hemoglobin. Further understanding of this relationship may lead to understanding of some of the other manifestations of sicklemia. REFERENCES 1. Pauling, L., Itano, fI. A., Singer, S. J. and Wells, I. C.: Sickle cell anemia, a molecular disease, Science 110: 543, 1949. 2. Moser, K. M., and Shea, J. G.: The relationship between pulmonary infarction, cor p2`lmonale and the sickle states, Am. J. Med. 22: 561, (April) 1957. 3. Cooley, J. C., Peterson, W. L., Engel, C. E., and Jernigan, J. P.: Clinical triad of massive splenic infarction, sicklemia trait and high altitude flying, J. Am. Med. Assn. 154: 111, 1954. 4. Smith, E. W., and Conley, C. L.: Sicklemia and infarction of the spleen during aerial flight. Electrophoresis of the hemoglobin in 15 cases, Bull. Johns Hopkins fIosp. 96: 35, (.lan.) 1955. 5. Henry, M. D., and Chapman, A. Z.: Vitreous hemorrhage and retinopathy associ- ated with sickle-cell disease, Am. J. Ophth. 38: 204, 1954. 6. Hannon, J. F.: Vitreous hemorrhages associated with sickle cell-hemoglobin C disease, Am. J. Ophth. 42: 707, (Nov.) 1956. 7~ Keitel, H. G., Thompson, D., and Itano, H. A.: Hyposthenuria in sickle cell anemia, a reversible renal defect, J. Clin. Invest. 35: 998, 1956.

THE THALASSEMIA SYNDROMES* AMOZ I. CHERNOFF The thalassemia syndromes are perhaps one of the least lively defined of the hereditary hemolytic diseases from the standpoint of genetic background, classification, basic biochemical abnormalities, and clinical and hematologic findings. It is hardly necessary to mention the difficulties encountered in fitting in the varied clinical pictures of thalassemia with the simple concept of heterozygosity or homozygosity for the responsible abnormal gene. It would seem most appropriate to consider that the thalassemia group of diseases is caused by a series of multiple interrelated genetic defects, not necessarily closely linked, which in various combinations give rise to a graduated series of hematologic aberrations, starting with the mildest asymptomatic state, in which the diagnosis can often only be inferred, and ending with the severe chronic microcytic hypochromic hemolytic anemia referred to as Cooley's anemia. It seems, furthermore, entirely possible that at least one of the genes involved in this syndrome is either identical with or closely related to the gene for fetal hemoglobin. This concept gains some support from ~ series of observations which we have made on adult members of at least five families in whom a very high level of Hb F`, up to 70-80 per cent, has been encountered but with peripheral blood findings only minimally suggestive of thalassemia. Different members of the same family group may show similar or more marked changes of thalassemia with or without the alterations in the concen tration of Hb F. Comparable kinships have been brought to my attention by several investigators in the New York area as well as from other parts of the country. It seems reasonable, consequently, to consider a modified genetic scheme, based almost entirely on speculation, as to the hereditary pattern of thalassemia. HYPOTHETICAL GENETIC FACTORS IN THALASSEMIA A- Enzymatic defect: Fe- E. P. reaction B - Abnormalities of red cell morphology C- Fetal hemoglobin factor Etc. THEORETICAL COMBINATIONS ABC/ABC Cooley's Anemia ABC/abc Thalassemia trait ABc/abc Minimal thalasse- mia, no Hb F aBC/abC High Hb F. min imal symptoms Ftc FIG. 1. For the sake of discussion, we may pick out three genes, not necessarily on the same chromosome' as playing a role in these syndromes (iRg. 1~. 'A' may be related to the enzymatic defect probably responsible for the inability to * Some of the studies reported in this publication were supported by United States Public Health Service Grant No. A-1615. 283

284 PART V. CLINICAL CHARACTERIST: :CS incorporate Fe into the erythrocyte protoporphyrin. 'B' may be assigned to the defect resulting in morphologic alterations such as anisocytosis, poikilocytosis, ovalocytosis, and target cells, and 'C' to the role played by Hb F. Other letters might be assigned to stippling, stromal defects, and so forth, although all or most of these may be involved in a single genetic aberration. The full blown heterozygote or homozygote would have all three of these hypothetical abnormalities. Others may have only the abnormalities related to 'B' and 'C' and manifest minimal symptoms with high levels of Hb F. Still others may have 'A' and 'B' present without the abnormality of 'C' and consequently demonstrate a thalassemia syndrome with normal levels of Hb F. Such a scheme would perhaps permit a better explanation for the wide spectrum of hematologic and clinical findings encountered in this group of diseases. TH ALASSEMI THALASSEMIA ~ ~ TRAIT FIG. 2.—Genetics of thalas- semia enamor ( after Valentine NORMAL THALASSEMIA THALASSEMIA and Neel). MAJOR TRAIT = GENE fOR THALASSEMIA For the sake of practical discussion, however, it seems best to continue the use of the simpler genetic concept proposed by Valentine and Neel pre- sented in fig. 2. In this instance, the thalassemia trait is considered to be the heterozygote for an abnormal thalassemia gene, and Cooley's anemia, the homozygote. We will continue to recognize, however, that the situation is undoubtedly much more complex than indicated in this figure. The desir- ability for accepting this less complicated system becomes obvious when it is recalled that thalassemia may be encountered in combination with other well recognized hereditary hematologic defects such as Hbs S. C, E, H and possibly D, as well as with elliptocytosis, hereditary spherocytosis, etc. Most if not all of these abnormalities are transmitted by genes located on chromo- somes different from those involved in the thalassemia states as evidenced by family studies in which one or both abnormalities may be passed on by a single parent to his or her child. The widespread distribution of the thalassemia defect is known to you all and need not be discussed except to point out the large foci of this disorder in the Mediterranean basin and the southern part of Asia. Thalassemia, how- ever, is found in all areas of the world and we have recently been impressed with its prevalence in the American Negro. The anthropologic implications of these observations provide interesting material for discussion but cannot be dealt with here.

THE THALASSEMIA SYNDROMES—CHERNOFF 28 i The most constant feature of the thalassemia syndromes is the extreme variability, from patient to patient, of the clinical symptomatology, physical findings and hematologic picture. It would serve no useful purpose to review the wide range of observations which may be encountered in uncomplicated thalassemia patients. The findings in the thalassemia-hemoglobin diseases parallel those of the aforementioned group in regards to nature, severity, and variability of the signs and symptoms. All may present as hypochromic micro- cytic hemolytic anemias of variable severity. All may demonstrate moderate to marked splenomegaly and hepatomegaly. Only a few have unique features which help to suggest the true nature of the disease. Thus, sickling in com- bination with thalassemia suggests thalassemia-lIb S disease. Greatly in- creased numbers of target cells in an otherwise uncomplicated case of thalas- semia may point to a combination with fIb C. The absence of Hb F and the presence of inclusion bodies in the red cells points to thalassemia-Hb H disease. In most instances, only a thorough study of parents, siblings and children, coupled with careful hematologic evaluation and hemoglobin analysis, will permit one to make a definitive diagnosis of thalassemia or one of its variants. The discovery of an abnormal hemoglobin in the patient's red cells, as well as in one of the parents (except in the fIb H syndromes), is of great significance. Finally, the determination of fIb F will be of importance since all of the thalassemia variants save those due to Hb lI may have significantly increased amounts of the fetal pigment. It is of interest that in spite of the presumed heterozygosity for the thalassemia gene and the abnormal hemoglobin, Hb A is rarely found on hemoglobin analysis. This problem has been dealt with in a recent publication and the suggestion was made that the absence of lIb A may be explained on the basis of suppression of the overt effects of the gene for Hb A by the thalassemia gene either directly or by virtue of the increase in Mb }I.' Recently Schwartz and co-workers have postulated a similar mech- anism in a complex family carrying stigmata of thalassemia, Hb S and Hb G.3 Furthermore, in a recent study of a family with Hb S and a possible new hemoglobin compound, Durham lRo. 1 the same evidence of suppression of Hb A exists. Consequently, the absence ot the adult compound does not ., . ~ . . necessarily imply the homo7v~0us state for the abnormal hemoglobin and ~ . _, at, . . .. , D must be interpreted in the light of the more recent observations described above. Since the Endings in thalassemia-IIb E disease parallel those of the other syndromes mentioned above, we will discuss briefly the findings in this group of diseases.' Hb E is characterized by its unique electrophoretic mobility, occupying a position midway between that of Hb C and Hb S on paper elec- trophoresis, at an alkaline pII. In acid solution it migrates more slowly than either Hb S or C and may thus be easily identified. Hb E occurs primarily in Southeast Asia, with its peak prevalence in Thailand, but with a significant incidence in Burma, Indonesia, and the regions formerly known as Indochina. Lesser numbers of patients are seen in Ceylon, India and Persia, with sporadic

286 PART V. CLINICAL CHARACTERISTICS reports from other areas all probably ire individuals related to the Southeast Asian group of nations. The heterozygous form of fIb E, the Hb E trait, is a completely benign situation. Homozygous . .. . . . . . . . Hb E disease is characterized as an extremely mace hemo~yt~c anemia with m~crocytic normochromic red cells and little in the way of abnormal physical findings, except minimal splenomegaly. Its most striking feature outside of the genetic and hemoglobin abnormalities is the presence of up to 60-80 per cent target cells and the consequent shift in the osmotic fragility curve to the right. Thalassemia-Hb E disease has been recognized with increasing frequency in Thailand, Burma, and Indonesia and except in a few minor respects, mimics Cooley's anemia. The severest cases are in children, but individuals in their thirties have been encountered. The physical findings of enormous hepato- megaly and splenomegaly are seen in the younger age groups, but moderate to minimal organ enlargement may be encountered in the adult. Similar varia- tions are related to observations concerning weakness, fatigue, dyspnea on effort, lack of development, icterus, signs of hemolysis and bone changes. Transfusion therapy may be required as often as in the most severe example of Cooley's anemia but tends to be less of a necessity than in the latter disease. Splenectomy has been of some help in controlling the mechanical difficulties resulting from the huge organ and may also cut down on a high transfusion requirement, although no evidence of an extra-corpuscular defect has been obtained. Finally, hemoglobin analysis usually demonstrates from 20-40 per cent Hb Fat, with the remainder being Hb E. Hb A has rarely been encoun- tered in this syndrome. In summary, we have reviewed some of the many problems related to this complex and interesting group of diseases. It is apparent that much more careful genetic, hematologic and biochemical studies will be required before our understanding of this syndrome is complete. The elucidation of the role of the abnormal hemoglobins has fortunately given an impetus to further study in this area and it is only a matter of time before we will have ~ more precise foundation upon which to base our knowledge of thalassemia. REFERENCES 1. Valentine, W. N., and Neel, J. V.: Hematologic and genetic study of transmission of thalassemia (Cooley's anemia: Mediterranean anemia), Arch. Int. Med. 74: 185-196, 1944. 2. Chernoff, A. I., Minnich, V., Na-Nakorn, S., Tuchinda, S., Kashemsant, C., and Chernod, R.: Studies on hemoglobin E. I. The clinical, hematologic, and genetic characteristics of the hemoglobin E syndromes, J. Lab. 8c Clin. Med. 47: 455- 489, 1956. 3. Schwartz, H. C., Spaet, T. H., Zuelzer, W. W., Neel, J. V., Robinson, A. R., and Kaufman, S. F.: Combinations of hemoglobin G. hemoglobin S and thalassemia occurring in one family, Blood 12: 238-250, 1957.

HEMOGLOBIN C DISEASES HELEN M. RANNEY The electrophoretic properties of hemoglobin C were described in 1950 by Itano and Neel,5 and the clinical findings accompanying the presence of this abnormal hemoglobin in the heterozygous state and in combination with sickle cell hemoglobin were reported by Kaplan, Zuelzer and Neel.7 The in- troduction of kilter paper electrophoresis greatly facilitated the identification of hemoglobin C, and the occurrence of this abnormal hemoglobin in four con~- binations has been described. These combinations are: (1) hemoglobin C trait, where hemoglobin C is found together with normal adult hemoglobin, (~) sickle cell-hemoglobi~2 C disease, in which hemoglobin C and hemoglobin S occur in approximately equal amounts, (3) hemoglobin C disease where vir- tually all the hemoglobin is of this abnormal variety and (4) hemoglobin C- thalassemia in which the hemoglobin electrophoretic pattern resembles that of hemoglobin C disease, but in which the affected individual has a single genetic factor for hemoglobin C in addition to a gene for thalassemia. This report is concerned with the clinical manifestations associated with the presence of hemoglobin C in hemoglobin C trait, hemoglobin C disease, and hemoglobin C-thalassemia. Little will be said about sickle-cell hemoglobin C disease, since Dr. E. W. Smith has already covered the important aspects of that disorder. Hemoglobin C trait. The combination of hemoglobin C and normal adult hemoglobin in asymptomatic individuals was first detected in family studies;7 however, large scale surveys for abnormal hemoglobins revealed hemoglobin C trait in 2 to 3 per cent of American Negroes. A Very high ~ncidences of hemoglobin C were detected in certain areas of West Africa; indeed, in some communities of the northern Gold Coast (now Ghana), more than 20 per cent of the individuals studied were found to have hemoglobin C.9 No clinical symptoms have been associated with hemoglobin C trait; the only observed abnormality in these individuals has been an increased number of target cells on blood smears. We have encountered a single patient with hemoglobin Cal trait and unexplained hematuria, but the association was probably fortuitous. The hemoglobin of individuals with hemoglobin C trait has been tom- posed of approximately 30 to 45 per cent hemoglobin C, with the larger re- maining fraction being normal adult hemoglobin. No significant increase in alkali-denaturable hemoglobin has been observed. Sickle cell-hemoglobin C disease. In terms of the frequency of the disease and the severity of symptoms, sickle cell-hemoglobin C disease is the most important of the disorders associated with the presence of hemoglobin C. ~ This study has been supported by Grant A-1017 of the National Institute of Arthritis and Metabolic Diseases, U. S. Public Health Service. 287

288 PART V. CLINICAL CHARACTERISTICS The large number of reported cases attests to the fact that this is a common disorder in American Negroes. An increased incidence of crises during preg- nancy, bone infarcts, particularly in the femoral head, and ocular changes have been encountered. Our particular interest in patients with sickle cell-hemo- globin C disease has been a study of the mode of inheritance of hemoglobin C and sickle cell hemoglobin. Studies of eight offspring of sickle cell and normal individuals revealed only hemoglobin C trait or sickle cell trait in the off- spring (figs. 1 and 2~; it seems probable that genes responsible for sickle cell hemoglobin and hemoglobin C are allelic or are closely linked.~3 FIGS. 1 and 2. Filter paper electrophoretic patterns of hemoglobin. Veronal buffer, pH 8.6. Offspring of S/C x A/A had either hemoglobin C trait or sickle cell trait. Hemoglobin C disease. The term "hemoglobin C disease" in this report refers to the clinical manifestations of the patient who is, or who is pre- sumed to be, homozygous for the gene for hemoglobin C. Hemoglobin C disease, therefore, occurs in approximately one-quarter of the offspring of marriages of two individuals, each possessing a single gene for hemoglobin C (fig. 3~; most commonly, of course, each parent would be expected to have hemoglobin C trait. Since many of the patients with hemoglobin C disease were first detected in adult life, genetic proof of homozygosity has been fre- quently lacking in reported cases. The offspring of the marriage of an indi- vidual with hemoglobin C disease to an individual levity normal hemoglobin FIG. 3. Child with hemoglobin C disease and increased fetal hemo- globin ( rapid component ) .~3 Note resemblance of pattern to that of propositus in figure 7.

HEMOGLOBIN C DISEASES—RANNEY 289 have shown ire every reported instance hemoglobin C trait (fig. 4~. The finding of hemoglobin C trait in offspring does not prove homozygosity, but the absence of hemoglobin C in offspring would prove heterozygosity of the parent with hemoglobin C. The analysis of the hemoglobin of parents and offspring of individuals with hemoglobin C disease is the most reliable method of distinguishing hemoglobin C disease from hemoglobin C-thalas- semia. FIG. 4.—Hemoglobin C disease in mother. Each child had hemoglobin C trait. :. ~ The following observations on hemoglobin C disease are based upon data from 34 patients;], 3, 4' 6, s, 1o-l7, 10 '1-'' all but one have previously been reported in the American or British literature. The outstanding features of hemoglobin C disease may be summarized as follows: 1) splenomegaly, 2) a mild hemolytic process, with or without an attendant anemia? and 3) large renumbers of target cells in the stained smears. Most of the cases have been detected in the course of evaluation for complaints unrelated to hemoglobin C disease or were found incidental to the investigation of hemoglobin patterns of families. It may properly be inferred, therefore, that this is a benign disorder. The electrophoretic pattern of hemoglobin in hemoglobin C disease consists virtually entirely of hemoglobin C; two casesS 13 have shown an increase in fetal hemoglobin (figs. 3 and 4~. In table I are summarized some of the features of hemoglobin C disease. The age range extended from 4 to 79 years; in view of sampling bias such as might be introduced by the study of patients at Veterans' hospitals, the pre- dominance of males is of doubtful significance. The occurrence of hemo- globin C disease in non-Negro populations was noted by Diggs et al., who observed the disease in a male of Italian extraction and by Lewis and co- workers,l1 who reported three cases in a white South African family. W have recently observed another South African man of Dutch and French ancestry with hemoglobin C disease. Anemia, as indicated above, in uncomplicated hemoglobin C disease is mild or absent in the reported cases; the only reported case with severe

290 PART V. CLINICAL CHARACTERISTICS TABLE I HE~CGECBIN C DISEASE ( 34 cases ) Ages: 4-79 yrs. Males 23 Females 1 1 Dutch West South Race or Negro Italian Indian -African White Nationality 27 1 2 4 Anemia: Severe Mild None Splenomegaly: 32 of 34 cases Male Female 3 19 Approximately one-third had normoblasts on smear; target cells were a constant feature, varying from 10 to 90~o. anemia was a 79-year-old man with an infection.~5 In table I most of the patients with anemia are women; this finding may be related to the fact that hemoglobin values are normally lower in women than in men, and perhaps hemolytic process may become manifest as anemia more readily in females. Studies of the survival time of erythrocytes in hemoglobin C disease have invariably disclosed a hemolytic mechanism despite the absence of anemia (table II). Erythrocyte survival times of 40 to 60 days, with one-half survival times of 13 to 24 days were observed.S' 15, i7, 2~, 9~, 94 The data are consistent with the assumption that the shortened survival time is related to an intra- corpuscular defect. The only exception to the latter statement is the second patient of Lange and co-workers;S their patient had an infection during the course of the erythrocyte survival study. TABLE II ERYTHRCCYTE SURVIVAL IN HEMOGLOBIN C DISEASE Author Method Pt. cells Normal Pt. cells to normal cells to in pt. recipient pt. recipient days days days Spaet Ashby ct al. agglut. 55 Singers' Ashby mean 13 et al. agglut. Weinstein Cry half—19 et al.04 Terry Ashby 42 106 et al.20 Hb. sep. LangeS Cry normal av. 21 et al. short av. 24

HEMOGLOBIN C DISEASES RANNEY 291 The more readily available laboratory tests for a hemolytic process usually have yielded less impressive data. Reticulocytosis has, in general, been less than 5 per cent, although normoblastic hyperplasia of the bone marrow has been found. Nucleated erythrocytes have been found in many of the peripheral blood smears. The most impressive finding on blood smear was the increased number of target cells, frequently with erythrocyte "folding" (fig. 5~. How- ever, in some cases the target cells have comprised only 10 to 30 per cent of the erythrocytes. Obviously the number of target cells carrot be used to distinguish hemoglobin C disease from hemoglobin C trait, since 20 to 30 per cent target cells have been seen in hemn~lohin (A frnit :-- :. F`IG. 5.—Blood smear of patient with hemoglobin C disease. Note target cells and erythrocyte "folding." F`IG. 6.—"Intra-erythrocytic crystals" in a patient with hemoglobin C disease after splenectomy (Diggs et al.~). Shown at higher magnification than slide in figure 5. Splenomegaly is an almost constant feature of hemoglobin C disease. Only twos 93 of the thirty-four cases summarized in this review lacked a palpable spleen, and one of these was a child of three and a half years. Spl~enectomy was carried out in four cases of hemoglobin C disease:' id, ]7, 25 in three, the procedure was done for mechanical enlargement of the organ, and in the fourth'' a mild anemia and significant thrombocytopenia were relieved by splenectomy. In two of the four patients subjected to splenectomy an extra- ordinary appearance of some of the erythrocytes was noted following splenec- tomy Wing. 6~. The exact nature of these hemoglobin masses in erythrocytes is Dracula to ascertain; they are believed to represent hemoglobin crystals by

292 PART V. CLINICAL CHARACTERISTICS Riggs and co-workers.4 Wheby et al.>' have noted similar changes in the blood smear of a patient with hemoglobin C disease following splenectomy. The mechanism of the effects of splenectomy upon formed elements of the circulating blood is little understood, and these Endings add another intriguing observation in that held. In summary, hemoglobin C disease is a benign hemolytic disorder, occurring chiefly but not entirely in Negroes. Splenomegaly and target cells are more constant findings than is anemia. Only one patient has developed evidence of "hypersplenism"; patients with anemia and thrombocytopenia returned to normal following splenectomy. Hemoglobin C-~halassemia. The combination of thalassemia and hemo- globin C has been described in several patients. Is _6 The diagnosis for four of the reported cases has rested upon the demonstration of thalassemia in one parent of the affected individual and hemoglobin C trait in the other parent (fig. 7 ). The clinical picture which accompanies this combination of genetic factors has been quite variable. Anemia is a prominent feature in two cases and FIG. 7. Propositus whose hemo- globin was mostly of the C variety had hemoglobin C-thalassemia. Note absence of abnormal hemo- globin of father who had thalas- semia minor with an increased A.' - hemoglobin. . ~ FIG. 8. Blood smear of patient with hemoglobin C-thalassemia. Hypochromia, target cells and nucleated erythrocytes are seen.

HEMOGLOBIN C DISEASES RANNEY 293 splenomegaly is seen in three cases. Microcytosis, hypochromia, target cells (fig. 8), arid, in some cases, microspherocytosis is seen on smears. Ire table III are summarized the findings of reported cases of hemoglobin C-thalassemia. Three of the cases occurred in Negroes and the remaining three in patients of Italian extraction. Reticulocytosis was usually not prominent feature except during a hemolytic episode in the author's case. A great variation in the amount of hemoglobin C was noted. The case of Zuelzer and Kaplan'' was the most severely anemic but showed only 29 per cereal hemoglobin C with no increase in fetal hemoglobin. Values of more than 90 per cent hemoglobin C were noted by Erlandson et al.;2 their patients had hemoglobin electrc~pl~oretic patterns indistinguishable from those of patier~ts with hemoglobin C disease. While most of the reported patients have had some increment of normal adult hemoglobin in addition to hemoglobins C' and A, the amount of hemoglobin A nary be so small tot accurate determi- nation is difficult. Consequently, a study of the hemoglobin of other members of the family is a more reliable way of establishing the diagnosis of hemoglobin C-thalassemia than analysis of the hemoglobin of the affected individual alone. The sixth case was ire many respects unusual. The patient was initially seen at the Presbyterian Hospital in 1941, at which time splenomegaly, a severe hemolytic anemia with 32 per cent reticulocytosis and a decreased osmotic fragility were found. Following; splenectomy, her hemoglobin stabi- lized at 8 to ~ O grams per cent with 2 to 4 per cent reticulocytes. The large amount of hemoglobin C (78 per cent) in this patient has been ac- companied by the appearance of occasional "intraerythrocytic" crystals. Hemoglobin C-thalassemia is an uncommon disorder associated with the simultaneous presence of genetic factors for hemoglobin C and thalassemia. While all the patients showed microcytosis and target cells, splenomegaly appeared in only half the cases, and two of the six cases were markedly anemic. TABLE III HEMOGLOBIN C-THALASSEMIA DISEASE Zuelzer and"; Singer e! alit Kaplan Erlandson e' alp Ranney Age: 68 29 6 10 14 36 Race or Nationality of parents: Negro Negro Negro Italian Italian Italian ( Sicily) ( Sicily) Splenomegaly: 0 0 0 yes yes yes spl enectoms Hemoglobin, gum/,,: 12.7 11.5 6.1 9-11 9-11 5-10 Microcytic: yes yes yes yes yes yes Reticulocytes, C/G 3.8 2.0 3.6 2.3 2.3 32-0.5 Osmotic fragility: deer. deer. deer. deer. deer. deer. Hemoglobin C, %: 77 74 29 93 90 78 Fetal hemoglobin, /: 0 2.7 <2 1.4 0.4 5

294 PART V. CLINICAL CHARACTERISTICS A severe hemolytic anemia in one case was alleviated by splenectomy. In view of the variation in clinical symptoms and in the amounts of hemoglobin C present, hematologic studies of the family are usually needed to establish the diagnosis. Summary. 1. Hemoglobin C trait is art asymptomatic state occurring in 2 to 3 per cent of American Negroes, with much higher incidence in certain areas of Africa. 2. Hemoglobin C disease is a mild disorder occurring predominantly in Negroes. Splenomegaly' target cells on blood smears, and a mild hemolyti~ process with or without anemia are prominent features. The hemoglobin is virtually all of the "C" variety. 3. Hemoglobin C-thalassemia is accompanied by greater variability in the clinical findings than hemoglobin C disease. The amount of hemoglobin C in this rare disorder has varied from 29 per cent to over 90 per cent; conse- quently, family studies are recommended for distinguishing between hemo- globin C disease and hemoglobin C-thalassemia. ~1ckrzowledgments: Figures 1, 2, 3 and 4 were reproduced by permission from the Journal of Clinical Investigation 33: pp. 1636 and 1637, ~ 954. Figure 6 was reproduced by permission from the article by Dr. L. W. Diggs en al., Blood 9: p. 1174, 1954. REF~EREN CES 2. 3. 4. 7. 1. Diggs, L. W., Kraus, A. P., Morrison, D. B., and Rudnicki, R. P. T.: Intraery- throcytic crystals in a white patient with hemoglobin C in the absence of other types of hemoglobin, Blood 9: 1172, 1954. Erlandson, M., Smith, C. H., and Schulman, I.: Thalassemia-hemoglobin C disease in white siblings, Pediatrics, 17: 740, 1956. Hartz, W. H., and Schwartz, S. O.: Hemoglobin C disease, Blood 10: 235, 1955. Huisman, T. H. J., van der Schaaf, P. C., and van der Sar, A.: Some characteristic properties of hemoglobin C, Blood 10: 1079, 1955. Itano, H. A., and Neel, J. V.: A new inherited abnormality of human hemoglobin, Proc. Nat. Acad. Sci. 56: 613, 1950. Jensen, W. N., Schoefield, R. A., and Agner, R.: Clinical and necropsy findings in hemoglobin C disease, Blood 12: 74, 1957. Kaplan, E., Zuelzer, W. W., and Peel, J. V.: A new inherited abnormality of hemoglobin and its interaction with sickle cell hemoglobin, Blood 6: 1240, 1951. 8. Lange, R. D., and Hagen, P. S.: Hemoglobin C disease in identical twins, Am. J. Med. Sci. 229: 655, 1955. 9. Lehmann, H.: Distribution of abnormal hemoglobins, J. Clin. Path. 9: 180, 1956. 10. Levin, W. C., Schneider, R. G., Cudd, J. A., and Johnson, J. E., Jr.: A family with homozygous hemoglobin C and sickle cell trait union. A clinical, hematological and electrophoretic study, J. Lab. and Clin. Med. 42: 918, 1953. 1 1. Lewis, S. M., Anderson, C. G., and Baskind, E.: Homozygous haemoglobin-C disease in a white family with special reference to blood autolysis studies, Brit. J. Haemat. 3: 68, 1957. _. Motulsky, A. G., Paul, M. H., and Durrum, E. L.: Paper electrophoresis of abnormal hemoglobins and its clinical applications, Blood 9: 897, 1954.

HEMOGLOBIN C DISEASES—:IlANNEY 295 15. 1 3. Ranney, H. M.: Observations on the inheritance of sickle cell hemoglobin and hemoglobin C, i. Clin. Invest. 33: 1634, 1954. 14. Ranney, H. M., Larson, D. L.' and McCormacl<, G. H., Jr.: Some clinical, bio- chemical and genetic observations on hemoglobin C, J. Clin. Invest. 32: 1277, 1953. Ransone, J. W., and Lange, R. D.: Homozygous hemoglobin C disease in a 79 year old man with gout, Ann. Int Med. 46: 420, 1957. 16. Schwart%, S. O., and Hartz, W. H., Jr.: Mediterranean anemia in the Negro, Blood 10: 1256, 1955. 17. Singer, K., Chapman, A. Z., Goldberg, S. R., Rubinstein, H. M., and Rosenblum, S. A.: Studies on abnormal hemoglobins. IX. Pure (homozygous) hemoglobin C disease, Blood 9: 1023, 1954. 18. Singer, K., Kraus, A. P., Singer, L., Rubinstein, H. M., and Goldberg, S. R.: Studies on abnormal hemoglobins. X. A new syndrome: Hemoglobin C-thalas- semia disease, Blood 9: 1032, 1954. 19. Schneider, R. G.: Incidence of hemoglobin C trait in 505 normal Negroes: a family with homozygous hemoglobin C and sickle-cell trait union, J. Lab. and Clin. Med. 44: 133, 1954. 20. Smith, E. W., and Conley, C. L.: Filter paper electrophoresis of human hemo- globins, with special reference to the incidence and clinical significance of hemoglobin C, Bull. Johns Hopkins Hosp. °3: 94, 1953. 21. Spaet, T. H., Alway, :R. PI., and Ward, G.: Homozygous type 'C" hemoglobin, Pediatrics 12: 483, 1953. 22. Terry, D. W., Motulsky, A. G., and Rath, C. E.: Homozygous hemoglobin C, New Eng. l. Med. 251: 365, 1954. 23. Watson, R. J.: The hereditary anemias, Bull. N. Y. Acad. Med. ]0: 106, 1954. 24. Weinstein, I. M., Spurling, C. I., Klein, H., and Necheles, T. F.: Radioactive sodium chromate for the study of survival of red blood cells. III. The abnormal hemoglobin syndromes, Blood 9: 1155, 1954. 25. Wheby, M. S., Thorup, O. A., and Leavell, B. S.: Homozygous hemoglobin C disease in siblings: Further comment on intraerythrocytic crystals, Blood 1~1: 266, 1956. 26. Zuelzer, W. W., and Kaplan, E.: Thalassemia-hemoglobin C disease, Blood 9: 1047, 1954. DISCUSSION Dr. W. f. Zuelzer: The subjects on ~Thich I might have anything to say have been ~rery amply and nicely covered. The only comment I would like to make is in respect to Hb C combinations which, as Dr. Ranney has said, can vary quite a lot in their physiologic expressions. There again, we may have some evidence of the kind that Dr. Neel touched on this morning. Under certain conditions at least, we might 1O0JA; upon these variants as not neces- sarily abnormal. The cases which were described by Dr. Singer and his group showed a minimum of physiologic disturbance. The case we obser~red and some that Dr. Rarlney herself described, showed a great deal of severe anemia. The point is that in these interaction effects, or so-called interaction effects, we

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