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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

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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

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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-

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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-

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

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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.)

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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.