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Splenic function in sickle cell disease in the Eastern Province of Saudi Arabia
Splenic function in sickle cell disease in the Eastern Province of Saudi Arabia The sickle cell disease that occurs in the Eastern Province o f Saudi Arabia is reported to be clinically benign. It is biochemically characterized b)' high levels o f fetal hemoglobin. Twenty-four Saudi patients with sickle cell disease were compared with 22 American patients. ,,Is a group, the Saudi patients were less anemic attd had less hemolysis, microcytic RBC, and much higher levels o f Hb F Splenic function was assessed by enumeration o f pocked RBC\ Seventeen Saudi patients had low numbers o f Pk RBC, indicating normal or nearly normal splenic function, whereas all American patients had markedl)' decreased splenic function attd high numbers o f Pk RBC. Low levels o f Pk RBC were strongly associated with high levels o f lib F: The genetic basis o f the mihler sickle cell disease in Saudi Arabia has not been elucidated, but may involve multiple genetic factors. Although the sickle cell disease in Arab patients o f eastern Saudi Arabia is often less severe than that in America. it is f a r from "'benign, "" attd some patients have severe clinical courses similar to those in patients in the IVest. (J Prot~trR 10.&714, 1984)
Baker AI-Awamy, M.D., Ph.D., Wendell A. Wilson, M.D., and ltoward A. Pearson, M . D . D a m m a m , S a u d i A r a b i a , a n d N e w H a v e n , C o n n .
TIlE SICKLE
C E L L DISEASE that occurs in Shiite Moslems of the Arabian gulf area, especially the Eastern Province of Saudi Arabia, has striking clinical and hematologic differences from that observed elsewhere in the world. The disease is reported to be clinically mild, with only moderate hemolytic anemia?.-' The most striking biochemical feature is t l b F levels averaging 20%. Such high levels are rarely seen in American patients after early childhood?-~ Much of the severe morbidity and mortality in sickle cell
Front the Departments o f Pediatrics. King Faisal University College o f Medicine and )'ale UniversiO' School o f Medicine. Supported in part by the Saudi Arabian National Center f o r Science and, Technology. Some o f the Anwrican patients described in this report are enrolled in the Comprehensive Stud)' o f Sickle Cell Diseases supported by the National lleart. Lung attd Blood Institute, National Institutes o f llealth. Presented in part at the Meeting o f the American Society o f llematology, December 1982. and the APS]SPR Meetings, Washington, D.C:. May 1983. Reprint requests: lIoward A. Pearson. M.D., Department o f Pediatrics, )'ale University School o f Medicine, 333 Cedar St., New llaven, CT 06510.
7 14
The Journal o f P E D I A T R I C S
anemia can be related to aberrations of splenic function? Overwhelming bacterial sepsis and acute splenic sequestration are the principal causes of the inordinately high early mortality in black children with sickle cell anemia in the United States and Jamaica? .7 Splenic dysfunction is nearly invariable in patients with sickle cell anemia in the Western hemisphere? .~ Between 5 months and 5 years of
See related article, p. 734.
lib F Hb S lib SS IIPFII Pk RBC
Fetal hemoglobin Sickle hemoglobin Ilomozygous lib S disease ltercditary persistence of fetal hemoglobin "Pocked" red blood cells
age, virtually all patients become "functionally hyposplenic,"as reflected in the lack of splenic uptake of 99roTesulfur colloid, a percentage of "pocked red ceils" determined by interference phase-contrast microscopy >3.5%, and a relatively high incidence of overwhelming bacterial sepsis and meningitis) .9 The presence of >3.5% circulating Pk RBC also has a high correlation with nonvisualization of the
Volume 104 Number 5
Splenic function in sickle cell disease
715
Table. Hematologic measurements in Saudi and American patients
Hb
Reticuloo'tes
Mean corpuscular volume
(%)
Oq)
Patients
Age
Pk RBC
ttb F
(n)
(yr)
(%)
(%)
Saudi Arabian Low Pk RBC (<3.5%)
17
13.7 ___ 1.0
1.2 _+ 0.8
18.3 + 5.8
I 1.5 -_. 1.6
4.0 --. 2.5
7 0 . 0 _.+ 7.8
H i g h Pk R B C
7
17.3 + 5.6
21.2 + 8.9
9.1 + 4 . 0
10.2 __. 2.5
5.7 --- 1.8
78.0 +__ 5.4
22
12.9 + 6.2
14.5 _+ 4.1
5.2 _+ 2.2
8.3 + 0.7
11.4 --. 3.9
89.3 __. 5.3
r
(>3.5%) American Values are mean • 1 SD.
spleen by radionuclide scanning, a~We compared Pk RBC, hematologic values, and Hb F levels in a group of Saudi patients with sickle cell disease with those in a matched group of American patients with homozygous Hb S disease. PATIENTS
AND METHODS
Twenty-four Saudi Arabs (15 males, nine females) aged 9 months to 40 years, living in the Eastern Province of Saudi Arabia, were randomly selected from the Qatif Community Hospital roster of patients with sickle cell disease. For comparison, 22 American patients with sickle cell anemia were chosen from the sickle cell clinic of YaleNew Haven Hospital. American patients were chosen to correspond to the ages and genders of the Saudi patients, although none was older than 26 years. The diagnosis of SS disease in the Saudi patients was based on hemoglobin electrophoretic patterns on cellulose acetate at pH 8.2 and agar gel at 6.0, which showed hemoglobins S, F, and A2 and the absence of Hb A. Although insufficient blood was available to perform quantitative hemoglobin A, determination by column chromatography in the Saudi patients, densitometric scans of cellulose acetate electrophoretic patterns revealed Hb A, levels <3.5% in all instances. Family studies in many of the Saudi patients showed both parents to have sickle cell trait. Similar diagnostic criteria were used in the American patients. Erythrocyte indices were determined with a calibrated electronic Coulter counter. Hb F was quantitated by the alkali denaturation method. 't Distribution of Hb F in the RBC was assessed by the acid elution method of Kleihauer et al. ~2 and had a heterogenous distribution in all patients. Splenic function was assessed by quantitating the percent of Pk RBC. 8-~3Two drops of venous blood were fixed in buffered 3% gluteraldehyde, pH 7.4. One thousand consecutive RBC were examined under an interference
phase-contrast microscope with Nomarski optics for the presence of one or more apparent surface indentations, or "pocks." Normal eusplenie individuals have <2% Pk RBC, and anatomically asplenic persons have 12% to 30% (.~ 20%) Pk RBC." RESULTS As a group, the Saudi patients had considerably higher levels of total Hb and Hb F and lower levels of reticulocytes, MCV, and Pk RBC than the American patients. The Saudi patients fell into two distinct groups with respect to Pk RBC: 17 had normal or near normal levels (<3.5%), and seven had high levels. Significant differences were observed when the characteristics of the seven Saudi patients with a high proportion of Pk RBC were compared with those with low Pk RBC (Table). The seven patients with high Pk RBC had lower levels of Hb F, were more anemic, had higher reticulocyte counts, and had less microcytosis than those with low Pk RBC. Linear regression analysis revealed a significant relationship between high Hb F and low Pk RBC (correlation coefficient, P = 0.005) (Figure). Mean corpuscular volume also correlated with Pk RBC but at a much lower level of significance (P = 0.06). The Saudi patients with low Pk RBC had more splenomegaly (6/17 vs 0/7) and had received transfusions less frequently (9/17 vs 6/7) than those with higher levels. DISCUSSION This study shows that more than two thirds of Arab patients with sickle cell disease have normal or nearly normal splenic function, as reflected by low percentages of circulating Pk RBC. When compared with American patients, S a u ~ patients as a group had lesser degrees of hemolytic anemia, more microcytosis, and strikingly higher levels of Hb F. Microcytosis in patients with Hb SS disease usually indicates the concomitant presence of a-thalassemia. a-Thalassemia, associated with deletion of one or two
7 16
AI-Awamy, Wilson, and Pearson
The Journal of Pediatrics May 1984
9
32
28
N
24 20 % "POCKED" 16 RBC 12 8
4 0 0
I
OI 9
4
8
i Oqu ~ I~ 12
~0
16 20 %HbF
e~O0 I 24
28
I
32
Figure. Fetal hemoglobin and Pk RBC in Saudi patients.
alpha genes, has a frequency of 30% and 2%, respectively, in black Americans? 5 It has been suggested that o~-thalassemia may reduce the severity of Hb SS disease, probably by reducing the mean corpuscular Hb S concentration? 6 However, a relationship between low red cell indices and lesser clinical severity has not been confirmed by other studies." Cord blood studies in the Eastern Province of Saudi Arabia have shown the presence of Barts Hb, "t4, which is an indicator of a-thalassemia in about 50% of individuals,ts The gene for fl-thalassemia is also prevalent in eastern Saudi Arabia, and 14% of individuals with apparent SS disease have been recently shown, on the basis of family studies, to have Hb S fl~ thalassemia? 9 These individuals with Hb S fl~ thalassemia were virtually indistinguishable, both clinically and hematologically, from homozygous Hb SS patients; unlike American patients, most had normal levels of Hb A2.~9 Another genetic condition that might interact with sickle cell disease and result in increased levels of Hb F is the so-called heterocellular hereditary persistence of fetal hemoglobin. This condition is associated in the heterozygous state with slight elevations of Hb F (2% to 3%). 20 Although this,condition has not been noted in previous screening studies from Saudi Arabia, 2~ we found slightly elevated Hb F levels (2% to 4%) in several individuals with sickle cell trait studied as controls in our spleen studies. Therefore, a condition resembling heterocellular HPFH may also be in the Saudi gene pool. Considering the rich prevalence of these various hemoglobin genetic abnormalities in this region, it is likely that many of the Arab patients had Hb SS a-thalassemia, and possibly some had Hb S fl~ thalassemia disease and heterocellular HPFH-SS disease. Precise determination of the genotype of individu-
al patients will require intensive studies, including family studies, globin synthetic chain analysis, and gene mapping. Until these types of exhaustive analyses are done in large numbers of patients, the precise basis of Saudi sickle cell states should be considered undefined, and the genetically noncommittal term "sickle cell disease" should be used. In the Saudi patients we described, normal splenic function had a highly significant correlation with high Hb F levels. Further, the level of Pk RBC correlated with clinical and hematologic severity. Splenic function correlated less strongly with microcytosis, indicating that high levels of Hb F may be the more important determinant of normal splenic function in these patients. Persistence of splenic function should protect the Saudi with sickle cell disease from severe or overwhelming bacterial infection during early infancy, as it does in Hb SC disease in the United States?--'-" However, since splenomegaly persists in many of these patients, sequestration crises might be a continuing risk. 7 Although the sickle cell disease in these patients appears to be mild when compared with that in American patients, it is in many instances far from asymptomatic and should not be characterized as "benign." Fifteen of the 24 patients had been hospitalized, 11 five or more times. Fifteen of the 24 had received blood transfusions on one or more occasions. The precise morbidity and mortality of Arabian sickle cell disease awaits a prospective long-term study of a cohort of affected infants diagnosed at birth. There is currently a great deal of interest in the possibility of treating sickle cell disease and thalassemia by manipulating gene function. Short-term treatment of a few patients with Hb SS with 5-azacytidine has reactivated 7-gene activity and increased the level of Hb F.2~--'4The experience with Saudi Arabian patients indicates that, when Hb F is heterogenously distributed in the RBC population, a quite high level of Hb F (> 15%) will have to be attained to reduce intravascular sickling sufficiently to maintain the integrity of the spleen.
REFERENCES I. Perrine RP, Brown M J, Clegg JB, et al: Benign sickle cell anemia. Lancet 2:1163, 1972. 2. Gelp AP: Benign sickle ecll disease in Saudi Arabia: Survival estimates and population dynamics. Clin Genet 15:307, 1979. 3. Pcmbrcy ME, Wood WG, Weatherall DJ, Perrine RP: Foetal haemoglobin production and the sickle gene in the oases of Eastern Saudi Arabia. Br J tlaematol 40:415, 1978. 4. Wrightston RN, Huisman THJ: On the levels of hemoglobins F and A2 in sickle cell anemia and some related disorders. Am J Clin Pathol 61:375, 1974. 5. Pearson HA, Spencer RP, Cornelius EA: Functional asplenia in sickle cell anemia. N Engl J Med 281:923, 1969.
|'olume 104 Number 5
6. Barrctt-Connor E: Bacterial infection and sickle cell anemia. Medicine 50:97, 1971. 7. Topley JM, Rogers DW, Stevens MCG, Serjeant GR: Acute splenic sequestration and hypersplenism in the first five years in homozygous sickle cell disease. Arch Dis Child 56:765, 1981. 8. Pearson tlA, Mclntosh S, Ritchey AK, et al: Developmental aspects of splenic function in sickle cell diseases. Blood 53:358, 1978. 9. Powars DR: Natural history of sickle cell disease: The first ten )cars. Semin Itematol 12:267, 1975. 10. Pcarson ItA, Chlicotte R, Sullivan E, Gallagher D: Splenic function in sickle cell disease in America and Saudi Arabia: Cross-ethnic correlates. Pcdiatr Res 17:240A, 1983. I1. Singer K, Chernoff AI, Singer L: Studies on abnormal hemoglobins. I. Their demonstration in sickle cell anemia and other hematologic disorders by means of alkali denaturation. Blood 6:413, 1951. 12. Kleihaucr E; Braun 1t, Betke K: Demonstration yon fetalem tlamoglobin in der erythrocyten eines Blutarstrache. Kiln Wochcnschr 33:637, 1957. 13. Itolyroyd CP, Gardner FIt: Aquisition ofautophagic vacuoles by human erythrocytes: Physiological role of the spleen. Blood 36:566, 1970. 14. Pearson tlA, Johnston D, Smith KA, Touloukian R J: The born again spleen: Return of splenic function after splenectomy for trauma. N Engl J Med 298:1389, 1978. 15. Dozy AM, Kan YY, Embury SH, et al: Alpha globin gene
Splenic function in sickle cell disease
16.
17.
18. 19.
20.
21. 22. 23.
24.
7 17
organization in blacks precludes the severe form of disease. Nature 280:605, 1979. Embury SH, Dozy AM, Miller J, et al: Concurrent sickle cell anemia and thalassemia: Effect on severity of anemia. N Engl J Mcd 306:270, 1982. Powars DR, Schroeder WA, Weiss JM, et al: Lack of influence of fetal hemoglobin levels or erythrocyte indices on the severity of sickle cell anemia. J Clin Invest 65:732, 1980. Pcmbrcy ME, Weatherall D J, Clegg JB, et al: Haemoglobin Barts in Saudi Arabia. Br J Haematol 29:221, 1975. Pembrey ME, Perrine RP, Wood WG, Weatherall D J: Sickle thalassemia in eastern Saudi Arabia. Am J Hum Genet 32:26, 1980. Serjcant YR, Serjeant BE, Mason K: tleterocellular hereditary persistence of fetal haemoglobin and homozygous sickle cell disease. Lancet 1:795, 1977. Zago MA, Wood WG, Clark JG, et al: Genetic control of F cell in human adults. Blood 53:977, 1979. Powars D, Overturf GD, Wilkins J: Commentary: Infections in sickle cell and SC disease. J PEI)IA'rR 103:242, 1983. Ley T J, DeSimonc C, Noguchi C, et al: 5-Azacytidine selectivly increases fetal hemoglobin synthesis in patients with beta thalasscmia. N Engl J Med 307:1469, 1982. Dover G J, Charache S, Smith K: Results presented at the 3rd Conference on Cellular and Molecular Regulation of Hemoglobin Switching. Seattle, September 13 to 16, 1982.
Baker AI-Awamy, M.D., Ph.D., Wendell A. Wilson, M.D., and ltoward A. Pearson, M . D . D a m m a m , S a u d i A r a b i a , a n d N e w H a v e n , C o n n .
TIlE SICKLE
C E L L DISEASE that occurs in Shiite Moslems of the Arabian gulf area, especially the Eastern Province of Saudi Arabia, has striking clinical and hematologic differences from that observed elsewhere in the world. The disease is reported to be clinically mild, with only moderate hemolytic anemia?.-' The most striking biochemical feature is t l b F levels averaging 20%. Such high levels are rarely seen in American patients after early childhood?-~ Much of the severe morbidity and mortality in sickle cell
Front the Departments o f Pediatrics. King Faisal University College o f Medicine and )'ale UniversiO' School o f Medicine. Supported in part by the Saudi Arabian National Center f o r Science and, Technology. Some o f the Anwrican patients described in this report are enrolled in the Comprehensive Stud)' o f Sickle Cell Diseases supported by the National lleart. Lung attd Blood Institute, National Institutes o f llealth. Presented in part at the Meeting o f the American Society o f llematology, December 1982. and the APS]SPR Meetings, Washington, D.C:. May 1983. Reprint requests: lIoward A. Pearson. M.D., Department o f Pediatrics, )'ale University School o f Medicine, 333 Cedar St., New llaven, CT 06510.
7 14
The Journal o f P E D I A T R I C S
anemia can be related to aberrations of splenic function? Overwhelming bacterial sepsis and acute splenic sequestration are the principal causes of the inordinately high early mortality in black children with sickle cell anemia in the United States and Jamaica? .7 Splenic dysfunction is nearly invariable in patients with sickle cell anemia in the Western hemisphere? .~ Between 5 months and 5 years of
See related article, p. 734.
lib F Hb S lib SS IIPFII Pk RBC
Fetal hemoglobin Sickle hemoglobin Ilomozygous lib S disease ltercditary persistence of fetal hemoglobin "Pocked" red blood cells
age, virtually all patients become "functionally hyposplenic,"as reflected in the lack of splenic uptake of 99roTesulfur colloid, a percentage of "pocked red ceils" determined by interference phase-contrast microscopy >3.5%, and a relatively high incidence of overwhelming bacterial sepsis and meningitis) .9 The presence of >3.5% circulating Pk RBC also has a high correlation with nonvisualization of the
Volume 104 Number 5
Splenic function in sickle cell disease
715
Table. Hematologic measurements in Saudi and American patients
Hb
Reticuloo'tes
Mean corpuscular volume
(%)
Oq)
Patients
Age
Pk RBC
ttb F
(n)
(yr)
(%)
(%)
Saudi Arabian Low Pk RBC (<3.5%)
17
13.7 ___ 1.0
1.2 _+ 0.8
18.3 + 5.8
I 1.5 -_. 1.6
4.0 --. 2.5
7 0 . 0 _.+ 7.8
H i g h Pk R B C
7
17.3 + 5.6
21.2 + 8.9
9.1 + 4 . 0
10.2 __. 2.5
5.7 --- 1.8
78.0 +__ 5.4
22
12.9 + 6.2
14.5 _+ 4.1
5.2 _+ 2.2
8.3 + 0.7
11.4 --. 3.9
89.3 __. 5.3
r
(>3.5%) American Values are mean • 1 SD.
spleen by radionuclide scanning, a~We compared Pk RBC, hematologic values, and Hb F levels in a group of Saudi patients with sickle cell disease with those in a matched group of American patients with homozygous Hb S disease. PATIENTS
AND METHODS
Twenty-four Saudi Arabs (15 males, nine females) aged 9 months to 40 years, living in the Eastern Province of Saudi Arabia, were randomly selected from the Qatif Community Hospital roster of patients with sickle cell disease. For comparison, 22 American patients with sickle cell anemia were chosen from the sickle cell clinic of YaleNew Haven Hospital. American patients were chosen to correspond to the ages and genders of the Saudi patients, although none was older than 26 years. The diagnosis of SS disease in the Saudi patients was based on hemoglobin electrophoretic patterns on cellulose acetate at pH 8.2 and agar gel at 6.0, which showed hemoglobins S, F, and A2 and the absence of Hb A. Although insufficient blood was available to perform quantitative hemoglobin A, determination by column chromatography in the Saudi patients, densitometric scans of cellulose acetate electrophoretic patterns revealed Hb A, levels <3.5% in all instances. Family studies in many of the Saudi patients showed both parents to have sickle cell trait. Similar diagnostic criteria were used in the American patients. Erythrocyte indices were determined with a calibrated electronic Coulter counter. Hb F was quantitated by the alkali denaturation method. 't Distribution of Hb F in the RBC was assessed by the acid elution method of Kleihauer et al. ~2 and had a heterogenous distribution in all patients. Splenic function was assessed by quantitating the percent of Pk RBC. 8-~3Two drops of venous blood were fixed in buffered 3% gluteraldehyde, pH 7.4. One thousand consecutive RBC were examined under an interference
phase-contrast microscope with Nomarski optics for the presence of one or more apparent surface indentations, or "pocks." Normal eusplenie individuals have <2% Pk RBC, and anatomically asplenic persons have 12% to 30% (.~ 20%) Pk RBC." RESULTS As a group, the Saudi patients had considerably higher levels of total Hb and Hb F and lower levels of reticulocytes, MCV, and Pk RBC than the American patients. The Saudi patients fell into two distinct groups with respect to Pk RBC: 17 had normal or near normal levels (<3.5%), and seven had high levels. Significant differences were observed when the characteristics of the seven Saudi patients with a high proportion of Pk RBC were compared with those with low Pk RBC (Table). The seven patients with high Pk RBC had lower levels of Hb F, were more anemic, had higher reticulocyte counts, and had less microcytosis than those with low Pk RBC. Linear regression analysis revealed a significant relationship between high Hb F and low Pk RBC (correlation coefficient, P = 0.005) (Figure). Mean corpuscular volume also correlated with Pk RBC but at a much lower level of significance (P = 0.06). The Saudi patients with low Pk RBC had more splenomegaly (6/17 vs 0/7) and had received transfusions less frequently (9/17 vs 6/7) than those with higher levels. DISCUSSION This study shows that more than two thirds of Arab patients with sickle cell disease have normal or nearly normal splenic function, as reflected by low percentages of circulating Pk RBC. When compared with American patients, S a u ~ patients as a group had lesser degrees of hemolytic anemia, more microcytosis, and strikingly higher levels of Hb F. Microcytosis in patients with Hb SS disease usually indicates the concomitant presence of a-thalassemia. a-Thalassemia, associated with deletion of one or two
7 16
AI-Awamy, Wilson, and Pearson
The Journal of Pediatrics May 1984
9
32
28
N
24 20 % "POCKED" 16 RBC 12 8
4 0 0
I
OI 9
4
8
i Oqu ~ I~ 12
~0
16 20 %HbF
e~O0 I 24
28
I
32
Figure. Fetal hemoglobin and Pk RBC in Saudi patients.
alpha genes, has a frequency of 30% and 2%, respectively, in black Americans? 5 It has been suggested that o~-thalassemia may reduce the severity of Hb SS disease, probably by reducing the mean corpuscular Hb S concentration? 6 However, a relationship between low red cell indices and lesser clinical severity has not been confirmed by other studies." Cord blood studies in the Eastern Province of Saudi Arabia have shown the presence of Barts Hb, "t4, which is an indicator of a-thalassemia in about 50% of individuals,ts The gene for fl-thalassemia is also prevalent in eastern Saudi Arabia, and 14% of individuals with apparent SS disease have been recently shown, on the basis of family studies, to have Hb S fl~ thalassemia? 9 These individuals with Hb S fl~ thalassemia were virtually indistinguishable, both clinically and hematologically, from homozygous Hb SS patients; unlike American patients, most had normal levels of Hb A2.~9 Another genetic condition that might interact with sickle cell disease and result in increased levels of Hb F is the so-called heterocellular hereditary persistence of fetal hemoglobin. This condition is associated in the heterozygous state with slight elevations of Hb F (2% to 3%). 20 Although this,condition has not been noted in previous screening studies from Saudi Arabia, 2~ we found slightly elevated Hb F levels (2% to 4%) in several individuals with sickle cell trait studied as controls in our spleen studies. Therefore, a condition resembling heterocellular HPFH may also be in the Saudi gene pool. Considering the rich prevalence of these various hemoglobin genetic abnormalities in this region, it is likely that many of the Arab patients had Hb SS a-thalassemia, and possibly some had Hb S fl~ thalassemia disease and heterocellular HPFH-SS disease. Precise determination of the genotype of individu-
al patients will require intensive studies, including family studies, globin synthetic chain analysis, and gene mapping. Until these types of exhaustive analyses are done in large numbers of patients, the precise basis of Saudi sickle cell states should be considered undefined, and the genetically noncommittal term "sickle cell disease" should be used. In the Saudi patients we described, normal splenic function had a highly significant correlation with high Hb F levels. Further, the level of Pk RBC correlated with clinical and hematologic severity. Splenic function correlated less strongly with microcytosis, indicating that high levels of Hb F may be the more important determinant of normal splenic function in these patients. Persistence of splenic function should protect the Saudi with sickle cell disease from severe or overwhelming bacterial infection during early infancy, as it does in Hb SC disease in the United States?--'-" However, since splenomegaly persists in many of these patients, sequestration crises might be a continuing risk. 7 Although the sickle cell disease in these patients appears to be mild when compared with that in American patients, it is in many instances far from asymptomatic and should not be characterized as "benign." Fifteen of the 24 patients had been hospitalized, 11 five or more times. Fifteen of the 24 had received blood transfusions on one or more occasions. The precise morbidity and mortality of Arabian sickle cell disease awaits a prospective long-term study of a cohort of affected infants diagnosed at birth. There is currently a great deal of interest in the possibility of treating sickle cell disease and thalassemia by manipulating gene function. Short-term treatment of a few patients with Hb SS with 5-azacytidine has reactivated 7-gene activity and increased the level of Hb F.2~--'4The experience with Saudi Arabian patients indicates that, when Hb F is heterogenously distributed in the RBC population, a quite high level of Hb F (> 15%) will have to be attained to reduce intravascular sickling sufficiently to maintain the integrity of the spleen.
REFERENCES I. Perrine RP, Brown M J, Clegg JB, et al: Benign sickle cell anemia. Lancet 2:1163, 1972. 2. Gelp AP: Benign sickle ecll disease in Saudi Arabia: Survival estimates and population dynamics. Clin Genet 15:307, 1979. 3. Pcmbrcy ME, Wood WG, Weatherall DJ, Perrine RP: Foetal haemoglobin production and the sickle gene in the oases of Eastern Saudi Arabia. Br J tlaematol 40:415, 1978. 4. Wrightston RN, Huisman THJ: On the levels of hemoglobins F and A2 in sickle cell anemia and some related disorders. Am J Clin Pathol 61:375, 1974. 5. Pearson HA, Spencer RP, Cornelius EA: Functional asplenia in sickle cell anemia. N Engl J Med 281:923, 1969.
|'olume 104 Number 5
6. Barrctt-Connor E: Bacterial infection and sickle cell anemia. Medicine 50:97, 1971. 7. Topley JM, Rogers DW, Stevens MCG, Serjeant GR: Acute splenic sequestration and hypersplenism in the first five years in homozygous sickle cell disease. Arch Dis Child 56:765, 1981. 8. Pearson tlA, Mclntosh S, Ritchey AK, et al: Developmental aspects of splenic function in sickle cell diseases. Blood 53:358, 1978. 9. Powars DR: Natural history of sickle cell disease: The first ten )cars. Semin Itematol 12:267, 1975. 10. Pcarson ItA, Chlicotte R, Sullivan E, Gallagher D: Splenic function in sickle cell disease in America and Saudi Arabia: Cross-ethnic correlates. Pcdiatr Res 17:240A, 1983. I1. Singer K, Chernoff AI, Singer L: Studies on abnormal hemoglobins. I. Their demonstration in sickle cell anemia and other hematologic disorders by means of alkali denaturation. Blood 6:413, 1951. 12. Kleihaucr E; Braun 1t, Betke K: Demonstration yon fetalem tlamoglobin in der erythrocyten eines Blutarstrache. Kiln Wochcnschr 33:637, 1957. 13. Itolyroyd CP, Gardner FIt: Aquisition ofautophagic vacuoles by human erythrocytes: Physiological role of the spleen. Blood 36:566, 1970. 14. Pearson tlA, Johnston D, Smith KA, Touloukian R J: The born again spleen: Return of splenic function after splenectomy for trauma. N Engl J Med 298:1389, 1978. 15. Dozy AM, Kan YY, Embury SH, et al: Alpha globin gene
Splenic function in sickle cell disease
16.
17.
18. 19.
20.
21. 22. 23.
24.
7 17
organization in blacks precludes the severe form of disease. Nature 280:605, 1979. Embury SH, Dozy AM, Miller J, et al: Concurrent sickle cell anemia and thalassemia: Effect on severity of anemia. N Engl J Mcd 306:270, 1982. Powars DR, Schroeder WA, Weiss JM, et al: Lack of influence of fetal hemoglobin levels or erythrocyte indices on the severity of sickle cell anemia. J Clin Invest 65:732, 1980. Pcmbrcy ME, Weatherall D J, Clegg JB, et al: Haemoglobin Barts in Saudi Arabia. Br J Haematol 29:221, 1975. Pembrey ME, Perrine RP, Wood WG, Weatherall D J: Sickle thalassemia in eastern Saudi Arabia. Am J Hum Genet 32:26, 1980. Serjcant YR, Serjeant BE, Mason K: tleterocellular hereditary persistence of fetal haemoglobin and homozygous sickle cell disease. Lancet 1:795, 1977. Zago MA, Wood WG, Clark JG, et al: Genetic control of F cell in human adults. Blood 53:977, 1979. Powars D, Overturf GD, Wilkins J: Commentary: Infections in sickle cell and SC disease. J PEI)IA'rR 103:242, 1983. Ley T J, DeSimonc C, Noguchi C, et al: 5-Azacytidine selectivly increases fetal hemoglobin synthesis in patients with beta thalasscmia. N Engl J Med 307:1469, 1982. Dover G J, Charache S, Smith K: Results presented at the 3rd Conference on Cellular and Molecular Regulation of Hemoglobin Switching. Seattle, September 13 to 16, 1982.