HEMOGLOBIN, 2 ( 5 ) , 447-451
Hemoglobin Downloaded from informahealthcare.com by Nyu Medical Center on 01/09/15 For personal use only.
HEMOGLOBIN POTOMAC:
(1978)
CLINICAL PICTURE, BIOSYNTHESIS AND STABILITY
The o c c u r r e n c e of hemoglobin Potomac (6101 Glu+Asp), a n abnormal hemoglobin w i t h i n c r e a s e d oxygen a f f i n i t y , h a s been p r e v i o u s l y r e p o r t e d i n n i n e members of one k i n d r e d (1). We now p r e s e n t t h e second o c c u r r e n c e of t h i s hemoglobin, i n a 26 y e a r o l d w h i t e female of mixed n o r t h e r n European e x t r a c t i o n , and r e p o r t t h e c l i n i c a l p i c t u r e and s t u d i e s of t h e s t a b i l i t y and b i o s y n t h e s i s of t h e abnormal hemoglobin. CASE REPORT
L.W., a 26 y e a r o l d w h i t e f e m a l e of mixed n o r t h e r n European e x t r a c t i o n , w a s r e f e r r e d t o Thomas J e f f e r s o n U n i v e r s i t y H o s p i t a l i n J u l y , 1 9 7 6 , f o r e v a l u a t i o n of an e l e v a t e d h e m a t o c r i t . She had p r e v i o u s l y been i n good h e a l t h b u t had a vague memory o f b e i n g t o l d d u r i n g c h i l d h o o d t h a t s h e w a s "polycythemic". She t o o k no m e d i c a t i o n s o t h e r t h a n N o r i n y l and smoked t e n c i g a r e t t e s d a i l y . She had been p r e g n a n t t h r e e t i m e s , h a v i n g two e a r l y s p o n t a n e o u s a b o r t i o n s and d e l i v e r i n g a h e a l t h y f e m a l e i n f a n t w i t h o u t d i f f i c u l t y i n 1 9 7 5 . T h e r e was no h i s t o r y of menometrorrhagia. P h y s i c a l e x a m i n a t i o n showed h e r t o be a h e a l t h y a p p e a r i n g w h i t e f e m a l e w i t h o u t c y a n o s i s o r p l e t h o r a . The v i t a l s i g n s were w i t h i n normal l i m i t s and t h e r e w a s no e v i d e n c e of hepatomegaly, splenomegaly o r c l u b b i n g . L a b o r a t o r y e x a m i n a t i o n showed a hemoglobin o f 1 6 . 1 g / d l ; h e m a t o c r i t , 5 1 % ; r e d blood c e l l c o u n t , 5.05 x 1 0 l 2 / 1 ; normal r e d c e l l i n d i c e s , r e t i c u l o c y t e c o u n t , 2 . 5 % ; w h i t e blood c e l l c o u n t , 9 . 5 x 1 0 9 / 1 (normal d i f f e r e n t i a l ) ; and p l a t e l e t c o u n t , 262 x 1 0 9 / l . A l l blood c h e m i s t r i e s , i n c l u d i n g serum u r i c a c i d , w e r e w i t h i n normal l i m i t s . The l e u k o c y t e a l k a l i n e p h o s p h a t a s e was s l i g h t l y e l e v a t e d a t 1 6 2 u n i t s (normal, 2 0 - 1 2 0 ) and t h e serum Her r e d c e l l mass w a s 41.3 ml/kg (normal, B12 and f o l i c a c i d were normal. 2 4 - 3 8 ) and h e r hemoglobin mass w a s 6 7 1 g ( p r e d i c t e d , 4 6 1 g ) . The blood volume w a s e l e v a t e d t o 4017 m l ( p r e d i c t e d , 3 2 2 2 m l ) , t h e serum i r o n was 257 mg/dl and On follow-up v i s i t s d u r i n g t h e n e x t two t h e i r o n b i n d i n g c a p a c i t y 4 5 8 mg/dl. y e a r s h e r h e m a t o c r i t ranged between 47 and 50% and t h e hemoglobin between 15.5 and 16.5 g / d l . The p a t i e n t h a s c o n t i n u e d t o do w e l l d u r i n g t h i s p e r i o d w i t h vague minor c o m p l a i n t s and no e v i d e n c e of t h r o m b o p h l e b i t i s o r o t h e r symptoms
Received:
June 9, 1978;
Accepted:
J u l y 24, 1978
447 Copyright 0 1 9 7 8 by Marcel Dekker, Inc. All Rights Reserved. Neither this work nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system. without permission in writing from the publisher.
448
SHORT COMMUNICATION
a s s o c i a t e d w i t h polycythemia. I n January, 1 9 7 8 , s h e experienced l e f t r e n a l c o l i c and passed calcium o x a l a t e s t o n e s a t a n o t h e r h o s p i t a l . Hematologic examination of t h e p a t i e n t ' s mother, daughter, two s i s t e r s and a n i e c e a l l showed a completely normal blood count, hemoglobin e l e c t r o p h o r e s i s p a t t e r n and oxygen P50. There w a s no known r e l a t i o n s h i p between t h e p r o p o s i t a and t h e kindred w i t h Hb Potomac p r e v i o u s l y r e p o r t e d (1).
Hemoglobin Downloaded from informahealthcare.com by Nyu Medical Center on 01/09/15 For personal use only.
FUNCTIONAL AND STRUCTURAL STUDIES The f u n c t i o n a l and s t r u c t u r a l s t u d i e s c a r r i e d o u t , with t h e a p p r o p r i a t e r e f e r e n c e , are shown i n Table I. The e l e c t r o p h o r e t i c a n a l y s e s showed a p a t t e r n i d e n t i c a l t o t h a t of hemoglobin A ( 2 ) . The l e v e l of f e t a l hemoglobin was l e s s than 2% ( 3 ) and t h e p r o p o r t i o n of hemoglobin A2 was 2 . 6 % ( 4 ) . No u n s t a b l e hemoglobin was demonstrable by s t u d i e s f o r i n c l u s i o n b o d i e s and t h e h e a t s t a b i l i t y of t h e hemoglobin i n both oxy and m e t forms was normal (7,8). The oxygen e q u i l i b r i u m curve of a whole blood suspension showed a b i p h a s i c curve c o n s i s t i n g of a h i g h a f f i n i t y h y p e r b o l i c component of abnormal hemoglobin and a sigmoidal curve of normal hemoglobin, s i m i l a r t o t h a t r e p o r t e d by Charache e t a 1 (1). The P50 v a l u e w a s 12.5 mmHg a t pH 7 . 4 and a t 37". The oxygen e q u i l i b r i u m of t h e hemolysate, a f t e r d i a l y s i s t o remove o r g a n i c phosphates, a l s o showed i n c r e a s e d oxygen a f f i n i t y . Globin was prepared and t h e g l o b i n c h a i n s from t h e p a t i e n t ' s hemoglobin w e t e s e p a r a t e d by chromatography on CM c e l l u l o s e i n 8M u r e a (5). A f t e r t h e i s o l a t e d c h a i n s were f i n g e r p r i n t e d ( 1 2 ) t h e s p o t s of t h e f i n g e r p r i n t s were e l u t e d s e p a r a t e l y and hydrolyzed with 6 N H C 1 and t h e amino a c i d composition determined. Except f o r 8-TpXI, a l l a and B t r y p t i c p e p t i d e s showed t h e same The a s p a r t i c a c i d of t h e p a t i e n t ' s components as t h o s e of normal Hb A. b-TpXI was i n c r e a s e d by 0 . 3 7 compared t o normal B-TpXI, w h i l e glutamic a c i d of t h i s p e p t i d e was decreased by 0 . 3 6 i n comparison t o normal (Table II), e s t a b l i s h i n g t h e abnormal, hemoglobin a s Hb Potomac (B-101 glu+asp) (1).
TABLE I TESTS OF STRUCTURE AND FUNCTION TEST
NORMAL VALUE
E l e c t r o p h o r e s i s on S t a r c h g e l , pH 8.6 C e l l u l o s e A c e t a t e , pH 8 . 6 Agar g e l , pH 6 . 0 Finger p r i n t
HbA HbA HbA HbA
I s o e l e c t r i c f o c u s i n g , pH 6-8 Globin c h a i n s e p a r a t i o n
PROPOSITA
2
HbA HbA HbA HbA
2 12
abBA
aA+BA
6
a 46A
aA+ BA
5
10
Functional Studies P50 whole c e l l s (mmHg) 2-3 DPG (nmlml blood)
23.2-27.3 1.6-2.6
12.5 2.62
S t a b i l i t y Studies Heat s t a b i l i t y ( 6 0 " ) Mechanical Heinz Bodies BCB s t a i n Isopropanol s t a b i l i t y (37")
normal normal negative negative normal
normal normal negative negative normal
I
REFERENCE
2
11
I
SHORT COMMUNICATION
449
TABLE I1 AMINO ACID COMPOSITION OF THE PEPTIDS BTpXI FROM HbpoTOuC+HbA
Amino acid
BTpXI
Peptide BTpXI HbPotomac+HbA
HbA
Hemoglobin Downloaded from informahealthcare.com by Nyu Medical Center on 01/09/15 For personal use only.
Molar ratio Histidine Argine Aspartic Acid Glutamic Acid Proline Valine Leucine Phenylalanine
0.98 1.00 2.37 0.64 1.00 0.98 1.02 1.00
-I "_0 I I X
W
$
0.6
-
IZ la
U
m
- w
FRACTION
NUMBER
FIGURE 1. CMC chromatography in 8M urea of globin from the erythrocytes of the proposita after intact cells were incubated with [14C] valine for 1 hour at 37'. Incorporation of radioactivity (dashed line) indicates equal rates of synthesis of alpha and beta chains.
450
SHORT COMMUNICATION
The synthesia40f the alpha and beta globin chains was studied by incubating whole bleod with C valine for one hour at 37' as previously described (13). Following separation of the alpha and beta chains of globin the radioactivity incorporated into the alpha and beta chains (a/@ ratio) was 1.0, indicating balanced globin synthesis (figure 1).
Hemoglobin Downloaded from informahealthcare.com by Nyu Medical Center on 01/09/15 For personal use only.
DISCUSSION The clinical picture of the proposita is similar to the case previously reported (1). There is a modest elevation in hemoglobin and hematocrit, and no identifiable symptomatology associated with the erythrocytosis. The association between hemoglobin with increased oxygen affinity and erythrocytosis has now been well documented (14) and there is a general inverse relationship between the degree of erythrocytosis and the P50 of the abnormal hemoglobin. The site of the amino acid substitution in hemoglobin Potomac is at the a152 interface, a site where other substitutions are associated with increased oxygen affinity (1). Globin synthesis of this patient was balanced and there was no evidence to suggest instability of the abnormal hemoglobin, which is in keeping with the equal amounts of normal and abnormal beta chains in circulating red cells. The initial report of the occurrence of hemoglobin Potomac speculated on placental oxygen transport in mothers who were carriers of a high affinity hemoglobin (1). Review of the literature by these workers did not show that families with high-affinity hemoglobin have a decreased survival value of the fetus of an affected mother. It is noteworthy that this patient, with an oxygen affinity approximately twice normal, had two early spontaneous abortions prior to delivering a healthy infant. However, no conclusions can be made concerning the effect of this hemoglobin in early pregnancy. This research was supported by USPHS grants AM 13431, AM 16691, HL 18226, and HL 20750.
Cardeza Foundation for Hematologic Research, Jefferson Medical College, Philadelphia, Pennsylvania 19107
RONALD N. RUBIN SAMIR K. BALLAS JEAN ATWATER EDWARD R. BURKA
The Children's Hospital of Philadelphia and the Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
KAZUHIKO ADACHI TOSHIO ASAKURA ELIAS SCHWARTZ
REFERENCES
1. Charache, S . , Jacobson, R., Brimhall, B., Murphy, E.A., Hathaway, P., Winslow, R., Jones, R., Rath, C. and Simkovich, J.: Blood 2:331, 1978. 2 . Huisman, T. and Jonxis, J.: The Hemoglobinopathies. Techniques for Identification. M. Dekker. Inc., New York, 1977. 3. Betke, K., Marti, H. and Schlicht, I.: Nature =:1877. 1959. 4. Huisman, T., Schroeder, W., Brodie, A. and Mayson, S.: J. Lab. Clin. Med. %:700, 1975. 5. Clegg, J.B., Naughton, M.A. and Weatherall, D.J.: J. Mol. Bio. e:91. 1966.
SHORT COMMUNICATION 6. 7. 8. 9.
45 1
Hemoglobin Downloaded from informahealthcare.com by Nyu Medical Center on 01/09/15 For personal use only.
Drysdale, J., Righetti, P. and Bunn, H.: Biochim, Biophys. Acta 2 : 4 2 , 1 9 7 1 Carrell., R. and Kay, R . : Brit. J. Haemat. 23:615, 1 9 7 2 . Charache, S . , Modzar, A. and Gessner, U.: JTClin. Invest. %:834, 1969. Asakura, T., Adachi, K., Sono, M., Friedman, S. and Schwartz, E . : Biochem. Biophys. Res. Corn. x : 7 8 0 , 1 9 7 4 . 10. Winslow, R . et. al.: J. Biol. Chem. =:2331, 1977. 11. Bunn, H. and Briehl, R.: J. Clin. Invest. 2:1088, 1970. 1 2 . Baglioni, C.: Biochim. Biophys. Acta. %:392, 1961. Hemoglobin 1_:651, 1 9 7 7 . 1 3 . Ballas, S.K., Atwater, J. and Burka, E.R.: 14. Billingham, A . : Brit. Med. Bull. 2 : 2 3 4 , 1 9 7 6 .
Hemoglobin Downloaded from informahealthcare.com by Nyu Medical Center on 01/09/15 For personal use only.
HEMOGLOBIN POTOMAC:
(1978)
CLINICAL PICTURE, BIOSYNTHESIS AND STABILITY
The o c c u r r e n c e of hemoglobin Potomac (6101 Glu+Asp), a n abnormal hemoglobin w i t h i n c r e a s e d oxygen a f f i n i t y , h a s been p r e v i o u s l y r e p o r t e d i n n i n e members of one k i n d r e d (1). We now p r e s e n t t h e second o c c u r r e n c e of t h i s hemoglobin, i n a 26 y e a r o l d w h i t e female of mixed n o r t h e r n European e x t r a c t i o n , and r e p o r t t h e c l i n i c a l p i c t u r e and s t u d i e s of t h e s t a b i l i t y and b i o s y n t h e s i s of t h e abnormal hemoglobin. CASE REPORT
L.W., a 26 y e a r o l d w h i t e f e m a l e of mixed n o r t h e r n European e x t r a c t i o n , w a s r e f e r r e d t o Thomas J e f f e r s o n U n i v e r s i t y H o s p i t a l i n J u l y , 1 9 7 6 , f o r e v a l u a t i o n of an e l e v a t e d h e m a t o c r i t . She had p r e v i o u s l y been i n good h e a l t h b u t had a vague memory o f b e i n g t o l d d u r i n g c h i l d h o o d t h a t s h e w a s "polycythemic". She t o o k no m e d i c a t i o n s o t h e r t h a n N o r i n y l and smoked t e n c i g a r e t t e s d a i l y . She had been p r e g n a n t t h r e e t i m e s , h a v i n g two e a r l y s p o n t a n e o u s a b o r t i o n s and d e l i v e r i n g a h e a l t h y f e m a l e i n f a n t w i t h o u t d i f f i c u l t y i n 1 9 7 5 . T h e r e was no h i s t o r y of menometrorrhagia. P h y s i c a l e x a m i n a t i o n showed h e r t o be a h e a l t h y a p p e a r i n g w h i t e f e m a l e w i t h o u t c y a n o s i s o r p l e t h o r a . The v i t a l s i g n s were w i t h i n normal l i m i t s and t h e r e w a s no e v i d e n c e of hepatomegaly, splenomegaly o r c l u b b i n g . L a b o r a t o r y e x a m i n a t i o n showed a hemoglobin o f 1 6 . 1 g / d l ; h e m a t o c r i t , 5 1 % ; r e d blood c e l l c o u n t , 5.05 x 1 0 l 2 / 1 ; normal r e d c e l l i n d i c e s , r e t i c u l o c y t e c o u n t , 2 . 5 % ; w h i t e blood c e l l c o u n t , 9 . 5 x 1 0 9 / 1 (normal d i f f e r e n t i a l ) ; and p l a t e l e t c o u n t , 262 x 1 0 9 / l . A l l blood c h e m i s t r i e s , i n c l u d i n g serum u r i c a c i d , w e r e w i t h i n normal l i m i t s . The l e u k o c y t e a l k a l i n e p h o s p h a t a s e was s l i g h t l y e l e v a t e d a t 1 6 2 u n i t s (normal, 2 0 - 1 2 0 ) and t h e serum Her r e d c e l l mass w a s 41.3 ml/kg (normal, B12 and f o l i c a c i d were normal. 2 4 - 3 8 ) and h e r hemoglobin mass w a s 6 7 1 g ( p r e d i c t e d , 4 6 1 g ) . The blood volume w a s e l e v a t e d t o 4017 m l ( p r e d i c t e d , 3 2 2 2 m l ) , t h e serum i r o n was 257 mg/dl and On follow-up v i s i t s d u r i n g t h e n e x t two t h e i r o n b i n d i n g c a p a c i t y 4 5 8 mg/dl. y e a r s h e r h e m a t o c r i t ranged between 47 and 50% and t h e hemoglobin between 15.5 and 16.5 g / d l . The p a t i e n t h a s c o n t i n u e d t o do w e l l d u r i n g t h i s p e r i o d w i t h vague minor c o m p l a i n t s and no e v i d e n c e of t h r o m b o p h l e b i t i s o r o t h e r symptoms
Received:
June 9, 1978;
Accepted:
J u l y 24, 1978
447 Copyright 0 1 9 7 8 by Marcel Dekker, Inc. All Rights Reserved. Neither this work nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system. without permission in writing from the publisher.
448
SHORT COMMUNICATION
a s s o c i a t e d w i t h polycythemia. I n January, 1 9 7 8 , s h e experienced l e f t r e n a l c o l i c and passed calcium o x a l a t e s t o n e s a t a n o t h e r h o s p i t a l . Hematologic examination of t h e p a t i e n t ' s mother, daughter, two s i s t e r s and a n i e c e a l l showed a completely normal blood count, hemoglobin e l e c t r o p h o r e s i s p a t t e r n and oxygen P50. There w a s no known r e l a t i o n s h i p between t h e p r o p o s i t a and t h e kindred w i t h Hb Potomac p r e v i o u s l y r e p o r t e d (1).
Hemoglobin Downloaded from informahealthcare.com by Nyu Medical Center on 01/09/15 For personal use only.
FUNCTIONAL AND STRUCTURAL STUDIES The f u n c t i o n a l and s t r u c t u r a l s t u d i e s c a r r i e d o u t , with t h e a p p r o p r i a t e r e f e r e n c e , are shown i n Table I. The e l e c t r o p h o r e t i c a n a l y s e s showed a p a t t e r n i d e n t i c a l t o t h a t of hemoglobin A ( 2 ) . The l e v e l of f e t a l hemoglobin was l e s s than 2% ( 3 ) and t h e p r o p o r t i o n of hemoglobin A2 was 2 . 6 % ( 4 ) . No u n s t a b l e hemoglobin was demonstrable by s t u d i e s f o r i n c l u s i o n b o d i e s and t h e h e a t s t a b i l i t y of t h e hemoglobin i n both oxy and m e t forms was normal (7,8). The oxygen e q u i l i b r i u m curve of a whole blood suspension showed a b i p h a s i c curve c o n s i s t i n g of a h i g h a f f i n i t y h y p e r b o l i c component of abnormal hemoglobin and a sigmoidal curve of normal hemoglobin, s i m i l a r t o t h a t r e p o r t e d by Charache e t a 1 (1). The P50 v a l u e w a s 12.5 mmHg a t pH 7 . 4 and a t 37". The oxygen e q u i l i b r i u m of t h e hemolysate, a f t e r d i a l y s i s t o remove o r g a n i c phosphates, a l s o showed i n c r e a s e d oxygen a f f i n i t y . Globin was prepared and t h e g l o b i n c h a i n s from t h e p a t i e n t ' s hemoglobin w e t e s e p a r a t e d by chromatography on CM c e l l u l o s e i n 8M u r e a (5). A f t e r t h e i s o l a t e d c h a i n s were f i n g e r p r i n t e d ( 1 2 ) t h e s p o t s of t h e f i n g e r p r i n t s were e l u t e d s e p a r a t e l y and hydrolyzed with 6 N H C 1 and t h e amino a c i d composition determined. Except f o r 8-TpXI, a l l a and B t r y p t i c p e p t i d e s showed t h e same The a s p a r t i c a c i d of t h e p a t i e n t ' s components as t h o s e of normal Hb A. b-TpXI was i n c r e a s e d by 0 . 3 7 compared t o normal B-TpXI, w h i l e glutamic a c i d of t h i s p e p t i d e was decreased by 0 . 3 6 i n comparison t o normal (Table II), e s t a b l i s h i n g t h e abnormal, hemoglobin a s Hb Potomac (B-101 glu+asp) (1).
TABLE I TESTS OF STRUCTURE AND FUNCTION TEST
NORMAL VALUE
E l e c t r o p h o r e s i s on S t a r c h g e l , pH 8.6 C e l l u l o s e A c e t a t e , pH 8 . 6 Agar g e l , pH 6 . 0 Finger p r i n t
HbA HbA HbA HbA
I s o e l e c t r i c f o c u s i n g , pH 6-8 Globin c h a i n s e p a r a t i o n
PROPOSITA
2
HbA HbA HbA HbA
2 12
abBA
aA+BA
6
a 46A
aA+ BA
5
10
Functional Studies P50 whole c e l l s (mmHg) 2-3 DPG (nmlml blood)
23.2-27.3 1.6-2.6
12.5 2.62
S t a b i l i t y Studies Heat s t a b i l i t y ( 6 0 " ) Mechanical Heinz Bodies BCB s t a i n Isopropanol s t a b i l i t y (37")
normal normal negative negative normal
normal normal negative negative normal
I
REFERENCE
2
11
I
SHORT COMMUNICATION
449
TABLE I1 AMINO ACID COMPOSITION OF THE PEPTIDS BTpXI FROM HbpoTOuC+HbA
Amino acid
BTpXI
Peptide BTpXI HbPotomac+HbA
HbA
Hemoglobin Downloaded from informahealthcare.com by Nyu Medical Center on 01/09/15 For personal use only.
Molar ratio Histidine Argine Aspartic Acid Glutamic Acid Proline Valine Leucine Phenylalanine
0.98 1.00 2.37 0.64 1.00 0.98 1.02 1.00
-I "_0 I I X
W
$
0.6
-
IZ la
U
m
- w
FRACTION
NUMBER
FIGURE 1. CMC chromatography in 8M urea of globin from the erythrocytes of the proposita after intact cells were incubated with [14C] valine for 1 hour at 37'. Incorporation of radioactivity (dashed line) indicates equal rates of synthesis of alpha and beta chains.
450
SHORT COMMUNICATION
The synthesia40f the alpha and beta globin chains was studied by incubating whole bleod with C valine for one hour at 37' as previously described (13). Following separation of the alpha and beta chains of globin the radioactivity incorporated into the alpha and beta chains (a/@ ratio) was 1.0, indicating balanced globin synthesis (figure 1).
Hemoglobin Downloaded from informahealthcare.com by Nyu Medical Center on 01/09/15 For personal use only.
DISCUSSION The clinical picture of the proposita is similar to the case previously reported (1). There is a modest elevation in hemoglobin and hematocrit, and no identifiable symptomatology associated with the erythrocytosis. The association between hemoglobin with increased oxygen affinity and erythrocytosis has now been well documented (14) and there is a general inverse relationship between the degree of erythrocytosis and the P50 of the abnormal hemoglobin. The site of the amino acid substitution in hemoglobin Potomac is at the a152 interface, a site where other substitutions are associated with increased oxygen affinity (1). Globin synthesis of this patient was balanced and there was no evidence to suggest instability of the abnormal hemoglobin, which is in keeping with the equal amounts of normal and abnormal beta chains in circulating red cells. The initial report of the occurrence of hemoglobin Potomac speculated on placental oxygen transport in mothers who were carriers of a high affinity hemoglobin (1). Review of the literature by these workers did not show that families with high-affinity hemoglobin have a decreased survival value of the fetus of an affected mother. It is noteworthy that this patient, with an oxygen affinity approximately twice normal, had two early spontaneous abortions prior to delivering a healthy infant. However, no conclusions can be made concerning the effect of this hemoglobin in early pregnancy. This research was supported by USPHS grants AM 13431, AM 16691, HL 18226, and HL 20750.
Cardeza Foundation for Hematologic Research, Jefferson Medical College, Philadelphia, Pennsylvania 19107
RONALD N. RUBIN SAMIR K. BALLAS JEAN ATWATER EDWARD R. BURKA
The Children's Hospital of Philadelphia and the Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
KAZUHIKO ADACHI TOSHIO ASAKURA ELIAS SCHWARTZ
REFERENCES
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SHORT COMMUNICATION 6. 7. 8. 9.
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