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α Thalassemia in polynesians
A H S I K A C ‘ I S 0 1 ; ANNIJAI. MEE‘I ING
Anti-E occurred 4 times more frequently in females and there was no apparent race predilection. I n 99 individuals in whom a clinical history was available, 95 had a history of transfusion or pregnancy. In 4 cases the antibody was apparently naturally occurring. This f‘igure may be lower than reported in the literature because clinical information on low titre antibodies was difficult to obtain. In 97 case, there was sufficient antibody activity to differentiate IgG and IgM types by the Dithiothreitol Test: 82 showed the resistant IgC pattern, while 15 were inhibited implying IgM antibody activity. Monospecific antisera indicated that 7 within the IgG group were mixtures of IgG and IgA. The anti-E was not implicated in causing any hemolytic transfusion reactions in this series. Seven patients delivered babies whose cord blood dixdosed a positive direct antiglobulin test, and anti-E was eluted from their red cells. Four were not significantly or only mildly affected, while 3 infants required exchange transfusions (two of them also had anti-D feto-maternal incompatibility). I t is concluded that most anti-E antibodies seen in Auckland are not naturally occurring, but usually are sequelae of transfusion or pregnancy. The antibody uncommonly results in hemolytic disease of the newborn, but because of the predominant IgG nature of the antibody, it should always be regarded with caution in compatibility testing.
a THALASSEMIA IN POLYNESIANS
R. J . TK F NTT. ,
P . BKOCK AND H. K K O N L N H E R G Huemutology Department, Koyul Prince Alfred Hospital, Cut?iperduwn. N . S. W . WI1 KINSON, J .
YAKAS,
Polynesian peoples are found scattered throughout many islands over a large area of the Pacific in the form of a triangle bounded by Hawaii at the apex, New Zealand to the south-west and Easter Island the southeast. To the present time, a thalassemia has not been described in Polynesians, and this has been attributed to absence of the anopheline vector for malaria in this region. However, recent data based on hemoglobin Bart’s levels from a cord blood survey conducted at the National Women’s Hospital in Auckland would suggest that a thalassemia may be found in Maoris and Cook Islanders, both of them Polynesian races. One problem inherent in most epidemiological studies of a thalassemia is that definitive evidence of the disorder is not provided unless biosynthetic studies or recombinam DNA techniques such as gene mapping are utilized. Moreover, underlying a thalassemia genotypes may only be determined by gene mapping. We have studied a family of Cook Islanders [family R] and two other individuals [TN-a Cook Islander, BK-a Maori]. Family R came to our attention because 10% hemoglobin Bart’s was detected in cord blood from i-ecently delivered twins. Hematological data including red blood cell indices, hemoglobin A, and hemoglobin EPG from both parents were normal. Hemoglobin H inclusion bodies were not detected. A 5 yr-old child of family R had a hemoglobin of 12.3 g/dl, MCV 65.2 fl, MCH 21.9 pg. Hemoglobin A,, hemoglobin EPG, ferritin levels were normal. Blood film showed target cells. Gene mapping DNA from the above five individuals demonstrated a+ thalassemia [ - a / a a in both parents; -@/-a in the 3 children]. The second example of a thalassemia in Cook Islanders was detected in a 24 yr-old man [TN] referred for investigation of low MCV [73.3 fl] and target cells in the peripheral blood. There were the only abnormal hernatological findings. Gene mapping DNA from TN showed heterozygous a+thalassemia [ - a / a a ] . Finally, a trace of hemoglobin Bart’s was detected in cord blood from a New Zealand Maori [BK]. MCV [I02 f l ] and MCH [32.3 pg] levels in this infant were low for a newborn. Gene mapping confirmed heterozygous a+ thalassemia. More extensive mapping studies were undertaken in all the above examples of a thalassemia and these showed the a+ haplotype [-a/] to be the usual [3.7 kb] deletion found in other areas of the world. Definitive evidence is now available that a thalassemia may be present in Polynesians.
475
HEMOGLOBIN WOODVILLE: a6(A4) ASPARTIC ACID-TYROSINE P . F. C o r m,* S. B A K H E K ,R~. - E. SAGE* AND H . K K O N ~ N H F K*Huemutology C~* Depuriilicnt, Ro.vul Prince Alfred Hospital, Cutnperdo urn, N.S . U’. I-CIiriicul f iuerr~aiolo~.v-Otzcol~~~y Depurriiient, The Queen Elizuheth Hosprial, U1oodville, S. A .
Hemoglobin Woodville was found in a Vietnarnesc woman following detection of an abnormal hemoglobin by routine electrophoretic screening. The variant form accounted for 9% of thc total hemoglobin and migrated on cellulose acetate near the Hh F pmition. The Hb F level was 0.3% by the alkaline denaturation method. Structural analysis This demonstrated a new substitution in the alpha chain, a6 Asp’Tyr. substitution does not alter the stability of the hemoglobin tetramer. Thc aspartic acid in position 6 is an external residue participating in molecular contacts with both alpha chains. I t forins a 5aIt bridge with a127(H 10) Lysine of the same alpha chain and lies i n close proximity to a 2 141(HC3)Arginine which is also salt linked to al 127 Lysine. Three other amino acid substitutions are known for the oh position, H b Sawara (Asp-+Ala), Hb Dunn (Asp-Asn) and Hb Ferndown (Asp-Val). The effects of altering the salt bridge between ah Asp and a127 Lys are documented for H b Sawara, which displays a high oxygen affinity. H b Woodville is currently being investigated for similar functional changes. All other hematological parameters are normal.
HEPARIN INDUCED ACUTE ADRENAL INSUFFICIENCY-A NEW HYPOTHESIS. ACUTE ADRENAL INSUFFICIENCY A COMPLICATION OF HEPARIN-INDUCED THROMBOCYTOPENIA SYNDROME (HITTS)
CHKISTOPHFR A R I H U KSIMON , J . B. G R A N TWII , I lAh1 K . M U R R A Y , JAMESP . ISBISTFR, J O H N N. STlFl A N D C H K I S T O I ~ I ~ fs. ~ KLALJEK Huemutology Department, Royul Norih Shore Hospiid, St. Leonurds, Sydney Adrenal insufficiency in association with anticoagulant therapy is well documented in the literature. I t has been presumed rather than proven, that the initiating pathogenetic event has been adrenal hemorrhage. Three cases of adrenal insufficiency occurring during heparin therapy are reported. In these cases features consistent with the heparin induced thrombocytopenia-thrombosis (HITT) syndrome were present. The HITT syndrome has been reported with increasing frequency in recent years. In this disorder, heparin dependent antiplatelet antibodies develop inducing platelet aggregation which may be enough to cause large intravascular platelet-fibrin thrombin. Hence in the HITT syndrome, heparin actually causes thrombosis. A recanalized adrenal vein thrombus was found in the first case. Hemorrhagic infarction was present in the third case but the adrenal vein could not be demonstrated. Biopsy was not done in the second case. The clinical findings in the 3 patients were consistent with the HITT syndrome.These features raise the possibility that some cases of adrenal insufficiency during heparin therapy may be caused by thrombotic infarction of the adrenal tissue with hemorrhage occurring as a secondary event. A review of the literature is given and the pathogenesis of this entity is discussed. A literature review also suggests that many cases of adrenal hemorrhage due to warfarin may have been due to the concomitant heparin therapy.
MONOCLONAL ANTIBODIES TO HUMAN FACTOR Vlll
SUSANE. FRANCIS, DOUcil A S E. JOSHUA, THOMAS EXNEK AN11 HARRY K K O N E N B E R G Haeinutology Depurtment, Royal Prince Alfred Hospital, Camperdown, N.S. W . Four monoclonal antibodies have been produced which recognize different epitopes of the factor VII1R:Ag molecule. Hybrid supernatants after cell fusion were screened by solid phase radioimmunoassay in the
Anti-E occurred 4 times more frequently in females and there was no apparent race predilection. I n 99 individuals in whom a clinical history was available, 95 had a history of transfusion or pregnancy. In 4 cases the antibody was apparently naturally occurring. This f‘igure may be lower than reported in the literature because clinical information on low titre antibodies was difficult to obtain. In 97 case, there was sufficient antibody activity to differentiate IgG and IgM types by the Dithiothreitol Test: 82 showed the resistant IgC pattern, while 15 were inhibited implying IgM antibody activity. Monospecific antisera indicated that 7 within the IgG group were mixtures of IgG and IgA. The anti-E was not implicated in causing any hemolytic transfusion reactions in this series. Seven patients delivered babies whose cord blood dixdosed a positive direct antiglobulin test, and anti-E was eluted from their red cells. Four were not significantly or only mildly affected, while 3 infants required exchange transfusions (two of them also had anti-D feto-maternal incompatibility). I t is concluded that most anti-E antibodies seen in Auckland are not naturally occurring, but usually are sequelae of transfusion or pregnancy. The antibody uncommonly results in hemolytic disease of the newborn, but because of the predominant IgG nature of the antibody, it should always be regarded with caution in compatibility testing.
a THALASSEMIA IN POLYNESIANS
R. J . TK F NTT. ,
P . BKOCK AND H. K K O N L N H E R G Huemutology Department, Koyul Prince Alfred Hospital, Cut?iperduwn. N . S. W . WI1 KINSON, J .
YAKAS,
Polynesian peoples are found scattered throughout many islands over a large area of the Pacific in the form of a triangle bounded by Hawaii at the apex, New Zealand to the south-west and Easter Island the southeast. To the present time, a thalassemia has not been described in Polynesians, and this has been attributed to absence of the anopheline vector for malaria in this region. However, recent data based on hemoglobin Bart’s levels from a cord blood survey conducted at the National Women’s Hospital in Auckland would suggest that a thalassemia may be found in Maoris and Cook Islanders, both of them Polynesian races. One problem inherent in most epidemiological studies of a thalassemia is that definitive evidence of the disorder is not provided unless biosynthetic studies or recombinam DNA techniques such as gene mapping are utilized. Moreover, underlying a thalassemia genotypes may only be determined by gene mapping. We have studied a family of Cook Islanders [family R] and two other individuals [TN-a Cook Islander, BK-a Maori]. Family R came to our attention because 10% hemoglobin Bart’s was detected in cord blood from i-ecently delivered twins. Hematological data including red blood cell indices, hemoglobin A, and hemoglobin EPG from both parents were normal. Hemoglobin H inclusion bodies were not detected. A 5 yr-old child of family R had a hemoglobin of 12.3 g/dl, MCV 65.2 fl, MCH 21.9 pg. Hemoglobin A,, hemoglobin EPG, ferritin levels were normal. Blood film showed target cells. Gene mapping DNA from the above five individuals demonstrated a+ thalassemia [ - a / a a in both parents; -@/-a in the 3 children]. The second example of a thalassemia in Cook Islanders was detected in a 24 yr-old man [TN] referred for investigation of low MCV [73.3 fl] and target cells in the peripheral blood. There were the only abnormal hernatological findings. Gene mapping DNA from TN showed heterozygous a+thalassemia [ - a / a a ] . Finally, a trace of hemoglobin Bart’s was detected in cord blood from a New Zealand Maori [BK]. MCV [I02 f l ] and MCH [32.3 pg] levels in this infant were low for a newborn. Gene mapping confirmed heterozygous a+ thalassemia. More extensive mapping studies were undertaken in all the above examples of a thalassemia and these showed the a+ haplotype [-a/] to be the usual [3.7 kb] deletion found in other areas of the world. Definitive evidence is now available that a thalassemia may be present in Polynesians.
475
HEMOGLOBIN WOODVILLE: a6(A4) ASPARTIC ACID-TYROSINE P . F. C o r m,* S. B A K H E K ,R~. - E. SAGE* AND H . K K O N ~ N H F K*Huemutology C~* Depuriilicnt, Ro.vul Prince Alfred Hospital, Cutnperdo urn, N.S . U’. I-CIiriicul f iuerr~aiolo~.v-Otzcol~~~y Depurriiient, The Queen Elizuheth Hosprial, U1oodville, S. A .
Hemoglobin Woodville was found in a Vietnarnesc woman following detection of an abnormal hemoglobin by routine electrophoretic screening. The variant form accounted for 9% of thc total hemoglobin and migrated on cellulose acetate near the Hh F pmition. The Hb F level was 0.3% by the alkaline denaturation method. Structural analysis This demonstrated a new substitution in the alpha chain, a6 Asp’Tyr. substitution does not alter the stability of the hemoglobin tetramer. Thc aspartic acid in position 6 is an external residue participating in molecular contacts with both alpha chains. I t forins a 5aIt bridge with a127(H 10) Lysine of the same alpha chain and lies i n close proximity to a 2 141(HC3)Arginine which is also salt linked to al 127 Lysine. Three other amino acid substitutions are known for the oh position, H b Sawara (Asp-+Ala), Hb Dunn (Asp-Asn) and Hb Ferndown (Asp-Val). The effects of altering the salt bridge between ah Asp and a127 Lys are documented for H b Sawara, which displays a high oxygen affinity. H b Woodville is currently being investigated for similar functional changes. All other hematological parameters are normal.
HEPARIN INDUCED ACUTE ADRENAL INSUFFICIENCY-A NEW HYPOTHESIS. ACUTE ADRENAL INSUFFICIENCY A COMPLICATION OF HEPARIN-INDUCED THROMBOCYTOPENIA SYNDROME (HITTS)
CHKISTOPHFR A R I H U KSIMON , J . B. G R A N TWII , I lAh1 K . M U R R A Y , JAMESP . ISBISTFR, J O H N N. STlFl A N D C H K I S T O I ~ I ~ fs. ~ KLALJEK Huemutology Department, Royul Norih Shore Hospiid, St. Leonurds, Sydney Adrenal insufficiency in association with anticoagulant therapy is well documented in the literature. I t has been presumed rather than proven, that the initiating pathogenetic event has been adrenal hemorrhage. Three cases of adrenal insufficiency occurring during heparin therapy are reported. In these cases features consistent with the heparin induced thrombocytopenia-thrombosis (HITT) syndrome were present. The HITT syndrome has been reported with increasing frequency in recent years. In this disorder, heparin dependent antiplatelet antibodies develop inducing platelet aggregation which may be enough to cause large intravascular platelet-fibrin thrombin. Hence in the HITT syndrome, heparin actually causes thrombosis. A recanalized adrenal vein thrombus was found in the first case. Hemorrhagic infarction was present in the third case but the adrenal vein could not be demonstrated. Biopsy was not done in the second case. The clinical findings in the 3 patients were consistent with the HITT syndrome.These features raise the possibility that some cases of adrenal insufficiency during heparin therapy may be caused by thrombotic infarction of the adrenal tissue with hemorrhage occurring as a secondary event. A review of the literature is given and the pathogenesis of this entity is discussed. A literature review also suggests that many cases of adrenal hemorrhage due to warfarin may have been due to the concomitant heparin therapy.
MONOCLONAL ANTIBODIES TO HUMAN FACTOR Vlll
SUSANE. FRANCIS, DOUcil A S E. JOSHUA, THOMAS EXNEK AN11 HARRY K K O N E N B E R G Haeinutology Depurtment, Royal Prince Alfred Hospital, Camperdown, N.S. W . Four monoclonal antibodies have been produced which recognize different epitopes of the factor VII1R:Ag molecule. Hybrid supernatants after cell fusion were screened by solid phase radioimmunoassay in the