D. Todd

Molecular defects in Hb H hydrops fetalis

The molecular defect in two unique cases of Hb H hydrops fetalis has been characterized. Both cases are due to co‐inheritance of a ‘non‐deletion’ defect affecting the α2 gene: at codon 30 (ΔGAG, Glu) and codon 59 (G u2003→u2003 A, Gly →u2003 Asp) respectively, and a ζ‐α thalassaemia (thal) 1 or α thal 1 genotype. These two non‐deletion defects, unlike previously described cases, resulted in severe anaemia of the fetuses and emphasize the importance of performing prenatal diagnosis for these families.

Deep Vein Thrombosis and Changes in Coagulation and Fibrinolysis after Gynaecological Operations in Chinese: the Effect of Oral Contraceptives and Malignant Disease

Of 154 Chinese patients who underwent gynaecological operations, four showed a positive 125I fibrinogen leg scan for venous thrombosis, an overall incidence of 2.6%. In those who were on oral contraceptives and had major pelvic surgery for benign conditions, the incidence was 10.5%; in those who had Wertheim hysterectomy for carcinoma of cervix, it was 6.7%. This confirms the rarity of post‐operative thromboembolism in the Chinese. Fragment E showed a biphasic rise after major operation due to tissue injury and venous thrombosis. In patients with malignancy, the postoperative ‘fibrinolytic shutdown’, represented by decreased plasminogen activator together with increased α1, antitrypsin and C inhibitor levels, was more marked. In addition, α2 macroglobulin level was lower and fell significantly after operation. In patients on oral contraceptives, fragment E levels were higher after surgery and there was no decrease in plasminogen activator levels. Antithrombin III levels did not fall except in three of the four patients with venous thrombosis. A marked increase in fragment E level and a decrease in antithrombin III level might be useful diagnostic markers for postoperative venous thrombosis.

Organization of the ζ‐α genes in Chinese

Summary. Analysis of α and ζ genes in 101 healthy normals and hospitalized patients with non‐haematological diseases revealed a 3% incidence of α thalassaemia in the local Chinese population of Hong Kong. Triple α genes were found in only one person while triple ζ genes were more prevalent, occurring in 13 subjects. Studies of 28 unselected patients with Hb H disease indicated a predominance of the rightward χ gene deletion. The extent of α gene deletion in homozygous α thalassaemia 1 was at least 18.1 kb, beginning from the BamH I site 3’to the ζ1 gene and includes the Φα, α2 and α1 genes. Nineteen of the 20 chromosomes bearing the α thalassaemia 1 deletion had identical ζ‐intergenic hypervariable region suggesting a common origin of this mutation. The co‐inheritance of α thalassaemia in β thalassaemia subjects was 8%, but did not ameliorate the clinical features of those with homozygous β thalassaemia

Characteristics and distribution of β thalassemia haplotypes in South China

SummaryEleven restriction site polymorphisms in the β-globin gene cluster were determined in 48 Chinese with homozygous β-thalassemia and their parents. Seven haplotypes were identified as associated with the βthal chromosome and 25 with the βA chromosome. The distribution of the various βthal haplotypes in different regions of South China was mapped and discussed in relation to prenatal diagnosis and migration of the Chinese people.

The determination of antithrombin III by radioimmunoassay and its clinical application

Summary. A radioimmunoassay (RIA) had been developed for the determination of antithrombin III (AT III) in man. The detection limit was 25 μ/dl. AT III‐RIA level and biological activity (anti‐Xa) was significantly correlated (r=0.737, P<0.001). Plasma levels in 36 healthy males (mean ± SD, 19.9±2.5 mg/dl) and 21 healthy females (19.1 ± 2.4 mg/dl) were similar. Serial AT III measurements in normal menstruating females showed lower levels during midcycle and higher concentrations during menstruation. In carcinomas, the AT III levels were lower than normal, particularly in hepatocellular carcinoma. In cirrhosis of liver, the levels were markedly decreased and in some patients were below that found in congenital AT III deficiency. Patients with deep vein thrombosis and patients with heart valve replacement had lowere levels than normal, while patients with cerebral vascular occlusion had normal levels. The possible use of AT III as a diagnostic tool of post‐operative deep vein thrombosis was demonstrated in one patient after hysterectomy. The increased sensitivity, specificity and precision of this type of assay offer distinct advantages over existing methods of AT III estimation.

Different Forms of Hb H Disease in the Chinese

A marked genetic and clinical variability of the Hb H syndrome occurs because of the molecular heterogeneity of alpha-thalassemia (thal). The hallmark is the presence of excess beta chains forming Hb H (beta tetramer). In the Chinese, classical Hb H disease presents as alpha-thalassemia intermedia and is due to a double heterozygosity for two deletional forms of alpha-thal, alpha-thal-1 and alpha-thal-2. The majority of cases with an alpha-thal-1 defect have a deletion of at least 18.1 kb starting 3 to the zeta 1 gene which includes the psi alpha and the two alpha genes; it is similar to that described in Thais. However, two families had a deletion of the entire zeta-alpha gene cluster, i.e. zeta-alpha-thal-1. Of 33 alpha-thal-2 defects studied, 26 were the rightward deletion (alpha -3.7 kb, all type I defects) and seven the leftward deletion (alpha -4.2 kb); one of the latter was associated with Hb Q. About 10% of the alpha-thal defects belong to the nondeletion type, the most common form being Hb Constant Spring (CS). This anomaly, when coinherited with alpha-thal-1, produces Hb H-CS disease which has a most marked anemia and splenomegaly due to the instability of the alpha-CS chain. Hb Quong Sze produces an alpha-thal-2 because of the unstable alpha-Quong Sze chain. One patient who inherited classical Hb H disease and Hb New York (NY) [alpha 113(G15)Val----Glu] had severe anemia, and required frequent blood transfusions due to the deleterious effect of an increased alpha-NY chain turnover.(ABSTRACT TRUNCATED AT 250 WORDS)

Globin Chain Synthesis in Haemoglobin New York (β 113 Valine→Glutamic acid

The presence of Hb New York was confirmed in a Chinese family in which affected members have occasional red cells with Hb H‐like inclusions and a relative decrease in α chain synthesis, suggestive of a coexisting α thalassaemia trait. However, globin gene mapping and DNA hybridization revealed no deletion of the α genome. Timed‐incubation experiments showed that the rate of synthesis of βNY chain was greater than that of normal β chain in the early periods. Chromatographic separation of Hb NY and Hb A before chain analysis revealed preferential binding of newly synthesized α chains to βNY, with a four‐fold increase in specific activity of the αHbny chains. It is concluded that βNY chain is being synthesized more rapidly and its increased turnover may account for this presentation of apparent a chain deficiency.