Prawase Wasi

Clinical manifestation of beta-thalassemia/hemoglobin E disease.

Purpose To review the clinical manifestation and changes in hematologic parameters of patients with &bgr;-thalassemia/hemoglobin (Hb) E. Materials and Methods Retrospective analysis of the clinical manifestation of 378 patients with &bgr;-thalassemia/Hb E attending the hematology clinic at Siriraj Hospital between 1957 and 1982. Results A wide spectrum of clinical phenotypes has been observed. Most patients show clinical symptoms by 10 years of age. The majority of patients survive with or without occasional transfusion. Splenectomy was performed in 26.5% of patients. Patients come to the hospital because of anemia, fever, abdominal mass, and jaundice. Gastrointestinal tract disturbances are the most common presenting symptoms (34.6%), especially abdominal pain (10%) and cholecystitis (5.1%). Respiratory tract infections were found in 21.8% of patients and cardiovascular complications, including congestive heart failure, occurred in 11.9%. Other less common symptoms and complications included bone pain, chronic leg ulcers, paraplegia and hypertension-associated convulsions, and cerebral hemorrhage after multiple blood transfusion. Patients usually die between 20 to 40 years of age (67%), mainly from congestive heart failure and septicemia. Septicemia was often caused by Gram-negative bacteria. Conclusion These clinical features observed in patients with &bgr;-thalassemia/Hb E are probably the results of chronic anemia and iron overload. The study of the life history and clinical courses of patients with &bgr;-thalassemia/Hb E should provide important information for the better management of these patients.

Genetic factors affecting clinical severity in beta-thalassemia syndromes.

Purpose Heterogeneity in the clinical manifestation of &bgr;-thalassemic diseases may occur from the nature of &bgr;-globin gene mutations, &agr;-thalassemia gene interaction, or differences in the amount of hemoglobin (Hb) F production. This study was conducted to determine whether these genetic determinant factors can predict phenotypic severity of patients with &bgr;-thalassemia and to assess the relationship between the genotype and phenotype of the disease. Materials and Methods A total of 144 patients with &bgr;-thalassemia were divided into mild (46 patients), intermediate (55 patients), and severe groups (43 patients). DNA analysis based on polymerase chain reaction technique was performed to characterize types of &bgr;-thalassemia mutation, interaction of &agr;-thalassemia, and Xmn I polymorphism 5´ to G&ggr;-globin gene. Results Two alleles of mild &bgr;-thalassemia mutation (&bgr;+/&bgr;+-thalassemia or &bgr;+-thalassemia/Hb E) resulted in a mild clinical symptom whereas two alleles of severe &bgr;-thalassemia mutation (&bgr;o/&bgr;o) produced a severe clinical phenotype. Compound heterozygosity for mild and severe alleles of &bgr;-thalassemia (&bgr;o/&bgr;+-thalassemia or &bgr;o-thalassemia/Hb E) led to variable severity of anemia. Coinheritance of &agr;-thalassemia alleviated the severity of &bgr;-thalassemia disease in those patients with at least one allele of the mild &bgr;-thalassemia genotype. DNA polymorphism at position -158 nt 5´ to the G&ggr;-globin gene was demonstrated by Xmn I restriction enzyme. Homozygote of the Xmn I site, +/+, was found to have a strong linkage with high Hb F levels and high hemoglobin production in two patients who had mild clinical symptoms. However, some patients who had Xmn I site −/− also had mild clinical symptoms because the Xmn I− was found to be associated with &bgr;+-thalassemia mutation. Conclusion Types of &bgr;-thalassemia mutation and coinheritance of &agr;-thalassemia in the patient who has at least one allele of the mild &bgr;-thalassemia genotype are predictive for the clinical severity of the disease. However, a mild clinical symptom in some patients with &bgr;o/&bgr;+-thalassemia or &bgr;o-thalassemia/Hb E who do not have a detectable &agr;-thalassemia haplotype and no linkage with Xmn I++ suggests that there are other confounding factors responsible for the severity differences of the disease.

A SYNDROME OF HYPERTENSION, CONVULSION, AND CEREBRAL HÆMORRHAGE IN THALASSÆMIC PATIENTS AFTER MULTIPLE BLOOD-TRANSFUSIONS

Various combinations of hypertension, convulsion, severe headache, and cerebral haemorrhage appeared in eight thalassaemic patients after they had received 3--7 units of blood in preparation for splenectomy. Intracranial haemorrhage definitely developed in four patients, three of whom died. At necropsy the brains showed changes similar to those of hypertensive cerebral haemorrhage and hypertensive encephalopathy. It is believed that hypertension initiates this syndrome. Since the episodes often occurred days, as long as 15 days, after the last unit of blood was transfused, hypertension did not seem to result from volume overload, but probably from vasopressive substances provided by or occurring in association with multiple blood-transfusions. Host factors may also contribute.

Paroxysmal Nocturnal Haemoglobinuria in Thailand with Special Reference to an Association with Aplastic Anaemia

Eighty‐five cases of PNH in Thailand were analysed, with emphasis on the comparison with European series and on an association with aplastic anaemia. Compared with European series, two points emerge: (1) the disease in Thai affects individuals of younger age group with a tendency to male preponderance; (2) the incidence of arterial and venous thrombosis is relatively rare. In association with aplastic anaemia, two main categories of PNH patients, are described, which differ in their clinical and laboratory citeria.

Serum Ferritin Levels in Thalassemias and the Effect of Splenectomy

Iron overload is a constant and the more important complication in thalassemia. Serum ferritin concentration accurately reflects body iron stores. A total of 245 thalassemic patients aged 12-55 years were examined, 71 having Hb H disease and 174 beta-thalassemia/Hb E disease. The patients received minimal or no blood transfusions. 73 patients with beta-thalassemia/Hb E were studied 1-28 years after splenectomy. The serum ferritin levels in both Hb H and beta-thalassemia/Hb E patients were higher than normal. They were higher in beta-thalassemia/Hb E than Hb H disease. Most striking was the significantly higher serum ferritin levels in splenectomized patients with beta-thalassemia/Hb E disease than in the nonsplenectomized ones. The observation is compatible with previous observations that splenectomy in thalassemia is associated with increased iron deposition and increased transferrin iron saturation. The further increase in iron overload after splenectomy in thalassemia should be borne in considering removal of this organ.

Homozygous haemoglobin constant spring: A need for revision of concept

SummaryTwenty-two patients with mild haemolytic anaemia and haemoglobin (Hb) Constant Spring (CS) of around 6% were studied because they were suspected of having homozygous Hb CS. Family studies revealed Hb CS trait in both parents of eight patients, supporting that they were homozygous for Hb CS. The other patients were included because they had clinical and haematological features similar to the diagnosed cases of homozygous Hb CS. Heterozygosity and homozygosity for Hb CS are clearly distinguishable in that the former is asymptomatic but the latter is associated with overt haemolytic anaemia, and the levels of Hb CS in the two conditions of less than 1% and around 6%, respectively, do not overlap. The findings in homozygous Hb CS contracdict prediction. There are four a-structural genes per normal human diploid genome. Hb CS trait is believed to be almost equivalent to a-thalassaemia 2 or a loss of one a-gene because HB CS, an a-variant, is barely or not detectable. Homozygosity for Hb CS has thus been predicted to be equivalent to a-thalassaemia 1 or a loss of two genes. The latter is asymptomatic and associated with microcytic-hypochromic red cells. However, Hb CS homozygosity presents with mild overt haemolytic anaemia and normal sized red cells. Pathogenesis associated with Hb CS inheritance is more complex than originally believed. There is a possibility that the unstable aCS mRNAs precipitate and aggregate leading to pathology of red cells and to the basophilic stippling appearance, so striking in this syndrome.

Haematological Data in 312 Cases of β‐Thalassaemia Trait in Thailand

Summary. The haematological data are presented in 312 individuals of Thai or Chinese extraction with the high A2β‐thalassaemia trait. The mean haemoglobin concentrations were 12.1 g% among males and 10.8 g% among eemalcs; 54% of the subjects were not anaemic and all were asymptomatic. Low MCV, MCH and MCHC values were found in 67%, 81% and 6% respectively; erythrocytosis was detected in 34%. Variable hypochromia and microcytosis were usually present, but leptocytosis and red cell basophilic stippling were often absent. Decreased red cell osmotic fragility was always detected. Fifteen cases were found to have normal red cell morphology and 17 normal red cell osmotic fragility. The reticulocyte counts, although ranged up to 12%, were normal in the majority. The serum iron levels and unsaturated iron binding capacity were normal except in 11% of the cases where the scrum iron levels were lower than 50 μg%. Haemoglobin A2 levels varied from 3.4 to 7.8% with a normal distribution and a mean of 5.2%. Haemoglobin F levels varied from o to 7.8% with 58% elevated values. Analysis of variance revealed intrafamilial segregation of both haemoglobin A2 and haemoglobin F levels. The literature is reviewed and findings are compared.

Activation of monocytes for the immune clearance of red cells in β°-thalassaernia/HbE

Summary We have recently provided evidence that IgG antibodies play a role in the destruction of red cells in thalassaemia syndromes. In order further to delineate factors involved in the clearance of thalassaemic cells, monocytes of 30 Thai patients with β°‐thal/HbE (17 non‐splenectomized and 13 splenectomized) and 16 normal controls were examined for their ability to bind and phagocytose normal red cells coated with IgG anti‐Rh(D). In β°‐thal/HbE. the mean number of red cells attached to the monocytes was approximately 3‐fold greater than in normal controls and the number ingested 30% higher. Among the non‐splenectomized patients, the number of red cells attached to and ingested by the monocytes, correlated inversely with mean basal Hb levels, suggesting that activation of mononuclear phagocytes for the immune clearance of red cells is a factor in determining the severity of the anaemia. As Fc‐gamma‐RI is of primary importance in the recognition of IgG‐coated red cells by monocytes, leucocytes from 10 β°‐thallHbE patients (four non‐splenectomized and six splenectomized) and five normal controls were investigated for their expression of Fc‐gamma‐RI by flow cytometry. In β°‐thallHbE there was an approximately 3‐fold increase in the percentage of leucocytes expressing this receptor: the receptor was up‐regulated on monocytes and induced on granulocytes. The up‐regulation of Fc‐gamma‐RI in β°‐thallHbE is likely to be an important component in the activation of monocytes and in mediating their enhanced effector function towards antibody‐coated cells.

Increased transferrin iron saturation in splenectomized thalassaemic patients.

In severe P-thalassaemic diseases iron overload with progressive liver damage is a serious complication (Risdon et al, 1975). Splenectomized thalassaemic patients definitely have more iron deposition in liver parcnchynial cells than non-splenectomized cases (Witzleben & Wyatt, 1961; Bhamarapravati et al , 1967; Berry & Marshall, 1967; Okon et al, 1976; Sonakul et al , 1978). Thus it is important to investigate the effect of splenectomy on the body iron status. We wish to report increased transferrin iron saturation in splenectomized thalassaemic patients, an observation not previously recognized. Both P-thalassaemia/haemoglobin (Hb) E and Hb H diseases were diagnosed according to the criteria previously described (Wasi et al, 1969, 1974). Thirty-five cases of P-thalassaemia/HbE had had splenectomy for 5-27 years. The plasma iron and total iron binding capacity were determind by the ICSH standard method (1971, 1972). The results are summarized in Table I and Fig 1. Both thalassaemic groups had significantly higher mean values for plasma iron and transferrin iron saturation (P< 0401). There was a remarkable increase in transferrin iron saturation in splenectomized thalassaemic patients. As shown in Table I, when compared to 22 non-splenectomized patients who were more anaemic, the splenectomized patients still had remarkably higher transferrin iron saturation. The transferrin iron saturation values in these patients showed minimal correlation with the haemoglobin levels, ages or duration of splenectomy, the Y values being -0.14, -0.03 and

SERUM-IMMUNOGLOBULIN LEVELS IN THALASSÆMIA AND THE EFFECTS OF SPLENECTOMY

Abstract Serum-immunoglobulin (Ig) G, A, and M levels were estimated by a single radial immunodiffusion technique in 128 patients with thalassaemic diseases, including 42 splenectomised cases. The mean values were higher than normal for the three classes of immunoglobulin in non-splenectomised patients. Splenectomy in thalassaemia was found to be definitely associated with increased IgA and decreased IgM levels—findings not known before. Increased IgA may have occurred from increased liver damage after splenectomy and/or from decreased catabolism from removal of the spleen. The reduction of IgM after splenectomy indicates that this organ significantly synthesises this immunoglobulin. The relative deficit of IgM production may be partly responsible for increased infections after splenectomy.