Successful bone marrow transplant for Fanconi anaemia in transformation.

We present a patient who was diagnosed as suffering from Fanconi anaemia at the age of 36 years. At the time of diagnosis his bone marrow showed features of pre-leukaemic transformation. He received an allogeneic bone marrow transplant (BMT) from his HLA-identical sibling. The post-transplant course was unremarkable with evidence of trilineage engraftment at day +32 and no acute or chronic GVHD. He is well with sustained engraftment and no haematological evidence of Fanconi anaemia 18 months post-transplant.

Detection of important abnormalities of the differential count using the Coulter STKR blood counter.

An assessment of the three part differential provided by the Coulter STKR blood counter showed good correlation when compared with an 800 cell manual differential. Satisfactory flagging of eosinophilia, basophilia, and the presence of immature cells was found. The use of variables derived from the STKR in conjunction with interpretive reporting and user-defined flagging enabled this department to reduce considerably the numbers of films requiring manual differential counts.

Shoshin beriberi: an underdiagnosed condition?

Shoshin beriberi, a fulminant form of heart failure due to thiamine deficiency has a different presentation to the classical form of beriberi heart failure. It is characterized by a cold periphery, low blood pressure, renal shutdown and a severe metabolic acidosis. The true incidence is unknown. Two patients were seen within a few months in a general hospital and in both dietary deficiency of thiamine was a major factor.

Pregnancy management and outcomes in women with thalassaemia major.

The health background, management and outcomes of 25 pregnancies in 18 women with transfusion dependent beta thalassaemia are described with particular consideration of appropriate preconceptual guidance for such women. This is an observation study of women attending three collaborating London hospitals. Nine of the pregnancies required induction of ovulation. Two pregnancies were complicated by diabetes and three by hepatitis C. One patient was hepatitis B positive. Two pregnancies were in women with cardiac problems, one of whom died of cardiac failure nine months after delivery of a live child. Two of the pregnancies miscarried and three were terminated, with the others resulting in 21 live children (including one set of twins). 14 of the pregnancies were delivered by caesarean section. After pregnancy five women developed secondary amenorrhoea, two developed cardiac problems and two developed diabetes.

Sickle cell disease.

SCD is a major health problem requiring lifelong multidisciplinary care to manage the wide range of medical and social consequences. A number of new approaches offer the potential to have an impact on the natural history of this disease.

A home blood transfusion programme for beta-thalassaemia patients.

Although home transfusion programmes are relatively common in the USA (Anon, 1990, Home Care in the 1990s. Council on Scientific Affairs. Journal of the American Medical Association, 263, 1241-1244), this type of treatment has only recently been considered in Britain and, where it is in operation, is generally supervised by trained nursing staff or via a hospice. North Middlesex Hospital now has 3 years experience of a home transfusion programme operating for beta-thalassaemia major patients, in which relatives are trained and responsible for supervision of the red-cell transfusions at home. For families who request this service, and who are willing and able to undertake it responsibly, the scheme offers the advantages of improved patient comfort, reduced absences from education or employment and reduced hospital bed usage. Patients and their carers express improved satisfaction with the treatment delivered in this way.

Hypercoagulable states.

PIP: A prethrombotic or hypercoagulable state is one in which the hemostatic balance is disturbed, with increasing procoagulant activity or decreasing activity of intrinsic anticoagulant properties. A basic problem in the study of hypercoagulable states is that it cannot be determined with certainty whether changes in hemostatic variables are causative or consequences of thromboses that have already occurred. This chapter discusses the ways in which various physiologic and pathologic states may be associated with alterations in hemostatic systems and, by weighting the balance in favor of readier coagulability, may predispose to thrombosis. Physiologic conditions discussed include stress, cold, pregnancy, oral contraceptives (OCs), aging, and smoking. It is noted that major alterations in blood coagulability, rheology, and flow during pregnancy combine to increase the risk of thrombosis, especially venous. The risk that venous thromboembolism will occur is increased 10-fold in OC users. The increased risk may be related to alterations in hemostatic variables that occur gradually over the 1st year of use, with no further subsequent increase. At present, no individual laboratory test is capable of identifying patients at risk of thrombosis, but a number of variables in combination (e.g., obesity, age, presence of varocose veins, euglobulin lysis time, level of fibrinogen degradation products) may provide a useful indication. In the absence of reliable predictive indicators, assessment and management efforts should be directed in 3 ways. 1st, simple tests should be undertaken in all individuals in whom thromboembolism has occurred to diagnose treatable predisposing factors. 2nd, efforts should be directed toward refining a safe, effective prophylactic regimen. 3rd, a few selected patients (e.g., those who have their 1st thrombotic episode before age 30 years) should be investigated in greater detail.^ieng

Clinical management of severe sickle cell disease.

Patients affected by sickle cell disease encounter varied and often severe clinical problems directly related to their condition and are at greater risk than the general population from particular infections, thrombosis and certain surgical pathologies. The current clinical management policies for the severe acute problems arising in these patients, and measures undertaken to prevent these where possible, are discussed.

The effect of ovarian steroids on sickle cell deformability.

Sickle cell disease (SCD) is an incurable debilitating disease affecting the Afro-Caribbean population. The combined oral contraceptive pill (COCP), an effective and popular method of contraception, is often denied to women with SCD for fear that the disease process may have a synergistic effect on the coagulation changes associated with contraceptive steroids. In this study red cell deformability was assessed in 10 women with SCD and 10 comparable women with normal AA haemoglobin. Neither group was on exogenous hormones. The red cells were taken in the follicular phase of the menstrual cycle when women have low endogenous levels of oestradiol and progesterone. The effect of the steroids contained in the COCP on red blood cells was simulated by incubation with therapeutic concentrations of oestradiol and progesterone. Red cell deformability is a measure of the ease with which erythrocytes flow through small capillaries and was assessed using the parameters red cell transit time (RCTT) and clogging rate (CR). Therapeutic concentrations of oestradiol and progesterone did not appear to influence red cell deformability in women with SCD or normal AA haemoglobin.

Red cell deformability in oral contraceptive pill users with sickle cell anaemia.

The use of the combined oral contraceptive pill (COCP) in women with sickle cell anaemia (SCA) is controversial, as contraceptive steroids are thought to adversely affect erythrocyte deformability. This observational study was performed to investigate whether hormonal contraception influenced erythrocyte deformability in women with SCA. 30 women with SCA using various contraceptive modalities: COCP (n = 10); progestogen only (PO) contraception (n = 10) and non-hormonal contraception (n = 10) were recruited. Erythrocyte deformability was assessed using the clogging rate (CR) and red cell transit time (RCTT). There was no statistical difference in the mean CR and RCTT between the three groups of women (one-way ANOVA). Current contraceptive steroids do not appear to impair red cell deformability in women with SCA.

Psychosocial and clinical burden of thalassaemia intermedia and its implications for prenatal diagnosis.

Twenty eight patients with thalassaemia intermedia and their parents were interviewed using specifically designed questionnaires to evaluate psychosocial burden. Hospital notes were analysed for clinical burden. A wide variation was found for both patients and parents, ranging from virtually unaffected to severely affected. Normal sexual function and setting up a family were mentioned by patients and parents as being particularly important for quality of life. Over half (58%) of the patients had problems with sexual maturation and functioning, and continuous monitoring of all patients with thalassaemia intermedia by a paediatric endocrinologist is therefore strongly indicated. Most parents said, in light of their experiences, that they would opt for prenatal diagnosis and termination of affected pregnancies even if a genotype predicting the mild form of disorder were discovered.

The effects of neonatal screening for sickle cell disorders on lifetime treatment costs and early deaths avoided: a modelling approach.

BACKGROUND: The aim of the study was to calculate the cost to the UK National Health Service of providing treatment services for patients with sickle cell disorders. The rates of differential morbidity and mortality, in the first 10 years of life, between screen-detected early diagnosed and clinically presenting late diagnosed cohorts of sickle cell disorder patients are also estimated. METHOD: A cost model was developed, based on predictions of survival and the incidence of sickle cell disorder-related events. Direct data from the NHS are lacking, so data were incorporated from disparate sources. Patients with sickle cell disorders were divided into two categories: those with sickle cell anaemia and those with sickle HbC disease. RESULTS: Differentiating between sickle cell anaemia and sickle HbC disorder patients, the results show that the undiscounted (discounted at 6 per cent) lifetime treatment costs range from pound sterling 92323 (pound sterling 24917) to pound sterling 185614 (pound sterling 53861). The number of early deaths avoided per 100 births, as a result of early diagnosis through screening, ranges from 0.57 to 1.25. CONCLUSIONS: The resulting estimates may act as a guide to those involved in the planning of health care provision with regard to the resources required to treat sickle cell disorder patients. Such information may also be incorporated into the evaluation of both antenatal and neonatal screening programmes for sickle cell disorders.

Moderate reduction of beta-globin gene transcript by a novel mutation in the 5' untranslated region: a study of its interaction with other genotypes in two families.

We have identified two individuals of Greek Cypriot origin with thalassemia intermedia. Molecular analysis has shown that each individual is a compound heterozygote for a previously described beta zero thalassemia allele and a novel mutation, C-->G in position +33, in the 5' untranslated region of the beta globin gene. In both families the beta +33 allele is associated with the same beta haplotype (-++- ) suggesting that it is likely to be of a single origin, beta-cDNAs from normal and mutant beta alleles were isolated from peripheral blood reticulocytes using the technique of reverse transcription-polymerase chain reaction. Because the beta +33 (C-->G) mutation creates a cutting site for the restriction enzyme NlalV, we could demonstrate by differential restriction analysis that the beta gene with +33 mutation showed 25% to 35% residual activity compared with normal. The additive effect of this moderate deficit in beta globin production with the beta zero thalassemia mutation would explain the clinical phenotypes observed in the two probands. In contrast, two siblings of one proband who were also compound heterozygotes for the same beta thalassemia mutations, as well as heterozygotes for a nondeletional alpha thalassemia variant, and two other compound heterozygotes for the beta +33 and a beta+ thalassemia allele were completely asymptomatic. Individuals heterozygous for the beta +33 C-G mutation alone are clinically and hematologically silent, with normal red blood cell indices and normal levels of hemoglobin (Hb) A2. A direct relationship between genotypic and phenotypic severity is clearly demonstrated in these cases with obvious implications for prenatal diagnosis.

An evaluation of the Coulter VCS differential counter.

An evaluation of the Coulter VCS (volume, conductivity, light scatter) automated differential counter demonstrated satisfactory correlations with manual 800-cell differential counts for neutrophils, lymphocytes, monocytes and eosinophils. For the detection of abnormal cells, 12.2% of samples gave false-negative results on the VCS, and 13.4% gave false-positive results. However, only 0.8% of the false-negatives would be expected to be picked up by a standard 100-cell manual differential count. Carry-over accorded to manufacturer's specifications and throughput was 60 samples/h. Reference normal ranges have been established and the instrument's precision and performance with leucopenic and neonatal blood samples assessed.

Combination therapy with interferon alpha and ribavirin for chronic hepatitis C virus infection in thalassaemic patients.

Hepatitis C virus (HCV) infection is common in multi-transfused thalassaemic patients, and, in combination with transfusional iron overload, can result in progressive liver disease. Therapy with interferon-alpha causes a sustained loss of HCV in only 15-25% of patients, and there is as yet no established effective therapy for those who fail to respond. We have conducted a pilot study of combination anti-viral therapy for patients who failed to respond, or relapsed after an initial response to single-agent interferon-alpha. Patients were treated for 6 months with interferon-alpha 2b, given subcutaneously three mega units thrice weekly, together with ribavirin, orally 1 g daily. 11 patients were enrolled, their median age was 24.9 years. 8/10 evaluable patients had cirrhosis on biopsy, five were infected with HCV type 1 and all but one had initial HCV RNA titres > 10(6) genomes/ml. Five patients (45.5%) had a sustained virological response with loss of serum HCV RNA for > 6 months after finishing therapy. There was no clear association between response to therapy and age, histology, HCV genotype, or HCV RNA titre. Transfusion requirements were significantly increased during the treatment phase, probably due to ribavirin-induced haemolysis, and this necessitated intensification of iron chelation therapy. Serum ferritin levels decreased significantly in those who responded. These results suggest that combination therapy is potent in clearing HCV infection, and may provide effective second-line therapy for thalassaemic patients who have failed to respond to interferon-alpha monotherapy.

High prevalence of low bone mass in thalassaemia major.

Cooley's original description of beta-thalassaemia major included marked bone deformities as a characteristic feature. These were thought to be due to expansion of haemopoiesis attempting to compensate for the congenital anaemia. Regular blood transfusions from infancy prevents these skeletal problems. Nevertheless, symptoms due to bone disease frequently occur in adult patients. Osteoporosis has not previously been reported as a cause of severe morbidity in thalassaemia major. The present study shows a high prevalence of low bone mass among thalassaemia major patients and analyses the predisposing causes. Bone density scans were performed in 82 patients with transfusion-dependent beta thalassaemia. Factors known to be associated with low bone mass such as gender, endocrine disorders and lifestyle activities, together with factors specific to the thalassaemia and its management, were included in a series of univariate analyses to ascertain any significant associations. 42 (51%) of the patients had severely low bone mass and a further 37 (45%) had low bone mass. The three factors showing a statistically significant association with severely low bone mass were male sex, 24/38 (63%) males had severely low bone mass, compared with 18/44 (41%) females, the lack of spontaneous puberty, 22/32 (69%) who required therapeutic induction of pubertal development had severely low bone mass, compared with 19/47 (40%) with spontaneous puberty and diabetes, 8/10 (80%) diabetic patients had severely low bone mass, compared with 23/56 (41%) with normal glucose tolerance. There was no association between the bone mineral density measurements and the haematological characteristics or treatment details of these patients. Severely low and low bone mass are common findings in patients with beta-thalassaemia major despite optimal transfusion and iron chelation. The associated features suggest that the severely low bone mass is due to endocrine abnormalities, in contrast to the haematological causes of bone disease characteristically seen in untreated thalassaemics.