Detection of ß-Thalassemia Carriers by Red Cell Parameters Obtained from Automatic Counters using Mathematical Formulas.

BACKGROUND: ß-thalassemia major is a severe disease with high morbidity. The world prevalence of carriers is around 1.5-7%. The present study aimed to find a reliable formula for detecting ß-thalassemia carriers using an extensive database of more than 22,000 samples obtained from a homogeneous population of childbearing age women with 3161 (13.6%) of ß-thalassemia carriers and to check previously published formulas. METHODS: We applied a mathematical method based on the support vector machine (SVM) algorithm in the search for a reliable formula that can differentiate between thalassemia carriers and non-carriers, including normal counts or counts suspected to belong to iron-deficient women. RESULTS: Shine's formula and our SVM formula showed >98% sensitivity and >99.77% negative predictive value (NPV). All other published formulas gave inferior results. CONCLUSIONS: We found a reliable formula that can be incorporated into any automatic blood counter to alert health providers to the possibility of a woman being a ß-thalassemia carrier. A further simple hemoglobin characterization by HPLC analysis should be performed to confirm the diagnosis, and subsequent family studies should be carried out. Our SVM formula is currently limited to women of fertility age until further analysis in other groups can be performed.

A homozygous PIGO mutation associated with severe infantile epileptic encephalopathy and corpus callosum hypoplasia, but normal alkaline phosphatase levels.

We describe two sisters from a consanguineous Arab family with global developmental delay, dystrophy, axial hypotonia, epileptic encephalopathy dominated by intractable complex partial seizures that were resistant to various anti-epileptic treatments. Dysmorphic features comprised low set ears, hypertelorism, upslanting palpebral fissures, a broad nasal bridge, and blue sclera with elongated eyelashes. Brain MRI in both children showed a corpus callosum hypoplasia that was evident already in utero and evolving cortical atrophy. Autozygosity mapping in combination with Whole Exome Sequencing revealed a homozygous missense mutation in the PIGO gene [c.765G > A, NM_032634.3] that affected a highly conserved methionine in the alkaline phosphatase-like core domain of the protein [p.(Met255Ile), NP_116023.2]. PIGO encodes the GPI-ethanolamine phosphate transferase 3, which is crucial for the final synthetic step of the glycosylphosphatidylinositol-anchor that attaches many enzymes to their cell surfaces, such as the alkaline phosphatase and granulocyte surface markers. Interestingly, measurement of serum alkaline phosphatase activities in both children was normal or only slightly elevated. Quantification of granulocyte surface antigens CD16/24/59 yielded reduced levels only for CD59. Phenotype analysis of our and other published patients with PIGO mutations reveals a more severe affectation and predominantly neurological presentation in individuals carrying a mutation in the alkaline phosphatase-like core domain thereby hinting towards a genotype-phenotype relation for PIGO gene mutations.

Hb TAYBE: clinical and morphological findings IN 43 patients.

UNLABELLED: Hereditary sequence variants in globin genes are usually silent and are rarer in α-globin chains than ß-globin chains. Some may lead to an unstable protein with a hemolytic or thalassemic phenotype. Hb Taybe is an unstable α-chain hemoglobin variant caused by the deletion of a threonine residue at codon 38 or 39 of the α1 globin gene. This deletion results in a structural abnormality that affects the α1 ß2 contact and the α1 ß1 interface, producing a highly unstable Hb. OBJECTIVE: We describe the clinical, laboratory, and morphological characteristics of 43 patients with Hb Taybe, sixteen of whom are heterozygous, eight are homozygous, and nineteen are double heterozygous for Hb Taybe and other α-gene mutations or deletions. RESULTS: The clinical presentation is very variable from a mild hemolytic anemia to the need for red cell transfusion. Morphological characteristics include erythroid hyperplasia, defective hemoglobin production, and dyserythropoietic features. On electron microscopy dyserythropoiesis and cytoplasmic precipitation of globin compatible optical dense material is seen. CONCLUSIONS: This is the largest report of Hb Taybe patients. Previous reported cohorts are not related to these cases. We conclude that patients carrying Hb Taybe have a unique hematological and clinical phenotype distinct from other hemoglobinopathies and from congenital dyserythropoietic anemia.

Prevention of ß Thalassemia in Northern Israel - a Cost-Benefit Analysis.

BACKGROUND: ß Thalassemia major is characterized by hemolytic anemia, ineffective erythropoiesis and hemosiderosis. About 4% of the world population carries a Thalassemia gene. Management includes blood transfusions and iron chelation. However, this treatment is costly, and population screening may be significantly more cost beneficial. PURPOSE: The purpose of the current study is to analyze the cost of running a prevention program for ß Thalassemia in Israel and to compare it to the actual expenses incurred by treating Thalassemia patients. METHODS: THREE COST PARAMETERS WERE ANALYZED AND COMPARED: the prevention program, routine treatment of patients and treatment of complications. An estimation of the expenses needed to treat patients who present with complications was calculated based on our ongoing experience in treating deteriorating patients. RESULTS AND CONCLUSIONS: The cost of preventing one affected newborn was $63,660 compared to $1,971,380 for treatment of a patient during 50 years (mean annual cost: $39,427). Thus, the prevention of 45 affected newborns over a ten year period represents a net saving of $88.5 million to the health budget. Even after deducting the cost of the prevention program ($413.795/year), the program still represents a benefit of $76 million over ten years. Each prevented case could pay the screening and prevention program for 4.6 years.

Incidental findings of variant hemoglobin during hemoglobin A(1c) testing.

A variant hemoglobin fraction may be an incidental finding during HbA(1c) analysis using the G8 Tosoh HPLC analyzer, but it is unclear if the retention times and fraction patterns can reliably predict the findings of a high-performance liquid chromatography (HPLC) ß-thalassemia program (Bio Rad Variant II analyzer). We chose 100 samples sent for HbA(1c) determinations (G8 Tosoh) with an incidental finding of variant hemoglobin and did a reflex test using the Bio Rad Variant II analyzer (ß-thalassemia program). Two observers attempted to predict the results with that analyzer from fraction patterns and retention times of the hemoglobin variants detected with the G8. They independently identified all hemoglobin variants (HbS, Hb Setif, HbC, and HbD) by their patterns and retention times. We conclude that HPLC confirmation of certain variant hemoglobin fractions found incidentally during HbA(1c) testing on the G8 Tosoh is not necessary.

Non-therapeutic anti-FXa levels are common among medical ward patients treated with enoxaparin.

Thromboembolism is treated with a weight-adjusted enoxaparin dose without the need for laboratory monitoring. This study aims to determine the prevalence of sub and supra-therapeutic anti-factor Xa (aFXa) levels among medical ward patients treated with enoxaparin, and to identify potential factors associated with non-therapeutic aFXa levels. aFXa levels were measured in a cohort of medical ward patients treated with curative enoxaparin regimen (1 mg/kg bid) in the Ha'emek Medical Center in the northeastern area of Israel. The relative risk (RR) ratio for sub and supra-therapeutic aFXa levels was estimated in demographic and clinical subgroups. Of the 294 included patients, only 78.6% had therapeutic aFXa levels, while 13.3% and 8.1% had sub and supra-therapeutic levels, respectively. On univariate analysis, females, smoking, BMI ≥ 30, and cancer were significantly associated with supra-therapeutic aFXa levels; fibrates and warfarin use were significantly associated with sub-therapeutic aFXa levels (P < 0.05). On multivariate analysis, females and patients with cancer were independently at increased risk for supra-therapeutic levels RR 3.35(95% CI 1.50, 7.48), RR 3.61(95% CI 1.50, 8.70), respectively. Fibrates and warfarin were associated with sub-therapeutic levels RR 2.99(95% CI 1.44, 6.20), RR 3.42(95% CI 1.73, 6.76), respectively. Standard curative enoxaparin regimen is associated with increased risk for supra-therapeutic aFXa levels in females and patients with cancer and sub-therapeutic levels in patients treated with fibrates and warfarin. This may suggest the need for anticoagulation monitoring in high-risk patients with these conditions.

Origin and expansion of four different beta globin mutations in a single Arab village.

In Israel, as in several countries of the Mediterranean basin, beta-thalassemia is frequent among Arabs, and many different mutations in the beta globin gene have been identified. In a single Arab village, three different thalassemia mutations, as well as the sickle-cell mutation, were characterized. Using genealogical data as well as the results of screening in the village population, we were able to demonstrate/speculate on how mutations were introduced into the village and how they later expanded. The sickle-cell mutation became particularly prevalent in the village as the result of a founder effect due to a preference for consanguineous marriages.

Hypereosinophilic syndrome in a child presenting as eosinophilic pharyngitis.

A 3-year-old child with idiopathic hypereosinophilic syndrome (IHES) presented with sore throat and pharyngeal exudate. Recurrent throat cultures were negative and microscopic section of the exudate revealed an extensive eosinophilic infiltration. Fourteen months later, the child still has marked hypereosinophilia and pharyngeal involvement without other organ involvement. Eosinophilic pharyngitis may be a target organ in IHES. The benign clinical course and the laboratory characteristics are described.