Lucia Zalman

Response to hydroxyurea therapy in β-thalassemia

Although a relatively small number of previous studies suggest a modest response to hydroxyurea (HU) therapy in β‐thalassemia, more recent investigations have revealed that some transfusion‐dependent patients can become transfusion‐independent following HU therapy. Patients with Gγ XmnI polymorphism, several β‐globin mutations, and α‐thalassemia deletions were inconsistently reported to have significant responses to HU therapy. To better predict who may respond, we retrospectively evaluated the clinical response and the molecular background of 18 β‐thalassemia patients treated with HU for a mean of 46 months. The majority of transfusion‐dependent patients responded to HU therapy with 9 out of 11 (82%) becoming transfusion‐independent. Five thalassemia intermedia (TI) patients receiving occasional blood transfusion did not require any additional transfusions following therapy and two TI patients who had never received transfusions had a 2 g/dl increase in their hemoglobin level. The majority of β‐thalassemia major patients who became transfusion‐independent (7/9) were either homozygous (5) or heterozygous (2) for the XmnI polymorphism. No correlation was identified between response to therapy and the presence of specific β‐thalassemia mutations or α‐globin deletions. We conclude that further analysis of the degree of response of transfusion‐dependent β‐thalassemia patients to HU therapy, as well as, the impact of their genetic background on this response is required to identify patients likely to have significant response. Am. J. Hematol., 2008.

Effect of hydroxyurea in sickle cell anemia: a clinical trial in children and teenagers with severe sickle cell anemia and sickle cell beta-thalassemia.

This study evaluated the efficacy of hydroxyurea treatment in the prevention of vaso-occlusive crises among children and teenagers with severe sickle cell anemia and sickle cell beta-thalassemia. Nineteen children and young adults with severe sickle cell disease were enrolled to the hydroxyurea treatment trial. The incidence of vaso-occlusive crises, acute chest syndrome, hemolytic crises, splenic sequestration episodes, blood transfusions, and hospital days in the 2 years before hydroxyurea (HU) treatment were compared with the same parameters in the first 2 years of treatment. The patients received a mean dose of 21.3 mg/kg/day daily and were treated during a mean period of 40.3 +/- 14 months (range 20 to 68 months). Significant increases were observed after 1 month in the Hgb, MCV, MCH, and MCHC levels and were more notable after 3 months. The increase in the Hgb F level became important after 3 months of HU therapy and was highly significant (p < .001) beyond 6 months. No differences were observed in the RDW, reticulocyte count, Hgb S, and Hgb A2. Severe neutropenia was observed in one case. A decrease in the frequency of vaso-occlusive crises, acute chest syndrome, hemolytic crises, blood transfusions, and days spent in the hospital was demonstrated during the HU treatment period compared to the same period before. The clinical and laboratory response to HU was dramatic in severely affected sickle cell anemia (SCA) patients. The response to HU in children and teenagers with severe sickle cell anemia is similar to the response in adults, and no severe adverse effects were observed.

VENOUS THROMBOEMBOLISM, FACTOR V LEIDEN, AND METHYLENETETRAHYDROFOLATE REDUCTASE IN A SICKLE CELL ANEMIA PATIENT

Vaso-occlusive crisis is the most common cause of morbidity in patients with sickle cell anemia (SCA). Central nervous system involvement that leads to hemiplegia is the most frequent neurological complication in those patients. Peripheral deep venous thromboembolism was not reported in SCA patients. Activated protein C resistance is associated with an increased risk of thrombophilia. The authors report an SCA patient with recurrent cerebrovascular accident and deep venous thrombosis. Activated protein C resistance due to factor V Leiden heterozygous and heterozygocity for the methylenetetrahydrofolate reductase were diagnosed and suspected to be the risk factors that contribute to the development of the deep vein thrombosis in this SCA patient.

Legg-Calvé-Perthes disease, protein C deficiency, and β-thalassemia major : Report of two cases

Legg-Calve-Perthes disease is an idiopathic osteonecrosis or avascular necrosis of the capital femoral epiphysis and the associated complications thereof occurring in an immature growing child. The association between osteonecrosis of the femoral head and thrombophilia was postulated by Glueck in 1994. We describe Legg-Calve-Perthes disease associated with protein C deficiency and beta-thalassemia major in two children among a cohort of 79 beta-thalassemia patients treated in our clinic. The association of thrombophilia, aseptic necrosis of the femoral head, and beta-thalassemia has not been previously described in the literature.

A PIGN mutation responsible for multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1) in an Israeli-Arab family

Mutations in the PIGN gene involved in the glycosylphoshatidylinositol (GPI) anchor biosynthesis pathway cause Multiple Congenital Anomalies–Hypotonia–Seizures syndrome 1 (MCAHS1). The syndrome manifests developmental delay, hypotonia, and epilepsy, combined with multiple congenital anomalies. We report on the identification of a homozygous novel c.755A>T (p.D252V) deleterious mutation in a patient with Israeli–Arab origin with MCAHS1. The mutated PIGN caused a significant decrease of the overall GPI‐anchored proteins and CD24 expression. Our results, strongly support previously published data, that partial depletion of GPI‐anchored proteins is sufficient to cause severe phenotypic expression.

Small-platelet thrombocytopenia in a family with autosomal recessive inheritance pattern

We describe the clinical and laboratory features of a family of Arab ancestry and consanguinity. Five affected individuals were diagnosed in two sibships. All affected members have small platelets, severe to moderate thrombocytopenia of neonatal onset, increased bleeding tendency and bleeding complications such as: life‐threatening massive hemoperitoneum due to corpus luteum rupture during ovulation and severe mucosal bleeding. The familial involvement and early onset of the disease support the presence of a congenital genetic disorder with an autosomal recessive inheritance pattern. This does not fit the clinical spectrum of any of the currently known thrombocytopenia disorders. Pediatr Blood Cancer 2013;60:E128–E130.