Pharmacokinetics of arginine butyrate in patients with hemoglobinopathy

Recent reports have demonstrated improvement in the clinical status and hemoglobin levels with use of intravenous arginine butyrate in patients with homozygous β-thalassemia and sickle cell disease.

To allow optimalization of therapy, we conducted pharmacokinetic studies in nine patients, five with sickle cell disease and four with β-thalassemia, treated with continuous intravenous infusion of arginine butyrate.

The disappearance of the drug after discontinuation was characterized by a biphasic elimination with an initial rapid phase followed by a slower phase. Redistribution was noted in five of the patients after 11.2 ± 4.0 min. The short half life was the result of both rapid clearance rate of 93.6 ± 31.9 ml/kg/min and small Vc (0.21 ± 0.26 l/kg) and Vss (0.31 ± 0.37 l/kg).

While preliminary results of the effectiveness of arginine butyrate are encouraging with a rise of γ-globin mRNA and F reticulocytes in some patients, the rapid elimination of this agent will probably limit its current use to administration by continuous infusion.     

A Family with Hemoglobin Hirosaki

A 48-year-old man had a 30-year history of hemolytic anemia of undetermined cause. Spherocytes were not observed, osmotic fragility was normal, and red cell enzyme activities were normal. His brother and daughter also had hemolytic anemia. The brother had previously undergone splenectomy, and the anemia had been ameliorated. In the proband and daughter, no abnormal hemoglobin was apparent in the results of isoelectric focusing and DEAE anion-exchange high-performance liquid chromatography analyses. On evaluation with the isopropanol test, unstable hemoglobin was not observed in the proband but was detected in the daughter. There was also a decreased ratio of 3 globin/3 globin chain production. Analysis of the 32 gene demonstrated the presence of a mutation (alpha43 [CE1] Phe --> Leu), hemoglobin Hirosaki.     

Immunisation anti-érythrocytaire et anti-HLA au cours des hémoglobinopathies

AimEvaluate the anti-erythrocyte and anti-HLA immunization rates in hemoglobinopathies.Patients and methodsCross-sectional study (October 2009–March 2010) on 83 patients followed for hemoglobinopathies. The irregular antibodies research is realized by two techniques: indirect Coombs and enzymatic technique on gel cards. The search for anti-HLA class I antibodies is done by complement dependent lymphocytotoxicity.ResultsThe mean age was 30 years (14–64 years), the sex ratio M/F is 0.84. Our series included 42 cases of sickle cell disease (29 homozygous sickle cell anemia and 13 sickle-thalassemia) and 41 cases of thalassemia syndromes (26 major and 15 intermediate). The anti-erythrocyte alloimmunization rate is 10.84% without difference between thalassemia syndromes and sickle cell disease. The autoimmunization rate (22.89%) is higher in thalassemia syndromes (41.46%) than in the sickle cell disease (7.14%) (P < 0.001). The anti-HLA immunization rate is 31.6% without difference between thalassemia syndromes and sickle cell disease. The young age, transfusion at a young age and the total number of transfusions are the factors that increase the risk of anti-erythrocyte autoimmunization. No clinicobiological parameter does influence the anti-erythrocyte and anti-HLA alloimmunization. There is no significant association between anti-erythrocyte and anti-HLA immunization.ConclusionThe erythrocyte and anti-HLA anti-immunization rates are high in our series. Preventive strategy is needed to ensure optimal blood safety.     

Identification of Hb Q-India (64 Asp→His) in Thailand

More than 30 different hemoglobin variants either affecting  or β globin chains have been identified in Thailand. The large variety in the different forms of hemoglobinopathy contributes to several complicated interactions, since different types of defective globin alleles are prevalent in Thailand and nearly 30-40% of the population are carriers of either  or β thalassemia (thal). Many rare and novel abnormal globin variants in Thai subjects have been identified in our laboratory within the past few years; including Hb Lepore-Hollandia, homozygous Hb Tak, Hb Dhonburi, Hb G-Makassar, Hb G-Coushatta, Hb New York, Hb Paksè and Hb Pak Num Po. In addition to these, here we report, for the first time, the identification of Hb Q-India, an innocuous  globin variant, in a Thai family with Indian ancestry. This report highlights the complexity associated with identifying unknown globin variants within a population that has a heterogeneous repertoire of globin chain disorders.     

新疆喀什地区血红蛋白病的研究

目的：研究新疆喀什地区血红蛋白病的发生及特点。方法：异常血红蛋白携带者调查采用微量电泳法。地中海贫血先证者筛查按两步筛选方案进行。异常血红蛋白的一级结构分析应用指纹分析技术完成。地中海贫血基因鉴定用ＰＣＲ／ＡＳＯ技术实施。结果：喀什地区异常血红蛋白平均发生率为０．８％，地中海贫血发生率为３．０７％，两者均明显高于全国和新疆的平均水平。８例异常血红蛋白一级结构分析发现ＨｂＪＴａｓｈｉｋｕｅｒｇａｎ［α１９（ＡＢ１）Ａｌａ→Ｇｌｕ］和ＨｂＤＰｕｎｊａｂ［β１２１（ＧＨ４）Ｇｌｕ→Ｇｌｎ］两种变异体。１０例β地中海贫血进行基因鉴定，确定了ＣＤ８（－ＡＡ）、ＣＤ８／９（＋Ｇ）、ＣＤｓ４１／４２（－ＴＴＣＴ）和ＩＶ－Ⅰ－５（Ｇ→Ｃ）等四种基因突变型。其中的ＨｂＪＴａｓｈｉｋｕｅｒｇａｎ［α１９（ＡＢ１）Ａｌａ→Ｇｌｕ］系世界首次报道，ＣＤ８（－ＡＡ）和ＣＤｓ８／９（＋Ｇ）为在中国人中首次发现。结论：对喀什地区血红蛋白病的研究表明，异常血红蛋白和地中海贫血的类型特点既有别于我国其它地区，又与邻近的中亚等国不完全相同，形成了该地区独有的遗传特征。     

A Dutch Family with Hb Debrousse: Severe Anemia After Parvovirus B19 Infection

Hb Debrousse [β96(FG3)Leu→Pro] is an unstable hemoglobin (Hb) variant with high oxygen affinity. We describe a case of chronic compensated hemolysis in a 39-year-old woman in whom the variant was found. Soon after the diagnosis was made, she and her son were admitted to the hospital with severe anemia due to Parvovirus B19 infection. The son also appeared to have the Hb Debrousse variant. Parvovirus B19 infection is a life-threatening disease in patients with (compensated) hemolysis.     

张掖地区异常血红蛋白和地中海贫血的研究

目的：研究甘肃省张掖地区异常血红蛋白和地中海贫血发病情况。方法：在张掖地区普查异常血红蛋白１０９００人，普查地中海贫血２１６１人。结果：检出异常血红蛋白携带者１２人，平均发生率为０．１１％。检出地中海贫血先证者４人，平均发生率为０．１８％。应用指纹分析技术分析１１例异常血红蛋白，鉴定６种变异体，即ＨｂＧＴａｉｐｅｉ，ＨｂＧＣｏｕｓｈａｔａ，ＨｂＮｅｗＹｏｒｋ，ＨｂＪＢａｎｇｋｏｋ，ＨｂＤＰｕｎｊａｂ和ＨｂＵｂⅠ－Ⅱ。应用ＰＣＲ／ＡＳＯ技术鉴定３例β地贫，均为ＣＤ１７（Ａ→Ｔ）杂合子。发现该地区以ＨｂＧＴａｉｐｅｉ和βＣＤ１７（Ａ→Ｔ）等基因突变为主，类似中原汉族的基本特征，但有部份ＨｂＧＣｏｕｓｈａｔａ和ＨｂＤＰｕｎｊａｂ变异体存在。结论：张掖地区人口融合了其他蒙古人种和高加索人的血缘，与该地的人口变迁及“丝绸之路”的影响一致。     

Molecular and hematological profiles of hemoglobin EE disease with different forms of α-thalassemia

We describe hematologic and DNA characterization of hemoglobin (Hb) E homozygote with various forms of α-thalassemia in Thai individuals. Altogether, 131 unrelated adult subjects with Hb EE at routine Hb analysis were studied. Forty-two cases were found to carry α-thalassemia with ten different genotypes. These included 21 cases with α⁺-thalassemia heterozygote (–α^3.7/αα), one case with α⁺-thalassemia heterozygote (–α^4.2/αα), six cases with Hb Constant Spring heterozygote (α^CSα/αα), four cases with homozygous α⁺-thalassemia (–α^3.7/–α^3.7), one case with homozygous α⁺-thalassemia (–α^4.2/–α^4.2), two cases with compound α⁺-thalassemia/Hb Constant Spring (–α^3.7/α^CSα), one case with compound α⁺-thalassemia/Hb Paksé (–α^3.7/α^PSα), four cases with α⁰-thalassemia heterozygote (––^SEA/αα), and, unexpectedly, two cases with compound α⁰-thalassemia/α⁺-thalassemia [(––^SEA/–α^3.7) and (––^SEA/–α^4.2)]. The hematological expression of these Hb E homozygotes with various forms of α-thalassemia was presented comparatively with those of the 89 cases of pure Hb E homozygotes. Overlapping levels of Hb E, Hb F, and other hematological parameters were observed which did not predict clinical severity, indicating a need for α-globin gene analysis for accurate diagnosis and improved genetic counseling.     

Impact of sickle cell disease and thalassemias in infants on birth outcomes

Objective

The contribution of sickle cell disease (SCD) and other common thalassemias in infants to adverse birth outcomes is under-studied. We therefore sought to compare adverse birth outcomes in infants with and without hemoglobinopathy.

Study design

Retrospective cohort study utilizing a population-based dataset from Florida (1998–2007, n = 1,564,038). The primary outcomes were low birthweight (LBW), very low birthweight (VLBW), preterm birth (PTB), very preterm birth (VPTB) and small for gestational age (SGA). We used propensity scores to match infants with hemoglobinopathy to those without hemoglobinopathy on selected variables. To approximate relative risks, we generated adjusted odds ratios (AOR) and 95% confidence intervals (CI) from logistic regression models and accounted for the matched design using generalized estimating equations framework.

Results

Infants with SCD or thalassemia had a heightened risk for LBW (AOR = 1.58, 95% CI: 1.29–1.93), VLBW (AOR = 3.01, 95% CI: 2.12–4.25), PTB (AOR = 1.36, 95% CI: 1.12–1.65), VPTB (AOR = 2.70, 95% CI: 1.93–3.78), and neurological conditions (AOR = 2.04, 95% CI: 1.48–2.81) compared to infants without hemoglobinopathy.

Conclusion

Infants with SCD or thalassemia experience considerably higher risks for multiple infant morbidities. Our findings are potentially important in prenatal counseling, as well as for targeted care of affected pregnancies in the prenatal period.