Rheologic predictors of the severity of the painful sickle cell crisis

Deformable sickle erythrocytes have been reported by Mohandas and Evans to be more adherent to vascular endothelium than rigid irreversibly sickled cells (ISC). To define the clinical implications of this finding we have determined genetic, hematological, clinical, and rheological characteristics of sickle erythrocytes obtained from 65 patients with sickle cell anemia and fetal hemoglobin (Hb F) levels less than 15%. The alpha-globin gene number had a significant effect on the hematological parameters, the percentage of dense cells, ISC number, and HB A2 levels. The presence or absence of alpha thalassemia, however, had no effect on the frequency and severity of the sickle cell painful crisis (r = 0.06, P greater than .05). RBC deformability, determined by an ektacytometer, showed great heterogeneity among patients with three or four alpha-globin genes. Linear regression analyses of the data showed significant positive correlation of the frequency and severity of the painful crisis with RBC deformability (r = 0.49, P less than .001), and negative correlations with the percentage of dense cells (r = -0.37, P = .002), and the percentage of ISC (r = -0.46, P less than .001). We propose that the more deformable the sickle RBC are, the greater their adherence to vascular endothelium, and the more they cause vaso-occlusive crises, RBC deformability and the percentage of dense cells (or ISC) seem to have a predictive value of the frequency and severity of painful crises in sickle cell anemia.

Download Full-text

Rheologic predictors of the severity of the painful sickle cell crisis

Blood ◽

10.1182/blood.v72.4.1216.1216 ◽

1988 ◽

Vol 72 (4) ◽

pp. 1216-1223 ◽

Cited By ~ 94

Author(s):

SK Ballas ◽

J Larner ◽

ED Smith ◽

S Surrey ◽

E Schwartz ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Vascular Endothelium ◽

Hematological Parameters ◽

Globin Gene ◽

Globin Genes ◽

Sickle Erythrocytes ◽

Alpha Globin ◽

Painful Crisis ◽

Rbc Deformability

Abstract Deformable sickle erythrocytes have been reported by Mohandas and Evans to be more adherent to vascular endothelium than rigid irreversibly sickled cells (ISC). To define the clinical implications of this finding we have determined genetic, hematological, clinical, and rheological characteristics of sickle erythrocytes obtained from 65 patients with sickle cell anemia and fetal hemoglobin (Hb F) levels less than 15%. The alpha-globin gene number had a significant effect on the hematological parameters, the percentage of dense cells, ISC number, and HB A2 levels. The presence or absence of alpha thalassemia, however, had no effect on the frequency and severity of the sickle cell painful crisis (r = 0.06, P greater than .05). RBC deformability, determined by an ektacytometer, showed great heterogeneity among patients with three or four alpha-globin genes. Linear regression analyses of the data showed significant positive correlation of the frequency and severity of the painful crisis with RBC deformability (r = 0.49, P less than .001), and negative correlations with the percentage of dense cells (r = -0.37, P = .002), and the percentage of ISC (r = -0.46, P less than .001). We propose that the more deformable the sickle RBC are, the greater their adherence to vascular endothelium, and the more they cause vaso-occlusive crises, RBC deformability and the percentage of dense cells (or ISC) seem to have a predictive value of the frequency and severity of painful crises in sickle cell anemia.

Download Full-text

Influence of Globin Gene Modifiers on Baseline and Hydroxyurea-Induced Fetal Hemoglobin Levels in Children with Sickle Cell Anemia.

Blood ◽

10.1182/blood.v106.11.3171.3171 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3171-3171

Author(s):

Russell E. Ware ◽

Barry Eggleston ◽

Tatiana Abramova ◽

Sherri A. Zimmerman ◽

Alice Lail ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Globin Gene ◽

Fetal Hemoglobin ◽

Globin Genes ◽

Beta Globin ◽

Gene Number ◽

Gamma Globin ◽

Alpha Globin ◽

Hydroxyurea Therapy

Abstract Fetal hemoglobin (HbF) is recognized as a major determinant of clinical disease severity in children and adults with sickle cell anemia (SCA). Patients with elevated HbF levels have a milder disease course, and many current therapeutic protocols for SCA include pharmacological induction of HbF. However, baseline and treatment HbF levels vary widely due to presumed genetic and environmental factors. Recognized globin gene modifiers of HbF include the beta globin haplotype and a potential contribution from concomitant alpha thalassemia. To characterize more fully the influence of globin gene modifiers on both baseline and treatment HbF levels, we retrospectively determined the beta globin haplotype (Benin, CAR, Senegal, Cameroon, or Arab-Indian) by selective gamma globin gene nucleotide sequencing and the alpha globin gene number (2, 3, or 4) by PCR for 67 African-American children with SCA receiving hydroxyurea therapy at stable maximal tolerated dose (MTD). The four beta globin haplotypes and frequencies identified in our cohort of children include Benin (0.61), CAR (0.17), Senegal (0.12), and Cameroon (0.10). The number of alpha globin genes and frequencies identified were 4 genes (0.72), 3 genes (0.25) and 2 genes (0.03). Baseline and MTD HbF levels were analyzed according to each variable. The average baseline HbF value for the entire cohort of children was 7.7 ± 4.4% (median 7.6%, range 1.3 – 19.3%), while the average treatment HbF value was 23.9 ± 7.2 % (median 22.9%, range 10.2 – 40.7%). All 67 children increased their HbF in response to hydroxyurea therapy (median 16.7%, range 5.0 – 28.8%). There was a modest but statistically significant correlation between the baseline and treatment HbF (r=0.66, p<.0001). The estimated effect of one unit change in baseline HbF on treatment HbF was 1.11 (95% CI of 0.78, 1.43). When baseline %HbF was analyzed according to the beta globin haplotype, the overall ANOVA had a p-value of 0.02, indicating a statistically significant influence. Further analysis confirmed associations previously identified in adults with SCA, i.e. children with at least one copy of the CAR haplotype had a lower baseline HbF (5.9% vs 8.4%, p=.05), while those with at least one copy of the Senegal haplotype had a higher baseline HbF (11.1% vs 6.7%, p<.001). When hydroxyurea MTD (treatment) HbF values were analyzed according to beta globin haplotype while adjusting for baseline HbF, however, the effect of beta globin haplotype was not statistically significant (p=.13). Analyses of HbF according to alpha globin gene number revealed no statistically significant effects on either baseline or treatment HbF values. Taken together, these data support the hypothesis that beta globin haplotype significant influences baseline HbF values for children with SCA, but has no significant effects on hydroxyurea MTD HbF values. Accordingly, children with SCA should be offered hydroxyurea based solely on clinical indications, without consideration of baseline HbF or beta globin haplotype. Even children with low baseline HbF values or the CAR beta globin haplotype can respond to hydroxyurea therapy with an elevated %HbF. Future studies designed to identify genetic modifiers of treatment HbF values should focus on sequence polymorphisms in non-globin genes that have trans-acting effects on gamma globin gene expression.

Download Full-text

An analysis of fetal hemoglobin variation in sickle cell disease: the relative contributions of the X-linked factor, beta-globin haplotypes, alpha-globin gene number, gender, and age

Blood ◽

10.1182/blood.v85.4.1111.bloodjournal8541111 ◽

1995 ◽

Vol 85 (4) ◽

pp. 1111-1117 ◽

Cited By ~ 79

Author(s):

YC Chang ◽

KD Smith ◽

RD Moore ◽

GR Serjeant ◽

GJ Dover

Keyword(s):

Sickle Cell ◽

Globin Gene ◽

Fetal Hemoglobin ◽

Globin Genes ◽

Beta Globin ◽

Gene Number ◽

Cohort Group ◽

Five Factors ◽

F Cells ◽

Alpha Globin

Five factors have been shown to influence the 20-fold variation of fetal hemoglobin (Hb F) levels in sickle cell anemia (SS): age, sex, the alpha-globin gene number, beta-globin haplotypes, and an X-linked locus that regulates the production of Hb F-containing erythrocytes (F cells), ie, the F-cell production (FCP) locus. To determine the relative importance of these factors, we studied 257 Jamaican SS subjects from a Cohort group identified by newborn screening and from a Sib Pair study. Linear regression analyses showed that each variable, when analyzed alone, had a significant association with Hb F levels (P < .05). Multiple regression analysis, including all variables, showed that the FCP locus is the strongest predictor, accounting for 40% of Hb F variation. beta-Globin haplotypes, alpha-globin genes, and age accounted for less than 10% of the variation. The association between the beta-globin haplotypes and Hb F levels becomes apparent if the influence of the FCP locus is removed by analyzing only individuals with the same FCP phenotype. Thus, the FCP locus is the most important factor identified to date in determining Hb F levels. The variation within each FCP phenotype is modulated by factors associated with the three common beta-globin haplotypes and other as yet unidentified factor(s).

Download Full-text

Fetal Hemoglobin in Sickle Hemoglobinopathies: High HbF Genotypes and Phenotypes

Journal of Clinical Medicine ◽

10.3390/jcm9113782 ◽

2020 ◽

Vol 9 (11) ◽

pp. 3782

Author(s):

Martin H. Steinberg

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Globin Gene ◽

Point Mutations ◽

Fetal Hemoglobin ◽

Gene Deletions ◽

Total Hemoglobin ◽

Sickle Erythrocytes ◽

Hereditary Persistence ◽

Very High

Fetal hemoglobin (HbF) usually consists of 4 to 10% of total hemoglobin in adults of African descent with sickle cell anemia. Rarely, their HbF levels reach more than 30%. High HbF levels are sometimes a result of β-globin gene deletions or point mutations in the promoters of the HbF genes. Collectively, the phenotype caused by these mutations is called hereditary persistence of fetal hemoglobin, or HPFH. The pancellularity of HbF associated with these mutations inhibits sickle hemoglobin polymerization in most sickle erythrocytes so that these patients usually have inconsequential hemolysis and few, if any, vasoocclusive complications. Unusually high HbF can also be associated with variants of the major repressors of the HbF genes, BCL11A and MYB. Perhaps most often, we lack an explanation for very high HbF levels in sickle cell anemia.

Download Full-text

Alpha globin gene number: population and restriction endonuclease studies

Blood ◽

10.1182/blood.v55.4.706.706 ◽

1980 ◽

Vol 55 (4) ◽

pp. 706-708 ◽

Cited By ~ 27

Author(s):

G Brittenham ◽

B Lozoff ◽

JW Harris ◽

YW Kan ◽

AM Dozy ◽

...

Keyword(s):

Restriction Endonuclease ◽

Sickle Cell ◽

Genetic Model ◽

Sickle Cell Trait ◽

Globin Gene ◽

Restriction Endonuclease Analysis ◽

Globin Genes ◽

Gene Number ◽

Alpha Globin ◽

Study Population

Abstract Restriction endonuclease analysis was used to test a proposed genetic model using alpha-globin gene number to account for the observed distributions of the proportions of hemoglobin (Hb) S in sickle cell trait. In a subsample of specimens collected during a population survey in India, these studies confirmed that the postulated genotype was present in 22 of the 23 individuals examined. In the study population, the number of alpha-globin genes explains about 90% of the variance in the proportion of HbS in sickle cell trait (r2 = 0.895, p less than 10(- 10)).

Download Full-text

The cellular basis for different fetal hemoglobin levels among sickle cell individuals with two, three, and four alpha-globin genes

Blood ◽

10.1182/blood.v69.1.341.bloodjournal691341 ◽

1987 ◽

Vol 69 (1) ◽

pp. 341-344 ◽

Cited By ~ 1

Author(s):

GJ Dover ◽

VT Chang ◽

SH Boyer ◽

GR Serjeant ◽

S Antonarakis ◽

...

Keyword(s):

Sickle Cell ◽

Globin Gene ◽

Fetal Hemoglobin ◽

Enrichment Ratio ◽

Globin Genes ◽

Cell Production ◽

Gene Number ◽

Alpha Thalassemia ◽

F Cells ◽

Alpha Globin

Fetal hemoglobin (HbF) levels vary widely among individuals with sickle cell anemia (SS). Previous studies have suggested that HbF levels in SS individuals with alpha-thalassemia (two or three functional alpha- globin genes) are lower than HbF levels in SS individuals with four normal alpha-globin genes. Using immunocytochemical techniques, we studied F cell production as measured by % F reticulocytes, the amount of HbF per F cell, and the preferential survival of F cells versus non- F cells in 51 subjects with four alpha genes, 32 subjects with three alpha genes, and 18 subjects with two alpha genes. Comparison between alpha-globin gene groups was performed for the total sample as well as for a subset of 82 individuals who had replicate samples and a further subset of 39 age-matched individuals. %HbF levels were 6.8, 4.9, and 4.5 percent for the total four-, three-, and two-alpha-globin-gene groups, respectively. The percentage of F reticulocytes, percentage HbF per F cell, and the enrichment ratio (% F cell/% F reticulocytes) did not change significantly with alpha-globin gene number. Moreover, no correlation existed between alpha-globin gene number and the absolute number of F cells in any group studied. However, there was a strong inverse correlation (r = -0.407, P = .0001) between non-F cell levels (1.7 +/- 2, 2.2 +/- 5, 3.0 +/- 1.0 X 10(12)/L) and decreasing alpha- globin gene number. These data suggest that falling HbF levels among SS individuals with lessened numbers of alpha-globin genes reflect prolonged survival of non-F cells and are not due to intrinsic differences in F cell production or in the amount of HbF per F cell. The improved survival of non-F cells in SS alpha-thalassemia is presumed to be due to the lower MCHC observed in such individuals.

Download Full-text

Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia [see comments]

Blood ◽

10.1182/blood.v79.10.2555.bloodjournal79102555 ◽

1992 ◽

Vol 79 (10) ◽

pp. 2555-2565 ◽

Cited By ~ 1

Author(s):

S Charache ◽

GJ Dover ◽

RD Moore ◽

S Eckert ◽

SK Ballas ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Globin Gene ◽

Fetal Hemoglobin ◽

White Blood Count ◽

Open Label ◽

Hemoglobin F ◽

Drug Plasma ◽

Alpha Globin ◽

Clinically Significant

Patients with sickle cell anemia were treated with daily doses of hydroxyurea, to assess pharmacokinetics, toxicity, and increase in fetal hemoglobin (Hb) production in response to the drug. Plasma hydroxyurea clearances were not a useful guide to maximum tolerated doses of the drug. The mean daily single oral dose that could be maintained for at least 16 weeks was 21 mg/kg (range, 10 to 35 mg/kg). Among 32 patients, last HbF levels were 1.9% to 26.3% (mean, 14.9%) with increases in HbF over initial values of 1.4% to 20.2% (mean, 11.2%). The most significant predictors of last HbF were last plasma hydroxyurea level, initial white blood count and initial HbF concentration. Last HbF was not related to beta globin haplotype or alpha globin gene number. No serious toxicity was encountered. Clinically significant bone marrow depression was avoided, and chromosome abnormalities after 2 years of treatment were no greater than those observed before treatment. The period of observation has been too short to evaluate the risk of carcinogenesis. Patient's red cells developed striking macrocytosis. Median red cell Hb concentrations did not change. Hb concentrations increased, on average 1.2 g/dL, but serum erythropoietin levels increased. Patients' body weights increased, and some returned to work or school, but no conclusions regarding therapeutic efficacy could be drawn from this uncontrolled open-label study.

Download Full-text

Re-Assessing the Red Blood Cell Lifespan in Sickle Cell Anemia: Does Size Matter?

Blood ◽

10.1182/blood-2018-99-110592 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4877-4877

Author(s):

Norman Alan Mazer ◽

Tomas Tomka ◽

Michael Winter ◽

Annette Koerner ◽

Samir K. Ballas

Keyword(s):

Sickle Cell ◽

Transit Time ◽

Sickle Cell Anemia ◽

Total Bilirubin ◽

Globin Gene ◽

Globin Genes ◽

Survival Times ◽

Gene Group ◽

F Cells ◽

Good Agreement

Abstract Background: Does the size of RBCs in sickle cell anemia (SCA) influence their lifespan? According to Ballas and Marcolina's study of 26 SCA patients (Hemoglobin 2000), the half-life of 51Cr labelled RBCs (T1/2) had a statistically significant negative correlation with MCV (p = 0.009), that was described by the regression equation: T1/2 (days) = 9.3 - 0.22 x [MCV (fL) - 87]. We have used this equation to derive a quantitative relationship between the RBC lifespan (LSRBC) and RBC size (MCV) and have tested this relationship with the data of Higgs et al. (N Engl J Med 1982) in SCA patients with and without concomitant α-thalassemia. We also reassessed the RBC survival kinetics of non-F-cells in 12 SCA patients (Franco et al. Blood 2006) to explore a size effect. A mechanistic hypothesis for a causal relationship between RBC size and LSRBC is proposed. Methods: The numerical relationship between LSRBC and T1/2 was derived using Engstedt's theoretical model (Acta Med Scand. Suppl. 1957) for the case of auto-transfusion in patients with hemolytic anemia. Combining this relationship with the experimental regression equation of T1/2 vs. MCV yielded a prediction of the dependence of LSRBC vs. MCV, which was accurately represented by a 2nd degree polynomial. This dependence was used to estimate the LSRBC values corresponding to the 3 groups of SCA patients studied by Higgs et al. (N Engl J Med 1982), whose mean MCV values were 90.1 fL (4 α-globin genes), 84.4 fL (3 α-globin genes) and 71.2 fL (2 α-globin genes). For comparison, we estimated LSRBC values for patients with 4 and 2 α-globin genes directly from the T1/2 values reported by De Ceulaer et al. (N Engl J Med 1983). An indirect estimate of LSRBC was derived from the ratio of the reticulocyte lifespan to the % reticulocytes reported in the 3 groups, with the former parameter set to 1.82 days in order to match the LSRBC prediction of the 4 α-globin gene group. A further estimate was derived from the levels of total bilirubin, Hb and MCHC using a theoretical expression that was also adjusted to match the 4 α-globin gene prediction. From the data on RBC survival kinetics in SCA patients reported by Franco et al. (Blood 2006), we estimated the T50% survival times of non-F-cells and explored their relationship to MCV. Results: The dependence of LSRBC vs. MCV derived from Ballas and Marcolina's data (Hemoglobin 2000) shows a marked decrease from 25 days to 10 days as MCV increases from 73 to 101 fL (Figure 1). Using this relationship, a corresponding increase in the predicted LSRBC values is shown for the SCA patients of Higgs et al. (N Engl J Med 1982) with α-gene numbers corresponding to 4 (no α-thalassemia), 3 (heterozygous α-thalassemia) and 2 (homozygous α-thalassemia), respectively (Figure 2). The estimated LSRBC values derived from the data of De Ceulaer et al. (N Engl J Med 1983) in patients with 4 and 2 α-globin genes are in good agreement with our predictions (Figure 2). Indirect estimates of LSRBC, based on the % reticulocytes and total bilirubin levels reported by of Higgs et al. and adjusted to match the 4 α-globin gene group, are also in good agreement with the predicted LSRBC values for the 3 and 2 α-globin gene groups (Figure 2). Lastly the T50% survival times for non-F-cells derived from Franco et al. (Blood 2006) are seen to be inversely related to the MCV with a variation of about 3-fold (Figure 3). Discussion: Our reassessment of literature data in SCA patients illustrates a strong inverse relationship between the RBC lifespan and RBC size (MCV). The confounding of this finding by the presence of hetero- and homozygous α-thalassemia in the lower MCV groups cannot be excluded, nor can the influence of the MCHC, which varies weakly with MCV. Nonetheless, we suggest that this relationship could result from the following causal mechanism. Smaller RBCs (initially in the oxygenated state) should have a shorter capillary transit time than larger RBCs, as seen in theoretical simulations (Secomb and Hsu, Biophysical journal. 1996) and experimental studies (Du et al. PNAS 2015). A shorter transit time should limit the time for deoxygenation and HbS polymerization; leading to less sickling, less cell damage and less hemolysis. The reduced rate of hemolysis should result in a longer RBC lifespan. Our quantitative analysis and causal hypothesis suggest that size matters in the lifespan of sickle cells. The clinical and therapeutic implications of this hypothesis require further consideration. Disclosures Mazer: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Tomka:Roche: Employment. Winter:Roche: Employment. Koerner:F. Hoffmann-La Roche Ltd: Employment.

Download Full-text

Mechanistic Insights into Forced Chromatin Looping Mediated Activation of Fetal Globin Gene Expression

Blood ◽

10.1182/blood.v124.21.331.331 ◽

2014 ◽

Vol 124 (21) ◽

pp. 331-331

Author(s):

Caroline Bartman ◽

Gerd A. Blobel ◽

Jeremy Grevet ◽

Chris C.S. Hsiung ◽

Jeremy W. Rupon ◽

...

Keyword(s):

Gene Expression ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Conflicts Of Interest ◽

Globin Gene ◽

Gene Promoters ◽

Globin Genes ◽

Chromatin Architecture ◽

Chromatin Looping ◽

Globin Promoter

Abstract The β-globin enhancer, called locus control region (LCR), is required for high level expression of all b-type globin genes. The LCR is in physical proximity with the genes it controls, with contacts shifting from embryonic (ε) to fetal (γ) and finally to adult (δ and β) globin gene promoters during development. In prior studies we showed that forced chromatin contacts between the LCR and the β-globin promoter led to transcriptional activation, suggesting that LCR-promoter looping causally underlies β-globin transcription (Deng et al. Cell 2012). In these studies, the transcription co-factor Ldb1 was tethered to the β-globin promoter using artificial zinc finger (ZF) DNA binding proteins, to trigger the promoter-LCR interaction. We subsequently showed that tethering Ldb1 to the promoters of developmentally silenced embryonic or fetal globin genes reactivated their expression in adult erythroblasts in a manner dependent on looped contacts with the LCR (Deng et al. Cell 2014). This work established a novel strategy to raise fetal globin expression in patients with sickle cell anemia. To examine mechanistically the effects of chromatin looping on gene expression we performed single molecule RNA FISH experiments to precisely measure transcription output at individual alleles before and after enforced LCR-γ-globin looping. The experiments were carried out in primary human erythroblasts, which produce elevated levels of γ-globin when exposed to culture conditions. Preliminary data suggest that the majority of transcripts emerge from the β-globin gene with a smaller fraction of transcripts coming from the γ-globin gene as expected. Among cells producing any type of globin primary transcripts, a significant fraction (25%-35%) of cells co-express γ- and β-globin. Importantly, γ- and β-globin are frequently transcribed from the same allele. Forced juxtaposition of the LCR and the γ-globin promoter increases the number of alleles expressing only γ-globin while reducing the number of alleles expressing only the β-globin gene. This result is consistent with the γ- and β-globin genes competing for LCR activity, and emphasizes the usefulness of this approach in the context of sickle cell anemia in which not only elevated levels of fetal hemoglobin but also reduction of the mutant hemoglobin are desirable. Surprisingly, however, the proportion of alleles co-expressing γ-globin and β-globin remains largely constant. We are testing whether co-expression from the same allele is LCR independent. Finally, our studies suggest that LCR-promoter contacts increase the probability of transcription of a given allele. We will also present work addressing the critical question as to how alteration of chromatin architecture overcomes the action of transcriptional repressive complexes, such as Bcl11a, which normally maintain embryonic and fetal globin genes in a repressed state throughout adulthood. In sum, our studies produce a deeper understanding of the interplay of chromatin architecture and gene expression in a system that holds great potential for therapeutic application in patients with hemoglobinopathies. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia [see comments]

Blood ◽

10.1182/blood.v79.10.2555.2555 ◽

1992 ◽

Vol 79 (10) ◽

pp. 2555-2565 ◽

Cited By ~ 296

Author(s):

S Charache ◽

GJ Dover ◽

RD Moore ◽

S Eckert ◽

SK Ballas ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Globin Gene ◽

Fetal Hemoglobin ◽

White Blood Count ◽

Open Label ◽

Hemoglobin F ◽

Drug Plasma ◽

Alpha Globin ◽

Clinically Significant

Abstract Patients with sickle cell anemia were treated with daily doses of hydroxyurea, to assess pharmacokinetics, toxicity, and increase in fetal hemoglobin (Hb) production in response to the drug. Plasma hydroxyurea clearances were not a useful guide to maximum tolerated doses of the drug. The mean daily single oral dose that could be maintained for at least 16 weeks was 21 mg/kg (range, 10 to 35 mg/kg). Among 32 patients, last HbF levels were 1.9% to 26.3% (mean, 14.9%) with increases in HbF over initial values of 1.4% to 20.2% (mean, 11.2%). The most significant predictors of last HbF were last plasma hydroxyurea level, initial white blood count and initial HbF concentration. Last HbF was not related to beta globin haplotype or alpha globin gene number. No serious toxicity was encountered. Clinically significant bone marrow depression was avoided, and chromosome abnormalities after 2 years of treatment were no greater than those observed before treatment. The period of observation has been too short to evaluate the risk of carcinogenesis. Patient's red cells developed striking macrocytosis. Median red cell Hb concentrations did not change. Hb concentrations increased, on average 1.2 g/dL, but serum erythropoietin levels increased. Patients' body weights increased, and some returned to work or school, but no conclusions regarding therapeutic efficacy could be drawn from this uncontrolled open-label study.

Download Full-text