Hydroxyurea Induces Expression of HbF and Increase of P50 in High Oxygen Affinity Hemoglobinopathy.
Bibliographic record
Abstract
Abstract Introduction: A 38-year-old causasian male with hepatomegaly, splenomegaly and erythrocytosis (Ht 69.2%, Hb 217 g/L, MCV 76fl, normal WBC and platelets counts) presented with flank pain found to be a renal artery thrombosis. He had a history of increased Ht since birth without bone marrow (BM), cardiac, pulmonary, renal or cerebral anomalies and for which a diagnosis of a high oxygen affinity hemoglobinopathy was made. The disease had previously been uncomplicated without therapy. Initial evaluation in our center revealed a normal BM morphology, a normal karyotype and an abnormal Hb HPLC (elevated HbF (4.9%) and an abnormal Hb eluting after normal HbA1). The red cell mass was increased at 74.9 ml/kg (normal = 26.5 ml/kg). The oxygen (O2) P50 saturation determined from the Hb-O2 dissociation curve using an Hemox-Analyser was markedly decreased at 6 mmHg (normal = 27 mmHg). α and β globins (gb) HPLC demonstrated normal α, but 100% abnormal β-gb. A diagnosis of a double heterozygote for β-gb gene was established: an allele with mutation causing high affinity for O2 and an allele causing β-thalassemia (thal) minor. Anticoagulation and serial phlebotomies did not improve the erythrocytosis. Therapy with hydroxyurea (HU) was therefore proposed to the patient. Objectives: To determine the β-gb genotype and to evaluate the effect of HU therapy at maximally tolerated dose (MTD) on induction of HbF and its effect on Ht, P50, red cell mass, 2,3-DPG and total HbNO concentrations. Methods and results: Sequencing of the β-gb locus was done by RT-PCR amplified mRNA and by PCR amplified DNA, using primers spanning almost the entire gene (−450 to 601 bp, excluding a small portion of IVS2). Two mutations were identified: Leu96→Val (339C→G) in exon 2, producing Hb Regina, a high O2 affinity hemoglobin variant, and IVS1-110 G/A, a frequent mutation causing β-thal minor. Therapy with HU was initiated at 7 mg/kg/day. Dose was increased to MTD resulting in a dose of 25 mg/kg/day. Table 1 summarizes variations in relevant parameters while on HU therapy. Conclusion: HU rapidly induced HgF and improved measured parameters in this patient with a high O2 affinity Hb/β-thal minor. HU’s effect in this case did not seem to be strictly related to its anti-proliferation properties. Induction of HbF and subsequent increase in P50 probably reduced Epo production (data pending) and erythropoiesis. Modifications in other mediators of O2 release were also modified by HU. The changes in HbNO are not totally consistant with the rest of the data, being increased at 3 months but decreased at 6 months. While on HU therapy, the patient did not present any new complications (thrombotic or other) and clinically reported an improved exercise tolerance. Further evaluation will focus on epigenetic factors affecting HbF expression and correlation of NO level with plasma L-arginine concentration. Time HU dose (mg/kg) Ht (%) HbF (%) P50 (mm/Hg) 2,3-DPG (umol/g Hb) Total HbNO (nM) Red cell mass (ml/kg) NA: not available, TBD: to be determined Baseline 0 61.1 3.6 6 21.3 242.7 74.9 3 months 21 69.4 9.1 6 19.0 694.3 NA 6 months 25 56.9 15.1 9 21.4 105.8 NA 8 months 25 46.7 25.4 TBD TBD TBD 51.7
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".