International Journal of Hematology

International Journal of Hematology | Vol. 10, No. 5, May 2019 | pp. 33–40
DOI: 10.46882/2019/IJH/000113

Review Article

Title: Structural biology and targeted biochemical inhibition of IDH1 and IDH2 mutations in acute myeloid leukemia cells

Names of Authors: M. A. Bello¹, O. R. Eze²

Authors’ Affiliations: ¹Department of Haematology, Aminu Kano Teaching Hospital, Kano, Nigeria; ²Department of Pathology, University of Benin, Benin City, Nigeria

Abstract: Somatic mutations within the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes create neomorphic enzymatic activities that alter cellular differentiation pathways in acute myeloid leukemia. This comprehensive review synthesizes current insights into the structural structural biology of these variants, highlighting how point mutations at key arginine residues (IDH1 R132, IDH2 R140/R172) drive the abnormal reduction of alpha-ketoglutarate into the oncometabolite 2-hydroxyglutarate (2-HG). The accumulation of 2-hydroxyglutarate competitively inhibits alpha-ketoglutarate-dependent dioxygenases, driving widespread DNA hypermethylation and blocking myeloid progenitor maturation. Evolving management models highlight small-molecule targeted inhibitors, including ivosidenib (AG-120) for IDH1 and enasidenib (AG-221) for IDH2. These agents bind to the allosteric pockets of mutant dimers, suppressing oncometabolite production and releasing the differentiation block without inducing cytotoxic marrow aplasia. However, treatment can precipitate differentiation syndrome, requiring swift corticosteroid protocols. This review outlines clear biomarker tracking systems, 2-hydroxyglutarate clearance monitoring, and combination schedules designed to bypass resistance and optimize outcomes in IDH-mutated myeloid leukemias.

Keywords: Acute myeloid leukemia, IDH1 mutation, IDH2 mutation, 2-hydroxyglutarate, differentiation therapy

Manuscript Timeline: Received: February 12, 2019; Revised: March 22, 2019; Accepted: April 10, 2019; Published: May 18, 2019

International Journal of Hematology | Vol. 10, No. 6, June 2019 | pp. 41–48
DOI: 10.46882/2019/IJH/000114

Original Article

Title: Impact of systemic hydroxyurea on plasma asymmetric dimethylarginine concentrations and macrovascular stress in adult sickle cell anemia

Names of Authors: S. T. Adeyemi¹, U. V. Okoye², W. X. Salami³

Authors’ Affiliations: ¹Department of Haematology and Blood Transfusion, Obafemi Awolowo University, Ile-Ife, Nigeria; ²Department of Medicine, University of Nigeria Teaching Hospital, Enugu, Nigeria; ³Department of Paediatrics, Ahmadu Bello University, Zaria, Nigeria

Abstract: Endothelial cell nitric oxide synthase inhibition by elevated asymmetric dimethylarginine (ADMA) drives severe pulmonary vascular remodeling in sickle cell disease. This prospective cohort study evaluated the long-term impact of optimized hydroxyurea therapy on plasma asymmetric dimethylarginine concentrations and pulmonary hypertension risk metrics in 50 adult patients with steady-state sickle cell anemia (HbSS). Hydroxyurea was titrated up to the maximum tolerated dose (15 to 25 mg/kg/day) over 12 months, with tricuspid regurgitant jet velocity (TRJV) monitored via Doppler echocardiography. Baseline mean asymmetric dimethylarginine levels fell significantly from 1.84 ± 0.32 μmol/L to 0.92 ± 0.15 μmol/L at month 12 (P < 0.001). Concurrently, the proportion of patients presenting with high-risk tricuspid velocities (TRJV ≥ 2.5 m/s) dropped from 36.0% to 14.0%. Reductions in asymmetric dimethylarginine levels correlated positively with fetal hemoglobin increases (r = 0.54, P < 0.01) and drops in absolute reticulocyte counts. These findings confirm that hydroxyurea successfully mitigates competitive inhibitors of nitric oxide synthesis, providing an accessible pharmacological pathway for reducing chronic macrovascular endothelial stress in adult sickle cell variants.

Keywords: Sickle cell anemia, hydroxyurea, asymmetric dimethylarginine, tricuspid regurgitant jet velocity, endothelial dysfunction

Manuscript Timeline: Received: March 15, 2019; Revised: April 24, 2019; Accepted: May 12, 2019; Published: June 19, 2019

International Journal of Hematology | Vol. 9, No. 12, December 2018 | pp. 89–96
DOI: 10.46882/2018/IJH/000108

Original Article

Title: Evaluation of automated reticulocyte maturation parameters and zinc protoporphyrin variants in separating iron deficiency from beta-thalassemia trait profiles

Names of Authors: Q. S. Abubakar¹, U. T. Maina²

Authors’ Affiliations: ¹Department of Haematology, National Hospital, Abuja, Nigeria; ²Department of Pathology, Bayero University, Kano, Nigeria

Abstract: Ineffective iron utilization and hemoglobin production variations generate overlapping microcytic red blood cell indices, requiring rapid laboratory differentiation models. This prospective diagnostic study evaluated the performance of automated immature reticulocyte fractions (IRF) and zinc protoporphyrin (ZPP) variants for separating absolute iron deficiency anemia from beta-thalassemia trait carriers. Evaluations were conducted on 135 adult patients presenting with persistent microcytosis (MCV < 76 fl). Diagnoses were validated using serum ferritin and high-performance liquid chromatography (HPLC) to measure hemoglobin A2 levels. Absolute iron deficiency was confirmed in 85 patients, while 50 were diagnosed with beta-thalassemia trait (HbA2 > 3.5%). The mean immature reticulocyte fraction was significantly higher in beta-thalassemia trait carriers compared to the iron-deficient cohort (0.28 ± 0.06 versus 0.12 ± 0.03, P < 0.001), reflecting an accelerated erythroid drive. Conversely, zinc protoporphyrin ratios were markedly elevated in absolute iron deficiency. Receiver operating characteristic analysis established a combined IRF and ZPP model that achieved a diagnostic sensitivity of 91.2% and a specificity of 88.4% for identifying thalassemia traits. Utilizing automated reticulocyte maturity indices provides an efficient, low-cost asset for screening inherited hemoglobin anomalies before completing advanced chromatography.

Keywords: Immature reticulocyte fraction, zinc protoporphyrin, iron deficiency anemia, beta-thalassemia trait, cell counter indices

Manuscript Timeline: Received: September 15, 2018; Revised: October 22, 2018; Accepted: November 11, 2018; Published: December 14, 2018

International Journal of Hematology | Vol. 9, No. 9, September 2018 | pp. 65–72
DOI: 10.46882/2018/IJH/000105

Original Article

Title: Screening for lupus anticoagulant using an integrated dRVVT and dilute Russell's viper venom clotting time mix protocol in patients with unprovoked lower limb venous thrombosis

Names of Authors: Y. Z. Ibrahim¹, A. B. Okafor², C. D. Danjuma³

Authors’ Affiliations: ¹Department of Haematology, Usmanu Danfodiyo University Teaching Hospital, Sokoto, Nigeria; ²Department of Pathology, University of Ibadan, Ibadan, Nigeria; ³Department of Haematology, University of Maiduguri, Maiduguri, Nigeria

Abstract: Phospholipid-dependent autoantibodies require precise laboratory confirmation parameters to differentiate circulating anticoagulants from coagulation factor deficiencies. This prospective diagnostic study evaluated the performance of an integrated dilute Russell’s viper venom time (dRVVT) screening and confirmation mix protocol in 70 adult patients presenting with acute, unprovoked lower limb deep vein thrombosis. Patient plasma underwent initial 1:1 mixing steps with normal pooled plasma to exclude simple factor deficiencies, followed by high-phospholipid corrections to calculate confirmatory ratios. Lupus anticoagulant presence was confirmed in 22.8% (16 of 70) of the thromboembolic cohort. The integrated mix-confirmation protocol achieved a diagnostic sensitivity of 93.7% and a specificity of 90.7% when cross-validated against standard international guidelines. Mixing indexes correlated positively with a history of recurrent thrombotic episodes (r = 0.48, P < 0.05). Utilizing this integrated mix loop reduces false-positive results caused by baseline variations in clotting factors, providing a cost-effective and accurate thrombophilia risk-profiling asset for specialized clinical pathology laboratories.

Keywords: Lupus anticoagulant, diluted Russell’s viper venom time, mixing studies, venous thrombosis, thrombophilia screening

Manuscript Timeline: Received: June 14, 2018; Revised: July 22, 2018; Accepted: August 11, 2018; Published: September 15, 2018

International Journal of Hematology | Vol. 9, No. 7, July 2018 | pp. 49–56
DOI: 10.46882/2018/IJH/000103

Review Article

Title: Structural architecture and chemical inhibition mechanisms of the FLT3 receptor tyrosine kinase pathways in acute myeloid leukemia cells

Names of Authors: M. A. Bello¹, O. R. Eze²

Authors’ Affiliations: ¹Department of Haematology, Aminu Kano Teaching Hospital, Kano, Nigeria; ²Department of Pathology, University of Benin, Benin City, Nigeria

Abstract: Activating mutations in the Fms-like tyrosine kinase 3 (FLT3) receptor occur frequently in acute myeloid leukemia, translating to a high relapse rate and short survival duration. This review synthesizes current knowledge on the molecular structural architecture of FLT3 mutations, contrasting internal tandem duplications (FLT3-ITD) within the juxtamembrane domain with point mutations in the tyrosine kinase domain (FLT3-TKD). These structural alterations disrupt auto-inhibitory loops, leading to continuous ligand-independent autophosphorylation and the activation of downstream STAT5, MAPK, and PI3K/Akt signaling networks. Traditional intensive chemotherapy regimens fail to achieve durable remission in patients with high FLT3-ITD mutant allele fractions. Evolving clinical models highlight the therapeutic integration of small-molecule FLT3 inhibitors. First-generation multi-kinase inhibitors like midostaurin and selective second-generation agents like gilteritinib act by blocking ATP-binding pockets within the mutated kinase domains. However, secondary drug resistance often emerges via novel point mutations or microenvironmental cytokine overrides. This review provides a clinical decision-making algorithm incorporating early molecular testing, mutant allele ratio calculation, and maintenance inhibitor pathways to maximize survival outcomes in FLT3-mutated acute myeloid leukemia.

Keywords: Acute myeloid leukemia, FLT3-ITD mutation, juxtamembrane domain, gilteritinib, tyrosine kinase inhibitor

Manuscript Timeline: Received: April 15, 2018; Revised: May 22, 2018; Accepted: June 12, 2018; Published: July 18, 2018

International Journal of Hematology | Vol. 9, No. 1, January 2018 | pp. 1–8
DOI: 10.46882/2018/IJH/000097

Case Report

Title: Acquired pure white cell aplasia associated with chronic large granular lymphocytic leukemia: Successful resolution with low-dose methotrexate

Names of Authors: K. L. Musa¹, M. N. Lawal², O. P. Dikko³

Authors’ Affiliations: ¹Department of Haematology, Federal Medical Centre, Katsina, Nigeria; ²Department of Medicine, Bayero University, Kano, Nigeria; ³Department of Pathology, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria

Abstract: Acquired pure white cell aplasia is an exceptionally rare bone marrow failure syndrome characterized by an absolute absence of granulocytic precursors with preserved erythropoiesis and megakaryopoiesis. We report a 58-year-old female presenting with recurrent, severe soft tissue infections, a total white blood cell count of 0.8 × 10⁹/L, and an absolute neutrophil count of 0.0 × 10⁹/L lasting 4 weeks. Bone marrow aspirate and trephine biopsy examinations confirmed a complete lack of myeloid maturation past the myeloblast stage. Flow cytometric analysis of peripheral blood lymphocytes identified a clonal expansion of T-cell large granular lymphocytes co-expressing CD3, CD8, and CD57, confirming an underlying large granular lymphocytic leukemia. Immunomodulatory therapy utilizing low-dose oral methotrexate (10 mg weekly) was initiated. Granulopoietic recovery commenced by week 4, achieving sustained normalization of the absolute neutrophil count (2.4 × 10⁹/L) by month 3 of therapy. The patient remained infection-free and in complete hematological remission at a 12-month follow-up. This case demonstrates that low-dose methotrexate effectively suppresses the auto-reactive cytotoxic clones driving myeloid arrest.

Keywords: Pure white cell aplasia, large granular lymphocytic leukemia, agranulocytosis, methotrexate, marrow failure

Manuscript Timeline: Received: October 18, 2017; Revised: November 25, 2017; Accepted: December 14, 2017; Published: January 18, 2018