International Journal of Hematology

International Journal of Hematology | Vol. 15, No. 6, June 2024 | pp. 41–48
DOI: 10.46882/2024/IJH/000172

Original Article

Title: Prevalence and molecular profiles of PPM1D and TP53 somatic mutations in therapy-related myelodysplastic syndrome variants

Names of Authors: G. M. Babalola¹, I. N. Nwosu², K. S. Abubakar³

Authors’ Affiliations: ¹Department of Haematology and Blood Transfusion, Lagos University Teaching Hospital, Lagos, Nigeria; ²Department of Medicine, University of Nigeria, Nsukka, Nigeria; ³Department of Pathology, Bayero University, Kano, Nigeria

Abstract: Genotoxic stress from prior cytotoxic regimens selects for chemoresistant stem cell clones harboring specific mutations, expanding the risk of therapy-related myeloid neoplasms. This cross-sectional study investigated the mutational prevalence and clinical phenotypes of protein phosphatase Mn2+/Mg2+ dependent 1D (PPM1D) and tumor suppressor TP53 gene variations in 64 adult lymphoma survivors presenting with persistent, unexplained cytopenias post-chemotherapy. Genomic DNA was isolated from bone marrow aspirates, followed by deep next-generation sequencing assays. PPM1D exon 6 mutations were detected in 14.1% (9 of 64) of the cytopenic survivors, while TP53 variations occurred in 10.9% (7 of 64). Overlapping mutations in both DNA-damage response genes were documented in 3.1% of cases. Clinical phenotype models revealed that sub-clones with PPM1D variants exhibited extreme survival advantages under cisplatin or etoposide exposure, correlating with prolonged neutropenia and progressive marrow dysplasia consistent with therapy-related myelodysplastic syndrome. Screening for these chemoresistant variants provides essential molecular tracking vectors, helping pathologists separate benign marrow suppression from emerging pre-leukemic clonal shifts.

Keywords: Clonal hematopoiesis, PPM1D mutation, TP53 mutation, therapy-related myelodysplastic syndrome, next-generation sequencing

Manuscript Timeline: Received: March 20, 2024; Revised: April 25, 2024; Accepted: May 12, 2024; Published: June 18, 2024

International Journal of Hematology | Vol. 15, No. 10, October 2024 | pp. 73–80
DOI: 10.46882/2024/IJH/000176

Original Article

Title: Evaluation of baseline plasma protein C activity as an independent predictor of recurrent macrovascular thrombosis in lupus glomerulonephritis

Names of Authors: E. F. Chinedu¹, G. H. Haruna², I. J. Balogun³

Authors’ Affiliations: ¹Department of Haematology, University of Nigeria Teaching Hospital, Enugu, Nigeria; ²Department of Medicine, Lagos State University Teaching Hospital, Ikeja, Nigeria; ³Department of Chemical Pathology, University of Ilorin, Ilorin, Nigeria

Abstract: Massive renal loss of low-molecular-weight regulatory proteins via porous glomerular structures creates a severe hypercoagulable state in nephrotic-range lupus glomerulonephritis, but the predictive utility of functional protein C tracking remains under-analyzed. This prospective study evaluated baseline plasma free protein S and protein C functional activity in 54 adult patients presenting with active lupus glomerulonephritis to track correlations with serum albumin depletion and 1-year thromboembolic outcomes. Protein C activity was quantified via chromogenic substrate assays prior to initiating intensive immunosuppressive therapies. Severe protein C activity reduction (< 55.0%) was identified in 29.6% (16 of 54) of the nephrotic patients. Multivariable Cox proportional hazards analysis revealed that baseline protein C activity below 55.0% was an independent predictor of acute deep vein thrombosis or pulmonary embolism within a 12-month observation window (hazard ratio = 3.84, P < 0.01). Protein C depression correlated inversely with serum albumin levels (r = -0.65, P < 0.001) and positively with D-dimer concentrations. Screening for functional protein C activity provides clear prognostic utility, helping identify high-risk autoimmune renal populations requiring early prophylactic anticoagulation.

Keywords: Lupus glomerulonephritis, protein C activity, hypercoagulability, albuminuria, thromboembolism

Manuscript Timeline: Received: July 20, 2024; Revised: August 25, 2024; Accepted: September 12, 2024; Published: October 14, 2024

International Journal of Hematology | Vol. 15, No. 7, July 2024 | pp. 49–56
DOI: 10.46882/2024/IJH/000173

Review Article

Title: Structural mechanics and targeted biochemical inhibition of the menin-KMT2A interaction loops in mixed-lineage leukemias

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: Chromosomal translocations involving the lysine methyltransferase 2A (KMT2A) gene drive high-risk leukemic transformations characterized by poor clinical outcomes and limited response to intensive multi-agent regimens. This comprehensive review examines the molecular structural mechanics of the oncogenic KMT2A-fusion protein complex, detailing its mandatory dependence on the small-molecule cofactor menin to sustain high transcription levels of homeobox (HOXA) and MEIS1 target genes. This continuous up-regulation effectively blocks hematopoietic differentiation, locking mixed-lineage myeloblasts or lymphoblasts in proliferative loops. Evolving therapeutic models focus on blocking this binding site using highly selective, small-molecule menin inhibitors like revumenib (SNDX-5613) and ziftomenib. These inhibitors sit directly within the hydrophobic central pocket of menin, disrupting the KMT2A interaction, down-regulating HOXA machinery, and inducing rapid morphologic differentiation. However, secondary drug resistance point mutations within the menin binding pocket present ongoing challenges. This review details structural biomarkers, mutant variant tracking, and clinical combination schedules designed to optimize menin-inhibition and maximize survival outcomes in KMT2A-rearranged mixed-lineage leukemias.

Keywords: Mixed-lineage leukemia, KMT2A rearrangement, menin inhibitors, revumenib, differentiation block

Manuscript Timeline: Received: April 18, 2024; Revised: May 22, 2024; Accepted: June 10, 2024; Published: July 15, 2024

International Journal of Hematology | Vol. 15, No. 8, August 2024 | pp. 57–64
DOI: 10.46882/2024/IJH/000174

Original Article

Title: Impact of systemic hydroxyurea on plasma soluble thrombomodulin levels and microvascular velocity tracking in pediatric 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: Continuous endothelial cell desquamation and low nitric oxide states fuel widespread microvascular shearing and high pulmonary pressures in sickle cell anemia. This prospective cohort study evaluated the long-term impact of optimized hydroxyurea therapy on plasma soluble thrombomodulin (sTM) levels, an index of direct endothelial injury, and tricuspid regurgitant jet velocity (TRJV) shifts in 50 pediatric patients presenting with steady-state sickle cell anemia (HbSS). Hydroxyurea was administered at maximum tolerated doses (15 to 25 mg/kg/day) and monitored over 12 months. Plasma markers were quantified via an enzyme-linked immunosorbent assay, and velocities were tracked using Doppler echocardiography. Baseline mean soluble thrombomodulin levels fell significantly from 14.2 ± 3.8 ng/ml to 6.2 ± 1.1 ng/ml at month 12 (P < 0.001). Concurrently, the proportion of patients presenting with high-risk velocity metrics (TRJV ≥ 2.5 m/s) fell from 36.0% to 14.0%. Thrombomodulin suppression correlated strongly with an increase in fetal hemoglobin from 5.2% to 15.6% and a drop in serum lactate dehydrogenase. These findings confirm that hydroxyurea successfully preserves endothelial integrity, limiting vascular damage and progressive cardiopulmonary remodeling in pediatric sickle cell variants.

Keywords: Sickle cell anemia, hydroxyurea, thrombomodulin, endothelial injury, tricuspid regurgitant jet velocity

Manuscript Timeline: Received: May 12, 2024; Revised: June 20, 2024; Accepted: July 09, 2024; Published: August 14, 2024

International Journal of Hematology | Vol. 15, No. 1, January 2024 | pp. 1–8
DOI: 10.46882/2024/IJH/000167

Case Report

Title: Spontaneous massive retroperitoneal hemorrhage secondary to acquired Factor XI inhibitor development in an elderly patient: Eradication with azathioprine and low-dose steroids

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

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

Abstract: Spontaneous development of neutralizing autoantibodies directed against contact activation pathway components is an exceptionally rare clinical condition that causes catastrophic bleeding events in elderly populations. We report a 74-year-old male who presented with sudden, unprovoked left flank pain, lower abdominal distension, and hypovolemic shock. Abdominal computed tomography confirmed a massive retroperitoneal hematoma measuring 12.4 × 8.5 cm without prior trauma or anticoagulant exposure. Coagulation profiles demonstrated isolated, severe prolongation of activated partial thromboplastin time (92.4 seconds) with a normal prothrombin time. A 1:1 mixing study with normal pooled plasma failed to correct the activated partial thromboplastin time, indicating a specific intrinsic pathway inhibitor. Functional assays confirmed severely depressed Factor XI activity (< 1.5%), and a Bethesda assay quantified a Factor XI inhibitor titer of 18.0 Bethesda Units. Hemostasis was achieved using recombinant activated Factor VII bypassing agents (90 μg/kg every 3 hours) alongside supportive measures. Subsequent immunosuppressive therapy with oral prednisone paired with azathioprine (100 mg daily) successfully cleared the inhibitor (0 BU) and normalized Factor XI activity by week 8. This case demonstrates that acquired Factor XI autoantibodies require immediate diagnostic differentiation and multi-modal therapeutic strategies.

Keywords: Acquired factor XI inhibitor, retroperitoneal hemorrhage, intrinsic pathway, bypassing agents, azathioprine

Manuscript Timeline: Received: October 18, 2023; Revised: November 25, 2023; Accepted: December 14, 2023; Published: January 18, 2024

International Journal of Hematology | Vol. 15, No. 12, December 2024 | pp. 89–96
DOI: 10.46882/2024/IJH/000178

Original Article

Title: Evaluation of automated immature reticulocyte fraction and red blood cell fragmentation flags in separating iron deficiency from microangiopathic hemolytic anemia variants

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: Severe microcytic anemia fragments can mimic schistocytes on automated counters, requiring robust laboratory separation parameters to prevent inappropriate therapeutic decisions. This prospective diagnostic study evaluated the performance of automated immature reticulocyte fractions (IRF) and fragmented red blood cell (FRC) flags for separating absolute iron deficiency anemia from microangiopathic hemolytic anemia variants. Evaluations were conducted on 125 adult patients presenting with thrombocytopenia and microcytosis, and diagnoses were validated via serum ferritin, complement functional assays, and manual visual blood film schistocyte counts. Microangiopathic hemolytic anemia was confirmed in 50 cases, while 75 presented with severe iron deficiency anemia. The mean immature reticulocyte fraction was significantly higher in the microangiopathic cohort compared to the iron-deficient group (0.34 ± 0.08 versus 0.12 ± 0.03, P < 0.001), reflecting an intense bone marrow response. Conversely, automated fragmentation flags were elevated in both groups. Receiver operating characteristic analysis established a combined IRF and FRC model that achieved a diagnostic sensitivity of 91.2% and a specificity of 88.4% for identifying true microangiopathic processes. Utilizing automated reticulocyte maturity indices provides an efficient, low-cost asset for screening destructive hemolytic conditions.

Keywords: Immature reticulocyte fraction, fragmented red cells, iron deficiency anemia, schistocytes, cell counter indices

Manuscript Timeline: Received: September 15, 2024; Revised: October 22, 2024; Accepted: November 10, 2024; Published: December 14, 2024