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Abstract Iron overload causes cognitive impairment in thalassemia patients. The gut-brain axis plays an important role in cognitive function. However, the association between gut/blood microbiome, cognition, and iron burden in thalassemia patients has not been thoroughly investigated. We aimed to determine those associations in thalassemia patients with different blood-transfusion regimens. Sixty participants: healthy controls, transfusion-dependent thalassemia (TDT) patients, and non-transfusion-dependent (NTDT) patients, were recruited to evaluate iron overload, cognition, and gut/blood microbiome. TDT patients exhibited greater iron overload than NTDT patients. Most thalassemia patients developed gut dysbiosis, and approximately 25% of the patients developed minor cognitive impairment. Increased Fusobacteriota and Verrucomicrobiota with decreased Fibrobacterota were observed in both TDT and NTDT groups. TDT patients showed more abundant beneficial bacteria: Verrucomicrobia. Iron overload was correlated with cognitive impairment. Increased Butyricimonas and decreased Paraclostridium were associated with higher cognitive function. No trace of blood microbiota was observed. Differences in blood bacterial profiles of thalassemia patients and controls were insignificant. These findings suggest iron overload plays a role in the imbalance of gut microbiota and impaired cognitive function in thalassemia patients. Harnessing probiotic potential from those microbes could prevent the gut-brain disturbance in thalassemia patients.

AbstractBackground Thalassemia is the most prevalent hereditary anaemia worldwide. Severe forms of thalassemia can lead to reduced life expectancy due to disease-related complications.Objectives To investigate the survival of thalassemia patients across varying disease severity, causes of death and related clinical factors.Patients and methods We conducted a retrospective review of thalassemia patients who received medical care at Chiang Mai University Hospital. The analysis focused on survival outcomes, and potential associations between clinical factors and patient survival.Results A total of 789 patients were included in our study cohort. Among them, 38.1% had Hb H disease, 35.4% had Hb E/beta-thalassemia and 26.5% had beta-thalassemia major. Half of the patients (50.1%) required regular transfusions. Sixty-five patients (8.2%) had deceased. The predominant causes of mortality were infection-related (36.9%) and cardiac complications (27.7%). Transfusion-dependent thalassemia (TDT) (adjusted HR 3.68, 95% CI 1.39–9.72, p = 0.008) and a mean serum ferritin level ≥3000 ng/mL (adjusted HR 4.18, 95% CI 2.20–7.92, p

Reactivation of fetal hemoglobin (HbF, α2γ2) potentially alleviates clinical presentation in β-thalassemia. Prolyl hydroxylase domain enzymes (PHDs) play roles in the canonical oxygen-sensing pathway and maintain the stability of cellular hypoxia-inducible factor α (HIF-α) in response to low oxygen levels or hypoxia. Pharmacological inhibition of PHDs has been shown to increase HbF production in erythroid progenitors derived from healthy donors. Here, we demonstrated the relationship between PHD2, the main PHD isoform, and clinical phenotypes in β0-thalassemia/HbE disease. Although the targeted sequencing annotated several common variants within EGLN1, the gene encoding PHD2, none of these variants were located in the functional domains of PHD2 and were irrelevant to the clinical phenotypes. CRISPR-mediated EGLN1 modifications at the functional regions; however, led to significantly reduce PHD2 expression and increase HbF expression levels in severe β-thalassemia erythroblasts. Moreover, these beneficial phenotypes were independent to the two well-known HbF regulators including BCL11A and GATA1. Our findings introduce an additional mechanism for HbF regulation in β-thalassemia and propose that targeting the canonical oxygen-sensing pathway, particularly PHD2 functional domains, might offer a promising therapeutic strategy to β-thalassemia diseases.

IntroductionElevated ambient pollution exposure is potentially linked to thromboembolism. However, the mechanisms by which particulate matter (PM) interferes with the balance of hemostatic system remain unclear. This study investigates PM-mediated hemostatic changes in individuals across unique seasonal variations of ambient pollution.MethodsThis prospective study was conducted between February and July 2020 during alterations in ambient pollution in Chiang Mai, Thailand. Blood tests from 30 healthy subjects were assessed at four-week intervals, four times in total. Various coagulation tests, including prothrombin time (PT), activated partial thromboplastin time (aPTT), von Willebrand factor (vWF), platelet count, and platelet functions, were evaluated. A mixed-effects model was used to analyze the impact of high PM2.5 and PM10 on hemostatic parameters.ResultsThirty male subjects with mean age of 38.9 ± 8.2 years, were included. High levels of PM2.5 and PM10 were significantly associated with PT shortening, with no such effect observed in aPTT. PM2.5 and PM10 values also positively correlated with vWF function, while vWF antigen levels remained unchanged. Soluble P-selectin showed a strong positive association with PM2.5 and PM10 levels. Platelet function analysis revealed no correlation with PM values.ConclusionShort-term exposure to elevated PM2.5 and PM10 concentrations was linked to shortened PT and enhanced vWF function in healthy individuals. Exploring the impact of these changes on clinically relevant thrombosis is crucial. Additional studies on the pathogenesis of pollution-related thrombosis are warranted for maintaining good health.

There are limited data regarding the impact of disease-related complications on the survival of multiple myeloma (MM) patients. The primary objective of this study was to determine the prevalence of disease-related complications, including hypercalcemia, renal insufficiency, anemia, and bone lytic lesions in MM patients. The secondary objectives were to determine clinical characteristics, treatment outcomes, and the association of disease-related complications and mortality. A retrospective chart review of MM patients from November 2014 to December 2019 was conducted. A total of 200 MM patients were enrolled. The median age at diagnosis was 63 years. The bone lytic lesion was the most common disease-related complication found in 85% during first-line therapy, followed by anemia (71.5%), renal insufficiency (28.5%), and hypercalcemia (20%). While anemia was the most common complication during the second (51.2%) and third-line therapy (72%). The development of skeletal-related events (SREs) after treatment is a disease-related complication that is associated with decreased overall survival (HR 4.030, 95% CI 1.97–8.24, p < 0.001). The most common disease-related complication of MM at initial diagnosis is bone lytic lesions, whereas anemia is more common with subsequent relapses. The presence of SRE after treatment is associated with the increased mortality of MM patients.

Background/Objectives: Rivaroxaban and dabigatran are commonly used for thromboembolic disease management in active cancer patients. However, limited research explores the impact of concurrent chemotherapy on the pharmacodynamics of direct oral anticoagulants (DOAC). The aim of our study was to evaluate the impact of combined chemotherapy with rivaroxaban and dabigatran on the pharmacodynamics in patients with diffuse large B-cell lymphoma (DLBCL).; Methods: This was a prospective, pharmacodynamic study. Eligible subjects were ≥18 years old, diagnosed with DLBCL and initiating R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy. The enrolled adults received either rivaroxaban (10 mg once daily) or dabigatran etixalate (110 mg twice daily). Plasma anti-factor Xa (FXa) in participants on rivaroxaban and diluted thrombin time (dTT) in participants on dabigatran were assessed over the dosing interval before and after R-CHOP administration. Pharmacodynamic parameters of rivaroxaban and dabigatran were determined using a non-compartmental analysis.; Results: Twenty-six adults participated, with twelve in the rivaroxaban group and fourteen in the dabigatran group. The mean age was 59 ± 14.4 years. In the rivaroxaban group, the AUEC of FXa inhibition showed no significant change after R-CHOP (mean difference 3.8 ng·h/mL, 95% confidence interval (CI) −155.4 to 163.0, p = 0.96). Similarly, in the dabigatran group, the AUEC of dTT remained unchanged post R-CHOP (mean difference 54.41 ng·h/mL, 95% CI −99.09 to 207.9 ng/mL, p = 0.46). However, the median time-to-peak dTT was significantly faster with R-CHOP (3 h, [min–max, 1.5–8] compared to without it (4 h, [min–max, 3–8], p = 0.04); Conclusions: Concurrent R-CHOP chemotherapy did not significantly impact FXa inhibition by rivaroxaban or dTT by dabigatran. The time-to-peak dTT was faster when dabigatran was administered with R-CHOP.

BackgroundA common complication of thalassemia is secondary osteoporosis. This study aimed to assess the prevalence and factors associated with low BMD in thalassemic patients.MethodThis is a cross-sectional study. Eligible patients were males aged within 18–49 years or premenopausal women diagnosed with thalassemia in Chiang Mai University Hospital between July 2021 and July 2022. The diagnosis of low BMD by dual-energy x-ray absorptiometry (DXA) was defined as a Z-score of -2.0 SD or lower in either the lumbar spine or femoral neck. Clinical factors associated with low BMD were analyzed using a logistic regression model.ResultsPrevalence of low BMD was 62.4% from 210 patients with a mean age of 29.7 ± 7.6 years. The predominant clinical characteristics of low BMD thalassemia patients were being female, transfusion-dependent (TDT) and a history of splenectomy. From multivariable analysis, the independent variables associated with low BMD were transfusion dependency (odds ratio, OR 2.36; 95%CI 1.28 to 4.38; p=0.006) and body mass index (BMI) (OR 0.71; 95%CI 0.61 to 0.82; p

IntroductionHyperuricemia is a common complication of hematologic malignancies, and hyperuricosuria in this population has shown conflicting results. This study aimed to determine the prevalence of hyperuricemia and parameters associated with serum uric acid (SUA) and urine uric acid (UUA) in patients with lymphoma and myeloproliferative neoplasms (MPN).MethodsThis cross-sectional study included adult patients with newly diagnosed lymphoma and MPN at the university-based hospital. Clinical characteristics were collected, and independent risk factors for hyperuricemia and hyperuricosuria were determined using multiple logistic regression.ResultsOne hundred and sixty-five patients were included with a median age of 55 years (45.5–64) and 51.5% were males. There were 91 patients (55.2%) with lymphoma and 74 cases (44.8%) of MPN. Overall, hyperuricemia was prevalent in 43.6% with a median SUA of 6.3 mg/dl (4.6–8) and hyperuricosuria was detected in 39.4% with a median 24-h UUA of 545 mg (365.4–991). Hyperuricemia was observed in patients with lymphoma and MPN in 20.9% and 71.6%, respectively, and hyperuricosuria in 15.4% and 68.9%, respectively. In lymphoma patients, estimated glomerular filtration rate (eGFR)

Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin lymphoma (NHL) that accounts for approximately 25-40% of all NHL cases. The objective of this study was to investigate the protein expression, clinical impact, and prognostic role of MYC, BCL2, and Ki-67 in Thai DLBCL patients. A retrospective analysis was conducted on 100 DLBCL patients diagnosed between January 2018 and December 2019. Immunohistochemistry was used to assess the expression of MYC, BCL2, and Ki-67. The study revealed a significant association between extranodal involvement and positive cases of MYC and BCL2. MYC expressions were associated with Ki-67 expression, while BCL2 positivity was associated with the non-germinal center B-cell (non-GCB) subtype. However, there were no significant differences in the three-year overall survival (OS) and three-year progression-free survival (PFS) rates when using cut-off points of ≥ 40% for MYC, ≥ 50% for BCL2, and ≥ 70% for Ki-67. Notably, DLBCL cases with co-expression of MYC and BCL2 exhibited significantly inferior three-year OS compared to other cases (0% vs. 53%; p = 0.020). Multivariate analysis identified age ≥ 60 years and Eastern Cooperative Oncology Group (ECOG) performance status as independent prognostic factors. In conclusion, MYC, BCL2, and Ki-67 expression can serve as prognostic biomarkers; however, their prognostic value may vary based on the specific cut-off values used. Therefore, determining the appropriate threshold for each biomarker based on individual laboratory analyses and clinical outcomes is crucial.

β−Thalassemia patients suffer from ineffective erythropoiesis and increased red blood cell (RBC) hemolysis. Blood transfusion, erythropoietic enhancement, and antioxidant supplementation can ameliorate chronic anemia. Green tea extract (GTE) is comprised of catechin derivatives, of which epigallocatechin−3−gallate (EGCG) is the most abundant, presenting free−radical scavenging, iron−chelating, and erythropoiesis−protective effects. The present study aimed to evaluate the effects of GTE tablets on the primary outcome of erythropoiesis and oxidative stress parameters in transfusion−dependent β−thalassemia (TDT) patients. Twenty−seven TDT patients were randomly divided into placebo and GTE tablet (50 and 100 mg EGCG equivalent) groups and assigned to consume the product once daily for 60 days. Blood was collected for analysis of hematological, biochemical, and oxidative stress parameters. Accordingly, consumption of GTE tablets improved blood hemoglobin levels when compared with the placebo; however, there were more responders to the GTE tablets. Interestingly, amounts of nonheme iron in RBC membranes tended to decrease in both GTE tablet groups when compared with the placebo. Importantly, consumption of GTE tablets lowered plasma levels of erythroferrone (p < 0.05) and reduced bilirubin non−significantly and dose−independently. Thus, GTE tablets could improve RBC hemolysis and modulate erythropoiesis regulators in transfusion−dependent thalassemia patients.

AbstractObjectives To compare the efficacy and side effects of salvage chemotherapy between etoposide, methylprednisolone, cytarabine and cisplatin (ESHAP) and ifosfamide, carboplatin and etoposide plus dexamethasone (DICE) for relapsed or refractory diffuse large B-cell lymphoma (DLBCL).Methods Medical records of patients with relapsed or refractory DLBCL receiving second-line ESHAP or DICE chemotherapy with or without rituximab from January 2007 to November 2022 were retrospectively reviewed. The primary objective was progression-free survival (PFS). The secondary objectives were overall survival (OS), overall response rate (ORR) and adverse events (AEs).Results Seventy patients were enrolled including 21 patients who received ESHAP and 49 patients who received the DICE regimen. Six patients (28.6%) and 19 patients (38.8%) in the ESHAP and DICE groups underwent ASCT, respectively. The ORR was 47.6% for ESHAP and 53.1% for DICE (p = .67). The two-year PFS was 14.3% for ESHAP and 26.5% for DICE (p = .33) with median PFS of 5 months and 14 months, respectively (hazard ratio 0.74; 95% CI 0.39–1.36, p = .330). The two-year OS was 14.3% for ESHAP and 26.5% for DICE (p = .37) with median OS of 8 months and 19 months, respectively. Patients in ESHAP group have more all-grade renal impairment than DICE group (23.8% vs. 6.1%, p = .047).Discussion and conclusions Efficacy between ESHAP and DICE regimens as salvage chemotherapy for relapsed or refractory DLBCL was not significantly different in terms of two-year PFS, two-year OS and ORR. DICE regimen had less renal AE than ESHAP.

Introduction To determine the prevalence, clinical outcomes, and factors associated with hydroxyurea (HU) resistance or intolerance among polycythemia vera (PV) and essential thrombocythemia (ET) patients.Methods This study was a retrospective cohort study including PV and ET patients diagnosed by WHO criteria and treated with HU between January 2000 and June 2020. Clinical features, laboratory data, and resistance or intolerance of HU were collected. The prevalence, clinical outcomes, and associated factors of HU resistance or intolerance were analyzed.Results There were 260 patients including 144 ET and 116 PV. The prevalence of HU resistance or intolerance was 11.9% (31 patients) which was more frequent in ET patients (14.6% vs. 8.6% in PV). Patients who had HU resistance or intolerance significantly increased the risk of bleeding events (HR 2.64; 95% CI 1.19–5.85, P = 0.017). The risk factors of HU resistance or intolerance were low baseline hemoglobin levels (HR 0.90; 95%CI 0.84–0.97, P = 0.01), age more than 60 years old (HR 3.98; 95% CI 2.08–7.62, P

IntroductionThe optimal secondary thromboprophylactic strategies for patients with antiphospholipid syndrome (APS) and arterial thrombosis remain controversial. This study aimed to evaluate the comparative efficacy and safety of various antithrombotic strategies in APS with arterial thrombosis.MethodsA comprehensive literature search was conducted using OVID MEDLINE, EMBASE, Web of Science, and the Cochrane Controlled Register of Trials (CENTRAL) from inception until 30 September 2022, with no language restrictions. The inclusion criteria for eligible studies were as follows: inclusion of APS patients with arterial thrombosis, treatment with either antiplatelet agents, warfarin, direct oral anticoagulants (DOACs), or a combination of these therapies, and reporting of recurrent thrombotic events.ResultsWe conducted a frequentist random-effects network meta-analysis (NMA) involving 13 studies with a total of 719 participants, comprising six randomized and seven non-randomized studies. In comparison to single antiplatelet therapy (SAPT), the combined use of antiplatelet and warfarin demonstrated a significant reduction in the risk of recurrent overall thrombosis, with a risk ratio (RR) of 0.41 (95% CI 0.20 to 0.85). Dual antiplatelet therapy (DAPT) showed a lower risk of recurrent arterial thrombosis compared to SAPT although the difference did not reach statistical significance, with an RR of 0.29 (95% CI 0.08 to 1.07). DOAC was associated with a significant increase in the risk of recurrent arterial thrombosis, with an RR of 4.06 (95% CI 1.33 to 12.40) when compared to SAPT. There was no significant difference in major bleeding among various antithrombotic strategies.DiscussionBased on this NMA, the combination of warfarin and antiplatelet therapy appears to be an effective approach in preventing recurrent overall thrombosis in APS patients with a history of arterial thrombosis. While DAPT may also show promise in preventing recurrent arterial thrombosis, further studies are needed to confirm its efficacy. Conversely, the use of DOACs was found to significantly increase the risk of recurrent arterial thrombosis.

BackgroundWith adequate blood transfusion and iron chelation, thalassemia patients have a longer life expectancy and experience long-term metabolic complications, including osteoporosis, fractures, and bone pain. Alendronate, an oral bisphosphonate, is currently used to treat various types of osteoporosis. However, the efficacy for the treatment of thalassemia-associated osteoporosis remains unclear.MethodsWe conducted a randomized controlled trial to evaluate the efficacy of alendronate for the treatment of osteoporosis in thalassemia patients. Patients were included if they were males (18–50 years) or premenopausal females with low bone mineral density (BMD) (Z-score < -2.0 SD) or positive vertebral deformities from vertebral fracture analysis (VFA). Stratified randomization was performed according to sex and transfusion status. Patients were 1:1 allocated to receive once weekly alendronate 70 mg orally or placebo for a total duration of 12 months. BMD and VFA were re-evaluated at 12 months. Markers of bone resorption (C-terminal crosslinking telopeptide of type I collagen; CTX) and bone formation (Procollagen type I N-terminal propeptide; P1NP), and pain scores were measured at baseline, 6 months, and 12 months. The primary outcome was the change of BMD. The secondary endpoints were changes in bone turnover markers (BTM) and pain scores.ResultsA total of 51 patients received the study drug, 28 patients were assigned to receive alendronate and 23 patients to receive placebo. At 12 months, patients in the alendronate group had significant improvement of BMD at L1-L4 compared to their baseline (0.72 ± 0.11 vs 0.69 ± 0.11 g/cm2, p = 0.004), while there was no change in the placebo group (0.69 ± 0.09 vs 0.70 ± 0.06 g/cm2, p = 0.814). There was no significant change of BMD at femoral neck in both groups. Serum BTMs were significantly decreased among patients receiving alendronate at 6 and 12 months. The mean back pain score was significantly reduced compared to the baseline in both groups (p = 0.003). Side effects were rarely found and led to a discontinuation of the study drug in 1 patient (grade 3 fatigue).ConclusionAlendronate 70 mg orally once weekly for 12 months effectively improves BMD at L-spine, reduces serum BTMs, and alleviates back pain in thalassemia patients with osteoporosis. The treatment was well tolerated and had a good safety profile.

Amphotericin B (AmpB) deoxycholate is the available first-line drug used to treat visceral leishmaniasis caused by Leishmania (Mundinia) martiniquensis, however, some cases of AmpB treatment failure have been reported in Thailand. Resistance to drugs is known to affect parasite fitness with a potential impact on parasite transmission but still little is known about the effect of resistance to drugs on L. martiniquensis. Here we aimed to gain insight into the fitness changes occurring after treatment failure or in vitro-induced resistance to AmpB. L. martiniquensis parasites isolated from a patient before (LSCM1) and after relapse (LSCM1-6) were compared for in vitro and in vivo fitness changes together with an in vitro induced AmpB-resistant parasite generated from LSCM1 parasites (AmpBRP2i). Results revealed increased metacyclogenesis of the AmpBPR2i and LSCM1-6 strains (AmpB-resistant strains) compared to the LSCM1 strain and increased fitness with respect to growth and infectivity. The LSCM1-6 and AmpBRP2i strains were present in mice for longer periods compared to the LSCM1 strain, but no clinical signs of the disease were observed. These results suggest that the AmpB-resistant parasites could be more efficiently transmitted to humans and maintained in asymptomatic hosts longer than the susceptible strain. The asymptomatic hosts therefore may represent “reservoirs” for the resistant parasites enhancing transmission. The results in this study advocate an urgent need to search and monitor for AmpB-resistant L. martiniquensis in patients with relapsing leishmaniasis and in asymptomatic patients, especially, in HIV/Leishmania coinfected patients.

IntroductionThis study aimed to evaluate the performance of the D-index, a calculated measure of neutropenic burden, in predicting the risk of invasive fungal infections (IFIs) in acute myeloid leukemia (AML) patients.MethodsA retrospective study of adult AML patients who received the first induction chemotherapy and developed febrile neutropenia was conducted. Clinical characteristics, laboratory data, and the calculation of the D-index and cumulative D-index (c-D-index) were collected and analyzed between patients with and without IFIs.ResultsA total of 101 patients were included, with 16 (15.8%) patients who developed IFIs. Clinical characteristics, antifungal prophylaxis, and AML cytogenetic risk were similar between patients with or without IFIs. The results showed that the D-index and c-D-index were more effective in predicting IFIs than the duration of neutropenia. With the D-index cutoff of 7083, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 81.3%, 83.5%, 48.2%, and 95.9%, respectively. c-D-index at 5625 revealed sensitivity, specificity, PPV, and NPV for IFIs of 68.8%, 68.2%, 28.9%, and 92.1%, respectively. Using this cutoff of c-D-index, patients without IFIs were overtreated with an antifungal regimen in 45 (52.9%) cases.ConclusionThe D-index and c-D-index were helpful indicators for defining the risk of IFIs in AML patients with febrile neutropenia.

BackgroundDespite the conflicting data, the positivity of antiphospholipid antibodies (aPL) in cancer patients may be associated with an increased risk of thrombosis.ObjectiveTo identify the prevalence and impact of aPL on venous thromboembolic events (VTE) and arterial thrombosis (ATE) in ambulatory cancer patients.MethodsIn this single-center, prospective cohort study, we enrolled newly diagnosed ambulatory cancer patients receiving chemotherapy. Non-cancer controls were age- and sex-matched. Participants were evaluated for aPL. Primary outcomes were the composite outcome of VTE or ATE and the prevalence of aPL positivity in cancer patients. Secondary outcomes included the risk of VTE and ATE in cancer patients and all-cause mortality at six-month follow-up duration.ResultsThere were 137 cases and 137 controls with mean age of 56.0±12.3 and 55.5±12.1 years, respectively. Cancer patients were more likely to have positive aPL compared to controls, with the risk difference of 9.4% (95%CI 1.5 to 17.5). Composite of ATE or VTE occurred in 9 (6.6%) in cancer patients and 2 (1.5%) in controls. Cancer patients with aPL positivity were associated with higher risk of ATE or VTE (risk ratio [RR] 3.6, 95% CI 1.04-12.4). Positive LA in cancer patients were associated with higher risk of composites of ATE or VTE (RR 5.3 95%CI 1.3-21.0), whereas the anti-β2-GPI positivity were associated with increased risk of VTE (RR 4.7, 95%CI 1.1-19.2).ConclusionaPL was more prevalent in active cancer patients and positive aPL in cancer patients was associated with arterial or venous thrombosis.

Abstract Background Gaucher disease (GD) is a rare lysosomal storage disorder, characterized by hepatosplenomegaly and pancytopenia, with or without neurologic involvement. The disorder is categorized into three phenotypes: GD type 1 or nonneuronopathic GD; GD type 2 or acute neuronopathic GD; and GD type 3 or chronic neuronopathic GD. The purposes of this study were to describe clinical characteristics of Thai GD in patients diagnosed and/or followed up during 2010–2018 and to perform re-genotyping including analysis of GBA recombinant alleles which had not been investigated in Thai patients before. Results There were 27 patients from seven medical centers, enrolled in the study. All the cases had pediatric onset. GD3 (44.5%) was the most common phenotype, followed by GD2 (40.7%) and GD1 (14.8%), with one case of neonatal GD. The median age of onset for GD1, GD2, and GD3 was 72, 4 and 12 months, respectively, suggesting relatively earlier onset of GD1 and GD3 in Thai patients. All patients with GD1 and most patients with GD3 received ERT. Four patients with GD3 had ERT followed by HSCT. Patients with GD3 who received no or late ERT showed unfavorable outcomes. We identified 14 variants including two novel (p.S384F and p.W533*) and 12 reported pathogenic variants: p.L483P, p.N409S, p.R159W, p.P305A, p.A175G, p.D448H, p.V414L, IVS2+1G>A, IVS6-1G>C, IVS7+1G>C, IVS9-3C>G, and Rec1a. The p.L483P was the most prevalent allele found in this study, at 66% (33/50 alleles), followed by IVS2+1G>A, Rec1a, and IVS6-1G>C. Twenty-four percent of patients were reassigned with validated genotypes, most of whom (4 of 6) were patients with GD2. The [p.S384F + p.W533*] being compounded with p.L483P, was found in the patient with neonatal GD, suggesting that the p.S384F could potentiate the deleterious effect of the p.W533*, and/or vice versa. Conclusions Neuronopathic GD was strikingly prevalent among Thai affected population. Homozygous p.L483P was the most common genotype identified in Thai patients. Recombinant allele Rec1a and splicing mutations were associated with GD2 and severe cases of GD3. Mutation spectrum could be useful for designing stepwise molecular analysis, genetic screenings in population, and new therapeutic research for neuronopathic GD.

Abstract Although an increased fibroblast growth factor 21 (FGF21) level was related to mild cognitive impairment (MCI) in metabolic syndrome patients, any association regarding FGF21 and MCI in thalassemia patients as well as mechanistic insight are questionable. Therefore, the objectives of this study were: (1) to investigate the prevalence and associative risk factors of MCI in thalassemia patients, (2) to evaluate the association between levels of FGF21 and MCI in thalassemia patients, and (3) to investigate brain FGF21 signaling in iron-overload thalassemia. Thalassemia patients were enrolled onto the study (n = 131). Montreal cognitive assessment (MoCA) was used to determine cognitive performance. Plasma FGF21 level was determined in all patients. Iron-overload β-thalassemic (HT) mice were used to investigate brain FGF21 level and signaling, the expression of synaptic proteins, and Alzheimer’s like pathology. We found that 70% of thalassemia patients developed MCI. FGF21 level was positively correlated with the MCI. Interestingly, brain FGF21 resistance, as indicated by increased brain FGF21 levels with impaired FGF21 signaling, was found in iron-overload HT mice. The reduced synaptic protein expression and increased Alzheimer’s like pathology were also observed. These suggest that FGF21 may play a role in MCI in thalassemia patients.

Background: Iron overload cardiomyopathy is the most common cause of death in patients with transfusion-dependent thalassemia. Aim: The aim of this study was to determine the efficacy of carvedilol treatment in patients with transfusion-dependent thalassemia who had left ventricular diastolic dysfunction. Methods: Eighteen patients with transfusion-dependent thalassemia who had left ventricular diastolic dysfunction were enrolled. All patients had normal left ventricular systolic function and were given carvedilol with the target dose of 0.8 mg/kg/day. Ventricular function and the level of cardiac iron were assessed by echocardiography and magnetic resonance imaging at 0, 3, and 6 months. Results: The median age of the patients was 19 years (range 13–25 years). Four patients had severe left ventricular Grade III diastolic dysfunction and fourteen patients had Grade II diastolic dysfunction. The grade of left ventricular diastolic dysfunction was improved at 3 months after the carvedilol treatment. The Doppler parameters, including pulmonary vein atrial reversal velocity, pulmonary vein atrial reversal duration, and the difference of pulmonary vein atrial reversal and the mitral valve atrial contraction wave duration at 3 months after the carvedilol treatment, were significantly lower than these parameters before the treatment. Conclusions: Among patients with transfusion-dependent thalassemia who had left ventricular diastolic dysfunction without systolic dysfunction, treatment with carvedilol for 3 months was associated with improvement in Doppler parameters of left ventricular diastolic function. However, this finding and its clinical significance need to be confirmed in further double-blind controlled studies.

Abstract Background Cardiorenal syndrome (CRS), a serious condition with high morbidity and mortality, is characterized by the coexistence of cardiac abnormality and renal dysfunction. There is limited information about CRS in association thalassemia. This study aimed to investigate the prevalence of CRS in thalassemia patients and also associated risk factors. Methods Thalassemia patients who attended the out-patient clinic of a tertiary care university hospital from October 2016 to September 2017 were enrolled onto this cross-sectional study. Clinical and laboratory findings from 2 consecutive visits, 3 months apart, were assessed. The criteria for diagnosis of CRS was based on a system proposed by Ronco and McCullough. Cardiac abnormalities are assessed by clinical presentation, establishment of acute or chronic heart failure using definitions from 2016 ESC guidelines or from structural abnormalities shown in an echocardiogram. Renal dysfunction was defined as chronic kidney disease according to the 2012 KDIGO guidelines. Results Out of 90 thalassemia patients, 25 (27.8%) had CRS. The multivariable analysis showed a significant association between CRS and extramedullary hematopoiesis (EMH) (odds ratio (OR) 20.55, p = 0.016); thalassemia type [β0/βE vs β0/β0 thalassemia (OR 0.005, p = 0.002)]; pulmonary hypertension (OR 178.1, p = 0.001); elevated serum NT-proBNP (OR 1.028, p = 0.022), and elevated 24-h urine magnesium (OR 1.913, p = 0.016). There was no association found between CRS and frequency of blood transfusion, serum ferritin, liver iron concentration, cardiac T2*, type of iron chelating agents, or urine neutrophil gelatinase-associated lipocalin level. Conclusions CRS is relatively common in thalassemia patients. Its occurrence is associated with laboratory parameters which are easily measured in clinical practice.

Abstract Background Thalassemia is a hereditary hemolytic anemia with a severity ranging from mild, non-transfusion dependent to severe chronic anemia requiring lifelong transfusion. Transfusional iron overload is a major complication in patients with transfusion-dependent thalassemia (TDT). Telomeres are sequences of nucleotides forming the end caps of chromosomes that act as a DNA repair system. Iron overload in thalassemia can cause increased oxidative stress which leads to cellular damage and senescence. This may result in telomere length shortening. The degree of telomere length shortening may reflect the severity of thalassemia. Methods This research aimed to study the leukocyte telomere length in patients with TDT in comparison to non-thalassemic individuals and to identify the clinical and laboratory parameters that are associated with telomere length. We conducted a cross-sectional study in patients with TDT aged ≥18 years. Leukocyte telomere length was measured by real-time quantitative PCR. Results Sixty-five patients with TDT were enrolled onto the study. There were 37 female patients (54.4%). The median age was 27 (18–57) years, and mean pre-transfusion hemoglobin level was 7.1 (± 1.07) g/dL. The mean telomere to single copy gene (T/S) ratios of patients with TDT and the controls were 0.72 ± 0.18 and 0.99 ± 0.25, respectively (p

Anti-platelet factor 4 (anti-PF4) antibodies were identified as pathogenic antibodies for vaccine-induced immune thrombocytopenia and thrombosis (VITT) in subjects receiving ChAdOx1 nCoV-19 vaccinations. We performed a prospective cohort study to determine the prevalence of anti-PF4 and the effect of the ChAdOx1 nCoV-19 vaccine on anti-PF4 in healthy Thai subjects. Anti-PF4 antibodies were measured before and four weeks after receiving the first vaccination. Participants with detectable antibodies were scheduled for repeat anti-PF4 analysis at 12 weeks after the second vaccination. Of 396 participants, ten participants (2.53%; 95% confidence interval [CI], 1.22–4.59) were positive for anti-PF4 before receiving vaccinations. Twelve people (3.03%; 95% CI, 1.58–5.23) had detectable anti-PF4 after the first vaccination. There was no difference in the optical density (OD) values of anti-PF4 antibodies when comparisons were made between pre-vaccination and four weeks after the first vaccination (p = 0.0779). There was also no significant difference in OD values in participants with detectable antibodies. No subjects experienced thrombotic complications. Pain at the injection site was associated with an increased risk of being anti-PF4 positive at an odds ratio of 3.44 (95% CI, 1.06–11.18). To conclude, the prevalence of anti-PF4 was low in Thais and did not significantly change over time.

The intestinal bacterial flora of febrile neutropenic patients has been found to be significantly diverse. However, there are few reports of alterations of in adult acute myeloid leukemia (AML) patients. Stool samples of each treatment-naïve AML patient were collected the day before initiation of induction chemotherapy (pretreatment), on the first date of neutropenic fever and first date of bone marrow recovery. Bacterial DNA was extracted from stool samples and bacterial 16s ribosomal RNA genes were sequenced by next-generation sequencing. Relative abundance, overall richness, Shannon's diversity index and Simpson's diversity index were calculated. No antimicrobial prophylaxis was in placed in all participants. Ten cases of AML patients (4 male and 6 female) were included with a median age of 39 years (range: 19-49) and all of patients developed febrile neutropenia. Firmicutes dominated during the period of neutropenic fever, subsequently declining after bone marrow recovery a pattern in contrast to that shown by Bacteroidetes and Proteobacteria. Enterococcus was more abundant in the febrile neutropenia period compared to pretreatment (mean difference +20.2; p < 0.0001) while Escherichia notably declined during the same period (mean difference -11.2; p = 0.0064). At the operational taxonomic unit (OTU) level, there was a significantly higher level of overall richness in the pretreatment period than in the febrile neutropenic episode (mean OTU of 203.1 vs. 131.7; p = 0.012). Both of the diversity indexes of Shannon and Simpson showed a significant decrease during the febrile neutropenic period. Adult AML patients with a first episode of febrile neutropenia after initial intensive chemotherapy demonstrated a significant decrease in gut microbiota diversity and the level of diversity remained constant despite recovery of bone marrow.

Lymphoma can present with either lymphadenopathy or extranodal involvement. There are limited clinicopathological data pertaining to the occurrence of primary extranodal lymphoma (pENL) in Thailand. This was a retrospective study conducted at Chiang-Mai University Hospital from 2012 to 2016. Patients 18 years of age and over and with a diagnosis of pENL were enrolled onto study. Data related to clinical presentations, histology, stage, treatment and response were collected. There were 104 pENL patients with a median age of 63 years included. The most common presentation was gastrointestinal symptoms (41%), followed by ear, nose, and throat symptoms (35%). Diffuse large B-cell lymphoma (DLBCL) was the most common morphological subtype (60%), followed by marginal zone lymphoma (15%). The majority of patients presented with stage II disease (55%). The five-year overall survival rate was 71%. The factors associated with mortality were hemoglobin

Establishment and analysis of mean platelet volume (MPV) may be helpful in the discrimination between underproduction or over-destruction of platelets as the causes of thrombocytopenia. The primary objective is to find the cut-off point of MPV for distinguishing causes of thrombocytopenia. The secondary objective is to validate the cut-off value of the MPV by using bone marrow examination. Thrombocytopenic patients were enrolled in a training set and a receiving operating characteristics (ROC) curve was plotted to obtain the cut-off value of MPV. A validation set of patients was recruited to validate the cut-off value. The training set included 240 patients. Half with with underproductive (n=120) and half with over-destructive thrombocytopenia (n=120). The best cut-off value of MPV was 8.8 fL. The validation set included 119 patients in total, again in 2 groups, those with underproductive (n=84) and those with overdestructive thrombocytopenia (n=35). The sensitivity, specificity, PPV and NPV when MPV ≥8.8 fL indicating over-destructive thrombocytopenia were 77%, 89%, 89% and 77%, respectively. MPV is useful for differentiating the cause of thrombocytopenia. The value of MPV ≥8.8 fL has acceptable sensitivity and specificity for diagnosis of over-destructive thrombocytopenia.

Despite advances in our knowledge and attempts to improve therapies, β-thalassemia remains a prevalent disorder with increased risk for the development of cardiomyopathy. Using an untargeted discovery-based lipidomic workflow, we uncovered that transfusion-dependent thalassemia (TDT) patients had a unique circulating lipidomic signature consisting of 387 lipid features, allowing their significant discrimination from healthy controls (Q-value < 0.01). In particular, TDT patients had elevated triacylglycerols and long-chain acylcarnitines, albeit lower ether phospholipids or plasmalogens, sphingomyelins, and cholesterol esters, reminiscent of that previously characterized in cardiometabolic diseases resulting from mitochondrial and peroxisomal dysfunction. Discriminating lipid (sub)classes correlated differentially with clinical parameters, reflecting blood (ether phospholipids) and iron (cholesterol ester) status or heart function (triacylglycerols). We also tested 15 potential serum biomarkers related to cardiometabolic disease and found that both lipocalin-2 and, for the first time, endocan-1 levels were significantly elevated in TDT patients and showed a strong correlation with blood parameters and three ether diacylglycerophosphatidylcholine species. In conclusion, this study identifies new characteristics of TDT patients which may have relevance in developing biomarkers and therapeutics.

This study aims to find the cut-off value and diagnostic accuracy of the use of RDW as initial investigation in enabling the differentiation between IDA and NTDT patients. Patients with microcytic anemia were enrolled in the training set and used to plot a receiving operating characteristics (ROC) curve to obtain the cut-off value of RDW. A second set of patients were included in the validation set and used to analyze the diagnostic accuracy. We recruited 94 IDA and 64 NTDT patients into the training set. The area under the curve of the ROC in the training set was 0.803. The best cut-off value of RDW in the diagnosis of NTDT was 21.0% with a sensitivity and specificity of 81.3% and 55.3% respectively. In the validation set, there were 34 IDA and 58 NTDT patients using the cut-off value of >21.0% to validate. The sensitivity, specificity, positive predictive value and negative predictive value were 84.5%, 70.6%, 83.1% and 72.7% respectively. We can therefore conclude that RDW >21.0% is useful in differentiating between IDA and NTDT patients with high diagnostic accuracy

Background: There were some reports of peripheral artery occlusive disease (PAOD) associated with nilotinib usage in chronic myeloid leukemia (CML). These complications in other tyrosine kinase inhibitors are revealed as unknown. Materials and methods: We determined the prevalence of PAOD in patients with CML as compared with matched-control population by cross-sectional case-control study. Peripheral artery occlusive disease was screened by ankle-brachial index (ABI). Results: In total, 78 CML and 156 matched-control patients were included. The median age was 55 years. In all, 61 (78.2%) were on imatinib and 13 (16.7%) were on nilotinib, whereas 4 patients (5.2%) were on dasatinib. Prevalence of low ABI (

The aim of the present paper is to evaluate the efficacy and safety of colchicine and dapsone combination therapy in cases of steroid-dependent, relapsed and refractory immune thrombocytopenia (ITP). This is a retrospective study of ITP patients who attended the Hematology Clinic at Chiang Mai University Hospital (Thailand) from 1 January 2008 to 30 September 2014. Medical records and clinical data were reviewed for efficacy and adverse effects. Sixty-four ITP patients received the combination therapy. The median age was 46 years and 70.3% were female. The majority (65.6%) were relapsed ITP patients. Median platelet count before starting treatment was 22.6×109/L. The response rate was 82.8%, with 75.0% of patients having a complete response. Median time to response was 8 weeks. The response rate was higher in relapsed patients (90.4%) compared to refractory (61.5%) and steroid-dependent patients (77.8%). Steroid treatment was discontinued in 30 patients (50%) following combination therapy. The most common side effect was hemolysis due to dapsone which was found in eight patients (12.5%). We can therefore conclude that combination therapy with colchicine and dapsone is an alternative second-line therapy option in relapsed ITP cases with acceptable side effects.

Iron overload cardiomyopathy remains the major cause of death in patients with transfusion-dependent thalassemia. Cardiac T2* magnetic resonance imaging is costly yet effective in detecting cardiac iron accumulation in the heart. Heart rate variability (HRV) has been used to evaluate cardiac autonomic function and is depressed in cases of thalassemia. We evaluated whether HRV could be used as an indicator for early identification of cardiac iron deposition.One hundred and one patients with transfusion-dependent thalassemia were enrolled in this study. The correlation between recorded HRV and hemoglobin, non-transferrin bound iron (NTBI), serum ferritin and cardiac T2* were evaluated.The median age was 18 years (range 8-59 years). The patient group with a 5-year mean serum ferritin >5,000 ng/mL included significantly more homozygous β-thalassemia and splenectomized patients, had lower hemoglobin levels, and had more cardiac iron deposit than all other groups. Anemia strongly influenced all domains of HRV. After adjusting for anemia, neither serum ferritin nor NTBI impacted the HRV. However cardiac T2* was an independent predictor of HRV, even after adjusting for anemia. For receiver operative characteristic (ROC) curve analysis of cardiac T2* ≤20 ms, only mean ferritin in the last 12 months and the average of the standard deviation of all R-R intervals for all five-minute segments in the 24-hour recording were predictors for cardiac T2* ≤20 ms, with area under the ROC curve of 0.961 (p

Thrombosis is a major complication of polycythemia vera (PV) and also a well-known complication of thalassemia. We reported a case of non-atherosclerotic ST-segment elevation myocardial infarction (STEMI) in a 17- year-old man with concurrent post-splenectomized hemoglobin H-Constant Spring disease and JAK2 V617F mutation-positive PV. The patient initially presented with extreme thrombocytosis (platelet counts greater than 1,000,000/μL) and three months later developed an acute STEMI. Coronary artery angiography revealed an acute clot in the right coronary artery without atherosclerotic plaque. He was treated with plateletpheresis, hydroxyurea and antiplatelet agents. The platelet count decreased and his symptoms improved. This case represents the importance of early diagnosis, awareness of the increased risk for thrombotic complications, and early treatment of PV in patients who have underlying thalassemia with marked thrombocytosis.

Iron-overload cardiomyopathy is a major cause of death in thalassemia patients due to the lack of an early detection strategy. Although cardiac magnetic resonance (CMR) T2* is used for early detection of cardiac iron accumulation, its availability is limited. Heart rate variability (HRV) has been used to evaluate cardiac autonomic function and found to be depressed in thalassemia. However, its direct correlation with cardiac iron accumulation has never been investigated. We investigated whether HRV can be used as an alternative indicator for early identification of cardiac iron deposition in thalassemia patients.Ninety-nine non-transfusion dependent thalassemia patients (23.00 (17.00, 32.75) years, 35 male) were enrolled. The correlation between HRV recorded using 24-hour Holter monitoring and non-transferrin bound iron (NTBI), hemoglobin (Hb), serum ferritin, LV ejection fraction (LVEF), and CMR-T2* were determined.The median NTBI value was 3.15 (1.11, 6.59) μM. Both time and frequency domains of HRV showed a significant correlation with the NTBI level, supporting HRV as a marker of iron overload. Moreover, the LF/HF ratio showed a significant correlation with CMR-T2* with the receiver operating characteristic (ROC) curve of 0.684±0.063, suggesting that it could represent the cardiac iron deposit in thalassemia patients. HRV was also significantly correlated with serum ferritin and Hb.This novel finding regarding the correlation between HRV and CMR-T2* indicates that HRV could be a potential marker in identifying early cardiac iron deposition prior to the development of LV dysfunction, and may be used as an alternative to CMR-T2* for screening cardiac iron status in thalassemia patients.

Background. Nontransfusion dependent thalassemia (NTDT) is a milder form of thalassemia that does not require regular transfusion. It is associated with many complications, which differ from that found in transfusion-dependent thalassemia (TDT). Currently available information is mostly derived from beta-NTDT; consequently, more data is needed to describe complications found in the alpha-NTDT form of this disease. Methods. We retrospectively reviewed the medical records of NTDT patients from January 2012 to December 2013. Complications related to thalassemia were reviewed and compared. Results. One hundred patients included 60 females with a median age of 38 years. The majority (54 patients) had alpha-thalassemia. Overall, 83 patients had one or more complications. The three most common complications were cholelithiasis (35%), abnormal liver function (29%), and extramedullary hematopoiesis (EMH) (25%). EMH, cardiomyopathy, cholelithiasis, and pulmonary hypertension were more commonly seen in beta-thalassemia. Osteoporosis was the only complication that was more common in alpha-thalassemia. The risk factors significantly related to EMH were beta-thalassemia type and hemoglobin < 8 g/dL. The risk factors related to osteoporosis were female gender and age > 40 years. Iron overload (ferritin > 800 ng/mL) was the only risk factor for abnormal liver function. Conclusion. The prevalence of alpha-NTDT complications was lower and different from beta-thalassemia.

Since 1996, there have been several case reports of autochthonous visceral leishmaniasis in Thailand. Here we report a case in a 52-year-old Thai male from northern Thailand, who presented with subacute fever, huge splenomegaly and pancytopenia. Bone marrow aspiration revealed numerous amastigotes within macrophages. Isolation of Leishmania LSCM1 into culture and DNA sequence analysis (ribosomal RNA ITS-1 and large subunit of RNA polymerase II) revealed the parasites to be members of the Leishmania enriettii complex, and apparently identical to L. martiniquensis previously reported from the Caribbean island of Martinique. This is the first report of visceral leishmaniasis caused by L. martiniquensis from the region. Moreover, the majority of parasites previously identified as "L. siamensis" also appear to be L. martiniquensis.

Objective: Rare disease Background: Thalassemia and hemoglobin (Hb) variants are the most common hereditary red blood cell disorders worldwide. Alpha-thalassemia and alpha-globin variants are caused by mutations of the alpha-globin genes (HBA2 and HBA1), resulting in impaired alpha-globin production and structurally abnormal globin, respectively. Clinical severity of alpha-thalassemia correlates with the number of affected alpha-globin genes, yielding a spectrum of clinical manifestations from mild to severe anemia. Routine diagnosis involves Hb analysis and PCR-based methods, yet identifying rare variants necessitates comprehensive clinical and hematologic laboratory data. The knowledge of phenotype and genotype correlation is useful for genetic counseling and treatment planning. Case Report: A 59-year-old Thai woman presented with chronic anemia. Her baseline Hb level ranged between 8.0 and 9.0 g/dL, with no history of transfusion. Physical examination showed mild pallor, without enlarged liver and spleen. Laboratory investigations showed microcytic, hypochromic anemia and abnormal Hb peak by Hb analysis (retention time 4.58 min by HPLC method). Common alpha-globin gene deletions, including the Southeast-Asian/Thai 3.7 kb and 4.2 kb deletions were tested using gap-PCR, with none of these deletions detected. Direct DNA sequencing revealed a compound heterozygosity of Hb Jax (HBA2: c.44G>C) and Hb Constant Spring (HBA2: c.427T>C). Conclusions: Compound heterozygosity of Hb Jax and Hb Constant Spring results in microcytic anemia. Hb Jax can be identified by Hb analysis, and diagnosis can be confirmed by direct DNA sequencing method. Coinheritance of Hb Jax and alpha-globin variants should be considered in cases with microcytic anemia and a specific Hb peak seen in Hb chromatogram. [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukemia (AML) with febrile neutropenia (FN) had a higher incidence among hematologic malignancies. The varied incidence and risk factors predictive of FN among patients with AML were reported. Hence, this study aimed to evaluate the incidence and risk factors associated with FN in AML patients who underwent the induction phase of chemotherapy. Material and Methods: In this retrospective cohort study, patients who were newly diagnosed with AML and receiving the induction phase of the idarubicin/cytarabine 3+7 regimen or 2+5 were included between January 2008 and December 2021. The primary outcome was an incidence of FN. Risk factors for FN and the causative pathogen were presented as secondary outcomes. The Kaplan-Meier and Cox-proportional hazard models evaluated the relationship between risk factors and FN. Results: A hundred and forty-one eligible patients with a mean age of 40.7 years (standard deviation [SD] = 13.4 years) were enrolled. Among these patients, 92.2% had an Eastern Cooperative Oncology Group score of 1-2. Twenty-five patients (17.7%) received the 2+5 regimen, and 116 (82.3%) underwent the 3=7 regimen. The average length of hospital stay was 33.9 days (SD = 7.0 days). The median absolute neutrophil count was 1,784.8 cells/mm3 (interquartile range [IQR] = 4,880.1 cells/mm3). Sixty-four (45.4%) of patients received granulocyte colony stimulating factor. The incidence of FN among patients with AML during the induction phase was 88.7%. The median time to FN was 6 days (IQR = 7.0 days). There was no significance in univariate and multivariable analyses for potential risk factors associated with FN. Gram-positive bacteria were identified as the predominant isolates, and Enterococci spp. was the most common pathogen. Conclusion: This study revealed a high incidence of FN among newly diagnosed AML patients receiving induction-phase chemotherapy. With some limitations, a significant association between FN and risk factors was not determined. [ABSTRACT FROM AUTHOR]