Molecular characteristics of hereditary red blood cell membrane disorders in Thailand: a multi-center registry.

Red blood cell (RBC) membrane disorders represent a significant category of hereditary hemolytic anemia; however, information from Southeast Asia is limited. We established a national registry aiming to characterize RBC membrane disorders and their molecular features in Thailand. A total of 100 patients (99 kindreds) diagnosed with RBC membrane disorders between 2011 and 2020 from seven university hospitals were enrolled. The most prevalent disorders observed were hereditary elliptocytosis (HE; n=33), hereditary pyropoikilocytosis (HPP; n=28), hereditary spherocytosis (HS; n=19), Southeast Asian ovalocytosis (SAO; n=10 of 9 kindreds), and two cases of homozygous SAO. The remaining cases were grouped as unclassified membrane disorder. Seventy-six patients (76%) were molecularly confirmed by PCR, direct DNA sequencing, or hi-throughput sequencing. The primary causative gene for HE and HPP was SPTB, accounting for 28 out of 29 studied alleles for HE and 56 of 56 studied alleles for HPP. In the case of HS, dominant sporadic mutations in the ANK1 gene (n=4) and SPTB gene (n=3) were identified as the underlying cause. Notably, the four most common variants causing HE and HPP were SPTB Providence (c.6055 T>C), SPTB Buffalo (c.6074 T>G), SPTB Chiang Mai (c.6224 A>G), and SPTB c.6171__82delins TGCCCAGCT. These recurrent SPTB mutations accounted for 79 out of 84 mutated SPTB alleles (94%). In summary, HE and hereditary HPP associated with recurrent SPTB mutations are the predominant types of RBC membrane disorders observed in Thailand. These findings have significant implications for the clinical management and future research of RBC membrane disorders in the region.

Incidence of venous thromboembolism and predictive ability of age-adjusted international prognostic index for prediction of venous thromboembolism in Asian patients with diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is one of the malignancies at high risk for the development of venous thromboembolism (VTE). We aimed to evaluate the incidence of VTE and the predictive ability of the age-adjusted international prognostic index (aaIPI) for the prediction of VTE among DLBCL patients. This was a retrospective cohort study including adult patients with newly diagnosed DLBCL. Differences in VTE occurrence within one year after diagnosis of DLBCL were estimated across aaIPI groups using the Kaplan-Meier model, Cox's model, and Gray's model with deaths regarded as competing events. Five hundred and ninety-one newly diagnosed DLBCL patients with a median age of 58 (range 16-93) years were included in this study. At a median follow-up time of 365 (range 2-365) days, VTE events were objectively diagnosed in 32 patients, giving a one-year cumulative incidence of VTE of 5.4% (95% confidence interval [CI], 3.7-7.6). Patients with aaIPI ≥ 2 had a significantly higher risk of VTE than patients with aaIPI < 2 (hazard ratio, 3.5; 95% CI, 1.6-7.8; p = 0.001 based on Cox's model and sub-distribution hazard ratio, 3.0; 95% CI, 1.3-6.7; p = 0.007 using Gray's model). The C-statistic of aaIPI was 0.65 (95% CI, 0.58-0.72). We demonstrated that the incidence of VTE in Asian DLBCL patients was not uncommon. The aaIPI was effective in determining the risk of VTE in DLBCL patients, even when including death as a competing event. aaIPI may be helpful in identifying patients at higher risk of VTE in DLBCL patients.

A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent ß-Thalassemia.

BACKGROUND: Patients with transfusion-dependent ß-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor ß superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS: In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent ß-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS: A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 µg per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. CONCLUSIONS: The percentage of patients with transfusion-dependent ß-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.).

Thalassemia-related complications in pediatric, adolescent, and young adult patients with transfusion-dependent thalassemia: A multicenter study in Thailand.

INTRODUCTION: Management of transfusion-dependent thalassemia (TDT) can be challenging due to numerous potential disease-related complications and comorbidities in particular age groups. The objective of this study was to report thalassemia-related complications and risk factors in pediatric, adolescent, and young adult patients with TDT. METHODS: A multicenter web-based registry was conducted in patients with TDT aged 25 years and younger from eight university hospitals covering all parts of Thailand. Factors significantly associated with each complication were analyzed by logistic regression methods. RESULTS: Of 605 patients, 267 thalassemia-related complications were reported from 231 pediatric, adolescent, and young adult patients with TDT patients (38.2%). The most common complications were infections, followed by cholelithiasis and growth failure. Splenectomy and elevated pre-transfusion hemoglobin were statistically significant risk factors for infections (adjusted odds ratio [AOR] = 2.3, 95% confidence interval [CI]: 1.2-4.5, p-value = .01 and AOR = 1.5, 95% CI: 1.2-1.7, p-value < .005, respectively). There were two statistically significant risk factors conferred endocrinopathies, including older age (AOR = 1.06, 95% CI: 1.01-1.1, p-value = .01) and being male (AOR = 2.4, 95% CI: 1.4-4.0, p-value = .002). CONCLUSION: Nearly 40% of the patients in this cohort had thalassemia-related complications. Periodic surveillance and optimal care for respective complications may minimize comorbidities in pediatric, adolescent, and young adult patients with TDT.

The long-term efficacy in blood transfusions, hematologic parameter changes, and complications after splenectomy in patients with transfusion-dependent thalassemia.

BACKGROUND: A splenectomy can reduce transfusion requirements in patients with thalassemia. However, the role of a splenectomy remains controversial because its efficacy has not yet been fully determined and there are concerns over potential complications. The purpose of this study was to assess the efficacy, potential changes in hematologic parameters, and any complications associated with splenectomy. METHODS: Medical records of 50 patients with transfusion-dependent thalassemia (TDT) who had undergone a splenectomy, along with those of 20 control subjects with intact spleens, were retrospectively reviewed. RESULTS: The primary outcomes indicate the efficacy of a splenectomy in reducing red cell transfusions. Fifty TDT post-splenectomy patients were included in this study, of which 28 (56%) were female. The median age of all patients was 20.5 (18-28 years of age). Twenty-seven patients (54%) transformed from TDT to non-transfusion-dependent thalassemia (NTDT) after the splenectomy; 100% with Hb H disease, 58.3% with beta-thalassemia/Hb E disease, and 23.5% with homozygous beta-thalassemia. According to multivariable logistic regression analysis, Hb H disease (adjusted OR 55.23, 95% CI 1.35-22.8.10) and receiving a splenectomy at > ten years of age (adjusted OR 25.36, 95% CI 1.62-396.47) were associated with higher responses. The prevalence of pulmonary hypertension and thromboembolic events were similar between the splenectomy patients and non-splenectomy patients. CONCLUSION: Splenectomy reduced transfusion requirements in TDT patients. The predictive factors as a response to a splenectomy included Hb H disease amongthose receiving a splenectomy at > ten years of age.

Impact of dabigatran dose on drug levels in asian patients with atrial fibrillation or venous thromboembolism: evidence from pharmacological to clinical outcomes.

Dabigatran is commonly used in atrial fibrillation (AF) or venous thromboembolism (VTE). However, there was limited data on dabigatran levels in Asian patients. This study aimed to investigate plasma levels of dabigatran 110 mg (D110) or 150 mg (D150) twice daily and their impact on clinical outcomes in Thai patients. This was a prospective cohort study including patients who were diagnosed with AF or VTE and were prescribed either D110 or D150. Plasma dabigatran levels were measured using the diluted thrombin time method. All patients were observed for bleeding and thrombotic complications for 12 months after enrollment. Ninety patients were included in the study (45 in the D110 group and 45 in the D150 group). For the D110 group, there was no significant difference in trough and peak levels in patients with creatinine clearance (CrCl) < 50 ml/min compared to those with CrCl ≥ 50 ml/min. For the D150 group, patients with CrCl < 50 ml/min had significantly higher trough and peak levels compared to those with CrCl ≥ 50 ml/min (P = 0.016 for trough, P = 0.005 for peak). Multivariate regression analysis showed females and low CrCl were independent risk factors for high dabigatran levels. Most patients (83.33%) who experienced bleeding complications had peak levels within the expected range. D150 was associated with higher plasma dabigatran levels, especially in those with impaired renal function.

Red blood cell alloimmunization and other transfusion-related complications in patients with transfusion-dependent thalassemia: A multi-center study in Thailand.

BACKGROUND: Thalassemia is a common genetic disease in Southeast Asia. Red blood cell (RBC) transfusion is an essential treatment for severe forms of thalassemia. We performed a study to demonstrate RBC alloimmunization and other transfusion-related complications in patients with transfusion-dependent thalassemia (TDT). STUDY DESIGN AND METHODS: A multi-center web-based registry of TDT was conducted in eight medical centers across Thailand. Thalassemia information, transfusion therapy, and transfusion-related complications were collected. Factors associated with each complication were demonstrated using the logistic regression analysis. RESULTS: Of 1000 patients recruited for the study, 449 were males (44.9%). The mean age was 23.9 ± 15.4 years. The majority of patients, 738 (73.8%) had hemoglobin E/beta-thalassemia. In the study, 421 transfusion-related complications were reported from 357 patients (35.7%). Alloimmunization was the most common complication which was found in 156 patients (15.6%) with 284 positive antibody tests. The most frequent antibodies against RBC were anti-E (80/284, 28.2%) followed by anti-Mia (45/284, 15.8%) and anti-c (32/284, 11.3%). Age ≥3 years at initial blood transfusion, splenomegaly, higher frequencies, and volumes of transfusion were significant factors associated with alloimmunization. None of the patients had to terminate blood transfusion due to multiple alloantibodies. Other commonly seen complications were allergic reactions (130, 13.0%), autoimmune hemolytic anemia (70, 7.0%) and febrile non-hemolytic transfusion reaction (54, 5.4%). CONCLUSIONS: Transfusion-related complications, especially alloimmunization, were common among Thai patients with TDT. Extended RBC antigen-matching for the Rh system and Mia should be implemented to prevent the development of alloantibodies in multi-transfused patients.

Prevalence and characteristics of inflammatory rheumatic diseases in patients with thalassemia.

Reports of inflammatory rheumatic diseases (IRD) in thalassemia are limited. This study aimed to determine the prevalence and clinical characteristics of IRD in patients with thalassemia disease. Consecutive adult patients with thalassemia disease, confirmed by hemoglobin typing, attending the Hematology Clinic between June 2019 and May 2021 were invited to join this study. All of them had their history taken and a physical examination for IRD. Those with IRD had their medical records reviewed. Sixty-three patients (transfusion-dependent in 50) were included in this study. There was α-, ß-, and co-inheritance of α- and ß-thalassemia in 22.22%, 73.02%, and 4.76% of the patients, respectively, with ß-thalassemia/Hb E disease in 53.97%. Twenty-three patients had IRD (rheumatoid arthritis in 9, gout in 6, systemic lupus erythematosus in 3, spondyloarthropathy in 2, and one patient each with dermatomyositis, overlap syndrome, and unclassified polyarthralgia). Clinical manifestations and laboratory findings were similar to IRD patients in general. In 40 patients without IRD, direct and indirect Coombs tests and antinuclear antibody (ANA) were positive in 51.72%, 27.59%, and 10.26%, respectively. When comparing among these 40 patients, between those with non-transfusion-dependent thalassemia (n = 10) and those with transfusion-dependent thalassemia (n = 30), the latter had non-significantly more positive direct Coombs (60.87% vs. 16.67%), indirect Coombs (30.43% vs. 16.67%), and ANA tests (13.33% vs. 0%). The prevalence of IRD in patients with thalassemia disease was rather high. Positive direct Coombs test and ANA were common in transfusion-dependent patients.

The Long-Term Efficacy of Deferiprone in Thalassemia Patients With Iron Overload: Real-World Data from the Registry Database.

Deferiprone (DFP) is an oral iron-chelating agent that is widely used in thalassemia patients with iron overload. This study aimed to investigate the long-term efficacy of DFP monotherapy on serum ferritin (SF) and adverse events. All thalassemia patients aged 15 years or older who received DFP monotherapy were identified from the thalassemia registry database between November 2008 and October 2019. After treatment, patients who achieved a target SF level, defined as <1000.0 ng/mL in transfusion-dependent thalassemia (TDT) and <800.0 ng/mL in non-TDT (NTDT) for two consecutive visits, were categorized as the achievable group. We used multivariate analysis to identify factors that contribute to differences between groups. One hundred and five patients were enrolled in the study with a median age of 28 (19-41) years and median initial SF level of 1399.0 (1141.0-2169.0) ng/mL. Of these, 61.0% carried Hb E (HBB: c.79G>A)/ß-thalassemia (ß-thal) and 60.0% were TDT patients. The median DFP dose was 63 (47-73) mg/kg/d and the median follow-up duration of treatment was 36 (20-54) months. A total of 58 (55.24%) patients were in the achievable group. The initial SF level <1350.0 ng/mL was significantly associated with achieving a targeted SF level (p = 0.002). Ten adverse events resulted in withholding DFP. The most common was gastrointestinal irritation in four patients and three patients with agranulocytosis. In conclusion, DFP is an effective iron chelator in thalassemia patients. Slightly more than half the patients (55.0%) achieved a target SF level. Lower SF levels at the beginning were an important factor.

Telomere shortening correlates with disease severity in hemoglobin H disease patients.

Hemoglobin H (Hb H) disease is the most significant health problem of the α-thalassemia syndromes. The Hb disease patients are categorized based on their genotype to deletional and nondeletional, with the latter genotype presents the more severe clinical symptoms. Since telomere length is an indicator of biological aging and health, we hypothesized that telomere length could reflect Hb H disease's severity. In this study, we recruited 48 deletional and 47 nondeletional Hb H disease patients, along with 109 normal controls, for telomere length assessment. The leukocyte telomere length was assessed by monochromatic multiplex real-time PCR and reported as the telomere to single-copy gene (T/S) ratio. When telomere length was adjusted for age, the analysis of covariance between the control and the two Hb H disease groups revealed no significant difference. However, the telomere shortening rate was more rapid in the nondeletional Hb H disease group than those of the control and deletional Hb H disease groups. Gender analysis found that male patients have a significantly lower T/S ratio than females in the nondeletional group but not in the control and deletional groups. In the two disease groups, the T/S ratio was not influenced by ferritin level or transfusion burden but was positively correlated with the absolute reticulocyte count.

Outcome of patients with newly diagnosed primary CNS lymphoma after high-dose methotrexate followed by consolidation whole-brain radiotherapy and cytarabine: an 8-year cohort study.

BACKGROUND: Addition of cytarabine to high-dose methotrexate (HD-MTX) chemotherapy improves outcome of primary CNS lymphoma (PCNSL); however, the combination therapy increases toxicity. Sequential chemotherapy and cranial radiation may decrease toxicity without altering efficacy. METHODS: This was a single-center, retrospective cohort study of consecutive newly diagnosed immunocompetent PCNSL patients treated with HD-MTX (5 cycles of 3 g/m2 every 2 weeks) followed by consolidation whole-brain radiotherapy (WBRT) and cytarabine (2 cycles of 3 g/m2/d for 2 days every 3 weeks) from January 2013 to December 2020. Initial WBRT before HD-MTX was allowed in patients with significant disability or brain edema at presentation. Primary outcome was progression-free survival (PFS). Key secondary outcomes were response rate, treatment-related toxicity, and overall survival (OS). RESULTS: Of 41 patients, 25 patients had a complete response (CR) and ten patients had a partial response, inferring an overall response rate (ORR) of 85.4% and a CR rate of 60.9%. More than 90% of patients were able to tolerate and complete the HD-MTX. The incidence of ≥ grade 3 hematologic and non-hematologic toxicities were 4.8% and 17.1%, respectively. Treatment-related mortality rate was 2.4%. There was no difference in toxicity between patients with age < 60 and ≥ 60 years. At the median follow-up duration of 39.8 months, the median PFS was 35.2 months (95% CI 12.4-69.3) and median OS was 46.5 months (95% CI 21.8-NR). CONCLUSION: High-dose methotrexate followed by consolidation whole-brain radiotherapy and cytarabine has acceptable efficacy, great tolerability, and low toxicity in newly diagnosed PCNSL patients.

Correlation Between Serum Ferritin and Viral Hepatitis in Thalassemia Patients.

Serum ferritin is an acute phase protein; importantly, its level is noticeably increased in response to iron overload and systemic inflammation. The iron overload status in thalassemia patients has been recognized as a potential way to measure liver iron concentration (LIC) levels using magnetic resonance imaging (MRI). The aim of this study was to investigate the effect of chronic viral hepatitis on the level of serum ferritin in patients with thalassemia. A cross-sectional study was conducted involving chronic viral hepatitis infection. Mean serum ferritin and LIC levels were recorded. The LIC values were used to divide the patients into two groups; a higher LIC group (>5 mg Fe/g) and a lower LIC group (<5 mg Fe/g). Mean serum ferritin levels were then compared between the two LIC groups. We identified 32 thalassemia patients comprising of 13 chronic viral hepatitis patients, seven patients with hepatitis B virus (HBV), and six patients with hepatitis C virus (HCV). With regard to the group with higher LIC values, the mean serum ferritin levels in the hepatitis group were significantly higher than for those in the non hepatitis group (1776 ± 488 vs. 967 ± 860 ng/mL, p = 0.03). Furthermore, the linear correlation between the mean serum ferritin levels and the viral load in the non transfusion-dependent thalassemia (NTDT) group were found to be significantly correlated (r = 0.7, p = 0.04). Chronic viral hepatitis was determined to be a possible casualty of disproportionately high ferritin levels in the NTDT group.

The effects of text messaging for promoting the retention of the first-time blood donors, a randomized controlled study (TEXT study).

BACKGROUND: Donor recruiting remains a challenging process to obtain sufficient blood product supply worldwide. This was a randomized controlled trial aimed to evaluate the efficacy of text messaging for promoting the retention of first-time blood donors. STUDY DESIGN AND METHODS: Participants enrolled were 18 years of age or older who were first-time blood donors and able to understand text messages. Participants were randomized in a 1:1 ratio (text group vs control group). Only participants who were allocated in the "text group" received a text message once their blood product was dispatched from the transfusion service. The content of the text message was "We would like to inform you that your blood has been used for patients on the date (DD/MM/YY)." The primary outcome of the study was the rate of returning at 9 months after the first donation. RESULTS: In an intention-to-treat analysis, 1270 participants were allocated to the text group and 1270 participants to the control group. The primary outcome occurred in 199 in the text group (22.4 per 100 donor-years) and 152 in the control group (16.9 per 100 donor-years). The incidence rate ratio was 1.31 (95% confidence interval, 1.06-1.63; P = .005). The number needed to treat was 22. The median time to return for blood donation was 112 days (interquartile range [IQR], 98-146) in the text group and 113 days (IQR, 97-144) in the control group. CONCLUSION: Among first-time blood donors, text messaging after blood product being dispatched is an effective and simple intervention to increase the retention rate for subsequent donations.

Comparison of hemoglobin and hematocrit levels at 1, 4 and 24 h after red blood cell transfusion.

Previous studies have shown that equilibration following a red cell transfusion had occurred by 24 h. A shorter time to follow the hemoglobin (Hb) and hematocrit (Hct) after transfusion may help physicians to provide earlier and more pertinent treatment. This was a prospective study conducted from December 2014 to August 2015. This research aimed to determine the equilibration time point of the level of Hb and Hct after one unit red blood cell (RBC) transfusion. Patients were randomized into three groups and Hb level and Hct were assessed at one, four or 24 h after transfusion. The mean differences in Hb level and Hct before and after transfusion were compared between each group. Sixty patients were eligible for enrollment onto this study; 20 patients were therefore allocated to each group. The median age was 51 years old, male predominating (83.33%). The most common indication for transfusion was post-operative anemia (88.33%). There were no significant differences between the baseline characteristics baseline Hb, Hct and volume of RBC transfusion in each group. The mean differences in Hb (g/dl)/Hct (%) level at the different time points of one, four and 24 h were 1.21/3.62, 1.19/3.63, and 0.95/3.09 respectively (P = 0.109 and P = 0.398, respectively). The equilibration of Hb and Hct did not differ between one, four and 24 h after a RBC transfusion. The target Hb and Hct can be determined at one hour after transfusion.

N-acetylcysteine Restored Heart Rate Variability and Prevented Serious Adverse Events in Transfusion-dependent Thalassemia Patients: a Double-blind Single Center Randomized Controlled Trial.

Regular blood transfusions in transfusion-dependent thalassemia (TDT) patients can lead to iron overload, causing oxidative stress and sympathovagal imbalance, resulting in increased cardiac complications. We hypothesized that administrating of N-acetylcysteine (NAC) prevents serious adverse events including cardiac complications in TDT patients by reducing systemic oxidative stress and balancing cardiac sympathovagal control. This study was double-blind, randomized control trial, investigating in 59 Thai TDT patients. After randomization, the participants were divided into two groups. The control group received standard care of TDT patient plus placebo, whereas the intervention group received 600 mg of NAC orally for six months. Serum 8-isoprostane, TNF-alpha, IL-10, 24-hour ECG monitoring, echocardiograms and the incidence of thalassemia-related complications were collected. At baseline, no significant difference in any parameters between the control and the intervention groups. At the end of intervention, the incidence of serious adverse events (i.e. infection, worsening thalassemia) was significantly higher in the control group when compared with the intervention group (24.1% vs. 3.3%, p=0.019) (Chi-square test; absolute risk reduction=20.8%, number needed to treat=4.8). The control group also had significantly lower time-dependent HRV parameters, compared with the intervention group (p=0.025 and 0.030, independent t-test). Treatment with NAC restored HRV and reduced serious adverse event in TDT patients, however, no difference in cardiac complications could be demonstrated. NAC could prevent serious adverse events in TDT patients. The proposed mechanism might be the balancing of sympathovagal control.

Cardiorenal syndrome in thalassemia patients.

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 [ß0/ßE vs ß0/ß0 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.

Hyperuricemia, urine uric excretion, and associated complications in thalassemia patients.

Thalassemia patients have a high cell turnover rate due to chronic hemolysis and ineffective erythropoiesis; therefore, hyperuricemia is anticipated. This study aimed to identify the prevalence of hyperuricemia, gout and nephrolithiasis, conditions associated with serum uric acid (SUA), and urine uric acid excretion (UUA) in thalassemia patients. This was a cross-sectional study in patients aged 15 years or older at Chiang Mai University Hospital. All patients had blood and 24-h urine collection test. We enrolled 112 thalassemia patients in which 67.0% were female, 64.3% had beta thalassemia/Hb E, 76.8% were transfusion dependent, and 59.8% were post splenectomy. The median age was 29 (16-58) years. Mean SUA was 6.7 ± 2.0 mg/dl and hyperuricemia (SUA > 6.8 mg/dl) was found in 47 cases (45.2%). Intact spleen (ORs 4.3, 95%CI 1.55-12.50, p = 0.01) and lower FEuric (ORs 2.08, 95%CI 1.35-3.33, p < 0.01) were associated with hyperuricemia significantly. Seven (6.3%) had gouty arthritis and nine (8%) had microscopic hematuria, one case being confirmed nephrolithiasis. The mean UUA excretion was 981.3 ± 335.0 mg/day and UUA hyperexcretion (> 700 mg/24 h) was found in 83.3%. UUA hyperexcretion patients had renal hyperfiltration 46%, glomerular dysfunction 84%, and tubular dysfunction 7.7%. From our study, hyperuricemia was found in approximately 40% of thalassemia patients but gouty arthritis occurred only in few patients (6%). This may be explained by urinary uric hyperexcretion which is found in over 80%. The significant risk factors for hyperuricemia were intact spleen and lower fraction excretion of uric acid.

FLT3, a prognostic biomarker for acute myeloid leukemia (AML): Quantitative monitoring with a simple anti-FLT3 interaction and flow cytometric method.

BACKGROUND: Overexpression of fms-like tyrosine kinase 3 (FLT3) protein in leukemia is highly related to poor prognosis and reduced survival rate in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients. Simple but efficient quantification of FLT3 protein levels on the leukemic cell surface using flow cytometry had been developed for rapid determination of FLT3 on intact cell surface. METHODS: Quantitation protocol for FLT3 biomarker in clinical samples was developed and validated. Cell model selection for calibration curve construction was identified and evaluated. Selected antibody concentrations, cell density, and incubation time were evaluated for most appropriate conditions. Comparison of the developed FLT3 determination protocol with the conventional Western blot analysis was performed. RESULTS: EoL-1 cell line was selected for using as positive control cells. Calibration curve (20%-120% of FLT3 positive cells) and quality control (QC) levels were constructed and evaluated. The results demonstrated good linearity (r2  > 0.99). The intra- and inter-day precision and accuracy, expressed as the coefficient of variation (%CV) and % recovery, were <20% and fell in 80%-120% in all cases. When compared with Western blotting results, FLT3 protein expression levels in leukemia patient's bone marrow samples were demonstrated in the same trend. CONCLUSIONS: The effective, reliable, rapid, and economical analytical technique using the developed flow cytometric method was demonstrated for FLT3 protein determination on leukemic cell surface. This method provided a practical analysis of FLT-3 biomarker levels which is valuable for physician decision in acute leukemia treatment.

PREVALENCE AND RISK FACTORS FOR CARDIAC IRON OVERLOAD AND CARDIOVASCULAR COMPLICATIONS AMONG PATIENTS WITH THALASSEMIA IN NORTHERN THAILAND.

Cardiovascular complications are the most common cause of death among thalassemia patients in Thailand. In this study, we evaluated the prevalence of cardiac iron overload, cardiovascular complications and the associated risk factors. The information obtained will serve as a guidance for surveillance, prevention and early treatment of the complications. We conducted a cross sectional study of Thai patients with thalassemia attending Chiang Mai University Hospital, Thailand. Cardiac T2* magnetic resonance imaging (CMR T2*) was used to evaluate the myocardial iron deposition and echocardiography was used to evaluate the cardiac function and to identify pulmonary hypertension. Ninety-one patients were included in the study; 64% females with a median age of 31 (16-75) years. Of the total study subjects, 49% had homozygous ß thalassemia, 32% had ß thalassemia/Hb E disease, and 19% had Hb H disease. Half the participants were transfusion-dependent and 84% had received iron chelation. The CMR T2* showed cardiac iron overload in 10 patients (11%). The maximum ferritin level in the previous 3 years was higher among the patients with cardiac iron overload (6,310 ng/ml) than among the patients without cardiac iron overload (3,352 ng/ml) (p=0.001). Twenty-one patients (23%) had cardiovascular complications. Cardiomyopathy was seen in 8% of patients [17% in patients with transfusion-dependent thalassemia (TDT) and none in patients with non-transfusion-dependent thalassemia (NTDT)] and pulmonary hypertension in 15% of patients (14% in patients with TDT and 16% in patients with NTDT). TDT and cardiac iron overload were significantly associated with cardiomyopathy. No risk factors were found to be significantly associated with pulmonary hypertension. In summary, cardiac iron overload and cardiomyopathy are important complications in TDT while pulmonary hypertension is seen in both TDT and NTDT. Iron chelation and monitoring of serum ferritin level will prevent cardiac iron overload and cardiomyopathy. Interval monitoring with echocardiography will help with early identification of the cardiac complications.