Phase 3 randomized COMMODORE 2 trial: Crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria naive to complement inhibition.

Crovalimab is a novel C5 complement inhibitor that enables rapid and sustained C5 inhibition with subcutaneous, low-volume self-administration every 4 weeks. COMMODORE 2 (NCT04434092) is a global, randomized, open-label, multicenter, phase 3 trial evaluating the non-inferiority of crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria not previously treated with C5 inhibition. C5 inhibitor-naive patients with lactate dehydrogenase (LDH) ≥2 × upper limit of normal (ULN) were randomized 2:1 to crovalimab or eculizumab. Co-primary efficacy endpoints were proportion of patients with hemolysis control (centrally assessed LDH ≤1.5 × ULN) and proportion with transfusion avoidance. Secondary efficacy endpoints were proportions of patients with breakthrough hemolysis, stabilized hemoglobin, and change in FACIT-Fatigue score. The primary treatment period was 24 weeks. Two hundred and four patients were randomized (135 crovalimab; 69 eculizumab). Crovalimab was non-inferior to eculizumab in the co-primary endpoints of hemolysis control (79.3% vs. 79.0%; odds ratio, 1.0 [95% CI, 0.6, 1.8]) and transfusion avoidance (65.7% vs. 68.1%; weighted difference, -2.8 [-15.7, 11.1]), and in the secondary efficacy endpoints of breakthrough hemolysis (10.4% vs. 14.5%; weighted difference, -3.9 [-14.8, 5.3]) and hemoglobin stabilization (63.4% vs. 60.9%; weighted difference, 2.2 [-11.4, 16.3]). A clinically meaningful improvement in FACIT-Fatigue score occurred in both arms. Complete terminal complement activity inhibition was generally maintained with crovalimab. The safety profiles of crovalimab and eculizumab were similar with no meningococcal infections. Most patients who switched from eculizumab to crovalimab after the primary treatment period preferred crovalimab. These data demonstrate the positive benefit-risk profile of crovalimab.

Germline HAVCR2 mutations and their relation to the clinical spectrum of subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis: results from a multicenter study and meta-analysis.

Germline HAVCR2 mutations are frequently detected in subcutaneous panniculitis-like T-cell lymphoma (SPTCL) patients with/without hemophagocytic lymphohistiocytosis (HLH) but factors associated with variable manifestations remain undetermined. To evaluate clinical variations and associated factors in SPTCL and/or HLH with/without HAVCR2 mutations, we performed direct sequencing of HAVCR2 exon 2 using DNA from patients with SPTCL or idiopathic HLH/HLH-like systemic illnesses, defined by HLH alone without secondary causes. The systematic review and individual patient data (IPD) level meta-analysis which included the present and previously published studies reporting HAVCR2 mutations in SPTCL with/without HLH populations was subsequently conducted using random-effects meta-analysis and multivariate logistic regression. Among 34 patients enrolled, ten of 28 SPTCL patients developed HLH/HLH-like systemic illnesses. Six cases with HAVCR2Y82C mutation manifested with HLH without panniculitis. Male sex (P=0.03) and age <18 years (P=0.04) were associated with HLH, corresponding to the inverse correlation between age and HLH-2004 score (r=-0.40; P=0.02). Homozygous HAVCR2Y82C mutation was more common in the presence of HLH compared with the absence (75.0% vs. 44.4%; P=0.02). Using IPD from the present and the other three eligible cohorts (N=127), male sex, heterozygous and homozygous/compound heterozygous HAVCR2 mutations were associated with HLH by the adjusted odds ratio of 2.93 (95% confidence interval [CI]: 1.22-7.06), 4.77 (95% CI: 1.05-21.63) and 8.48 (95% CI: 2.98-24.10), respectively. Patients with male sex and/or germline HAVCR2 mutations showed an increased risk of developing HLH. Younger patients tended to manifest with HLH, while older patients typically presented with SPTCL with less frequent HLH/HLH-like systemic illnesses.

How do we translate gaps and unmet needs of blood management for thalassemia into a collaborative implementation framework?

BACKGROUND AND OBJECTIVE: The mainstay of management for thalassemia is regular blood transfusions. However, gaps and unmet needs of blood services for thalassemia are still not clearly identified and addressed in Thailand, a country prevalent with thalassemia. What can be a collaborative implementation framework that helps advance practices and policies relating to blood management for thalassemia? METHODS: The first Blood & Beyond Roundtable Discussion was held in July 2022 to gather the current situation, gaps, and unmet needs of blood services for thalassemia from multidisciplinary experts and thalassemic patients. The Implementation Guide as suggested by the Centre for Effective Services was applied as a tool to consolidate information from the discussions and construct the collaborative implementation framework. RESULTS: The National Blood Center and hospitals in Thailand followed the missions specified in the National Blood Policy and the standard guidelines to ensure the best practice of blood management for thalassemia. However, there were six gaps and unmet needs identified from the discussions. After all discussion points were mapped onto the framework, an implementation plan comprised of five specific activities became clear and actionable. CONCLUSION: Without the complete information from both experts and patients, the implementation plan would not have been successfully constructed. The method that we employed to translate all information into the framework can be adapted by other countries to develop their own specific framework efficiently.

Viscoelastometric versus standard coagulation tests to guide periprocedural transfusion in adults with cirrhosis: A meta-analysis of randomized controlled trials.

BACKGROUND AND OBJECTIVES: Due to rebalanced haemostasis in cirrhosis, viscoelastometric testing (VET) is more accurate than standard coagulation tests (SCTs) in preprocedural haemostatic evaluation, resulting in decreased unnecessary transfusion. We aimed to determine the impact of VET-guided strategy on postprocedural bleeding, periprocedural transfusion rates and quantities, transfusion-related adverse events (TRAEs), lengths of stay (LOS) and mortality from randomized controlled trials (RCTs) of cirrhotic patients. METHODS: PubMed and EMBASE were searched for RCTs comparing VET-guided with SCT-guided transfusion in cirrhotic adults undergoing esophagogastroduodenoscopy, liver transplantation or other invasive interventions. Using random-effects models, the pooled risk ratios (RRs) and/or mean differences (MDs) of postprocedural bleeding-free events and the other outcomes were estimated alongside 95% confidence intervals (CIs). RESULTS: Of seven included RCTs (n = 421; 72.2% men; mean age 49.1 years), VET-guided transfusion did not change postprocedural bleeding-free statuses (RR 1.05; 95% CI 0.94-1.17). However, VET-based algorithms decreased the rates of fresh frozen plasma (FFP; RR 0.52; 95% CI 0.35-0.77) and platelet transfusions (RR 0.34; 95% CI 0.16-0.73), the quantities of transfused FFP (MD -1.39 units; 95% CI -2.18 to -0.60), platelets (MD -1.06 units; 95% CI -2.01 to -0.12) and cryoprecipitate (MD -7.13 units; 95% CI -14.20 to -0.07) and the risk of TRAEs (RR 0.42; 95% CI 0.27-0.65). The overall mortality rates and LOS were not significantly different between two groups. CONCLUSION: Compared with conventional SCT-guided, VET-guided strategy decreases periprocedural plasma and platelet transfusions and TRAEs, without increasing haemorrhagic complications, LOS or mortality in cirrhosis.

Expression of Programmed Cell Death-1 and Programmed Cell Death Ligands in Nodal Peripheral T-Cell Lymphoma: Expression Pattern and Potential Prognostic Relevance.

Programmed cell death (PD)/PD-ligands (PD-Ls) pathway plays an important role in the regulation of physiologic immune response. Several cancers, including lymphoma exhibit abnormal PD-1/PD-Ls expression, which may contribute to treatment failure, progression, and inferior outcomes. PD-1/PD-Ls expression has predominantly been described in B-cell lymphoma; such data in peripheral T-cell lymphoma (PTCL) is limited. We described PD-1/PD-Ls expression patterns and associations with clinical characteristics and outcomes, in patients with systemic PTCLs. Correlation between PD-1/PD-Ls expression and outcomes was analyzed in patients who received lymphoma-specific therapy. PD-1/PD-Ls expression was observed across all common PTCL histologies at different proportions (PD-1 0%-76.9%, PD-L1 38.5%-62.5%, and PD-L2 62.5%-100%) with PD-1 being highly expressed in angioimmunoblastic T-cell lymphoma. Baseline characteristics were comparable between PD-1/PD-Ls expression status. Of 47 patients who received lymphoma-specific therapy, outcomes were similar across all PD-L1/PD-L2 subgroups. In the Cox proportional hazard analysis, treatment response was the only factor associated with survival outcomes. However, PD-1/PD-Ls expression, either in lymphoma or stroma, was not a predictor for survival outcomes. In conclusion, differential PD-1/PD-Ls expressions were observed among various histological PTCL subtypes. In this study, we were unable to demonstrate an association between PD-1/PD-Ls expression, clinical characteristics, treatment response, and outcomes of PTCL patients.

Mutated JAK2 signal transduction in human induced pluripotent stem cell (iPSC)-derived megakaryocytes.

Janus kinase 2 (JAK2) gene mutations are the main drivers for polycythemia vera (PV) and essential thrombocythemia (ET). The mechanisms of single altered gene causing two different diseases are unclear. Additionally, novel treatments specifically targeting mutated JAK2 proteins are needed. In this study, the induced pluripotent stem cells (iPSCs) were virally transduced to express wild-type JAK2 (JAK2WT), JAK2p.V617F (JAK2V617F) or JAK2p.N542_E543del (JAK2exon12) under a doxycycline-inducible system. The modified iPSCs which were differentiated into megakaryocytes in the presence vs. absence of doxycycline were compared to ensure that the differences were solely from mutated JAK2 expressions. The JAK2V617-expressing iPSCs yielded significantly higher numbers of megakaryocytes consistent with the ET phenotype, while there was no enhancement by JAK2exon12 expression compatible with the pure erythrocytosis in humans. Capillary Western analyses revealed significantly greater JAK2 phosphorylation in iPSCs carrying JAK2V617F but not in JAK2WT and JAK2exon12 iPSCs. Activation of STAT3, STAT5 and AKT was increased by JAK2V617F, while they were decreased in JAK2exon12 iPSCs. Notably, interferon alpha and/or arsenic trioxide inhibited megakaryocytes proliferation and reduced JAK2, STAT3, STAT5 and AKT phosphorylation in mutant JAK2-expressing iPSCs compared with those without induction. In conclusion, JAK2V617F expression in iPSCs preferentially promoted megakaryocytes with a signaling profile distinctive from JAK2exon12 expression. Treatments with interferon alpha or arsenic trioxide preferentially suppressed the mutated over wild-type JAK2 signaling. This iPSC model is helpful in mechanistic studies and novel therapy screen for myeloproliferative neoplasm.

Randomised controlled trial of glucose-6-phosphate dehydrogenase deficient versus non-deficient red blood cell transfusion in patients with hypoproliferative anaemia.

BACKGROUND: Recent studies revealed the glucose-6-phosphate dehydrogenase (G-6-PD) deficiency prevalence of 7.7-10% among Thai blood donors. Transfusion of red blood cells (RBCs) from these subjects potentially causes haemolysis in recipients. METHODS: RBC units from the National Blood Centre were sampled to assess G-6-PD levels using spectrophotometry. Patients with pure underproduction anaemia requiring blood transfusion were randomised to receive G-6-PD-deficient versus normal ABO-matched RBCs. Pre- and 48-h post-transfusion indirect bilirubin, haemoglobin, haematocrit, lactate dehydrogenase (LDH) and haptoglobin were measured. RESULTS: From April 2020 to March 2021, 374 RBC units were tested for G-6-PD, and that 25 were found to be G-6-PD deficient. Twelve units of G-6-PD-deficient RBCs and 14 units of normal RBCs were given to patients who met the inclusion criteria. The median (interquartile range) increases of indirect bilirubin in G-6-PD-deficient (N = 11) versus normal RBCs (N = 13) were + 0.12 (0.27) versus + 0.01 (1.3) mg/dl, p = 0.030), respectively. The median increases of haemoglobin were 1.00 (0.50) versus + 0.80 (0.95), p = 0.910, respectively. The increases in haematocrit were 2.59 (1.9) versus 2.29 (2.1), p = 0.733, respectively. There were no significant differences in changes of LDH and haptoglobin levels and no transfusion reactions. DISCUSSION: G-6-PD-deficient packed red cells were associated with mildly elevated indirect bilirubin after transfusion, but there was no observed clinical symptoms.

Thrombosis with thrombocytopenia after the second ChAdOx1 nCoV-19 vaccination: A possible immunological mechanism independent of anti-platelet factor 4 antibody.

BACKGROUND: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a distinctive syndrome characterized by unusual site thrombosis accompanied by thrombocytopenia following adenoviral vector vaccines against severe acute respiratory syndrome coronavirus 2. Platelet-activating anti-platelet factor 4-dependent antibodies (anti-PF4 Abs) have been identified as pathogenic antibodies in almost all patients. OBJECTIVE: We proposed an immunological mechanism of VITT independent of anti-PF4 Abs. METHODS: Case report. RESULTS: A 68-year-old Thai woman developed pulmonary embolism and deep vein thrombosis with thrombocytopenia one week after the second ChAdOx1 nCoV-19 vaccination with undetectable anti-PF4 Abs. The platelet count responded rapidly to intravenous immunoglobulin and steroids. Therefore, the high clinical suspicion is essential for early recognition and prompt management irrespective of anti-PF4 Ab results. CONCLUSIONS: We hypothesize that platelet and endothelial activation following ChAdOx1 nCoV-19 vaccination may lead to generation of pathogenic antibodies which account for VITT independent of anti-PF4 Abs.

Adult aplastic anemia in Thailand: incidence and treatment outcome from a prospective nationwide population-based study.

The incidence and outcomes of aplastic anemia (AA) in Asia remain limited. This study aimed to explore the incidence and outcomes of patients with adult AA across the country of Thailand. This is a prospective multi-center nationwide population-based observational study of AA patients aged at least 15 years old, diagnosed from August 2014 to July 2016, with a longitudinal follow-up period over 2 years. There were 348 newly diagnosed adult AA patients during the enrollment period, giving an annual incidence of 4.6 per million. The incidence of severe (SAA) and very severe aplastic anemia (VSAA) (3.8 per million) was higher than non-severe AA (NSAA, 0.8 per million). The peak incidence was observed in the patients aged from 80 to 89 years old (14.4 per million). The 2-year overall survival (OS) in NSAA, SAA, and VSAA were 65.5%, 49.3%, and 20.1%, respectively (P < 0.001). With regard to the response to immunosuppressive therapy, the overall response rate (ORR) in SAA/VSAA treated with rabbit anti-thymocyte globulin with/without cyclosporin A (rATG ± CsA) were significantly superior to those treated with CsA alone, or anabolic steroids (44.4% vs 36.4% and 31.2%, respectively, P < 0.001). The 2-year OS in SAA/VSAA treated with rATG ± CsA, CsA, and anabolic steroids were 54.8%, 54.5%, and 37.6% (P = 0.037), respectively. The incidence of adult AA in Thailand is higher than those in Western countries, and the peak incidence is in the elderly. rATG ± CsA provided a better response than anabolic steroids, translating to the superior survival in SAA/VSAA treated with rATG ± CsA.

Thromboembolic and hemorrhagic risks after vaccination against SARS-CoV-2: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Thromboembolic and bleeding events after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are major public concerns leading to vaccine hesitancy. Due to low incidence, an individual randomized controlled trial (RCT) is underpowered to determine whether SARS-CoV-2 vaccines increase the risks of thromboembolism and hemorrhage. METHODS: We performed a literature search using PubMed, EMBASE, Cochrane, medRxiv databases, and reference lists of relevant articles to identify RCTs that reported thromboembolic, hemorrhagic events, and thromboembolism/hemorrhage-related death after SARS-CoV-2 vaccination. The primary aim of this systematic review and meta-analysis was to estimate the pooled thromboembolic risk related to SARS-CoV-2 vaccines compared to placebo. The secondary outcomes included estimating the risks of arterial thromboembolism (ATE), venous thromboembolisms (VTE), hemorrhage, thrombocytopenia, and thromboembolism/hemorrhage-related death. RESULTS: Eight RCTs of 4 vaccine platforms comprised of 195,196 participants were retrieved. SARS-CoV-2 vaccines were not associated with an increased risk of overall thromboembolism (risk ratio [RR], 1.14; 95% CI [confidence interval], 0.61-2.14; I2 = 35%), ATE (RR, 0.97; 95% CI, 0.46-2.06; I2 = 21%), VTE (RR, 1.47; 95% CI, 0.72-2.99; I2 = 0%), hemorrhage (RR, 0.97; 95% CI, 0.35-2.68; I2 = 0), and thromboembolism/hemorrhage-related death (RR, 0.53; 95% CI, 0.16-1.79; I2 = 0). Compared to the baseline estimated risk of these outcomes in participants administered placebos, the risk differences with vaccines were very small and not statistically significant. These findings were consistent in the subgroup analysis across 4 vaccine platforms. CONCLUSION: Vaccines against SARS-CoV-2 are not associated with an increased risk of thromboembolism, hemorrhage, and thromboembolism/hemorrhage-related death.

Regulation of platelet numbers and sizes by signaling pathways.

Either the glycoprotein (GP) Ib deficiency or hyper-function in humans can cause macrothrombocytopenia, the molecular mechanisms of which remain unclear. Herein, the investigations for disease pathogenesis were performed in the human induced pluripotent stem cell (hiPSC) model. The hiPSCs carrying a gain-of-function GP1BA p.M255V mutation which was described in platelet-type von Willebrand disease (PT-VWD) were generated using CRISPR/Cas9. The GP1BA-null hiPSCs were previously derived from a Bernard-Soulier syndrome (BSS) patient. After full megakaryocyte differentiation in culture, both hiPSC mutations showed large proplatelet tips under fluorescence microscopy and yielded fewer but larger platelets compared with those of wild-type cells. The Capillary Western analyses revealed the lower ERK1/2 activation and higher MLC2 (Myosin light chain 2) phosphorylation in megakaryocytes with mutated GPIb. Adding a mitogen-activated protein kinase (MAPK) pathway inhibitor to wild-type hiPSCs recapitulated the phenotypes of GPIb mutations and increased MLC2 phosphorylation. Notably, a ROCK inhibitor which could inhibit MLC2 phosphorylation rescued the macrothrombocytopenia phenotypes of both GPIb alterations and wild-type hiPSCs with a MAPK inhibitor. In conclusion, the genetically modified hiPSCs can be used to model disorders of proplatelet formation. Both loss- and gain-of-function GPIb reduced MAPK/ERK activation but enhanced ROCK/MLC2 phosphorylation resulting in dysregulated platelet generation.

High B-cell activating factor levels in multi-transfused thalassemia patients.

OBJECTIVES: To assess the associations between B-cell activating factor (BAFF) and alloimmunisation in multi-transfused thalassemia. BACKGROUND: Red blood cell (RBC) alloimmunisation is a complication of multi-transfused thalassemia. BAFF is promoting B cells that produce alloantibodies. METHODS/MATERIALS: Multi-transfused thalassemia, 15 years or older, were recruited in the cohort study. Alloantibodies and BAFF levels were analysed. RESULTS: Of 114 patients, the overall prevalence of RBC alloimmunisation was 29.8%. The most common alloantibodies were anti-E, anti-Mia and anti-c. BAFF levels were different among the three groups; the patients with baseline alloantibodies (median ± interquartile range 1251 ± 474 pg/ml), without alloantibodies (1098 ± 453) and healthy controls (719 ± 306), p < 0.001. The BAFF level was elevated in the >25 years old patients (vs. the <25, p = 0.011) and the buffy-coat-reduced blood recipients (vs. the pre-storage leukocyte-depletion, p = 0.005). Absolute lymphocyte count was higher in the patients without baseline alloantibodies (vs. with baseline alloantibodies, p = 0.049) and the splenectomised patients (vs. the non-splenectomised patients, p < 0.001). Of the 72 patients without baseline antibodies, four who developed new antibodies showed no statistically different BAFF levels compared with those without new antibodies after 40-month follow-up (1296 ± 734 vs. 1062 ± 460, p = 0.491). In multivariate analysis, BAFF to absolute lymphocyte ratio was independently associated with RBC alloimmunisation (odds ratio 3.07, 95% confidence interval 1.124-8.369, p = 0.029). CONCLUSION: B-cell activating factor (BAFF) levels were elevated in multi-transfused thalassemia and the BAFF to absolute lymphocyte ratio was associated with red blood cell (RBC) alloimmunisation.

Inhibitory Mechanisms of Lusianthridin on Human Platelet Aggregation.

Lusianthridin is a phenanthrene derivative isolated from Dendrobium venustum. Some phenanthrene compounds have antiplatelet aggregation activities via undefined pathways. This study aims to determine the inhibitory effects and potential mechanisms of lusianthridin on platelet aggregation. The results indicated that lusianthridin inhibited arachidonic acid, collagen, and adenosine diphosphate (ADP)-stimulated platelet aggregation (IC50 of 0.02 ± 0.001 mM, 0.14 ± 0.018 mM, and 0.22 ± 0.046 mM, respectively). Lusianthridin also increased the delaying time of arachidonic acid-stimulated and the lag time of collagen-stimulated and showed a more selective effect on the secondary wave of ADP-stimulated aggregations. Molecular docking studies revealed that lusianthridin bound to the entrance site of the cyclooxygenase-1 (COX-1) enzyme and probably the active region of the cyclooxygenase-2 (COX-2) enzyme. In addition, lusianthridin showed inhibitory effects on both COX-1 and COX-2 enzymatic activities (IC50 value of 10.81 ± 1.12 µM and 0.17 ± 1.62 µM, respectively). Furthermore, lusianthridin significantly inhibited ADP-induced suppression of cAMP formation in platelets at 0.4 mM concentration (p < 0.05). These findings suggested that possible mechanisms of lusianthridin on the antiplatelet effects might act via arachidonic acid-thromboxane and adenylate cyclase pathways.

Causes and outcomes of hypereosinophilia in a tropical country.

BACKGROUND: Hypereosinophilia (HE), defined by blood eosinophils > 1.5 ? 109/L persisting over one month, is commonly found in clinical practice. OBJECTIVE: This study aimed to explore etiologies, clinical characteristics, and outcome of HE. METHODS: The HE patients from a single center in Thailand during 2014-2019 were retrospectively reviewed. RESULTS: Among 166 HE patients, 102 (61.5%) cases had reactive HE (HER) of which 52% was due to parasitic infestations. Two-thirds of these patients were diagnosed based on the patients' response to empirical anti-parasite therapy. Without secondary causes, eosinophil-related symptoms were found in 20 (12.0%) patients (Hypereosinophilic syndrome: HES) of which three of them had myeloid neoplasms (HESN) and one case had lymphocytic variant HES (L-HES). Among 11 of 16 idiopathic HES (HESI) patients who were treated with systemic steroid, nine (81.8%) patients responded well, and two cases obtained symptom improvement with stable eosinophilia. There was 44 (26.5%) asymptomatic HE of undetermined significance (HEUS) and 37 (84.1%) of them had HE for more than 6 months before diagnosis. Marked eosinophilia (> 10 ? 109/L) was more common in HES (37.5%), but it was also found in HER (16.7%) and HEUS (11.4%). During the median follow-up period of 16 months, 82.9% (34/41) of HEUS cases remained asymptomatic while seven (17.1%) patients spontaneously recovered. CONCLUSIONS: A therapeutic trial of anti-parasite is reasonable for asymptomatic HE in tropical countries. Most HESI responded to systemic corticosteroids and HEUS showed benign courses without therapy.

Antiplatelet activity of deferiprone through cyclooxygenase-1 inhibition.

Thalassemia patients are susceptible to both iron overload and thromboembolism. Deferiprone is an iron chelator that shows an antiplatelet activity and thus may alleviate platelet hyperactivation in thalassemia. Therefore, this study aimed to characterize the inhibitory effects and mechanisms of deferiprone on normal human platelets. The results illustrated that deferiprone inhibited platelet aggregation at the iron chelating concentrations (0.08-0.25 mmol/l). Deferiprone inhibited human platelet aggregation stimulated by arachidonic acid and ADP more potently than epinephrine and collagen, with the IC50 of 0.24 mmol/l and 0.25 mmol/l vs. 3.36 mmol/l and 3.73 mmol/l, respectively. Interestingly, deferiprone significantly inhibited COX-1 activity, with the IC50 of 0.33 mmol/l, and slightly increased cAMP level at the high concentration of 4 mmol/l. Moreover, the results from molecular docking showed that deferiprone interacted closely with key residues in the peroxidase active site of COX-1. These results suggested that deferiprone possessed antiplatelet activity mainly through the inhibition of COX-1 activity.

Clinical impacts of DNA-based typing and provision of antigen-matched red blood cell units for chronically transfused patients with thalassemia.

CONCLUSIONS: Blood transfusion, the main therapy for patients with severe thalassemia, is challenged by alloantibodies that can lead to hemolytic transfusion reactions. The use of prophylactic antigen-matched units is recommended, but serologic typing, before the first transfusion, is rarely performed and is not reliable after chronic transfusion. Patient DNA-based typing is a promising strategy, but clinical outcome data are lacking. The aim of this study was to determine the benefits of antigenmatched transfusion guided by DNA-based typing in terms of new alloantibody formation and increases in mean pretransfusion hemoglobin (Hb) levels. We performed DNA-based typing on samples from 24 transfusion-dependent patients with thalassemia who had no serologic phenotyping performed before the first transfusion. These patients were then transfused with antigen-matched donor RBC units that were typed serologically. New alloantibody formation and mean pre-transfusion Hb levels were evaluated after implementing this extended common antigen-matching transfusion protocol. Sixty-three percent of the patients in this study were diagnosed as having beta-thalassemia Hb E. Alloantibodies were already present in 87.5 percent (21/24) of these patients, and most of these antibodies were multiple and/ or unidentified. After the enrollment, there were 717 transfusion episodes comprising 1209 RBC units. The number of RBC units transfused to each patient ranged from 22 to 119 units. At the median duration of 25.5 months (range 10-34 months), no new alloantibodies were detected since the beginning of the protocol. Seventy-four transfusion episodes in six patients were crossmatch-positive due to autoantibodies (patients 2, 4, 8, 9, and 14) or anti-Chido (patient 18) that had been identified before the study. There were no hemolytic transfusion reactions in this study. Five patients (patients 1, 2, 12, 15, and 20) showed increased mean pre-transfusion Hb levels (≥1 g/dL) and one patient (patient 16) had longer intervals between transfusions (compared with those before the protocol), suggesting longer RBC survival, although there was no statistical difference in the whole group. Our study highlights the benefits of DNA-based typing in chronically transfused patients with thalassemia who had no phenotyping data before the first transfusion. Patient DNA-based typing for antigen-matched transfusion is safe in thalassemia and allows us to obtain better-matched blood units for complicated patients.

Thrombosis and Bleeding Risk Scores Are Strongly Associated with Mortality in Hospitalized Patients with COVID-19: A Multicenter Cohort Study.

Background: Internationally established guidelines mention pharmacological prophylaxis for all hospitalized COVID-19 patients. However, there are concerns regarding the efficacy and safety of anticoagulants. This study investigated the associations between thrombosis/bleeding risk scores and clinical outcomes. Methods: We conducted a retrospective review of adult patients admitted to two hospitals between 2021 and 2022. We analyzed clinical data, laboratory results, low molecular weight heparin (LMWH) use, thrombosis, bleeding, and 30-day survival. Results: Of the 160 patients, 69.4% were female, and the median age was 59 years. The rates of thrombotic complications and mortality were 12.5% and 36.3%, respectively. LMWH prophylaxis was administered to 73 of the patients (45.6%). The patients with high Padua prediction scores (PPS) and high IMPROVEVTE scores had a significantly higher risk of venous thromboembolism (VTE) compared to those with low scores (30.8% vs. 9.0%, p = 0.006 and 25.6% vs. 7.7%, p = 0.006). Similarly, elevated IMPROVEVTE and IMPROVEBRS scores were associated with increased mortality (hazard ratios of 7.49 and 6.27, respectively; p < 0.001). Interestingly, LMWH use was not associated with a decreased incidence of VTE when stratified by risk groups. Conclusions: this study suggests that COVID-19 patients with high thrombosis and bleeding risk scores have a higher mortality rate.

Prevalence and clinical outcomes of germline variants among patients with myeloid neoplasms.

AIMS: Myeloid neoplasms (MNs) with germline predisposition have been recognised as a distinct entity. Emerging evidence suggests that sporadic myelodysplastic syndromes may also harbour undetected germline predispositions. We investigated germline alterations in a cohort of 122 adult Thai MNs. METHODS: MN patients were recruited and tested for germline variants using deep targeted next-generation sequencing. The germline variant was filtered using American College of Medical Genetics classifications and then evaluated for the association with clinical characteristics and outcomes. RESULTS: Our findings revealed pathogenic/likely pathogenic germline alterations in 12 (10%) of the patients. These germline lesions were commonly found in the DNA damage response pathway (n=6, 50%). We also identified novel deleterious FANCA A1219GfsTer59 variants in two patients diagnosed with secondary acute myeloid leukaemia (sAML) from aplastic anaemia and AML with myelodysplasia related. Among sAML, individuals with germline mutations had inferior overall survival compared with those with wild-type alleles (2 months vs 12 months) with HR 4.7 (95% CI 1.0 to 20), p=0.037. Therefore, the presence of pathogenic or likely pathogenic mutations may be linked to inferior survival outcomes. CONCLUSIONS: Our study highlighted that the prevalence of germline predisposition in Southeast Asian populations is comparable to that in Caucasians. This underscores the importance of germline genetic testing within the Asian population.