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Objectives: A sensitive screening for the coexistence of α0-thalassemia and the hemoglobin E (Hb E) trait is important to identify at-risk couples for hydrops fetalis. However, previous cutoff valu...

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.

We reported three cases of immune thrombocytopenia (ITP) that developed within 6 weeks after ChAdOx1 nCoV-19 vaccination. Antiplatelet factor 4 antibodies were undetectable in all three cases. Therefore, vaccine-induced immune thrombotic thrombocytopenia was very unlikely. Other potential causes of thrombocytopenia were excluded. Their clinical presentations, severity of thrombocytopenia and outcomes were varied. Only one ITP case, an 80-year-old man, received ITP treatments and achieved complete response after 2 weeks of eltrombopag. An 84-year-old man had spontaneous complete remission, and a 55-year-old woman had partial platelet recovery without ITP treatments. Among 107 720 Thais administered the ChAdOx1 vaccine between 16 March and 10 May 2021, these three ITP cases resulted in an estimated risk of ITP of at least one per 36 000 doses, which was approximately similar to the risk of ITP after measles-mumps-rubella immunization. This raises the concern of an increased risk of ITP after ChAdOx1 vaccination.

Pulmonary hypertension (PH) is the commonest cardiac complication in β-thalassemia intermedia, including β-thalassemia/hemoglobin E (β-thal/HbE), and is strongly associated with splenectomy. We aimed to define the prevalence and comprehensively explore mechanisms of PH in β-thal/HbE patients receiving regular transfusion and iron chelation, which were reported to alleviate PH.β-Thal/HbE patients receiving regular transfusion and iron chelation over one year were enrolled. Patients at risk for PH were defined by tricuspid-regurgitant-jet-velocity (TRV) ≥ 2.5 m/s. Laboratory and echocardiographic variables were compared with healthy controls.There were 68 β-thal/HbE, including 31 (45.6%) splenectomized patients, and 38 controls included for analysis. PH was detected in 29 β-thal/HbE (42.6%). β-Thal/HbE with PH had a significant reduction in nitric oxide metabolites (NOx) but elevations in thrombin-antithrombin (TAT) complex, soluble thrombomodulin (sTM), endothelin-1 (ET-1) and flow-mediated dilation (FMD) values compared to those without PH (all, p 0.05). TRV was significantly correlated with NOx, TAT, sTM, ET-1 and FMD values (r = -0.514, r = 0.281, r = 0.313, r = 0.245 and r = -0.474; all p 0.05). Erythropoietic activity, serum ferritin, circulating total tissue factor (TF) antigen, microparticle-associated TF activity, microparticle's procoagulant activity and soluble p-selectin levels were not different between PH and non-PH subgroups. Notably, there were no significant associations between splenectomy and PH.PH remains prevalent in β-thal/HbE patients receiving long-term transfusion and iron chelation. PH is not associated with splenectomy status but correlated with NO depletion, TF-independent hypercoagulability and endothelial perturbation.

The disease burden of AF is greater in Asia-Pacific than other areas of the world. Direct oral anticoagulants (DOACs) have emerged as effective alternatives to vitamin K antagonists (VKA) for preventing thromboembolic events in patients with AF. The Asian Pacific Society of Cardiology developed this consensus statement to guide physicians in the management of AF in Asian populations. Statements were developed by an expert consensus panel who reviewed the available data from patients in Asia-Pacific. Consensus statements were developed then put to an online vote. The resulting 17 statements provide guidance on the assessment of stroke risk of AF patients in the region, the appropriate use of DOACs in these patients, as well as the concomitant use of DOACs and antiplatelets, and the transition to DOACs from VKAs and vice versa. The periprocedural management of patients on DOAC therapy and the management of patients with bleeding while on DOACs are also discussed. ispartof: EUROPEAN CARDIOLOGY REVIEW vol:16 ispartof: location:England status: published

Heparin thromboprophylaxis is routinely administered during hospitalization for COVID-19. Because of the immune stimulation related to COVID-19, there is ongoing concern regarding a heightened incidence of heparin-induced thrombocytopenia (HIT). We performed a literature search using PubMed, EMBASE, Cochrane, and medRxiv database to identify studies that reported clinical and laboratory characteristics and/or the incidence of HIT in patients with COVID-19. The primary aim was to systematically review the clinical features and outcomes of patients with COVID-19 with confirmed HIT. The secondary objective was to perform a meta-analysis to estimate the incidence of HIT in hospitalized patients with COVID-19. A meta-analysis of 7 studies including 5849 patients revealed the pooled incidence of HIT in COVID-19 of 0.8% (95% confidence interval [CI], 0.2%-3.2%; I2 = 89%). The estimated incidences were 1.2% (95% CI, 0.3%-3.9%; I2 = 65%) vs 0.1% (95% CI, 0.0%-0.4%; I2 = 0%) in therapeutic vs prophylactic heparin subgroups, respectively. The pooled incidences of HIT were higher in critically ill patients with COVID-19 (2.2%; 95% CI, 0.6%-8.3%; I2 = 72.5%) compared with noncritically ill patients (0.1%; 95% CI, 0.0%-0.4%: I2 = 0%). There were 19 cases of confirmed HIT and 1 with autoimmune HIT for clinical and laboratory characterization. The median time from heparin initiation to HIT diagnosis was 13.5 days (interquartile range, 10.75-16.25 days). Twelve (63%) developed thromboembolism after heparin therapy. In conclusion, the incidence of HIT in patients with COVID-19 was comparable to patients without COVID-19, with higher incidences with therapeutic anticoagulation and in critically ill patients.

Hypercoagulability in coronavirus disease 2019 (COVID-19) may aggravate disease severity during hospitalization but the reported survival benefits from anticoagulation (AC) vary among studies. We performed a literature research to estimate pooled odds ratios (ORs) of in-hospital mortality and major bleeding comparing among intermediate-to-therapeutic dose AC, prophylactic dose AC, and no AC. Until October 22, 2020, PubMed, EMBASE, and Cochrane Library Database were searched for studies reporting AC utilization and mortality in COVID-19. Studies with suspected risk of bias were excluded before the synthesis of pooled ORs with 95% confidence intervals (CIs) using random-effects models. Of 37 identified studies (N = 19,510), 17 (N = 17,833) were aggregated in the meta-analysis. The overall mortality rate was 23.1% (95% CI 18.7-28.2). The pooled odds of mortality comparing anticoagulated to non-anticoagulated patients were similar, but lower in prophylactic dose AC group (OR 0.83; 95% CI 0.73-0.95). Notably, intermediate-to-therapeutic dose AC increased mortality (OR 1.60; 95% CI 1.11-2.31) and major bleeding compared to prophylactic dose AC (OR 3.33; 95% CI 2.34-4.72). Our findings support the optimal efficacy and safety profiles of prophylactic dose AC in hospitalized COVID-19 patients.

Coagulation activation has been reported in several cohorts of patients Coronavirus Disease 2019 (COVID-19). However, the true burden of systemic coagulopathy in COVID-19 remains unknown. In this systematic review and meta-analysis, we performed a literature search using PubMed, EMBASE, and Cochrane Database to identify studies that reported the prevalence of systemic coagulopathy using established criteria in patients with COVID-19. The primary outcome was the prevalence of systemic coagulopathy (disseminated intravascular coagulation [DIC] and/or sepsis-induced coagulopathy [SIC]). Pooled prevalences and 95% confidence intervals [CIs] were calculated using random-effects model. A total of 5 studies including 1210 patients with confirmed COVID-19 were included. The pooled prevalence of systemic coagulopathy was 7.1% (95%CI: 3.2%,15.3%, I2 = 93%). The pooled prevalence of DIC (N = 721) and SIC (N = 639) were 4.3% (95%CI 1.7%, 10.4%, I2 = 84%) and 16.2% (95%CI: 9.3%, 26.8%, I2 = 74%), respectively. Only 2 studies reported the prevalence of elevated D-dimer levels with the pooled prevalence of 84.6% (95%CI: 52.0%,96.5%, I2 = 94%). Average D-dimer and fibrinogen levels were remarkably increased, while platelet counts, PT, and aPTT ratios were minimally affected in COVID-19. The estimated prevalence of systemic coagulopathy in patients with COVID-19 was low despite D-dimer elevation in most patients. Relatively low systemic coagulopathy in COVID-19 may contribute to the high incidence of thrombosis rather than bleeding in patients with COVID-19.

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.

Background Vaccine‐induced immune thrombotic thrombocytopenia (VITT) is a rare distinctive syndrome characterized by unusual site thrombosis accompanied by thrombocytopenia after ChAdOx1 nCoV‐19 vaccination. Platelet‐activating anti–platelet factor 4–dependent antibodies (anti‐PF4 Abs) were detected in most cases of VITT. To date, data from Asian countries are lacking. Objectives To determine the prevalence of thrombocytopenia, anti‐PF4 Abs, and D‐dimer elevation in Thai people administered the ChAdOx1 vaccine. Patients/Methods A total of 521 vaccinated and 146 nonvaccinated subjects were enrolled. Blood samples were collected to determine platelet counts, anti‐PF4 Abs using ELISA and D‐dimer levels 5 to 30 days after the first vaccination. Results None of the participants developed thrombocytopenia or had significantly decreased platelet counts from baseline after ChAdOx1 vaccination. The frequencies of anti‐PF4 Abs between vaccinated (16/521; 3.1%; 95% confidence interval [CI], 1.8‐4.9) and nonvaccinated Thai people (6/146; 4.1%; 95% CI, 1.5‐8.7) were similar. None of the detectable anti‐PF4 Abs activated platelets in vitro. The average D‐dimer levels between vaccinated and control groups were similar (282.2 ± 286.3 vs 267.8 ± 219.3 ng/mL; P = 0.58). Four vaccinated and one nonvaccinated participants had markedly elevated D‐dimer levels >2000 ng/mL without detectable anti‐PF4 Abs. Imaging studies of these asymptomatic subjects revealed incidental pulmonary embolism in a vaccinated elderly woman. Conclusions This study demonstrated a low prevalence of thrombocytopenia and pathogenic anti‐PF4 Abs after ChAdOx1 vaccination. D‐dimer testing revealed no significant coagulation activation. Routine tests for platelet counts, anti‐PF4 Abs, and D‐dimer levels are not recommended for VITT screening without clinical suspicion.

Purpose To report a case of daratumumab-induced bilateral angle closure glaucoma and myopia that showed no recurrence after repeated drug administration with prophylactic cycloplegia. Observations A 63-year-old man with relapsing multiple myeloma presented with acute bilateral eye pain and blurred vision 14 hours after first daratumumab infusion. Eye examination revealed raised intraocular pressure and shallow anterior chamber. Anterior segment ocular coherence tomography and ultrasound biomicroscopy showed ciliochoroidal effusions in both eyes. The diagnosis of bilateral acute angle closure glaucoma and induced myopia was made. Cycloplegia- and intraocular-pressure-lowering medications were given, which gradually deepened the anterior chambers and normalized intraocular pressure and refraction. The ciliochoroidal effusions completely resolved on day 14. The cycloplegic was given as a premedication for subsequent infusions. There was no recurrence of effusion throughout his 6-month daratumumab treatment course. Conclusions and importance Daratumumab can induce ciliochoroidal effusion, which results in acute secondary angle closure and myopia. The potential prophylactic effect of the cycloplegic drug may enable continuation of daratumumab infusion under close monitoring.

Mechanisms of vascular disorders in β-thalassemia/HbE patients remain poorly understood. In the present study, we aimed to determine the presence of endothelial dysfunction and its association with altered vascular mediators in this population. Forty-three β-thalassemia/HbE patients without clinically documented vascular symptoms and 43 age–sex-matched healthy controls were enrolled. Endothelial function was assessed using flow-mediated dilatation (FMD) before and after administration of nitroglycerine (NTG). β-Thalassemia/HbE patients showed a significant endothelial dysfunction using FMD. The percentage change in the brachial artery diameter before NTG was significantly lower in the thalassemia group compared to the control (5.0 ± 5.9 vs. 9.0 ± 4.0%, p

Correlations between bleeding symptoms and von Willebrand factor (VWF) levels may help to predict hemorrhagic severity in the Westerners with von Willebrand disease (VWD), but data in Asians are lacking. In this study, Thai patients with VWF levels

Objectives: The outcomes of primary central nervous system lymphoma (PCNSL) are much improved with multi-modality regimens. Unfortunately, in limited-resource countries, chemo-radiotherapy is the only option of curative-intent treatment. This study aimed to evaluate the effects of low-dose whole brain radiotherapy (WBRT) as a consolidation on disease control and long-term neurocognitive functions. Methods: We conducted a retrospective single-center study enrolling PCNSL patients from 2011 to May 2016 to evaluate the real-life treatment outcome and neurotoxicity from treatment especially radiotherapy. Results: Thirty-seven newly diagnosed immunocompetent PCNSL patients were treated with a high-dose methotrexate-based regimen with or without WBRT. The median age was 56 (range 16–78) years old. After chemotherapy, the overall response and complete response (CR) rates were 59.5% and 43.2%, respectively. All 6 partial response (PR) patients and 6 of 16 CR patients underwent radiotherapy. In 22 patients who achieved CR, the progression-free survival (PFS) of patients without WBRT was significantly inferior to the WBRT group with the hazard ratio of 4.7 (95% confidence interval 1.14–19.82, p = 0.03). The 3-year PFS were 35% and 78.75%, respectively, but there was no difference in overall survival. The serial Montreal Cognitive Assessment evaluations (20–72 months post chemotherapy) of 10 long-term CR patients revealed one dementia among three patients without WBRT and five mild cognitive impairments in seven patients with WBRT. Except for the dementia case, all the other patients can perform daily activities without assistance. Conclusion: The low-dose WBRT consolidation is associated with lower PCNSL relapses with only mild neurocognitive toxicity.

Thalassemia is the most common monogenetic disorder worldwide, with 60 000 infants with thalassemia major born annually.1 Survival often depends on regular blood transfusions to correct anemia and to reduce ineffective erythropoiesis, but these transfusions can result in iron overload and organ failure unless chelation therapy is undertaken. Serum ferritin levels continue to be used as a guide to chelation but are unreliable, and the availability of cardiovascular magnetic resonance (CMR) T2* imaging has transformed patient management by allowing organ-specific quantification of iron content. Countries with a high prevalence of thalassemia major have CMR, but magnet time is expensive and analytic expertise lacking. The aim of TIC-TOC (Thailand and UK International Collaboration in Thalassaemia Optimising Ultrafast CMR) was to investigate whether ultrafast CMR mapping could provide reliable immediate diagnoses of heart and liver iron content, eliminating the need for complex analysis, thus reducing costs to a level within local resources. The research received approval by the Institutional Review Board of the Faculty of Medicine at Chulalongkorn University. All participants provided written informed consent.

Case 1-2013: a 30-year-old man with chronic rhino-sino-orbital infiltration and nephritic/nephrotic syndrome

Although natural anticoagulant deficiencies are the established causes of thrombosis, their roles in bleeding are not fully studied. The objective is to correlate haemostatic factors with haemorrhagic symptoms quantified by a standardized questionnaire. Adult subjects were recruited from Bangkok and nearby provinces as part of routine health surveys/checkups. The validated MCMDM-1VWD form was used to assess their bleeding symptoms. At the same time, von Willebrand factor (VWF) activity, free protein S levels and protein C activity were measured. There were 5196 individuals. The mean age was 44.3 years (range 15-99) and 41% were male subjects. The mean bleeding score was -0.28 and 95% of subjects had scores between -2 and +2. The scores were lower in female subjects than in male subjects (-0.35 vs. -0.16, P < 0.001). Bleeding scores correlated negatively with age, VWF and protein C activities (Spearman's ρ-0.258, -0.091 and -0.098, respectively, all P < 0.001), but did not significantly correlate with protein S levels. Using multivariate analysis, female gender, VWF below 100 IU dL(-1), protein C below 100 IU dL(-1) and protein S over 150 IU dL(-1) significantly related to high (≥3) bleeding scores (adjusted odds ratio 1.95, 1.83, 1.56 and 2.84, P = 0.001, 0.001, 0.039 and 0.017, respectively). These findings may suggest interacting roles of VWF and natural anticoagulants in modifying bleeding symptoms.

SummaryThromboprophylaxis for venous thromboembolism (VTE) failed to reduce overall mortality in hospitalised medical patients. As a VTE prediction model for Asians is still lacking, this study aimed to identify very high risk patients who would be the main target for prevention. In 2009, medical patients admitted to King Chulalongkorn Memorial hospital, a tertiary care centre, were prospectively evaluated for risk factors. The high-risk cohort was monitored for symptomatic VTE until six weeks after discharge. No heparin prophylaxis was given. Of 1,290 high-risk patients, 27 (2.1%, 95% confidence interval [CI] 1.3–2.9) developed proven VTE, 25.9% of which were diagnosed after discharge. Cases with VTE stayed longer in the hospital (median 18 vs. 11 days, p < 0.001). The significant risk factors in a multivariate analysis were autoimmune disease, solid tumours, family history of VTE, varicose vein and oestrogen with the relative risks of 11.8, 4.7, 120.3, 40.1 and 17.1 (p < 0.001, 0.001, 0.001, 0.002 and 0.038), respectively. Either autoimmune disease or solid tumours were found in 63% of VTE with the relative risk of 4.5 (95% CI 2.1–9.7, p < 0.001). In contrast, previously reported VTE scores in western patients could not stratify the VTE risks, but all the scores predicted higher mortality. In conclusion, VTE is common in Asian hospitalised medical patients. Patients with autoimmune disease and those with solid tumours are highly susceptible to VTE. A prophylactic strategy in these groups is required.

Acquired haemophilia A (AHA) is an uncommon, but potentially fatal, bleeding diathesis caused by autoantibodies against circulating coagulation factor VIII (FVIII). The incidence is approximately 0.15 cases per 100 000 person-years. The underlying causes of AHA can be identified in approximately half of the patients, of which malignancies account for 10-20%. Heretofore, there has been only one case report of AHA concomitant with chronic myelomonocytic leukaemia (CMMoL), which previously was a subtype of the myelodysplastic syndrome. In this article, we report two more cases of AHA with CMMoL in our hospital and review possible causal relations between these two rare blood disorders.

Introduction : Chronic anemia impairs quality of life and adversely affects survival in patients with MDS. Recombinant erythropoietin (EPO) has been proven in maintaining hemoglobin (Hb) level and reducing red blood cell (RBC) transfusion in this group of patients. However, there were limited reports of EPO-β in MDS patients especially in Asian populations. Method: We have conducted a phase IV, multicenter, prospective, open labelled study in patients with low/intermediate-1 risk MDS to evaluate safety and efficacy of EPO-β 30,000 or 60,000 IU/week up to 12 weeks (NCT02145026). Patients with baseline Hb < 10g/dL were eligible if they required RBC transfusion < 4 unit/ 8 weeks and serum erythropoietin < 500 mU/ml. All enrolled patients will start EPO-β 30,000 IU weekly and their erythroid response will be assessed at week 4 and every 4 weeks thereafter until the end of study. If hemoglobin level reaches ≥ 12 g/dL at any time, EPO-β should be discontinued until Hb levels are ≤ 10 g/dL. While patients with Hb level is less than 12 g/dL and increased less than 1 g/dL from baseline level, a 60,000 IU weekly of EPO-β will be administered subcutaneously until week 12. Up to the clinical cut-off date for this interim analysis, 58 patients were screened, 27 of which were eligible for safety analysis whereas 25 patients were eligible for primary efficacy analysis to evaluate response according to International Working Group (IWG 2006) response criteria in MDS. Results: The median age of patients was 74.6 (range; 53.1-88.5), 18 (67%) were female. Three major subtypes of MDS were refractory cytopenia with multi-lineage dysplasia (RCMD, 44%), refractory cytopenia with uni-lineage dysplasia (RCUD, 32%) and refractory anemia with ring sideroblasts (RARS, 16%). Baseline Hb, hematocrit (Hct) and serum EPO were 8.1±1.3 g/dL, 25.2±3.7% and 89.5±116.6 mU/ml respectively. Twenty-five patients (92%) had serum EPO ≤ 200 mU/ml. There were 16 patients (64.0%) achieved hematologic improvement on erythroid (HI-E), while 6 patients (24.0%) achieved hematologic improvement on platelet (HI-P). Eleven patients (44.0%) (68% of responding patients) achieved Hb≥12 g/dL. Sixteen of 23 patients (69.6%) with serum EPO ≤ 200mU/ml achieved HI-E. Proportion of patients who required at least one RBC transfusion was reduced from 37% (n=10) to 11% (n=3) at the end of the study. By univariate analysis, none of baseline characteristics, including age, gender, comorbidity and MDS subtype, predicted response to EPO-β. From 27 patients eligible for safety analysis, there were 14 adverse events (AEs) and one serious adverse event (SAE) were reported in 13 patients (48.1%). The most frequently reported AEs were increased blood pressure (28.6%; all grade1), infections (21.4%) and gastrointestinal disorders (14.3%). There was no major AEs or SAEs which considered to be related to study drug by the investigators including hypertension, pure red cell aplasia (PRCA), thromboembolism and seizure. Conclusions Preliminary results suggest efficacy and safety of EPO-β in the treatment of anemia in low/intermediate-1 risk MDS patients. Two-third of patients demonstrated HI-E. There were no new unknown AEs found in this study and no SAEs considered related to study drug. Disclosures Charnwiboonsri: Roche (Thailand) Ltd.: Employment.

Background Thalassemia syndromes are highly prevalent in Southeast Asia. In Thailand, high performance liquid chromatography (HPLC) is the most common technique routinely performed in diagnosis of thalassemia and hemoglobinopathies, while isoelectric focusing (IEF) is rarely employed. We compared the diagnostic utility of IEF and HPLC in neonatal screening for thalassemia and non-sickling hemoglobinopathies. Methods Two-hundred and forty-one cord blood samples were analyzed using IEF and HPLC, β-thalassemia short program. The results were correlated with red cell indices and molecular analyses. Hemoglobin (Hb) Bart's was quantified only on IEF. Results Of 241 newborns, IEF and HPLC yielded 85.4% and 76.4% sensitivity to identify α-thalassemia syndrome, respectively. HbBart's ≥ 2% yielded 100% sensitivity to identify 2 α-globin gene deletions and/or mutations, while MCV ≤ 95 fl and MCH ≤ 30 pg yielded 100% sensitivity to identify 2 α-globin gene deletions. DNA analysis revealed HbE mutation in all 61 subjects with HbA2 > 1% on both IEF and HPLC. Conclusion IEF is an effective method in neonatal screening for thalassemia and non-sickling hemoglobinopathies. The HbBart's level, MCV and MCH are helpful for identifying α-thalassemia. The presence of HbA2 higher than 1% in cord blood indicates HbE carriers in Southeast Asian newborns.

Heparin-induced thrombocytopenia (HIT) is a serious immunological complication of heparin administration. Diagnosis of HIT is challenging, especially in critically ill patients. The clinical scoring model for predicting HIT is helpful for guiding clinical decision. We analysed data of patients who underwent the heparin-induced platelet aggregation (HPA) test from 2006 to 2010 and compared diagnostic performance of the novel model HIT expert probability ('HEP'), which has been validated in a population mainly comprising surgical patients first, by the previously published model '4Ts' score. Clinical courses of the patients were also reviewed to ensure that HPA test results were accurate. There were 47 suspected HIT patients. The majority was from medical (70.2%) and/or critical care (61.7%) units. Ten (21.3%) yielded positive HPA. Among positive HPA patients, eight were medical patients. The HEP score ranged from -3 to 13, whereas the 4Ts score ranged from 3 to 7 in positive HPA patients. Both HEP and 4Ts scores were significantly higher in positive HPA than in negative HPA patients (5.35 vs. 1.81, P=0.010 and 4.85 vs. 3.32, P=0.001, respectively). The HEP score did not display better diagnostic performance than the 4Ts score, with receiver operating characteristic (ROC) area under curve of 0.72 and 0.79 (P=0.31), respectively. The HEP score did not show better diagnostic performance than the 4Ts score for predicting HIT in our population. A large prospective validation in different sets of patients is warranted.

Background Solid tumor is the strongest risk factor for VTE in Thai medical in-patients. This study aimed to identify the markers predicting symptomatic VTE in this group. Methods Solid tumor patients admitted to the medical wards from June 2007 to December 2009 were monitored for VTE symptoms, excluding patients with VTE on admission. Anticoagulant prophylaxis was not given. Cases were all symptomatic VTE within 6weeks after discharge. The controls were active solid tumor in-patients admitted in 2009 and did not develop VTE. The cases and controls were compared for the risk factors of VTE and complete blood count (CBC) on admission. Results There were 28 radiology-confirmed VTE cases during the 2.5-year study period. There were 280 solid tumor patients without VTE as the controls. There was no difference in age (58.4 vs . 61.6years), sex (53.6% vs . 64.3% male), presence of leg paralysis, acute infection and obesity between cases and controls, respectively. The cases showed higher absolute monocyte counts compared with the controls (0.76 vs . 0.56×10 9 /L, p 0.013), but there were no differences in other CBC parameters. In a multivariate analysis, cancer of unknown primary (Odds ratio [OR] 13.7, 95% confidence interval [CI] 2.74-68.7, p 0.001), biliary cancer (OR 6.6, 95% CI 1.80-24.3, p 0.004) and a monocyte count over 0.5×10 9 /L (OR 5.0, 95% CI 1.62-15.5, p 0.005) significantly associated with VTE. Conclusion Metastatic diseases with obscured primary sites, biliary carcinomas and higher monocyte counts on admission are related to subsequent VTE in hospitalized cancer patients.

Background: Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin administration. Diagnosis of HIT is a clinical challenge. The 4Ts scoring model (0-3 low, 4-5 intermediate, 6-8 high probability of HIT) has been validated in several studies including the recent meta-analysis (Blood 2012;120:4160-7), which demonstrated that a low probability 4Ts score conferred a high negative predictive value (0.998; 95% CI, 0.970-1.000) for excluding HIT. Some experts propose a diagnostic approach for HIT based on the 4Ts scoring model and exclude HIT in patients with a low probability score without serologic testing for HIT. Another recently constructed model 'HIT expert probability' (HEP) score (< 2 unlikely, ≥ 2 likely) demonstrated better diagnostic performance in mainly surgical patients. However, in critically ill patients who receive heparin, other concomitant causes of thrombocytopenia are common and may interfere with clinically diagnosis of HIT. In this study, we aimed to determine the diagnostic accuracy of the 4Ts and the HEP score for excluding HIT in a population of critically ill patients. Methods: Consecutive patients admitted in critical care units during 2006-2015 were included in this study. Clinical and laboratory data of individuals were retrospectively reviewed from medical records. The 4Ts and the HEP score were blindly computed by two independent reviewers (NU and RV). The rapid particle gel immunoassay (platelet factor 4/heparin-PaGIA) was used for HIT screening. Subjects yielding positive PaGIA were sent for the confirmatory testing using the in-house platelet aggregometry measuring heparin-induced platelet aggregation (HPA). However, during the shortage of PaGIA, HPA was performed in all cases. HPA using platelet-rich plasma from healthy donors with known reactive platelets was performed as previously described with a few modification. Aggregation values of at least 20% above negative controls in the presence of 0.5 or 1.0 U/ml of heparin, which were subsequently inhibited by the addition of 100 U/ml of heparin, were defined as positive results. Results: There were 92 critically ill patients with suspected for HIT. Among them, 56 (60.9%), 33 (35.9%) and 3 (3.3%) yielded low, intermediate and high probability 4Ts score, respectively, while 33 (35.9%) and 59 (64.1%) yielded unlikely and likely high probability HEP score, respectively. Of 78 with obtainable PaGIA, 25 cases (37.2%; 6/6 HPA+ and 19/72 HPA-) yielded positive results. Eleven patients (12.0%) yielded positive results for HPA were diagnosed as HIT. There were 6 (54.5%) developing thrombosis (4 new proven and 2 progressive). Clinical data of all documented HIT were summarized in the table 1. Documented HIT was diagnosed in 5.4%, 18.2% and 66.7% of low, intermediate and high probability 4Ts score, respectively, whereas HIT was demonstrated in 9.4% and14.3% of unlikely and likely probability HEP score, respectively. The receiver operating characteristic curve analysis demonstrated that the 4Ts score was tended to display better diagnostic performance than the HEP score with the area under curve of 0.740 and 0.587 (P = 0.053), respectively. The HIT cases with low pre-test probability scores were due to concomitant causes of thrombocytopenia resulting in earlier onset, lower nadir of platelet counts and/or more minus scores from alternative etiologies of thrombocytopenia. Conclusions: The diagnostic performance of the 4Ts and the HEP score is limited in complicated and/or critically ill patients due to multiple etiologies affecting onset and severity of thrombocytopenia. Both low probability 4Ts score and unlikely HEP score are unsafe for excluding HIT in this patient group. Table 1. Clinical characteristics of patients documented heparin-induced thrombocytopenia Case Age (years)/ sex Patient type Heparin type Thrombosis PaGIA 4Ts score HEP score 1 61/ M CVT UFH New + 2 -6 2 37/ M CCU UFH, LMWH Progressive NA 3 -3 3 74/ F CVT UFH No NA 3 3 4 83/ M GenS UFH, LMWH New + 4 -6 5 80/ F Med LMWH No + 4 6 6 62/ M CCU UFH No NA 5 4 7 51/ M CCU UFH No NA 5 5 8 80/ M Med UFH No + 5 6 9 76/ M CCU UFH Progressive NA 5 10 10 50/ F Med UFH, LMWH New + 6 5 11 87/ M CCU UFH New + 7 9 M: male, F: female, CVT: cardiovascular thoracic surgery, CCU: coronary care unit, GenS: general surgery, Med: medicine, UFH: unfractionated heparin, LMWH: low molecular weight heparin, NA: not available Disclosures No relevant conflicts of interest to declare.

Abstract 4202 Background: Thalassemia and non-sickling hemoglobinopathies are highly prevalent in Southeast Asia. High performance liquid chromatography (HPLC), β-thalassemia short program, is the most common technique routinely used in this region, while IEF is rarely employed. However, HPLC, β-thalassemia short program, cannnot quantify HbBart's, as well as HbH. In addition, the acetylated HbF, which is frequently found in cord blood, interferes with the HbBart's and HbH peaks on HPLC. We primarily aim to compare diagnostic utilities of IEF and HPLC in fetal cord blood screening for prenatal diagnosis of thalassemia and non-sickling hemoglobinopathies in Thailand. Methods: One-hundred and two cord bloods from the National Cord Blood Bank and fetuses of high risk couples were analyzed using IEF and HPLC, β-thalassemia short program, and correlated with red cell indices and DNA analyses. HbBart's was quantified only on the IEF method. The sensitivity and specificity to screen for α-globin and β-globin gene mutations were determined. Results: Of 88 cases showing HbBart's on hemoglobin analysis, IEF yielded 98.9% sensitivity to identify at least one α-globin gene defect (−α−3.7, -α−4.2, -αCS, -αPS, –SEA, –Thai, -α−3.7/-α−3.7 and -α−3.7/-αCS), while HPLC yielded only 83.7% sensitivity to detect at least one α-globin gene defect. All missing cases on HPLC were single α-globin gene deletion that had HbBart's less than 1.5% of total hemoglobin measured on IEF. Hb Constant Spring (CS) and Hb Pakse (PS) heterozygotes (N = 11) had small amount of HbBart's less than 3%, but neither HbCS nor HbPS was detectable on both tests. HbBart's ≥ 2% yielded 100% sensitivity to identify two α-globin gene defects, while HbBart's ≥ 3% yielded 100% specificity to diagnose two α-globin gene defects. MCV and MCH are the most helpful red cell parameter in screening for α-thalassemia. MCV ≤ 95 fL yielded 100% sensitivity to identify two α-globin gene deletions, while MCV ≤ 90 fL yielded 100% specificity to identify two α-globin gene deletions. In addition, MCH ≤ 30 pg yielded 100% sensitivity and 100% specificity to identify two α-globin gene deletions. Thirty two cord bloods showed HbA2/E, ranging from 1.9–15.6%. DNA analysis using a reverse dot blot technique for detecting common β-thalassemia mutations in Thailand demonstrated HbE mutation in all cases, while no β-thalassemia mutations were identified. Therefore, detectable HbA2 in cord blood usually represents HbE, not HbA2. Three HbE heterozygotes with two α-globin gene deletions demonstrated high HbBart's and low MCV, as well as low MCH, similar to those with two α-globin gene deletions alone. On the other hand, HbE heterozygotes with single α-globin gene defects could not be differentiated from pure HbE heterozygotes. Conclusion: IEF is superior to HPLC β-short program in screening for α-globin gene defects in prenatal cord blood analysis. The amount of HbBart's, MCV and MCH are helpful for identifying α-thalassemia. The presence of HbA2 in cord blood indicates HbE mutation, but not β-thalassemia. Disclosures: Sutcharitchan: Novartis: Research Funding.

Abstract 3804 Introduction: Hemostasis is maintained by a delicate balance between numerous activators and inhibitors. Present concept posits that mild bleeding phenotypes are multi-factorial and resulting from minor variations in numerous components of the system. Although natural anticoagulant protein deficiencies are the established causes of thrombotic disorders, their roles in bleeding diathesis have not been reported. Currently, hemorrhagic symptoms can be accurately quantified using the standardized questionnaire. We hypothesized that a weak effect of each factor on bleeding symptoms could be demonstrated, if we employed a sufficiently large sample size. Method: The adult subjects were recruited from Bangkok and nearby provinces as parts of health surveys/check-ups. Current pregnancy, known bleeding disorders and anti-platelet drug or anticoagulant uses were excluded. The modified questionnaire based on the validated MCMDM-1VWD form was applied with assistances by trained interviewers to assess bleeding symptoms. Von Willebrand factor (vWF) activity (Collagen binding activity) and free protein S levels were determined using ELISA methods. Protein C activity was measured using a chromogenic assay. Results: A total of 5,208 Thai individuals participated in the study. The mean (±SD) age was 44.3 (± 13.7) yrs, ranging from 15–99 years, and 2129 (40.9%) were male. The mean bleeding score was -0.28 (±1.14), ranging from -3 to 7. There were 38 (0.73%) high hemorrhagic scores (≥4). The scores were significantly lower in female than in male (-0.36 vs. -0.16, respectively). This discrepancy vanished after excluding scores on post-partum bleeding. Among women, 17.9% of them were taking female hormone. There was no different in vWF, protein C and protein S levels between women with and without estrogen uses. The bleeding scores were negatively correlated with age, vWF and protein C activities (γ= −0.23, −0.09, and −0.09, respectively, all p< 0.001) but not with protein S levels. If the items on dental and surgical procedures were omitted from the score calculation, the correlation between age and hemorrhagic scores was not found. Therefore, the sex and age differences in bleeding scores were likely due to higher probabilities of experiencing uneventful hemostatic challenges, which yielded negative scores, in healthy women and elderly. Using multivariate regression analysis, age (β= -0.22, p< 0.001), male sex (β= 0.08, p 150 U/ml) protein C levels (β= -0.04, p=0.003), high (> 150 U/ml) protein S levels (β= 0.04, p=0.005) and vWF activity below 30 IU/L (β= 0.03, p=0.021) were significantly associated with bleeding scores. A subgroup of 180 subjects (3.4%) showed low vWF activity (≤50 IU/L). In this group, the mean bleeding score (-0.16) was not different from that of the higher vWF group and only 2 individuals (0.04% of total population) had abnormal hemorrhagic scores (≥4) suggesting that there were other factors influencing bleeding severity in this subgroup. In a multivariate regression analysis, bleeding scores in the low vWF group were significantly correlated with protein S levels (β= 0.26, p= 0.003) and vWF activity below 30 IU/L (β= 0.15, p=0.046) but not with age, sex and protein C activity. Conclusion: Our population-based data revealed the relationships of vWF, protein C and protein S levels with hemorrhagic history. The negative correlation between protein C activity and bleeding is unexpected and needs further investigations. These findings may suggest the novel roles of natural anticoagulants in modifying bleeding symptoms. Disclosures: No relevant conflicts of interest to declare.