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To find the prevalence and risk factors of pulmonary hypertension (PHT) in adult patients with hemoglobin E/β-thalassemia disease (E/β-Thal).One hundred and ten clinically stable E/β-Thal outpatients, sixty-one of whom had undergone splenectomy, were prospectively studied using their clinical profiles, selected blood tests, chest roentgenogram, and transthoracic echocardiogram. Based on the pulmonary artery systolic pressure (PASP) values estimated by the echocardiogram of ≥36 mmHg, they were dichotomized into those with (PHT+) and without (PHT-) PHT.PHT was found in 41 (37.3%) patients without gender preponderance. It was not due to the left heart and was not severe (PASP = 46.3 ± 10.4 mmHg). PASP was higher in splenectomized patients (48.0 ± 11 vs. 40.3 ± 4.7 mmHg (P = 0.004)). PHT was found in 32 of 61 (52.5%) splenectomized patients, mostly (53%) in the second decade, and rarely (6.3%) during the first 5 yr after splenectomy. PHT+ patients had more hemolysis (P = 0.001-0.04 depending on the parameters), more asplenic cases (P 0.001), and higher serum soluble vascular cell adhesion molecule-1 (sVCAM-1) and high-sensitivity C-reactive protein levels (P = 0.004 and 0.008, respectively). Strong risk factors by univariate analysis were serum sVCAM-1 levels ≥1600 ng/mL, serum cell-free Hb ≥ 3 mg/dL, asplenia, and amount of NRBCs/100 WBCs40.Prevalence of PHT in E/β-Thal patients was 37.3% without gender preponderance. Those with severe hemolysis and asplenia invariably had severer PHT. Strong risk factors were asplenia and associated markedly elevated values of sVCAM-1, cell-free Hb, and NRBCs in blood.

The hypercoagulable state is well recognized in patients with severe β-thalassemia disease. One of the mechanisms of chronic hypercoagulable state is the abnormal expression of phosphatidylserine on red blood cells (RBC). This study aimed to determine the coagulable state in patients with severe β-thalassemia disease following successful stem cell transplantation (SCT). Subjects were classified into three groups: normal controls (NC), β-thalassemia disease receiving regular transfusion (Thal-RT) and β-thalassemia disease post SCT (Thal-SCT). Sixty eight subjects, aged 3–17 years, consisting of 21 NC, 28 Thal-RT and 19 Thal-SCT were enrolled. After SCT, the annexin V level in Thal-SCT was normalized. At the median follow-up time of 70.3 (50.9-84.2) months after SCT, the levels of coagulation markers (thrombin antithrombin complex, prothrombin fragment and D-dimer) and anticoagulation proteins (protein C, S and antithrombin activities) returned to the levels similar to controls.

Venous thromboembolism (VTE) has been reported to be less common among Thais than Caucasians. Whether this observation reflects genetic or environmental factors, or both, is uncertain. To identify genetic and acquired risk factors of Thai patients with VTE, we enrolled in the study 105 consecutive Thai patients (34 men, 71 women) who had an objectively confirmed history of VTE. A complete clinical summary was obtained from each patient, with emphasis on personal and family history of VTE, as well as circumstantial vascular risk factors (surgery, immobilization, pregnancy, postpartum condition, trauma, oral contraceptive use, and malignancy). Of the 105 patients, 19% were found to have a malignancy. The mean age at the time of the first thrombotic episode was 52.1 years (range, 29-76 years), compared with 42.6 years (range, 17-82 years) for the patients without malignancy. Of the 85 patients without malignancy, 12.3% had protein S deficiency, 8.9% had protein C deficiency, 4.7% had antithrombin deficiency, 10.4% had antiphospholipid antibody, 30.4% had an elevated factor VIII level, 26.8% had an elevated factor XI level, 5.3% had hyperhomocysteinemia, and 16.5% were on oral contraceptives before the thrombotic episode. Factor V Leiden, the G20210A prothrombin gene mutation, and homozygosity for the C677T methylenetetrahydrofolate reductase (MTHFR) gene variant were not found. The VTE in 7.1% of the patients was considered to be secondary to recent surgery, trauma, and/or immobilization. Compared with studies of Caucasian patients, there were significant differences in the risk factors for VTE, with protein S deficiency and protein C deficiency being more common in the Thai patients. In contrast, factor V Leiden, the G20210A prothrombin gene mutation, and the C677T MTHFR gene mutation are not genetic risk factors among Thai patients with VTE. Malignancy and the use of oral contraceptives were the most common acquired risk factors for VTE in the Thai patients.

Increased frequency of thrombosis has been observed in patients with hemoglobin E/beta-thalassemia (Hb E/beta-thal) disease, particularly those who have previously been splenectomized. We compared various hemostatic and thrombotic markers in blood from 15 Hb E/beta-thal patients who were not splenectomized (NS), 15 who had been splenectomized (S), and 15 normal controls (NC). Levels of plasma thrombin-antithrombin, beta2 thromboglobulin, C-reactive protein, tissue plasminogen activator antigen were significantly higher in the S group than in either the NS or the NC groups, and levels of prothrombin fragment 1.2 were significantly higher in the S than in the NC group. Levels of plasminogen activator inhibitor-1 antigen were significantly higher in the S than in the NS group. Levels of protein C, protein S, antithrombin, and fibrinogen were significantly lower in the S and NS groups than in the NC group. Plasma lipoprotein(a) levels in the S and NS groups were not statistically different from NC. Our findings indicated that there is evidence of chronic low-grade coagulation and platelet activation, chronic low-grade inflammation, endothelial cell injury, impaired fibrinolysis, and decreased naturally occurring anticoagulants in splenectomized Hb E/beta-thal patients. These changes may account for the increased risk of thrombosis in these patients.

The relationship between asplenia and thrombophilia in β-thalassemia disease patients is not yet completely understood. One hundred and ten adult hemoglobin (Hb) E/β-thalassemia (E/β-Thal) disease outpatients, dichotomized according to the presence or absence of the spleen, were prospectively studied for evidence of intravascular hemolysis (IVH) and vascular endothelial cell (EC) activation. Biomarkers of IVH (serum cell-free Hb), EC [soluble E-selectin (sE-selectin) and soluble vascular cell adhesion molecule 1 (sVCAM-1)], platelet and EC [soluble P-selectin (sP-selectin)], inflammation [high-sensitivity C-reactive protein (hs-CRP)], and coagulation [thrombin-antithrombin complexes (TAT)] activation, as well as other selected blood tests were determined. The 61 splenectomized patients had a more severe hemolytic disease and higher levels of cell-free Hb and ferritin (p = 0.003), sE-selectin, sP-selectin, hs-CRP, and TAT (p < 0.05). However, serum levels of sVCAM-1 were not different between the two groups. The findings suggested IVH and EC activation. Together with chronic iron overload and chronic low-grade inflammation activation, the findings extend our understanding of the mechanism of thrombophilia in splenectomized E/β-Thal disease patients.

Aged or abnormal red blood cells with exposed phosphatidylserine (PSRBCs) are cleared from the circulation by splenic macrophages. In asplenic patients, other mononuclear phagocytic cells in tissues and in circulation may function in this capacity. To better understand these changes and the relationship among splenic status, PS-RBCs, blood monocytes, and serum tumor necrosis factor (TNF-α), a product of mononuclear phagocyte activation, patients with hemoglobin E/β-thalassemia (E/β-Thal) were studied. Whole blood of 20 nonsplenectomized, 20 splenectomized E/β-Thal patients, and 20 healthy subjects was assayed for PS-RBCs; for monocytes, activated monocytes, and monocyte response to lipopolysaccharide stimulation; and serum was assayed for TNF-α. Asplenic E/β-Thal patients had significantly increased (P < 0.05) amounts of PS-RBCs, monocytes, activated monocytes, and levels of serum TNF-α. The amount of PS-RBCs correlated with levels of serum TNF-α, but the amount of activated monocytes did not correlate with either the amount of PS-RBCs or levels of serum TNF-α. Monocyte response to lipopolysaccharide stimulation in asplenic patients was not as efficient as in the other patients or in normals (77 vs. 404, and 304 folds increment, respectively). The results suggest that splenectomy in E/β-Thal patients led to an increased amount of PSRBCs and activation in the mononuclear phagocytic system.

The effect of parenteral glutamine dipeptide (Gln) supplementation on neutrophil phagocytosis, superoxide anion generation (SAG), prevention of chemotherapy-induced side-effects and cost-effectiveness was examined in a pilot study of acute myeloid leukaemia (AML) patients receiving chemotherapy. Sixteen AML patients were randomized to receive intravenous supplementation with Gln (30 g/day) or an equivalent quantity (25 g/day) of a standard amino acid mixture (control) on days 1 − 5 of chemotherapy. Complete blood count was evaluated twice a week until hospital discharge, and neutrophil phagocytosis and SAG were measured when absolute neutrophil count reached > 500 /μl. Patients were observed for development of infection, mucositis and diarrhoea. In Gln-treated patients, the percentage of neutrophil phagocytosis and the SAG levels were significantly higher than in control patients (20.5 ± 6.0% and 18.9 ± 2.9 nmol/106 neutrophils per 10 min, respectively). The Gln-treated patients lost significantly less weight, tended to have shorter in-patient duration and had less severe oral mucositis than controls. This pilot study provides preliminary indication that parenteral Gln supplementation enhances neutrophil phagocytic function, maintains nutritional status and is cost effective. Parenteral Gln may also prevent oral mucositis, although further studies involving more patients need to be undertaken to confirm this and the other results.

Antibodies to beta(2)-glycoprotein I (anti-beta(2)-GPI) have been reported to have stronger association with clinical antiphospholipid syndrome (APS) than anticardiolipin antibodies (aCL) and lupus anticoagulant (LAC). We investigated the sensitivity and specificity of ELISA for anti-beta(2)-GPI in Thai systemic lupus erythematosus (SLE) patients with clinical features of APS and compared the results with IgG/IgM aCL and LAC to find the test with the best association. The hospital records of 151 Thai SLE patients whose sera had been sent for either IgG/IgM anticardiolipin antibodies or lupus anticoagulant testing were reviewed. Sera of patients either without complete clinical records or those with APS-related manifestations other than vascular thrombosis and pregnancy morbidity (according to the international consensus statement on preliminary classification criteria for definite APS) were excluded. For the remaining subjects (112 patients), their sera were tested for anti-beta(2)-GPI antibody, IgG and IgM anticardiolipin, and lupus anticoagulant. The sensitivity and specificity of each method were compared by using the chi-square test. Among the 112 (74.2%) SLE patients in the study, 35 (31.3%) presented with preliminary clinical criteria for APS (i.e., vascular thrombosis and pregnancy morbidity) whereas 77 (68.7%) did not. The sensitivity and specificity of anti-beta(2)-GPI determination were 57.1 and 79.2%, respectively, whereas those of IgG aCL were 25.7 and 94.8%, of IgM aCL were 5.7 and 98.7%, and of LAC were 44.8 and 77.3%, respectively. The accuracy of the four tests showed similar association with clinical APS (accuracy of test = 72.3, 73.2, 69.6, and 68.3%, respectively). Concerning the sensitivity, specificity, and difficulty of the methods, the combination of anti-beta(2)-GPI and IgG aCL tests was the best for the diagnosis of APS in Thai SLE patients.

Introduction Pulmonary hypertension (PHT) associated with thalassemia hemoglobinopathy is now an accepted clinical entity. Due to a high prevalence of thalassemia hemoglobinpathy worldwide, it is the most common entity of PHT. Despite the commonness, its pathogenesis is not yet completely understood. Although asplenia is a known risk factor, PHT does not develop in all splenectomized patients. The present study was therefore done to search for other associated features. Patients and Methods Sixty-one clinically stable splenectomized hemoglobin E/β-thalassemia disease (E/β-Thal) adult outpatients, on no medication aside from folic acid and who received no blood transfusion in the preceding 4 weeks, were prospectively studied. All gave written informed consent, and study protocol was approved by the institution ethics committee on studies in humans (#0774/2548). Transthoracic echocardiogram was used to evaluate cardiac function and to estimate pulmonary artery systolic pressure (PASP). PHT was defined as an estimated PASP ≥36 mmHg. Clinical features and laboratory data were dichotomized according to the presence (PHT+) or absence (PHT-) of PHT, and statistical analysis was done by STATA version 10 (Stata Corp, Texas), considering a P value

Abstract 2156 Introduction: Clinically significant pulmonary arterial hypertension (PAH) has been reported in splenectomized hemoglobin E/β-Thalassemia patients. Like primary PAH, the underlying basis is hypercoagulability related thrombotic pulmonary arteriopathy, which results in an increased pulmonary vascular resistance. In the non-splenectomized counterparts with no clear evidence of hypercoagulability only mild PAH is found. To evaluate role of splenomegaly and the accompanying increased blood volume in the pathogenesis of PAH in this group of patients, we studied the relationship between spleen volume and PA pressure. Patients and Methods: Nineteen clinically stable hemoglobin E/β-Thalassemia outpatients, on no medication aside from folic acid and who received no blood transfusion in the preceding 4 weeks were first analyzed in this ongoing study. All gave written informed consent, and study protocol was approved by the institution ethics committee on studies in humans (ID 07–53-01). PA pressure (PAP) was estimated by a single echocardiologist (T.Y.) using Philips iE33 echocardiographic system with a S5 probe (Philips Medical Systems, Andover, MA). Spleen volume was determined by CT scan with non-contrast, 320-slice, 3 mm axial cut (Aquilion one, Toshiba, Japan). Statistical analysis of clinical and laboratory data was done by SPSS version 18 (SPSS Inc, Chicago, Ill), considering a P value Conclusions: Non-splenectomized patients with hemoglobin E/β-Thalassemia have elevated PAP in proportion to spleen size, likely secondary to elevated blood volume. This situation is distinct from the pathologic PAH that results from increased pulmonary vascular resistance in splenectomized patients. Disclosures: No relevant conflicts of interest to declare.

Abstract 2014 Poster Board I-1036 Introduction: Clinical manifestations of blood hypercoagulability, such as pulmonary arterial hypertension (PAH) and ischemic stroke, are well known in patients with thalassemia. We herein present evidence that the hypercoagulable state in β-Thalassemia disease patients is to a significant extent the result of prior splenectomy. Patients and Methods: One hundred and ten clinically stable hemoglobin E/β-Thalassemia outpatients, on no medication aside from folic acid and who received no blood transfusion in the preceding 4 weeks were studied. All gave written informed consent, and study protocol was approved by the institution ethics committee on studies in humans (#0774/2548). Echocardiogram was used to estimate systolic PA pressure (SPAP). Clinical features and laboratory data were stratified according to the presence or absence of the spleen, and statistical analysis was done by STATA version 10 (Stata Corp, Texas), considering a P value Results: Of the 110 patients, 61 were asplenic and females comprised 51% in both groups. Selected statistically significant results are shown in the table . Results Asplenic (61 Patients) Non-splenectomized (49 Patients) P value Age at 1st transfusion (median) 4.7 years 17 years Total transfusions (median) 35 units PRBC 13 units PRBC 0.005 Systolic pulmonary artery pressure 37.1 +/- 14.6 mm Hg 28.8 +/- 7.6 mm Hg Cardiomegaly 50.9% 27.3% 0.013 Extramedullary hematopoiesis 50.9% 27.3% 0.013 RBC count 3.19 +/- 0.57 × 106/μL 3.87 +/- 1.09 × 106/μL Corrected reticulocyte count (median) 5.2% 1.4% Nucleated RBC (median) 581/100 WBCs 5/100 WBCs Corrected WBC count 9.72 +/- 4.2 × 103/μL 6.71 +/- 2.3 × 103/μL Platelet count 726 +/- 215 × 103/μL 243 +/- 115 × 103/μL Serum ferritin (median) 1,892 ng/mL 1,050 ng/mL 0.001 ALT (median) 65.5 u/L 44.5 u/L 0.004 AST (median) 64 u/L 36 u/L 0.001 Free hemoglobin (median) 4.2 mg/dL 2.5 mg/dL 0.001 C-reactive protein (high sens) (median) 2.7 mg/L 1.2 mg/L 0.012 Thrombin-antithrombin complexes 3.5 μg/L 1.1 μg/L Soluble P-selectin 113.4 +/- 31.2 ng/mL 56.4 +/- 32.1 ng/mL Soluble E-selectin 43.3 +/- 21.5 ng/mL 29.5 +/- 18.4 ng/mL 0.003 Conclusions: In comparison with non-splenectomized hemoglobin E/β-Thalassemia patients, asplenic ones have higher SPAP, more severe hemolysis, more liver impairment and chronic iron overload, significant chronic low grade inflammation, and evidence of coagulation activation. Splenectomy should be more judiciously applied than heretofore, and if performed, measures to blunt or prevent a subsequent hypercoagulable and inflammatory state, which could lead to PAH should be initiated. Disclosures: No relevant conflicts of interest to declare.

2015 Poster Board I-1037 Introduction: Pulmonary arterial hypertension (PAH) associated with thalassemia (Thal) hemoglobinopathy is now an accepted clinical entity. Most of the reports are in sickle cell disease and splenectomized β-Thal patients. Once manifested, it connotes poor prognosis. We herein present its prevalence and predictors in hemoglobin E/β-Thal (E/β-Thal) patients. Patients and Methods: One hundred and ten clinically stable E/β-Thal outpatients, on no medication aside from folic acid and who received no blood transfusion in the preceding 4 weeks were studied. All gave written informed consent, and study protocol was approved by the institution ethics committee on studies in humans (#0774/2548). Echocardiogram was used to estimate systolic PA pressure (SPAP). PAH was defined as an estimated SPAP ≥36 mmHg. Clinical features and laboratory data were stratified according to the presence or absence of PAH, and statistical analysis was done by STATA version 10 (Stata Corp, Texas), considering a P value

• Corticosteroids, cyclophosphamide, and splenectomy were employed in the treatment of 43 patients with immunologic thrombocytopenic purpura. All received corticosteroids initially; 22 patients received corticosteroids and cyclophosphamide, and six received drug treatment and underwent splenectomy. Of those receiving corticosteroids alone, 11 had excellent responses and ten had good responses. Of those receiving corticosteroids and cyclophosphamide, responses to treatment were excellent in six, good in eight, and fair in two. Of those receiving drug treatment and undergoing splenectomy, the responses to treatment were excellent in four, good in one, and fair in one. The duration required for induction of remission indicated the prognosis for patients; excellent responses were observed at 1, 2.4, and 4 months in groups treated, respectively, with corticosteroids, corticosteroids and cyclophosphamide, and drugs plus splenectomy. (Arch Intern Med140:636-638, 1980)

Histamine, serum complement factor 3 (C′ 3 ) and platelets were studied in 33 Plasmodium falciparum patients. Elevation of histamine level in the blood was found during acute infection but was more marked in the group of patients with systemic complications. A correlation between histamine changes, clinical complications, reduction of C′ 3 and degree of thrombocytopenia was observed. The possible role of histamine in the development of complications in P. falciparum infection and the possible release of this substance through the activation of complement system and immune destruction of platelets were discussed.