Hepatocellular carcinoma in thalassemia: A critical review

Due to blood transfusions, thalassemics are often infected with either hepatitis C virus (HCV) or hepatitis B virus and often have hemochromatosis. Hepatocellular carcinoma (HCC) has emerged in thalassemics only recently as a result of the improvement in thalassemia outcomes. In fact, a prospective study estimated an HCC incidence in β-thalassemia of about 2%. Although data are scanty, HCC screening in thalassemics with risk factors for HCC should be carried out. HCV treatments have some efficacy in HCV infected thalassemics despite partial contraindication to ribavirin and iron overload. However, there are no data on how HCV treatment translates into HCC prevention. Preliminary data suggest that HCC treatment in thalassemics should generally have the same outcomes as in non-thalassemics. Although coexistence of severe comorbidities makes liver transplantation challenging, this therapeutic possibility should not be precluded for well selected HCC β-thalassemia patients. In fact, 2 transfusion dependent adult HCC β-thalassemia patients have recently undergone successful liver transplantation with a good outcome. In conclusion, HCC seems to be a developing issue in thalassemia and HCC screening should be carried out. HCC treatment, including liver transplantation, can be performed in selected patients. A multidisciplinary effort is needed for management.     

Effects of zinc supplementation on linear growth in beta-thalassemia (a new approach)

Linear growth was evaluated in 32 patients with beta-thalassemia major. At the beginning of the study of 40.6% of the patients were below the 10th percentile with biochemical evidence of zinc deficiency. Effects of zinc supplementation on growth velocity (height) were assessed in a controlled manner. Twenty-one children received oral zinc sulphate for a period of 1 to 7 years (15 early- and 6 late-supplemented cases), while the remaining 11 thalassemics were maintained only on conventional transfusion therapy. The mean height velocity of early-zinc supplemented children was significantly greater than that of normal children (P less than 0.01). An increase in height was also observed in the patients who received delayed zinc retardation. The present study demonstrated that zinc deficiency is one of the factors responsible for retarded linear growth in beta-thalassemia major. Only the patients who received zinc supplementation showed an acceleration of growth in height. Administration of zinc could, therefore, be considered as an effective adjuvant therapy in homozygous beta-thalassemia.     

Abnormalities in lung function among multiply-transfused thalassemia patients: results from a thalassemia center in Malaysia

The aim of this study was to: (1) determine the prevalence and patterns of lung dysfunction among transfusion dependent thalassemics; (2) determine the associated factors that might contribute to this problem. This was a cross-sectional study involving 66 patients with transfusion dependent thalassemia aged 10 years and above. All patients underwent physical examination, standardized pulmonary function tests including spirometry, lung volume, and the carbon monoxide diffusion capacity. A restrictive pattern of lung dysfunction was observed in 22 patients (33.3%) and none showed the presence of obstructive ventilatory impairment. A reduction in the carbon monoxide diffusion capacity (DLCO) was seen 87.9% of the patients, including 7.6% who had evidence of hypoxemia. Ten patients showed a reduction in the FEF25-75% although they did not fulfil the criteria for small airway disease. No correlation was found between lung dysfunction and serum ferritin levels in the patients. Restrictive lung dysfunction and diffusion impairment were the predominant abnormalities found in our cohort of patients.     

Serum erythropoietin levels in thalassemia major and intermedia

Serum erythropoietin (EPO) levels were determined by enzyme linked immunosorbent assay (ELISA) in 61 thalassemic patients, consisting of 23 thalassemia major (TM) patients with multiple transfusion, 38 patients with thalassemia intermedia (TI). Thirty-two normal controls were also studied. The mean serum EPO levels were significantly higher in both groups with TM (165.96 +/- 17.31 mlU/ml) and TI (126.43 +/- 50.56 mlU/ml) compared with the control group (8.33 +/- 3.91 mlU/ml). The mean value of hematocrit (Hct) in the patients with TM (18.70 +/- 3.51%) was lower than those with TI (25.24 +/- 4.19 %) whereas the mean serum EPO level were significantly higher in TM than TI patients. An inverse correlation between the serum values of EPO and Hct was observed in both TI and TM patients, however this correlation was significant only in TI (r = -0.61, p<0.001). These data showed that serum EPO levels increased in all thalassemia patients despite repeated transfusion. Multiple transfusion may modulate the response of serum EPO to the degree of anemia, resulting in increased EPO levels and independent anemia in the TM patients.     

Adult height and adult sitting height in childhood medulloblastoma survivors

Outcome in adult height and sitting height is poor in children surviving medulloblastoma due to craniospinal irradiation (CSRT) and chemotherapy. We evaluated adult height and sitting height in 51 medulloblastoma patients stratified into four groups: G1, GH-deficient (GHD) patients treated with 23-39 Gy CSRT but not treated with GH [recombinant human (rh)GH]; G2, patients treated with rhGH; G3, patients who were not GHD; and G4, patients treated with 18 Gy CSRT and rhGH. Standing/sitting height of each group was compared with parental height and previously reported outcome studies. The rhGH dose was 0.3 mg/kg.wk, a higher dose compared with other reports of adult heights. The adult heights were significantly taller in group G2 [mean height SD score (SDS) = -1.86] than that achieved in previous studies (P < 0.0001), but not different from group G3, non-GHD (mean SDS = -1.55). The tallest stature achieved was in group G4 (18 Gy CSRT), a height SDS of -1.01. Sitting heights were significantly less than the normal population, with mean SDS of -2.96 but -1.62 in group G4. We conclude that adult heights but not sitting heights in medulloblastoma survivors are significantly improved with the higher dose of rhGH. The lower dose of CSRT further improves not only adult height but also sitting height.     

Preventation of thalassemia in Australia

Screening for thalassemia and other hemoglobinopathies in the major maternity hospitals in Melbourne, Australia has shown that 6% of the patient population carries a clinically significant genetic abnormality. The most common of these are beta-thalassemia (3%). HbS (1.8%), HbE (0.5%) and alpha0 thalassemia (0.4%). Approximately 60 prenatal diagnoses for the clinically significant combinations of these abnormal genes are performed annually in the 2 major centers of Melbourne and Sydney. The majority of these prenatal diagnoses are for beta-thalassemia major (65%). whilst 11% are for Bart's hydrops fetalis, 8% for HbE/beta-thalassemia. 6% for HbS/beta-thalassemia, 2% for sickle cell anemia and the remaining 8% for other combinations of thalassemia/hemoglobinopathies. Of the 178 patients with beta-thalassemia major, sickle cell disease or beta-thalassemia in combination with HbE or HbS, only 5 are less than 5 years old, reflecting both the success of the screening program and the increasing acceptance by couples of 1st trimester prenatal diagnosis.     

Auxology is a valuable instrument for the clinical diagnosis of SHOX haploinsufficiency in school-age children with unexplained short stature

SHOX (short stature homeobox-containing gene) mutations causing haploinsufficiency have been reported in some individuals with idiopathic short stature and in many patients with Leri-Weill-dyschondrosteosis. Around 80% of SHOX mutations are complete gene deletions, whereas diverse point mutations account for the rest. The aim of this study was to estimate the prevalence of SHOX mutations in children with idiopathic short stature and to give an unbiased characterization of the haploinsufficiency phenotype of such children. We recruited 140 children (61 girls), in our clinic, with idiopathic short stature, which was defined by the presence of normal IGF-I and free T(4); a normal karyotype in females; the absence of endomysium antibodies, of chronic organic, psychological, or syndromatic disease; and by the lack of clear signs of any osteodysplasia. Height, arm span, and sitting height were recorded, and subischial leg length was calculated. Two highly polymorphic microsatellite markers located around the SHOX coding region (CA-SHOX repeat and DXYS233) were PCR-amplified with fluorescent primers and separated in an automatic sequencing machine. Analysis of parental DNA was performed in the probands who had only one fragment size of each of both markers. SHOX haploinsufficiency caused by a SHOX deletion was confirmed in three probands (2%), all females, who carried a de novo deletion through loss of the paternal allele. Their auxological data revealed a significant shortening of arms and legs in the presence of a low-normal sitting height, when compared with the other 137 children tested. Therefore, the extremities-trunk ratio (sum of leg length and arm span, divided by sitting height) for total height was significantly lower in the three SHOX haploinsufficient probands, in comparison with the whole group. This observation was confirmed with the auxological data of five additional patients (four females) previously diagnosed with SHOX haploinsufficiency; all but the youngest girl had height-adjusted extremities-trunk ratios more than 1 SD below the mean. All children with SHOX haploinsufficiency exhibited at least one characteristic radiological sign of Leri-Weill-dyschondrosteosis in their left-hand radiography, namely triangularization of the distal radial epiphysis, pyramidalization of the distal carpal row, or lucency of the distal ulnar border of the radius. Our observations suggest that it is rational to limit SHOX mutation screening to children with an extremities-trunk ratio less than 1.95 + 1/2 height (m) and to add a critical judgment of the hand radiography.     

Serum ferritin level as a predictor of impaired growth and puberty in thalassemia major patients

OBJECTIVE: Previous studies suggested that in patients with thalassemia major, initiating deferoxamine (DFO) therapy before puberty can prevent iron-induced failure of growth and puberty. However, early initiation of chelation has also been associated with DFO toxicity. The aim of this retrospective study was to determine the prevalence rates of endocrine complications and DFO bone toxicity in our thalassemia major patients and to correlate them with the degree of iron chelation. METHODS: Thirty-nine patients with thalassemia major were followed for a median of 16.3 yr (range 2-28). Individual mean serum ferritin level during the study period was calculated using repeated annual measurements. Bone DFO toxicity was assessed by wrist and spine radiographs; endocrine dysfunction by anthropometric measurements and pubertal stage; and hypogonadotropic hypogonadism by lack of luteinizing hormone response to gonadotropin-releasing hormone. RESULTS: Chelation therapy was initiated at median age 4.9 yr. Mean serum ferritin level during the study period was 2698 +/- 1444 ng/mL. Hypogonadism was noted in 59% of the patients who reached pubertal age, and short stature was found in 36% of patients who reached final height. Mean ferritin level of 2500 ng/mL during puberty was the cut-off for hypogonadism, and ferritin level of 3000 ng/mL during prepuberty was the cut-off for final short stature. None of the patients who attained final height had signs of DFO bone toxicity. CONCLUSIONS: High serum ferritin levels during puberty are a risk factor for hypogonadism, and high serum ferritin levels during the first decade of life predict final short stature. It remains to be determined whether improving chelation by earlier initiation of DFO or by the combined use of DFO and deferiprone will lead to better growth and sexual development without DFO toxicity.     

Seroprevalence of hepatitis B, hepatitis C, CMV and HIV in multiply transfused thalassemia patients: results from a thalassemia day care center in Malaysia

Regular blood transfusions for patients with thalassemia have improved their overall survival although these transfusions carry a definite risk of the transmission of certain viruses. Infection with hepatitis B virus (HBV), hepatitis C virus (HCV), cytomegalovirus (CMV) and human immunodeficiency virus (HIV) leads to complications which contribute to the morbidity and mortality of patients with thalassemia. We analyzed the blood samples taken from 85 transfusion dependent thalassemics receiving treatment at the day care center in Hospital Universiti Kebangsaan Malaysia and found that the seroprevalence rates for HBV, HCV and CMV were 2.4%, 22.4% and 91.8% respectively. None of the patients tested positive for HIV. Those positive for HBV and HCV will require further tests and treatment if chronic hepatitis is confirmed.     

Body proportions during 6 years of GH treatment in children with short stature born small for gestational age participating in a randomised, double-blind, dose-response trial

The aim of this study was to assess body proportions in children with short stature born small for gestational age (SGA) before and during 6 years of growth hormone (GH) treatment. A prospective randomised double-blind dose-response study comparing the effects of 3 vs. 6 IU GH/m2/day. Seventy-nine children with short stature (height SD-score < -1.88) born small for gestational age (birth length SD-score < -1.88). Before and during GH treatment, height, sitting height (SH), hand (Hand) and foot length (Foot), biacromial (Biac) and biiliacal diameter (Biil) were measured. All results were adjusted for age and sex, and expressed as SD-scores (SDS) using reference values for healthy Dutch children. To describe the size of SH, Hand, Foot, Biac, and Biil in relation to height, these values were adjusted for the SDS of height. At baseline, these short children had small hands and feet and narrow shoulders and pelvis compared to healthy peers. Height and SH, were, however, even more affected. Consequently, on average, these children had relatively large hands and feet, and relatively broad shoulders and pelvis compared to their height, but a normal sitting height in proportion to height. In most of the individuals, the values for body proportions were, however, within the normal range. During 6 years of GH treatment the SD-scores of all measurements increased significantly towards values more close to zero. The mean size of Hand, Foot, and Biil decreased in proportion to height. The mean SH increased relatively more than height, however, to values well within the normal range. The mean Biac in relation to height had not changed after 6 years of GH treatment. No differences in the 6-year changes in body proportions were found between the two GH dosage groups. Untreated short children born small for gestational age have, on average, relatively large hands and feet, and broad shoulders and pelvis, but a normal sitting height compared to height. The increase in height during 6 years of GH treatment is accompanied by an improvement of the proportions of the size of hands, feet, and biiliacal diameter, in relation to height. The increase in height appeared to be the result of the increase in sitting height as well as leg length, but the sitting height SD-score increased slightly more than that of leg length. The changes in body proportion during GH treatment were dose-independent. Thus, 6-year continuous GH treatment with either 3 or 6 IU/m2/day in children with short stature born small for gestational age does not negatively influence body proportions.     

Advances in the allogeneic transplantation for thalassemia

Hematopoietic stem cell transplantation (HSCT) remains the only curative option for patients with thalassemia. Current results of transplantation in patients aged less than 17 years from matched related donors offer 80% to 87% probability of cure according to risk classes. Adult thalassemics treated with myeloablative conditioning continue to have inferior results because of their advanced stage of disease. With the introduction of high-resolution tissue typing techniques transplant centres worldwide are able to offer allogeneic HSCT to a much larger cohort of patients who could not benefit from transplantation because of lack of matched family donor. Although limited number of patients treated, results of transplant from unrelated matched donors are comparable to those obtained using sibling donors. Graft failure or rejection remains a significant cause of transplant failure in patients with thalassemia making difficult to perform reduced intensity conditioning regimens. Mixed chimerism is a common phenomenon after transplantation and is a risk factor for rejection. Ex-thalassemics still carry the clinical complications acquired during years of transfusion and chelation therapy. Longer follow-up and management of these complications in ex-thalassemics are essential.     

The hypercoagulable state in thalassemia.

Thalassemia is a congenital hemolytic disorder caused by a partial or complete deficiency of alpha- or beta-globin chain synthesis. Homozygous carriers of beta-globin gene defects suffer from severe anemia and other serious complications from early childhood. The disease is treated by chronic blood transfusion. However, this can cause severe iron overload resulting in progressive organ failure. Some forms of alpha thalassemia are also associated with a similar clinical picture. Despite the difficulties associated with treatment, standards of care for thalassemic patients have improved in recent years, resulting in almost doubling of the average life expectancy. As a consequence, additional previously undescribed, complications are now being recognized. In particular, profound hemostatic changes have been observed in patients with beta-thalassemia major (beta-TM) and beta-thalassemia intermedia (beta-TI) and also in patients with alpha thalassemia (hemoglobin H disease). The presence of a higher than normal incidence of thromboembolic events, mainly in beta-TI, and the existence of prothrombotic hemostatic anomalies in the majority of the patients, even from a very young age, have led to the recognition of the existence of a chronic hypercoagulable state in thalassemic patients. Despite the appearance of numerous publications on the frequent occurrence of thromboembolic complications in thalassemia, this complication has not been emphasized or comprehensively reviewed. This review summarizes the current literature and discusses possible mechanisms of the lifelong hypercoagulable state that exists in thalassemia.     

Congestive heart failure and treatment in thalassemia major

The homozygous beta-thalassemias are a group of genetically inherited hemoglobin (Hb) disorders characterized by dyserythropoietic anemia. According to the degree of anemia, two main forms, sharing a common basic molecular mechanism, are distinguished: thalassemia major (TM) and thalassemia intermedia (TI). The severity of the clinical phenotype differentiates the two forms. Thalassemia major usually presents as a severe anemia requiring life-long transfusion therapy for survival. The dramatic improvement in life expectancy of beta-thalassemia (thal) patients achieved during the past few decades by virtue of therapeutic advances, has motivated investigators' interest in a better understanding of the clinical consequences of this genetic defect. Heart complications still represent the leading cause of mortality from the disease. The mechanisms of cardiac injury along with its treatment and prevention have attracted the main research efforts in this field. In this review, we present existing knowledge and our personal experience of 30 years of follow-up of over 1,000 thalassemic patients, regarding the basis of the cardiac injury, the clinical findings and the global strategy of the therapeutic intervention in TM patients who develop congestive heart failure (CHF).     

GROWTH HORMONE TREATMENT IN CHILDREN WITH CRANIOPHARYNGIOMA: FINAL GROWTH STATUS

Twenty-seven out of thirty craniopharyngioma patients treated with human growth hormone (hGH) for 2 years or more (average 4·5 years) reached final adult heights above the population third centile, though none was above the fiftieth centile. However, only twelve of twenty-eight patients had final heights above the lower limits to be expected from their parents' heights. All patients eventually had long legs relative to sitting height (final mean subischial leg length SDS =+ 0·2, final mean sitting height SDS = -3·0). Twenty-nine patients were TSH-deficient, twenty-two were ACTH-deficient, thirteen were deficient in ADH and all had total (85%) or partial (15%) gonado-trophin deficiency. Following the administration of testosterone or hCG the boys had, on average, only half the normal adolescent growth spurt. This may have been due to the lateness of starting androgens in these patients and we recommend, when considering height, that testosterone or hCG should be started when a bone age of 13·0 ‘years’ is reached or when a lower bone age has remained unchanged for a year. The girls showed no adolescent height spurt; the average increase after oestrogen treatment commenced was 1·7 cm.     

Cholelithiasis in thalassemia major

Objectives: Aim of this study was to evaluate prevalence and characteristics of cholelithiasis in a large population of patients with thalassemia major (TM). Methods: Data from 858 consecutive patients with transfusion‐dependent thalassemia at five major Italian centers were analyzed. In these centers, a complete abdomen ultrasonography is performed yearly after the beginning of the transfusion regimen. The role of co‐inheriting Gilbert’s syndrome genotype was investigated studying the promoter region of the UGT1‐A1 gene by automated sequencing. Results: Thirty percent of TM patients had gallstones. The Gilbert’s genotype [homozygosity for (TA)₇ motif at UGT1A promoter gene], influenced both the prevalence of cholelithiasis and the age at which it developed. Conclusions: Cholelithiasis has a remarkable frequency and precocity in patients with TM and especially in those with (TA)₇/(TA)₇ UGT1‐A1 genotype. An early biliary ultrasonography is recommended from childhood and a closer follow‐up in patients with thalassemia and associated Gilbert’s syndrome may be indicated.     

Activated peripheral blood and endothelial cells in thalassemia patients

BACKGROUND AND OBJECTIVES: Thalassemia patients have alterations in the expression of some activation and adhesion molecules on peripheral blood lymphocytes. We studied cell surface antigens on peripheral blood cells associated with the activation of these cells and soluble molecules produced by activated endothelium. DESIGN AND METHODS: We investigated the expression of CD11b, CD18, CD35, CD43, CD44, and CD69 on the peripheral blood monocytes, Cd11b, CD18, CD35, CD43, CD44, CD67 on peripheral blood neutrophils and CD38 and CD69 on peripheral blood lymphocytes. We studied 68 transfusion-dependent thalassemics (group A), 10 transfusion non-dependent thalassemics (group B), 18 beta-thalassemia carriers (group C), and 28 normal individuals. Relative fluorescence intensity was used to determine the antigen density. Analysis was performed with an EPICS ELITE flow cytometer. Furthermore, soluble intercelullar adhesion molecule 1 (sICAM-1), soluble vascular adhesion molecule 1 (sVCAM-1), and E-selectin, tumor necrosis factor (TNF) alpha, and interleukin (IL) 1beta were measured in the plasma of patients by enzyme-linked immunometric assay. Results: The expression of CD11b, CD18, and CD69 on the monocytes of group A was significantly greater than in groups B and C and in controls, while CD44 was significantly downregulated in group A. CD11b, CD18, CD35, CD44, and CD67 on the surface of neutrophils and CD38 and CD69 on the surface of lymphocytes were also overexpressed in group A. CD44 was downregulated on the monocytes and upregulated on the neutrophils of the patients compared to controls. The levels of sICAM-1, sVCAM-1, E-selectin, TNF-alpha, and IL-1beta in the serum of patients in groups A and B were higher than those in group C and the controls. CONCLUSION: Endothelial activation markers are significantly increased in thalassemia patients, and activated blood cells circulate in the peripheral blood. These may be related to the vascular complications in these patients and might be useful markers for the follow-up of the vascular disease.     

Cardiorespiratory response to exercise in patients with thalassemia major

The cardiorespiratory response to exercise was examined in 13 patients, 12 to 22 yr of age, who were in stable condition while receiving regular transfusions for thalassemia major. Before transfusion (Hgb, 10.8 g/dl), the patients had reduced peak oxygen consumption for body weight (by 25%, p less than 0.002) in comparison with 20 age- and sex-matched control subjects (Hgb, 13.8 g/dl). The ventilatory equivalent for carbon dioxide was significantly reduced at all work rates, and end-tidal PCO2 was abnormally high (46.3 versus 40.7 mm Hg, p less than 0.001), but ventilatory reserve, as estimated from pulmonary function tests, was normal. Both heart rate and cardiac output (as estimated by the indirect Fick method) were abnormally high during exercise; at an oxygen consumption of 19 ml/min/kg, heart rate was 13% higher (p less than 0.01) and, at 16 ml/min/kg, cardiac output was 28% higher (p less than 0.001) in the patients than in the control subjects. Nine patients were retested 3 to 8 days after transfusion (Hgb, 13.0 g/dl, p50, 26.4 mm Hg). Neither ventilatory nor circulatory abnormalities improved significantly. In patients 12 to 22 yr of age in stable condition with thalassemia major, we conclude: cardiac output, estimated by the CO2 rebreathing method, is high and arteriovenous O2 extraction is low during exercise; the high cardiac output during exercise is associated with hypoventilation; the high cardiac output is independent of short-term changes in hemoglobin concentration associated with transfusion.     

Haplotypes and levels of fetal hemoglobin and G gamma to A gamma ratios in Mediterranean patients with thalassemia minor and major

This study concerned the gamma chain composition of Hb F and the haplotypes of 44 patients with beta-thalassemia major or intermedia and many of their relatives. Seventeen patients came from Northern (Turkish) Cyprus, 12 from the Istanbul area, and 15 from Macedonia and Bulgaria. Analysis of the A gamma T-G gamma-A gamma I ratio was made by HPLC, while haplotyping involved seven restriction sites. Specific haplotypes were present in certain populations; haplotype I [1] is the dominant type among North Cypriot thalassemia patients. Numerous types were seen in the patients from the Balkan countries. A direct relationship between the A gamma to G gamma ratios and the haplotypes, which exists among black beta-thalassemia heterozygotes [3], was also observed among these Mediterranean patients, although such analyses were considerably complicated by extensive blood transfusion therapy. Haplotypes without the Hinc II restriction site within the psi beta gene were associated with lower G gamma values than those that had this polymorphic site. The A gamma T chain was observed in a small number of beta-thalassemia homozygotes and heterozygotes. Three thalassemia chromosomes with slightly different haplotypes and one normal chromosome with a related haplotype were associated with the gamma 75 Ile----Thr substitution. A few patients with a thalassemia intermedia were heterozygotes for beta-thalassemia with either haplotypes V or VII [1] while the "nonthalassemic" chromosome had a haplotype I, which is the most common "beta-thalassemic" haplotype among the Mediterranean population(s). Detailed analyses of this chromosome have not been completed.     

Pulmonary hypertension in thalassemia: association with platelet activation and hypercoagulable state

The pathogenesis of pulmonary hypertension (PAH), a serious complication in thalassemia, is not well understood. Thromboembolism has been postulated as one of the causative factors; however, there are currently limited specific data on its role. To examine whether increased platelet activation and hypercoagulability are linked to PAH, 25 beta-thalassemia major and beta-thalassemia intermedia patients were evaluated with Doppler echocardiograms for estimation of pulmonary artery pressure and with laboratory assays for indications of a prothrombotic state. The association of clinical variables and abnormal coagulation assays with PAH was determined. PAH was identified in 17 (68%) patients; mean pulmonary artery systolic pressure was 39.8 +/- 5.4 mm Hg. PAH was significantly associated with prior splenectomy, older age, and evidence for chronic hemolysis, diagnosed in both transfused (n = 10) and nontransfused (n = 7) patients. Increased platelet activation, measured by P-selectin, was significantly associated with PAH (P = 0.001). Increased thrombin-antithrombin III level was more prevalent in the presence of PAH, but increased fibrinolysis or low protein C levels were not. This study underscores the role of platelet activation in the development of PAH and stresses its occurrence even among patients who are regularly transfused, especially those who are older and have had splenectomies.