ALBERT

Description: The “Optimal Liver Iron” range in iron overloaded patients with thalassemia has been established by Olivieri and Brittenham (Blood, 1997) as 1–2.2 mg/g wet weight liver using direct measurement or calculated as 3.2 to 7 mg/g dry liver weight based on a 3.33 correction factor for body water. This report describes the relationship between liver iron concentration (LIC) measured by SQUID biosusceptometry (BLS, wet weight) compared to liver biopsy (dry weight), in patients with thalassemia (THAL) or sickle cell disease (SCD). A total of 38 chronically transfused patients (THAL n=19, SCD n=19) were prospectively assessed for LIC measured by BLS and liver biopsy within 2 month of each other. Most BLS results were submitted to data repository before receiving iron concentration from liver biopsy. LIC was measured by a low temperature SQUID biosusceptometer system (Ferritometer®) under the standardized Hamburg-Torino-Oakland protocol. Iron in fresh tissue and paraffin embedded liver biopsy samples was measured at Mayo clinics by Inductively Coupled Plasma Mass Spectrometer (ICP-MS). Subjects ranged in age from 5 to 40 years (median: 18 y). Median LIC (n=38) measured by SQUID was 1777 (365–4883) [mg/g wet weight], median LIC by biopsy (fresh tissue) was 10861(1854–32864) [mg/g dry weight]. After excluding the subjects with BMI〉30 kg/m2 (n=5), the Spearman rank correlation between wet weight LIC assessed by BLS and dry weight LIC from fresh tissue sample measured by ICP-MS was highly significant (RS=0.90, p

Description: Background : Reduced bone mineral density (BMD) has been reported in adults and children with sickle cell anemia (SCA). Dual energy x-ray absorptiometry (DXA) is routinely used for measuring BMD because of less radiation exposure and lower cost. However, changes in vertebral body shape, marrow hyperplasia and bone infarction due to SCA may affect the evaluation of BMD with DXA. Hence, we compared DXA with quantitative computerized tomography (QCT), which measures true volumetric density, and may be less influenced by bone changes. Methods : The study enrolled children between 9–19 years of age with SCA, and one or more severe manifestations: 〉2 hospital admissions/year, growth failure, avascular necrosis, or regular red cell transfusions for sickle cell-related complications. BMD of lumbar spine was determined by performing DXA of lumbar spine (Hologic Delphi-A, Bedford, MA). The apparent volumetric bone mineral density (BMAD) was calculated from bone mineral content, and compared to age, sex and ethnicity-matched reference data. BMD of the lumbar spine was also measured by QCT (Mindways Software, San Francisco, CA), and compared to age and sex-appropriate reference data. Results : The study has enrolled 25 patients (13 females and 12 males), of which 16 were younger than 14 years. In 6 children the height was 6 months, including 10 who had been transfused for 〉2 years. Calcium intake, assessed by a standardized questionnaire, was less than recommended dietary allowance in 13 patients. The z-score for BMAD determined by DXA was 〉 −1.0 in 8, between −1.0 and −2.0 in 5, and 〈 −2.0 in 12 patients. The z-score for lumbar spine by QCT was 〉 −1.0 in 20, between −1.0 and −2.0 in 1 and 〈 −2.0 in 4 patients. DXA-derived BMD (areal density) and BMAD (apparent volumetric density) z-scores did not differ significantly (p=0.16). On the other hand, the paired values of z-scores by DXA (BMAD) and QCT were significantly different (p=.002). When z-scores were categorized as greater or less than −1.0, the results were concordant in 13 (both DXA and QCT normal in 8, and both DXA and QCT abnormal in 5), and discordant in 12 cases (abnormal DXA with normal QCT in every case). Among patients in discordant group, 9/12 had been on regular red cell transfusions for 〉6 months, compared to 4/13 with concordant results (p=.047). There was no difference in the serum ferritin values between the two groups (p=.685). No significant difference in the prevalence of low BMAD z-scores was detected between groups based upon age, calcium intake, or growth failure. Five out of the 12 patients with BMAD z-score 〈 −2.0 were not on regular transfusion program. Conclusions : Almost half of the children with SCA had BMD below −2 standard deviations compared to age-matched controls. Low BMD was observed in chronically transfused as well as non-transfused children. In comparison, 16% of the patients were classified as low BMD (z 〈 −2.0) by QCT. The paired DXA/QCT results were discordant in half of the sample, with patients on regular transfusions for 〉6 months more likely to have normal QCT results. It is likely that the reduction in marrow hyperplasia following initiation of regular transfusions may disproportionately affect the trabecular BMD measured by QCT. Longitudinal evaluation of BMD in patients starting on transfusion program could help to define the effect of transfusions on measures of BMD in SCA.

Description: Abstract 3155 Poster Board III-92 Background Standard of practice recommends slow transfusion (i.e., 5 ml per kg over 4 hours) for children with a hemoglobin level less than 5.0 g per dL secondary to severe chronic anemia (Principles and Practice of Pediatric Oncology. 4th ed. 2002:1206). Transfusion-associated circulatory overload (TACO) remains a theoretical problem but usually manifests in patients with poor underlying cardiopulmonary status and specifically in the very young (i.e., neonates) and the very elderly (ISBT Science Series 2009;4:63-71). As no evidence exists as to what rate of transfusion for children with severe chronic anemia would be unsafe, our Pediatric Intensive Care Unit (PICU) has been utilizing a more liberal transfusion practice intermittently for the last ten years. Methods After institutional review board approval, we reviewed all patients admitted to the PICU over the last ten years with a hemoglobin less than 5.0 g per dL. Patients transfused an average of less than 5 ml per kg over 4 hours were excluded. The remaining patients transfused greater than 5 ml per kg over 4 hours had a more extensive chart review and those patients diagnosed by ICD9 code with acute blood loss were further excluded. For the remaining patients who met the criteria for severe chronic anemia and received greater than 5 ml per kg averaged over 4 hours, we documented vitals including heart rate, respiratory rate, systolic and diastolic blood pressure, oxygen saturation and inputs/outputs as well as diuretic usage and chest radiograph findings to analyze for signs of TACO. We further compared these patients to a control group that received slow transfusions. Statistical analysis was done using one- and two-sample t-tests. Results 17 patients with a median age of 2.2 years (range 4 mos-12 yrs) received transfusions which met our inclusion and exclusion criteria, with a median transfusion rate of 10 ml/kg/4 hrs (range 6.8-49.6). No patient had an adverse event or changes in their vitals consistent with TACO. Heart rate dropped significantly although not statistically more than the randomly assigned control population (one-sample t-test, t=3.277, p=0.002, two-sample t-test, t=0.68, p=0.25). No patient in either group had a new oxygen requirement or worsening of their chest radiograph. Diuretics and oxygen supplementation were used in both groups empirically only. Discussion TACO appears to be a theoretical risk in the normal pediatric population; therefore, slow transfusion is likely an unwarranted anecdotal practice for children with severe chronic anemia. Both the study patients and control group had a statistically significant drop in heart rate with transfusion, emphasizing the safety of any rate of transfusion in our population. Rate of transfusion must be based on multiple factors including convenience, timeliness of procedures and of transport to an appropriate care facility, risk of alloimmunization, wastage of blood, stress for the family and need for PICU monitoring. Jayabose et al. reported similar results in 1993 (Am J Pediatr Hematol/Oncol 1993;15:324-7), but institutional practice has not changed. Although with a small preliminary sample size, we report a similar retrospective safety profile emphasizing the lack of risk for more liberal transfusion rates in pediatric patients with severe chronic anemia. Disclosures No relevant conflicts of interest to declare.

Description: Chronic transfusion therapy is being used more frequently to prevent and treat the complications of sickle cell disease. Previous studies have shown that the iron overload that results from such therapy in other patient populations is associated with significant morbidity and mortality. In this study we examined the extent of iron overload as well as the presence of liver injury and the predictive value of ferritin in estimating iron overload in children with sickle cell disease who receive chronic red blood cell transfusions. A poor correlation was observed between serum ferritin and the quantitative iron on liver biopsy (mean 13.68 ± 6.64 mg/g dry weight;R = 0.350, P = .142). Quantitative iron was highly correlated with the months of transfusion (R = 0.795, P 

Description: Abstract 264 Background: Approximately half of sickle cell anemia (SCA) patients will develop aseptic necrosis (AVN) of the hips, with the majority of cases progressing to total collapse of the femoral head. Total hip arthroplasty (THR) in patients with SCA has been associated with high rates of perioperative complications and eventual failure of the prosthesis. Previous studies have suggested that hip coring decompression (HCD) is effective in decreasing pain and slowing the progression of AVN. In the most recent study of HCD in SCA, the mean surgical time was 1.1 hours and anesthesia time 2.1 hours; associated blood loss was 56cc. The length of hospital stay (LOS) was 5 days with a mean of 3 days postoperatively. We report a surgical approach designed to decrease surgical time while at the same time improving perfusion to the effected tissue with repeated small bone fenestrations. Patients and Methods: From 11/1/2009 to 7/1/2010, 8 patients (10 hips) with SCA underwent HCD for femoral AVN: 3 females and 5 males with an average age of 31.3 years (median 25.5, range 11 to 50). 5 patients had SS and 3 SC disease. Seven hips were diagnosed as Ficat stage II and 3 as stage III. Physical exams and pain assessments were performed before surgery and at follow-up by the same orthopedic surgeon. The clinical protocol includes a two day hospital stay: admission the day before surgery with overnight hydration at 1.5× maintenance fluids, postoperative management of pain and hydration, and discharge after PT evaluation and instruction. Patients are fully ambulatory at discharge and given exercise instructions by physical therapists. Description of Procedure and Physical Therapy Plan: Under anesthesia, patients are placed in a lateral position on a bean-bag and bony prominences are well padded; an axillary roll is used. The hip, thigh, and mid part of the leg are sterilely prepared and draped, allowing rotation of the leg. The fluoroscopic C-Arm is placed underneath the bed, so that a true AP of affected hip is obtained. The fluoroscopic image determines the starting point for the initial 0.5 cm incision with a 15-blade. The drill (with a 5.0 bit) is then advanced to the proximal lateral cortex of the femur, distal to the greater trochanter. Under radiographic guidance, drill position is confirmed and advanced to the affected area of the femoral head. The drill is then withdrawn to the cortex (but within the cortical window) and advanced in different directions to achieve 3 adequate core channels. Prior to applying dressings, a six-inch long 18-gauge needle on a 10 cc syringe, containing 0.25% Marcaine with epinephrine is placed into the affected hip joint, under fluoroscopic guidance, and a small volume of the anesthetic is injected for relief of postoperative pain and pain associated with synovitis. Results: The average surgical and anesthesia time in minutes were: 15.9 ± 6.6 and 53.4 ± 18.1 respectively; mean blood loss was less than 10 cc. Three procedures were performed under conscious sedation without tracheal intubation. Two procedures were performed during an admission for acute pain; the remaining 8 were scheduled surgical admissions. The average LOS for the scheduled procedures was 5 days (3.5 days postoperative). No complications were reported in the immediate or 6-week postoperative periods. In this series of 10 hips, all patients were fully weight bearing and ambulatory at discharge. Prior to surgery, all 10 hips were rated as a 10 on a 10-point pain scale. At the 6 week follow-up exam, 8/10 hips were rated as pain free, one hip was rated as a 1/10 and one hip remained a 10/10. The two patients undergoing surgery during acute pain episode involving the affected hip received immediate relief and were able to be discharged early. Conclusion: The modified HCD technique utilizing small, repeated fenestrations is safe and is associated with reduced operative times, reduced anesthesia time, and negligible blood loss compared to previous studies of HCD for femoral AVN in SCA. Preliminary data indicates it is effective in decreasing the pain associate with AVN. We plan to follow these and future patients for 5 years with serial radiographs and evaluations utilizing the validated, reliable Children's Hospital Oakland Hip Evaluation Scale. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4774 Renal medullary carcinoma (RMC) is a highly aggressive malignant neoplasm originally thought to be unique to individuals with sickle cell trait (SCT). Common symptoms include hematuria, abdominal pain, and weight loss. The disease is usually metastatic at presentation and is almost universally fatal within months of diagnosis. Herein, we describe an adolescent with homozygous hemoglobin SS (Hgb SS) and RMC. This is the third case of RMC reported in Hgb SS, and the first case with prior hydroxyurea therapy (Dimashkieh Arch Pathol Lab Med 2003 and Swartz Urology 2002). In addition to five reported cases in individuals with hemoglobin SC, it now appears that RMC is not unique to individuals with SCT and should instead be considered more inclusively related to the family of sickle hemoglobinopathies (Davis Am J Surg Pathol 1995, Luthra Intern Med 2010, Baig J Natl Med Assoc 2006, Swartz Urology 2002). A 13 year-old African American male with Hgb SS, treated with hydroxyurea since 2 months of age, presented with a several month history of recurrent abdominal pain and microscopic hematuria. An abdominal ultrasound demonstrated normal appearing kidneys that measured 8.4 cm and 9.7 cm on the right and left sides, respectively. He continued to have abdominal pain, often associated with intermittent sickle cell extremity pain. A repeat sonogram was obtained 9 months after the initial ultrasound due to a new complaint of scrotal pain. The formerly normal left kidney now had a 5 cm mass in the mid-to-lower pole, along with moderate caliceal dilation and cortical thinning of the superior pole. Computed tomography (CT) and positron emission tomography scans confirmed the renal mass along with local invasion into the psoas muscle, liver metastases, pulmonary metastases, and retroperitoneal lymphadenopathy. Multiple core needle biopsy specimens were obtained from the left kidney, diagnostic of RMC. Histopathology showed widespread areas of necrosis with only a few areas of viable tumor. The viable tumor cells formed gland-like structures and had infiltrating sheets with rhabdoid features, eosinophilic cytoplasm, and prominent nucleoli. Immunohistochemical analysis demonstrated strong positivity for EMA, P53 (〉95%), and PAX8. CD117 was mostly negative, however there were focal areas of weak cytoplasmic reactivity. ALK-1 immunostain, INI-1, p63, and hepar-1 were all negative. Fluorescence in situ hybridization showed no evidence of t(9;22) BCR;ABL rearrangement but did show extra copies of the BCR gene in 73% of cells. Neoadjuvant chemotherapy with 3 cycles of carboplatin, gemcitabine, and paclitaxel and one cycle of carboplatin, gemcitabine and bortezomib resulted in an improvement on imaging in the primary tumor and metastatic sites. A left radical nephrectomy and lymph node dissection were then performed. Pathology showed 10–20% focally viable renal medullary carcinoma within the kidney with evidence of vascular invasion and positive margins. The sampled lymph nodes were free of tumor. Several weeks later he underwent thoracoscopic resection of left pleural and pulmonary nodules, both of which were positive for metastatic disease. Over the next 11 months, he received 5 cycles of chemotherapy consisting of alternating cycles of carboplatin, gemcitabine, paclitaxel and carboplatin, gemcitabine and bortezomib, followed by 5 additional cycles of methotrexate, vinblastine, doxorubicin and cisplatin. Palliative radiation therapy delivered to the psoas muscle for pain management was beneficial. After a brief initial response to therapy, interval imaging studies demonstrated stable disease followed by subsequent florid progression. Given disease progression, his therapy was changed to the tyrosine kinase and vascular endothelial growth factor receptor antagonist, axitinib. Sixteen months from the time diagnosis, he is ambulatory but with widespread metastatic disease. This case highlights the need for a heightened index of suspicion for RMC in all patients with sickle hemoglobinopathies, not just those with SCT. The lack of sensitivity of renal ultrasound in this case and two others suggests that CT may be required for early diagnosis of RMC (Blitman AJR 2005 and Wesche Pediatr Pathol Lab Med 1998). While hydroxyurea is an effective medication with an excellent safety margin in sickle cell disease, the carcinogenic risk of long-term exposure in sick cell disease remains unknown. Disclosures: Off Label Use: Hydroxyurea for sickle cell disease modulation.

Description: Introduction: Compliance with Desferrioxamine is the most important factor determining morbidity and mortality in transfusion dependent thalassemia patients. Clinical and laboratory methods to assess compliance are essential in modifying patient treatment and determining efficacy of therapy. Simple screening tools for patient compliance assessment needs to be developed and must be correlated with reliable measurement of iron stores. Objective: The purpose of this study is to assess a simple compliance tool and compare it with quantitative iron stores. Methods and Patients: A Likert Numerical Scale assessed Adherence to a chelation program. This scale rated adherence to compliance from 1 (poor) to 5 (excellent). 90 transfusion dependent thalassemia patients underwent a brief interview, followed by the administration of the Likert Numerical scale to both the patient and their corresponding physician. This was followed by quantitation of their Serum Ferritin (SF) and liver iron concentration (LIC) utilizing the LTc- SQUID biosusceptometer (Ferritometer ®, Model 5700, Tristan Technologies, San Diego, USA). A subset of patients was followed serially to determine if compliance and liver iron changed as a result of the initial testing. Results: LIC was assessed in a total of 90 transfusion-dependent patients with a mean age of 17 years (4 – 48 y). The average duration of transfusion and chelation therapy was 14.6 y (range: 1 – 42) and 12.1 y (1 – 40 yrs), respectively. The median value for LIC was 2307 μg/g-liver (range: 364 – 7570). 78 % of patients rated themselves as very compliant (4 or 5) yet 40% of these patients had elevated LIC 〉 2500μg/g-liver. 92% of the patients received an identical rating from their physician (Spearman rank RS = 0.9). 19/28 patients with high compliance ratings had elevated LIC (〉 2500 μg/g) secondary to recent onset of chelation therapy or inadequate Desferrioxamine dosing when compared to their PRBC cc/kg/y requirements. In 9 compliant patients, no apparent explanation for their elevated liver iron could be found. A subgroup of 16 patients with a mean age of 17 years (3 – 44y) underwent serial LIC and SF measurements. The median interval between first and last measurements was 10 month (range: 4–15). At the time of first SQUID measurement, the median values for LIC and SF were1202 μg/g-liv (893–6167) and 1502 μg/l (660–4496) respectively. Following counseling concerning the liver iron results, DFO dose changes occurred and compliance rose from 1 (poorest) to 5 (excellent) in 7/8 patients studied. The LIC decreased by 25% (7–60%) as the compliance rate improved. In contrast, the SF fluctuated, but at the time of study testing, 10 patients had a significant increase in serum ferritin despite a lower LIC. Conclusion: Patient compliance can be adequately assessed and result in improved iron balance. However, SF may underestimate compliance and result in inadequate management. We recommend all patients undergo serial assessment of compliance accompanied with LIC and necessary counseling containing their iron stores.

Description: BACKGROUND: β thalassemia is one of the most common single gene disorders. Hematopoietic stem cell transplantation (HCT) from a human leukocyte antigen (HLA)-identical sibling donor is a curative option that minimizes the risk of graft-versus-host disease, compared to alternative donor HCT. In families that have an affected child, preimplantation genetic diagnosis (PGD) can be utilized to select an unaffected embryo that is HLA-identical. Briefly, this procedure requires in vitro fertilization, oocyte retrieval, fertilization and blastomere biopsy for preimplantation analysis and identification of unaffected HLA-identical embryos. After delivery, umbilical cord blood from the sibling donor is collected for HCT. In our institution, PGD has been pursued as a therapeutic option by families with thalassemia. The estimated cost of this uninsured procedure is $20,000 per cycle. METHODS: Families affected with β thalassemia who attempted PGD were identified and reviewed for indication, attempted cycles, successful pregnancy and transplantation outcome. RESULTS: Eight identified families affected by thalassemia underwent PGD. The diagnosis of their affected children included: 6 cases of β thalassemia major and 2 cases of transfusion dependent E β thalassemia patients. A total of 14 cycles of PGD were attempted, ranging from 1–4 attempts per family. Following successful identification of HLA-identical cells, 2 pregnancies occurred (1 early miscarriage, 1 successful delivery). This pregnancy resulted in the engraftment of a β thalassemia child. CONCLUSION: PGD including selection of HLA-identical sibling embryos is a novel, therapeutic approach for patients with β thalassemia. While this offers the possibility of recruiting a suitable donor for HCT, it is limited by significant financial and emotional burdens that it places on families affected with β thalassemia. Improvements in its efficiency and cost will make this a more viable option for affected families.

Description: Abstract 1059 Background: Moyamoya disease is a progressive cerebrovascular complication of sickle cell anemia characterized by collateral arterial formation in response to progressive stenosis of the large intracranial arteries. Despite chronic transfusions, moyamoya is associated with a high risk of stroke recurrence. Encephaloduroarteriosynangiosis (EDAS) is a surgical technique used to reestablish or augment cerebral perfusion in patients with moyamoya disease. However, evidence for its efficacy in SCA patients is limited. We initiated a prospective study to determine whether EDAS is safe and increases blood flow to ischemic areas of brain in SCA patients with moyamoya. Methods/Results: SCA patients who had complete or partial obstruction of the dICA with progression to moyamoya disease were eligible for EDAS. Progressive cognitive decline, dystonia and persistent seizures were also factors influencing eligibility. Seven SCA patients (age: median 16yrs, range 4–23yrs; sex: 5F/2M ) with moyamoya disease underwent encephaloduroarteriosynangiosis (EDAS) procedures between 3/2007 and 9/2010. All 7 patients were regularly transfused for a history of stroke or MRA-documented ICA stenosis. Complete or partial obstruction of the dICA with moyamoya changes was detected on MRA scans and confirmed by cerebral angiography. Bilateral (n = 2) or unilateral (n = 5) encephaloduroarteriosynangiosis procedures in which the superficial temporal artery is transplanted through a small craniotomy with dural and arachnoid opening and sutured to the pia were performed. Perfusion MR-weighted imaging was performed pre- and post-operatively to evaluate changes in relative cerebral blood volume and time to peak enhancement. Results: All patients have remained free of neurovascular complications and have had no new ischemic changes on MRI with an average follow-up of 26 months. All patients subjectively reported improvement in overall well-being. A decrease in the frequency of headaches (n=1), resolution of seizures (n=2) and improved gait (n=1) were also observed. Collateral anastomoses between external and internal carotid arteries were established by MRA in all patients. All 4 patients who had pre and post-procedure MRA perfusion imaging showed a reduction in the delay of time to peak enhancement in the affected territory after EDAS. Conclusion: Our results indicate that EDAS is a safe and effective surgical procedure to re-establish blood flow to ischemic brain tissue in patients with SCA who develop moyamoya disease. MRA perfusion imaging may be a useful tool to evaluate improved perfusion status after EDAS. Further examination of neuropsychologic correlates, such as executive function, with EDAS procedures in these patients is presently underway. Disclosures: Vichinsky: Novartis: Research Funding; Apotex: Research Funding.

Description: Pulmonary hypertension (PHT) is a complication that is associated with high mortality rate. It is increasingly recognized in thalassemia intermedia (TI) as a leading factor in heart failure and death. Undetected PHT has been reported in 60–75% of patients. Data on PHT and thalassemia major is limited. However, these patients have many risk factors for PHT, including splenectomy, red cell phosphatidylserine exposure, coagulation abnormalities and iron overload. Since chronic hemolysis continues despite transfusion, these patients are also at risk for hemolysis-associated PHT. This is a recently described syndrome where free hemoglobin scavenges nitrous oxide and catalyzes the formation of reactive oxygen species. The purpose of this study is to determine the prevalence of PHT in transfused thalassemia patients and its risk factors. We compared the echocardiogram of 28 patients with their transfusion history, iron stores, chest x-ray, age, hemoglobin level, splenectomy status and cardiac function. The prevalence of PHT in this population was 57%. Sixteen of the 28 patients had a tricuspid regurgitant jet velocity ≥2.5 m/s, indicating PHT. 5 patients had a jet velocity ≥ 2.9 m/s suggestive of moderate PHT. Patients with PHT were more likely to be older (29±10 vs. 24±7 years without PHT, r=0.52, p=0.01) and male (56%). 41% of the female patients undergoing echocardiogram exam had PHT, while 82% of the men screened had PHT (p=0.03). PHT was also inversely related to ferritin level (r=−0.46, p=0.02). A history of an abnormal CXR occurred more frequently in the PHT group (38% vs. 8%, p=0.08), but did not reach statistical significance. However, there was no difference in hemoglobin level, creatinine, splenectomy rate (63% vs. 58%) or abnormal cardiac function between patients with PHT vs. those without PHT. Two of the 16 patients with PHT have initiated therapy with hypertransfusion or sildenafil. An intermittently transfused 25-year-old female patient lowered the tricuspid jet velocity from 3.2 to 2.4 m/s following hypertransfusion program. The second patient, a 44-year-old chronically transfused female, lowered her tricuspid jet velocity from 3 to 2.3 m/s within one month of sildenafil therapy. In conclusion, PHT is a common complication in transfused thalassemia patients that is under recognized and under treated. In contrast to other complications, adequate chelation and low iron stores are not protective. Since secondary PHT is associated with a high mortality and morbidity, annual screening with echocardiogram for all thalassemia patients is recommended. Early identification of PHT and its risk factors may prevent the irreversible cardiomyopathy that may develop. Prospective studies evaluating therapies, including hypertransfusion, sildenafil and arginine are needed.