Haemoglobin Bart's Hydrops Fetalis: Charting the Past and Envisioning the Future.

Haemoglobin Bart's hydrops fetalis syndrome (BHFS) represents the most severe form of α-thalassaemia, arising from deletion of the duplicated α-globin genes from both alleles. The absence of α-globin leads to the formation of non-functional haemoglobin Bart's (γ4) or haemoglobin H (HbH: ß4) resulting in severe anaemia, tissue hypoxia, and, in some cases, variable congenital or neurocognitive abnormalities. BHFS is the most common cause of hydrops fetalis in Southeast Asia; however, owing to global migration, the burden of this condition is increasing worldwide. With the availability of intensive perinatal care and intrauterine transfusions, an increasing number of patients survive with this condition. The current approach to long-term management of survivors involves regular blood transfusions and iron chelation, a task made challenging by the need for intensified transfusions to suppress the production of non-functional HbH-containing erythrocytes. While our knowledge of outcomes of this condition is evolving, it seems, in comparison to individuals with transfusion-dependent ß-thalassaemia, those with BHFS may face an elevated risk of complications arising from chronic anaemia and hypoxia, ongoing haemolysis, iron overload, and from their respective treatments. Although stem cell transplantation remains a viable option for a select few, it is not without potential side effects. Looking ahead, potential advancements in the form of genetic engineering and innovative therapeutic approaches, such as the reactivation of embryonic α-like globin gene expression, hold promise for furthering the treatment of this condition. Prevention remains a crucial aspect of care, particularly in areas with high prevalence or limited resources.

Optimizing transfusion therapy for survivors of Haemoglobin Bart's hydrops fetalis syndrome: Defining the targets for haemoglobin-H fraction and "functional" haemoglobin level.

Owing to the unique pathophysiology of anaemia in haemoglobin Bart's hydrops fetalis (HBHF), a transfusion strategy based on beta-thalassemia guidelines is suboptimal for chronically transfused HBHF patients. A more aggressive transfusion aimed at reducing the proportion of non-functional HbH and improving the "functional" haemoglobin (f-Hb) can lead to reduced haemolysis and improved tissue oxygenation. However, the optimal transfusion targets for these parameters are not yet defined. In this retrospective, longitudinal study on four chronically transfused patients with HBHF, we used receiver operating characteristic curves to find a pre-transfusion f-Hb of 106 g/l and a HbH of 16.1% to be the optimal thresholds to achieve a normal soluble transferrin receptor and lactate dehydrogenase, respectively.

Mild Hereditary Spherocytosis without Accompanying Hereditary Haemochromatosis: An Unrecognised Cause of Iron Overload.

Hereditary spherocytosis (HS) is a common inherited haemolytic anaemia and has great variability in its presentation. Non-transfusion iron overload in HS has only been reported with co-inheritance of hereditary haemochromatosis (HHC). We present 4 unrelated patients of East Asian ethnicity with mild HS and significant non-transfusion iron overload in the absence of known disease-causing mutations in HHC genes. We hypothesise that, in patients with mild HS, life-long chronic haemolysis and erythropoietic drive may promote iron absorption. This suggests that mild HS may not be entirely benign, and that patients with mild HS should be monitored for iron overload.

Screening for thalassemia carriers in populations with a high rate of iron deficiency: revisiting the applicability of the Mentzer Index and the effect of iron deficiency on Hb A2 levels.

Differentiating between ß-thalassemia (ß-thal) minor and iron deficiency has important implications in thalassemia carrier screening. Several complete blood count (CBC)-based equations have been proposed for differentiating these two conditions. The applicability of these equations in populations with high rates of iron deficiency and ß-thal minor, where patients can have both conditions, is limited. In addition, there have been conflicting reports on the possible effect of iron deficiency on Hb A2 level with possible consequences for thalassemia screening programs. Here, we demonstrate that in our population the Mentzer Index separates individuals with ß-thal minor from those without ß-thal minor, regardless of their iron status. Iron deficiency also does not reduce Hb A2 levels in ß-thal minor patients. Correction of iron deficiency is not required for diagnosis of ß-thal minor using high performance liquid chromatography (HPLC).

Risk factors for hyperferritinemia secondary to red blood cell transfusions in pediatric cancer patients.

BACKGROUND: Transfusion of packed red blood cells is common in pediatric cancer patients who receive chemotherapy. This study was done to identify characteristics of pediatric cancer patients at risk of hyperferritinemia secondary to frequent transfusions. PROCEDURE: In this retrospective chart review, all pediatric cancer patients who completed chemotherapy from January 2007 to January 2012 and had an assessment of serum ferritin 6 months after the end of treatment were included. Variables included: age, sex, type of cancer diagnosis, weight and body surface area (BSA) at the time of diagnosis, number of transfusions, total transfused volume (TTV), total transfused volume per body weight (TVPBW), and weight and BSA change from the time of diagnosis to the time of ferritin check. RESULTS: Of 109 eligible patients, 85 (78%) received transfusions. Sixteen patients (14.7%) had ferritin levels > 200 µg/L and four (3.7%) had ferritin levels > 1,000 µg/L. Although age, weight and BSA at cancer diagnosis, number of transfusions and TVPBW were correlated with the level of ferritin, independent risk factors were TTV (range 1,961-30,090 ml in patients with hyperferritinemia, P < 0.001) and BSA change from the time of diagnosis to the time of ferritin check (range -0.15 to 0.31 m(2) in patients with hyperferritinemia, P < 0.001). Increase in BSA was correlated with reduction of hyperferritinemia in follow-up ferritin measurements (P = 0.049). CONCLUSIONS: In addition to TTV, change in BSA is an independent predictor for the degree and possibly persistence of hyperferritinemia in pediatric cancer patients and should be considered in decisions to initiate interventions.

Between Scylla and Charybdis: thrombosis in children with hemophilia.

Thromboembolism is an infrequent complication in children with hemophilia that has been traditionally associated with the presence of a central venous access device. Novel rebalancing agents have shown promising results as prophylactic therapies to minimize the risk of bleeding but both thromboembolism and thrombotic microangiopathy have been reported as complications. The management of thrombosis in children with hemophilia is particularly challenging given the inherent risk of bleeding. In this paper, we present clinical vignettes to review the literature, highlight challenges, and describe our approach to managing thromboembolism in children with hemophilia.

Outcomes of haemoglobin Bart's hydrops fetalis following intrauterine transfusion in Ontario, Canada.

OBJECTIVES: With improved access to intrauterine transfusion (IUT), more fetuses with haemoglobin Bart's hydrops fetalis (HBHF; homozygous α0-thalassaemia) will survive. DESIGN: To evaluate the long-term outcome of affected fetuses with and without IUT in Ontario, Canada, we retrospectively collected data on IUTs and pregnancy outcomes in all cases of HBHF, from 1989 to 2014. Clinical outcome and neurocognitive profiles of long-term survivors were also collected and compared with data from 24 patients with transfusion-dependent ß-thalassaemia (TDT-ß). RESULTS: Of the 99 affected pregnancies (93 prenatally diagnosed), 68 resulted in miscarriage or elective termination of pregnancy. Twelve mothers (12%) continued their pregnancies without IUT, and none of those newborns survived the first week of life. All 13 fetuses that received IUT(s) were live-born, but 3 died due to severe hydrops at birth and 1 died due to infection. The remaining nine survivors, in comparison with TDT-ß patients, had earlier iron overload requiring iron chelation therapy. Endocrinopathies and short stature were more frequent in these patients. Neurocognitive outcome was not significantly affected in five patients who were assessed, and none were diagnosed with intellectual impairment. In three patients, MRI studies demonstrated brain white matter changes in keeping with 'silent' ischaemic infarcts. CONCLUSIONS: In patients with HBHF, IUT is associated with improved survival. While acceptable neurocognitive outcome can be expected, these patients have more clinical complications compared with their TDT-ß counterparts. The clinical and neurocognitive outcomes of HBHF should be discussed in detail when counselling and offering IUT for patients.

Outcomes and risk factors of massive and submassive pulmonary embolism in children: a retrospective cohort study.

BACKGROUND: Little is known about severe pulmonary embolism in children. We aimed to report pulmonary embolism outcomes, identify risk factors for unfavourable outcomes, and evaluate the discriminative ability of two clinical-severity indices in children. METHODS: In this retrospective cohort study, we included consecutive patients aged 18 years or younger with acute pulmonary embolism, objectively diagnosed radiologically or pathologically, between Jan 1, 2000, and Dec 31, 2016, from two Canadian paediatric hospitals (The Hospital for Sick Children, Toronto, ON, and the Children's Hospital of Eastern Ontario, Ottawa, ON). Exclusion criteria were sudden death without radiological or pathological pulmonary embolism confirmation and non-thromboembolic pulmonary embolism. The primary outcome was a composite of unfavourable outcomes of pulmonary embolism-related death and pulmonary embolism recurrence or progression. Potential predictors of the composite unfavourable outcome (ie, age at pulmonary embolism diagnosis, sex, underlying cardiac disease, severity of the pulmonary embolism, presence of a central venous catheter, associated venous thromboembolism, family history of thrombosis, treatment modalities, thrombophilia, obesity, and recent surgery) were explored with logistic regression. We calculated pulmonary embolism severity index (PESI) and simplified PESI (sPESI) using age-adjusted parameters; we estimated the ability of PESI and sPESI to predict mortality using receiver-operating characteristic (ROC) curve analysis. FINDINGS: Of the 170 patients included, 37 (22%) had massive, 12 (7%) submassive, and 121 (71%) non-massive pulmonary embolism. Patients with massive or submassive pulmonary embolism were younger (median age 12·5 years [IQR 0·6-15·1] vs 14·4 years [9·3-16·1], p<0·0001), more likely to have a cardiac condition (16 [33%] vs 17 [14%] patients, p=0·009), and had more central venous catheters (29 [59%] vs 48 [40%] patients, p=0·027) than patients with non-massive pulmonary embolism. Aggressive treatment modalities were more commonly used in massive or submassive pulmonary embolism (22 [45%] vs 7 [6%] patients, p<0·0001). Of the predictors tested, only pulmonary embolism severity was associated with the composite unfavourable outcome in the multivariable analysis (odds ratio 3·53, 95% CI 1·69-7·36; p=0·011). The area under the ROC curve for PESI to predict 30-day mortality was 0·76 (95% CI 0·64-0·87). Sensitivity of sPESI was 100% and specificity was 30%. INTERPRETATION: Massive or submassive pulmonary embolism led to higher rates of unfavourable outcomes than non-massive pulmonary embolism in children. Further adaptations of PESI and sPESI are required to improve their clinical usefulness in paediatric patients. FUNDING: Trainee Start-Up Fund (The Hospital for Sick Children).

International medical response to a natural disaster: lessons learned from the Bam earthquake experience.

An earthquake measuring 6.5 on the Richter scale devastated Bam, Iran on the morning of 26 December 2003. Due to the great health demands and collapse of health facilities, international aid could have been a great resource in the area. Despite sufficient amounts and types of resources provided by international teams, the efficacy of international assistance was not supported in Bam, as has been experienced in similar events in other countries. Based on the observations in the region and collecting and analyzing documents about the disaster, this manuscript provides an overview of the medical needs during the disaster and describes the international medical response. The lessons learned include: (1) necessity of developing a national search and rescue strategy; (2) designing an alarm system; (3) establishing an international incident command system; (4) increasing the efficacy of the arrival and implementation of a foreign field hospital; and (5) developing a flowchart for deploying international assistance.

Thalassaemia in children: from quality of care to quality of life.

Over the past few decades, there has been a remarkable improvement in the survival of patients with thalassaemia in developed countries. Availability of safe blood transfusions, effective and accessible iron chelating medications, the introduction of new and non-invasive methods of tissue iron assessment and other advances in multidisciplinary care of thalassaemia patients have all contributed to better outcomes. This, however, may not be true for patients who are born in countries where the resources are limited. Unfortunately, transfusion-transmitted infections are still major concerns in these countries where paradoxically thalassaemia is most common. Moreover, oral iron chelators and MRI for monitoring of iron status may not be widely accessible or affordable, which may result in poor compliance and suboptimal iron chelation. All of these limitations will lead to reduced survival and increased thalassaemia-related complications and subsequently will affect the patient's quality of life. In countries with limited resources, together with improvement of clinical care, strategies to control the disease burden, such as public education, screening programmes and appropriate counselling, should be put in place. Much can be done to improve the situation by developing partnerships between developed countries and those with limited resources. Future research should also particularly focus on patient's quality of life as an important outcome of care.