Zehra Fadoo

New developments in the management of congenital Factor XIII deficiency

Congenital Factor XIII (FXIII) deficiency is a rare, inherited, autosomal recessive coagulation disorder. Most mutations of this condition are found in the A-subunit with almost half these being missense mutations. Globally, approximately one in three million people suffer from this deficiency. Factor XIII deficiency is associated with severe life threatening bleeding, intracranial hemorrhage, impaired wound healing, and recurrent pregnancy losses. FXIII is known to have a potential role in mediating inflammatory processes, insulin resistance, bone metabolism, neoplasia, and angiogenesis. The algorithm provided for FXIII diagnosis and classification will enable prompt identification and early intervention for controlling potential life threatening complications. Prophylactic replacement therapy using blood products containing FXIII such as fresh frozen plasma, cryoprecipitate, or using FXIII concentrate remains the mainstay for the management of FXIII deficiency. In most parts of the world, cryoprecipitate and plasma transfusions are the only treatments available. Management developments have revealed the effectiveness and safety of recombinant FXIII concentrate for prophylaxis and treatment. The aim of this review is to provide an overview of advancements made in the management of FXIII deficiency from the time it was first detected, highlighting novel developments made in recent years. Greater research is warranted in identifying novel approaches to manage FXIII deficiency in light of its underlying pathophysiology.Congenital Factor XIII (FXIII) deficiency is a rare, inherited, autosomal recessive coagulation disorder. Most mutations of this condition are found in the A-subunit with almost half these being missense mutations. Globally, approximately one in three million people suffer from this deficiency. Factor XIII deficiency is associated with severe life threatening bleeding, intracranial hemorrhage, impaired wound healing, and recurrent pregnancy losses. FXIII is known to have a potential role in mediating inflammatory processes, insulin resistance, bone metabolism, neoplasia, and angiogenesis. The algorithm provided for FXIII diagnosis and classification will enable prompt identification and early intervention for controlling potential life threatening complications. Prophylactic replacement therapy using blood products containing FXIII such as fresh frozen plasma, cryoprecipitate, or using FXIII concentrate remains the mainstay for the management of FXIII deficiency. In most parts of the world, cryoprecipitate and plasma transfusions are the only treatments available. Management developments have revealed the effectiveness and safety of recombinant FXIII concentrate for prophylaxis and treatment. The aim of this review is to provide an overview of advancements made in the management of FXIII deficiency from the time it was first detected, highlighting novel developments made in recent years. Greater research is warranted in identifying novel approaches to manage FXIII deficiency in light of its underlying pathophysiology.

Acute myeloid leukemia in a patient with thrombocytopenia with absent radii syndrome.

Hereditary amegakaryocytopoiesis associated with skeletal anomalies, especially affecting the upper limbs, is called thrombocytopenia with absent radii (TAR) syndrome (1). In addition to the radial agenesis, defects of phalanges, humeri, lower limbs, and cardiac abnormalities may be present (2). The thrombocytopenia is variable in severity and some of the patients may require repeated platelet transfusions. The deaths from TAR syndrome are usually sequelae of massive bleeding or infection (3). Most of the patients who survive have a spontaneous increase in megakaryocytopoiesis, usually by age 1 year. There have been two reported cases in the literature of children with TAR syndrome in whom leukemia developed (4,5). This article reports yet another infant with TAR syndrome in whom acute myeloid leukemia developed at age 1 year.

Chromosomal abnormalities in Pakistani children with acute lymphoblastic leukemia.

BACKGROUND Cytogenetic abnormalities have important implications in diagnosis and prognosis of acute leukemia and are now considered an important part of the diagnostic workup at presentation. Karyotype, if known at the time of diagnosis, guides physicians to plan appropriate management strategies for their patients. AIM AND OBJECTIVES To determine the cytogenetic profile of acute lymphoblastic leukemia (ALL) in Pakistani children in order to have insights regarding behavior of the disease. MATERIALS AND METHODS A retrospective analysis of all the cases of ALL (<15years old) diagnosed at Aga Khan University from January 2006 to June 2011 was performed. Cytogenetic analysis was made for all cases using the trypsin-Giemsa banding technique. Karyotypes were interpreted using the International System for Human Cytogenetic Nomenclature (ISCN) criteria. RESULTS A total of 153 patients were diagnosed as ALL during the study period, of which 127 samples successfully yielded metaphase chromosomes. The male to female ratio was 1.8:1. A normal karyotype was present in 51.2% (n=65) of the cases whereas 48.8% (n=62) had an abnormal karyotype. Most of the abnormal cases showed hyperdiploidy(13.4%) followed by t(9;22)(q34;q11.2) (7.08%). CONCLUSIONS This study revealed a relative lack of good prognostic cytogenetic aberrations in Pakistani children with ALL.

Spectrum of Atypical Clinical Presentations in Patients with Biallelic PRF1 Missense Mutations

Perforin, encoded by PRF1, is a pore‐forming protein crucial for lymphocyte cytotoxicity. Biallelic PRF1 nonsense mutations invariably result in early‐onset hemophagocytic lymphohistiocytosis (HLH), termed familial HLH type 2 (FHL2). In contrast, biallelic PRF1 missense mutations may give rise to later‐onset disease and more variable manifestations.

Pediatric lymphoma: a 10-year experience at a tertiary care hospital in Pakistan.

Lymphoma is the third most common childhood malignancy. Less information is available on this disease and its outcome from our country. We present here a single institute experience. A retrospective study was carried out at Aga Khan University Hospital, Karachi on children (<15 y) diagnosed with lymphoma from 1998 to 2007. Sixty-eight patients were identified. Fifty-one children were diagnosed as non-Hodgkin lymphoma (NHL). Mean age of presentation was 8.4 years with male-to-female ratio of 5.8 : 1. Most common histopathologic subtype of NHL was Burkitt lymphoma (55%). Abdominal mass was the main presenting feature of Burkitt and diffuse large B cell lymphoma. T-lymphoblastic lymphoma presented mainly as mediastinal mass. Ten children died, 4 secondary to tumor lysis syndrome, 5 because of disease progression, and 1 with chemotherapy-induced toxicity. One-third of the patients left without treatment. Seventeen children were diagnosed as Hodgkin lymphoma with mixed cellularity as the commonest subtype (65%). Overall survival of children with NHL and Hodgkin lymphoma was 62% and 94%, respectively. A greater proportion of NHL, advanced stage, and profound male preponderance were observed. Improvement in survival can only be achieved with increasing awareness, identifying and tackling causes of abandonment, early referral, and better supportive care.

Vaccination guidelines for children with cancer and hematopoietic stem cell transplantation living in resource‐poor countries

There is no consensus on the immunization guidelines for immunocompromised children. Some recommendations are, however, available for children living in developed countries. The spectrum of infectious diseases is different in resource‐poor countries. Vaccinations against some of these infections are not a part of the immunization schedule for children living in developed countries. We have tried to include vaccinations against diseases, which are still prevalent and a major cause of morbidity and mortality in resource‐poor countries. In these guidelines, the focus has been on the vaccine‐preventable diseases prevalent in Pakistan but the same can be applied to other resource‐poor countries. Pediatr Blood Cancer 2010; 54:3–7.

Clinical features and induction outcome of childhood acute lymphoblastic leukemia in a lower/middle income population: A multi-institutional report from Pakistan

Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood. Some evidence suggests differences in clinical and cytogenetic characteristics of ALL based on geographic and ethnic variations. However, data on ALL characteristics and early outcome of therapy from low/middle‐income countries such as Pakistan are scanty.

Peripherally Inserted Central Venous Catheters in Pediatric Hematology/Oncology Patients in Tertiary Care Setting: A Developing Country Experience.

Purpose: Peripherally inserted central venous catheters (PICC) have been successfully used to provide central access for chemotherapy and frequent transfusions. The purpose of this study was to assess the feasibility of PICCs and determine PICC-related complications in pediatric hematology/oncology patients in a resource-poor setting. Methods: All pediatric patients (age below 16 y) with hematologic and malignant disorders who underwent PICC line insertion at Aga Khan University Hospital from January 2008 to June 2010 were enrolled in the study. Demographic features, primary diagnosis, catheter days, complications, and reasons for removal of device were recorded. Results: Total of 36 PICC lines were inserted in 32 pediatric patients. Complication rate of 5.29/1000 catheter days was recorded. Our study showed comparable complication profile such as infection rate, occlusion, breakage, and dislodgement. The median catheter life was found to be 69 days. Conclusions: We conclude that PICC lines are feasible in a resource-poor setting and recommend its use for chemotherapy administration and prolonged venous access.

Risk factors for complicated varicella infection in pediatric oncology patients at a tertiary health care facility in Pakistan.

INTRODUCTION Varicella zoster infection (VZI) is well recognized as a potential cause of morbidity and mortality in immunocompromised pediatric oncology patients (POP). The purpose of this study was to describe the clinical profile and risk factors for complications and outcomes of VZI in POP treated with acyclovir. METHODOLOGY Medical records of all POP with a discharge diagnosis of VZI over a period of seven years (2005-2011) were reviewed. The demographic features, underlying malignancy, risk factors for VZI, complications, and outcomes were recorded. RESULTS Thirty-six POP with VZI were identified. Leukemia was the most common underlying malignancy (n = 20, 58.8%), followed by lymphoma (n = 7, 20.6%) and solid organ tumors (n = 7, 20.6%). Most of the cases (41%) were observed in children under five. All patients were treated with acyclovir. Varicella-related complications developed in 10 (29%) patients. The most frequent complication was bloodstream infection (n = 3, 8.8%), followed by pneumonia (n = 2, 5.9%), skin infection (n = 2, 5.9%), hepatitis, renal failure, and encephalitis. Independent risk factors associated with complications were age < five years, weight for age < fifth percentile, delay in seeking care (> seven days after onset of symptoms) and severe neutropenia (ANC < 500/cm). One child died secondary to varicella encephalitis. CONCLUSION Our data suggests that young age, poor health-seeking behavior, severe neutropenia, and being underweight are the major risk factors for the development of varicella-related complications in POP in developing countries. These complications could be favorably modified through active immunization of immunocompetent children.

Effect of L-type calcium channel blocker (amlodipine) on myocardial iron deposition in patients with thalassaemia with moderate-to-severe myocardial iron deposition: protocol for a randomised, controlled trial

Introduction Sideroblastic cardiomyopathy secondary to repeated blood transfusions is a feared complication in thalassaemia. Control of myocardial iron is thus becoming the cornerstone of thalassaemia management. Recent evidence suggests a role for L-type Ca2+ channels in mediating iron uptake by the heart. Blocking the cellular iron uptake through these channels may add to the benefit of therapy to standard chelation in reducing myocardial iron. We aim to determine the efficacy of amlodipine (a calcium channel blocker) as an adjunct to standard aggressive chelation in retarding myocardial iron deposition in thalassaemics with or without cardiomyopathy. Outcomes The primary outcome is to compare the efficacy of amlodipine+chelation (intervention) versus standard chelation (control) in retarding myocardial iron deposition. Secondary outcomes include the effect of amlodipine therapy on systolic and diastolic function, strain and strain rate and liver iron content. Methods and analysis This is a single-centre, parallel-group, prospective randomised control trial. Twenty patients will be randomised in a 1:1 allocation ratio into the intervention and control arms. In addition to conventional echocardiography, MRI T2* values for assessment of cardiac and liver iron load will be obtained at baseline and at 6 and 12 months. Cardiac T2* will be reported as the geometric mean and per cent coefficient of variation, and an increase in cardiac T2* values from baseline will be used as an end point to compare the efficacy of therapy. A p Value of <0.05 will be considered significant. Study setting Department of Pediatric and Child Health, Aga Khan University Hospital, Karachi, Pakistan. Ethics and dissemination This study has been approved by the Ethics Review Committee and Clinical Trials Unit at The Aga Khan University with respect to scientific content and compliance with applicable research and human subjects regulations. Findings will be reported through scientific publications and research conferences and project summary papers for participants. Trial registration number ClinicalTrials.Gov. Registration no: NCT02065492.