Clinico-Pathological Profile And Outcomes Of Patients With Polycythaemia Vera, Essential Thrombocythaemia And Idiopathic Myelofibrosis: A Tertiary Care Center Experience From Southern Pakistan.

BACKGROUND: The "Philadelphia Negative Classic Myeloproliferative Neoplasms" include polycythaemia vera (PV), essential thrombocythaemia (ET) and idiopathic myelofibrosis (IMF). These three disorders share several clinical and laboratory features including JAK2 V617F mutation. Our objectives were to determine the clinico-pathological profile and outcomes of Pakistani patients with polycythaemia vera (PV), essential thrombocythaemia (ET) and idiopathic myelofibrosis (IMF) in order to have an insight regarding behaviour of these conditions. METHODS: A retrospective analysis of all the cases of PV, ET and IMF diagnosed at our institute from January 1995 to December 2013 was performed. Age, gender, clinical presentation, laboratory investigations, treatment provided and duration of follow-up were included for analysis. Appropriate statistics were utilized for calculation of data. RESULTS: A total of 58 patients were diagnosed as PV, ET or IMF during the study period. Male to female ratio was 1.1:1. Forty five percent (n=27) patients came to medical attention due to abnormal laboratory results, 3 had cerebrovascular events, 3 had pruritus, and 1 patient each with gangrene and Budd-Chiari syndrome. Haemorrhage was not seen in any patient. Sixty percent (n=35) patients were treated with phlebotomy, hydroxyurea and aspirin alone or in combination. None of the patients transformed to myelofibrosis (MF) or myelodysplasia (MDS) during the mean (±SD) follow-up period of 57.2±50 months. One patient with ET transformed to acute myeloid leukaemia 9 years after the diagnosis. CONCLUSIONS: This study demonstrated a relatively more benign form of PV, ET and IMF with lesser frequency of symptoms, good response to treatment and less likelihood of transformation to MF, MDS or AML.

Monitoring and reporting transfusion reactions as a quality indicator - a clinical audit.

BACKGROUND AND OBJECTIVE: This audit was conducted as a part of a quality assurance activity to assess the frequency of receiving completely filled out blood transfusion reaction forms which were accompanied by the required samples. Once this information is known, we will elevate the bar each year to achieve 100% compliance. The sub-aim was to evaluate the frequency of the reported transfusion reactions. MATERIALS AND METHODS: The study was conducted from 1st April 2010 to 30th April 2011. The information was evaluated and the frequency of receiving completely filled blood transfusion reaction forms was assessed. The variables identified were the type of transfusion reaction, the blood component transfused, the health care personnel filling the form, and whether there was legible handwriting and a completely filled form. Transfusion reactions were reported as a percentage of the total number of units transfused. RESULTS: During the study period, 17,880 packed red cells, 13,200 platelets, 13,620 fresh frozen plasma and 2256 cryoprecipitate were transfused and 106 transfusion reactions (0.23%) were reported. Of these, febrile non hemolytic transfusion reaction was the most common (47%), the majority caused by packed red cells. CONCLUSION: Eighty-four percent of the transfusion reaction forms were completely filled as per our criteria. Febrile non hemolytic transfusion reactions were the most common reactions reported.

Estimating window period blood donations for human immunodeficiency virus Type 1, hepatitis C virus, and hepatitis B virus by nucleic acid amplification testing in Southern Pakistan.

BACKGROUND: Recently, strategic planning was initiated by the National Blood Transfusion Services Pakistan to improve its blood bank facilities. Emphasis has been placed on appropriate screening of blood products. Located in the southern region, Aga Khan University Hospital is a 700-bed tertiary care academic institute with comprehensive blood banking. Screening of blood donors has been based on verbal screening and serologic testing to date. Additionally, the need of implementing nucleic acid testing (NAT) was considered in 2011 because of an upsurge in hepatitis epidemiology. The aim of this study was to analyze the efficacy of this additional donor screening program and to evaluate the impact of NAT on the yield and residual risk of transfusion-transmissible viral infections. STUDY DESIGN AND METHODS: A total of 42,830 blood donations collected between 2011 and 2012 were screened for routine serologic assays. Only serologically negative donors (n=41,304) were tested for NAT. The frequency of viral infections was evaluated through serologic techniques and NAT yield for viral agents was estimated for computing window period donors. Residual risk per million donors was computed for viral infections in seronegative blood donors. RESULTS: Serologic work-up showed 1571 abnormal screening results in 1526 blood donors with the following results: hepatitis C virus antibodies (anti-HCV; n=708), hepatitis B surface antigen (n=555), human immunodeficiency virus antibodies (anti-HIV; n=29), malaria (n=30), VDRL (n=249), and coinfection (n=45). Thirty-five NAT-reactive samples were identified: HIV-1, one; HCV, 27; and hepatitis B virus (HBV), seven. Incident rates per 10(5) donors were highest for HCV (453.3) followed by HBV (171.5) and HIV (72.2). Calculated residual risk per million donors was highest at 1 in 10,900 for HBV, intermediate at 1 in 13,900 for HCV, and least at 1 in 62,600 for HIV. CONCLUSION: Incidence rates and estimated residual risk indicate that the current risk of transfusion-transmitted viral infections attributable to blood donation is relatively high in this country. The study recommends the parallel use of both serology and NAT screening of donated blood in countries that have high seroprevalence of these viral infections.

Root cause analysis of non-infectious transfusion complications and the lessons learnt.

BACKGROUND: Transfusion of blood and blood products can be associated with hazards which may be at times fatal. Timely reporting of transfusion reactions is imperative for root cause analysis and their prevention in future. METHODS: We retrospectively reviewed the transfusion reactions at our institution during last seven years. The data was retrieved from our computerized blood bank information system and by reviewing the medical charts of patients. The frequency of adverse effects, implicated products, wrong blood transfusion and its outcome were observed. RESULTS AND CONCLUSIONS: During study period (2006-2012), a total of 393,662 blood or blood products were transfused. There were 458 adverse events with an estimated rate of 1.16 per 1000 blood products administered. During 2011-2012, 121 transfusion reactions were reported of 119,921 transfused units. The most common adverse effects were allergic reactions (70 episodes of 121 or 57.8%) followed by febrile non hemolytic transfusion reactions or FNHTR (43 events of 121 or 35.5%). Transfusion associated dyspnea, circulatory overload and transfusion associated lung injury were less frequent. During the study period, 142,066 red cell units were transfused with nine recognized ABO-mismatch transfusions and two fatalities. The computed incidence of ABO-mismatch transfusion was 1 in 15,785 with a mortality rate of 1 in 71,033 units transfused. Etiology included: errors in final bed side check (n=5), blood bank clerical errors (n=3) and mislabeled tube (n=1). A review of these cases prompted hospital transfusion committee for re-enforcing policies and protocols to minimize accidental ABO incompatible transfusions. We concluded that urticaria and FNHTR are the most frequent transfusion reactions in our setting. ABO mismatched blood transfusions are rare but preventable errors and result mainly from clerical imprecisions.

Acute transfusion reactions encountered in patients at a tertiary care center.

OBJECTIVE: To determine the frequency and type of Acute Transfusion Reactions (ATRs) occurring in inpatients, reported to the transfusion service at Aga Khan University Hospital, Karachi, Pakistan. METHODS: This was a three years and seven months (from January 2005 till July 2008) retrospective review of all the transfusion reactions that were reported to the transfusion service at Aga Khan University Hospital, Karachi, Pakistan. All the reactions were clinically evaluated by the blood bank physician. Transfusion reactions occurring during or within four hours after transfusion were evaluated and classified by standard and recognized definitions defined by American Association of Blood Banks. RESULTS: The acute transfusion reactions (ATRs) reported during the study period were 212. However, out of these 212 ATRs, 182 ATRs were confirmed by blood bank physician, and included febrile non haemolytic reactions [89 (41.9%)], allergic reaction [73 (34.4%)], isolated hypotension [3 (1.4%)], haemolytic reaction [4 (1.8%)] and bacterial contamination [2 (0.9%)]. Eleven (5.1%) ATRs were unclassifiable and were thus labeled as non specific reaction. CONCLUSION: The frequency of transfusion reactions in our patients was found to be 0.082%. Febrile non haemolytic reaction was the most frequent transfusion reaction followed by allergic reaction. This may be an under reported figure. There is a need for establishing a haemovigilance system for critical analysis of blood transfusion events.

Successful use of rituximab in Evans syndrome and refractory immune thrombocytopenic purpura.

Immune cytopenias are mediated by auto-antibodies produced by B-lymphocytes. Conventional treatment of immune-mediated haematological disorders includes immunosuppression with steroids and other immune modulating therapies and in some refractory cases, splenectomy. Response rates to conventional and second-line agents are variable and a proportion of patients require lifelong immunosuppression to maintain the disease in remission. Rituximab, an anti- CD 20 monoclonal antibody has gained widespread acceptance in the management of B-cell malignancies. Additionally, it has been used to treat the disorders associated with autoantibody production. We report herein the successful use of Rituximab in the treatment of two patients with autoimmune cytopenias one had Evan's syndrome and other had refractory immune thrombocytopenic purpura. Both of these patients are still in remission at 16 and 25 months following treatment.

Multivessel Percutaneous Coronary Intervention in a Patient With Bernard-Soulier Syndrome.

Bernard-Soulier syndrome, a congenital bleeding disorder, can rarely present with atherosclerosis and thrombosis. Acute coronary syndrome in such patients present a unique challenge as no standard set of guidelines exist for successful treatment. (Level of Difficulty: Intermediate.).

Karachi Cancer Registry (KCR): Age-Standardized Incidence Rate by Age-Group and Gender in a Mega City of Pakistan.

OBJECTIVES: To estimate the cancer incidence by age group and gender for the population of Karachi Division by analyzing the Karachi Cancer Registry data of 2017-19. SETTINGS: The population of Karachi division is 16.1 million according to national census 2017. 'Karachi Cancer Registry' which is a part of 'National Cancer Registry' is collecting data from eight major hospitals in Karachi since 2017. For outcome measures, cancer counts and the age standardized incidence rates (ASIR) per 100,000 population were computed for age groups (0-14, 15-19 and ≥20 years), in both genders and all cancer site/type. METHODS: The population denominators were based on the population of Karachi division estimated at 16.1 million in the population census, 2017. Counts and age-standardized incidence rates (ASIR) were calculated for each of the three age categories. RESULTS: From Jan 2017 till Dec 2019 a total of 33,309 malignant cases were recorded in KCR database comprising 17,490 (52.5%) females and 15,819 (47.5%) males. ASIRs in age groups 0-14, 15-19 and ≥ 20 years, among female were 11.5, 2.4 and 223.6 and in males were 17.6, 3.2 and 216.7 respectively. The commonest diagnosis in children, adolescent and adults were (1) among females: children; bone (3.12),  leukemia (2.09) brain/CNS (1.26); in adolescents: bone (0.78), brain/CNS (0.27), connective and soft tissue (0.11), in adults: breast cancer (76.07), oral cancer (16.68) and ovary (10.89) respectively, and (2) among males: children; bone (4.56),  leukemia (2.79) and brain/CNS (1.88); in adolescent; bone (1.19), brain/CNS (0.31) and leukemia (0.21) and in adults: oral cancer (42.83), liver (16.10) and bone (13.37) respectively. CONCLUSION: Oral Cancer, a largely preventable cancer is the leading cancer in Karachi adult males while in female adults Breast Cancer is the leading cancer followed by Oral Cancer. In children and adolescents Bone, Leukemia and Brain/CNS malignancies are most common.
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Population study of 1311 C/T polymorphism of Glucose 6 Phosphate Dehydrogenase gene in Pakistan - an analysis of 715 X-chromosomes.

BACKGROUND: Nucleotide 1311 polymorphism at exon 11 of G6PD gene is widely prevalent in various populations of the world. The aim of the study was to evaluate 1311 polymorphism in subjects carrying G6PD Mediterranean gene and in general population living in Pakistan. RESULTS: Patients already known to be G6PD deficient were tested for 563C-T (G6PD Mediterranean) and 1311 C-T mutation through RFLP based PCR and gene sequencing. A control group not known to be G6PD deficient was tested for 1311C/T only.C-T transition at nt 1311 was detected in 60/234 X-chromosomes with 563 C-T mutation (gene frequency of 0.26) while in 130 of normal 402 X-chromosomes (gene frequency of 0.32). CONCLUSION: We conclude that 1311 T is a frequent polymorphism both in general populations and in subjects with G6PD Mediterranean gene in Pakistan. The prevalence is higher compared to most of the populations of the world. The present study will help in understanding genetic basis of G6PD deficiency in Pakistani population and in developing ancestral links of its various ethnic groups.

Presentation of a patient with palpable purpuric rash.

Henoch Shonlein purpura (HSP) is a form of systemic vasculitis characterized by deposition of IgA dominant immune complexes in the small vessels. The triad of palpable purpuric rash on lower extremities, abdominal or renal involvement and arthritis is the typical presentation in this condition. The disease primarily affects children and is less common in adults. We report a case of a young female who presented with palpable purpura on legs, classical symptoms of HSP i.e. arthritis and off and on abdominal pain.

Oral iron chelation therapy with deferiprone in patients with Thalassemia Major.

OBJECTIVE: To determine the efficacy and adverse effects of deferiprone in patients with Thalassemia Major. METHODS: A prospective case series study was conducted at the Fatimid Foundation Blood Bank and Haematological Diseases center Lahore. A total of 87 patients entered into the study between September 2005 and November 2006. Deferiprone was given at subsidized rates at a dose of 75/mg/day for seven days. Physical examination and initial Laboratory investigations were done in all patients at the start of the study. Physical and laboratory data were filled on a questionnaire and analyzed using SPSS version 10.0. RESULTS: Eighty seven patients with mean age of 10.0 +/- 4.33 years (range 4-27 years) were included in the study. Mean follow up was 8 +/- 3.94 months (range 2-12 months). The mean Ferritin at the start of study was 4656 +/- 2052.5 ug/L (range 1200-14630 ug/L) and at the end of study period was 4139 +/- 1710.4 ug/L (range 749-8961) (p < 0.001). Adverse events were joint pains in 10% patients, gastrointestinal symptoms in 11% and no adverse events in 79% patients. There was no evidence of agranulocytosis in any patient. CONCLUSION: Deferiprone was well tolerated, had few adverse effects and was effective in lowering the patient's serum ferritin level.

Frequency and clinical spectrum of rare inherited coagulopathies--a tricenter study.

OBJECTIVE: To determine the frequency of rare inherited coagulopathies at three centers of haematology in Karachi and to study the clinical spectrum and laboratory data of these coagulopathies. METHODS: This was a descriptive study conducted from September 2003 to December 2004 on subjects from Aga Khan University Hospital, Husaini Blood Bank and Fatimid Blood Transfusion Centre. All the subjects with bleeding tendency without any acquired causes of bleeding were selected for further investigation, and were asked relevant questions as present in the questionnaire. Screening tests including platelet count, PT, APTT and bleeding time were performed on all patients and subsequently, specific tests including factor assay, clot solubility test, platelet aggregation and vWFAg were performed. RESULTS: In total, 1100 patients were evaluated for bleeding tendency at the three centers and 65 patients were diagnosed to have inherited coagulopathy other than haemophilia A and B. Out of these 65 patients, 33 (50.7%) were males and 32 (49.2%) were females. Rare inherited coagulopathies that were found in our population included deficiency of factor VII {n = 21 (32.3%)}, factor X {n = 17 (26.1%)}, factor XIII {n =14 (21.5%)}, factor V {n = 9 (13.8%)}, fibrinogen {n = 2 (3%)}, prothrombin {n = 1 (1.5%)} and factor XII {n = 1 (1.5%)}. CONCLUSION: Inherited coagulopathies other than haemophilia A and B were noted in the study population.

Clinical audit to assess delays in chemotherapy administration at daycare oncology center at a tertiary care hospital in Karachi, Pakistan.

AIM: There were delays reported by patients in chemotherapy administration in daycare oncology. Therefore, we decided to audit all processes which are involved in chemotherapy administration. The objective was to improve our service by decreasing the time between admission and initiation of chemotherapy and identify the reasons for delays. MATERIALS AND METHODS: The audit was conducted in three parts. In Review I, audit tool was developed and information documented of 109 patients receiving chemotherapy at daycare center from April 14 to May 13, 2015. Five processes were assessed out of which delay in initial assessment by the nurse was the only factor identified leading to delay in chemotherapy. Review II was done from March 1 to 31, 2016 of 208 patients after increasing the number of nurses and Review III from June 7 to August 25, 2016 of 287 patients by dividing the initial assessment process at two different areas to decrease delay in initial assessment. RESULTS: Seventy-two percent of patients had their initial assessment done within 15 min of arrival in daycare in the first audit. In the second part of audit this percentage decreased to 55%, and finally, in the third part of the audit, percentage was improved and increased to 75% after separating initial assessment process into two areas (P < 0.001, Kruskal-Wallis test). CONCLUSION: After separating initial assessment process into two different areas, delays in chemotherapy administration were reduced.

Distribution of Chromosomal Abnormalities Commonly Observed in Adult Acute Myeloid Leukemia in Pakistan as Predictors of Prognosis

Objectives: The heterogenous response to treatment in acute myeloid leukemia (AML) can be attributed largely to the difference in cytogenetic features identified in between cases. Cytogenetic analysis in acute leukemia is now routinely used to assist patient management, particularly in terms of diagnosis, disease monitoring, prognosis and risk stratification. Knowing about cytogenetic profile at the time of diagnosis is important in order to take critical decisions in management of these patients. The study was conducted to determine the distribution of cytogenetic abnormalities in Pakistani adult patients with AML in order to have insights regarding behavior of the disease. Methods: A retrospective analysis of all the cases of AML (≥15years old) diagnosed at Aga Khan University from January 2011 to December 2016 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 321 patients were diagnosed with AML during the study period, of which 288 samples successfully yielded metaphase chromosomes. The male to female ratio was 1.7:1. A normal karyotype was present in 61% (n=176) of the cases whereas, 39% (n=112) had an abnormal karyotype. Of the abnormal cases, t (8;21) (q22;q22) and t (15;17) (q22;q12) were identified in 8.3% and 4.9% cases respectively. Adverse prognostic cytogenetic subgroups including complex karyotype, monosomy 7 and t(6;9)(p23;q34) were identified in 9%, 1% and 0.7% patients respectively. Conclusions: This largest cytogenetic data in adult AML from Pakistan showed comparable prevalence of favorable prognostic karyotype to international data. The prevalence of specific adverse prognostic karyotype was low.

Diagnostic importance of bone marrow examination in non-hematological disorders.

OBJECTIVE: To evaluate the frequency of involvement of bone marrow with non-haematologic disorders and to observe the significance of bone marrow examination in establishing primary diagnosis of the same. METHODS: It was a descriptive study that extended from January 2003 to September 2005. A total of 4569 bone marrow aspirate and trephines were reported during this period. Only the non-haematological disorders were analyzed for their clinical and laboratory parameter. RESULTS: During the study period, 63 patients (1.4%) were diagnosed to have non-haematological diseases detected primarily through bone marrow examination. The mean age of patients at time of procedure was 33 years (range 6 months to 89 years), with male to female ratio of 3.2:1. Anaemia was the most frequent clinical finding followed by splenomegaly and weight loss. In adults metastatic tumors were the commonest disorder, followed by chronic granulomatous disease/reaction. However in children, storage disorders were more prevalent followed by haemophagocytosis as the second commonest non-haaematological disease. CONCLUSION: Metastatic solid tumors were the frequent non-hematologic disorder involving bone marrow in adult patients while storage diseases were most common among children. Hence, bone marrow examination is a useful laboratory tool in asserting the diagnosis of various non-haematological malignancies and other miscellaneous disorders.

Chronic ITP: analysis of various factors at presentation which predict failure to first line treatment and their response to second line therapy.

OBJECTIVE: To observe the significance of various factors in chronic idiopathic thrombocytopenic purpura (ITP) which predict the response of first line (corticosteroids) and second line therapy (splenectomy) and to evaluate their response to second line therapy. METHODS: This was a descriptive, prospective study conducted from August 2004 till January 2006. Patients of all age groups and both genders with diagnosis of chronic ITP were included. Treatment protocol and criteria for response assessment was explained. RESULTS: During 17 months period, 86 patients with chronic ITP were analyzed. Non-responders to first line therapy were 74 patients who ultimately required splenectomy. Complete response (CR) was had in 37 (50.7%) patients, 10 (13.7%) and 27 (36.5%) had partial response (PR) and no response (NR) respectively. Analysis of variables like younger age, sex and low platelet count at presentation failed to show any significant influence on response to first line treatment. However response to splenectomy was found to be higher in patients who had initial complete or partial response with steroids and later relapsed and the platelet count was more than 300x10(9)/L on day 14 of surgery. CONCLUSION: Splenectomy remains the most effective treatment of chronic ITP. No significant factor was identified which predicted initial response to first line treatment. However patients who initially responded to steroids and had platelet counts above 300 X109/L about a fortnight after splenectomy showed promising results post-operatively (p=0.003 and p=0.001).

Thrombocytosis: age dependent aetiology and analysis of platelet indices for differential diagnosis.

To identify the etiology of thrombocytosis in various age groups and to evaluate the effectiveness of platelet indices in differentiating reactive and clonal thrombocytosis, an observational, prospective review of patients with platelet count of 600 x 10(9)/L or more performed by using coulter counter STKS (Coulter Electronic, Kerfeld, Germany). Extreme thrombocytosis defined as platelet count of 1000 x 10(9)/L or more. Of 1068 patients, 91.8% had reactive and 8.2% had clonal thrombocytosis. Frequent causes of reactive thrombocytosis were infections (44.9%), tissue injury (11.4%) and rebound thrombocytosis (10.2%). Fifty-five patients had extreme thrombocytosis, main aetiologies were secondary and clonal thrombocytosis that seen in 72.7% and 27.3% of cases respectively. Comparison of platelet indices showed; that cases with reactive thrombocytosis had low mean platelet volume and platelet distribution width. We concluded that thrombocytosis could be a response to various physiological and pathological processes. Low MPV and PDW in patients with high platelet counts strongly suggest reactive etiology.

Pattern of chromosomal abnormalities in adult acute lymphoblastic leukemia.

OBJECTIVES: To study the pattern of chromosomal abnormalities in adult patients with acute lymphoblastic leukemia. STUDY DESIGN: A retrospective study. PLACE AND DURATION OF STUDY: January 1998 to June 2005 at the Cytogenetics department, Aga Khan University Hospital, Karachi. PATIENTS AND METHODS: A retrospective analysis of cytogenetic studies was carried out in patients who were diagnosed as ALL and were more than 15 years of age. Cytogenetic analysis was performed using a trypsin-Giemsa banding technique. Karyotypes were interpreted using International System for Cytogenetics Nomenclature (1995) criteria. RESULTS: The requests were received for cytogenetic analysis of bone marrow specimens in 69 patients who were diagnosed as ALL. Cytogenetic results were available in 62 patients; out of which 51 were males and 11 were females. 44 patients (70%) were found to have a normal karyotype. In 18 patients (29%), abnormal karyotype was found. CONCLUSION: Cytogenetic studies should be part of the initial work up of every patient with ALL. Larger scale studies will help refine our understanding of the less common chromosomal patterns and conduct multivariate analysis to define the relative prognostic value of karyotypic results.

Fludarabine induced autoimmune haemolytic anaemia in a patient with chronic lymphocytic leukaemia.

Autoimmune haemolytic anaemia following fludarabine is an uncommon complication and previously treated patients are at higher risk. We describe a case of 57-year old lady with chronic lymphocytic leukaemia; she received intermittent courses of alkylating agents and purine analogue, fludarabine. Reintroduction of fludarabine for her relapsing disease induced autoimmune haemolytic anaemia. Numbers of cases have been reported regarding autoimmune haemolytic anaemia following fludarabine administration, but none have been published from our part of the world. Normally T-cell suppresses autoreactive lymphocytes that can produce autoantibodies. Suppression of T-cells by fludarabine, in addition to the underlying disease process appears to be a contributory factor for autoimmune haemolytic anaemia.

Waldenstrom's macroglobulinemia terminating in acute myeloid leukemia.

Waldenstrom's macroglobulinemia (WM) is a rare condition, accounting for approximately 2% of haematologic malignancies. The most common causes of death in these patients are progression of the malignant lymphoproliferative process, infection and cardiac failure. Acute leukemia is a rare event in the clinical course of WM. A number of case reports have documented the development of terminal acute leukemia in patients with WM following prolonged chemotherapy. We describe a case of an elderly man who was a diagnosed case of WM and treated with chlorambucil and cyclophosphamide. Four years later, he developed acute leukemia.