Salam Alkindi

Imatinib in pregnancy

To the Editor: Chronic myeloid leukemia (CML) is a myeloproliferative disorder seen predominantly in adults and not infrequently discovered incidentally during pregnancy. It is characterized by the presence of Philadelphia chromosome in almost 95% of cases (1). The abnormal chromosome occurs as a result of reciprocal translocation between the long arm of chromosomes 9 and 22; t(9;22) (2, 3). This translocation leads to the formation of a fusion gene BCR-ABL, with increased production of abl-tyrosine kinase, a molecule that plays a critical role in cell proliferation and may thus play a significant role in the abnormal cell growth seen in CML (3, 4). The introduction of imatinib (Glivec; Novartis, UK), an inhibitor for abl-tyrosine kinase, has made a considerable impact on the outcome and quality of life of patients with CML (5). Although the drug is well tolerated by patients with few side effects, experience with this drug during pregnancy in humans is rather limited (6). The drug is found to be teratogenic in mice but not in rabbits and data on the human fetus is limited (6). Here we report the outcome of two patients with CML who became pregnant while on imatinib.

Orbital involvement in sickle cell disease: A report of five cases and review literature

Purpose To present five cases of orbital infarction in sickle cell disease and review relevant literature.Method We reviewed the hospital records of 5 patients with sickle cell disease who developed a periorbital swelling during a vaso-occlusive crisis and were managed at our hospital between April 1992 and June 2000.Results The 5 patients (4 with homozygous sickle cell disease and 1 with sickle cell-β-thalassaemia disease) were aged 6-15 years with a history of multiple admissions for vaso-occlusive crises. The periorbital swelling spread to the orbit in 4 cases and resulted in proptosis (2 cases), restriction of ocular motility and visual impairment. In all 4 cases, computed tomography and/or magnetic resonance imaging of the orbits showed a mass adjacent to the orbital wall. In 2 cases the mass was identified as a haematoma. Orbital wall infarction was demonstrated in 3 cases by bone/bone marrow scintigraphy. Epidural haematomas were detected by computed tomography in one case. All patients received intravenous fluids, analgesics, broad spectrum antibiotics and steroids, as well as simple or exchange transfusion, and responded well to medical management.Conclusions Infarction of orbital bones during vaso-occlusive crises in sickle cell disease presents acutely with a rapidly progressive periorbital swelling. Haematomas frequently complicate the condition and, along with the inflammatory swelling, may lead to orbital compression syndrome. The condition is therefore sight-threatening, and necessitates prompt diagnosis and appropriate management for resolution without adverse sequelae. Imaging techniques are invaluable in the evaluation of patients. The majority of cases resolve with conservative treatment that includes steps to combat the vaso-occlusive crisis and use of systemic steroids under antibiotic cover.

Forecasting Hemoglobinopathy Burden Through Neonatal Screening in Omani Neonates

To evaluate the incidence of hemoglobinopathies in Omani subjects and to forecast its future burden on health resources, we initiated a prospective neonatal screening program in two major cities of the Sultanate of Oman. Consecutive cord blood samples from a total of 7,837 neonates were analyzed for complete blood counts and for hemoglobin (Hb) profile by high performance liquid chromatography (HPLC). No case with Hb H (β4) was detected. We observed that the overall incidence of α-thalassemia (α-thal) was 48.5% [based on the presence of Hb Barts (γ4)] and the β-globin-related abnormalities accounted for 9.5% of the samples (4.8% sickle cell trait, 2.6% β-thal trait, 0.9% Hb E trait, 0.8% Hb D trait, 0.08% Hb C trait, 0.3% sickle cell disease and 0.08% homozygous β-thal). This is also the first large study to establish reference ranges of cord red blood cell (RBC) indices for Omani neonates.

Successful treatment of severe thrombocytopenia with romiplostim in a pregnant patient with systemic lupus erythematosus

We present a case of a pregnant woman at 27 weeks of gestation with systemic lupus erythematosus who developed severe thrombocytopenia presenting with melena, epistaxis, gum bleeding and frank hematuria. She was resistant to most treatment modalities, including steroids, intravenous immunoglobulins (IVIG), rituximab, IV cyclophosphamide and eltrombopag. She responded to romiplostim with normalization of her platelet count, which enabled her to be delivered safely at 34 weeks of gestation.

Orbital Infarction in Sickle Cell Disease

PURPOSE To determine the role of hematological and genetic factors in the development of orbital infarction in sickle cell disease. DESIGN Retrospective, noncomparative case series. METHODS Fourteen sickle cell disease patients were diagnosed with orbital infarction during a vaso-occlusive crisis. Clinical and radiological findings were reviewed retrospectively. Sickle cell disease patients without orbital infarction were recruited as controls after matching for disease severity. Sickle haplotypes were determined for all patients. Differences between groups were evaluated statistically. RESULTS Patients with orbital infarction in sickle cell disease presented with acute periorbital pain and swelling with or without proptosis, ophthalmoplegia, and visual impairment during a vaso-occlusive crisis. Radiological findings included orbital soft tissue swelling (100%), hematoma (orbital, 36%; intracranial, 21%), and abnormal bone marrow intensities. Severity of orbital involvement was unrelated to that of the systemic disease (Pearson correlation coefficient, -0.1567). Affected patients predominantly had the Benin haplotype (P < .00782). CONCLUSIONS Orbital infarction is a potential threat to vision in sickle cell disease patients. Magnetic resonance imaging is more specific than computed tomography or nuclear scintigraphy in the evaluation of orbital changes. The degree of severity of the orbital manifestations appears unrelated to the severity of sickle cell disease. Patients with the Benin haplotype are more likely to develop orbital infarction during vaso-occlusive crises.

Complex t(8;13;21)(q22;q14;q22)–A Novel Variant of t(8;21) in a Patient with Acute Myeloid Leukemia (AML–M2)

Variants of the t(8;21)(q22;q22) involving chromosome 8, 21, and other chromosomes account for about 3% of all t(8;21)(q22;q22) in acute myeloid leukemia (AML) patients. We report a case of AML-M2 with t(8;13;21)(q22;q14;q22), not reported earlier. Using a dual-color fluorescence in situ hybridization (FISH) analysis with ETO and AML1 probes, we demonstrate an ETO/AML1 fusion signal on the derivative chromosome 8. Whole chromosome painting probes were used for chromosomes 8 and 13, to demonstrate the three-way translocation t(8;13;21)(q22;q14;q22). Involvement of chromosome region 13q14 has never been reported earlier, although region 13q12 as a variant in AML with t(8;21) has been reported earlier. The possible role of genes in this region in leukemogenesis, its response to the treatment and its clinical implications are discussed.

Warfarin pharmacogenetics: development of a dosing algorithm for Omani patients

The objective of our present study was to develop a warfarin dosing algorithm for the Omani patients, as performances of warfarin dosing algorithms vary across populations with impact on the daily maintenance dose. We studied the functional polymorphisms of CYP2C9, CYP4F2 and VKORC1 genes to evaluate their impact on the warfarin maintenance dose in an admixed Omani patient cohort with Caucasian, African and Asian ancestries. We observed a 64-fold inter-patient variability for warfarin to achieve stable international normalized ratio in these patients. Univariate analysis revealed that age, gender, weight, atrial fibrillation, deep vein thrombosis/pulmonary embolism and variant genotypes of CYP2C9 and VKORC1 loci were significantly associated with warfarin dose in the studied patient population. However, multiple regression model showed that only the atrial fibrillation, and homozygous CYP2C9 variant genotypes (*2/*3 and *3/*3) and VKORC1 GA and AA genotypes remained significant. A multivariate model, which included demographic, clinical and pharmacogenetic variables together explained 63% of the overall inter-patient variability in warfarin dose requirement in this microgeographically defined, ethnically admixed Omani patient cohort on warfarin. This locally developed model performed much better than the International Warfarin Pharmacogenetics Consortium (IWPC) model as the latter could only explain 34% of the inter-patient variability in Omani patients. VKORC1 3673G>A polymorphism emerged as the single most important predictor of warfarin dose variability, even in this admixed population (partial R2=0.45).

Sickle cell–haemoglobin E (HbSE) compound heterozygosity: a clinical and haematological study

The paucity of clinical reports in the world literature suggests that, as a disease entity, haemoglobin SE compound heterozygosity is of negligible importance. In view of the significant community prevalence of this haemoglobinopathy in the Sultanate of Oman where it is the second most prevalent sickling disorder, a hospital study of 12 SE compound heterozygotes from six unrelated Arab families was undertaken to determine their clinico‐haematological features. Our findings were compared with those reviewed in the literature. Clinical and haematological evaluation was carried out by conventional methods including chromatographic haemoglobin analysis. At least 50% of those studied were asymptomatic throughout the study period but sickling‐related complications occurred in the rest and included the acute chest syndrome (1/12), severe vaso‐occlusive skeletal pain (2/12), frontal bossing (1/12) possibly indicative of significant chronic haemolysis and recurrent infections of the urinary tract (1/12). Steady‐state haemoglobin levels fell within the reference range while MCV and MCH values were, as expected, reduced in most cases; nevertheless, concomitant inheritance of α‐thalassaemia trait was also likely. Red cell morphology was striking by the absence or rarity of pseudo‐sickled cells in the blood films of many patients during the steady state and in crises. Bearing in mind the prevalence of 0.05% of SE compound heterozygosity in Oman, the findings in this single study of the largest number of SE patients and their relatives confirm the predominantly asymptomatic nature of this sickling disorder in individuals in the community at large. HbF levels do not appear to explain the heterogeneous nature of this haemoglobinopathy. Correlation of the variable clinical and haematological features of SE cases with their α‐globin gene status and β‐cluster haplotypes (linked to the βs‐ and βe‐genes) merits a separate investigation, which is being currently organized.

Arterial and venous thrombotic complications with thalidomide in multiple myeloma.

Multiple myeloma (MM) is a malignant proliferation of plasma cells resulting in hyperproteinemia and hyperviscosity with a 10% risk of venous thrombosis (1). In recent years, thalidomide is increasingly being used either as a single agent or as combination chemotherapy. The benefits of thalidomide in MM are thought to occur due to its effect on angiogenesis, downregulation of tumor necrosis factor, interference with stromal cells/myeloma adhesive properties, and stimulation of natural killer cells (2). However, it is now clear that there is an associated 10e25% increased risk of thrombosis. Several reports have predominantly demonstrated venous thrombosis (3e5); however; we wish to highlight the occurrence of both venous as well as arterial thrombosis. We have treated 32 patients with MM during the last 2 years with thalidomide alone or in combination with other chemotherapeutic agents. Thalidomide was started orally at a dose of 100 mg at bedtime for 2 weeks and then increased by 100 mg to reach a maintenance dose ranging from 100 to 400 mg, with some acceptable CNS and hematopoietic toxicity. In this cohort, we also have encountered nine (28.12%) episodes of thrombosis as outlined in Table 1. These episodes include two deep vein thrombosis (DVT), one pulmonary embolus (PE), one distal arterial thrombosis, two non-ST elevation myocardial infarctions (NSEMI), and one stroke (CVA). Two patients died suddenly at home, with a typical presentation of PE. DVT was diagnosed by compression ultrasonograpy, and PE and CVA were diagnosed by CT and MRI studies, whereas myocardial infarction was diagnosed by electrocardiography along with relevant biochemical parameters such as serum creatine kinase (CK-MB) and troponin studies. All thrombotic events occurred in patients not routinely anticoagulated. Five of the thrombotic episodes happened within the first month of commencing therapy, with all other episodes occurring within 2e5 months after commencing thalidomide. All DVT and PE patients were anticoagulated with a therapeutic dosage of low molecular weight heparin followed by warfarin, and anticoagulation was withheld after 6 months of treatment. Seven of our patients (five with documented thrombosis and two with sudden death) were receiving concomitant therapy with dexamethasone, with none receiving

Splenectomy for haematological disorders: a single center study in 150 patients from Oman.

BACKGROUND Haematological disorders, in particular sickle cell disease (SCD) and thalassaemia, are relatively common in Oman. We report our experience of splenectomy for haematological disorders and review the literature on splenectomy role in their management. OBJECTIVES To review our experience in the management of 150 patients with haematological disorders undergoing splenectomy with emphasis on indications and outcome. To compare our experience with those reported from outside this region. METHODS The records of 150 patients who underwent splenectomy over a thirteen year period were reviewed retrospectively, analyzing the age and sex of the patients, indication for splenectomy, operative procedures, complications, peri-operative management and outcome. RESULTS Of the 150 patients, 96 (64%) had SCD and 34 (22.6%) had beta-thalassaemia; the rest comprised patients with refractory idiopathic thrombocytopenic purpura (ITP) n=12, hereditary spherocytosis (HS) n=6, and auto-immune haemolytic anaemia (AHA) n=2. In SCD patients, the main indications for splenectomy were recurrent splenic sequestration (60.4%) and hypersplenism (36.4%), whereas in thalassaemic patients it was increased requirement of packed red blood cells (PRBC) transfusion (mean 310 ml, range 242-372 of PRBC/kg/year). All patients received prophylactic antibiotics and vaccination against pneumococcal infection and when the vaccine was available for Haemophilus influenzae. PRBC and platelet concentrates as well as intravenous fluids were infused preoperatively as per protocol. Concomitant procedures at laparotomy included liver biopsy (14.6%) and cholecystectomy (8.6%). The postoperative morbidity was low (8.6%) and there was no mortality. All patients were maintained on long term penicillin and proguanil, and the mean follow-up was 4.6 years. In SCD patients splenectomy eliminated the risks of life threatening acute splenic sequestration and improved significantly the blood counts of the hypersplenic cases, while in thalassaemic patients it reduced significantly the mean transfusion requirement by 100ml PRBC/kg/year (p<0.0001). Of the patients with refractory ITP, two thirds had a good response to splenectomy (p<0.0001). All HS and AHA patients benefited from splenectomy. CONCLUSION The predominant indications for splenectomy were recurrent acute splenic sequestration and hypersplenism in SCD patients, and increased transfusion demand in the thalassaemics. Overall, splenectomy proved beneficial in eliminating the risk of splenic sequestration in SCD patients, in improving the blood counts in SCD with hypersplenism and in reducing transfusion requirement in thalassaemic patients, while in ITP group two thirds of the patients benefited.