Fibrosis and bone marrow: understanding causation and pathobiology.

Bone marrow fibrosis represents an important structural change in the marrow that interferes with some of its normal functions. The aetiopathogenesis of fibrosis is not well established except in its primary form. The present review consolidates current understanding of marrow fibrosis. We searched PubMed without time restriction using key words: bone marrow and fibrosis as the main stem against the terms: growth factors, cytokines and chemokines, morphology, megakaryocytes and platelets, myeloproliferative disorders, myelodysplastic syndrome, collagen biosynthesis, mesenchymal stem cells, vitamins and minerals and hormones, and mechanism of tissue fibrosis. Tissue marrow fibrosis-related papers were short listed and analysed for the review. It emerged that bone marrow fibrosis is the outcome of complex interactions between growth factors, cytokines, chemokines and hormones together with their facilitators and inhibitors. Fibrogenesis is initiated by mobilisation of special immunophenotypic subsets of mesenchymal stem cells in the marrow that transform into fibroblasts. Fibrogenic stimuli may arise from neoplastic haemopoietic or non-hematopoietic cells, as well as immune cells involved in infections and inflammatory conditions. Autoimmunity is involved in a small subset of patients with marrow fibrosis. Megakaryocytes and platelets are either directly involved or are important intermediaries in stimulating mesenchymal stem cells. MMPs, TIMPs, TGF-ß, PDGRF, and basic FGF and CRCXL4 chemokines are involved in these processes. Genetic and epigenetic changes underlie many of these conditions.

Molecular insights into hereditary elliptocytosis and pyropoikilocytosis: NGS uncovers multiple potential candidate genes.

Hereditary elliptocytosis (HE) and pyropoikilocytosis (HPP) are considered a group of hemolytic anemias (HE/HPP) due to inherited abnormalities of erythrocyte membrane proteins with a worldwide distribution. Most cases are associated with molecular abnormalities linked to spectrin, band 4.1, and ankyrin. The present study aimed to identify significant molecular signatures on a target panel of 8 genes using whole exome sequencing (WES) in 9 Bahraini patients with elliptocytosis. Case selection was based on presence of anemia not associated with iron deficiency or hemoglobinopathy and demonstrating > 50% elliptocytes in blood smears. The c.779 T > C mutation of SPTA1 (Spectrin alpha), which is a known deleterious missense mutation that inhibits normal association of spectrin molecules to form tetramers, was seen in 4 patients in homozygous (n = 1) and heterozygous (n = 3) states. The αLELY abnormality in association with compound heterozygous mutations in SPTA1 was present in 5 patients (2 associated with the SPTA1 c.779 T > C variant; 3 with c.3487 T > G and various other SPTA1 mutations of uncertain/unknown significance). Seven patients had SPTB (Spectrin beta) mutations, predicted as likely benign by in silico analysis. A novel EPB41 (Erythrocyte Membrane Protein Band 4.1) mutation with potential deleterious impact was also seen. Finally, 2 cases showed an InDel (insertion-deletion mutations) abnormality in the gene that codes for the mechanosensitive ion-channel PIEZO (Piezo Type Mechanosensitive Ion Channel Component 1). PIEZO mutations are reported to cause red cell dehydration but have not been previously described in HE/HPP. Results of this study confirm the involvement of previously reported abnormalities in SPTA1 and suggest possible involvement of other candidate genes in a disorder involving polygenic interactions.

The Platelet Count and its Implications in Sickle Cell Disease Patients Admitted for Intensive Care.

BACKGROUND AND AIMS: In sickle cell disease (SCD) patients admitted for intensive care, evaluation of platelet counts in different types of sickle cell complications and its prognostic relevance are not well-studied. Illuminating these aspects were the objectives of this study. MATERIALS AND METHODS: A chart review of 136 adult SCD patients consecutively admitted to our Intensive Care Unit (ICU) was done. The prognosis on day 1 was assessed by Acute Physiology and Chronic Health Evaluation (APACHE II) and multiple organ dysfunction scores (MODS). Receiver operating characteristic (ROC) curves evaluated the ability of platelet counts, MODS, and APACHE II scores to predict survival. RESULTS: The most common types of crises were severe pain (n = 53), acute chest syndrome (n = 40), and infection (n = 18); 17 patients were nonsurvivors. Platelet counts varied widely (range, 19-838 × 109/L) with thrombocytopenia (n = 30) and thrombocytosis (n = 11). Counts correlated directly with leukocytes and reticulocytes; inversely with lactate dehydrogenase, APACHE, and MODS scores. Areas under ROC curve for platelets, MODS, and APACHE scores to predict survival were 0.73, 0.85, and 0.93, respectively. CONCLUSIONS: In severe sickle cell crisis thrombocytopenia is more common than thrombocytosis. In the ICU, day 1 platelet counts correlate inversely with prognostic scores and are significantly reduced in multi-organ failure and nonsurvivors. A platelet count above 175 × 109/L predicts patient survival with high specificity and positive predictive value but lacks sensitivity.

The Effect of Hydroxyurea Therapy in Bahraini Sickle Cell Disease Patients.

Hydroxyurea (HU) is used as a disease-modifying agent in sickle cell disease (SCD). Its beneficial effects have been ascribed to inhibition of the sickling process through increase of fetal hemoglobin (HbF) levels and influence on multiple factors affecting adhesion of erythrocytes to vascular endothelium. The present study investigates the effect of HU in SCD patients who were grouped on the basis of association with α- and ß-thalassemia using routine laboratory methods. A retrospective cross-sectional chart-review was done of 51 adult Bahraini SCD patients attending Salmaniya Medical Complex, Bahrain. Four sub-groups of cases were identified: (i) homozygous sickle cell anemia, 24 cases; (ii) SCD with microcytosis, 16 cases; (iii) sickle α-thalassemia, seven cases; and (iv) sickle ß thalassemia, four cases. Documented laboratory and clinical data included hemoglobin level (Hb), hematocrit (Hct), red cell indices, hemoglobin fractions, hospital admissions (frequency), number of inpatient-days, pain episodes (frequency) and red cell transfusion requirement (number of units). Pre- and post-treatment data were compared. Hydroxyurea treatment led to highly significant reduction of HbS % and pain crisis episodes in all patient groups. Other changes such as increases of total hemoglobin, Hct and HbF and reduction of hospital admissions, inpatient days and red cell units transfused also occurred but with less consistent levels of significance within patient sub-groups. Treatment with HU is beneficial for all subgroups of Bahraini SCD patients, without or with α- and ß-thalassemia interactions.

Thrombomodulin gene proximal promoter polymorphisms in premature acute coronary syndrome patients in Bahrain.

Thrombomodulin is expressed on endothelial cells and monocytes (mTM) where it has an anticoagulant function. Enzymatic cleavage from the cell surface produces soluble thrombomodulin (sTM) in plasma. Abnormal levels of sTM and mutations in the thrombomodulin gene (THBD) are linked to cardiovascular disease. The aim of this study was to investigate THBD proximal promoter mutations and levels of sTM and mTM in men presenting with premature acute coronary syndrome (ACS). This prospective cross-sectional study included 100 adult men with premature ACS (age <55 years) and 60 healthy age-matched controls. Plasma sTM was assayed by ELISA. mTM expression was assessed by flow cytometry with CD141 antibody. The -33 G/A polymorphism was identified by PCR-restriction fragment length polymorphism analysis and the THBD proximal promoter region was sequenced. Significantly lower sTM (P < 0.001) and higher mTM (P < 0.001) were seen in ACS patients. Heterozygous THBD promoter polymorphisms -33 G/A and -9/-10 GG/AT were found in eight patients and five control individuals. In patients and control individuals, allele frequencies of A were 0.02 and 0.025, and that of AT were 0.025 and 0.017, respectively. There were no significant associations of these polymorphisms with ACS, sTM levels or mTM expression. THBD polymorphisms -33 G/A and -9/-10 GG/AT are present in low frequency in our patient population, and are more frequent in the South Asians as compared to the Arabs. The frequency of -33 G/A is lower, whereas that of -9/-10 GG/AT is higher than that reported in the Orientals. The presence of THBD proximal promoter polymorphisms do not explain variations in levels of sTM and mTM in this patient population.

Thrombotic microangiopathy in sickle cell disease crisis.

Thrombotic microangiopathy (TMA) in patients with sickle cell disease (SCD) is a rare complication. These patients manifest microangiopathic hemolytic anemia (MAHA) with laboratory evidence of hemolytic anemia, schistocytosis, and thrombocytopenia. This is the first report of the syndrome in a group of these patients. A retrospective chart analysis of 10 consecutively diagnosed patients in SCD crisis who were referred for therapeutic plasma exchange (TPE) after developing MAHA was done. Patients had chest pain, respiratory distress, fever, pulmonary infiltrates, jaundice, and neurological dysfunction with abnormal liver function and coagulation tests. MAHA was diagnosed after a median hospital stay of 5 days. Nine patients recovered completely following TPE with fluid replacement by fresh frozen plasma with or without cryo-poor plasma. Incomplete response to TPE in one case was due to the development of fresh complications. During a median follow-up period of 77 months, there was one recurrent episode and one death in SCD crisis but without evidence of MAHA. TMA is not a very rare complication among Bahraini SCD patients in crisis. Characteristic features of this disorder are acute chest syndrome, organ failure, leuco-erythroblastosis, and a combination of thrombocytopenia, LDH level >1,000 U/l, and schistocytes in blood smears. Management with TPE usually leads to complete recovery with little chance of short-term recurrence. Multiple pathogenetic mechanisms leading to increased von Willebrand factor and its multimers may form the basis of this syndrome.

Spectrum of malignant lymphomas in Bahrain. Leitmotif of a regional pattern.

OBJECTIVE: To determine the clinicopathologic features of malignant lymphomas in Bahraini patients. METHODS: A retrospective hospital-based study was conducted. All new cases of malignant lymphoma diagnosed during the period January 1996 to December 2001 at the Salmaniya Medical Complex in Bahrain were included in the study. RESULTS: Seventy-two cases met the inclusion criteria. This included 24 (33.3%) cases of Hodgkin's disease (HD) and 48 (66.7%) cases of Non-Hodgkin lymphomas (NHL). A young age at presentation (median 20 years) mixed cellularity histology, lack of extra nodal involvement and rare marrow involvement characterized HD. The majority of NHL showed diffuse high or intermediate grade lesions. A high number of primary extra nodal neoplasms (41.7% of NHL) and frequent involvement of the gastrointestinal tract with Helicobacter pylori-associated gastric lymphomas were notable features among NHL cases. Immunohistochemical staining in 30 cases showed 26 cases (86.7%) of B cell and 4 cases of T cell origin. CONCLUSION: The study highlights common features that distinguish malignant lymphoma reported from countries of the Arabian Gulf region. This pattern distinguishes them from the disease encountered in the Western world.

Hemolytic uremic syndrome in association with typhoid fever.

BACKGROUND: Hemolytic uremic syndrome (HUS) has been associated with typhoid fever caused by Salmonella typhi. The pathogenesis of HUS in the context of S typhi infection is not known. The authors report on a patient with typhoid fever in whom HUS and myocarditis developed during the course of his illness and in whom there was no evidence of a Shiga-toxin (Stx)-producing organism. METHODS: Antibodies directed against the Escherichia coli O157:H7 and S typhi lipopolysaccharide (LPS) were sought in the serum sample taken during the acute phase using line-blot immunoassays. Polymerase chain reaction was performed to detect the presence of stx1 and stx2 genes in the patient's S typhi isolate. RESULTS: There was no evidence for immunoglobulin (Ig) M and IgA against the LPS of E coli O157:H7, whereas anti-S typhi LPS IgM and IgA were strongly positive. In the polymerase chain reaction, DNA from the Stx-producing E coli controls yielded stx1 and stx2 fragments of the expected sizes on agarose gel electrophoresis, whereas no stx1 and stx2 fragments were obtained from the S typhi isolate. The S typhi did, however, yield a band when amplified with primers specific for viaB, an S typhi gene. CONCLUSION: S typhi may be responsible for some cases of HUS, and the inciting toxin may not be Stx.

Pernicious anemia in a young Bahraini female.

Pernicious anemia (PA) is an autoimmune disorder associated with atrophic gastritis, presence of antibodies to gastric parietal cells and intrinsic factor (IF) and vitamin B2 malabsorption leading to megaloblastic anemia. It has a comparatively higher prevalence in people of North European origin, is uncommon in Arabs and usually affects the elderly. This report, the first from Bahrain, describes a rare case of PA in young female. The presenting symptoms, clinical and laboratory features were similar to those described in classical elderly Caucasian patients. No association with any other autoimmune disease was detected.

Plasmacytoma of the rib in young male.

Solitary plasmacytoma of the 11th rib with soft tissue extension was seen in a 29-year-old male. Hematological and biochemical profiles did not reveal any systemic involvement. The 12-cm fusiform expansile lesion was excised and subjected to histopathological examination. The sections revealed sheets of plasma cells with focal cortical discontinuity and adjacent soft tissue invasion. This case is unique in view of the age of occurrence and the site of the lesion.

The Middle-East connection of Wolman Disease.

The clinical, laboratory and cytological features of 2 Bahraini infants with Wolman's disease are described. While one of the cases showed the classical diagnostic features, the other case exhibited a few atypical features such as lack of adrenal calcification and unusual morphology of vacuolated marrow macrophages. Literature review shows that this disorder may not be rare in this region.

Clinicopathological aspects of Chediak-Higashi syndrome in the accelerated phase.

This report describes clinical and laboratory features of a case of Chediak-Higashi syndrome that presented in the accelerated phase of the disorder. This female infant presented with a fever, marked neutropenia, large cytoplasmic granules in leukocytes and a constellation of features that suggested a virus-associated hemophagocytic syndrome. The clinical course was marked by limited response to the therapeutic agents that included ascorbate, cytotoxic agents and granulocyte colony-stimulating factor.