Clinical and Laboratory Features of Sickle Cell Disease S/D Punjab: Impact of HbF and Hydroxyurea.

Background: Sickle cell disease (SCD) is a major public health issue worldwide with high morbidity and mortality. SCD SD Punjab is the third most common genotype of SCD in Oman and is associated with several serious complications. The aim of the study is to establish the clinical and laboratory features of SCD patients with SD double heterozygotes and study the impact of haemoglobin F, hydroxyurea, and other modulators on the disease severity. Methods: We analysed the electronic medical records of 52 consecutive SCD patients who were diagnosed as double heterozygote SD Punjab between 2006 and 2022. The study was approved by the local medical research and ethics committee. The data captured included SCD-related complications and current clinical and laboratory indices. Data from other studies on other SCD genotypes were used as historical controls. Results: 52 patients (31 males, 21 females) who formed this cohort had a median age of 32 years with an interquartile range (IQR) of 21-39.8 years. 37(71.2%) had <3 VOC per year, whereas 15 (28.8%) patients had ≥3 vasooclusive (VOC) episodes per year. SCD-related complications included Acute Chest Syndrome (ACS) (48%), Gall stones (26.9%), Avascular necrosis (AVN) (28.8%), Stroke (13.5%) and splenic sequestration (7.7%), whereas 5 (9.6%) patients of this cohort died. Surgical and Autosplenectomy were seen in 18 (34.6%). These findings were similar to other SCD genotypes in this community. 19 (57.6%) were taking Hydroxyurea (HU) amongst the 33 patients who were prescribed HU. Haematological parameters showed a median (IQR) Hb (g/dl), MCV (fl), Retic count (%), WBC count(×109/L) and Platelet count(×109/L) of 9.7 (8.5-11.3), 74.9 (68.4-79.8), 4 (3.2-5.7), 9.9 (8.1-12.6) and 309 (239-428) respectively. The haemoglobin electrophoresis showed an elevated HbF, whereas serum bilirubin and LDH were elevated amongst the biochemical parameters. The use of hydroxyurea showed no impact on VOC, ACS, AVN, Stroke or mortality. Conclusion: SD Punjab is the third most common SCD genotype in Oman and was associated with recurrent VOC, ACS, AVN, and gall stones comparable to other SCD genotypes. Patients with > 3 VOC/year had significantly increased incidence of Stroke, AVN, and gallstones. However, HU was not associated with improved prognosis and better survival in this cohort of patients.

Correlation of Transient Elastography with Liver Iron Concentration and Serum Ferritin Levels in Patients with Transfusion-Dependent Thalassemia Major from Oman.

Aims: In a longitudinal study, we aimed to assess the correlation between ultrasound transient elastography (TE), serum ferritin (SF), liver iron content (LIC) by magnetic resonance imaging (MRI) T2* along with the fibrosis-4 (FIB-4) score as a screening tool to detect significant liver fibrosis among chronically transfusion-dependent beta-thalassemia (TDT) patients. Methods: The study was conducted at a tertiary health center treating TDT patients. Transient elastography was performed within 3 months of Liver MRI T2* examinations at the radiology department over a median of one-year duration. T-test for independent data or Mann-Whitney U test was used to analyze group differences. Spearman correlation with linear regression analysis was used to evaluate the correlation between TE liver stiffness measurements, Liver MRI T2* values, and SF levels. Results: In this study on 91 patients, the median age (IQR) of the subjects was 33 (9) years, and the median (IQR) body mass index was 23.8 (6.1) kg/m2. Median (IQR) TE by fibroscan, MRI T2*(3T), Liver iron concentration (LIC) by MRI Liver T2*, and SF levels were 6.38 (2.6) kPa, 32.4 (18) milliseconds, 7(9) g/dry wt., and 1881 (2969) ng/mL, respectively. TE measurements correlated with LIC g/dry wt. (rS =0.39, p=0.0001) and with SF level (rS =0.43, P=0.001) but not with MRI T2* values (rS =-0.24; P=0.98). Conclusion: In TDT patients, liver stiffness measured as TE decreased significantly with improved iron overload measured as LIC by MRI and SF levels. However, there was no correlation of TE with the fibrosis-4 (FIB-4) score.

The Effects of Terrain Properties Upon the Small Crater Population Distribution at Giordano Bruno: Implications for Lunar Chronology.

The distribution of impact craters on the ejecta of Giordano Bruno, a recent (<10 Ma) 22-km diameter crater within the lunar highlands, exhibits substantial variations. We surveyed craters D ≥ 10 m across a 1,323 km2 area of Giordano Bruno's ejecta and compared the distribution of craters with variations in thermophysical properties derived from the Lunar Reconnaissance Orbiter Diviner instrument. We used Diviner-derived rock abundance and nighttime regolith temperatures along with thermal model-predicted surface temperatures for a diversity of terrains to identify and isolate areas of the ejecta based on thermophysical properties such as bulk density and thermal conductivity. We found that thermophysical properties of the ejecta vary considerably both laterally and vertically, and consistently differ from typical regolith, indicating the presence of higher thermal inertia materials. Crater-size frequencies are significantly lower in areas with terrain properties exhibiting higher: rock abundance, nighttime temperatures, and/or modeled thermal inertia. This discrepancy in crater distribution increases for craters smaller than ∼25 m. These thermophysical variations indicate changes in the mechanical properties of the target materials. We suggest that these variations-specifically, terrain-dependent crater scaling variations and impactor-scale heterogeneities in material properties such as the presence or absence of large boulders-may influence crater diameters or inhibit crater production altogether in Giordano Bruno's ejecta; furthermore, these factors are size-dependent.

Safety Warning for ChAdOx1 nCov-19 Vaccine in Patients with Sickle Cell Disease.

Vaccines against acute respiratory syndrome Coronavirus 2(SARS-CoV2) are critical weapons to control the spread of the deadly Coronavirus 2019(COVId-19) virus worldwide. Although these vaccines are generally safe, their widespread use has produced reports of rare complications, including vaccine-induced immune thrombotic thrombocytopenia (VIITT), particularly in connection with ChAdOx1 nCov-19. We have identified three cases of sickle cell disease (SCD) experiencing a severe vaso-occlusive crisis (VOC) shortly after the vaccine. Despite being stable for a long time, they had fever with tachycardia, along with a significant rise in WBC, liver enzymes, particularly alkaline phosphate, with a remarkable drop in hemoglobin, and platelets and one of them had probably a fatal TTP like syndrome. Given these findings, physicians and patients should exercise caution when taking this type of vaccine and be aware of these safety concerns.

Impact of COVID-19 on vasooclusive crisis in patients with sickle cell anaemia.

OBJECTIVES: The study aimed to assess COVID-19 impact on the morbidity and mortality of vasooclusive crisis (VOC) in sickle cell anaemia (SCA) patients. METHODS: A prospective cohort study of 100 SCA patients; 50 with COVID-19 (COVID group) and 50 without (non-COVID group). All patients signed written informed consent. RESULTS: The COVID group had a significantly higher VOC episode median per year; 3 (IQR,1-6) vs 2 (IQR,2-12) (P < 0.05). The need for hospitalisation was similar in both groups. The non-COVID group had more history of culture-proven infection (P = 0.05). The COVID-group had more osteonecrosis (P < 0.05), splenic sequestration, splenomegaly and hepatic crisis (P = 0.05, 0.006, 0.02; respectively) and significantly higher (P < 0.05) symptoms of fever, cough, fatigue, abdominal pain and anosmia. Mean haemoglobin, lymphocyte subset, platelets, and reticulocytes were reduced in both groups, while lactate dehydrogenase and ferritin levels were significantly elevated. In the COVID group, the rise in white blood cell count, reticulocyte percentage, platelets and ferritin was subdued (P < 0.05). Two patients in the COVID group and 3 in the non-COVID group died; there was no statistically significant difference in mortality. CONCLUSIONS: Although COVID-19 may have triggered the onset of VOC, it did not significantly influence VOC-related morbidity or mortality in this SCA cohort.

Increased Vasoocclusive Crises in "O" Blood Group Sickle Cell Disease Patients: Association with Underlying Thrombospondin Levels.

OBJECTIVES: To explore the incidence of vaso-occlusive crisis (VOC) in Blood Group "O" sickle cell disease (SCD) patients, and correlate it with the blood group and thrombospondin (TSP) levels. METHODS: In 89 consecutive SCD patients, blood samples were obtained for von Williebrand factor (vWF:Ag) antigen, collagen binding activity (CBA), ristocetin binding activity (RCo), blood group typing, C-reactive protein (CRP), high performance liquid chromatography (HPLC), Serum TSP 1 and TSP 2 levels, complete blood counts (CBC), lactic dehydrogenase (LDH) levels, liver function (LFT) and renal function tests (RFT) during VOC episodes and in steady state conditions. RESULTS: In steady state SCD patients (n=72), "O" blood group patients (n=37) showed a significantly higher median serum TSP 1 and TSP 2 levels as compared to non-O blood group patients [n=35] [p <0.05, Mann-Whitney test]; with an inverse relation between vWF:Ag, Factor VIII:C and TSP levels. Furthermore, the serum TSP 1 and TSP 2 levels were significantly higher in patients presenting with acute VOC [n=17], as well as in those with repeated VOC's (group 1, n=16), especially amongst blood group "O" patients [p, <0.05, Mann-Whitney test]. CONCLUSIONS: The study demonstrates an inverse relation between TSP and vWF levels, in blood group "O" SCD patients, with an upregulation of the TSP levels. Expectedly, during active VOC crisis, the TSP 1 and TSP 2 levels were significantly elevated.

Spectrum of external catheter-related infections in children with acute leukemia-Single-center experience.

BACKGROUND: External catheters (ECs) are commonly used in children who are receiving treatment for acute leukemia. AIMS: To study the spectrum of microorganisms and to compare the rates of infection. METHODS: A total of 42 ECs were inserted, including 28 Port-A-Caths, 11 CVC lines and 3 Hickman lines. Single ECs were required for 19 patients (45.2%), whereas 2, 3 and 4 ECs were required in 8, 1 and 1 patients, respectively. RESULTS: Overall, 37 culture-documented infections were present in 18 (62%) patients who had ECs. Gram-positive microorganisms were identified in 20 cases, Gram-negative microorganisms in 14 cases and fungal infections in 3 cases. Of the 42 devices implanted, 10 out of 28 Port-A-Caths (35.7%), 2 out of 3 Hickman catheters (66.7%) and 9 out of 11 central venous catheters (81.8%) required removal due to infection. The average length of working life for the ports was 330.6 days (range: 40-1043 days). The median rate of complications due to infection was 2.84 infections per 1000 catheter days (interquartile range: -1.55 to 5.8), and the number of infections was correlated with the number of ports (Pearson's r=0.51; p<0.05).

Acquired pericentric inversion of chromosome 9 in acute myeloid leukemia.

Pericentric inversion of chromosome 9 involving the qh region is relatively common as a constitutional genetic aberration without any apparent phenotypic consequences. However, it has not been established as an acquired abnormality in cancer. Among the three patients reported so far in the literature with acquired inv(9), only one had acute myeloid leukemia (AML). Here we describe an unique case where both chromosomes 9 presented with an acquired pericentric inversion with breakpoints at 9p13 and 9q12 respectively, in a AML patient with aberrant CD7 and CD9 positivity. Additionally, one der(9) also showed short arm deletion at 9p21 to the centromeric region and including the p16 gene. The constitutional karyotype was normal. This is probably the first report describing an acquired inv(9) involving both chromosomes 9 in AML. The possible significance of this inversion is discussed.

Follicular dendritic cell hyperplasia in plasma cell variant of Castleman's disease with interfollicular Hodgkin's disease.

We report a case of a multicentric plasma cell (PC) variant of Castleman's disease (CD) in association with interfollicular type of classic Hodgkin's disease (HD), both diseases identified in the same lymph node. The histologic features of CD were the classic ones, with hyperplastic and atrophic follicles, some with prominent mantle zones, hyalinzed vessels, and a very rich polyclonal proliferation of PCs in the interfollicular region. The presence of LCA-negative, but CD30- and CD15-positive typical and atypical Reed-Sternberg (RS) cells in the interfollicular region confirmed the presence of HD. In addition, many of the RS cells stained positive for EBV. CD35- and CD21-positive follicular dendritic cell (FDC) hyperplasia was a striking feature, a finding that has not been well documented in the PC variant of CD.

Combined therapy with desferrioxamine and deferiprone in beta thalassemia major patients with transfusional iron overload.

Iron overload is the main cause of morbidity and mortality especially from heart failure in patients with beta thalassemia major (TM). Successful iron chelation is therefore essential for the optimal management of TM. Although desferrioxamine (DFX) has been the major iron-chelating treatment of transfusional iron overload, compliance is a major hindrance in achieving optimal therapeutic results. The availability of oral iron chelation with deferiprone (L(1)) since 1987 is useful but showed poor efficacy when used alone as compared to DFX. We therefore decided to compare DFX alone with a prospective combined therapy with DFX and L(1) in beta thalassemia major patients with iron overload. We studied 91 patients with beta thalassemia major (mean age+/-SD, 15.02+/-5.8; range 2-30 years) attending the day care unit for regular transfusional support. They received packed red cells every 3-4 weeks to maintain pretransfusion hemoglobin concentration above 9 g/dl. They had been receiving DFX at a daily dose of 40 mg kg(-1) day(-1) by subcutaneous infusion for 8-10 h on 4-5 nights each week for the past several years. However, due to various reasons, they had developed considerable transfusional iron overload. These patients were allocated to prospectively receive additional therapy with oral iron chelator L(1) at 75 mg kg(-1) day(-1) body weight in three divided doses with food after informed consent and continued to receive treatment with DFX as per the above dosage. Of the 91 patients, six developed severe gastrointestinal (GI) upset, two agranulocytosis, two arthropathy, one persistently raised liver enzymes, two died owing to sepsis, and two received allogeneic bone marrow transplantation. Amongst the remaining 76 patients, 21 were found noncompliant (not taking DFX regularly, but taking L(1) regularly). Thus, in the 55 evaluable patients {6-48 months on combination therapy; mean [(+/-SD)22+/-12 months]}, the mean serum ferritin (+/-SD) fell dramatically from 3,088 (+/-1,299) ng/ml (DFX alone) to 2,051 (+/-935) ng/ml (DFX and L(1); p<0.001). It is interesting to note that there was also a significant improvement in the myocardial function as assessed by the ejection fraction (p<0.004) and fractional shortening (p<0.05) in those patients (n=42) who could be studied after being on combination therapy for a minimum of 1 year. The study emphasizes that beta thalassemia major patients with transfusional iron overload can be successfully treated with a combination of DFX and L(1). Our results also demonstrate a significant statistical improvement after as little as 6 months of combination therapy. Furthermore, these improvements lead to a progressive fall in the mean serum ferritin. Lastly, the study also demonstrates significant improvement in the echocardiographic parameters of myocardial performance in these patients receiving combination therapy.

Role of antiidiotypic antibodies on the clinical course of idiopathic thrombocytopenic purpura.

The severity and clinical course of idiopathic thrombocytopenic purpura (ITP) vary from patient to patient. The factors responsible for this variation are not well understood. In this study we attempted to evaluate the role of antiidiotypic antibodies in the immunoregulation of the disease. We investigated 114 cases of chronic ITP in adults. We determined antiidiotypic antibodies against antiplatelet antibodies using (a) idiotype-binding enzyme-linked immunosorbent assay (ELISA), (b) paratope-blocking ELISA, and (c) Western blotting. Results indicated that 80.6%, 11.2%, and 8.3% of the patients, respectively, presented with antiidiotypes against antibodies to GPIIb/IIIa, GPIb/IX, and both GPIIb/IIIa and GPIb/IX. More than 70% of the patients who showed high levels of blocking of antiidiotypic antibodies went into complete remission, compared with less than 5% of patients who showed low levels of such antibodies (P <.01). Disease severity was also found to be inversely related (P < 0.01) to the degree of blocking of antiidiotypic antibodies. The results of this study suggest that antiidiotypic antibodies against antiplatelet antibodies are a potential prognostic marker in chronic ITP.

Deferiprone (L1) as an adjuvant therapy for Plasmodium falciparum malaria.

BACKGROUND & OBJECTIVES: Mortality due to Plasmodium falciparum infection remains high in India, hence any modality of treatment which can improve the outcome of this disease is worth exploring. The present study was undertaken to see whether addition of an oral iron chelator, deferiprone (L1) to the conventional treatment regime for P. falciparum infection improves the clinical course and final outcome. METHODS: In this prospective, randomised double blind trial, 45 consecutive patients with P. falciparum infection were randomised into two groups. Patients in Group I (control group, 21 patients) received standard quinine and doxycycline therapy along with supportive therapy and placebo capsules for 10 days. Patients in Group II (24 patients) received the same treatment as Group I but in place of placebo capsule received deferiprone capsules 75 mg/kg/day in 12 hourly divided doses. The parameters evaluated included the time taken in resolution of parasitaemia, fever and coma, differences in final outcome i.e., death or other severe complications, and side effects and deferiprone tolerance. RESULTS: Four patients in Group I and two in Group II died (P > 0.05). The resolution of fever and coma was significantly faster in Group II (P < 0.05) and parasitaemia cleared 24 h earlier in this Group. The drug was well tolerated and had no side effects. INTERPRETATION & CONCLUSION: Deferiprone (L1) seems to be a promising agent as an adjuvant in the treatment for severe P. falciparum malaria infection.

Spectrum of inherited bleeding disorders from Western India.

OBJECTIVE: The study was undertaken to assess the magnitude and diversity of different bleeding disorders in Western India. MATERIALS AND METHODS: 768 cases referred to our Institute for evaluation of an underlying bleeding diathesis were investigated appropriately to detect the cause of the abnormal hemostatic function. RESULTS: 630 patients were diagnosed to have hereditary bleeding diathesis. Amongst these, 598 patients had a coagulation disorder while only 32 patients had a platelet function abnormality. Amongst the coagulation disorders, hemophilia A (70.5%) was the most common disorder followed by hemophilia B (14%) and VWD (10.8%). Glanzman's thrombasthenia (84.3%) was the most common platelet function disorder followed by Bernard-Soulier syndrome (12.5%). Some rare disorders have also been diagnosed. CONCLUSION: In spite of their apparent rarity, India has a substantial number of cases of inherited bleeding disorders. A large number of these patients is referred to many tertiary care institutions. It is therefore desirable that district hospitals must develop their laboratories to detect most of these disorders so that the patients need not travel long distances to get an appropriate diagnosis and proper management. All 1st degree female relatives of severe and moderate hemophilia must get factor assays done because some of them may be vulnerable to post-procedural or post-traumatic bleeding.

Transfusion transmitted diseases in haemophilics from western India.

BACKGROUND & OBJECTIVES: Transfusion related human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) infections have been a major cause for morbidity and mortality in the haemophilic population in the west. The prevalence of these markers of transfusion transmitted viral diseases in severe and moderate haemophilia patients was studied. METHODS: The seropositivity for these viral markers was evaluated in 400 haemophilics (323 severe and 77 moderate) in a 5-year survey starting from 1995. First 188 of these patients were also tested for HCV. Serological tests for HIV, HBsAg and HCV were done by third generation ELISA; positive samples were also confirmed by Western blot. RESULTS: Fifteen of the 400 patients were found to be HIV positive (3.8%), 24/400 were HBsAg positive (6%) and 45/188 (23.9%) were positive for HCV (28 for both non-structural and core antigen, 13 for core only and 4 for non-structural antigen only). The lowest age of HIV positivity was 12 yr and that of HCV positivity was 8 yr. INTERPRETATION & CONCLUSION: The above study shows a reduction in blood product related HIV transmission in severe and moderately affected haemophilics but more stringent policy for blood product usage, universal hepatitis C screening, hepatitis B vaccination and continuous awareness programmes for medical staff, general public and patients is needed to reduce the incidence of these diseases in haemophilics.

Influence of auto-antibody specificities on the clinical course in patients with chronic and acute ITP.

It is now well established that the target antigens of platelet auto-antibodies are the GP IIb/IIIa and GP Ib/IX receptors. In our study, it was observed that the majority of patients had antibodies directed towards the GP IIb/IIIa receptor, whereas the number of patients having antibodies directed towards the GP Ib/IX receptor was much less. Also, we found that the patients in whom the auto-antibodies are directed towards the GP IIb/IIIa receptors usually have mild bleeding. On the other hand, the patients having auto-antibodies directed towards both GP IIb/IIIa and GP Ib/IX receptors have a severe bleeding diathesis, and usually show poor prognosis to treatment with corticosteroids.

Use of the dual force system to correct chronic knee deformities due to severe haemophilia.

In this study, the use of the dual force system to correct recent or relatively longstanding knee deformities in ten patients is described. (Nine of the patients had severe haemophilia and one had severe von Willebrand's disease.) The mean duration of deformity in these patients was 10 months. The mean range of movement at the affected knee joints increased from 50 degrees at pre-intervention to 110 degrees following 6 weeks of application of the dual force system. In nine of ten patients (90%) the residual flexion deformity ranged from 0 degrees to 10 degrees. The dual force system offers an easily affordable and effective means of correcting a flexion deformity of the knee joint in severely affected haemophilia and allied disorders. More extensive use of this technique in different centres is required to determine its place in the day-to-day management of such patients.