Biochemical Markers of Early Renal Dysfunction in Patients with ß-thalassemia Major: A Systematic Review and Meta-analysis.

BACKGROUND: Early diagnosis of renal dysfunction in ß-thalassemia major (ß- TM) may help take specific measures to delay irreversible damage and renal failure. Therefore, the present meta-analysis aimed to compare biochemical markers of premature renal dysfunction between ß-TM and healthy subjects and identify renal issues' prevalence in patients with ß-TM. METHODS: We searched PubMed, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Medline, Scopus, Web of Science, ScienceDirect, ProQuest, Google Scholar, and State Inpatient Databases (SIDs) without any language constraints for all relevant articles published up to April 2019. RESULTS: Out of 1458 articles published up to April 2019, 24 case-control and 22 crosssectional studies were investigated. The investigated levels of serum phosphorus, uric acid (UA), cystatin C, and ferritin were significantly different between ß-TM patients and controls. The albumin/creatinine ratio (ACR), N-acetyl-ß-D-glucosaminidase/creatinine (NAG/Cr) ratio, urinary and serum ß2 microglobulin (ß2MG), and serum ferritin levels were significantly higher in ß-TM patients than in healthy individuals. However, glomerular filtration rate, creatinine clearance, and pretransfusion hemoglobin indicated a significantly lower rate. The general prevalence of renal glomerular and/or tubular defects in patients with ß-TM was 50.22%. CONCLUSION: Urinary NAG, ß2MG, ACR, and Scys-C may be early markers of renal dysfunction in patients with ß-thalassemia major. An observation of elevated levels of these markers despite normal levels of other markers of renal dysfunction may indicate primary, subclinical injury to the renal tubules and glomeruli.

Frequency of Kell and Rh alloantibodies in Iranian Thalassemia Patients in Khorasan Razavi Province, Iran.

Background: Thalassemia is an inherited disease with anemia and hemolysis. Blood transfusion is a routine treatment for thalassemia patients; alloimmunization is one of the complications of blood transfusion, which is very serious for these patients, especially girls and young women. Materials and Methods: In this cross-sectional study, 446 thalassemia patients were examined. Demographic information of patients was extracted and recorded. The phenotype of ABO, Rh, and Kell antigens (tube method) with antisera from IMMUNDIANOSTICA Company (Germany) and the frequency of alloantibodies were determined. Results: 55.8% of the studied individuals were male, and 44.2% were female. Mean age of the studied patients was 19.94±10.63. The alloantibodies were detected in 7.5% of cell-pack receivers. The most prevalent phenotype of the ABO system was the O blood group (37.4%), and the most abundant antigen of the Rh group was 'e', which was found in 99.8% of the studied population. The most common alloantibody detected was Anti K (38.2%); concerning kell phenotype, (K_k+) and (K+k+) were found in 99.3% and 0.7% of patients, respectively. The frequency of Anti-D, Anti-C, Anti-c, and Anti-E was 23.5%, 14.7%, 2.9%, and 14.7%, respectively. Conclusion: According to the results of this paper, finding the compatible packed cells in terms of Kell and Rh systems antigens in addition to the ABO blood group is recommended to decrease the rate of alloantibodies in thalassemia patients.

von Willebrand factor neutralizing and non-neutralizing alloantibodies in 213 subjects with type 3 von Willebrand disease enrolled in 3WINTERS-IPS.

BACKGROUND: Type 3 von Willebrand disease (VWD) is the most severe form of this disease owing to the almost complete deficiency of von Willebrand factor (VWF). Replacement therapy with plasma-derived products containing VWF or recombinant VWF rarely cause the development of alloantibodies against VWF that may be accompanied by anaphylactic reactions. OBJECTIVE: The objective of this study was to assess the prevalence of anti-VWF alloantibodies in subjects with type 3 VWD enrolled in the 3WINTERS-IPS. METHODS: An indirect in-house enzyme-linked immunosorbent assay has been used to test all the alloantibodies against VWF. Neutralizing antibodies (inhibitors) have been tested with a Bethesda-based method by using a VWF collagen binding (VWF:CB) assay. Samples positive for anti-VWF antibodies were further tested with Bethesda-based methods by using the semiautomated gain-of-function glycoprotein-Ib binding (VWF:GPIbM) and a VWF antigen (VWF:Ag) enzyme-linked immunosorbent assay. RESULTS: In total, 18 of the 213 (8.4%) subjects tested positive for anti-VWF antibodies and 13 of 213 (6%) had VWF:CB inhibitors. These 13 were among the 18 with anti-VWF antibodies. Of the 5 without VWF:CB inhibitors, 3 had non-neutralizing antibodies, 1 only inhibitor against VWF:GPIbM, and one could not be tested further. Ten of the 13 subjects with VWF:CB inhibitors also had VWF:GPIbM inhibitors, 6 of whom also had VWF:Ag inhibitors. Subjects with inhibitors were homozygous for VWF null alleles (11/14), homozygous for a missense variant (1/14), or partially characterized (2/14). CONCLUSIONS: Anti-VWF antibodies were found in 8.4% of subjects with type 3 VWD, whereas neutralizing VWF inhibitors were found in 6%, mainly in subjects homozygous for VWF null alleles. Because inhibitors may be directed toward different VWF epitopes, their detection is dependent on the assay used.

Von Willebrand factor propeptide and pathophysiological mechanisms in European and Iranian patients with type 3 von Willebrand disease enrolled in the 3WINTERS-IPS study.

BACKGROUND: Type 3 von Willebrand disease (VWD) is a severe bleeding disorder caused by the virtually complete absence of von Willebrand factor (VWF). Pathophysiological mechanisms of VWD like defective synthesis, secretion, and clearance of VWF have previously been evaluated using ratios of VWF propeptide (VWFpp) over VWF antigen (VWF:Ag) and factor (F)VIII coagulant activity (FVIII:C) over VWF:Ag. OBJECTIVE: To investigate whether the VWFpp/VWF:Ag and FVIII:C/VWF:Ag ratios may also be applied to understand the pathophysiological mechanism underlying type 3 VWD and whether VWFpp is associated with bleeding severity. METHODS: European and Iranian type 3 patients were enrolled in the 3WINTERS-IPS study. Plasma samples and buffy coats were collected and a bleeding assessment tool was administered at enrolment. VWF:Ag, VWFpp, FVIII:C, and genetic analyses were performed centrally, to confirm patients' diagnoses. VWFpp/VWF:Ag and FVIII:C/VWF:Ag ratios were compared among different variant classes using the Mann-Whitney test. Median differences with 95% confidence intervals (CI) were estimated using the Hodges-Lehmann method. VWFpp association with bleeding symptoms was assessed using Spearman's rank correlation. RESULTS: Homozygosity/compound heterozygosity for missense variants showed higher VWFpp level and VWFpp/VWF:Ag ratio than homozygosity/compound heterozygosity for null variants ([VWFpp median difference, 1.4 IU/dl; 95% CI, 0.2-2.7; P = .016]; [VWFpp/VWF:Ag median difference, 1.4; 95% CI, 0-4.2; P = .054]). FVIII: C/VWF:Ag ratio was similarly increased in both. VWFpp level did not correlate with the bleeding symptoms (r = .024; P = .778). CONCLUSIONS: An increased VWFpp/VWF:Ag ratio is indicative of missense variants, whereas FVIII:C/VWF:Ag ratio does not discriminate missense from null alleles. The VWFpp level was not associated with the severity of bleeding phenotype.

Understanding the impact of COVID-19 pandemic on health-related quality of life amongst Iranian patients with beta thalassemia major: a grounded theory.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic and the resulting measures can impact daily life and healthcare management amongst patients with beta thalassemia major. METHODS: The Corbin and Strauss method of grounded theory was used to explore the impact of the COVID-19 pandemic on health-related quality of life (HRQoL) amongst Iranian patients with beta thalassemia major. Semi-structured interviews with 16 patients with thalassemia major in the eastern of Iran were performed. Data collection was conducted from 19 September through 18 November 2020. Collected data were recorded, transcribed, and coded to develop themes and subthemes. Paradigm components were sought to find out what happened to these patients and explore the process and events. RESULTS: Insights from these interviews led to five major themes: 'changing physical health', 'emotional and psychological reactions', 'changing the nature of relationships and the scope of social support', 'metamorphosis of ongoing healthcare, and 'functionality and adaptation to new realities.' The emerging core concept was labelled: 'maintaining well-being balance.' The COVID-19 pandemic disturbed the balance of life and health of the patients. Multiple strategies to maintain balance and reduce the negative effects of the COVID-19 pandemic on HRQoL were used by the patients, the healthcare team, and support systems. CONCLUSIONS: Due to the fear of COVID-19, the patients with beta thalassemia were less likely to contact healthcare professionals. They considered postponing blood transfusion and abandoned evaluating disease complications. Reduced access to the healthcare system and shifting resources from existing programmes to COVID-19 by the healthcare system were incompatible policies. These policies and strategies had strong and negative effects on the physical domain of HRQoL. The patients experienced a deterioration of emotional functioning. They reported a strong reduction in social functioning and felt lonely. Online interventions supporting mental health and social interactions and telemedicine can help during the times of social distancing and lockdowns.

Genotypes of European and Iranian patients with type 3 von Willebrand disease enrolled in 3WINTERS-IPS.

Type 3 von Willebrand disease (VWD3) is a rare and severe bleeding disorder characterized by often undetectable von Willebrand factor (VWF) plasma levels, a recessive inheritance pattern, and heterogeneous genotype. The objective of this study was to identify the VWF defects in 265 European and Iranian patients with VWD3 enrolled in 3WINTERS-IPS (Type 3 Von Willebrand International Registries Inhibitor Prospective Study). All analyses were performed in centralized laboratories. The VWF genotype was studied in 231 patients with available DNA (121 [115 families] from Europe [EU], and 110 [91 families] from Iran [IR]). Among 206 unrelated patients, 134 were homozygous (EU/IR = 57/77) and 50 were compound heterozygous (EU/IR = 43/7) for VWF variants. In 22 patients, no or only one variant was found. A total of 154 different VWF variants (EU/IR = 101/58 [5 shared]) were identified among the 379 affected alleles (EU/IR = 210/169), of which 48 (EU/IR = 18/30) were novel. The variants p.Arg1659*, p.Arg1853*, p.Arg2535*, p.Cys275Ser, and delEx1_Ex5 were found in both European and Iranian VWD3 patients. Sixty variants were identified only in a single allele (EU/IR = 50/10), whereas 18 were recurrent (≥3 patients) within 144 affected alleles. Nine large deletions and one large insertion were found. Although most variants predicted null alleles, 21% of patients carried at least 1 missense variant. VWD3 genotype was more heterogeneous in the European population than in the Iranian population, with nearly twice as many different variants. A higher number of novel variants were found in the Iranian VWD3 patients.

Bleeding symptoms in patients diagnosed as type 3 von Willebrand disease: Results from 3WINTERS-IPS, an international and collaborative cross-sectional study.

BACKGROUND: Type 3 von Willebrand's disease (VWD) patients present markedly reduced levels of von Willebrand factor and factor VIII. Because of its rarity, the bleeding phenotype of type 3 VWD is poorly described, as compared to type 1 VWD. AIMS: To evaluate the frequency and the severity of bleeding symptoms across age and sex groups in type 3 patients and to compare these with those observed in type 1 VWD patients to investigate any possible clustering of bleeding symptoms within type 3 patients. METHODS: We compared the bleeding phenotype and computed the bleeding score (BS) using the MCMDM-1VWD bleeding questionnaire in patients enrolled in the 3WINTERS-IPS and MCMDM-1VWD studies. RESULTS: In 223 unrelated type 3 VWD patients, both the BS and the number of clinically relevant bleeding symptoms were increased in type 3 as compared to type 1 VWD patients (15 versus 6 and 5 versus 3). Intracranial bleeding, oral cavity, hemarthroses, and deep hematomas were at least five-fold over-represented in type 3 VWD. A more severe bleeding phenotype was evident in patients having von Willebrand factor antigen levels < 20 IU/dL at diagnosis in the two merged cohorts. In type 3 patients, there was an apparent clustering of hemarthrosis with gastrointestinal bleeding and epistaxis, whereas bleeding after surgery or tooth extraction clusters with oral bleeding and menorrhagia. CONCLUSIONS: In the largest cohort of type 3 VWD patients, we were able to describe a distinct clinical phenotype that is associated with the presence of a more severe hemostatic defect.

Comparative evaluation of the safety and efficacy of recombinant FVIII in severe hemophilia A patients.

OBJECTIVE: This study compared the safety and efficacy of Safacto® versus xyntha® in patients with severe hemophilia A. METHODS: Thirty-three male patients with severe hemophilia A were randomly divided into two groups. Seventeen patients received Safacto® and 16 patients received Xyntha® for four consecutive times. The dosage of FVIII was 40-50 IU/kg for each injection. Plasma level of FVIII activity was evaluated before every injection, 15 minutes after the injection and one month after the start of the trial. The rate of factor VIII activity, pain and joint motion were also assessed before and after the treatment. RESULTS: Plasma level of FVIII clotting activity in Safacto® and Xyntha® were 1.96±0.5 IU/dl and 1.63±0.5 IU/dl and increased to 88.84±25.2 IU/dl and 100.09±17.8 IU/dl, respectively (P<0.001). Pain score and range of motion improvement were 9.3±0.9 and 8.7±0.1 in Safacto® (P=0.17); and 9.4±0.8 and 8.8±0.3 in Xyntha® (P=0.35), respectively. No allergic or other unfavorable reactions was observed with either of the preparations. CONCLUSION: This study showed that Safacto® has a favorable efficacy and safety profile.

The effect of an aerobic exercise program on the quality of life in children with cancer.

Khodashenas E, Badiee Z, Sohrabi M, Ghassemi A, Hosseinzade V. The effect of an aerobic exercise program on the quality of life in children with cancer. Turk J Pediatr 2017; 59: 678-683. Aerobic exercise such as physical activity plays an essential role for a healthy development for children undergoing chemotherapy and radiation therapy. The aim of this study was to examine the effectiveness of an aerobic exercise program on quality of life in children undergoing cancer treatment. Patients diagnosed with acute lymphoblastic leukemia (ALL), undergoing chemotherapy, were divided into two groups; the control group received the routine treatment with activities of daily living and the interventional group received routine treatment in addition to an aerobic exercise program. Data was collected using the pediatric quality of life questionnaires (PedsQL version 4) before and after the training program. We enrolled 20 cancer patients, who were referred to Dr. Sheikh Children`s Hospital in Mashhad, Iran; 8 (40%) and 12 (60%) of the patients were female and male, respectively. The results show a significant association in the pain and injury subscale (p=0.002), improving in interventional groups after test compared to the control groups. The reports of parents of the children`s quality of life showed significant association in the pain and injury subscale (P=0.002), and cognitive problems subscale at school (P=0.039). The regular exercise and psychosocial program intervention can improve wellbeing and thereby enhance efficacy of the children during treatment.

Evaluating the Correlation between Serum NT-proBNP Level and Diastolic Dysfunction Severity in Beta-Thalassemia Major Patients.

Background: N-terminal pro-brain natriuretic peptide (NT-proBNP) is a sensitive biomarker for the detection of asymptomatic left ventricular (LV) dysfunction. Since ß-thalassemia major patients suffer from early diastolic dysfunction due to iron deposition of chronic blood transfusion, we tried to evaluate the correlation between the serum NT-proBNP level and the severity of LV diastolic dysfunction determined by echocardiography in these patients. Methods: Fifty ß-thalassemia major patients with normal LV systolic function were studied by tissue Doppler echocardiography, and blood samples were taken at the same time to measure the serum NT-proBNP level. Using flow velocity through the mitral valve on the tissue velocity of the mitral annulus in early ventricular filling (E/E') as an LV diastolic function indicator, the patients were divided into 3 groups: group 1) no diastolic dysfunction (E/E' < 8), group 2) suspected diastolic dysfunction (E/E' = 8-15), and group 3) documented diastolic dysfunction (E/E' >15). Other variables assessed included sex, age, method of chelator therapy, and mean hemoglobin and ferritin levels for the past 2 years. Results: According to the echocardiographic findings of all the 50 patients (29 male and 21 female) with an age range of 11-35 years (mean = 17.98 y), 46% were classified in group 1, 54% in group 2, and none in group 3. The NT-proBNP level was 1070 ± 566 ng/mL in group 1 and 974 ± 515 ng/mL in group 2. The t-test showed no significant difference between groups 1 and 2 in the NT-proBNP level (p value = 0.536). Conclusion: Due to specific conditions in thalassemia major patients, the correlation between the serum NT-proBNP level and the severity of diastolic dysfunction seems to be not meaningful.

Psychological Aspects in Children and Adolescents With Major Thalassemia: A Case-Control Study.

BACKGROUND: Thalassemia is an inherited blood disease. It is a serious public health problem throughout the Mediterranean region, the Middle East and the Indian subcontinent, as well as in Southeast Asia. OBJECTIVES: Thalassemia is an inherited blood disease. It is a serious public health problem. In this study we assessed psychological aspects in Iranian children and adolescents with thalassemia major. PATIENTS AND METHODS: In this case-control study sixty healthy subjects aged 7-18 years and Sixty Patients with confirmed diagnosis of major thalassemia were enrolled. After obtaining informed consent from parents of all participating thalassemia patients and healthycontrols, we assessed psychological aspects and quality of life by Pediatric Quality of LifeTM (PedsQL™), Strengths and Difficulties Questionnaires (SDQ), State and Trait Anxiety, Children's Depression Inventory (CDI). RESULTS: The results of this study indicate that there are significant changes in depression, anxiety, QOL and behavioral screening between children with thalassemia major compared with healthy subjects by means of both parents and children reports. According to the results, children with thalassemia major have more psychological problems than healthy ones. Patients with thalassemia have a lower QOL than their peers (P = 0.001), the rate of depression is higher in this group (P = 0.015), Also behavioral problems in these children are more than healthy subjects (P = 0.009). CONCLUSIONS: We recommend appropriate treatment and counseling procedures in addition to specific treatment of thalassemia. According to the results we suggest to establish pediatric psychiatric clinics beside thalassemic clinics to cure psychological aspects of the disease.

Correlation between blood lead concentration and iron deficiency in Iranian children.

BACKGROUND: Iron deficiency anaemia is the most common nutritional anaemia among children. Lead toxicity is a serious health threat, especially in developing countries due to environmental pollution. It was thus aimed to investigate correlation between blood lead concentration and iron deficiency in children of Mashhad, Iran. MATERIALS AND METHODS: This cross sectional study was performed on children between 1 year and 10 years, in Imam Reza teaching hospital of Mashhad, Iran, in 2010. Indeed during complete blood count (CBC), we measured iron and total iron binding capacity (TIBC) by colorimetric methods, ferritin by radioimmune assay and blood lead concentration by atomic absorption method. Results were analysed by Statistical Package for Social Sciences (SPSS) (version 11.5), using statistical tests including independent sample t-test, Mann-Whitney U test, Spearman's test and analysis of variance (ANOVA) and Pearson's or Spearman's correlation coefficient. P value ≤ 0.05 was considered as a significant level. RESULTS: We studied 223 cases including 98 control children and 125 patients. All children had lead intoxication. Mean (±SD) blood lead concentration in the control group was 57.1 ± 25.3 (ranged 20-212) µg/dl and in the patient group was 57 ± 20.4 (ranged 10.9-159) µg/dl with no significant difference (P value = 0.713). We also did not find any correlation between blood lead concentration and haemoglobin, ferritin, iron, TIBC, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), white blood cells (WBC) and platelets. CONCLUSION: Based on these results, no correlation was found between blood lead concentration and iron deficiency in the children. Because all children had lead intoxication, further studies in highly polluted and a comparison with a low polluted area are necessary to make a general conclusion.

Association between HLA-DQB1 gene and patients with acute lymphoblastic leukemia (ALL).

Acute lymphoblastic leukemia (ALL) affects both children and adults. Survival in ALL has improved in recent decades due to recognition of its biological heterogeneity. Although children have higher remission and cure rates than adults, both populations have benefited from these improvements. Our aim in this study is to determine the association between HLA-DQB1 genes with childhood and adult ALL patients. To define this association, we compared HLA-DQB1 allele frequencies and allele carrier frequencies in a cohort of 135 adults and children with ALL with 150 controls, using polymerase chain reaction with sequence-specific primers. Allele carrier frequencies in childhood ALL show a deficiency in DQ2 (*0201) (P 0.049 and RR 0.75), but an increase in DQ5 (*0501-*0504) and DQ7 (*0301, *0304) compared to the control group (P 0.001 RR 1.89, P 0.003 RR 1.48, respectively). Allele carrier frequencies in adult ALL indicated an increase in DQ5 (*0501-*0504) (P0.045 RR 2.28). Allelic frequencies in childhood ALL revealed the same increase in DQ5 and DQ7, and a decrease in DQ2. In adult ALL it shows a decrease in DQ7. Therefore, our results in adult ALL were similar to childhood ALL addressing DQ5 allele carriers, which showed an increase in both age groups. We suggest that DQ5 could be more strongly considered as an ALL susceptibility allele, and that this allele may underlie a pathogenic phenotype with a major role in the immunologic process involved in both adults and children with ALL.

Role of the Lewis and ABO Blood Group Antigens in Helicobacter pylori Infection.

BACKGROUND: Helicobacter pylori infection is a major risk factor for chronic gastritis and gastric cancer. Some findings show increased frequencies of these diseases in individuals with type O blood and in secretors (expressing Le(b) antigen), but other studies have not found any relationship between blood groups and this infection. Given that H. pylori infection and gastric cancer are common in Iran, the assessment of the pathogenesis of this infection in relation to these blood groups could be valuable. METHODS: In a cross-sectional study, we determined the ABO and Lewis blood groups of participants using the tube method and evaluated the level of anti-H. pylori immunoglobulin G using an enzyme-linked immunosorbent assay. This study included 171 Iranian blood donors from Mashhad, Iran, during 2010. The significance of the differences in the frequencies of the Lewis and ABO phenotypes between individuals infected with and without H. Pylori infection were tested using the Chi-square test. A P-value < 0.05 was considered significant. RESULTS: H. pylori infection was found in 76.6% of the study subjects (n = 131). The most common ABO blood group was O (33.9%), and the most common Lewis blood group was Le(a-b+) (54.7%). The frequencies of the ABO, Lewis, and secretion phenotypes were not significantly different between the infected and uninfected subjects. CONCLUSION: We did not find any significant relationship between the Lewis, ABO, and secretion phenotypes and H. pylori infection.

Autoimmune Lymphoproliferative Syndrome (ALPS) in a Boy with Massive Lymphadenopathy.

Autoimmune lymphoproliferative syndrome (ALPS) is an uncommon nonmalignant lymphoproliferative disease which is characterized by chronic, persistent or recurrent lymphadenopathy, splenomegaly, hepatomegaly, immune cytopenia , hypergammaglobinemia and increased risk of lymphoma. We report a 2-year old boy with hepatosplenomegaly as first presentation. Petechial and purpuric rashes with massive cervical lymphadenopathies developed 10 months later.In laboratory tests anemia, thrombocytopenia and hypergammaglobinemia were observed. According to flocytometry increased double negative T cells and by apoptosis assay decrease apoptosis of lymphocytes accompanied clinical manifestations, thus diagnosis of ALPS was established. In conclusion; in all patients with massive lymphadenopathy and hepatosplenomegay; especially with cytopenia; ALPS should be considered.