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BACKGROUND: The assessment of clinical history is crucial before referring a patient for further laboratory testing. Bleeding assessment tools (BAT) are developed to standardize clinical evaluation. A small number of patients with congenital fibrinogen deficiencies (CFDs) have been evaluated with these tools without definitive results. AIMS: We compared the adequacy of the ISTH-BAT and the European network of rare bleeding disorders bleeding score system (EN-RBD-BSS) to identify patients with CFDs. The correlation between the two BATs and fibrinogen levels and patient clinical grade severity was further analyzed. METHODS: We included 100 Iranian patients with CFDs. Routine coagulation and fibrinogen-specific tests (fibrinogen antigen [Fg:Ag] and activity [Fg:C]) were performed. The ISTH-BAT and EN-RBD-BSS were used to assess the bleeding score (BS) of all patients. RESULTS: The ISTH-BAT and EN-RBD-BSS median (range) were 4 (0-16) and 2.21 (-1.49 to 6.71), with a statistically significant moderate correlation between the two systems (r = .597, P < .001). In patients with quantitative deficiencies (afibrinogenemia and hypofibrinogenemia), the correlation between Fg:C and the ISTH-BAT was moderately negative (r = -.4, P < .001), while the correlation between Fg:C and the EN-RBD-BSS was weakly negative (r = -.38, P < .001). Overall, 70% and 72% of patients with fibrinogen deficiencies were correctly identified by both the ISTH-BAT and EN-RBD-BSS, respectively. CONCLUSION: These results suggest that in addition to the ISTH-BAT, the EN-RBD-BSS may also be useful in identifying CFD patients. We found a significant level of sensitivity for detecting fibrinogen deficiency in the two BATs, and bleeding severity classification correctly identified severity grades in almost two-thirds of patients.
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Afibrinogenemia , Transtornos da Coagulação Sanguínea , Humanos , Afibrinogenemia/complicações , Afibrinogenemia/diagnóstico , Irã (Geográfico) , Hemorragia/diagnóstico , Hemorragia/etiologia , Transtornos da Coagulação Sanguínea/diagnóstico , Doenças Raras/diagnóstico , FibrinogênioRESUMO
INTRODUCTION: Congenital fibrinogen disorders (CFDs) are caused by mutations in the FGA, FGB and FGG genes and are classified as quantitative and qualitative fibrinogen defects. This study sought to determine the genetic background of CFDs in Iran and to examine the genotype-phenotype correlation. METHODS: Fourteen patients with a CFD diagnosis were included. Fibrinogen antigen and activity were measured by the immunoturbidimetric and Clauss methods respectively. Gene sequencing was performed following a polymerase chain reaction amplification of fibrinogen's genes. The ISTH Bleeding Assessment Tool was also evaluated for all cases. RESULTS: Patients were diagnosed with dysfibrinogenemia (n = 10), hypodysfibrinogenemia (n = 2) and afibrinogenemia (n = 2). Seven different mutations located on FGA exon 2 (57 %), exon 4 (7%), exon 5 (7%) and FGG exon 8 (29 %) were identified. In patients with qualitative deficiencies, mutations were including p.Arg38Thr, p.Arg35His, p.Arg35Cys, p.Val145Asp, and p.Arg301Cys and were including p.Gly316GlufsX105 and p.Trp52stop in afibrinogenemic patients. In dysfibrinogenemia, two hotspot mutations, FGA Arg35 and FGG Arg301 were identified in 60 % of patients and the remaining (40 %) had p.Arg38Thr mutation. The p.Val145Asp and two hotspot mutations, p.Arg35His, p.Arg35Cys, were identified for the first time in Iran. The overall median (range) bleeding score (BS) was 4 (0-6) in all patients and it was 3.5 (0-5) in dysfibrinogenemia. Cutaneous bleeding and menorrhagia were the most common bleeding manifestations. CONCLUSION: There was a weak genotype-phenotype correlation in CFDs and patients with dysfibrinogenemia were more symptomatic than in previous studies. Despite ethnic's differences, the prevalence of hotspot mutations in dysfibrinogenemia was similar to the other studies.
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Afibrinogenemia/congênito , Afibrinogenemia/epidemiologia , Adolescente , Adulto , Criança , Feminino , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Mutação , Adulto JovemRESUMO
BACKGROUND: Prophylaxis the current standard care for patients with severe hemophilia should be planned to optimize the replacement therapy and minimize bleeding. We report our single-center experience of tailored prophylaxis in children affected by hemophilia A (HA) and hemophilia B (HB). METHODS: This study was conducted on 55 patients, under 15 years, with HA (PWHA, n: 46) and HB (PWHB, n: 9) between 2015 and 2019. According to the phenotype, three prophylaxis regimens: 25-50 unit/kg once, twice, or three-times a week for PWHA, and two: 30-50 unit/kg once or twice a week for PWHB were administered. Following the occurrence of > 3 joint bleeding, or > 4 soft tissue bleeding, or one spontaneous major bleeding in the last 3 months, the prophylaxis regimen is changed. Annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR), target joints development, inhibitor development, and hemophilia joint health score (HJHS) also were assessed. RESULTS: A mean ± SD of 2520 ± 1045 IU/kg/yr coagulation factor (F) VIII was used to reduce ABR and AJBR from 1.02 ± 1.11 and 0.8 ± 1.3 (in the first year of the study) to 0.27 ± 0.44 (P < 0.001) and 0.19 ± 0.38 (P = 0.004) (at the end of the study) in PWHA, respectively. Furthermore, in PWHB, in the first year of the study, with using 2168 ± 1216 IU/kg coagulation FIX, ABR and AJBR were 0.19 ± 0.39 and 0.06 ± 0.1. At the end of the study, ABR and AJBR were 0.02 ± 0.05 (p = 0.156) and 0.01 ± 0.03 (p = 0.361), respectively. During the study period, the mean number of the target joints and mean HJHS were 0.25 ± 0.57 and 7.6 ± 2.1 for PWHA and 0 and 6.3 ± 1.8 for PWHB, respectively. Finally, 5 PWHA (11 %) did not need dose-escalation in their prophylaxis regimen, whereas 31 (67 %) and 10 (21 %) PWHA needed two and three infusions a week, respectively. In PWHB, 7 (78 %) and 2 (22 %) were adjusted to receive a once and twice weekly regimen, respectively. CONCLUSION: Our results suggest that tailored prophylaxis is an effective strategy to reduce the rate of bleeding and optimize the replacement therapy in children with hemophilia.
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Hemofilia A/tratamento farmacológico , Criança , Pré-Escolar , Feminino , Humanos , Irã (Geográfico) , Masculino , Estudos Prospectivos , Fatores de TempoRESUMO
Background: Overweight is related to increased risks of cardiovascular diseases and dyslipidemia, and reduced quality of life (QOL). Exercise training improves QOL and modifies cardiovascular risk factors and lipid profile. The present study was conducted to compare three types of exercise in terms of their short term effects on QOL and lipid profile in overweight individuals with moderate hemophilia A (IWMHA). Methods: This study was a randomized, controlled, assessor-blinded trial (IRCT20180128038541N1). Sixty IWMHA with a body mass index (BMI) of 25-30 kg/ m2 and a mean age of 35-55 years were randomly assigned to four groups of 15, namely aerobic training (AT), resistance training (RT), combined training (CT) and control. The intervention groups participated in 45-minute exercises three days a week for six weeks. The 36-item short-form health survey (SF-36) was used to measure QOL. Total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), waist-to-hip ratio (WHR), and waist circumference (WC) were measured before and after six weeks of training. For the data analysis using SPSS version 20, the ANCOVA was used to determine the differences among the four groups. Results: A significant decrease was observed in the intervention groups compared to the control group in terms of weight, BMI, LDL-C, TC, WHR, and WC (p<0.05). Significant increase was observed in HDL-C and SF-36 subscales in the intervention groups compared to the control group (p<0.001). There was no significant difference among the intervention groups (p>0.05). In comparison with the control group, more significant improvement was observed in the TC, TG, LDL-C, HDL-L, and SF-36 subscales in the CT group compared to the RT and AT groups. Conclusion: CT was the most effective training method in improving lipid profile and QOL in overweight IWMHA.
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A major problem of hemophilia A (HA) treatment is the development of factor VIII (FVIII) inhibitor, which usually occurs shortly after initiating replacement therapy. Several studies showed the correlation between inhibitor development and polymorphisms in inflammatory and immune response genes of HA patients; however, literature data are not available to prove this association in Iranian population. The aim of this study was to investigate a possible association between FVIII inhibitor formation and the polymorphisms of 16 inflammatory and immune response genes in Iranian severe HA patients (FVIII activity < 1%). This case-control study was performed on 55 patients with severe HA inhibitors and 45 samples without inhibitors from Iranian Comprehensive Hemophilia Care center. After extraction of whole genomic DNA from blood samples and design of primers for 16 genes, the genotyping was performed by Tetra primer ARMS PCR, and the validation of single nucleotide polymorphisms was determined by DNA sequencing. The data indicated that there was a significant association between inhibitor development, and F13A1 (TT), DOCK2 (CC& CT), and MAPK9 (TT) genotypes. Moreover, a considerably increased inhibitor risk carrying T, C, and T allele for F13A1, DOCK2, and MAPK9 genes was observed in patients with inhibitors, respectively. In contrast, there was no statistically significant difference between the genotypic and allelic frequencies for other genes in patients with inhibitors compared to patients without inhibitors. These results demonstrate that only polymorphisms in F13A1, DOCK2, and MAPK9 genes are associated with the risk of developing FVIII inhibitors in Iranian HA patients.
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Alelos , Inibidores dos Fatores de Coagulação Sanguínea/genética , Frequência do Gene , Fatores de Troca do Nucleotídeo Guanina/genética , Hemofilia A/genética , Proteína Quinase 9 Ativada por Mitógeno/genética , Polimorfismo Genético , Adulto , Fator VIII/genética , Proteínas Ativadoras de GTPase , Humanos , Irã (Geográfico) , MasculinoAssuntos
Betacoronavirus , Transtornos Herdados da Coagulação Sanguínea/sangue , Infecções por Coronavirus/sangue , Pandemias , Pneumonia Viral/sangue , Trombofilia/sangue , Adulto , Transtornos Herdados da Coagulação Sanguínea/complicações , COVID-19 , Infecções por Coronavirus/complicações , Resistência à Doença , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/complicações , Embolia Pulmonar/etiologia , Fatores de Risco , SARS-CoV-2 , Trombocitopenia/etiologia , Trombofilia/etiologia , Trombose Venosa/etiologiaRESUMO
Factor X deficiency is a rare bleeding disorder that affects almost 1â:â1000â000 people worldwide. It derives from multiple mutational changes in the factor X gene (F10). The main objective of the present study was to determine a consistent correlation between the clinical presentations and causative genotype. The phenotype and genotype of 17 Iranian patients with reduced factor X activity (FX:C) from 14 unrelated families were analyzed to screen factor X gene expression for any possible mutations and function alteration. Analysis of the sequencing results led to the identification of eight different mutations besides a single nucleotide variation. One of the mutations was novel (Leu487Phe) as studied by means of online analysis programs and molecular modeling. Eight patients were homozygote; three were heterozygote, while six out of 17 patients were symptomatic cases without any mutations. The Arg40Thr missense mutation was detected in three patients including two siblings and was associated with severe bleeding symptoms. Also, two patients were identified with Gly262Asp missense mutation which commonly presented with bleeding disorder. Each of the other patients was associated with a unique missense mutation including one novel mutation in which the tentative relation of the mutation to bleeding symptoms is reported. Mutations leading to a FX:C of less than 1% are associated with severe bleeding symptoms confirming the strong correlation between clinical severity and FX:C. The novel Leu487Phe mutation with FX:C of 13% may have possible negative effects on factor X protein function resulting in minor clinical manifestation.
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Deficiência do Fator X , Deficiência do Fator X/genética , Genótipo , Humanos , Irã (Geográfico) , Mutação , FenótipoRESUMO
Congenital combined bleeding disorders (CBDs) are extremely rare disorders which mainly occur in regions with a high rate of consanguineous marriage. These disorders can present with a variety of symptoms ranging from mucocutaneous bleeding to life-threatening episodes. This study aims to evaluate the prevalence and clinical course of Iranian patients with congenital CBDs. This study is conducted on 450 patients with CBDs who were referred to the Iranian Comprehensive Hemophilia Care Center (ICHCC) between 2010 and 2020. All these patients were diagnosed through evaluation of past medical history and coagulation laboratory investigation. Out of 450 patients, 33 were entered in this study. Having excluded cases with factor (F) V and FVIII deficiency, as well as those with hereditary combined Vitamin K dependent clotting factor deficiency (VKCFD), We found the most common CBDs to be FV-FVII deficiency (n: 6, 18.1%), together with FVII and FX deficiency (n: 6, 18.1%). The most common reason for referral of these patients to ICHCC was postoperative bleeding (14.3%). The mean of The International Society on Thrombosis and Hemostasis-Bleeding Assessment Tool (ISTH-BAT) and condensed MCMDM-1VWD bleeding assessment tool were 9.6 ± 4.79 and 9.1 ± 4.87, respectively (P < 0.005). In 10 females of reproductive age, the mean of Pictorial Bleeding Assessment Chart (PBAC) score was 649.3 ± 554. Among all patients, 23 (69.7%) received on-demand replacement therapy, whereas 5 patients (15.1%) received prophylaxis. In Iran, the coinheritance of bleeding disorders is surprisingly higher than expected. Moreover, patients with congenital CBDs may experience serious bleeding manifestations.
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Hemorragia/congênito , Adolescente , Adulto , Feminino , Humanos , Irã (Geográfico) , Masculino , Adulto JovemRESUMO
Coronavirus disease 2019 (COVID-19) is a new medical challenge for all individuals, especially for those with underlying disorders, such as congenital bleeding disorders (CBDs). Therefore, the pandemic might significantly change the behaviour of patients with CBDs and results in some challenges. In the present study, we assessed the main challenges of COVID-19 infection to patients with CBDs. Data were collected from medical files and interviews of patients with CBDs who had COVID-19 infection. Follow-ups were performed on patients who had active severe acute respiratory syndrome coronavirus 2 infection between April and October 2020. All patients were interviewed by an expert in order to collect the pertinent data. Some questions were about patients' preventive behaviors and feelings prior to infection, and some were about the consequences of infection on patients' replacement therapy and bleeding management. Among 25 patients, infection and death of loved ones (n: 7, 28%), and their own (n: 5, 20%) or family members' (n: 1, 4%) infection, and the resulting economic burden (n: 2, 8%) were main concerns. Six patients experienced depression during the pandemic. The pandemic caused all severely affected patients but one (n: 11, 92%) to abandon replacement therapy. However, two received on-demand therapy after exacerbation of their bleeding. Only one (25%) of four patients on prophylaxis received in-home therapy, whereas the others (75%) abandoned prophylaxis. It seems that COVID-19 infection has great consequences on the lives of patients with CBDs, causing some to take dangerous actions, such as abandonment of their treatment. Healthcare systems, and healthcare providers, should have an appropriate strategy for management of patients with CBDs that prevents infection and provides timely replacement therapy.
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Transtornos Herdados da Coagulação Sanguínea/complicações , COVID-19/complicações , Adolescente , Adulto , Transtornos Herdados da Coagulação Sanguínea/terapia , COVID-19/sangue , COVID-19/fisiopatologia , COVID-19/psicologia , Bases de Dados Factuais , Depressão/complicações , Feminino , Seguimentos , Hemorragia/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: Thrombotic diseases are caused by genetic and environmental factors. There are a number of well-characterized genetic defects that lead to increased risk of thrombosis. Results from previous studies have indicated that FXII is involved in pathogenesis of thrombophilic diseases. However, the results in this regard are highly controversial. Plasma FXII activity levels are strongly determined by a 46CγT polymorphism in the FXII gene. In the present study, the risk of thrombophilic diseases related to this polymorphism was investigated in a case-control study. METHODS: One hundred and sixty subjects were studied: 120 patients diagnosed with thrombophilia (96 venous thromboembolism, 24 arterial thrombosis), and 40 age-gender-matched controls. For each subject, FXII activity level was measured by a one-step clotting assay with FXII-deficient plasma, and 46CγT polymorphism was genotyped using a restriction fragment length polymorphism (RFLP) method. RESULTS: In this study, the previous observation that individuals with different genotypes for the 46 CγT polymorphism showed significant differences in Factor XII activity levels was confirmed. Most importantly, FXII activity ≤ 68% was associated with an increased risk of venous thrombosis with an adjusted OR of 4.7 (95%CI= 1.03-21.1, P=0.04). However, it was not a risk factor for arterial thrombosis with adjusted OR of 5 (95%CI= 0.91-27.1, P=0.09). In CT and TT genotype the adjusted ORs were respectively 2 (95%CI=0.9-4.4, P=0.11) and 2.3 (95%CI=0.45-11, P=0.48) for patients with venous thrombosis compared with the controls. Similarly, the adjusted ORs in arterial thrombosis were 1.2 (95%CI=0.4-3.6, P=0.76) for CT and 1.8 (95%CI=0.2-14.9, P=0.59) for TT genotype. Thus, we did not find any association of the mutated T allele in the heterozygous or homozygous state with an increased risk of both venous and arterial thrombosis. CONCLUSION: Lower FXII activity is not a risk factor; rather, it simply represents a risk marker for thrombosis.
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Type 2 von Willebrand disease (VWD) is the most common congenital bleeding disorder, with variable bleeding tendency and a complex laboratory phenotype. In the current study, we report the clinical and molecular profile of a large number of Iranian patients with type 2 VWD. All exons, intron-exon boundaries, and untranslated regions were sequenced by Sanger sequencing for direct mutation detection. All identified mutations were confirmed in family members and by relevant bioinformatics studies. A total of 136 patients with type 2 VWD were diagnosed, including 42 (30.9%), 32 (23.6%), 38 (27.9%), and 24 (17.6%) patients with type 2A, type 2B, type 2M, and type 2N, respectively. Epistaxis (49%), gum bleeding (30.2%), ecchymosis (23.2%), and menorrhagia (16.3%) were the most common clinical presentations, while miscarriage (2.3%) and umbilical cord bleeding (0.8%) were the rarest. Thirty mutations were identified within the VWF gene, nine (30%) being novel, with p.Arg1379Cys (n = 20), p.Val1316Met (n = 13), p.Arg1597Trp (n = 13), p.Arg1374Cys (n = 10), p.Ser1506Leu (n = 10), and p.Arg1308Cys (n = 9) the most common. Type 2 VWD is a hemorrhagic disorder with variable bleeding tendency and a heterogeneous molecular basis in patients in Iran.
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Doença de von Willebrand Tipo 2/genética , Equimose/etiologia , Epistaxe/etiologia , Éxons/genética , Feminino , Hemorragia Gengival/etiologia , Humanos , Íntrons/genética , Irã (Geográfico) , Masculino , Menorragia/etiologia , Mutação , Fatores de Tempo , Regiões não Traduzidas/genética , Doença de von Willebrand Tipo 2/complicações , Doença de von Willebrand Tipo 2/diagnósticoRESUMO
INTRODUCTION: Congenital fibrinogen disorders (CFDs) comprise the quantitative and qualitative fibrinogen molecule abnormalities that are caused by fibrinogen gene mutations. The objective of this cohort research was to study the molecular and clinical profiles of patients with CFDs. MATERIALS AND METHODS: Genomic DNA Sanger sequencing of 14 Iranian patients was performed to determine CFDs-causing mutations. The disorders were diagnosed by routine and specific (fibrinogen antigen and functional assay) coagulation tests, and clinical data were obtained from medical records. Molecular dynamics (MD) simulations were performed to investigate the effect of missense mutation on the protein structure. RESULTS: Thirteen out of 14 patients had afibrinogenemia while the remaining patient had dysfibrinogenemia. Umbilical cord bleeding was the most common clinical presentation (n: 9, ~70%) which led to the diagnosis of afibrinogenemia, while menorrhagia led to the diagnosis of dysfibrinogenemia. Six homozygous mutations were identified in afibrinogenemia: three previously described variants in FGA (p.Trp52Ter, p.Ser312AlafsTer109 and p.Gly316GlufsTer105), one in FBG (p.Gly430Asp), and two novel mutations in FGB (p.Gly430Arg) and FGG (p.His366ThrfsTer40), while the FGA (p.Arg38Thr) heterozygous mutation was identified in dysfibrinogenemia. MD simulation indicated that the FGA p. Arg38Thr mutation probably interferes with polymerization of fibrin monomers. CONCLUSIONS: In Iran, with its high rate of consanguinity, autosomal recessive afibrinogenemia with severe clinical presentations is relatively common due to heterogeneous molecular defects.
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Afibrinogenemia/diagnóstico , Afibrinogenemia/genética , Fibrinogênio/genética , Técnicas de Diagnóstico Molecular , Mutação , Fenótipo , Adolescente , Afibrinogenemia/sangue , Alelos , Substituição de Aminoácidos , Criança , Pré-Escolar , Feminino , Fibrinogênio/química , Frequência do Gene , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Heterozigoto , Humanos , Ligação de Hidrogênio , Lactente , Recém-Nascido , Irã (Geográfico) , Masculino , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Diagnóstico Molecular/normas , Simulação de Dinâmica Molecular , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
Objectives Development of neutralizing antibodies against factor VIII is the major complication in hemophilia care which makes replacement therapies ineffective. The reports showed that inflammatory cytokines play an important role in inhibitor production. In the present study, the relationship between inhibitor development and the polymorphisms of two cytokine genes was studied in severe hemophiliac patients from Iran. Methods In this case-control study, three polymorphisms of immune regulatory genes [TGF-ß (rs1982037) and IL-2 (rs2069762, rs4833248)] were analyzed in 100 Iranian hemophilia A patients divided into 55 inhibitor positive and 45 inhibitor negative patients using Tetra primer ARMS PCR, and DNA sequencing. Results The analysis of polymorphisms in the TGF-ß and IL-2 genes showed no association between the genotypes and the production of inhibitors (p > 0.05). Also, comparison of allele frequencies for TGF-ß and IL-2 genes between two groups indicated no significant differences associated with the development of FVIII inhibitors (p > 0.05). Discussion In contrast with some reports involving the correlation between polymorphisms of the TGF-ß1 and IL-2 genes and inhibitor development in the world, no statistically significant differences in analysis of the alleles and genotypes for TGF-ß and IL-2 genes were found between the inhibitor and non-inhibitor Iranian patients. Thus, other genetic markers influencing the immune response to replacement therapy in patients with hemophilia should be identified. Conclusions Regarding our results in molecular predisposition for inhibitor development, further studies of effective genetic markers are required as a prerequisite for the development of novel immunogenic therapeutic approaches in the future.
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Inibidores dos Fatores de Coagulação Sanguínea/sangue , Hemofilia A , Interleucina-2/genética , Polimorfismo Genético , Fator de Crescimento Transformador beta1/genética , Adolescente , Adulto , Inibidores dos Fatores de Coagulação Sanguínea/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Hemofilia A/sangue , Hemofilia A/genética , Humanos , Interleucina-2/sangue , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Fator de Crescimento Transformador beta1/sangueRESUMO
: Prevalence of inhibitors in Afghan hemophilia patients has not been reported previously. Our aim was to determine the prevalence of factor VIII inhibitors among hemophilia A patients from the Kabul province of Afghanistan to identify and characterize the pattern of inhibitor formation. Clinical information and blood samples were collected from three hemophilia centers in Kabul, Afghanistan. Plasma samples were obtained from 62 patients with severe (80.5%) and 15 patients with moderate hemophilia A (19.5%) in this cross-sectional study design. All the patients were receiving on-demand treatment. The Nijmegen modification of the Bethesda assay was used to detect inhibitors. Multiplex PCR, inverse-PCR, Multiplex ligation-dependent probe amplification and direct sequencing were performed for genotyping. Inhibitor activity was detected in one out of 15 (6.7%) patients with moderate hemophilia and in six out of 62 (9.7%) with severe disease. Apart from the intron 22 inversion, five different mutations including one missense, two large and two small deletions were detected. This is the first report showing that the prevalence of inhibitors in Afghan hemophilia A patients is much lower than in other populations.
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Fator VIII/imunologia , Hemofilia A/sangue , Adolescente , Adulto , Afeganistão/epidemiologia , Criança , Pré-Escolar , Estudos Transversais , Fator VIII/antagonistas & inibidores , Fator VIII/genética , Hemofilia A/genética , Humanos , Lactente , Masculino , Mutação , Prevalência , Adulto JovemAssuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Deficiência do Fator X/complicações , Hemorragia Gastrointestinal/etiologia , Pneumonia Viral/complicações , Betacoronavirus/isolamento & purificação , COVID-19 , Teste para COVID-19 , Cesárea , Técnicas de Laboratório Clínico , Consanguinidade , Infecções por Coronavirus/sangue , Infecções por Coronavirus/congênito , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/transmissão , Deficiência do Fator X/congênito , Feminino , Hemorragia Gastrointestinal/terapia , Hemostáticos/uso terapêutico , Humanos , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas , Pandemias , Plasma , Pneumonia Viral/sangue , Pneumonia Viral/congênito , Pneumonia Viral/transmissão , Gravidez , Complicações Infecciosas na Gravidez/virologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SARS-CoV-2 , Ácido Tranexâmico/uso terapêutico , Adulto JovemRESUMO
Platelet-type von Willebrand disease (PT-VWD) is a rare bleeding disorder with an intrinsic defect in platelets rather than von Willebrand factor (VWF), but has clinical and laboratory features similar to the more common type 2B VWD. The intriguing nature of the pathophysiology and molecular genetics of PT-VWD has created lengthy debate in literature regarding its discrimination from type 2B VWD, and essentially confirming DNA analysis as the gold standard in diagnosis and revealing pathologic mutations. In this report we identify a novel Asp235Tyrmutation in the GP1BA gene of two Iranian patients showing the PT-VWD phenotype who were originally misdiagnosed as type 2B VWD. By structural modelling of the mutant by introducing Tyr235 into the available crystal structure of the glycoprotein (GP)Ibα N-terminal domain, we observed the mutant Tyr235 generates a hydrophobic tip to the extended ß-switch loop of GPIbα. Further modelling of the resulting complex with VWFA1 indicates this could result in an enhanced interface compared to wild-type Asp235. This data provides an update to the present knowledge about this rare disorder, and confirms the necessity of genetic testing for accurate diagnosis, and the importance of studying natural mutations to better understand molecular aspects of GPIbα-VWFA1 interaction.