Search

Introduction: Various risk factors for inhibitor development in haemophilia A (HA) have been described but Indian data remains scanty. Aim: We aimed to evaluate the genetic changes in Indian HA‐patients that are associated with the development of inhibitors. Methods: All HA‐patients with inhibitors who availed coagulation‐laboratory services from January‐2015 till December‐2021 and had their samples preserved for DNA extraction were included in this study. An equal number of severity‐matched HA patients without inhibitors were also included as controls. Intron 22 and intron 1 inversions in Factor VIII gene were identified using inverse‐shifting‐PCR. Inversion‐negative patients were further assessed by targeted NGS, MLPA. Results: Thirty HA‐patients with inhibitors were identified. All had severe‐HA. Thirty severe‐HA‐patients without inhibitors were also included as controls. Intron 22 inversion (63.3%) and large deletions (15%) were the commonest variants identified. There was no difference in genetic variants in patients with low and high titre inhibitors. A3, A2 and C2 were the most common domains involved in inversion‐negative patients with inhibitors. However, there was no significant difference in domain involvement among inversion‐negative patients with and without inhibitors. Seven novel‐variants were identified, including three large deletions, one large duplication and two nonsense variants in inhibitor‐positive patients, and one frameshift variant in inhibitor‐negative patient. After adjusting for clinical risk‐factors, large deletions were independently associated with the presence of inhibitors [aOR:6.1 (1.41‐56.3)]. Conclusion: Intron 22 inversions are the commonest variant in Indian patients with severe‐HA. Large deletions predispose to inhibitor development independent of clinical risk factors. [ABSTRACT FROM AUTHOR]

Byline: Valliappan. Muthu, Ramesh. Narasimhan, Kuruswamy. Prasad, Jasmina. Ahluwalia, Mandeep. Garg, Digambar. Behera, Navneet. Singh Background: Venous thromboembolism (VTE) in cancer remains underdiagnosed. This prospective study aimed to evaluate the [...]

Introduction: The clot waveform analysis (CWA) provide valuable information beyond clotting time. The present study was planned to assess whether the activated partial thromboplastin time (aPTT)‐CWA can differentiate between hemophilia A (HA), hemophilia B (HB), or hemophilia A with inhibitors (HAWI). Methods: The aPTT‐CWA was generated by an optical detection system (ACL‐TOP™ 500 coagulation analyzer) and the other tests were performed as per instructions from the manufacturer in the kit. Results: A total of 75 samples (47‐HA, 16‐HAWI, and 12‐HB) with prolonged aPTT were recruited. On analyzing the quantitative aPTT‐CWA data of HA (non‐inhibitors) and HB samples, the width of acceleration 1 [+] peak was the differentiating finding. Among the significant parameters, the second derivative [+] peak was lower in both mild and moderate HA, equating to HB. The time for the height of 1/2 fibrin formation and width of velocity was significantly higher in mild, moderate and severe HA. The study did not show any significant differentiating finding while comparing HAWI and hemophilia A non‐inhibitors (HANI). In the subgroups of HAWI and HANI with aPTT <70 s and 70–100 s, the second derivative [+] peak (2A) was higher and the time for the height of 1/2 fibrin formation (1C) was lesser in HAWI. Conclusion: The aPTT‐CWA parameters may be supportive for the differentiation of hemophilia including its severity and the existence of inhibitors. [ABSTRACT FROM AUTHOR]

Introduction: Inherited Factor VII (FVII) deficiency is commonest among the rare bleeding disorders. A small number of patients present in infancy with severe bleeding, and many may remain asymptomatic but detected before surgery/invasive procedures. Genetic testing may be helpful in predictive testing/prenatal diagnosis in severe cases. Aim: Characterisation of clinical and genotypic spectrum of patients with inherited FVII deficiency. Methods: Retro‐prospectively, 35 cases with prolonged prothrombin time and FVII activity (FVII:C) <50 IU/dl were subjected to targeted resequencing. After in‐silico analysis, variant/s were validated by Sanger sequencing in index cases and family members. Haplotype analysis was done for F7 polymorphisms. Results: Severe FVII deficiency was found in 50% of patients (FVII:C ≤1 IU/dl), and 42.9% were asymptomatic. Clinical severity assessment revealed 17% severe, 17% moderate and 22.9% patients with mild bleeds. FVII levels ranged from.3 to 38 IU/dl. Molecular analysis revealed variants in 30/35 cases, of which 17 were homozygous, 10 were compound heterozygous and 3 were heterozygous. Twelve genetic variants were identified, one promoter variant c.‐30A>C; seven missense (c.215C>G, c.244T>C, c.253G>C, c.904G>A, c.961C>T, c.1109G>T, c.1211G>A), two deletions (c.21delG, c.868_870delATC), and one each of nonsense c.634C>T and splice‐site variant c.316+1G>A. Recurrent variants c.1109G>T and c.215C>G were found in 17 and 8 cases, 12 of the former cases were homozygous. They had the same haplotype, indicating the founder effect in North Indians. Conclusion: This is the largest cohort of FVII genotyping from India, confirming heterogeneity in terms of clinical manifestations, FVII activity and zygosity of the variants with a limited genotypic phenotypic correlation. [ABSTRACT FROM AUTHOR]

Introduction: Warfarin is widely used and will continue to be prescribed especially in developing countries due to its low cost. Given the huge patient load requiring anticoagulation, there is a need to develop strategies to optimize warfarin therapy for ensuring safe and effective anticoagulation. In the present work, we aimed at elucidating the association of genetic and nongenetic variables with warfarin dose requirement in patients attending the cardiovascular clinic in a tertiary care center of North India. Methods: This was a prospective study conducted over 1 year. Patient demographic and clinical details were captured in customized case record forms. Genotyping was done using the polymerase chain reaction-restriction fragment length polymorphism method. Pharmacogenetic influence of CYP2C9 (rs1799853 and rs1057910) and VKORC1 (rs9923231) variant alleles was studied. The association of genetic and nongenetic factors with warfarin dose was quantified using a stepwise multivariate linear regression model. Results: Two hundred and forty patients were screened. Data from 82 eligible patients were used for quantifying the association of genetic and nongenetic factors with warfarin dose. A descriptive model based on CYP2C9*3 (rs1057910) and VKORC1 (rs9923231) variant alleles and BMI was developed. The model explains nearly half of the interindividual variation in warfarin dose requirement. Conclusion: The model explains nearly half of the interindividual variation in warfarin dose in patients with atrial fibrillation and or requiring valve replacement. [ABSTRACT FROM AUTHOR]