Browsing by Author "Shetty, Shrimati"

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    Additional markers for genetic diagnosis of type 3 von Willebrand disease in Indian population.
    (2015-12) Kasatkar, Priyanka; Ghosh, Kanjaksha; Shetty, Shrimati
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    Alternate strategies for carrier detection and antenatal diagnosis in haemophilias in developing countries.
    (2003-01) Shetty, Shrimati; Ghosh, Kanjaksha; Mohanty, Dipika
    Carrier detection and prenatal diagnosis constitute an important component of haemophilia management . Recent advances in molecular biology allows us to use the tools of molecular biology to give such a diagnosis early in the pregnancy with a much higher confidence. Because of lyonisation, diagnosis of a carrier by factor assay is imperfect and hence lacks sensitivity. Molecular diagnosis in such cases is robust.There are several techniques by which this diagnosis can be made.Though the preferred method is to do direct mutation studies, yet the complexities of factor VIII and factor IX genes may not make this approach easy or cost effective. Hence depending on the capability of the laboratory, education status of the family, availability of data through several generations and economic situation of the country, a combination of these techniques need to be adopted for optimum results. These techniques are broadly classified as indirect techniques through linkage analysis or direct detection of affected genes by a combination of screening and sequencing techniques. Occasionally in our country even all the gene based techniques may prove inadequate and we may have to give prenatal diagnosis by antigen and clotting activity assay of the defective factor by cordocentesis between 17-20 weeks of gestation. For any prenatal diagnosis of haemophilia, prior detection of fetal sex either by USG or by molecular technique is necessary to decide whether any further work up is necessary or not? The present article describes various algorithms of carrier detection prenatal diagnosis of haemophilia that was found suitable in our country.
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    Combination of thrombophilia markers in acute myocardial infarction of the young.
    (2004-09-08) Khare, Amit; Ghosh, Kanjaksha; Shetty, Shrimati; Kulkarni, Bipin; Mohanty, Dipika
    BACKGROUND: The pathogenesis of arterial thrombotic disease involves multiple genetic and environmental factors related to atherosclerosis and thrombosis. But, there have been very few studies in India which have investigated some of the thrombophilia markers. AIM: To look for combined thrombophilia in MI patients. SETTINGS AND DESIGN: One hundred twenty patients of myocardial infarction (age below 40 yrs.) were recruited 8-10 weeks after stabilization. Hundred age and sex-matched healthy controls were also recruited in the present study. METHODS AND MATERIAL: Following thrombophilia markers were screened in these patients--plasma fibrinogen, protein C, protein S, antithrombin III, factor V Leiden, PT G20210A polymorphism, MTHFR C677T, homocysteine, fibrinogen b448 Arg/Lys polymorphism and CBS T833C mutation. STATISTICAL ANALYSIS: Statistical analysis was done using Statistical Package for Social Sciences (SPSS) version 10.0, SPSS Inc., Chicago, USA. RESULTS AND CONCLUSION: Elevated fibrinogen levels, homocysteine (p< 0.001 and homocysteine with odds ratio 6.26) and factor V Leiden (p=0.038) were independently associated with MI in our patients. A total of 37 patients (42.5%) had the presence of more than one thrombophilia markers in combination. Out of these, 10 had the presence of three markers in combination and 1 had five thrombophilia markers in combination. Only 2 controls had prothrombotic markers in combination. Combined prothrombotic risk factors were significant in cases in comparison to controls (p< 0.001). Further larger studies on a nationwide basis recruiting a large number of young MI patients should be done to substantiate these findings.
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    Fasting plasma homocysteine levels are increased in young patients with acute myocardial infarction from Western India.
    (2007-05-07) Ghosh, Kanjaksha; Khare, Amit; Shetty, Shrimati
    BACKGROUND: Fasting hyperhomocysteinemia is positively associated with atherothrombosis and acute myocardial infarction in several prospective and retrospective studies. In India folic acid deficiency is not uncommon, and subclinical folic acid deficiency is known to cause hyperhomocysteinemia without thrombocytopenia. OBJECTIVE: To observe the prevalence of plasma hyperhomocysteinemia in a cohort of patients with acute myocardial infarction after 2 weeks of oral folic acid therapy. MATERIAL AND METHODS: A cohort of 120 consecutive patients with acute myocardial infarction below the age of 40 years was tested for fasting hyperhomocysteinemia 8-10 weeks after AMI. Five hundred age and sex matched unrelated controls and 50 family controls were also studied for two mutations, MTHFR C677T and cystathionine Beta synthase (CBS) T833C mutations Parents of the AMI patients were also tested to see hyperhomocysteinemia in the family. The patients were given two weeks of oral folic acid therapy (folviteR - 5mg once daily) and fasting plasma homocysteine levels were measured again and the pattern of response was noted. Patients who responded partially or not responded at all to oral folic acid therapy received intramuscular injection of 1 mg of cyanoco-balamin ( NeurobionR,) and their level of plasma homocysteine were noted 1 week later. RESULTS: Sixty three out of 120 patients showed hyperhomocysteinemia compared to 9% of the age and sex matched controls. Fifty seven therapy percent of hyperhomocysteinemia patients responded completely to oral folvite. Subsequent vitamin B12 & B6 therapy normalized homocysteine levels in only 2/12 partial responders with less than 50 microg/l of plasma homocysteine levels, but none of the folate non responders and partial responders having plasma homocysteine levels above 50 microgm/l responded to the therapy. CONCLUSION: Hyperhomocysteinemia is common amongst young acute myocardial infarction patients from western India. The major cause of hyperhomocysteinemia in young myocardial infarction cases is folic acid deficiency. However a fair number of patients who did not respond to folic acid, also did not respond to vitamin B12 and B6 parenterally suggesting existence of defect in other pathways of homocysteine metabolism in a subset of our patients.
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    High heterozygosity frequency of three exonic SNPs of factor V gene (F5): implications for genetic diagnosis.
    (2015-07) Jadli, Anshul; Kulkarni, Bipin; Ghosh, Kanjaksha; Shetty, Shrimati
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    Hypercoagulable state in idiopathic ulcerative colitis: role of hyperhomocysteinemia and hyperfibrinogenemia.
    (2008-05-13) Banait, Vaibhav S; Sandeep, M S; Shetty, Shrimati; Bapat, Mukta R; Rathi, Pravin M; Ghosh, Kanjaksha; Mohanty, Dipika; Abraham, Philip
    BACKGROUND: Previous reports on hypercoagulable factors in inflammatory bowel diseases involve heterogeneous populations and patients on various medications. AIMS: To determine the frequency of thrombotic complications in ulcerative colitis (UC); to evaluate for hyperhomocysteinemia and its relationship to vitamin B12 and folate levels and methylene tetrahydrofolate reductase (MTHFR) mutation; and to evaluate for hyperfibrinogenemia and factor V Leiden mutation. METHODS: Eighty-six adult patients with UC were seen during the study period; 28 of them underwent blood tests and constituted the study population. Patients who received medications that affect these factors were among the 58 excluded. Tests were obtained at baseline and after 2 months during remission. Patients received folic acid in addition to treatment for UC. RESULTS: Vascular thrombotic events were noted in 4 patients during follow up. Hyperhomocysteinemia was detected in 11 (39.3%) patients (controls 15/100, p=0.007). Heterozygous state for MTHFR C677T mutation was found in 5 (17.9%) patients (controls: 0.2% homozygous, 13.6% heterozygous, p>0.05). Plasma homocysteine did not correlate with extent, severity or duration of disease, or with MTHFR C677T heterozygous state, but correlated with serum folic acid level (p=0.003) and BMI (p=0.03). With folate supplementation, homocysteine decreased significantly in patients who had hyperhomocysteinemia at baseline. Hyperfibrinogenemia was detected in 3 patients (none in 100 controls). Plasma fibrinogen was not affected by duration, extent or severity of UC and did not decrease with remission of disease. Only one patient had heterozygous factor V Leiden mutation. CONCLUSION: Vascular thrombosis occurred in less than a fifth of the UC population studied. Hyperhomocysteinemia reversible by folate supplementation and hyperfibrinogenemia were observed, but their contribution and that of factor V Leiden mutation appear to be insignificant.
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    Implications of human genome and modern cell biology research in management of cardiovascular diseases.
    (2005-05-04) Ghosh, Kanjaksha; Khare, Amit; Shetty, Shrimati
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    Possible impact of factor V Leiden genotype on warfarin induced bleeding.
    (2013-07) Gaikwad, Tejasvita; Ghosh, Kanjaksha; Shetty, Shrimati
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    Prenatal diagnosis in a haemophilia A family by both factor VIII activity and antigen measurements.
    (2003-09-09) Shetty, Shrimati; Ghosh, Kanjaksha; Mohanty, Dipika
    With the advent of molecular biology techniques prenatal diagnosis in haemophilia A is generally being performed by first trimester chorionic villus sampling followed by the DNA analysis using various polymorphic markers of factor VIII gene. Here we report antenatal diagnosis in a haemophilia A family performed in the second trimester by measuring both factor VIII:C and factor VIII:Ag in the fetal blood sample.
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    Prenatal diagnosis of von Willebrand disease in a family.
    (2005-07-29) Trasi, Sucheta; Mohanty, Dipika; Shetty, Shrimati; Ghosh, Kanjaksha
    We report the successful prenatal diagnosis of von Willebrand disease (VWD) in a family with type 3 severe VWD by the indirect method of gene tracking using polymorphic markers of intron 40 of the von Willebrand factor (VWF) gene. The couple had a daughter diagnosed to have type 3 VWD. Chorionic villus sampling (CVS) was done in the eleventh week of gestation of a subsequent pregnancy. The 3 VNTR polymorphic markers VWF1, VWF2 and VWF3 of intron 40 of the VWF gene were used for linkage studies. DNA in the affected VWD patient, the father and mother as well as in the CVS using VWF1 and VWF3 polymorphic markers revealed that the foetus was affected. The family chose to abort the foetus. In a subsequent pregnancy, similar investigation revealed a normal foetus. Prenatal diagnosis in families with a diagnosed case of VWD can be used to determine the status of the foetus. The technique is inexpensive.
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    Prevalence and spectrum of von Willebrand disease from western India.
    (2005-05-07) Trasi, Sucheta; Shetty, Shrimati; Ghosh, Kanjaksha; Mohanty, Dipika
    BACKGROUND AND OBJECTIVE: von Willebrand disease (VWD) is one of the most common inherited bleeding disorders in the west. Limited studies from India showed a prevalence of approximately 10 per cent of VWD among the cases with hereditary bleeding disorders. VWD remains an underdiagnosed entity in India. The prevalence of different subtypes of VWD is also not known which is essential for a proper management of these cases. The present study was thus undertaken to know the prevalence of VWD and its various subtypes in the western part of our country. METHODS: A total of 796 consecutive patients presented with various bleeding manifestations were analysed. The initial screening and confirmation tests for the diagnosis of VWD included bleeding time (BT), screening coagulation tests i.e., prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), factor VIII: C assay, ristocetin-induced platelet aggregation (RIPA) and VWF antigen (VWF:Ag) estimations. VWF multimer analysis, ristocetin cofactor activity (RCOF), VWF collagen binding assay (VWF: CBA), factor VIII : VWF binding assay were also done to classify and subtype these cases. RESULTS: The patients were subtyped as per the International Society of Thrombosis and Haemostasis (ISTH) criteria. Of the 796 patients screened, 58 were diagnosed as VWD. Of the 15 families with a positive family history of bleeding, 26 additional cases were diagnosed as VWD. Majority of the patients were type 3 (59.5%) with severe clinical manifestations, about 18 per cent of type 1 VWD patients were detected in this group while the prevalence of the qualitative variants of VWD i.e., type 2 VWD was found to be 19 per cent and the prevalence of various subtypes were type 2A (9.52%), type 2B (4.76%), type 2M (1.2%), type 2N (3.6%). INTERPRETATION AND CONCLUSION: The high prevalence of type 3 and a low prevalence of type 1 VWD which is in contrast to the western reports, suggests the low awareness of the disease as also the underdiagnosis of the mild cases in our country.
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    Thrombophilia and unexplained pregnancy loss in Indian patients.
    (2008-05-14) Vora, Sonal; Shetty, Shrimati; Salvi, Vinita; Satoskar, Purnima; Ghosh, Kanjaksha
    BACKGROUND: The role of acquired and congenital thrombophilias in the aetiology of unexplained pregnancy loss in the Indian population has not been studied in detail. We studied the association of acquired and inherited markers of thrombophilia in a large group of patients with unexplained pregnancy loss. METHODS: A total of 602 women with pregnancy loss were referred to us for evaluation of thrombophilia between April 2000 and June 2005. After investigations to rule out cytogenetic, hormonal, anatomical and microbiological causes, no cause was ascertained in 430 women for the pregnancy loss. Of these, 49 women, who had a history of only one pregnancy loss, were excluded. The remaining 381 women comprised the study group. These patients and 100 age-matched women who did not have any obstetric complication and had at least one normal healthy child (controls) underwent detailed investigations for the presence of thrombophilia markers. These included screening coagulations tests, tests for lupus anticoagulant (LA), IgG and IgM antibodies to anticardiolipin antibodies (ACA), beta2 glycoprotein 1 (beta2GP1) and annexin V. The genetic markers studied included protein C (PC), protein 5 (PS), antithrombin III (AT III), factor V Leiden (FVL), PT gene G20210A, MTHFR C677T, EPCR 23 bp insertion and PAI 4G/5G polymorphisms. RESULTS: Of the 381 women with pregnancy loss, 183 had 2 and 198 had > or = 3 pregnancy losses. Early pregnancy loss occurred in 136 patients, late pregnancy loss in 119, and both early and late pregnancy losses in 126. The strongest association was observed with ACA (OR 32.5, 95% CI: 8.6-21.8, p < 0.001) followed by annexin V (OR 17.1, 95% CI: 2.9-99.4, p < 0.001), LA (OR 8.2, 95% CI: 1.4-47.7, p = 0.01) and anti-beta2GP1 (OR 5.8, 95% CI: 1.6-22.1, p = 0.007). No association of antiphospholipid antibodies with the time of pregnancy loss was found except LA which was significantly associated with early pregnancy loss compared with late pregnancy loss (p < 0.05). The risk of pregnancy loss with PS deficiency (OR 17.8, 95% CI: 3.1-102.9, p < 0.001) was the highest observed for any heritable thrombophilia followed by PC deficiency (OR 5.8, 95% CI: 1-34, p = 0.06). There were no statistically significant differences in the frequency of any of the genetic thrombophilias studied between women with early and late pregnancy loss. A combination of > or = 2 genetic factors was observed in 41 (10.8%) while that of genetic and acquired risk factors were observed in 79 (20.7%) patients. No more than one risk factor was observed in any of the controls. In all, 176 (46.2%) patients had at least one acquired thrombophilia while 143 (37.5%) had at least one genetic thrombophilia marker. Overall, 288 patients (75.6%) had either an acquired, genetic or both markers of thrombophilia. CONCLUSION: Thrombophilia is an important factor in both early and late pregnancy losses. Women with unexplained pregnancy loss should be screened for the presence of thrombophilias.
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    von Willebrand disease: a laboratory approach.
    (2005-03-29) Trasi, Sucheta; Ghosh, Kanjaksha; Shetty, Shrimati; Mohanty, Dipika
    von Willebrand disease (VWD) is a common inherited bleeding disorder. Accurate diagnosis and classification of VWD is crucial for clinical management. A detailed clinical history, including that of bleeding, is required. A family and drug history are also important. Genetic factors such as blood group, and environmental factors such as stress, trauma, pregnancy and inflammation should also be considered. The age, ethnic group and hormonal status could also affect the von Willebrand factor (VWF) levels. No single test is robust enough to detect all variants of VWD. In view of the heterogeneity of the disease and limitations in assays, a battery of tests should be performed before a final diagnosis can be reached. These include the screening coagulation tests, factor VIII:C assay, VWF antigen assay, assessment of functional VWF which includes VWF ristocetin cofactor assays, VWF collagen binding assay, ristocetin-induced platelet aggregation and VWF multimer analysis. The newer ELISA techniques based on VWF binding with factor VIII glycoprotein (Gp) 1b and cerebrosides have also helped in determining certain unusual forms of VWD. The advent of new systems such as platelet function analysers (PFA), thromboelastography (TEG) and clot signature analysers (CSA), which are designed to assess either the primary platelet function or as a global haemostasis screen, have facilitated and simplified the diagnosis. However, few centres all over the world can perform all these expensive tests to provide a final diagnosis of VWD. We reviewed the laboratory investigations required for a diagnosis of VWD. Apart from congenital VWD, the possibility of acquired VWD should be considered in those with a negative past history of bleeding or in the presence of an underlying disease.
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    Warfarin pharmacogenetics: How close are we to clinical practice.
    (2013-07) Gaikwad, Tejasvita; Shetty, Shrimati; Ghosh, Kanjaksha