SummaryThe role of natural anticoagulants, fibrinolytic cascade factors and common prothrombotic gene polymorphisms in modulating disease severity were studied in 35 'clinically mild' and 37 'clinically severe' haemophilia patients with severe factor VIII or IX deficiency (<0AE01 IU/ml). Strong association of deficiencies of proteins C and S, antithrombin III, tissue factor pathway inhibitor and tissue plasminogen activator, together with factor V Leiden and endothelial protein C receptor 23 bp insertion polymorphisms were observed in the 'clinically milder' group as compared with the 'clinically severe' group. These results indicate a synergistic modulation of bleeding tendency in haemophilia patients by factors in the anticoagulant and fibrinolytic systems.

At this centre, 130 women with rare bleeding disorders (RBD) were investigated over the past 15 years. Fifty patients were above the age of menarche (age of menarche in India is 10 years). Of these 44 presented with menorrhagia. Other complications in these patients involved bleeding because of ruptured graffian follicle (1), severe haemorrhage following caesarean section (1), recurrent pregnancy losses (3), hysterectomy to control menorrhagia (2), laser ablation of endometrium (1) and irradiation of ovary (1). Three patients voluntarily chose to remain unmarried because of the problems associated with menorrhagia which they assumed will interfere with married life. All the 45 patients had iron deficiency anaemia. The spectrum of RBD in these patients comprised Glanzmann's thrombasthenia (17), Bernard-Soulier syndrome (2), storage pool disorder (2), factor V (FV) deficiency (3), combined FV and factor VIII deficiency (5), factor XI deficiency (3), factor XIII deficiency (1), factor X deficiency (5), factor VII deficiency (2), alpha(2)-antiplasmin deficiency (1) and afibrinogenemia (3). RBD in women is diagnosed late and often they are not optimally managed hence suffer both iatrogenic and non-iatrogenic complications in this country.

BackgroundThough rare in occurrence, patients with rare bleeding disorders (RBDs) are highly heterogeneous and may manifest with severe bleeding diathesis. Due to the high rate of consanguinity in many caste groups, these autosomal recessive bleeding disorders which are of rare occurrence in populations across the world, may not be as rare in India.ObjectivesTo comprehensively analyze the frequency and nature of mutations in Indian patients with RBDs.MethodsPubmed search was used (www.pubmed.com) to explore the published literature from India on RBDs using the key words “rare bleeding disorders”, “mutations”, “India”, “fibrinogen”, “afibrinogenemia”, “factor II deficiency”, “prothrombin” “factor VII deficiency”, “factor V deficiency”, “factor X deficiency”, “factor XI deficiency”, “combined factor V and VIII deficiency”, “factor XIII deficiency”, “Bernard Soulier syndrome” and “Glanzmanns thrombasthenia” in different combinations. A total of 60 relevant articles could be retrieved. The distribution of mutations from India was compared with that of the world literature by referring to the Human Gene Mutation Database (HGMD) (www.hgmd.org).ResultsTaken together, 181 mutations in 270 patients with different RBDs have been reported from India. Though the types of mutations reported from India and their percentage distribution with respect to the world data are largely similar, yet much higher percentage of small deletions, duplication mutations, insertions, indels were observed in this analysis. Besides the identification of novel mutations and polymorphisms, several common mutations have also been reported, which will allow to develop a strategy for mutation screening in Indian patients with RBDs.ConclusionThere is a need for a consortium of Institutions working on the molecular pathology of RBDs in India. This will facilitate a quicker and cheaper diagnosis of RBDs besides its utility in first trimester prenatal diagnosis of the affected families.

The integrin GPIIb-IIIa plays an important role in platelet activation and plug formation. Quantitative and qualitative dysfunction in this receptor causes Glanzmann's thrombasthenia (GT) and leads to a bleeding tendency. Mutations in the GPIIb or GPIIIa gene are known to be responsible for the inherited form of this disease, which is characterized by mucocutaneous bleeding and other clinically severe bleeding manifestations. GT is an autosomal inherited platelet function. Mutations in the GPIIIa gene but not GPIIb gene in GT patients from Western India have been studied. Hence, this study was designed and included for the first time two mutation detection strategies: single strand conformation polymorphism and conformation sensitive gel electrophoresis followed by sequencing. Patients diagnosed as GT in our laboratory were screened for mutations. We report 12 mutations in 13 patients, of which 11 are novel mutations. Six mutations were missense, four were deletions and two were splice junction mutations. The study thus identifies novel mutations in the GPIIb gene in patients from Western India, implicating the importance of certain amino acids in structure-function correlations as well as enabling prenatal diagnosis in these families.

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