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Abstract

Hemostasis research in India has a long history considering the fact that it is one of the youngest specialities in the world. If we take creation of prothrombin time (PT) test as one of the beginning of modern hemostsis research, then the specialty is no older than 60 years. School of Tropical Medicine Kolkata, Banaras Hindu University, All India Institute of Medical Sciences at Delhi, Christian Medical College at Vellore, Post Graduate Institute of Medical Education and Research at Chandigarh, and KEM Hospital at Mumbai contributed substantially in defining various bleeding disorders in our country. Unfortunately, some of these institutes are no longer as active in the field as they used to be. Currently, the Institute of Immunohaematology at Mumbai, Chrstian medical College at Vellore, and All India Institute of Medical Sciences at Delhi are actively engaged in hemostsis research in India. Developing prenatal diagnostic technologies, mutation detection of various hemostatic disorders, developing low-cost management technologies for hemophilia, and other bleeding disorders are becoming important present day research activity in the area of hemostasis in addition to age old areas of prevalence and unusual case description studies. Entry of many new corporate hospitals, development of structured postgraduate training program in hematology, and easy availability of instruments and reagents are likely to foster further growth in this area of medical research in India in future.

Keywords

bleeding blood coagulation factors hemostasis hypercoagulability platelet dysfunction venous thromboembolism

Introduction

Hemostasis is one of the prolific areas of hematological research today. Apart from regular research articles in the well-known international journals devoted to hematology research in general, that is, Blood, British Journal of Hematology, Hematologica, Acta Hematologica, European Hematology Journal, and The Hematology Journal, a large number of articles in the area of hemostasis appear in journals specially devoted to hemostasis research, that is, Thrombosis & Hemostasis, Platelets, Blood coagulation and fibrinolysis, and Hemostasis to name a few. The area of hemostasis research today is wider than it was about 50 to 60 years ago, when the major concern was investigation and diagnosis of bleeding disorders. In the present day scenario, hemostasis not only encompasses research in the area of bleeding disorders but also to thrombosis, multiorgan failure, tumor metastasis, cardiovascular disease, and so on. In this oration, I would like to take a stock of research work done in the area of thrombosis and hemostasis by the pioneers of this field in India. I would also like to summarize how our work measures upto international scientific community and finally I will hazard an informed guess work to peep into the future of thrombosis and hemostasis research in our country.

Thrombosis and Hemostasis Research in India: Past

It is a matter of great pride that research in blood coagulation in our country started as early as mid-1950s which was the early days of modern coagulation research. Research in this field as elsewhere in the world were severely restricted because standard tests of coagulation were still developing though the prothrombin time test as a screening coagulation test was developed long back by Quick,¹ the activated partial thromboplastin time (APTT) test was still being refined, cumbersome 2-stage thromboplastin generation test to assay factor VIII was not widely available. Prof N. N. Sen from Kolkata was developing a factor IX assay system at Oxford with Rosemary Biggs.² At that time, hemostasis research in its rudimentary form arose at several centers in India, and I will show in the subsequent paragraphs how the students trained in those centers later on got spread all over India and gave a robust face to hemostasis research in this country.

School of Tropical Medicine, Kolkata

This was one of the major centers of hematology research even before the days of independence. From early 1950s to early 1970s, this center dominated hematology research in this country under the Leadership of Prof J. B. Chatterjea and Prof C. R. Dasgupta along with their able colleagues, that is, Prof A. K. Basu, Sen, Dr Sushiela Swarup Mitra, to name a few. It was usual in those days to concentrate on the research work of the major problems of hematology, that is, hemoglobinopathies, nutritional anemia, hematological malignancies; hence of the 372 research works published by Chatterjea and his group,³ only a few were devoted to hemostasis. School of Tropical Medicine became an established center of hemostasis research between 1955 and 1972 particularly in the area of thrombocytopenia,⁴ hemostasis in systemic and infective disorders,⁵ and relative incidences of various inherited coagulation deficiencies in West Bengal⁶ along with Basu, Prof (Late) Sandhya Ghose, and Dr Manju Chatterjee. They initiated studies on circulating anticoagulants⁷ and fibrinolysis in leukemia.⁸ It may not be out of place to mention here that Chatterjea came back with a wealth of experience in the area of hemostasis research from the United States after working with celebrated hematologist of the day Dr William Damshek and Dr M. Stefanini and their work in the area of idiopathic thrombocytopenia were extensive, though some of their findings did not stand the test of time.^9–16 Hence Chatterjea has been aptly biographed as a leading personality in the world of Coagulation research.¹⁷ However, after the untimely demise of Chatterjea, the School of Tropical Medicine, Kolkatta, could not keep up its research steam and finally it declined as a center of study for hemostasis.

Bombay School of Hematologists

Dr J. G. Parekh and Dr J. C. Patel were the stalwarts in this field. Parekh, Patel with like-minded people established Bombay Hemaotology Group and Indian Society of Hematology (& Transfusion Medicine) on whose podium I am standing today. Parekh published widely in various areas of medicine, a large part of which following the tradition of the day were in the area of hemoglobinopathy and nutritional anemia. He established the Department of Hematology at J.J. Hospital (Grant Medical College), in 1956. Around the same time Patel started his Hematology unit at KEM Hospital (Seth G.S. Medical College). Parekh worked and published in the area of management of hemorrhagic disorders^18,19 defined von Willebrand disease in this country²⁰ and did some preliminary studies on prothrombin time in normal population.²¹

Patel established the Hematology unit at KEM Hospital in Mumbai. Apart from being a very good organizer, he was a good teacher and researcher, and his department of Hematology is still active. With his able disciple Prof B. C. Mehta, he worked on the causes of bleeding in hemorrhagic small pox,²² published an account of the causes of purpura²³ and a very interesting work on the temporary correction of factor VIII deficiency in hemophilia using spleen cell infusion.²⁴ Mehta who is still active published on the use of antifibrnolytics²⁵ for the control of menorrhagia and published an account of spectrum of bleeding disorders which he had come across in his center and reviewed the Indian literature on bleeding disorders²⁶ along with Dr M. B. Agarwal. Mehta also published many rare case reports and an investigative piece on consumptive coagulopathy and fibrinolysis in experimental acute pancreatitis. Around the same time as Mehta, Prof A. J. Desai established his own coagulation laboratory facility in T.N. Nair Medical College hospital in Mumbai, and reported many rare cases and worked in the area of platelet dysfunction.

Hence, in short it may be said that Mumbai developed 3 centers for Hemostasis research in the past, that is, J.J. Hospital and Grant Medical College, KEM Hospital, Seth G.S. Medical College, BYL Nair Hospital, and T.N. Medical College. However, at present Grant Medical College and T.N. Medical college declined as a center of hemostasis research. We will have occasion to talk about Seth G.S. Medical College and KEM Hospital later.

Delhi School of Hematologists

All India Institute of Medical Sciences (AIIMS) is one of the premier institutes in this country, and it has a glorious past in hemostasis research too. Prof A. K. Saraya was a pioneer in forwarding the concept of thrombopathy thrombasthenia. He developed techniques to study the contribution of platelets in coagulation process along with Dr Jaya Kasturi.^27–29 Prof S. K. Sood produced the first batch of cryoprecipitate for treatment of patients with hemophilia. In addition to publishing many interesting case reports and case series, the center did a lot of work in coagulation defects in autoimmune disorders, platelet function in diabetes mellitus, and so on. All India Institute of Medical Sciences has become stronger with the arrival of Prof Manorama Bhargava, who ushered in the present day research activities which are ongoing very actively in this center.

Christian Medical College, Vellore

Prof Selwyn J. Baker, a celebrated hematologist, was mainly interested in nutritional anemia research and his contribution in this area was seminal. He was followed by Dr R. C. Carman who did some important work in the area of snake bite and hemostasis—a hitherto neglected area of hemostasis research.³⁰ Subsequently with Dr Uma Kharduri and Dr Mammen Chandy, the present prolific era of hemostasis research started in CMC Vellore.

Benaras Hindu University School of Hematologists

Though Prof B. K. Dube and Prof (Mrs) R. K. Dube were late entrants in the past saga of hemostasis research in the country along with Mehta, Desai, Prof K. C. Das (Chandigarh), they overlap into the present day of research in thrombosis and hemostasis, the contribution to hemostasis research of Dube is substantial. Single handedly, he brought Benaras Hindu University (BHU) into the central area of hemostasis research in the country. He worked in the area of blood coagulation and fibrinolysis in various animal species,^31–33 hemostatic abnormalities in various systemic disorders, obstetric conditions, studied the platelet defect in postsplenectomy thrombocythemia³⁴ and published a host of case reports, case series in the area of rare coagulation disorders, thrombasthenia etc. It is unfortunate that the vigor of coagulation research was lost after Dube retired.

Chandigarh School of Hematologists

The story of hemostasis research in India will be incomplete without narrating the seminal contribution of hemostasis research of P.G.I.M.E.R, Chandigarh, under the leadership of Das and Dr Deepika Mohanty. Das from Calcutta School of Haematology migrated to P.G.I.M.E.R, Chandigarh, in the academic year 1965 to 1966. He developed one of the finest hemostasis laboratories in the country. There was difficulty in getting factor VIII-deficient (0%) plasma for assay of factor VIII. Worldwide there were efforts to produce a factor VIII deficient system to be used for factor VIII assay. Das devised a technique to use rabbit serum for this purpose,³⁵ and this assay system was successfully used for a long time in the center to diagnose factor VIII deficient cases. P.G.I.M.E.R, Chandigarh, published seminal studies on coagulation defects in systemic disorders,³⁶ snake bites,^37,38 and described the first patient with antithrombin III deficiency in an Indian family,³⁹ ushering in the research of thrombophilia in this country. In addition to these seminal contributions, a lot of interesting case reports and case series were published from this center. This hemostasis laboratory in late 1970s was the only laboratory in India, which used to do regular external quality assurance program with Dr Leon Poller at Withington Hospital, Manchester, UK. This department was already world famous for its research on vitamin B12 and folic acid, linked nutritional B12 and folate deficiency with bleeding diathesis.⁴⁰ Das migrated outside this country still active in hemostasis research. The Department of Hemostasis at P.G.I.M.E.R, Chandigarh, at present has special interest in factor V Leiden and thrombophilia research.

Thrombosis and Hemostasis Research in India—Present

I have taken 1982 to 1983 as the watershed to divide the story into past and present. The reasons for selecting 1982 to 1983 as the watershed in the history of hemostais research are severalfold. The most important reason being establishment of Haemophilia Federation of India by late Mr Ashok Verma, a patient with severe hemophilia. This organization subsequently established 63 centers all over the country. This society increased the awareness of congenital coagulation disorders. Meanwhile with more extensive availability of cryoprecipitate and factor concentrates from abroad, the patients with hemophilia could get better treatment. Indian Council of Medical Research initiated a task force for the collaborative study of hemophilia, to collate some data on various aspects of patients with hemophilia in India.⁴¹ Around that time, coronary artery bypass surgery and subsequently coronary angioplastry, streptokinase therapy and so on for acute myocardial infarction became more extensively available, and demand for coagulation studies in different parts of the country increased. Qualitatively, in early 1980s, patient care service in India started changing. Many corporate hospitals in Mumbai, Chennai, Hyderabad, and subsequently in Delhi started coming up and they were often associated with state-of-the-art laboratories which also included hemostasis laboratories. Thrombophilia started becoming an important problem and by that time in addition to antithrombin III, protein C, protein S deficiency, factor V Leiden mutation was also documented by Leiden Thrombophilia Group.

One of the major difficulties in starting a hemostasis laboratory in the past was the lack of availability of commercial reagents. Only handful of laboratories which involved in coagulation research was preparing their own thromboplastin and APTT reagents. Over the years as the economy of India opened up to the external world, coagulation reagents from some of the best companies in the world became easily available in the market. In addition, automated and semiautomated coagulometers, which became easily affordable also contributed to the spread of coagulation testing in the country. Another extremely important development in mid-1980s was the development of molecular biology techniques which reached the laboratories by early 1990s, paving the molecular revolution in coagulation research.

However, with all these developments, present day hemostasis research is also originating from few centers in India, though coagulation studies are more extensively available as the service from many government hospitals, corporate hospitals, and private laboratories.

Christian Medical College Vellore

Under the able guidance of Mammen Chandy, this center has become one of the important centers of hemostasis research today. Several important works on the management of surgery in hemophilia, von Willebrand disease,^42–44 mutations in hemophilia B,⁴⁵ international studies involving von Willebrand disease,⁴⁶ mutations in rare factor deficiencies^47,48 originated from this center. Indian Society of Haematology and Transfusion Medicine as well as Haemophilia Federation of India through this Institute and through active guidance of Prof Alok Srivastava runs a quality assurance program for the country and this will improve the quality of the data that comes out of the hemostasis laboratories in this country. The center also provides carrier detection and prenatal diagnosis facilities for patients with hemophilia. This center also highlighted the increased frequency of Glanzmann thrombosthemia in South India.

All India Institute of Medical Sciences

This center continues to be an active center in hemostasis research. Following Saraya, M. Bhargava continued her work in the area of hemophilia, von Willebrands disease and presently Professor Renu Saxena’s major interest is in the area of thrombophilia research.^49–53 Prof V. P. Choudhary heads the department and has published work in the area of von Willebrand disease⁵⁴ and use of soyabean for platelet function defects. Prof H. Pati, another illustrative worker in this field, has published his work in the area of afibrinogenemia and Budd Chiari syndrome. Prenatal diagnosis and carrier detection in hemophilia are now available in the Genetics department of the Institute with Dr Madhulika Kabra as well as with Prof I. C. Verma at Sir Gangaram Hospital, New Delhi.

National Institute of Immunohaematology, Mumbai

Hemostasis research was initiated in this institute by the former Director Dr Dipika Mohanty and myself with my colleague Dr Shrimati Shetty. Dr Mohanty came to this Institute with a wealth of experience in hemostasis research, which she gained from HammerSmith Hospital, London, and Oxford Hemophilia Centre. Mohanty and myself learned lot of our hemostasis work from Das’s laboratory, where she was instrumental in establishing von Willebrand factor (vWF) electroimmunuassay, the assay of platelet-related immunoglobulin, and initiated the work on hemostasis in leukemia⁵⁵ and in malaria.⁵⁶ We continued our work on hemostasis in malaria in the Institute⁵⁷ and initiated both functional and molecular biology studies in the area of coagulation disorders as well as in the thrombophilia. In association with Hematology Department of KEM Hospital and Hemophilia Society (Mumbai Chapter), several studies on treatment of hemophilia were published.^58–60 Several new techniques to assay inhibitors, to study the effect of epsilon amino caproic acid (EACA) on inhibitors, and to show the vVWF-binding activity to factor VIII was established.^61–64 One of the most extensive work on thrombophilia was published from this center.⁶⁵ Strong association of factor V Leiden with Budd Chiari syndrome was also published from this center.⁶⁶ This center was one of the first center in the country to document in intron 22 inversion in patients with hemophilia A, in the country.

One of the most extensive study on Glanzmann thrombasthenia with the mutations of GPIII gene was published from this center.^67–69 It may not be out of place to mention here that Uma Khanduri from CMC Vellore first pointed this disease to be common in South India.⁷⁰ One of the major contributions of this center is in the area of prenatal diagnosis where both molecular and phenotypic methods have been combined to be able to give the diagnosis for at-risk fetus in almost all the patients.^71-73

Another area on which this center has done phenomenal work is in the area of inhibitor formation in patients with hemophilia .^74-76 This center was one of the few centers in the world to point out that thrombophilia modifies the clinical phenotype of severe factor VIII or IX defined into milder one.

In short, for the past 12 years, this center, with which I am proud to be associated with, has worked almost every area of hemostasis research, and this Institute has been directly applicable to patient care and management. During this period, it has published more than 50 research articles in the area of thrombosis and hemostasis.

Other Centers in India

Many other centers are coming up and are actively contributing to hemostasis research in India. Army hospitals are actively involved in the work of thrombophilia and high-altitude complications. Many corporate hospitals like P.D. Hinduja hospital in Mumbai, Agarwal at the Bombay Hospital Medical Institute, Sunil Parekh in his clinic in Mumbai are actively contributing in hemostasis research. On the Eastern side of the country at the Institute of Hematology and Transfusion Medicine, Calcutta Medical College is doing some interesting work in platelet biology. Hemostasis work has been initiated in many other hospitals in India and they are going to come up in a big way in future. It is quite possible that I have missed a few centers which are conducting hemostasis research in this country.

Conclusions

Hemostasis research in India has now entered into a very active phase at present. Evaluation of the history shows that starting with individual case reports, establishing laboratory techniques and training people had been the past. The present has not only imbibed all these parameters but incorporated management strategies, trials, prenatal diagnosis, and molecular biology studies to illuminate the hemostasis and its byzantine interaction with other systems. In future, more and more molecular biological tools will be employed to understand the mutations in causing congenital coagulation disorders. Newer drugs will come up for specific indications and will need specific trials. Cardiovascular medicine and cancer medicine will embrace hemostasis research more and more keenly. Several centers have failed to maintain continuity in hemostasis research. The key to maintain the continuity is to train people in the laboratory, keep interest alive. Medical research is becoming costlier everyday but fortunately many funding organizations are ready to fund important research. Hence, we hope existing institutions will take note and continue to flourish, whereas hundreds of other center will come up in this country and will enrich our already rich heritage of hemostasis research.

Footnotes

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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