Professor Vijay V. Kakkar transition on the 100-year celebration of heparin discovery. A journey of science, teaching, kindness and affection.
Written by J. Fareed and E. Ramacciotti
Photo: Prof V. Kakkar chairing a session at the IUA World Congress in Prague, 2012
On November 5th, 2016, we have received, with great sadness, the news that Professor Vijay Kakkar passed away peacefully among friends in London after fighting a protracted illness.
Coincidentally, this is the year the world celebrates 100 years since the discovery of heparin, a life-saving drug whose clinical use was defined by Professor Kakkar. Despite a paralyzing reaction to the news, we felt it was imperative to write some words on his behalf not only for family and friends, but also for students, residents, researchers and professors worldwide that Professor Kakkar has always helped with extreme patience and happiness, and ultimately, for the millions of patients saved because of his persistence. If there would be a word to define Professor Kakkar, it would be persistence.
Following graduation from the Ghandi Medical College in Bhopal (India) in 1960 and completion of 1 year of compulsory internship, Professor Kakkar traveled to the United Kingdom in 1961 with the aim of completing his postgraduate surgical training. Professor Kakkar successfully completed fellowships from both the Royal College of Surgeons of England (FRCS) and Edinburgh (FRCSE) in 1964.
At that time, venous thromboembolism (VTE) was a disabling and frequently lethal disease, particularly among surgical and clinical patients. Professor Kakkar became intrigued by the relationship between prolonged surgeries and the occurrence of deep-venous thrombosis (DVT) and pulmonary embolism (PE). As a Research Fellow at King's College Hospital and Medical School in 1965, Professor Kakkar correlated the autopsy findings of massive PE in 2 patients to open abdominal surgeries (large bowel) performed by the head of the Department of Surgery, Prof J.G. Murray. His unquiet mind started to think of possible prophylactic methods to avoid DVT, PE and death of these patients.
It was difficult for Professor Kakkar to prove to his colleagues that these clots could kill both surgical and medically ill patients. Professor Kakkar jumped into basic sciences, and developed, with great persistence, the fibrinogen uptake test (FUT). This test allowed him to further understand that even small thrombi from surgical patients could progress to bigger thrombi, migrate and generate PE. He was beginning to understand the natural history of DVT in surgical patients. The results of his FUT studies also confirmed that advancing age, obesity, previous VTE, varicose veins and malignancy increased the likelihood of developing venous thromboembolism.
It was then time to find something to prevent the formation of these clots. Aggressive physiotherapy and elastic stockings were intensely used. Despite efforts to prevent stasis, 25 % of surgical patients developed VTE. Looking at pharmacological approaches, oral anticoagulants such as a vitamin K antagonist might have worked, but the high risk of bleeding led Professor Kakkar to come up with a simple yet effective solution: low dose of unfractionated heparin!
It was hard for Professor Kakkar to find support for his research. After writing to 6 heparin companies, 2 answered that heparin would never work as a prophylactic agent. Three never answered his letters, but one, the Choay company, provided the needed funds for his research. After many clinical trials, including one stopped due to high frequency of PE in the control group, Professor Kakkar established low dose of heparin as a therapy for preventing VTE in surgical patients.
In 1975, a major mortality outcome study ‘The International Multicenter Trial’ (Kakkar VV, et al. Prevention of fatal postoperative pulmonary embolism by low doses of heparin. Lancet 1975;306:45-64) validated Professor Kakkar’s original research into the prevention of peri and post-operative death from PE. This trial, considered the seminal work in the field, found that heparin prophylaxis reduces death from pulmonary embolism, saving seven lives for every 1,000 operated patients.
Clinicians were still concerned about bleeding. In 1979, after presentations at the ISTH meeting, the Loyola team in Chicago had the privilege of collaborating with Professor Kakkar on the quest to develop low-molecular weight heparin (LMWH). From 1978-1980, we have collaborated on a series of pre-clinical studies to define the pharmacology of LMWH.
In 1982, the first clinical evaluation of LMWH in the prevention of DVT was published. Since then, a continuous program of basic and clinical research has further evaluated these agents for the prevention of both arterial and venous thromboembolism, helping to establish LMWH as the gold standard for antithrombotic therapy over the past 30 years. These drugs are now used throughout the world and have resulted in the near eradication of deaths due to thrombosis in high risk patients undergoing major surgery, saving approximately 300,000 lives per year worldwide.
Over the course of his career, Professor Kakkar has received many awards. A Hunterian Professorship from the Royal College of Surgeons, the Gunnar Bayer Memorial Lecture, the David Patey Prize of the Surgical Society of Great Britain and Ireland, Visiting Professor of Harvard University, the James Finalyson Memorial Lecture, the Cross Memorial Lecture, the Wright-Schultz Award from the International Society of Thrombosis and Haemostasis for original and outstanding contribution in Thrombosis Research, the Freyer Memorial Lecture, Hon Fellowships of the Academy of Medicine in Singapore and the Association of Surgeons of India, a Lifetime Achievement Award from the International Union of Angiology for outstanding leadership in the investigation of thrombotic disorders and an annual award for medicine from the Guild of British Asians for outstanding contribution by Asian doctors to British medicine. Professor Kakkar was also awarded with an honorary doctor of science from Loyola University of Chicago, and in 2010, he was awarded an Order of the British Empire (OBE).
He was Founder President of the British Society of Haemostasis and Thrombosis and Founder President of the South Asian Society of Atherosclerosis and Thrombosis.
On his retirement from the University in 1997, he was awarded the title of Emeritus Professor of the University of London. His publications included over 680 original articles, six books and contributions to 44 text books.
To recognize his lifetime achievement and contributions in vascular medicine and surgery, the International Union of Angiology has established a bi-yearly lectureship in Professor Kakkar’s name. The first of this lectureship was awarded to Professor Sam Goldhaber of Brigham and Women’s Hospital in Boston for his contributions to advance the management of venous thrombosis at the joint meeting of the SFVM and IUA in Lyon, France on October 7, 2016.
More than a scientist, he was a great friend. His achievements will echo forever, through laboratories, hospitals, medical schools and research facilities. It is tough for me to write these words in such emotional moments. But we think always of the wise words of Dr. Seuss: “Don’t cry because it is over. Smile because it happened.”