History

In September 1962, writing in the Keio Journal of Medicine, Japanese researchers Shosuke and Utako Okamoto reported the invention of a new chemical entity that inhibited the enzymatic breakdown of fibrin by plasmin Initially referred to as AMCHA, this drug is now known as tranexamic acid or TXA.

Txa Facts

TXA FACTS

Invented in the 1960s by Japanese husband and wife research team.

Initially marketed for use in mild but troublesome bleeding such as heavy periods and tooth extraction.

Large trials in trauma and obstetrics showed that it reduces the risk of death due to bleeding by one third.

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Utako Okamoto

Co-inventor of tranexamic acid was born in Tokyo, Japan, on April 1, 1918, and died in Kobe, Japan, on April 21, 2016, aged 98 years.

 

Utako Okamoto graduated in medicine from Tokyo Women’s Medical University, in December, 1941. Intelligent, industrious and imaginative and with a passion to do public good, she began working as a research assistant in the university’s Department of Physiology. After meeting her husband Shosuke, they worked together to identify a drug that could prevent the breakdown of fibrin blood clots by the enzyme plasmin. They hoped that such a drug could reduce the death of mothers from post-partum haemorrhage - a major scourge at that time. Resources were limited and the advantage of blood based research was that if they needed blood they could use their own. Their first major breakthrough was the invention of epsilon-aminocaproic acid (EACA) the first antifibrinolytic drug. However, it soon became clear that a more potent was needed. Further years of research they identified tranexamic acid a much more potent anti-fibrinolytic agent.

When I discovered that Utako Okamoto was alive and well and living in Kobe I knew I had to meet her. When finally I did, I found a sprightly 92 year old still very much engaged with research, meeting with researchers, and reading journal articles. We discussed the results of the CRASH-2 trial and she was delighted to hear that her invention was saving lives around the world. I also told her about the Woman trial which was then on-going. She was sure that TXA would reduce death due to bleeding: “without doing the research I know the results” she told me. She died shortly before we un-blinded the trial at the age of 98. She was right.

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MEETING UTAKO

I first met Utako Okamoto, when she was 92 years old. We had just completed the CRASH-2 trial, a large multi-centre randomised trial which showed that giving tranexamic acid to bleeding trauma patients reduces their risk of death due to bleeding by one third. I wanted to find out when and where tranexamic acid was invented. Most of the information about tranexamic acid was in Japanese but my wife Ayumi Naito who is Japanese helped me to research its origins. We discovered that tranexamic acid was invented by a husband and wife research team Shosuke and Utako Okamoto working in the 1950s. Shosuke had died some years previously but that Utako was living in Kobe, Japan. We wanted to meet her. 

We met at her home in Kobe. In fact, the Okamoto home is also a laboratory. The sign on the front gate reads "Kobe Projects on Thrombosis and Haemostasis."  Utako was a 92-year old powerhouse, lively and vigorous and still very much engaged with research, meeting with researchers, and reading journal articles. We spoke for hours about the invention of tranexamic acid and the challenges of conducting research in a male dominated environment.

She began her career in 1936 by studying dentistry but soon changed to medicine. She enrolled at the Tokyo Women’s Medical University, graduating in December, 1941. She was intelligent and industrious and had a passion for medical research. In January 1942, she began her research career as a research assistant in the Department of Physiology. It was there that she met her future husband Shosuke Okamoto. From early on they decided on the principles that would guide their research over the coming years: (1) exceed global standards; (2) avoid current trends and (3) discover medicines for humanitarian benefit. Bearing in mind that large parts of Japan had been reduced to rubble after the Second World War, including the two atomic bombs in Hiroshima and Nagasaki, the desire to exceed global standards gives a sense of their drive.

Utako Okamoto

Her early career were not easy. Medicine and medical research were profoundly male dominated. She was once asked to leave a conference on the grounds that medical conferences were not for “women and children” and when she first presented her research she was ridiculed. “People said unkindly that they wondered if I was going to dance for them!” But she was no fool: "Men are always aware of the fundamental differences between men and women, and so cannot help but think of themselves as superior”, she told me “so I used that to my advantage by stroking their egos.” Initially she could compensate for the sex discrimination she faced by working longer and harder but things got more difficult when she had a child. “Until then I could compensate for the disadvantages of being a woman by working longer hours—10 hours per day instead of the 8 that the men worked.” There was no child care available at that time and so she had to bring her daughter to the lab in a basinet. Later they would open their own childcare facility in their lab in Kobe so that researchers could combine work and parenthood.

They started working on blood. They knew that there was an enzyme in the blood called plasmin that breaks down fibrin clots and they wanted to find a drug that would inhibit its action. They hope that such a drug might be an effective treatment for post-partum haemorrhage which was a leading cause of maternal death in Japan at that time. Research on blood could be done cheaply: “If there was not enough we could simply use our own” she told me. They started out by screening amino acids and found lysine to be highly inhibitory. They was astute biochemists and wondered if removing an amino group from the lysine molecule would increase its potency. It did and they had discovered the first in a new class of anti-fibrinolytic drugs - epsilon-amino-caproic acid (EACA). But they did not stop there and after more research revealed that a drug called tranexamic acid was 27 times more powerful than EACA. They published their results in the Keio Journal of Medicine in 1962. They tried to get their local obstetricians to evaluate its use in post-partum haemorrhage but they could not generate any interest. The drug was later produced and marketed as a treatment for heavy menstrual periods and the bleeding that accompanies tooth extraction. It would be many years before the full clinical potential of tranexamic acid would emerge.

On the basis of the CRASH-2 trial results, I presented Utako with a certificate of appreciation on behalf of the trial investigators. At that time the Woman trial was still recruiting patients and the results had not been revealed to anyone. But Utako told me that she knew the results. "I am absolutely sure that it's going to be effective – I don't need the research to know this." I promised to come back to tell her the results. Utako died two weeks after the trial reached its recruitment target of 20,000 patients. Ian Roberts

Tranexamic acid is a synthetic analogue of the amino acid lysine. It reduces bleeding by preventing the breakdown of fibrin clots.

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