Summary
A 30-year-old was in labor with her first child. Everything was going to plan … until it wasn’t. Dr. Azusa Nagao, a hematologist at Ogikubo Hospital in Tokyo, Japan, shares a case that illustrates how historically it was thought that women and people assigned female at birth could only be carriers of the disease, not have the disease themselves. This misunderstanding of hemophilia in women has led to women going undiagnosed and untreated with severe repercussions. For the patient in this story, it meant a frightening and dangerous birth experience that put her and her child at risk. Dr. Nagao also outlines efforts to educate patients and physicians about hemophilia, what to look for, and how to treat it.
Azusa Nagao, MD, MSc, PhD (Expected 2023)
Department of blood coagulation, Ogikubo Hospital
Dr. Azusa Nagao, MD, MSc, is a committed physician based in Tokyo, Japan. She currently serves at the Ogikubo Hospital, an esteemed hemophilia treatment center accredited by the Japanese Society of Thrombosis and Hemostasis. The center is dedicated to the comprehensive care of over 900 patients, both children and adults, who suffer from hemophilia A/B and other blood coagulation disorders.
Dr. Nagao’s academic journey began at the University of Kumamoto, where she earned her Bachelor’s degree in Biology and a Master’s degree in Medical Biology. During this period, she embarked on basic and medical science research, primarily focusing on cellular immunity against HIV. She then pursued her medical degree from the University of Shinsyu, Japan, graduating in 2009. Post-residency, she devoted two years to study the RNAi of mesenchymal stem cells at Keio University. This academic and research experience paved the way for Dr. Nagao’s specialization in diagnosing and treating bleeding and thrombotic disorders and HIV infection.
Despite her relative youth, Dr. Nagao has made remarkable contributions to her field. She has authored and co-authored over 20 scientific publications and actively participates in national and international meetings and congresses. She has also received three major grants and leads over 20 clinical trials. Her work transcends national boundaries with her involvement in clinical, educational, and research activities in various parts of the world, including Taiwan and Korea.
Dr. Nagao’s clinical research is driven by a passion for improving patient outcomes. Her studies include aging problems in hemophilia patients, pharmacokinetics of blood coagulation, issues related to hemophilia carriers, and the use of musculoskeletal ultrasound systems. Notably, she has received a significant grant for her role in the Japanese ADVANCE study. This project is a 10-year prospective registry aimed at investigating age-related comorbidities in people with hemophilia.
Apart from her primary roles, Dr. Nagao is actively involved in several initiatives. She is set to present the results of her prospective study on joint prognosis using joint echo at the ISTH. She is also part of Hemostasis Connect, a global effort to raise awareness about women with bleeding disorders. She was recently recognized with the WFH International Hemophilia Treatment Center Fellowship, leading to a five-week clinical training at the UC San Diego Hemophilia and Thrombosis Center. Additionally, she serves as a steering committee member for the Association for Haemophilia and Allied Disorders – Asia Pacific (ADHA-AP). Finally, she is contributing significantly to the establishment of the Japanese National Registry as a Deputy Chair.
In summary, while Dr. Nagao is still in the early stages of her career, her dedication, diverse background, and considerable experience showcase an unmistakable promise. She continues to demonstrate remarkable potential in the field of thrombosis and hemarthrosis, striving relentlessly towards new heights in patient care and research.
Transcript
DDx SEASON 9, EPISODE 2
Undoing the Long-Held Misunderstandings of Hemophilia in Women
Dr. Raj Bhardwaj: This season of DDx is sponsored by Sanofi. The case you’re about to hear is a real patient story.
A 30-year-old woman was pregnant with her first child. She went into labor and was rushed to the hospital.
The delivery was going as planned.
But then …
Dr. Azusa Nagao: She started to lose a lot of blood during childbirth. The doctor and the midwife were panicked. They had to give her a blood transfusion. And doctors didn’t know why she lost so much blood.
Dr. Bhardwaj: This is DDx, a podcast from Figure 1 about how doctors think.
I’m Dr. Raj Bhardwaj.
This season, we’re taking you inside the minds of doctors who specialize in the most common type of hemophilia, Hemophilia A — an inherited bleeding disorder which prevents the blood from clotting properly.
Today’s case is from Dr. Azusa Nagao, a hematologist at Ogikubo Hospital in Tokyo, Japan.
Her case illustrates how hemophilia, once thought to only affect men, can also have a severe impact on women and why women often go undiagnosed and untreated.
Dr. Nagao has been compensated by Sanofi for her participation in this episode.
CHAPTER 1 — CASE STUDY
Dr. Bhardwaj: Hemophilia is caused by a change in one of the genes that codes for clotting proteins. Those genes live on the X chromosome.
Typically, men have a single X chromosome and women have two. Having two X chromosomes means that if even one copy of the gene is damaged, the gene on the other X chromosome can compensate.
For decades, doctors thought this meant women could carry the genetic change, without being affected by the disease.
We now know that this isn’t always the case.
But the double X chromosome does mean hemophilia is less common in women. Women account for fewer than 1% of all hemophilia cases. And because it’s so rare in women, it also means that symptoms displayed by female carriers are often overlooked.
This is exactly what happened to the patient in today’s episode.
As you heard earlier, she lost an unusual amount of blood while giving birth to her first child. But she recovered from that delivery and she — and her doctors — didn’t think much about it after that.
It wasn’t until she noticed a problem with her first child, a baby boy, that her own health issues started to make sense.
Dr. Nagao: When her baby was around 8 months old, bruises started to appear. So the mom took the child to a neighborhood doctor. The doctor diagnosed the child with hemophilia and he was referred to my outpatient clinic.
Dr. Bhardwaj: They started treatment for her baby boy. But Dr. Nagao had a hunch that there was more to this case than meets the eye.
So she asked the young mother about her history with bleeding …
Dr. Nagao: She had nosebleeds a lot in her childhood. Once it started, it was difficult to stop. And her gums would bleed when brushing her teeth. This was so common since childhood that she didn’t know it was abnormal.
Dr. Bhardwaj: Her bleeding got worse when she reached puberty.
Dr. Nagao: Her menstrual bleeding was very heavy from her first menstruation. She was always tired from menstruation.
Dr. Bhardwaj: This patient was losing so much blood during menstruation, she would get winded from light physical activity like climbing stairs. And it was starting to impact her career.
Dr. Nagao: She must take the first day of her monthly menstruation off work. She says she feels dizzy and may faint if she doesn’t lie down. Promotions can be challenging if you miss a lot of work.
Dr. Bhardwaj: She was also forced to cancel social outings. Visiting hot springs — or “onsen” — is a very popular activity in Japan. It’s a tradition that’s been practiced for thousands of years between family and friends.
Dr. Nagao: There are many hotels for bathing in a hot spring and Japanese people often stay at such places on weekends. We cannot use hot springs during menstruation. So this patient hesitated to travel with friends and loved ones. She had to plan around her menstrual cycle. And if it changes, she have to cancel her trip.
Dr. Bhardwaj: On top of that, the patient recalled her unusual blood loss when giving birth. Hearing this, Dr. Nagao’s spidey senses started to tingle.
She decided to investigate further.
Dr. Nagao: On the first day we met, I gave her a blood test.
Dr. Bhardwaj: Dr. Nagao wanted to measure factor VIII (8) — a protein essential for blood clotting. If it’s low, the body has difficulty reducing blood loss from spontaneous or traumatic injuries.
Normal factor VIII levels are above 50%.
Dr. Nagao: The result showed that her factor VIII activity was around 30%, so I told her that she was a carrier of hemophilia.
Dr. Bhardwaj: After her diagnosis, Dr. Nagao explained that low levels of factor VIII were the cause of her patient’s excessive bleeding during menstruation.
She also discusses how a female hemophilia carrier can have a greater risk of bleeding during childbirth.
And that’s when things started to click for this patient.
Dr. Nagao: After I diagnosed her, she talked about how much she bleed during childbirth, and she felt angry. She felt like she wouldn’t have had to go through such a dangerous experience if she had known about her hemophilia.
Dr. Bhardwaj: If doctors knew this patient was a carrier, they would have realized there was a good chance that her unborn baby boy would have hemophilia.
Not knowing this put both the mother and child at risk.
Dr. Nagao: If she knew beforehand, she could choose to have a C section. C section is safer when giving birth to a baby boy with hemophilia. There is less intracranial bleeding.
Dr. Bhardwaj: Instead, doctors proceeded with a normal vaginal delivery, which was extremely risky.
Dr. Nagao: A forceps delivery and vacuum-assisted delivery are of course very dangerous for a baby boy with hemophilia. And she could have lost her life due to a hemorrhage during childbirth.
Dr. Bhardwaj: Dr. Nagao discussed treatment options and came up with a plan.
Dr. Nagao: We decided to focus on excessive menstruation, which was thought to be the most important factor in lowering quality of life.
Dr. Bhardwaj: First, they tried a type of hormone therapy which stimulates the release of factor VIII that’s naturally stored in the body. But this caused severe nausea for the patient.
So they switched tactics.
Dr. Nagao: So, she decided to inject herself during menstruation. I had her come to the clinic every Saturday when she was off work to practice self injection. It took about five times for her to master the technique.
Dr. Bhardwaj: And her quality of life significantly improved.
Dr. Nagao: She was amazed that such a world existed. She was prepared for the second child and could wait for its arrival with peace of mind.
Dr. Bhardwaj: Even mild hemophilia, if left untreated, can lead to dire consequences.
But Dr. Nagao’s work also has an emotional impact.
She says that Japanese culture is relatively conservative when it comes to discussing menstruation, even with family members or health professionals.
Dr. Nagao: That’s exactly why I’m engaged in awareness-raising activities. It is a pleasure to reach out to women and patients and see their quality of life increase. When these women get married, they bring their husband with them. When they become pregnant, I manage their pregnancies. And when they have children, I take care of them. It is a wonderful experience to see how my involvement has improved their prognosis and helped them to live a normal life.
CHAPTER 2 — LESSONS
Dr. Bhardwaj: A disproportionate number of women still suffer from hemophilia without receiving proper treatment.
The first step to solving this problem is education.
Dr. Nagao says that there are doctors who don’t understand how hemophilia works in women. Some still believe that being a carrier means a female patient will be unaffected by the disorder. So women are more likely to go undiagnosed and untreated.
Dr. Nagao: With such mindset, they might not even interview women about hemophilia. The idea that carriers can also manifest the disease has only very recently been accepted. Getting specialists to adopt this mindset is a challenge for the future.
Dr. Bhardwaj: It’s important that doctors ask female patients about menstruation. But Dr. Nagao also says many women might not know what constitutes heavy or excessive bleeding. Simply asking a patient, “Do you have heavy periods?” isn’t enough.
If a woman has never expressed concerns about her menstrual flow, it’s possible a hemophilia carrier could slip through the cracks.
Dr. Nagao has a strategy to prevent this from happening.
Dr. Nagao: Efforts are being made in various countries to popularize the catchphrase 7 2 1. It’s a self-diagnosis phrase for heavy menstruation that lasts longer than seven days, changing pads every two hours, blood clots larger than one euro.
Dr. Bhardwaj: … or blood clots about the size of a quarter.
And if you’re a doctor who’s diagnosed a man with hemophilia, be sure to talk to his female relatives. They may be carriers and not know it.
Dr. Nagao: We want women to know how much suffering they have been through. We can offer them treatment.
Dr. Bhardwaj: Thanks for speaking with us Dr. Nagao.
This is DDx, a podcast by Figure 1.
Figure 1 is an app that lets doctors share clinical images and knowledge about difficult to diagnose cases.
I’m Dr. Raj Bhardwaj, host and story editor of DDx.
Head over to figure1.com/ddx, where you can find full show notes, photos and speaker bios.
This season of DDx is sponsored by Sanofi.
Sanofi is a global healthcare company that develops and delivers medicines and vaccines for millions of people around the world.
Thanks for listening!