Mina Rajan was in her early 30s and a mother of two young children, fatigued from what she initially thought was a routine winter virus. Then her condition worsened, and she was admitted to the emergency room with her platelet count plummeting and her skin covered in red-purple splotches. She can still picture a “stone-faced” doctor diagnosing her and telling her and her husband that he felt it was important to be truthful with them.

“I’m not sure if this treatment is going to work,” she recalled the doctor explaining. “It’s a horrible, dreadful, fatal disease.”

Shocked and in tears, Rajan was taken to the ICU, hooked up to machines and had a central line catheter placed in her jugular vein to begin treatment. After undergoing whole body plasma exchange every day for the next three weeks, she finally felt better enough to go home — though she would face multiple relapses in years to come.

Rajan considers herself blessed to be alive today, starting with the fact that the stone-faced doctor 30 years ago was able to correctly diagnose her at all, and did it quickly enough to save her life.

Rajan has thrombotic thrombocytopenic purpura, or TTP, a rare blood disorder that affects fewer than 10 people in a million.

Since Rajan’s first TTP experience in 1994, much has been learned about the disease down to the molecular level, and that knowledge has been channeled into definitive blood tests and improved treatments. Historically, more than 90 percent of patients experiencing an acute TTP event died — sometimes within 24 to 48 hours. With the treatments available now, more than 95 percent of patients survive — a remarkable achievement in the field.

The University of Kansas School of Medicine has become a leading location for TTP research. Currently the school has three labs and a dozen researchers studying TTP in hopes of developing precision medicine to take aim at the disease. In the past five years, KU researchers led by Long Zheng, M.D., Ph.D., Russell J. Eilers Endowed professor and chair of the Department of Pathology and Laboratory Medicine and an internationally known expert on TTP, have received more than $7.5 million in extramural funding for TTP-focused projects, including seven active studies. The amount includes $6.6 million from the National Institutes of Health and other awards from non-profit groups. In addition to the university’s robust bench research, doctors now offer the latest TTP diagnostic tests and treatments on-site through The University of Kansas Health System.

“One of the big things about TTP is that it is one of the few true hematologic emergencies. If you don’t treat TTP, people will die,” said Konstantine Halkidis, M.D., Ph.D., assistant professor in the Department of Internal Medicine, Hematologic Malignancies and Cellular Therapeutics, whose lab is focused on TTP research.

KU’s research seeks to understand “major areas of need” for TTP patients, Halkidis said. Those include developing faster, more reliable and more accessible tests for TTP. They also include discovering more targeted therapies for patients, because it is still common for them to relapse and to suffer serious side effects from the current treatments.

“That’s why we’re so passionate about what we’re doing,” Halkidis said.

While TTP affects only a sliver of the world’s population, KU School of Medicine researchers also emphasize their work is bigger than TTP alone — “much bigger,” Zheng said. Zheng and his colleagues believe that better understanding the defective blood enzyme at the crux of TTP — called ADAMTS13 — will have broader implications for many more common clotting and inflammatory disorders. “I think we will see that in the next 10 years,” Zheng said.

Scary symptoms

The first case of what’s now known as TTP was documented a century ago, in a 16-year-old New York City girl who died a week after being admitted to the hospital. For decades, there was not much that could be done for TTP. It wasn’t until the 1950s that plasma exchange was attempted, which was adopted as the standard of care in the 1990s. It would be over 20 more years before the first drug to treat TTP, caplacizumab, was approved in the United States in 2019.

Developing caplacizumab relied on first understanding what was happening in the patients’ bloodstreams at the molecular level. In 2001, several groups of researchers across three continents — including Zheng in the United States — identified the culprit.

It is now known that patients with TTP are deficient in ADAMTS13, an enzyme that prevents over-active blood clotting. When ADAMTS13 is defective, platelets stick together and pile up unchecked in small blood vessels, causing micro-clots that can eventually lead to organ failure and death. Meanwhile, platelets are not available to conduct their healthy clotting duties, leading to unwanted bleeding in other places.

A calling card of TTP is red or purple bruising (purpura) or spots (petechiae) on the skin. Other symptoms include fatigue, fever, diarrhea, confusion, headaches, visual problems and stroke.

For new patients admitted to the emergency room in critical condition and ultimately diagnosed with TTP, “I had never heard of it” is a common part of their stories. So is fear.

Even though survival rates have improved, many patients experience relapses after a period of remission, and TTP treatments have historically been brutal to endure.

After her first episode of TTP, Rajan, a resident of Calgary, Canada, has relapsed four more times, each requiring weeks of hospitalization, daily plasma exchange and steroids or immunosuppressive drugs with debilitating side effects. She has suffered impaired vision, hives, hair loss, swelling, memory issues and fatigue, as well as deep depression that lingered for months after she went home. Her worst relapse was in 2011, when she was hospitalized three months before doctors finally established a regimen her body responded to.

As for many TTP survivors, emotional effects linger. Rajan said it’s still hard to tell her story without crying because her TTP emergencies have been so traumatizing. She has nightmares, and she’s hypervigilant about watching for signs of a relapse.

“I was on my deathbed. They couldn’t fix me,” Rajan said. “I just think there are angels around, and I’m here by miracle, honestly.”

Discovering a key enzyme

It was a long-term relapsing TTP patient he treated early in his career that first sparked Zheng’s interest in the disease — specifically its molecular underpinnings.

Zheng was assigned to the patient during the first week of his transfusion medicine rotation at Barnes-Jewish Hospital, Washington University School of Medicine in St. Louis. Day after day, he said, he wrote orders for plasma exchange. The same patient continued to come in and out of the hospital during Zheng’s entire residency.

At the time Zheng had only heard of TTP from a book. He began digging into the literature on TTP’s pathophysiology and noticed that these patients lacked an enzyme that cleaves a blood protein called Von Willebrand factor, but scientists had not firmly established much more than that.

Zheng wanted to figure out a better way to help this patient, and others, by going back to the laboratory to identify exactly what the mystery enzyme was. Zheng’s mentor, the renowned hematologist J. Evan Sadler, gave him his blessing to go ahead.

“I now understand that TTP patients are missing this enzyme that can cleave Von Willebrand factor, but its identity is not known, and I want to find out,” Zheng told his mentor. And Sadler said, “Good luck.”

“After two years of hard work, this Von Willebrand factor-cleaving enzyme was identified as a member of the ADAMTS family. As there were 12 members in the family at the time, I named it ADAMTS13,” Zheng said. The discovery and molecular cloning of ADAMTS13 opened doors to big advancements in TTP study, including an ADAMTS13 blood test to diagnose TTP around the globe.

The test has been a game-changer for patients. For example, it’s allowed Rajan to live a fairly normal life since her last relapse in 2017, because she now has her ADAMTS13 checked proactively. Doctors have found that her ADAMTS13 starts to run out about every two years, she said. A monoclonal antibody drug also used for cancer patients, called rituximab, helps get her levels back up before the situation turns into an emergency.

Since his arrival at the KU School of Medicine, Zheng has established on-site ADAMTS13 testing for TTP. That is important, because there are other disorders with symptoms similar to TTP but that require different treatments.

Previously doctors would take a blood sample from a suspected TTP patient and send it off elsewhere for testing, said Zhan Ye, M.D., Ph.D., associate professor in the Department of Pathology and Laboratory Medicine, and section director of Transfusion Service at The University of Kansas Hospital. It took days to get
results back.

But TTP patients can’t wait days to be treated.

So, doctors would begin plasma exchange treatments. If test results later came back negative for TTP, those treatments — costly, invasive and carrying risk of infection and other side effects — were a waste.

“We are really happy about the test, because now the turnaround time can be the same day. If doctors draw the sample in the morning, they can get the diagnosis in the afternoon,” Ye said. “It is definitely huge, for the patient side, the hospital side and the clinician side.”

Digging deeper to do better

KU Medical Center doctors also welcomed the arrival of caplacizumab for TTP patients. The drug is currently being used to supplement plasma exchange treatments but is also being tested for use in place of them.

“I’m particularly happy to be practicing medicine in the post-caplacizumab era, because I do think it’s a very important and very good drug for TTP,” Halkidis said. “Our primary method of treating the disease was plasma exchange and immunosuppression, but it didn’t work for everybody.”

Halkidis said caplacizumab basically gets right to the heart of the problem by stopping the little blood clots that are prevalent in patients with TTP. And that can lead to rapid improvement for patients who come in very sick from the disease.

On the downside, caplacizumab can have serious side effects, it can be prohibitively expensive, and it’s not available everywhere. A second TTP drug called Adzynma, which is a recombinant form of ADAMTS13, was approved in 2023 for use in patients who were born with ADAMTS13 deficiency. However, only a very small percent of TTP patients have the extremely rare hereditary, or congenital, form of TTP. The vast majority have immune-mediated TTP, which onsets later in life. Adzynma is still being studied for use in these patients.

KU School of Medicine research teams are zooming in on the bloodstream’s smallest molecules in hopes of making discoveries that could create better drugs and better, more cost-effective ways of delivering drugs for TTP.

Halkidis said that as a physician-scientist and a biochemist, this work is right up his alley.

“You want to understand how things work fundamentally, so that you can find new and novel solutions,” he said. “Research is so important to understanding disease and how we can get better at dealing with it. I do this because I think this is going to help people in the future.”

Another angle of the KU School of Medicine’s research aims to understand what triggers life-threatening events in TTP patients. Patients may go years with low ADAMTS13 and not know it until, suddenly, something hurtles them into a health emergency.

Pregnancy is one particularly worrisome trigger, Zheng said, adding that TTP affects one in 100,000 pregnant women, a much higher rate than the general population. Another KU School of Medicine researcher, Liang Zheng, Ph.D., assistant professor in the Department of Pathology and Laboratory Medicine, is leading an effort to investigate how pregnancy and postpartum trigger TTP.

Other conditions that cause stress and inflammation in the body can also become triggers, and that is where the bigger picture comes in for ADAMTS13, Long Zheng believes. Low ADAMTS13 has been associated with an increased risk for numerous serious health conditions. Low levels have also been found to predict mortality in hospitalized patients with low platelet counts, COVID-19, physical trauma and more. Zheng said he has recently submitted grants in hopes of obtaining additional funding to study the enzyme’s role in other medical conditions such as sepsis and pregnancy-associated complications like preeclampsia.

In addition to his ongoing research, Zheng has authored textbook chapters on the disease, plus developed best-practice guidelines for its diagnosis and treatment for the International Society on Thrombosis
and Haemostasis.

Zheng joined the KU School of Medicine in 2020 and catalyzed the TTP program here, including by recruiting Liang Zheng and Halkidis, who also is a member of United States Thrombotic Microangiopathy Consortium, formed to foster collaboration among scientists studying TTP and
related disorders.

“With many different scholars at different levels of training and stations in their careers, we study all aspects of the disease, from the basic pathophysiology, all the way to clinical and translational research,” Halkidis said. “Our group is robust and growing, and our research has been well-received. We hope that in the future, the strides that we’re making will help to change the clinical landscape for TTP treatment.”

Spero Cataland, M.D., a founder of the United States Thrombotic Microangiopathy Consortium, is professor of Internal Medicine in the Division of Hematology at the Wexner Medical Center at The Ohio State University. On behalf of the consortium, Cataland said the KU School of Medicine has achieved a critical mass of researchers with unique expertise that has led to important discoveries in the field of TTP.

“This expertise has led to studies to better characterize the immune response against the ADAMTS13 protease, the development of novel therapeutics and studies to better understand the mechanism for the development of cardiovascular and neurocognitive deficits in long-term survivors of TTP,” Cataland said. “The TTP research program at the University of Kansas Medical Center without question has laid the foundation for future clinical studies that will continue to improve the care of patients diagnosed with TTP well into the future.”

Awareness of a rare disease

However, all the advanced treatments in the world are no good if the disease is not accurately diagnosed in the first place to take advantage of them. Patients, doctors and researchers agree that simple awareness remains one of the biggest hurdles to treating TTP.

Ye said that in his own medical training, TTP was the first rare disease he was exposed to. In that case, the patient was flown by air ambulance to University of Pittsburgh Medical Center from out of state, after repeated trips to the emergency room with her TTP initially undiagnosed.

“The major thing is knowledge,” Ye said, especially for primary care and emergency room doctors. Even if they don’t have the expertise or tools to treat TTP at their locations, if they recognize the disease, they can refer the patient to a place that can help them, such as KU Medical Center. “When they eventually reach us, everything becomes easy because we know what
to do.”

Long Zheng said he has continued a practice that he started at a previous job of explaining TTP to future doctors attending the KU School of Medicine.

“Every year for the new first-year medical students, I give a one-hour lecture about TTP — how you recognize TTP, what kind of symptoms they have, what kind of diagnostic tools we have. Now every medical student since year-one knows about TTP. They must know it.”

As a TTP patient and an advocate for others with the disease volunteering for a Canadian foundation called Answering TTP, Rajan agreed. In addition to raising awareness, she encourages providers to consult TTP specialists and follow international guidelines that have been written
by them.

“We need to push that,” she said. “Don’t just look after patients, send them to the experts.”

Rajan is deeply grateful for TTP researchers’ discoveries so far and their commitment to saving lives. Her dream is for developments that will eliminate plasma exchange and make TTP drugs better and more accessible. She also wishes for more research on auto-immune diseases to understand why her antibodies attack ADAMTS13 in the first place.

Rajan said support from her husband and family over the years has been key to her survival of this difficult disease.

“In 1994, I wanted to live to see my children graduate from high school. In 2011, I wanted to live to see my children graduate from university,” she said.

She now has two grandchildren ages 1 and 3, who she travels across the country to
visit regularly.

“They’re my saving grace, I live for them