September 17 is International TTP Day and this year we are celebrating 100 Years of Advancements in TTP.

Improving outcomes for an extremely rare blood disorder affecting three people per one million.

In 1924, a 16-year-old girl was hospitalised at the Beth Israel Hospital in New York for an acute illness which included a diverse range of symptoms; and Dr Eli Moschcowitz was called in. She fell into a coma and died a week after admission. The autopsy revealed widespread microthrombi (small blood clots) in capillaries and various organs.

In 1947, K. Singer described a similar fatal case of a young girl whose autopsy findings were the same. After analysing another 11 patients, it was proposed this constituted a specific disease where thrombocytopenia resulted from microthrombi. The name “thrombotic thrombocytopenia purpura” was proposed.

In 1966, there had been 255 cases.

In 1978, Dr Upshaw published a case of a 29-year-old woman who had suffered from recurrent acute episodes starting at the age of 6 months. It was seen that antibiotics and corticosteroids were not working. Blood transfusions would normalise the platelet count and anaemia but there would still be relapses. Upshaw reasoned that a plasma factor that was missing might be the issue. At the next flare up, the patient was given fresh frozen plasma instead of whole blood. She showed a dramatic response and continued to receive plasma for several years.

Over the years, many researchers tried to work out what this plasma factor was. In 1982, Dr. Moake described ultra large von Willebrand factor (VWF) multimers in patients with a relapsing TTP. A deficiency in a VWF protease was assumed to explain the presence of the ultra large VWF.

It wasn’t until 2001 that three groups of researchers successfully purified the protease and Dr Zheng identified it as a new species of the ADAMTS (A Distintegrin And Metalloprotease with ThromboSpondin Type 1 motifs) family and was labelled ADAMTS13.

In the absence of ADAMTS13 activity, platelets spontaneously bind to the ultra large VWF resulting in microthrombi. These disperse microthrombi consume platelets causing thrombocytopenia, mechanically rupture red blood cells leading to anaemia and obstruct the microcirculation interfering with normal blood flow.

In 2005, a method became available to measure the ADAMTS13 activity in patients. Throughout the following years, more methods have become available which are quicker but are still not performed in many labs. The treatment with fresh frozen plasma was the most effective treatment. In the last few years more targeted therapies have become available to improve treatment.

Time line of major steps in the understanding and management TTP (Lämmle, B. et al., 2024).

The condition is rare, and still often misdiagnosed as some early symptoms can be similar to a virus or flu. Perth Blood Institute is using this milestone event to increase awareness of the disorder and to ensure timely diagnosis leads to better patient outcomes.

TTP is a fatal disease caused by a deficiency of the VWF cleaving enzyme, ADAMTS-13. ADAMTS-13 deficiency can be hereditary, but more often is an acquired disorder due to the production of inhibitory autoantibodies, which can be caused by virus.

Perth Blood Institute (PBI) is at the forefront of global TTP research, as it is a special interest area of Founder and Chairperson, Prof. Ross Baker. Our understanding of the disease has led to further research and a global standardisation study of ADAMTS13 testing.

It is known that TTP relapse is likely to happen in the first year, following the diagnosis. The PBI research team has identified the importance of measuring ADAMTS13 to ensure relapse is avoided and pre-emptive treatment can be considered.

The PBI team has employed new technology to efficiently diagnose this rare and life-threatening disease, where timely diagnosis is critical. Having access to cutting-edge equipment will accelerate benchmark research to bedside applications.

PBI’s research team leads the Asia Pacific Microangiopathy Thrombocytopenia (APMAT) Network across 24 leading centres in the Asia Pacific, to rapidly collect and bio-bank clinical material on many patients with Thrombotic Microangiopathy. The other area of study in this group is to standardise the testing of ADAMTS13.

We owe a debt of gratitude to the open minds that have led us to this point. We need to continue research into TTP as this steers new discoveries into the complexities of the disease to refine our understanding of the function of ADAMTS13, the mechanism of the disease and how we can improve the care for TTP patients. Two distinct types of TTP have been known for some time – iTTP (idiopathic) and cTTP (congenital). However recently it is thought there is a third form uTTP (unidentified mechanism).

Samantha, 34-year-old mum with TPP.

Samantha had been feeling unwell for several days but assumed she was fighting a virus. Having been to see a GP, who determined a similar diagnosis, Samantha went rapidly downhill and was unable to be woken. Samantha was in a coma for three days while the doctors conducted tests to determine what was the cause of her symptoms. On her initial admission to hospital Samantha’s platelet count was six, which is potentially fatal.

“Don’t ignore the signs like I did. I knew there was something odd happening, but I overlooked it, thinking it was a virus." (Samantha)

Messages from the Founding Director of PBI, Consultant Haematologist Professor Ross Baker.

“I am fortunate to meet inspiring TTP patients, who have survived this rare disease. Twenty years ago, doctors struggled to diagnose the condition and now we can quickly treat TTP patients and save lives.”

“I’m proud of PBI’s TTP research, where our work has standardised diagnostic ADAMTS-13 testing in the Asia Pacific region, and utilising the APMAT biobank, we are exploring new diagnostic algorithms and developing new molecular testing.”

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References

• Lämmle, B., Vanhoorelbeke, K., Kremer Hovinga, J. A., & Knöbl, P. (2024). 100 Years of Thrombotic Thrombocytopenic Purpura: A Story of Death and Life. Hamostaseologie, 44(1), 059–073. https://doi.org/10.1055/a-2223-9484
• Béranger, N., Coppo, P., Tsatsaris, V., Boisseau, P., Provôt, F., Delmas, Y., Poullin, P., Vanhoorelbeke, K., Veyradier, A., & Joly, B. S. (2024). Management and follow-up of pregnancy-onset thrombotic thrombocytopenic purpura: the French experience. Blood Advances, 8(1), 183–193. https://doi.org/10.1182/bloodadvances.2023011972
• Halkidis K, Lämmle B, Zheng XL. The history of thrombotic thrombocytopenic purpura research: a narrative review. Ann Blood. 2024 Jun 30;9:16. doi: 10.21037/aob-23-46