Thrombotic thrombocytopenic Purpura (TTP) is a rare blood disorder where small blood clots (microthrombi) develop in blood vessels anywhere in the body – this is the ‘thrombotic’ part of the condition. ‘Thrombocytopenic’ relates to an increased need for platelets (blood cell fragments needed for blood clotting) causing a deficiency which then leads to bleeding problems which is ‘purpura’, the purplish bruising that occurs just under the skin.

History

In 1924, Dr Eli Moschcowitz was presented with a 16-year-old girl who suddenly became unwell with fever, weakness, focal neurological symptoms (related to the nervous system), and severe thrombocytopenia (elevated bleeding). These symptoms were fatal and after an autopsy, they found an extensive spread of thrombi in the small arteries and capillaries of different organs. The cause of these diverse symptoms and outcome could not be explained.

It has taken nearly 100 years, but now with the enhanced molecular understanding of TTP, along with the contribution by survivors have allowed for significant innovations in diagnosis, treatment and management of this disease.

In the late 70s, case reports describing the effective treatment of patients with congenital or hereditary TTP (cTTP or hTTP) with infusions of plasma steered the result that a deficiency of an unknown plasma factor influenced the disease progression. In the early 80s, von Willebrand factor (vWF) was found to be a contributing component in the disease.

von Willebrand Factor

It seems TTP appears to be due to damage of the inner lining of blood vessels and the high circulation of vWF, which are proteins involved in blood clotting and platelet function. High levels of vWF accumulate when there is an absence of the enzyme ADAMTS-13, which is responsible for the cleaving or degradation of vWF.

ADAMTS-13

There are two sub-categories of TTP, as mentioned above cTTP, is defined by a persistent severe deficiency in ADAMTS-13 (<10%). Immune-mediated (or acquired) TTP (iTTP) is caused by ADAMTS-13 deficiency mediated by autoantibodies (approx. 90% of adult cases). An ADAMTS-13 deficiency is produced by an acquired autoimmune mechanism for the considerable majority of TTP cases.

Statistics

Data from a 2021 research review

• 1.5-6 cases per million per year in adults – iTTP.
• Women are 2-3 times more likely to develop iTTP.
• Those with an inherited deficiency of the ADAMTS-13 gene, the incidence is 3-5%. 
• The precise prevalence of cTTP is unclear, however an estimate is 0.5-2 cases per million.

There may be inconsistences in the data due to demographic factors for iTTP.

• France and Germany (mainly Caucasian) – approx. 1.5 cases per million/year.
• UK (regional areas) – 6 cases per million/year (however this data may be an overestimation as TTP was diagnosed clinically and did not factor in ADAMTS-13 measurements in all cases).
• USA – 2.99 cases per million/year (perhaps due to higher ratio of African Americans, where there is nearly an 8-fold increased incidence rate of TTP).

Data from a 2023 research review

• TTP impacts females more often – 55% to 79%.
• Immune-mediated TTP is approx. 30 times more common than iTTP among adults.
• Incidence of iTTP are 1.5-6.0 cases per million.
• The first episode typically occurs 30-50 years of age among Europeans and in the USA and around age 60 in Japan.
• Hereditary TTP is more frequent among paediatric patients.
• Paediatric TTP signify 10% of cases with an annual incidence of 0.09 cases per million.

TTP and pregnancy

Pregnancy is a well-defined predisposing factor for the development of acute episodes of TTP, signifying 10% to 30% of all TTP cases in adults and 17% occurring in women of childbearing age. Severe ADAMTS-13 deficiency has been recorded in between 1/17,000 to 1/200,000 pregnancies. Also, pregnancy has been found to be a trigger for adult-onset TTP in women with hTTP.

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To date, ADAMTS-13 is the only specific biological marker able to predict TTP relapses during the follow-up in clinical remission. There are ADAMTS-13 tests available, however the testing protocols currently being implemented internationally vary.

Perth Blood Institute (PBI) and our team at Murdoch University are involved in a study to develop a universal testing standard to diagnose TTP quickly, as early detection and accurate classification of people with TTP is crucial. The results of the study were presented at the 2023 International Society of Thrombosis and Haemostasis congress in London. Visit our website to read the presentation ISTH Congress 2023

Time is everything in regard to the formation of microthrombi, which can lead to organ damage and death. Availability to ADAMTS-13 activity tests is assisting to help make the essential determinations in the acute episode and throughout follow-up. Therefore, empowering timely and proactive interventions.

Our PBI clinical trials unit also conducting an observational trial to study the current practices in major medical centres around Australian and New Zealand. The clinical trial includes patients with TTP and is investigating those who present with significant haemorrhage and thromboembolism. To read more about the trial please visit our website APMAT1.

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To read about what it's like living with TTP, visit Sam's story.

For additional information about TTP please read our information leaflet. 

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References

• Gómez-Seguí, I., Izquierdo, C.P., Mingot Castellano, M.E. & de la Rubia Comos, J. (2023) An update on the pathogenesis and diagnosis of thrombotic thrombocytopenic purpura, Expert Review of Hematology, 16:1, 17-32, doi:10.1080/17474086.2023.2159803
• Sukumar, S., Lämmle, B., & Cataland, S.R. (2021). Thrombotic thrombocytopenic purpura: Pathophysiology, diagnosis, and management. J Clin Med. 2;10(3):536. doi: 10.3390/jcm10030536.