Extending the genetic understanding of Thrombotic Thrombocytopenic Purpura (TTP)

Thrombotic thrombocytopenic purpura (TTP) occurs due to a deficiency of an enzyme involved in blood clotting (ADAMTS13), and results in low platelets in the blood (thrombocytopenia), and the formation of harmful blood clots (microthrombi) throughout the circulation. TTP was first described a century ago (1924), yet the enzyme that is deficient was only discovered more recently (2001).

Over time, treatment has improved, but there are still many unanswered questions related to the pathogenesis, including genetic predisposition.

Context: TTP is a dangerous and potentially life-threatening condition affecting blood clotting, most commonly presents in adults in middle age, but can be diagnosed form birth until older age. There are two types of the condition. Congenital TTP (cTTP) is associated with mutations in ADAMTS13.

Immune TTP (iTTP) is due to the patient's own immune system producing antibodies against ADAMTS-13. Untreated, TTP has a mortality of >90%, and even when treated promptly, it can lead to harmful effects on organs throughout the body. Aside from the acute presentation, TTP requires lifelong follow up and treatment.

Challenges Addressed: Amongst those with iTTP there is great variability in the course of the disease. Treatment of the condition is intensive, and often requires intensive care support.

Following this initial treatment, the vast majority of iTTP patients enter a period of remission and are carefully monitored for a relapse of disease. cTTP requires regular (at least weekly) treatment to replace ADAMTS 13, currently plasma infusion, but in the future recombinant ADAMTS13 will be used. It would be useful to be able to predict which patients will relapse more frequently, and which may go many years with no further episodes of iTTP.

Further to this, patients with African or Caribbean ancestry often have more severe disease. Patients with these ancestries on average have a higher relapse rate and a shorter period of remission following treatment. This project will address this directly, and will aim to identify underlying genetic factors which may lead to this difference in disease course.

Over 200 mutations in ADAMTS-13 have been described in cTTP, with most leading to no detectable enzyme activity. It would be useful to form a database of these mutations which can be expanded as further mutations are described. This will allow correlation between mutations, enzyme activity and patient characteristics, to lead to new insights into this disease.