Cutting up clots: how a deficient enzyme leads to rare blood disease

In 1924, physician Eli Moschcowitz presented the world with a baffling new case: a teenager who had collapsed and died from a mysterious illness that left her body riddled with tiny blood clots.¹ Now known as thrombotic thrombocytopenic purpura (TTP), this rare disease features a dramatic reduction in platelets caused by clots that are formed in blood vessels. This can have potentially life-threatening consequences, damaging organs like the brain, kidneys and heart, and destroying red blood cells, leading to anaemia. Patients may also experience chronic symptoms including tiredness, fever, headaches, and more.

It took decades to determine, but scientists now know that the cause is a deficient enzyme: ADAMTS13.² Better understanding of this enzyme could create opportunities to help patients with blood clotting disorders.

The clot culprit

A key protein in the blood clotting process, called von Willebrand factor (VWF), protrudes as a long multimeric chain from the lining of blood vessels, unravelling as it encounters blood flow. Left unchecked, VWF molecules trap passing platelets and promote the development of tiny clots. Normally, ADAMTS13 acts as a natural scissor, keeping VWF pruned back. “When these long VWF multimers are not cleaved by ADAMTS13, VWF-platelet aggregation occurs, leading to TTP,” says Karen Vanhoorelbeke, a biochemist at the University of Leuven (KU Leuven), Belgium.

There are two types of ADAMTS13 deficiency: congenital TTP (cTTP), caused by mutations in the ADAMTS13 gene, and immune-mediated TTP (iTTP), caused by an autoimmune response to ADAMTS13. People with TTP can sometimes live for years without symptoms, Vanhoorelbeke explains. “Only with a trigger, like an infection, pregnancy, trauma or surgery, will TTP set in.”

Current management options either add donor plasma to the bloodstream to replace the deficient ADAMTS13 in cTTP, or partially exchange a patient’s plasma with donor plasma to treat acute cTTP and iTTP events – removing the autoantibodies and adding functional ADAMTS13 activity. Immune modulators, antibody therapy and corticosteroids to suppress antibody production can also be used to treat an acute iTTP event. Though these plasma therapies help many TTP patients to survive, they are time-consuming, insufficient in restoring ADAMTS13, and are associated with their own side effects, such as allergic reactions. Patients continue to experience risk of life-threatening clots, chronic symptoms and a reduced quality of life.

New directions

Researchers like Vanhoorelbeke are now targeting the ADAMTS13 enzyme itself. “We are focusing on an easy-to-use diagnostic immunoassay for measuring ADAMTS13 activity, something TTP patients could even use at home,” she says. Monitoring ADAMTS13 activity may be important to help control or prevent disease symptoms.

Other scientists are developing recombinant ADAMTS13 (rADAMTS13) that could be used to replace the missing enzyme in cTTP. Preliminary data from a phase 3 study of rADAMTS13 in cTTP, presented at the ISTH Congress but not yet peer-reviewed, demonstrated strong efficacy and a favourable safety profile compared to plasma-based therapies, and further studies are underway.³

Treating iTTP patients with rADAMTS13 is more complicated: the therapy needs to overcome ADAMTS13 autoantibodies. Researchers are exploring different rADAMTS13 dosing regimens and a phase 2 study is ongoing.⁴

Vanhoorelbeke hopes that rADAMTS13 could one day transform patients’ lives in the way that another recombinant protein, Factor VIII, has helped patients with the bleeding disorder haemophilia A. Decades of research have defined the impact of ADAMTS13 deficiency on blood clotting, and a century on, Moschcowitz’s observations are potentially translating into promise for patients in the rare disease he first described, and beyond.