Novel mechanisms of action of emerging therapies of hereditary thrombotic thrombocytopenic purpura

ABSTRACT

Introduction

Hereditary thrombotic thrombocytopenic purpura (hTTP) is caused by deficiency of plasma ADAMTS13 activity, resulting from ADAMTS13 mutations. ADAMTS13 cleaves ultra large von Willebrand factor (VWF), thus reducing its multimer sizes. Hereditary deficiency of plasma ADAMTS13 activity leads to the formation of excessive platelet-VWF aggregates in small arterioles and capillaries, resulting in hTTP.

Areas covered

PubMed search from 1956 to 2024 using thrombotic thrombocytopenic purpura and therapy identified 3,675 articles. Only the articles relevant to the topic were selected for discussion, which focuses on pathophysiology, clinical presentations, and mechanisms of action of emerging therapeutics for hTTP. Current therapies include infusion of plasma, or coagulation factor VIII, or recombinant ADAMTS13. Emerging therapies include anti-VWF A1 aptamers or nanobody and gene therapies with adeno-associated viral vector or self-inactivated lentiviral vector or a sleeping beauty transposon system for a long-term expression of a functional ADAMTS13 enzyme.

Expert opinion

Frequent plasma infusion remains to be the standard of care in most parts of the world, while recombinant ADAMTS13 has become the treatment of choice for hTTP in some of the Western countries. The success of gene therapies in preclinical models may hold a promise for future development of these novel approaches for a cure of hTTP.

KEYWORDS:

• TTP/HUS
• ADAMTS13
• von Willebrand factor
• therapeutic
• pathogenesis
• inflammation

Article highlights

• Hereditary thrombotic thrombocytopenic purpura (hTTP) is caused by an inherited deficiency of plasma ADAMTS13 activity, resulting from ADAMTS13 mutations.

• Diagnosis of hTTP relies on a high index of clinical suspicion and prompt laboratory testing for plasma ADAMTS13 activity.

• Plasma infusion remains to be the standard of care in most parts of the world, but recombinant ADAMTS13 has become the treatment of choice in some Western countries.

• Other therapeutic options, including anti-VWF A1 aptamer, anti-VWF nanobody, and gene therapies, should be explored and developed for treatment of hTTP in the future.

Declaration of interest

XL Zheng is a consultant for Alexion, Apollo, Argenx, BioMedica Diagnostics, GC

Biopharma, Kyowa Kirin, Sanofi, and Takeda, as well as a co-founder of Clotsolution.” The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the National Heart, Lung, and Blood Institute (HL157975-01A1, HL164016-01A1, and HL144552.)