An update on the pathogenesis and diagnosis of thrombotic thrombocytopenic purpura

ABSTRACT

Introduction

Severe ADAMTS13 deficiency defines thrombotic thrombocytopenic purpura (TTP). ADAMTS13 is responsible for VWF cleavage. In the absence of this enzyme, widespread thrombi formation occurs, causing microangiopathic anemia and thrombocytopenia and leading to ischemic organ injury. Understanding ADAMTS13 function is crucial to diagnose and manage TTP, both in the immune and hereditary forms.

Areas covered

The role of ADAMTS13 in coagulation homeostasis and the consequences of its deficiency are detailed. Other factors that modulate the consequences of ADAMTS13 deficiency are explained, such as complement system activation, genetic predisposition, or the presence of an inflammatory status. Clinical suspicion of TTP is crucial to start prompt treatment and avoid mortality and sequelae. Available techniques to diagnose this deficiency and detect autoantibodies or gene mutations are presented, as they have become faster and more available in recent years.

Expert opinion

A better knowledge of TTP pathophysiology is leading to an improvement in diagnosis and follow-up, as well as a customized treatment in patients with TTP. This scenario is necessary to define the role of new targeted therapies already available or coming soon and the need to better diagnose and monitor at the molecular level the evolution of the disease.

KEYWORDS:

• Immune thrombotic thrombocytopenic purpura
• ADAMTS13
• pathophysiology
• diagnosis

Article highlights

• New evidence on the pathophysiological mechanisms of TTP is coming, including the involvement of complement and the endothelium. This knowledge could be applied in the future for the development of other therapies in TTP.

• ADAMTS13 circulates in a closed conformation and adopts an open conformation when binding to VWF or certain non-neutralizing antibodies.

• Measuring ADMTS13 activity exclusively in reference centers is fading away, thanks to the incorporation of techniques such as chemiluminescence.

• The development of techniques that can determine the open conformation of ADAMTS13 as an expression of TTP activity will be very useful in situations where antibodies cannot be detected.

Declaration of interests

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.