In this video lecture, Dr. Long Zheng discusses:
- How the identification and cloning of ADAMTS13 revealed that impaired cleavage of ULVWF drives microvascular thrombosis in TTP.
- The distinction between congenital TTP caused by ADAMTS13 mutations and immune-mediated TTP caused by inhibitory autoantibodies, often directed at the cysteine-rich and spacer domains.
- Mechanistic evidence that inhibitory antibodies reduce catalytic efficiency (lower Vmax without changing Km) and the research strategy of engineering antibody-resistant ADAMTS13 variants that preserve activity.
Long Zheng, MD, PhD, is the Russel J Eilers Professor and Chair of Pathology and Laboratory Medicine at the University of Kansas Medical Center, Kansas City, Kansas. Dr. Zheng was among the first group of scientists who identified and cloned ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor. The deficiency of ADAMTS13 results in thrombotic thrombocytopenic purpura (TTP). Over the past decades, Dr. Zheng’s laboratory has made seminal contributions towards our understandings of the structure-function and regulation of ADAMTS13 protease and pathogenesis of TTP, and the role of ADAMTS13 in other inflammatory thrombotic disorders. Dr. Zheng’s research group have published more than 160 manuscripts in peer-reviewed journals including five chapters on TTP and related disorders in highly sought reference books.
(Video Lecture Summary)
Introduction and Case Presentation
In this video, Dr. Long Zheng discusses the pathogenesis of thrombotic thrombocytopenic purpura (TTP). He introduces the lecture with a case from his residency, then traces the historical and scientific discoveries that led to the identification of ADAMTS13, the protease central to the disease. Dr. Zheng begins with a 42-year-old woman who presented with blurred vision, gait disturbance, and disorientation. Laboratory evaluation showed severe thrombocytopenia, anemia, elevated LDH, and mild renal impairment, with imaging revealing small cerebral infarcts. A peripheral smear demonstrated schistocytes. The patient was diagnosed with TTP and treated with plasma exchange, a therapy initially understood only in broad terms of “removing toxins” and “replacing something beneficial.”
Historical Foundations
The first description of TTP was by Eli Moschcowitz in 1924, who documented a fatal case with widespread microvascular thrombosis. In 1982, Joel Moake observed unusually large von Willebrand factor (ULVWF) multimers in patients during remission, hypothesizing a missing vWF-cleaving protease. Later, Bohdan Lämmle and colleagues demonstrated absent vWF-cleaving activity in congenital TTP, while Tsai showed that inhibitory IgG in acute immune TTP could block protease function.
Identification of ADAMTS13
Through protein purification and sequencing, Dr. Zheng identified the missing protease as ADAMTS13, a large metalloprotease within the ADAMTS family. Its N-terminal domain provides catalytic activity, while cysteine-rich and spacer domains are critical for substrate recognition. The discovery clarified why plasma exchange works: it removes inhibitory antibodies and ULVWF while supplying functional ADAMTS13.
Congenital and Immune TTP
Congenital TTP accounts for fewer than 5% of cases and is caused by ADAMTS13 mutations leading to severe deficiency. Immune-mediated TTP makes up over 95% of cases and results from autoantibodies that either inhibit or accelerate clearance of ADAMTS13.
Autoantibody Targets and Mechanisms
Many inhibitory autoantibodies bind to the cysteine-rich and spacer domains, blocking or allosterically altering protease function. Epitope mapping has identified critical spacer loops (motifs A–E) that are essential for both antibody binding and enzymatic activity. Engineering ADAMTS13 variants that escape antibody binding while retaining activity has emerged as a potential therapeutic strategy.
Conclusion
Dr. Zheng emphasizes how the identification and cloning of ADAMTS13 transformed the understanding of TTP, distinguishing congenital from immune-mediated disease, clarifying the role of inhibitory antibodies, and enabling both rapid diagnostics and highly effective therapies that have dramatically improved patient survival.