In this video lecture, Dr. Azra Borogovac discusses:
- How biallelic mutations in ADAMTS13 cause severe enzyme deficiency, leading to ultra-large vWF multimers, microvascular thrombosis, and hemolytic anemia.
- Why hereditary TTP can present at any age but is highest-risk in newborns and pregnancy, and how diagnosis depends on ADAMTS13 activity and genetic confirmation.
- Current treatment strategies, highlighting the role of recombinant ADAMTS13 as the first FDA-approved therapy for both on-demand and preventive use.
Dr. Azra Borogovac pursued her training as a physician at the University of Massachusetts Medical School, where she also trained as a resident in internal medicine. She was a fellow in hematology/oncology and stem cell transplant and cellular therapy at the University of Oklahoma Health Sciences Center, later adding an M.S. in clinical and translational science there as well. In addition, she also completed a highly competitive yearlong program at the American Society of Hematology Clinical Translational Research Institute. A researcher seeking to improve treatment for blood cancers and ameliorate side effects, she leads clinical trials into protocols for targeted drugs, cellular therapies and blood stem cell transplants.
(Video Lecture Summary)
Introduction
In this video, Dr. Azra Borogovac discusses hereditary thrombotic thrombocytopenic purpura (hTTP), also known as congenital TTP or Upshaw–Schulman syndrome. She outlines its genetic basis, clinical spectrum, diagnostic approach, and modern treatment strategies, including recombinant ADAMTS13.
Pathophysiology and Genetics
Hereditary TTP results from biallelic mutations in the ADAMTS13 gene that reduce enzyme activity to ≤10%. Without functional ADAMTS13, ultra-large von Willebrand factor multimers persist, binding platelets and causing microvascular thrombosis, thrombocytopenia, and hemolytic anemia. Over 200 pathogenic variants have been identified, with disease onset ranging from infancy to adulthood.
Clinical Features and Risks
Although hereditary TTP accounts for only 3–5% of TTP cases, it has major clinical impact. Presentations are most common in the neonatal period and during pregnancy, when turbulent vascular flow can trigger flares. Symptoms range from asymptomatic cases discovered through family screening to severe disease with recurrent flares, renal injury, strokes, and neuropsychiatric complications. Mortality is higher than in the general population, beginning in early life.
Diagnosis
The diagnostic process begins with confirmation of severe ADAMTS13 deficiency (<10% activity). If antibodies are absent, hereditary disease should be suspected and confirmed by genetic testing. Identifying two pathogenic variants establishes the diagnosis, and sibling testing is recommended due to 25% recurrence risk.
Treatment and Prophylaxis
Management relies on ADAMTS13 replacement. Options include fresh frozen plasma, off-label plasma-derived concentrates, and recombinant ADAMTS13, which is FDA-approved for both prophylaxis and on-demand use. A 2024 phase 3 trial demonstrated superior prevention of acute and subacute events with recombinant therapy compared with standard care, alongside improved platelet counts and clinical outcomes.
Treatment is individualized. Not all patients require long-term prophylaxis, and decisions should consider disease severity, flare history, pregnancy status, comorbidities, access, and cost. During pregnancy, prophylaxis is essential from confirmation through six weeks postpartum.
Conclusion
Dr. Borogovac emphasizes that hereditary TTP is a lifelong, genetically driven disorder. Early recognition, ADAMTS13 replacement, and individualized prophylaxis strategies, especially during high-risk periods such as neonatal life and pregnancy, are critical for preventing complications and improving outcomes.