In this video lecture, Dr. Brian Carney discusses:
- A patient case that illustrates the hallmark clinical and laboratory findings of thrombotic thrombocytopenic purpura (TTP).
- The key diagnostic features of TTP, including anemia, thrombocytopenia, low haptoglobin, and schistocytes on peripheral smear.
- An overview of the lecture series that will explore major topics in TTP, beginning with this introductory framework.
Brian Carney, MD is an attending physician in the Division of Hematology and Hematologic Malignancies at Beth Israel Deaconess Medical Center (BIDMC) and an Assistant Professor of Medicine at Harvard Medical School. He is a clinical investigator with an interest in thrombotic microangiopathies. He serves as Medical Director of Apheresis Services at BIDMC.
(Video Lecture Summary)
Introduction and Case Presentation
Dr. Brian Carney opens the lecture with a case of a 57-year-old woman presenting with abdominal pain. Laboratory results revealed anemia (hemoglobin 7.9 g/dL), severe thrombocytopenia (platelet count of 11,000), and undetectable haptoglobin. A peripheral smear demonstrated numerous schistocytes, characteristic of thrombotic thrombocytopenic purpura (TTP). This case illustrates the clinical hallmarks of TTP: microangiopathic hemolytic anemia and thrombocytopenia.
History of TTP
The first description of TTP dates back to 1924 by Eli Moschcowitz, who noted anemia with widespread microvascular thrombosis. The condition was formally named in 1947. A 1966 review described the ‘classic pentad’ of symptoms: fever, anemia, thrombocytopenia, renal dysfunction, and neurologic findings, though Dr. Carney emphasizes that this pentad is rarely observed today. Mortality rates in the mid-20th century were near 90%, but treatments like plasma infusion and plasma exchange revolutionized outcomes. The discovery of ADAMTS13 deficiency in the late 20th century clarified the pathophysiology.
Pathophysiology
In normal physiology, ADAMTS13 cleaves von Willebrand factor (vWF) multimers, preventing excessive platelet aggregation. In TTP, ADAMTS13 activity is severely reduced. Most often due to autoantibodies resulting in accumulation of ultra-large vWF multimers. This drives uncontrolled platelet clumping, red cell fragmentation (schistocytes), tissue ischemia, and potential death if untreated. Most cases are acquired and immune-mediated, though secondary associations with autoimmune disease, infections, and other conditions exist.
Diagnosis
Diagnosis requires a high index of suspicion. Peripheral smear review is crucial for detecting schistocytes. Definitive diagnosis involves ADAMTS13 activity <10% with or without inhibitory antibodies, but treatment should not wait for confirmatory results. Clinical scoring systems such as the PLASMIC score help estimate pretest probability. Patients often present with neurologic findings (40–60%), fever (20%), bruising/petechiae, jaundice, and abdominal symptoms, but the full pentad is seen in only about 7% of cases.
Management
TTP is a medical emergency requiring immediate empiric therapy. The cornerstone is plasma exchange, which not only restores ADAMTS13 but also removes autoantibodies and ultra-large vWF multimers. Adjunctive treatments include corticosteroids and rituximab, which reduces relapse risk. Platelet transfusions should generally be avoided due to risk of arterial thrombosis. Caplacizumab, a nanobody targeting vWF-platelet interaction, represents a major advance. Clinical trials such as the Hercules study demonstrated that caplacizumab accelerates platelet recovery and reduces recurrence and death when added to standard therapy.
Conclusion
Dr. Carney concludes by emphasizing the dramatic improvement in TTP outcomes over the past century. Once nearly universally fatal, TTP now has survival rates exceeding 90% with modern therapies. Advances in understanding the role of ADAMTS13, combined with the advent of plasma exchange, immunosuppression, and targeted biologics like caplacizumab, have transformed the disease into a highly treatable condition.