- Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening thrombotic microangiopathy characterized by widespread formation of platelet-rich clots (microthrombi) in the small blood vessels throughout the body.
- These microthrombi cause a dual problem: they consume platelets, leading to thrombocytopenia (low platelet count), and they obstruct blood flow in the microcirculation, causing ischemic damage to various organs. The condition is considered a medical emergency because, without prompt treatment, it can rapidly progress to multi-organ failure and death.
- The underlying pathophysiology of most TTP cases involves a severe deficiency of ADAMTS13, a metalloprotease enzyme responsible for cleaving ultra-large multimers of von Willebrand factor (vWF) into smaller, less adhesive forms. When ADAMTS13 activity is deficient, these ultra-large vWF multimers persist in the circulation and promote uncontrolled platelet aggregation under high shear stress conditions in arterioles and capillaries. The deficiency of ADAMTS13 can be either acquired, due to autoantibodies that inhibit the enzyme’s function (immune-mediated TTP, or iTTP), or hereditary, due to mutations in the ADAMTS13 gene (congenital TTP, also known as Upshaw–Schulman syndrome).
- The clinical presentation of TTP can be variable, but classic descriptions include a “pentad” of features: thrombocytopenia, microangiopathic hemolytic anemia (MAHA), neurologic symptoms (such as confusion, headache, seizures, or stroke-like deficits), renal dysfunction, and fever. However, most patients do not present with all five signs; thrombocytopenia and MAHA are the most consistent features. MAHA occurs because red blood cells are mechanically damaged as they pass through microvessels obstructed by platelet-rich thrombi, leading to the presence of schistocytes (fragmented RBCs) on blood smear, elevated lactate dehydrogenase (LDH), and indirect hyperbilirubinemia.
- Diagnosis is based on clinical suspicion, laboratory evidence of thrombocytopenia and MAHA, and the exclusion of other causes of thrombotic microangiopathies. ADAMTS13 activity measurement confirms the diagnosis when levels are severely reduced (<10%), but this result may take time, so treatment is often initiated based on suspicion alone. The mainstay of treatment for immune-mediated TTP is therapeutic plasma exchange (TPE), which removes the autoantibodies and replenishes functional ADAMTS13. Adjunctive therapy includes immunosuppressive agents such as corticosteroids and rituximab to reduce antibody production. More recently, targeted therapies like caplacizumab, a nanobody that blocks vWF–platelet interaction, have been introduced to rapidly reduce microthrombus formation while definitive treatment takes effect.
- The prognosis of TTP has improved dramatically with the advent of plasma exchange, transforming what was once a disease with over 90% mortality into a condition with survival rates exceeding 80–90% when treated promptly. Nevertheless, patients remain at risk for relapses, chronic health issues related to organ damage, and long-term complications such as cognitive impairment or depression. For this reason, ongoing follow-up and monitoring of ADAMTS13 activity are recommended in both acute and remission phases. Understanding the interplay between vWF, ADAMTS13, and immune regulation has been key to advancing TTP management and has paved the way for more targeted, mechanism-based therapies.
