Thrombotic thrombocytopenic purpura (TTP) is a rare but serious blood disorder characterized by the formation of tiny clots in small blood vessels throughout the body. These clots can block blood flow to vital organs, causing damage and leading to a dangerous drop in platelet count, which is essential for blood clotting. Understanding what causes TTP involves exploring the complex interactions between the body’s clotting system, immune responses, and specific enzymes that regulate blood clot formation.
At the heart of TTP’s cause is a severe deficiency of an enzyme called ADAMTS13. This enzyme normally acts like a pair of molecular scissors, cutting large multimers of a protein called von Willebrand factor (VWF) into smaller, less sticky pieces. VWF is crucial for helping platelets stick to sites of blood vessel injury to form clots and stop bleeding. However, when ADAMTS13 is deficient or not working properly, unusually large VWF multimers accumulate in the bloodstream. These large multimers cause platelets to clump together abnormally inside small blood vessels, forming microthrombi (tiny clots) that can block blood flow and consume platelets, leading to thrombocytopenia (low platelet count).
The deficiency of ADAMTS13 in TTP can occur in two main ways:
1. **Acquired (immune-mediated) TTP:** This is the most common form and occurs when the body’s immune system mistakenly produces autoantibodies that inhibit ADAMTS13. These autoantibodies bind to ADAMTS13 and prevent it from cutting VWF properly. The exact trigger for this autoimmune response is not fully understood but may be linked to infections, pregnancy, certain medications, or other immune system disturbances. Because the enzyme is blocked, large VWF multimers accumulate, causing platelet clumping and clot formation.
2. **Inherited (congenital) TTP:** This rare form results from genetic mutations that cause a deficiency or dysfunction of ADAMTS13 from birth. People with inherited TTP have very low or absent ADAMTS13 activity due to mutations in the ADAMTS13 gene. Without enough functional enzyme, they are prone to episodes of clot formation and thrombocytopenia, often triggered by stress, infection, or pregnancy.
The formation of microthrombi in TTP leads to a cascade of problems. As platelets aggregate inappropriately, they are used up, causing thrombocytopenia. Red blood cells passing through these partially blocked small vessels get damaged, leading to microangiopathic hemolytic anemia—a condition where red blood cells are fragmented and destroyed. This destruction releases substances like lactate dehydrogenase (LDH) into the blood and reduces hemoglobin and haptoglobin levels. The clots can also impair blood flow to organs such as the brain and kidneys, causing neurological symptoms (confusion, headaches, seizures) and kidney dysfunction.
Several factors can precipitate or worsen TTP episodes. Infections are common triggers, likely because they stimulate the immune system and can increase the production of autoantibodies. In women, pregnancy and the use of oral contraceptives have been associated with TTP onset, possibly due to hormonal and immune changes. Certain medications and autoimmune diseases may also contribute to the development of TTP by promoting immune dysregulation.
The immune system’s role in acquired TTP is central. The autoantibodies that target ADAMTS13 are typically of the IgG type and interfere with the enzyme’s activity. This autoimmune attack may arise from a breakdown in immune tolerance, where the body fails to recognize ADAMTS13 as a self-protein and mistakenly attacks it. This process involves complex immune mechanisms, including the activation of B cells that produce the antibodies and possibly T cells that help sustain the autoimmune response.
Because TTP is a medical emergency, understandin
