Genetic thrombotic microangiopathy

Genetic thrombotic microangiopathy (genetic TMA) is a group of rare inherited disorders characterized by damage to the small blood vessels (microangiopathy), leading to the formation of blood clots (thrombi) in the microvasculature. This results in a triad of clinical features: microangiopathic hemolytic anemia (destruction of red blood cells as they pass through damaged small vessels), thrombocytopenia (low platelet count due to consumption in clot formation), and organ damage — most commonly affecting the kidneys, but also potentially the brain, heart, and other organs. Genetic TMA encompasses several conditions, including atypical hemolytic uremic syndrome (aHUS) caused by mutations in complement regulatory genes (such as CFH, CFI, MCP/CD46, CFB, C3, and THBD) and congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome) caused by mutations in the ADAMTS13 gene. Patients may present with acute kidney injury, hypertension, neurological symptoms (such as confusion or seizures), fatigue, and pallor related to anemia. The severity and age of onset can vary widely depending on the specific genetic defect involved. Some patients experience their first episode in infancy or childhood, while others may not present until adulthood, often triggered by infections, pregnancy, or other physiological stressors. Treatment depends on the underlying genetic cause. For complement-mediated TMA (aHUS), complement inhibitor therapy with eculizumab or ravulizumab has transformed outcomes by blocking the terminal complement pathway. For congenital TTP due to ADAMTS13 deficiency, regular plasma infusions or plasma exchange remain the mainstay of treatment. Supportive care including blood transfusions, dialysis for renal failure, and management of hypertension is also important. Genetic testing is essential for confirming the diagnosis, guiding treatment decisions, and providing appropriate genetic counseling to affected families.

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