ADAMTS13 is a protease that acts to cleave von Willebrand factor (vWF) into smaller monomers so they can be degraded. In TTP, the function of ADAMTS13 is decreased due to inhibition, deficiency or reduced activity. Defects can be hereditary or acquired with the formation of an ADAMTS13 autoantibody.
Due to decreased activity of ADAMTS13, vWF multimers are not degraded, and instead activate platelet adhesion. This leads to several downstream effects, including platelet consumption and activation of the complement system.
vWF multimers combine with platelets to form thrombi within the microvasculature of various organ systems. Formation of microthrombi consumes platelets and thrombocytopenia develops. These microthrombi may also cause mechanical shearing of red blood cells as they pass by, resulting in a condition called microangiopathic hemolytic anemia (MAHA).
The pentad of symptoms seen in TTP can be remembered with the acronym, FAT RN. F is for fever, A is for anemia, and T is for thrombocytopenia. The R in RN is for renal dysfunction, while the N is for neurologic abnormalities.
Fever is one of the first presenting symptoms of TTP, and occurs due to excessive activity of the complement system.
Microthrombi may shear red blood cells as they pass by and cause mechanical fragmentation of red blood cells, in a condition known as microangiopathic hemolytic anemia (MAHA). Peripheral blood smear shows schistocytes and labs will show an increased lactate dehydrogenase (LDH) due to cell lysis.
Platelets are consumed during the formation of microthrombi leading to severe thrombocytopenia. Patients may manifest with petechiae, ecchymosis and purpura. Labs will show a normal PT and PTT with an increased bleeding time.
Renal insufficiency occurs in TTP secondary to complement-mediated damage and microthrombi formation within renal vessels. Acute kidney injury (AKI) may develop in severe cases.
A wide range of neurologic symptoms can be seen with TTP when microthrombi form within the cerebral vasculature, with headache and confusion being the most common. Severe cases may present with transient focal neurologic deficits, seizures, stroke or coma.
Due to the high mortality of TTP, plasma exchange therapy (PEX) is indicated for empiric treatment of patients with presumed TTP. PEX prevents further microthrombi formation by removing ADAMTS13 autoantibodies and excess vWF multimers; this procedure can reverse the symptoms of early organ system damage.
Glucocorticoids are used in addition to PEX to reduce inhibitor propagation and prevent the need for emergent plasma exchange therapy.
In patients with refractory disease or multiple relapses, splenectomy may be a treatment option. In some patients, splenectomy is effective as it removes the source of lymphocytes producing the ADAMTS13 autoantibody.
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