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  • Updated 01.06.2024
  • Released 08.30.2019
  • Expires For CME 01.06.2027

Thrombotic thrombocytopenic purpura: neurologic complications



Thrombotic thrombocytopenic purpura is a serious condition that belongs to a group of disorders known as thrombotic microangiopathies. The disease is caused by the congenital or acquired deficiency of the metalloproteinase ADAMTS13, which is responsible for the cleavage of von Willebrand factor multimers. The decreased activity of ADAMTS13 leads to the accumulation of ultra-large von Willebrand factor multimers that enhance platelet agglutination and induce thrombosis of small arterioles and capillaries in most organs in the body, including the brain, kidney, and heart. Thrombotic thrombocytopenic purpura patients commonly have neurologic manifestations, and these may represent the initial symptoms for which patients seek medical attention. Left untreated, thrombotic thrombocytopenic purpura has a mortality rate of 85% to 90%. However, early recognition of the disease and proper management reduces the mortality rate to 10% to 20%.

Key points

• Thrombotic thrombocytopenic purpura belongs to a group of disorders known as thrombotic microangiopathies.

• It can affect previously healthy individuals of patients with autoimmune disorders.

• Thrombotic thrombocytopenic is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end organ damage.

• It is caused by the severe deficiency of ADAMTS13, which leads to the accumulation of ultra-large von Willebrand factor multimers that induce thrombosis.

• Ischemic stroke is one of the neurologic manifestations in thrombotic thrombocytopenic purpura.

• Plasma exchange is the mainstay treatment for thrombotic thrombocytopenic purpura.

• Caplacizumab has been approved by the U.S. Food and Drug Administration as adjunctive therapy for the treatment of thrombotic thrombocytopenic purpura.

Historical note and terminology

Thrombotic thrombocytopenic purpura and other microangiopathies, such as those associated with hematopoietic progenitor cell transplantation, pregnancy, drugs, and disseminated malignancy as well as hemolytic uremic syndrome belong to a class of disorders called thrombotic microangiopathies (37). As a group, thrombotic microangiopathies are characterized by microangiopathic hemolytic anemia with red blood cell fragmentation, thrombocytopenia, and end organ injury secondary to microvascular thrombosis. In particular, thrombotic thrombocytopenic purpura is associated with ADAMTS13 deficiency and elevated levels of ultra-large von Willebrand factor multimers in the plasma. Thrombotic thrombocytopenic purpura, which is also known as Moschcowitz disease, was first described by Eli Moschcowitz in 1924. He reported a 16-year-old girl who died after having an acute presentation of hemolytic anemia, thrombocytopenia, purpura, fever, and neurologic dysfunction (28). In 1982, Moake and colleagues reported four patients with chronic relapsing thrombotic thrombocytopenic purpura who had elevated plasma levels of von Willebrand factor multimers that caused spontaneous platelet agglutination. The authors hypothesized that thrombotic thrombocytopenic purpura was the result of a deficiency of a plasma von Willebrand factor–cleaving protease (27). In 1998, a similar presentation was described in different cohorts of patients with acquired thrombotic thrombocytopenic purpura (42). In this case, the formation of von Willebrand factor multimers was associated with antibodies against the von Willebrand factor–cleaving protease. At this point, it became clear that thrombotic thrombocytopenic purpura could be hereditary or acquired (idiopathic). In 1996, the von Willebrand factor–cleaving protease was isolated from human plasma (13). Because the activity of this enzyme was dependent on the presence of divalent metal ions, it was concluded that the von Willebrand factor–cleaving protease was a metalloproteinase. Based on partial protein sequencing in 2001, it was determined that the von Willebrand factor–cleaving protease was a novel member of the ADAMTS (A Disintegrin And Metalloproteinase with ThromboSpondin motifs) family of metalloproteinases. The gene encoding for ADAMTS is located on chromosome 9q34, and, according to the HUGO Gene Nomenclature Committee, it was designated as ADAMTS13 (45).

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