What causes thrombotic thrombocytopenic purpura (TTP)?

Updated: Feb 18, 2019
  • Author: Theodore Wun, MD, FACP; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP  more...
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Answer

The exact etiology of HUS and TTP is not clear, although much recent data are available on the role of bacterial Shiga toxin in HUS and of a deficiency in a protease designated ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) in TTP. HUS, and to some extent TTP, commonly occur following a diarrheal illness with enterohemorrhagic Escherichia coli O157:H7 and Shigella dysenteriae serotype I. These bacteria, besides causing bloody diarrhea, are able to secrete an exotoxin called Shiga toxin (in the case of Shigella) or Shigalike toxin (in the case of E coli).

These toxins can bind to certain cell membrane globotriaosylceramide receptors, which, depending on the cell in question, can lead to chemokine or cytokine secretion (colonic and renal epithelial cells), cellular activation (monocytes and platelets), or secretion of unusually large von Willebrand multimers (glomerular endothelial cells). Evidence for activation of the coagulation cascade in HUS also exists. The relative specificity of the toxin for renal endothelial cells versus other types of endothelial cells is unknown.

Drugs such as mitomycin, cyclosporine, cisplatin, bleomycin, quinine, and ticlopidine have been associated with HUS and TTP. Whether the drugs and/or their metabolites have a direct effect on the vascular endothelium or whether alteration of the endothelial cells results in a neoantigen that leads to autoantibody formation remains unknown.

Formation of endothelial cell autoantibodies may underlie the association of thrombotic microangiopathies and pregnancy.

Most sporadic cases of TTP appear to be associated with severe deficiency of ADAMTS13 activity due to autoantibodies against this protease. [3] Normally, ADAMTS13 cleaves the large multimers of von Willebrand factor when they are secreted from endothelial cells. In most patients with active TTP, unusually large von Willebrand multimers are found in plasma. These multimers can bind to platelets in the absence of physiologic stimulus, and this mechanism might underlie the white clot seen in pathologic specimens from patients with TTP.

Congenital TTP results from mutations in the gene for ADAMTS13. Why individuals with such mutations do not always have clinically apparent TTP remains unknown.

Pregnancy can precipitate TTP. Onset of TTP during pregnancy may represent acute acquired TTP or the first episode of congenital TTP. In a prospective study of pregnancy-associated TTP from the United Kingdom, TTP presented primarily in the third trimester or postpartum. [10]


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