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Immune Hematology pp 171–188Cite as

Pathophysiology of Thrombotic Thrombocytopenic Purpura

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Abstract

Thrombotic thrombocytopenic purpura (TTP) is a disorder characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, microvascular endothelial injury and thrombosis, as well as end-organ damage particularly of the central nervous system, kidneys, heart, and gastrointestinal tract. The pathogenesis of the disorder is secondary to deficiencies in ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), which is responsible for cleaving large multimers of von Willebrand factor (VWF). VWF normally functions to initiate formation of the platelet plug in primary hemostasis. In TTP, absence or deficiency of ADAMTS13 leads to persistence of ultra-large VWF (ULVWF) multimers with subsequent ULVWF-platelet adhesion and development of systemic microvascular thrombosis. Thrombocytopenia is secondary to platelet consumption in the formation of systemic microthrombi; MAHA and schistocytosis develop as a result of mechanical fragmentation as the red blood cells cross these platelet thrombi. Microvascular endothelial injury in TTP is well described, but the pathophysiologic mechanisms for this injury are not well characterized. Proposed mechanisms include direct injury by platelet-VWF thrombi, anti-endothelial cell antibodies, nitric oxide, oxidative stress, and neutrophil activation, as well as activation of the Fas pathway leading to endothelial cell apoptosis. Endothelial injury and thrombosis of the small vessels lead to impaired organ perfusion, further resulting in multi-organ failure, accounting for the significant morbidity and mortality observed in TTP. Severe ADAMTS13 deficiency is caused by congenital ADAMTS13 gene mutations or by acquired production of polyclonal autoantibodies directed against the metalloprotease. Autoantibody development in TTP can be triggered by infections or, more often, occur in the setting of other autoimmune phenomena. Other etiologies of acquired TTP include sepsis, liver disease, pancreatitis, pregnancy, HIV, cancer, organ transplant, and drugs. More recently, both in vitro and in vivo evidence have pointed toward over-activation of the alternative complement pathway, part of the innate immune system, in TTP, suggesting an additional immune mechanism in the pathogenesis of the disorder.

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    Sarah E. Sartain MD

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Sartain, S.E. (2018). Pathophysiology of Thrombotic Thrombocytopenic Purpura. In: Despotovic, J. (eds) Immune Hematology. Springer, Cham. https://doi.org/10.1007/978-3-319-73269-5_9

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