Description

• An acute syndrome of microangiopathic hemolytic anemia (MAHA) and consumptive thrombocytopenia with deposition of hyaline thrombi in terminal arterioles and capillaries leading to ischemic multiorgan damage
• Thrombotic thrombocytopenic purpura (TTP) is characterized by MAHA and thrombocytopenia, with or without the following signs and symptoms (1):
  • Neurologic symptoms
  • Renal dysfunction
  • Fever
  • Most patients do not show the historic pentad of MAHA, thrombocytopenia, renal dysfunction, neurologic abnormalities, and fever, because treatment is initiated before the pentad can develop.

Epidemiology

• Predominant age: 30–60 years; rare under age 20.
• Predominant sex: Female > Male (2:1)
• Incidence ratio in blacks to whites is 3:1
• The age–sex–race standardized incidence of clinically suspected TTP/hemolytic-uremic syndrome (HUS) is 11/million/yr in the US (2).

Risk Factors

• Pregnancy and oral contraceptives
• AIDS and early symptomatic HIV infection
• Autoimmune disease:
  • Antiphospholipid antibody syndrome
  • Systemic lupus erythematosus
  • Scleroderma
• Cancer
• Hematopoietic stem cell transplantation
• Drug toxicity:
  • Cancer chemotherapy:
    • Mitomycin C and gemcitabine
    • Bleomycin and cisplatin
  • Calcineurin inhibitors:
    • Tacrolimus and cyclosporine
  • Immune-mediated:
    • Quinine and quinidine
    • Ticlopidine and clopidogrel

Genetics
TTP is most often an acquired disorder. A congenital form of inherited TTP (Schulman-Upshaw syndrome) is due to a mutation at the ADAMTS13 metalloproteinase gene locus on chromosome 9q34. This rare form of TTP has an autosomal-recessive pattern of inheritance.

Pathophysiology

• In TTP, the aggregating agent responsible for platelet thrombi is unusually large von Willebrand factor (UL vWF) multimers, which are far larger than those found in normal plasma.
• A metalloproteinase, ADAMTS13, which normally enzymatically cleaves UL vWF multimers to prevent clumping within vessels, is deficient, defective, or absent, allowing UL vWF to react with platelets. This leads to the endothelial cell damage and disseminated thrombi characteristic of TTP.
• Arterioles most often affected are in the brain, kidney, pancreas, heart, and adrenal glands. Lungs and liver are relatively spared.

Etiology

• In familial TTP, patients have low or absent levels of ADAMTS13.
• In acquired idiopathic TTP, some studies have demonstrated IgG autoantibodies made to the metalloproteinase ADAMTS13 to receptors on the surfaces of platelets or to the surface of the endothelial cell. The trigger is unknown (3)[A].
• Endothelial injury, either directly from a drug/toxin or indirectly via platelet/neutrophil activation, has been proposed as a cause of secondary TTP, especially in those without ADAMTS13 deficiency:
  • Drug-induced (see “Risk Factors”)
  • Hematopoietic cell transplantation

Commonly Associated Conditions

• TTP and HUS have similar presentations with MAHA and thrombocytopenia and multiorgan involvement.
• TTP generally presents with minimal renal involvement and may have neurologic abnormalities, whereas the opposite tends to be more characteristic of HUS.
• However, patients with HUS and TTP may have both prominent renal and neurologic manifestations, often making the distinction unclear, leading to the hybrid name “TTP-HUS.”
• ADAMTS13 levels are diminished in adults with familial or acquired idiopathic TTP, but are normal in children diagnosed with HUS following infection with Escherichia coli (particularly type O157:H7) so-called “typical HUS.”