Thrombotic microangiopathy is a general term for the combination of microangiopathic hemolytic anemia and thrombocytopenia, often accompanied by signs and symptoms consistent with disseminated microvascular thrombosis. Thrombotic thrombocytopenic purpura (TTP) refers to thrombotic microangiopathy, without an obvious predisposing condition in the majority of cases. TTP is caused by autoantibodies to ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif member 13), a plasma metalloprotease that normally cleaves von Willebrand factor (VWF) and regulates VWF-dependent platelet aggregation. Inherited deficiency of ADAMTS13 causes congenital TTP, which typically responds to plasma infusion. Most patients with acquired TTP respond to plasma exchange and immunosuppressive therapy, although many have relapsing disease. Hemolytic uremic syndrome (HUS) refers to thrombotic microangiopathy that usually causes oliguric or anuric acute kidney injury. Ingestion of Shiga toxin–producing Escherichia coli can cause the most common or “typical” form of HUS that is usually preceded by bloody diarrhea. Inherited or acquired defects in the regulation of the alternative complement pathway cause HUS to be referred to as “atypical” because it occurs without a prodrome of bloody diarrhea. Secondary thrombotic microangiopathy can occur in association with autoimmune disease, metastatic cancer, infections, organ transplantation, and certain drugs. These variants of thrombotic microangiopathy differ in pathogenesis and prognosis but can be difficult to distinguish because their clinical features often overlap.
Acronyms and Abbreviations
ADAMTS, a disintegrin and metalloprotease with thrombospondin repeats; aHUS, atypical hemolytic uremic syndrome; ANA, antinuclear antibody; APS, antiphospholipid syndrome; aPTT, activated partial thromboplastin time; CFH, complement factor H; CFHR, complement factor H-related protein; DDAVP, desmopressin; DGKE, diacylglycerol kinase ε; Gb3, globotriaosylceramide 3; HELLP, hemolysis, elevated liver enzymes, low platelet count; HIT, heparin-induced thrombocytopenia; HUS, hemolytic uremic syndrome; LDH, lactate dehydrogenase; MCP, membrane cofactor protein; MMACHC, methylmalonic aciduria and homocystinuria type C protein; PT, prothrombin time; SLE, systemic lupus erythematosus; STEC, Shiga toxin–producing Escherichia coli; Stx, Shiga toxin; TM, thrombomodulin (gene name THBD); TTP, thrombotic thrombocytopenic purpura; VEGF, vascular endothelial growth factor; VWF, von Willebrand factor.
THROMBOTIC THROMBOCYTOPENIC PURPURA
DEFINITION AND HISTORY
Thrombotic thrombocytopenic purpura (TTP) refers to thrombotic microangiopathy without another apparent cause and without acute renal injury at presentation, although mild or modest renal insufficiency may be seen. Tissue injury can affect almost any organ but often results in neurologic and cardiac damage. TTP is associated with autoantibodies against the plasma metalloprotease ADAMTS13 (a member of the “a disintegrin and metalloprotease with thrombospondin repeats” family) that reduce plasma ADAMTS13 activity to less than 10% of normal.
Eli Moschcowitz reported the first detailed description of TTP in 1924.1 The patient was a 16-year-old girl with fever, severe anemia, leukocytosis, petechiae, abdominal pain and hemiparesis. Her renal function was not impaired, but her urine contained albumin, hyaline casts, and granular casts. She became comatose and died 2 weeks after her first symptoms. At autopsy, hyaline thrombi were found ...