Pathophysiology and management of thrombotic microangiopathies

Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are syndromes of microangiopathic hemolytic anemia, and thrombocytopenia in which endothelial dysfunction appears to be an important factor in the sequence of events leading to microvascular thrombosis. They are termed thrombotic microangiopathies (TMA). Differentiation of the several primary forms of TMA is crucial to predict disease outcome and to establish the most appropriate therapeutic approach. Typical verotoxin-associated HUS, mostly due to E.coli O157:H7 infection, is associated with prodromal diarrhea followed by acute renal failure, and considered a disease with a good outcome. Antibiotics are not necessary and antimotility agents are contraindicated. No specific therapies aimed at preventing or limiting the microangiopathic process have been proved to affect the course of the disease in children. Atypic HUS covers two clinical conditions: one characterized by severe gastrointestinal prodromes, acute onset anuria, and neurological involvement, and associated to high mortality rate; the second form without diarrhea prodromes but with progressive renal function deterioration and neurological involvement that resembles TTP. Supportive therapy is required in the diarrhea-associated form, while more specific therapies are needed in the latter form. Neurological symptoms usually dominate the clinical picture of acute TTP. Infusion or exchange of fresh frozen plasma have dramatically changed the outcome of a disease that in the sixties was almost invariably fatal. Relapsing episodes of TTP are being reported increasingly often because more patients recover from the initial acute episode thanks to improved treatments. Plasma infusion has been extensively used for this form of TTP, and remission of relapsing episodes documented in most cases. Plasma-resistant HUS or TTP have invariably a poor outcome if alternative treatments are not effective. Bilateral nephrectomy may be an effective rescue therapy for patients who failed to respond to plasma. Familial HUS/TTP is a form of TMA with recessive or dominant inheritance of unknown pathogenesis. The outcome is usually poor. In summary, a general consensus has been achieved that therapies (i.e. plasma exchange or infusion) aimed at stopping the microangiopathic process should always be tried in TTP and in adult and/or atypical forms of HUS to minimize the risk of death or long-term sequela. This approach is seldom effective in secondary forms whose outcome mainly depends on the prognosis of the underlying condition, and is not risk-effective in typical childhood HUS, that usually recovers spontaneously.