Thrombotic thrombocytopenic purpura: 2008 Update
ABSTRACTThrombotic thrombocytopenic purpura (TTP) is a spectrum of syndromes characterized by thrombocytopenia and microangiopathic hemolytic anemia, manifested by an elevated blood lactate dehydrogenase (LDH) concentration and red blood cell fragments. It classically occurs in patients with a hereditary or acquired lack of ADAMTS13, a metalloproteinase that cleaves large multimers of von Willebrand factor. Other TTP-like syndromes, including TTP associated with pregnancy, organ transplantation, and certain medications, likely have different underlying causes and may require different treatment. Unless TTP is recognized promptly and treated aggressively, most patients die of it.
KEY POINTS
- Strokes and renal insufficiency are end-stage manifestations of TTP; the condition is usually diagnosed before they occur.
- Classic TTP should be rapidly and aggressively treated with plasma exchange. Plasma infusion therapy plays a role for patients who cannot promptly receive plasma exchange or for patients with severe disease between episodes of plasma exchange.
- Antiplatelet therapy may be appropriate along with plasma exchange for patients without severe thrombocytopenia.
- If a renal transplant recipient develops systemic symptoms with TTP-like disease, one should consider modifying or withdrawing the immunosuppressive therapy, although this may result in loss of function and the need for transplant nephrectomy.
TTP AND RELATED SYNDROMES
Clinically, TTP encompasses a number of different but related syndromes, some of which have different physiologic bases.
TTP
TTP is characterized by moderate to severe thrombocytopenia, red cell fragmentation, and elevated LDH levels (due to red cell destruction and also muscle and organ ischemia). The pentad of features classically associated with TTP in the era before effective treatment (thrombocytopenia, fever, renal failure, neurologic deficit, and microangiopathic hemolytic anemia) is rarely seen in countries with advanced medical care: renal insufficiency and neurologic events are end-stage manifestations, and the disease should be recognizable well before these manifestations occur. Otherwise unexplained thrombocytopenia, microangiopathic hemolytic anemia, and an elevated LDH should strongly suggest TTP. TTP is the appropriate designation for adults with these clinical features, even in the presence of renal failure. TTP is uncommon in children.
Most patients present with nonspecific constitutional symptoms, such as weakness, abdominal pain, nausea, and vomiting. Typically, the family physician orders a complete blood cell count and finds that the platelet count and hemoglobin are low. Red cell fragments are noted in the peripheral blood smear. Further testing reveals an elevated LDH concentration.
HUS
HUS was initially described 30 years after TTP in children with acute renal failure in addition to thrombocytopenia and microangiopathic hemolytic anemia. The term “HUS” is currently used primarily to describe the condition in children.
In children, two forms of HUS exist:
Diarrhea-associated HUS is associated with diarrhea that is commonly bloody, due to an enterotoxin produced by Escherichia coli O157:H7.
Endemic diarrhea-associated HUS is much more common than HUS associated with epidemics. Endemic cases are caused by E coli O157:H7 present in the environment. Other patients present with clinically apparent HUS but the causal bacterium cannot be detected. The kidney transplant program at our center often sees young patients with this disease who do not have E coli O157:H7 infection, and the pathogenesis is not understood. Epidemic cases are less common but the outbreaks are dramatic. About 10 years ago, E coli O157:H7 entered the water supply in the small city of Walkerton, Ontario, and many people developed the epidemic form of HUS over a period of several weeks. Most such patients spontaneously recovered without plasma exchange, although many were left with impaired renal function.
Atypical HUS. Less often, HUS in children is not associated with a prodrome of diarrhea and is referred to as “atypical” HUS. These children often have a more prolonged and complicated course and resemble adults with TTP.
Familial TTP-HUS
Familial TTP-HUS is very rare. It may present with hemolysis and thrombocytopenia in childhood or early adulthood. Many patients present with renal insufficiency, and only careful evaluation reveals hemolysis and thrombocytopenia. The disease typically manifests acutely: a patient may have an upper respiratory tract infection and subsequently develop an episode of TTP-HUS. Episodes tend to recur, and multiple family members may also be affected.
Plasma infusion is an effective treatment, and plasma exchange is usually not required. Since more patients are now surviving well into adulthood, some are being seen to develop antibodies to the ADAMTS13 in the infused plasma, analogous to patients with severe hemophilia developing inhibitors to factor VIII. The disease may progress despite treatment: we have been treating a young woman who has had a series of catastrophic complications and now has chronic renal failure requiring hemodialysis (see discussion below).
Post-transplant microangiopathy
Post-transplant microangiopathy is most likely to develop after solid-organ or stem-cell allograft transplantation. Manifestations resemble those of TTP, but the mechanism is probably quite different. Multiple causes probably exist, depending on the setting.
Post-transplant microangiopathy does not respond to the usual therapies for TTP, although we treat it, like TTP, with corticosteroids, antiplatelet agents, and plasma exchange. Other centers do not use plasma exchange for these patients. Most patients have a poor prognosis, especially those with a transplant other than a kidney.
A spectrum of related syndromes
A number of diseases clinically resemble TTP. Enhanced diagnostic capacity and better molecular biologic techniques are revealing that they often have very different underlying causes and that in some cases they require different treatment.
