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.
Do antiplatelet agents have a role in acute TTP?
Most algorithms for managing acute TTP include the use of aspirin or dipyridamole (Persantine) or both, and there is some evidence in favor of this approach,4 but whether antiplatelet therapy should be used for inpatients with severe thrombocytopenia remains controversial. In our practice, we usually provide antiplatelet therapy even for patients with severe thrombocytopenia because we believe TTP involves platelet-mediated hypercoagulability rather than increased bleeding risk.
Do corticosteroids have a role?
Corticosteroids were widely used to treat TTP even before the disease was discovered to be immune mediated. In our center we routinely use them.
Unfortunately, few data exist on the efficacy of steroid therapy for TTP. As a result, we can only make a weak recommendation for its use: using the American College of Chest Physicians rating system for the strength of clinical evidence, it would receive a 2C recommendation. This is the weakest possible recommendation, being based on widespread use but poor-quality data.
Stopping vs tapering plasma exchange
Whether plasma exchange should be tapered or simply stopped is also controversial and not well studied. Nevertheless, a widespread clinical practice—once the platelet count returns to 200 × 109/L or higher and the patient looks and feels well—is to reduce the plasma exchange sessions to once every 3 days, then to once every 7 days, and then to once every 2 weeks.
In our practice, we taper plasma exchange in this fashion for a minimum of two treatments beyond what we think the patient really needs. As a result, we tend to treat about once every 2 weeks for weeks or even months after the acute illness.
Rituximab may help
Rituximab (Rituxan), a monoclonal antibody against mature B cells, is increasingly being used in treating TTP. Past and present treatments for TTP, including splenectomy, corticosteroids, and plasma exchange are immunomodulatory, so the use of rituximab may be justified. Case reports provided the rationale for a large, multicenter, randomized controlled trial, which is currently under way.5
CONDITIONS THAT ARE NOT TTP
Some conditions may be confused with TTP but are clearly something different:
Patients with isolated thrombocytopenia and normal blood smear findings and no coagulopathy most likely have idiopathic thrombocytopenia purpura or, in the correct clinical circumstance, heparin-induced thrombocytopenia.
A patient with an extremely low platelet count but no fragments or very few fragments with microangiopathic hemolytic anemia may have either drug-associated thrombocytopenia or disseminated intravascular coagulopathy, particularly if there is concomitant coagulopathy.
Many pregnancy-associated microangiopathies resemble TTP, and it may be difficult to differentiate them from TTP; if confusion as to the diagnosis exists, the patient should be treated with plasma exchange, as this therapy may be life-saving.
Many rheumatologic conditions are characterized by an acute illness with nonspecific findings, such as low-grade hemolysis and thrombocytopenia. For example, Wegener granulomatosis can present with evidence of hemolysis, thrombocytopenia, and renal impairment.
Systemic lupus erythematosus can also initially present with an “early-TTP”-like picture. Evidence of glomerulonephritis is not consistent with TTP, and urinary red cell casts makes the diagnosis of lupus more likely. Helmet cell fragments in the peripheral blood smear are supposedly more characteristic of TTP, but their presence is not diagnostic.
Scleroderma renal crisis can present like TTP, but because it is unlikely that a patient with known scleroderma would have a second rare disease, it is best to treat it as scleroderma, which does not require plasma exchange or plasma infusion.
In general, if the diagnosis is uncertain, the safest course is to treat the patient with plasma exchange, then try to establish the diagnosis, because TTP is fatal if not promptly treated. Although plasma exchange is probably overused, it is more innocuous than untreated TTP.
