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.
TOWARD DIAGNOSTIC CRITERIA
Ruutu et al,1 in a consensus conference, used rigorous methods to establish diagnostic criteria for microangiopathy associated with stem cell transplantation:
- More than 4% red blood cell fragments in the peripheral blood. A laboratory report that states that “few fragments” are present is not nearly as useful as one that estimates the quantity; eg, 1% fragments would have very different implications than 6% fragments.
- Thrombocytopenia—a platelet count of less than 50 × 109/L or more than a 50% reduction from previous counts
- Increased LDH concentration
- Reduced hemoglobin concentration or increased transfusion requirement
- Decrease in serum haptoglobin, which, like red blood cell fragments, is a marker of hemolysis rather than of reduced synthesis.
The ADAMTS13 level need not be assessed. Metalloproteinase deficiency need not be proved to diagnose TTP. Although our hospital is a TTP referral center, we do not routinely offer the test. Too often the test results cause confusion: a patient can have a normal level of ADAMTS13 and still have TTP that responds to plasma exchange, and levels can be low in conditions other than TTP.
THE CHALLENGES OF TREATMENT
Plasma exchange is the primary treatment for TTP
Rock et al2 performed a randomized trial in which 102 patients with TTP received either a 1.5-volume plasma exchange daily for 3 days and then 1-volume plasma exchanges as needed to control the disease or plasma infusion. Patients who received plasma exchange had a better initial response, a higher survival rate, and a lower rate of relapse than patients receiving plasma infusion. These findings established plasma exchange as the treatment of choice for TTP.
However, the trial had some inherent problems: patients who had plasma infusions tended to develop renal insufficiency and as a result did not receive as much plasma because they could not tolerate as much volume as those who had plasma exchange. Plasma exchange probably worked better because it could deliver more plasma over a fixed period of time, enabling patients to obtain more of the ADAMTS13 enzyme, rather than because it was an intrinsically better treatment. This interpretation is the basis for our occasional use of twice-daily plasma exchange in critically ill patients.
TTP is different from other autoimmune diseases such as idiopathic thrombocytopenia purpura, in which the primary treatments are immunosuppressive agents. Some evidence exists for treating TTP with immunosuppressive agents, but the primary treatment should be plasma exchange.
Plasma infusion is useful in some cases
Although small case series and our own experience provide evidence for the benefit of treating TTP with high-dose plasma infusions (25 mL/kg/day, or about 1.5 to 2.0 L/day for an average-sized adult), problems will likely arise with volume overload if the patient has any significant renal insufficiency. Dialysis or ultrafiltration may be used to treat volume overload; however, it is difficult to remove the large volumes of fluid required for high-volume plasma infusion.
Plasma infusion should be reserved for two situations:
- If plasma exchange cannot be promptly started
- For patients with very severe or refractory disease, between plasma exchange sessions.
Benefit of cryoprecipitate-poor plasma is uncertain
Fresh frozen plasma is believed to contain nearly physiologic levels of all of the plasma proteins. When plasma is cooled to around 4°C, a precipitate forms that contains a variety of substances, including the higher molecular weight multimers of von Willebrand factor. Because TTP involves excess large multimers, giving plasma in which the high molecular weight multimers have been removed should in theory be better. In many centers, such cryoprecipitate-poor plasma is routinely used to treat TTP.
However, evidence that cryoprecipitate-poor plasma is better is lacking. A large study in Canada evaluating this question was terminated because of a lack of patient accrual, a common fate of clinical trials of rare diseases. A randomized study in 17 patients failed to show an advantage of cryoprecipitate-poor plasma over regular plasma, but the study was too small to draw firm conclusions given large confidence intervals about the point estimate of the treatment effect.
Cryoprecipitate-poor plasma is more expensive than regular plasma and is not as available. We do not routinely use it in our center to initially manage patients with TTP, but we do use it for patients who are refractory to standard treatment.
Scott et al3 measured the concentration of ADAMTS13 in a variety of plasma products and found that there are significant amounts in cryoprecipitate. Although giving cryoprecipitate-poor plasma provides less of the high molecular weight multimers, which is desirable for patients with TTP, it also provides less ADAMTS13, which is not desirable.
