Information on Thrombotic Thrombocytopenic Purpura


What Treatment is used for Thrombotic Thrombocytopenic Purpura?

Prior to the 1970's, when few supportive and therapeutic measures where available, Thrombotic Thrombocytopenic Purpura was a fulminant disorder with an invariably fatal outcome. Since that time, newer modes of therapy, directed specifically at the underlying physiologic alterations, have greatly improved survival statistics. Some patients recover fully, whereas in others the disease assumes a more protracted course, characterized by recurrent episodes of TTP and exacerbations that include renal dysfunction.

Today, the treatment of Thrombotic Thrombocytopenic Purpura involves a daily single plasma volume exchange (plasmapheresis), which is continued until the platelet count normalizes and there is minimal hemolysis. Seriously ill patients may receive fresh frozen plasma infusions (without exchange) for several hours until plasmapheresis can be arranged. The plasma exchange must sometimes be continued for 10 days or longer to obtain a complete remission in seriously ill patients. Thrombotic Thrombocytopenic Purpura Treatment is first tapered and later discontinued if normal laboratory parameters are maintained.

Some additional case series have added antiplatelet agents (aspirin, dipyridamole) and corticosteroids (methylprednisolone) to the treatment regimen, as well as intravenous immunoglobulin (IVIg), Vincristine, and even spleenectomy - all of which are of uncertain benefit (according to most). In fact, 80-90% of patients who are aggressively treated with exchange plasmapheresis alone, now survive the initial episode of TTP. Investigators have not found any presenting factors that can predict which patients will have a favorable outcome after treatment for Thrombotic Thrombocytopenic Purpura. In fact, patients with significant renal failure have been found to have the same response to aggressive plasma exchange.

Many patients are noted to have a prompt exacerbation of their thrombocytopenia and hemolysis when plasma exchange is tapered, indicating that TTP can remain active, requiring continued treatment for control. Whereas the results of treating Thrombotic Thrombocytopenic Purpura with plasma exchange and infusion have been very encouraging, these procedures often result in circulatory overload and electrolyte disturbances in those patients whose renal function is already seriously compromised. In these patients, the additional use of hemodialysis to achieve rapid plasma exchange, volume control and correction of azotemia has become an important therapy in the management of TTP. 

Plasma exchange does not cure Thrombotic Thrombocytopenic Purpura, but rather controls the manifestations of the disease until a spontaneous remission occurs - referred to as a hematological remission. There are no clinical features that predict how long plasma exchange may be required and to date, there have been no randomized clinical trials to provide data for the management decisions for treating TTP. The decision to stop or continue treatment is empirical.

Treatment Outcomes in Patients with Thrombotic Thrombocytopenic Purpura:

In a published study by Hayward et al. in1994, 65 of 67 episodes of TTP were managed with plasma exchange between January 1977 and December 1988. Despite a dramatic improvement in outcome with the use of this therapy, 8% of the patients died, 21% had relapsing Thrombotic Thrombocytopenic Purpura, and most survivors (58%) experienced further, related health problems. 

In the study by Conlon et al. (1995) 68 patients were treated with plasma exchange from 1980 to 1992. Even with early initiation of treatment, mortality during the initial hospital admission was almost 25% and in retrospect, prognosis could not be predicted based on admission biochemical or clinical variables. Sixteen percent of the patients developed renal failure requiring dialysis. Those who survived to discharge, however, recovered renal function and became independent of dialysis.

Hollenbeck et al. (1998) reported on a retrospective analysis of the medical records of 45 patients with Thrombotic Thrombocytopenic Purpura treated with plasmapheresis at a German clinic from 1974 to 1995. The mortality rate was 7%; three patients died; one with manifest bleeding problems that progressed to cerebral hemorrhage; one died from intracerebral hemorrhage after his third plasma exchange treatment, and a third patient, who had entered remission after the 10th plasma exchange, died from septic shock due to oxacillin resistant staphylococci. There was no significant predictor of mortality and no correlation with death was found for age, gender, and prodromal disease, LDH levels on admission, platelet count, serum creatinine or blood pressure. At discharge, 15 of the 42 surviving patients had end-stage renal disease; 9 patients showed impaired renal function with serum creatinine levels up to 4.5 mg/dl, and 18 patients had serum creatinine levels below 1.3 mg/dl. Dialysis was discontinued in one patient 3 months after discharge, but a year later he again required dialysis. Two patients in whom creatinine levels ranged between 3.8 and 4.5 mg/dl at discharge, required dialysis after 3 and 6 years respectively. Four patients received a successful renal transplant 2-7 years after diagnosis. It was concluded, however, that plasma exchange reduced the relative risk to develop end-stage renal disease by 81.8% - a clear beneficial effect of plasma exchange on renal function.

Lara et al. (1999) reported on a retrospective analysis of 124 patients with Thrombotic Thrombocytopenic Purpura, most of who (122) were treated principally with plasmapheresis at the Sacramento Medical Foundation Blood Center between 1978 and 1998. Twelve of the 124 patients died within the first 30 days; 8 (67%) did not respond to plasma exchange and 1 had an initial complete response. Of the 86 patients with adequate follow-up data, 11(13%) relapsed following an initial response to therapy. Time to relapse was 3 weeks to 152 months. One of the 11 patients died of a myocardial infarction 13 years after the original diagnosis of TTP. The overall response rate was 77%. Surprisingly, the absence of fever appeared to be a risk factor for relapse, perhaps reflecting a suboptimal inflammatory response.

Dervenoulas et al. (2000) published a single-center experience of 48 cases of patients with Thrombotic Thrombocytopenic Purpura, in which 41 patients achieved complete remission, two had a partial response, and five had no response and died of progressive disease. Ten of the patients who had achieved remission relapsed within the first two years. Advanced age proved to be an adverse prognostic factor, but the most powerful factor predictive of treatment failure and poor outcome in this review was the presence of severe renal impairment (high serum creatinine levels above 2 mg%).

It is important to point out that the underlying cause of the TTP was variable in all of the studies of treatment outcome. However, there is one published study which reported on the treatment outcome (using plasma exchange) which involved the largest number of adult cases of Thrombotic Thrombocytopenic Purpura during an outbreak of Escherichia coli O157:H7. The outbreak occurred in 1996 in central Scotland and involved 22 patients. Plasma exchange was used in 16 patients and 4 of these patients were later treated with dialysis because of deteriorating renal function. Five (31%) of the 16 patients died. The most frequent complication was pulmonary edema.

According to George (2000), long-term follow-up of patients recovered from Thrombotic Thrombocytopenic Purpura has revealed an increasing frequency of recurrent episodes. Relapse is not the only concern after successful treatment. Chronic renal failure, defined by a creatinine clearance of less than 40 mL/min at one year after diagnosis occurs in one fourth of his patients. He points out that this is comparable to the experience with children after diarrhea-associated HUS, in whom the frequency of renal function abnormalities and hypertension increases during the long-term follow-up. Some patients who have been successfully treated for TTP also report minor but persistent problems with fatigue, memory and concentration.

With respect to both treatment and prognosis of TTP, there is a need to determine whether early intervention with any treatment can improve the rate of initial recovery, decrease the frequency of exacerbations and relapses, and decrease the risk for chronic renal failure. Long-term clinical follow-up studies on the outcomes of patients after recovery from an acute episode of Thrombotic Thrombocytopenic Purpura are necessary to document the risk for relapse, as well as the occurrence of renal failure and hypertension.

 

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