Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome Newsletter

James N. George, M.D.

The Oklahoma Blood Institute and University of Oklahoma

Patients. All patients with clinically suspected TTP-HUS for whom plasma exchange treatment is planned are included in our series. Some patients may not be treated with plasma exchange: patients may begin to recover before plasma exchange is initiated and then it is deferred; other patients may die before plasma exchange can be initiated. In some patients, plasma exchange is ordered for an autoimmune disease, such as systemic lupus erythematosis, or a complication of pregnancy, such as preeclampsia/HELLP syndrome. In these situations, some physicians may be suspicious that TTP-HUS is a coexisting problem, other physicians may not mention suspicion of TTP-HUS. Therefore our inclusion of patients in this case series sometimes requires arbitrary judgment. But what we have is an inception cohort of consecutive patients followed from a constant initial point in their illness. This case series is specifically not a case series of "Patients with TTP-HUS"; it is a case series of clinically suspected TTP-HUS, which is more relevant to the initial presentation to the clinician. Therefore our case series includes some patients in whom an alternative diagnosis became apparent and treatment was stopped. Our patient series began January 1, 1989; as of September 4, 2000 we have enrolled 227 patients.

Informed Consent. Each patient is asked to sign a consent form to allow us to continue our follow-up at regular intervals, forever. In addition to consenting to regular follow-up, we ask our patients to consent to the collection of a serum sample by the OBI, drawn just prior to the initial plasma exchange, to be used for assays of the von Willebrand factor-cleaving protease, or for future studies as more knowledge is gained into the pathogenesis of TTP-HUS. Our consent form also describes collection of samples for DNA analysis, both on blood and saliva. We do not currently collect these samples, but we anticipate this as part of future studies to analyze the VWF protease.

Data Collection. We have extensive data collection forms that we complete on every patient at presentation, and then an additional form completed at the end of their acute illness to document their clinical course and outcome. Follow-up forms are completed every six months. Once every year we ask our patients to complete a quality-of-life (QOL) survey to measure the completeness of their recovery. The QOL analysis was suggested in our patient group meetings by the consistent comments about persistent symptoms of lack of energy, difficulty in concentration, and difficulty with memory.

Follow-up. Therefore the major effort of our program is complete patient follow-up. Most all of our former patients are enthusiastic to participate; some would prefer not to be bothered. However with persistence and politeness, we have complete follow-up on 121 of 122 living patients . . . . and we have not given up on that one patient! Complete follow-up is essential, since we are documenting rare events, such as occurrence of relapses and complications of future pregnancies.

Patient Group Meetings. Beginning in September 1996 we have had three meetings per year at the OBI. These were initially conceived as a patient support group but, in fact, these are for former patients, not patients, and their need for support is much less than their need for information. The major issue faced by our former patients is their difficulty in understanding and explaining the serious illness from which they have recovered. They face a total lack of familiarity with TTP-HUS among friends and colleagues, and this creates a sense of isolation and frustration. An average of 15-20 former patients attend each session, and these sessions have been consistently valuable, for me as well as for our patients. From these meetings, I have learned a great deal about the issues and impact of this experience on our patients’ lives. The main program of these meetings is our progress report on our studies. This can be a formidable assignment: explaining data on TTP-HUS to patients who have had TTP-HUS! I feel like the chairman of the board reporting to my shareholders. These former patients are my constituents; they have the biggest stake of all in our data. We begin our fifth year with a meeting this month.

Current Projects. The main goal of our research is simply to understand the clinical course of this illness. When we began, we had no ability to predict the outcome of the disorder, the duration of treatment that would be required, the risk for exacerbations which would require renewed daily plasma exchange, the risk for relapses recurring after a remission was established. Additional work within the past year has involved a collaboration with the Blood Center of Southeastern Wisconsin at Milwaukee, where investigators have had long experience with studies of the structure and function of von Willebrand factor and recently with analysis of the von Willebrand factor-cleaving protease. Examples of our current projects are:

1. Clinical categories of patients with clinically suspected TTP-HUS. Without a precise definition and diagnosis of TTP-HUS, our patients represent diverse clinical disorders. We have developed a classification method based on clinical associations and presumed etiologies which has provided a better understanding of the course of their illness. Each patient is assigned to one category, although they may actually have features of more than one category. The clinical categories are: (1) bone marrow transplantation, (2) pregnancy/post-partum, (3) drug-induced, (4) presentation with bloody diarrhea, (5) additional or alternative diagnosis, and (6) idiopathic.
2. Evaluation of the incidence and changing clinical spectrum of TTP-HUS. The incidence of clinically suspected TTP-HUS in Oklahoma has increased seven-fold over the past 12 years, consistent with the experience in Canada. Part of this is increased awareness and recognition; part is due to resulting over-diagnosis. The incidence among patients who live in the Oklahoma City metropolitan area is twice that of patients who live in rural counties. When the increased incidence is analyzed according to clinical categories, most of the increased occurrence is related to the recognition of drug-induced TTP-HUS since 1994, and the marked increase in the category of patients with an additional or alternative diagnosis.
3. Bone marrow transplantation. Our analysis of 17 patients over ten years, 1989-1998, suggests that these patients, who are all extremely sick, may not have TTP-HUS but rather a combination of transplant-related complications which resemble TTP-HUS. Data on these patients were compared to the 245 patients transplanted at the University of Oklahoma during these ten years in whom TTP-HUS was not diagnosed. Patients who were diagnosed with TTP-HUS had (1) more severe disease for which the transplant was done, (2) a higher incidence of unrelated donors or mismatched sibling donors, (3) a higher frequency of bacterial, fungal, and viral sepsis, and (4) a higher frequency of grade 3-4 acute graft vs. host disease. This interpretation is consistent with the observed lack of response to plasma exchange. This analysis has resulted in a more conservative approach to the diagnosis of TTP-HUS among these patients and a more deliberate decision for initiation of plasma exchange.
4. Pregnancy. In all published series of TTP-HUS, most patient are women and many women present initially during pregnancy or in the post-partum period. In our experience, 73% of patients are women and 19 (14%) presented during pregnancy/post-partum. This is a difficult diagnosis because the clinical signs and symptoms of preeclampsia/HELLP syndrome overlap extensively with the signs and symptoms of TTP-HUS. Initiation of plasma exchange is often considered when the signs and symptoms are considered too severe to be explained by preeclampsia/HELLP syndrome, or when the illness progresses beyond several days following delivery. A major concern is how to advise women about future pregnancies. Among our patients, 13 women have had 20 pregnancies following an initial diagnosis of TTP-HUS. The outcome of the pregnancy appears more related to risk factors for obstetric complications rather than the history of TTP-HUS. In six women with risk factors (renal failure and hypertension from a previous episode of TTP-HUS, antiphospholipid antibody syndrome), there was only one live birth among 8 pregnancies. However in seven women with no risk factors, there were 10 live births among 12 pregnancies; the other two pregnancies terminated with spontaneous abortions at 6 and 12 weeks, similar to the outcomes in normal women. Five of 13 women each had one recurrence of TTP-HUS associated with a subsequent pregnancy; however four of these women had also had relapses of TTP-HUS when they were not pregnant. Our interpretation of these data is that if a woman has no risk factors for obstetric complication, a cautious decision for a subsequent pregnancy is appropriate; it seems inappropriate to advise against any future pregnancy.
5. Drug-induced TTP-HUS. Although recent publications have emphasized the occurrence of TTP-HUS following ticlopidine and clopidogrel, the ubiquitous use of quinine continues to be the major cause of drug-induced TTP-HUS among our patients. We have attributed the etiology of TTP-HUS to a drug in 21 patients; in 15 the etiology appeared to be sensitivity to quinine. These are sometimes arbitrary decisions. If a patient has been regularly taking a drug that is known to cause TTP-HUS, we assume it is the cause, even if the patient cannot tell us that she took the drug immediately before the onset of her illness. Sometimes a drug not known to cause TTP-HUS was given or begun just before an acute onset of TTP-HUS; we record these data and compare our experience with the experience of other physicians. Comparable to the original descriptions of quinine-induced TTP-HUS, our patients all presented with anuric acute renal failure. However distinct from previous reports which described complete recovery, three of our patients died and 7 of the 12 surviving patients have chronic renal failure, defined by a creatinine clearance of <40 ml per minute at one year.
6. Patients presenting with bloody diarrhea. We have isolated E. coli 0157 from two patients in our series; in another patient we isolated Shigella dysenteriae; in other patients an infectious etiology was suspected but specific cultures for E. coli 0157 were not performed. Although many of these patients had acute renal failure, consistent with published observations, some patients had minimal or no renal failure. Although some published observations suggest that these patients are not helped by plasma exchange treatment, the mortality and morbidity is great and our patients seem to respond promptly to plasma exchange. Our experience suggests that plasma exchange treatment is appropriate.
7. Patients with an additional or alternative diagnosis. We have developed the following sub-categories within this group of patients: (1) systemic infection, (2) systemic malignancy, (3) autoimmune disease, (4) malignant hypertension, (5) heparin-induced thrombocytopenia/thrombosis, and (7) multi-organ failure. These patients are usually acutely ill; their condition is often deteriorating; TTP-HUS is suggested as a possible and treatable diagnosis; and therefore plasma exchange treatment is initiated. In some patients, an additional disorder is apparent, such as an autoimmune disease. In other patients, an unsuspected alternative explanation is discovered and then plasma exchange therapy is stopped. This group of patients is distinct from our other patients because of their high mortality, consistent with the clinical setting in which these patients are diagnosed, and the rarity of relapses, which suggests that these patients do not have what we currently consider to be classical TTP-HUS. Only two of these 58 patients have relapsed, compared to 14/63 (22%) in our idiopathic category.
8. The distinction of TTP from HUS. Because of the description of a deficiency of the VWF-cleaving protease in patients described as having TTP, but not in patients described as having HUS, it is currently popular to describe TTP and HUS as distinct clinical syndromes. This has some precedent because in children the disease is distinct and epidemic, it is specifically termed HUS, and it is primarily manifested by acute renal failure following bloody diarrhea. In these children, hematologic recovery predictably occurs without plasma exchange. However among adults, our experience suggests that these disorders are clinically indistinguishable. Common dogma suggests that patients with HUS have more renal failure, fewer neurologic complications, less severe thrombocytopenia, and less severe hemolysis with less extreme elevation of serum LDH values. We addressed this issue by dividing our patients into three categories: (1) patients with acute renal failure, defined by an increase of serum creatinine of equal to or greater than 0.5 mg/ml/day for two consecutive days, or by a serum creatinine equal to or greater than 4.0 mg/dl plus dialysis; (2) patients with no renal failure, defined by all serum creatinine values <1.5 mg/dl; (3) the remaining patients were described as "intermediate". We documented that platelet counts were significantly higher at presentation in the patients with acute renal failure, but the range of all groups overlapped. There was no difference in hematocrit. LDH values were actually higher in patients with acute renal failure. The frequency of severe neurologic complications was also greater in patients with acute renal failure. Our interpretation is that patients with acute renal failure simply have more severe disease. Furthermore, the number of plasma exchange treatments required to achieve a hematologic remission is the same among all patients; there was no occurrence of resistance to plasma exchange. These data support the urgent initiation of plasma exchange treatment in all patients with clinically suspected TTP-HUS.

9. Long-term clinical outcomes. Major problems are chronic renal failure, which has occurred in 26/105 (25%) of our patients, and relapse of TTP-HUS. But beyond these overt adverse outcomes is the more subtle abnormality described frequently by our patients, that they have difficulty returning to their normal level of activity and recovering their previous level of energy. To document the existence and magnitude of these symptoms, we have developed a modification of a standard quality-of-life questionnaire. The etiology and clinical importance of these symptoms remain undefined.

This summary presents our current effort to better understand the cause, clinical course, and long-term outcomes of patients who have clinically suspected TTP-HUS.