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Post-Transplant Complications

Thrombotic thrombocytopenic purpura-like syndromes following bone marrow transplantation: an analysis of associated conditions and clinical outcomes

Abstract

The diagnosis and treatment of thrombotic thrombocytopenic purpura (TTP) in patients following BMT are often uncertain and unsuccessful. To better understand the evaluation and management of these patients, we describe 17 patients treated with plasma exchange for a presumptive diagnosis of TTP following BMT during a 10 year period, 1989–1998. Because of the uncertainty of the diagnosis, these patients are described as having a ‘TTP-like syndrome’. All 17 patients had received an allogeneic BMT. Comparison with the other 245 patients who had an allogeneic BMT during the same period demonstrated that patients with a TTP-like syndrome more frequently had unrelated and/or HLA-mismatched donors, and had also experienced more serious complications: grade III–IV acute GVHD and systemic bacterial, fungal, and viral infections. Three months after the diagnosis of the TTP-like syndrome, only four of 17 patients (24%) were alive; currently only one patient survives. These data emphasize: (1) the diagnosis of TTP following BMT is uncertain because of the presence of multiple BMT-associated complications. (2) The outcome of patients with TTP-like syndromes following BMT is poor. (3) Urgent intervention with plasma exchange when TTP is suspected following BMT may not always be appropriate. Alternative explanations for the signs and symptoms should be considered and treated aggressively. Bone Marrow Transplantation (2001) 27, 641–646.

Main

The number of patients diagnosed and treated for TTP has increased seven-fold since effective therapy with plasma exchange became available over 20 years ago.1 The availability of effective therapy, which has decreased mortality from 90%2 to 10–22%,3 has created an urgency for diagnosis which has resulted in decreased stringency of diagnostic criteria. No longer is the originally proposed pentad of thrombocytopenia, anemia, neurologic and renal abnormalities, and fever2 required for the diagnosis. Currently the presence of thrombocytopenia and microangiopathic hemolytic anemia, without an alternative clinically apparent etiology, are considered sufficient to make a diagnosis of TTP and to begin plasma exchange treatment.456 Since these clinical features are common among critically ill patients, the initial diagnosis is often uncertain.6 In no group of patients is diagnostic uncertainty a greater problem than in patients following BMT. This uncertainty is emphasized by the extreme variation of both the reported incidence of TTP following BMT (2–76% following allogeneic BMT, 0–27% following autologous BMT) and its mortality (0–93%).7 Inconsistency of diagnosis and clinical outcome may be inevitable in these patients who have multiple, severe complications which share many clinical features with TTP.

To assess our evaluation and management of patients in whom TTP was clinically suspected following BMT, we reviewed our experience for the 10 years, 1989–1998. During this time, 17 patients were treated with plasma exchange for clinically suspected TTP following BMT; all had had an allogeneic BMT, similar to other case series.8 The pre-existing conditions, comorbidities, and outcomes of these 17 patients were compared to the 245 patients receiving allogeneic BMT during this 10-year period who were not treated with plasma exchange for clinically suspected TTP.

Because of the uncertainty of the diagnosis, the 17 patients are described as having a ‘TTP-like syndrome’. The data emphasize that many, if not all, of the clinical features of these 17 patients may have been caused by BMT-related complications other than TTP, suggesting caution in making the diagnosis and initiating treatment for TTP following BMT. The diagnostic term ‘TTP’ is used for simplicity and is not considered to be exclusive of the diagnosis of hemolytic-uremic syndrome (HUS). In our experience these two syndromes, TTP and HUS, are clinically equivalent except for the degree of renal failure.6

Patients and methods

Patients with TTP-like syndromes following BMT

During the study period, 1 January 1989 to 31 December 1998, 17 patients were treated by plasma exchange for clinically suspected TTP following BMT. Plasma exchange treatment was used as the case definition for patient selection because it demonstrated commitment to the diagnosis of TTP. The day of the initial plasma exchange was defined as the day of diagnosis. Three additional patients who were treated only with intermittent plasma infusions for TTP-like syndromes are included in the group of 245 BMT patients who were not diagnosed with TTP (see below).

Systemic bacterial, fungal, or viral infections were described as comorbidities using two different time periods: (1) To describe events immediately surrounding the time of diagnosis of TTP, infections were documented during the 14 days preceding or following diagnosis; (2) To compare the incidence of infectious complications with BMT patients who were not diagnosed with TTP, a different method was required since there was no specific day in the course of the control BMT patients comparable to the day of diagnosis of TTP. For this comparison, all infections that occurred on days 6–113 following BMT, which represented the range of days of diagnosis of TTP (days 20–99 post BMT) plus/minus 14 days, were documented in both groups. In all patients with systemic viral infections and most patients with systemic bacterial or fungal infections, the infection was documented by isolation of the pathogenic organism. Patients were also designated as having systemic bacterial or fungal infections if their physician initiated empiric systemic therapy.

Patients with allogeneic BMT who were not diagnosed with TTP

During this 10-year period, bone marrow or peripheral blood stem cell transplants were performed on 748 patients. All 17 patients in whom TTP was diagnosed had had allogeneic transplants. Therefore, only the 245 other patients receiving allogeneic transplants were analyzed in the control group. Data for these 245 patients were collected prospectively by the University of Oklahoma Health Sciences Center BMT program; some of these data were provided by the International Bone Marrow Transplant Registry, Milwaukee, Wisconsin.

GVHD prophylaxis

All patients received cyclosporine for GVHD prophylaxis following allogeneic BMT. Cyclosporine was begun 1 day before marrow infusion at 1.5 mg/kg twice daily and continued for 6–12 months in the absence of active GVHD with the dose adjusted to maintain blood levels of 200–400 ng/ml. Most patients also received methotrexate and some patients also received prednisone for GVHD prophylaxis. Treatment of grade II–IV acute GVHD generally consisted of methylprednisolone, 1 mg/kg twice daily for 7–14 days, then tapered over 6–8 weeks. Higher doses of methylprednisolone and antilymphocyte globulin were used to treat relapsed or refractory acute GVHD.

Statistical methods

Data analysis was performed using SAS system for Windows, version 6.12. Clinical parameters were statistically compared between the two groups using the independent t-test, the chi-square test, or Fisher's exact test.

Results

Clinical characteristics of patients with TTP-like syndromes following BMT

During a 10-year period, 1 January 1989 to 31 December 1998, 17 patients were diagnosed with a TTP-like syndrome following allogeneic BMT and treated with plasma exchange, 6.6% of all patients receiving allogeneic BMT during these 10 years. No patients were diagnosed following autologous marrow or peripheral blood stem cell transplants. The diagnosis was made between 20 and 99 days post transplant. All patients were thrombocytopenic and anemic with an increased serum LDH level, 14 (82%) had an elevated serum creatinine, 11 (65%) had neurologic abnormalities (Table 1). Fever was not a diagnostic consideration in these patients. The two principal features that triggered consideration of a TTP-like syndrome were acute neurologic events and microangiopathic hemolysis, the latter suspected because of an increased serum LDH (Figure 1) and fragmented red cells on the peripheral blood smear. Increased serum LDH and the presence of fragmented red cells have also been the principal criteria in other case series of BMT-TTP.7891011 The reticulocyte index and presence of nucleated red cells were not systematically evaluated as possible diagnostic parameters. They may be of less diagnostic value than in non-BMT patients because of the process of marrow engraftment and the frequent presence of systemic infection and acute renal failure.

Table 1  Clinical characteristics of 17 patients with TTP-like syndromes following allogeneic BMT
Figure 1
figure1

Serum lactate dehydrogenase (LDH) values (U/l) for the 17 TTP-like syndrome patients. Day 0 is the day of diagnosis of TTP, defined as the day of the first plasma exchange treatment. The upper limit of normal for LDH is 190 U/l. Data are recorded at weekly intervals, beginning 1 week before the diagnosis of TTP. The broken lines represent the three patients who responded to plasma exchange by achieving a normal LDH value during plasma exchange treatment.

In contrast to the typical urgency for diagnosis and treatment of TTP in previously healthy patients, the diagnosis was often considered for several days in these patients before plasma exchange was begun. No data are available for the number of patients in whom the diagnosis of TTP was considered but then dismissed before plasma exchange treatment was begun. Our impression is that this occurred more often than the more confident diagnosis in the 17 patients treated with plasma exchange. In three patients in whom a diagnosis of TTP was considered, only intermittent plasma infusions were given. These patients are included in our control group because there was no consensus or commitment to the diagnosis of TTP, as was demonstrated by the initiation of plasma exchange treatment in the 17 patients.

Three patients (18%) responded by achieving a normal serum LDH level during the course of plasma exchange treatment. These three patients all had seizures at presentation which also resolved with treatment. One of these patients is alive 42 months following the TTP-like syndrome with severe chronic GVHD; the other two died of chronic GVHD 36 and 45 months following the TTP-like syndrome. The surviving patient was diagnosed following the occurrence of a grand mal seizure during a scheduled outpatient clinic appointment 75 days after his BMT (Table 1). Patients received between two and 30 plasma exchange treatments. In the three responding patients, plasma exchange treatments were stopped when the response was achieved. In the other 14 patients, plasma exchange treatments were stopped for the following reasons: death, seven patients; no response, two; patient refusal, one; sepsis with hypotension, one; gastrointestinal bleeding, one; venous access failure, one; plasma transfusion reactions, one. Serum LDH levels also decreased in several other patients with plasma exchange, but did not become normal. Even though there may be many other reasons for an increased LDH level in these patients, the use of a normal value as the definition of response discriminated patients who survived 36 months or more from patients whose survival was only 10 months or less. Among the 14 patients who did not achieve a normal serum LDH value, one patient survived for 10 months following the diagnosis of the TTP-like syndrome; 13 died within 11 weeks; eight died within 3 weeks; three died within 5 days. Causes of death were: infection, seven patients (aspergillus, four; candida, two; Staphylococcus epidermidis 1); regimen-related toxicity, three (liver failure, interstitial pneumonitis, diffuse alveolar hemorrhage); intracranial hemorrhage, two; acute GVHD, one; chronic GVHD, three. In one patient (Table 1, patient 13), the cause of death was attributed to TTP at an autopsy limited to her brain, which revealed multiple arteriolar thrombotic infarcts. However she also had bacterial, fungal, and viral sepsis within 2 weeks of the time of diagnosis of the TTP-like syndrome. Autopsies were performed in four other patients (Table 1, patients 4, 8, 12, 14), confirming the suspected cause of death as infection in each patient.

In all patients, cyclosporine was stopped either on the day of diagnosis of the TTP-like syndrome or in the preceding several days when the diagnosis was being considered. Cyclosporine blood levels at the time of diagnosis averaged 272 ng/ml for the 17 patients. However the variation was large, reflecting six patients in whom cyclosporine had been discontinued when the diagnosis of TTP was considered who had blood levels of 100 ng/ml or less. Three patients had cyclosporine blood levels over 500 ng/ml (Table 1, patients 2, 14, 16), 554–597 ng/ml. In seven patients cyclosporine was restarted for GVHD exacerbation while plasma exchange treatments continued. One of these patients apparently responded to plasma exchange treatment (Table 1, patient 5); the other six patients died 5–297 days after diagnosis of the TTP-like syndrome (Table 1, patients 1, 3, 6, 7, 9, 11). In none of the seven patients was there evidence of exacerbation of TTP. The cause of death in the six patients who died was aspergillus sepsis (two), intracranial hemorrhage (two), diffuse alveolar hemorrhage (one), and chronic GVHD (one).

Sixteen of 17 patients were being treated with glucocorticoids for GVHD at the time of diagnosis of the TTP-like syndrome (mean dose, 108 mg/day, range 20–250 mg/day). High doses of glucocorticoid, such as prednisone, 200 mg/day,12 may be effective for TTP. However only one of our patients treated with 200–250 mg/day of methylprednisolone was among the three responders (Table 1, patient 5); the other three patients (patients 2, 3, 11) died 31–297 days after diagnosis of the TTP-like syndrome with intracranial hemorrhage, interstitial pneumonitis, and chronic GVHD. Twelve of the patients were being treated with amphotericin B at the time of diagnosis of the TTP-like syndrome; none were being treated with antithymocyte globulin.

Remarkable among these 17 patients was the presence of critical complications. Systemic bacterial, fungal, and/or viral infections were present in 12 patients within 2 weeks preceding or following the diagnosis of the TTP-like syndrome. Severe (grade III or IV) acute GVHD was present in eight patients. Only three patients did not have at least one of these complications, however these three patients all had systemic infections between days 6 and 113.

Seven of 17 patients were diagnosed in one of the 10 years of this study, 1995; 0–3 patients per year were diagnosed in the other 9 years. The total number of allogeneic BMT patients was 13–17 per year from 1989 to 1992, and 28–38 per year from 1993 to 1998. During this 10-year period, five attending physicians had approximately equal responsibility for the care of these patients; one physician made the diagnosis of a TTP-like syndrome in 11 of the 17 patients.

Comparison of BMT patients with and without the diagnosis of a TTP-like syndrome

Patients’ ages were the same in both groups (Table 2). However, there were more women among the patients with a TTP-like syndrome. Two factors which predict a more complicated course and decreased survival were more frequent among the patients diagnosed with a TTP-like syndrome: an unrelated donor and a mismatch at one or more of the HLA A, B, or DR loci between donor and recipient. Patients diagnosed with a TTP-like syndrome more often had more severe disease for which the transplant was performed, but the difference was not statistically significant. All patients were in remission from their hematologic disease when the TTP-like syndrome was diagnosed. Not only were the patients diagnosed with a TTP-like syndrome at greater risk for complications, severe complications actually occurred with increased frequency. The occurrence of systemic infections and grade III or IV acute GVHD was greater among these 17 patients. Consistent with the greater risk factors and more complications, the 180 day mortality was also greater for these patients. The conditioning regimen and occurrence of veno-occlusive disease of the liver were not different between the two groups.

Table 2  Clinical characteristics of BMT patients who were diagnosed with TTP-like syndrome compared to BMT patients not diagnosed with TTP

Discussion

The diagnosis of TTP is difficult because there are no defining clinical or pathologic abnormalities. It can only be made by the presence of the characteristic clinical features, thrombocytopenia and microangiopathic hemolytic anemia, without an alternative explanation.45613 In this discussion TTP is not considered to be clinically distinct from HUS, except for the degree of renal failure,6 the term TTP is used for simplicity. The diagnosis of TTP following BMT is especially difficult because most patients are thrombocytopenic and anemic and many patients have fragmented red cells, the hallmark of microangiopathic hemolysis.89 Renal and neurological abnormalities and fever are also among the cardinal features of TTP,2 but they are also commonly caused by many diverse etiologies in patients following BMT. Therefore it should be anticipated that the diagnosis of TTP, often initially uncertain in patients who have not had BMT,6 will be even less certain in patients following BMT. The uncertainty of the diagnosis is reflected by the extremely variable frequency reported for the occurrence and mortality of TTP following BMT.7 The diagnosis of TTP relies on the clinical suspicion of the attending physician, and the variability of this factor is documented by the observation that the diagnosis was made by one of our five attending physicians in 11 of 17 patients. The uneven occurrence during the 10 years of this case series further emphasizes the subjectivity of the diagnosis of TTP following BMT. Since it is uncertain if these patients would be considered to have TTP by other hematologists, we describe them as having a ‘TTP-like syndrome’.

Patients with TTP-like syndromes had high-risk transplant procedures for severe disease, placing them at greater risk for serious complications, similar to previous reports.7 Furthermore, at the time of diagnosis of the TTP-like syndrome, they actually experienced a greater frequency of transplant-related complications, severe acute GVHD and systemic infections, also similar to previous reports.78 These data suggest that acute GVHD78 or infections complications714 could have been the actual etiology for the signs and symptoms, which were interpreted as diagnostic for TTP. However patients with TTP-like syndromes were not older than other BMT patients, as may have been expected among patients with more complications. The preponderance of women among the patients with TTP-like syndromes is similar to the greater frequency of women in case series of TTP in non-BMT patients.245 However other case series of patients with TTP-like syndromes following BMT have reported a preponderance of men.8

The pathogenesis of TTP is currently thought to involve diffuse endothelial damage, caused by a plasma factor resulting in endothelial cell apoptosis,1516 and deficiency of a plasma enzyme that cleaves von Willebrand factor (VWF), increasing the size of circulating VWF multimers.1718 Plasma activity of the VWF-cleaving protease has been reported to be normal in patients who were diagnosed with TTP following BMT.19 However, the diagnostic criteria for TTP described in that case series could also have encompassed disorders other than TTP.19 Even if absent, VWF-cleaving protease activity and unusually large VWF multimers were demonstrated in patients following BMT, the diagnosis of TTP would still be uncertain since these abnormalities may be common among patients with disseminated malignancy who do not have clinical features of TTP.20 Other disorders complicating BMT, such as acute GVHD and sepsis, may be associated with diffuse endothelial damage and disseminated microthrombi,71421 therefore the clinical features may resemble TTP. Intensity of GVHD prophylactic treatment has also been associated with TTP-like syndromes, but this may merely have reflected the increased diagnosis of TTP-like syndromes in patients with unrelated donors.22 Although cyclosporine prophylaxis was discontinued in all of our patients when the diagnosis of TTP was made, it was restarted for signs of GVHD exacerbation in seven. In none of these seven patients was there any evidence for TTP exacerbation and TTP was not the cause of death in any of these patients. The difficulty of diagnosis of TTP is not unique to patients who have had BMT. Among non-BMT patients, there are also patients diagnosed with TTP who have additional or alternative disorders which could cause their signs and symptoms.6 These patients have a very high mortality, similar to patients with TTP-like syndromes following BMT.

Although plasma exchange represents potentially curative treatment, creating a sense of urgency to initiate treatment, it also has a high risk of serious complications.23 In patients following BMT, the decision to initiate plasma exchange is more difficult than in non-BMT patients because (1) the diagnosis of TTP is even less certain; (2) the vulnerability for plasma exchange complications may be greater; and (3) the response to treatment is less.891024 Therefore a more cautious approach to this decision may be appropriate.

Although some have concluded that TTP is an under-recognised complication of BMT,7 the risk for over-diagnosis must be considered. Whether TTP is a distinct complication of BMT requiring specific treatment, or whether the clinical features suggesting the diagnosis of TTP after BMT are merely manifestations of multiple transplant-related complications,21 is uncertain in most patients. Therefore patients in published case series of TTP or thrombotic microangiopathy following BMT must be accurately described to allow objective assessment of their clinical features.

The data from our case series demonstrate that most patients in whom TTP is suspected following BMT have systemic infections and/or severe, acute GVHD. In these patients, no diagnostic criteria can distinguish TTP from these BMT-related complications. Rather than considering therapeutic options for TTP other than plasma exchange, it may be more appropriate to consider more intensive, perhaps empirical treatment of sepsis and/or GVHD before initiating plasma exchange. However in a patient with the acute onset of clinical features of TTP without a clinically apparent cause, plasma exchange may be appropriate and effective.25

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Acknowledgements

This work was supported by the Hemostasis Research Fund of the University of Oklahoma Health Sciences Center. We thank Dr Georgia Vogelsang for continuing critical advice.

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Roy, V., Rizvi, M., Vesely, S. et al. Thrombotic thrombocytopenic purpura-like syndromes following bone marrow transplantation: an analysis of associated conditions and clinical outcomes. Bone Marrow Transplant 27, 641–646 (2001). https://doi.org/10.1038/sj.bmt.1702849

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Keywords

  • thrombotic thrombocytopenic purpura
  • hemolytic uremic syndrome
  • plasmapheresis

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