Therapeutic plasma exchange for the treatment of thrombotic thrombocytopenic purpura: A retrospective multicenter study

Transfusion and Apheresis Science 36 (2007) 57–67 intl.elsevierhealth.com/journals/tras

Therapeutic plasma exchange for the treatment of thrombotic thrombocytopenic purpura: A retrospective multicenter study Fevzi Altuntas a,¤, Ismet Aydogdu b, Sibel Kabukcu c, Ismail Kocyigit a, Kerim CÂkÂm b, Ismail Sar a, M. Ali Erkut b, Bulent Eser a, Ahmet Ozturk d, Emin Kaya b, Mustafa Cetin a, Ali Keskin c, Ali Unal a a

Erciyes University, Faculty of Medicine, Department of Hematology and Hemapheresis Unit, 38039 Kayseri, Turkey b Ãnonu University, Faculty of Medicine, Department of Hematology and Hemapheresis Unit, Malatya, Turkey c Pamukkale University, Faculty of Medicine, Department of Hematology and Hemapheresis Unit, Denizli, Turkey d Erciyes University, Faculty of Medicine, Department of Statistics, Kayseri, Turkey Received 6 April 2006; accepted 30 May 2006

Abstract Background: Thrombotic thrombocytopenic purpura (TTP) is a rare disease that is fatal if it is not treated. Therapeutic plasma exchange (TPE) has resulted in excellent remission and survival rates in TTP patients. Material and methods: We describe our experience with 52 TTP patients treated with TPE during the past eight years (65% of the patients were females; patient median age D 34 years, range: 17–73). TPE was carried out 1–1.5 times plasma volume. Fresh frozen plasma (FFP) or cryosupernatant plasma (CSP) was used as the replacement Xuid. TPE was performed daily until normalization of serum LDH and recovery of the platelet count to >150 £ 109/dL; TPE was then slowly tapered. Clinical, laboratory data, the number of TPE, other given therapy modalities, treatment outcomes and survival rate were evaluated retrospectively. Results: Overall response (OR) and complete response (CR) rates were 77% and 60%, respectively. Response was excellent in 82.8% of the patients with primary TTP among whom 74.2% were CR. Additionally, there were statistical diVerences in terms of CR rate between patients with primary TTP and secondary TTP (74.2% vs. 29.4%; p D 0.005). OR and CR rates were 79% and 57.9% in patients on TPE alone and 75.8% and 60.6% in patients on TPE + prednisolone, respectively (p D 1 and p D 0.8). Additionally, there were no statistical diVerences in terms of OR and CR rates between patients on TPE with FFP and CSP (p D 0.25 and p D 0.16, respectively). The presence of fever and the number of TPE were statistically important factors inXuencing the probability of response in multivariate logistic regression analysis (p < 0.01 and p < 0.01, respectively). Additionally, in multivariate Cox’s regression analysis, the probability of survival was higher in patients who were responsive to treatment compared to patients who were unresponsive (p < 0.001). Conclusion: TPE is an eVective treatment for primary TTP; however, it may be used as adjunctive therapy for secondary TTP until it is under control. The addition of steroids to TPE had no advantage compared to TPE alone. CSP as replacement Xuid is not superior compared to FFP. Fever appears to be a bad prognostic indicator. Therefore, prolonged treatment with TPE may be needed in patients with fever. © 2006 Elsevier Ltd. All rights reserved. *

Corresponding author. Tel.: +90 352 437 49 37; fax: +90 352 437 93 48. E-mail address: [email protected] (F. Altuntas).

1473-0502/$ - see front matter © 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.transci.2006.05.014

58

F. Altuntas et al. / Transfusion and Apheresis Science 36 (2007) 57–67

Keywords: Therapeutic plasma exchange; Thrombotic thrombocytopenic purpura; Treatment; Outcome

1. Introduction Thrombotic thrombocytopenic purpura (TTP) is a rare, sometimes fatal disease typically characterized by a clinical pentad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA), neurological involvement, renal dysfunction and fever [1–3]. The triad of thrombocytopenia, schistocytosis, and elevated LDH levels is often suYcient to suggest the disorder [2]. Systemic microvascular aggregation of platelets has been implicated in the pathogenesis of the disease [4,5]. Recent studies have showed that vWF cleaving protease (vWF-CPase) activity is deWcient in patients with familial TTP and auto antibodies inhibiting vWF-CPase are present in patients with non-familial TTP [5–8]. Therefore, they act as a trigger for increased platelet aggregation [4,9]. TTP may be idiopathic, but it may also occur secondary to autoimmune diseases, pregnancy, bone marrow transplantation (BMT), malignancy, infection diseases and drugs [10–17]. Therapeutic plasma exchange (TPE) is the accepted method of treatment in patients with TTP [1,3,18–20]. Although TPE has increased the survival rate from 10% to greater than 90% [1,19–22], a subset of patients with resistant TTP still fails to respond to TPE or remains dependent on this procedure. Therefore, other treatment modalities including steroids, vincristine, cyclophosphamide, intravenous immunoglobulin (IVIG), rituximab, aspirin, dipyridamole and splenectomy have all been used to control the disease [3,23–30]. However, because of the rarity of randomized clinical trials, there is scant data regarding the eYcacy and safety of these agents. This retrospective study was performed as an analysis of our eight-year experience with TPE, other treatment modalities and treatment outcomes in adult patients with TTP. 2. Patients and methods This is a retrospective analysis of TTP requiring TPE in three University Hospitals between 1997 and 2005. The list of patients was obtained from the TPE log-book of the apheresis facility of our apheresis units. Laboratory and clinical data, such as initial presentation, concomitant diseases, drug intake,

treatment, i.e., therapeutic plasma exchange, plasma infusion, adjuvant and/or alternative agents, and outcome were also collected. The diagnosis of TTP was made when the patient presented with thrombocytopenia and MAHA with or without signs of renal dysfunction, neurological manifestation or fever. Thrombocytopenia was deWned as a platelet count below 150 £ 109/dL. MAHA was deWned by anemia, presence of red cell fragmentation on peripheral blood smear, reticulocytosis, high indirect bilirubin and lactate dehydrogenase (LDH) serum levels. Renal failure was deWned as serum creatinine (Cr) level >1.2 mg/dL, blood urea nitrogen (BUN) level >25 mg/dL, proteinuria and/or hematuria as deWned by the normal ranges of our laboratory. Fever was deWned as a body temperature above 38 °C. All patients underwent the following laboratory investigations prior to treatment; complete blood count, reticulocyte count, haptoglobin level, peripheral blood smear, direct antiglobulin test, biochemical tests such as serum alanine aminotransferase, aspartate aminotransferase, LDH, direct and indirect bilirubin, BUN, Cr, serological tests for hepatitis A, B and C virus, CMV, EBV, rubella, toxoplasma, brucella, tests for antinuclear antibodies, Anti-ds-DNA, RF and ANCA antibodies, coagulation studies for prothrombin time, activated partial thromboplastin time (APTT), Wbrinogen and d-dimer level, urine test, and blood and urine cultures and, if indicated, stool cultures. Laboratory tests were performed using standard laboratory procedures. The VWF-CPase activity was not carried out in our patients. TPE was immediately performed when clinical diagnosis of TTP was conWrmed by a hematologist. The TPE was carried out 1–1.5 times at the predicted plasma volume using Fresenius-AS 204 (Fresenius AG, Germany) and Fenwal CS 3000+ (Baxter, Healthcare, DeerWeld, IL, USA) apheresis devices. Plasma volumes were calculated for each patient using the patient’s body surface area (calculated using height and weight), sex, and hematocrit. Fresh frozen plasma (FFP) or cryosupernatant plasma (CSP) was used as the replacement product. During the treatment period, the patient’s progress was assessed based on clinical and laboratory parameters (hemoglobin (Hb), hematocrit, platelet count, LDH, peripheral blood smear for schistocytes, and

F. Altuntas et al. / Transfusion and Apheresis Science 36 (2007) 57–67

serum creatinine). TPE was performed daily until the disappearance of clinical symptoms, normalization of serum LDH and recovery of platelet counts to >150 £ 109/dL; treatment was then slowly tapered. Infusions of FFP were carried out for maintenance therapy until a response was maintained for at least 3 days. Platelet transfusions were not given if there was no severe bleeding, e.g. intracranial hemorrhage. Red cell transfusions were given for severe symptomatic anemia (Hb 6 8 g/dL). Complete response (CR) to treatment was deWned by a platelet count >150 £ 109/dL and normalization of LDH and the disappearance all clinical symptoms. Partial response (PR) was deWned as a platelet count >50 £ 109/dL or doubling of the initial platelet count and no new clinical events. Patients who maintained a CR for at least 2 weeks without treatment were considered to be in complete remission. Overall (OR) response was deWned as the total number of CR and PR. No response to treatment was considered in patients with no platelet response (platelet count <20 £ 109/dL) or the platelet increment was <100% or deterioration of the patient’s clinical status. Exacerbation is deWned as a drop in platelet count or an increase in LDH after initial improvement during the treatment period or within 2 weeks from the last TPE. Relapse is deWned as recurrence of any of the following after a complete remission: initial symptoms, MAHA, thrombocytopenia, deterioration of clinical status and laboratory values. 2.1. Statistics Data were expressed as the median, mean § SD or SE and the range. The Mann–Whitney U-test was used to compare quantitative variables such as age, number of TPE sessions, serum BUN, Cr, Hb and LDH level, duration of remission, follow-up time and time to CR. Kaplan–Meier survival curves were used to estimate cumulative frequency of an endpoint, and the log rank test was used to compare survival curves between groups. Pearson’s chisquared test and Fisher’s exact tests were used to determine the prognostic value of diVerent clinical and laboratory parameters on treatment outcomes. A univariate analysis with Cox’s regression was used to determine variables that had an eVect on survival. A multivariate analysis (Cox’s regression) was used to determine which variables had an independent eVect on survival. A univariate analysis with logistic regression was used to determine vari-

59

ables that had no eVect on response (CR + PR). A multivariate analysis with logistic regression was used to determine which variables had an independent eVect on response. Statistical signiWcance was set at P < 0.05. 3. Results 3.1. Clinical features Of the 52 TTP patients, 18 (35%) were men and 34 (65%) women. The median age was 34 (mean: 38.4 § 16.5, range: 17–73) years. All of the patients had anemia and thrombocytopenia upon presentation. Neurological manifestations were the chief presenting symptom in 34 (65.4%) of the patients, most frequently as headache, confusion, unusual behaviour, paresis, paresthesias, vertigo, ataxia, blurred vision, seizures and coma. Renal dysfunction was detected in 27 patients (52%). The most common Wnding of renal dysfunction was increased BUN level, serum Cr, microscopic hematuria and/or proteinuria. Three of 17 patients also required acute dialysis support. Fever was present in 16 of the 52 patients (30.8%) and the highest temperature at presentation was 38.9 °C (auxiliary measurement). The classical pentad picture was present only in 12 cases (23%). Twenty-nine (55.7%) of the patients had hemorrhagic manifestations including petechiae, purpura and/or echymoses, microscopic hematuria, epistaxis, vaginal bleeding, haemoptysis, gastrointestinal hemorrhage and intracranial bleeding. The clinical features and laboratory data at presentation are shown in Tables 1 and 2. 3.2. Patient characteristics In the study group, 35 patients (67.3%) presented with idiopathic TTP. Secondary reason and/or

Table 1 General patient characteristics and initial laboratory data Characteristics Median age (range) Female/male Mean hemoglobin level § SD (g/dL) Mean platelet count § SD (£109/L) Mean BUN level § SD (mg/dL) Mean creatinine level § SD (mg/dL) Mean LDH level § SD (U/L)

34 (17–73) 34/18 8.2 § 2.0 (4.6–12.8) 44.2 § 35.9 (4–137) 41.9 § 33.6 (7–188) 1.6 § 1.3 (0.5–6.2) 2727 § 1930 (834–11192)

Normal laboratory value for creatinine (0.8–1.2 mg/dL), BUN (2–25 mg/dL), LDH (<450 U/L).

60

F. Altuntas et al. / Transfusion and Apheresis Science 36 (2007) 57–67

Table 2 Presenting symptoms of patients Presenting symptoms

Number of cases (n D 52)

Anemia Thrombocytopenia Neurological involvement Renal dysfunction Fever Classical pentad

52 (100%) 52 (100%) 34 (65.4%) 27 (52%) 16 (30.8%) 12 (23%)

co-morbidities were identiWed in 17 (32.7%) of the patients: seven patients (13.5 %) were pregnant, four patients (7.7%) had malignancy two of whom were breast cancer, one was pancreatic carcinoma and one was non-Hodgkin lymphoma, three patients (5.7%) had systemic lupus erythematosus (SLE), two (3.8%) had undergone BMT for which they received conditioning regimens with busulfan and Xudarabine and were on cyclosporine-A (CsA) for prophylaxis of graft versus host disease (GVHD) and one patient (2%) had brucella infection. 3.3. Therapy characteristics All patients received TPE as initial therapy. Prednisolone together with TPE was administered in 33 patients (63.5%) at a standard dose of 1 mg/kg/day. FFP was used in 40 (76.9%) patients; the remaining 12 (23.1%) patients received CSP as a replacement product for TPE. In addition to TPE, in 15 patients a total of 18 other treatment modalities were used including the following: high dose methylprednisolone (1 g/day for 3 days, IV, and then 1 mg/kg/day); in three (16.6%) cases, vincristine (2 mg/weekly for 2 weeks, IV); in four (22.2%) patients, cyclophosphamide (single 1-g, IV bolus); in seven (38.9%) cases, intravenous immunoglobulin (IVIG) (1 g/kg/day for 3 days); in one (5.6%) patient; and, rituximab (375 mg/m2/week, 2 times) in one (5.5%) patient. In addition to these adjunctive therapies, one patient (5.6%) with brucellosis received TPE together with rifampicin (600 mg/day) and doxycycline (200 mg/ day) for 3 weeks. Splenectomy was also performed in one (5.6%) refractory patient to TPE and other treatment modalities. 3.4. Response to treatment The patients underwent a median of Wve (range D 1–45) sessions of TPE. In complete responders, the median number of exchanges was seven (range D 2–45).

Overall response to initial treatment was seen in 40/52 patients (OR rate D 77%): CR D 31 (60%), and PR D 9 (17%). No response to initial therapy was seen in 12 patients (23%). Median time to achieve a response was 10 days (range D 4–49 days); time to achieve CR was 10 days (range D 5–49 days). Overall responses to initial treatment were 75.8% (25/33) and 79% (15/19) in patients treated with TPE + prednisolone and TPE alone, respectively (p D 1). Although TPE + prednisolone resulted in a higher CR rate [60.6% (20/33) vs. 57.9% (11/19)] compared with TPE alone, the diVerence was not statistically signiWcant (p D 0.8). Median time to a CR was longer in patients on TPE + prednisolone compared to TPE alone, 11 days (range D 5–49 days) vs. 9 days (range D 7–12 days), respectively (p D 0.3). Overall responses to initial treatment were 91.6% (11/12) and 72.5% (29/40) in patients on TPE with FFP and CSP, respectively (p D 0.25). Although TPE with CSP resulted in a higher CR rate [83.3% (10/12) vs. 52.5% (21/40)] compared to TPE with FFP, the diVerence was not statistically signiWcant (p D 0.16). Median time to a CR was 11 days (range D 5–48) and 10 days (range D 5–49) in patients on TPE with CSP and FFP, respectively (p D 0.8) (Table 3). Although no statistical diVerences in terms of OR rate to initial treatment were noted between patients with primary and secondary TTP [82.8% (29/35) vs. 64.7% (11/17); p D 0.17], there were statistical diVerences in terms of CR rate to initial treatment between groups [74.2% (26/35) vs. 29.4% (5/17); p D 0.005]. Overall response and CR were achieved in 10 (55.5%) and six (33.3%) out of 18 other treatment modalities used with a median time to response of 11 days (range D 9–47) in 15 patients. Response rate to other treatment modalities are shown in Table 4. Six out of nine patients with primary TTP without a CR received other treatment modalities including high-dose methylprednisolone, vincristine, cyclophosphamide and rituximab; the remaining three patients passed away. Three (50%) out of six patients achieved a CR; two were on vincristine and one who also did not achieve CR with vincristine was on rituximab (n D 1) (Table 4). However, the remaining three patients remained unresponsive to other treatment modalities as well. These three unresponsive patients died. Nine out of 12 secondary patients received other treatment modalities including cyclophosphamide, IVIG, high-dose methylprednisolone, antibiotic and splenectomy; remaining two out of three patients

F. Altuntas et al. / Transfusion and Apheresis Science 36 (2007) 57–67

61

Table 3 Initial treatment regimens and replacement Xuids: comparison of treatment outcomes in TTP patients

Median time to CR daysa (range) OR, number of patientsa (%) CR, number of patientsa (%) Mortality ratea (%) Median no. TPE sessionsb (range) Median follow-up timeb months (range)

TPE + steroid (n D 33)

TPE alone (n D 19)

P

TPE with FFP (n D 40)

TPE with CSP (n D 12)

p

11 (5–49) 25 (75.8) 11 (60.6) 10 (33.6) 7 (1–45) 9 (3d–72m)

9 (7–12) 15 (79) 20 (57.9) 5 (26.3) 5 (1–11) 42 (3d–73m)

0.3 1 0.8 0.1 0.6 0.02

10 (5–49) 29 (72.5) 21 (52.5) 14 (35) 5 (1–45) 16 (3d–73m)

11 (5–48) 11 (91.6) 10 (83.3) 1 (8.3) 8 (1–45) 18 (3d–42m)

0.8 0.25 0.16 0.14 0.16 0.5

CR, complete response; OR, overall response; d, days; m, months; TPE, therapeutic plasma exchange; FFP, fresh frozen plasma; and CSP, cryosupernatant plasma. a Pearson’s chi-squared test was used. b Mann–Whitney U-test was used. Table 4 Other treatment regimens received by the patients

Vincristine (n D 4) Cyclophosphamide (n D 7)

IVIG (n D 1) High-dose methylprednisolone (n D 3)

Rituximab (n D 1) Splenectomy (n D 1) Antibiotic (n D 1)

Diagnosis

OR

CR

Primary (n D 4) SLE (n D 3) Malignancy (n D 3) Primary (n D 1) BMT Malignancy (n D 1) Primary (n D 1) SLE (n D 1) Primary (n D 1) Malignancy (n D 1) Brucella (n D 1)

4 (100%) 3 (42.8%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (33.3%) 1 (100%) 0 (0%) 1 (100%)

2 (50%) 2 (28.5%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (100%) 0 (0%) 1 (100%)

SLE, systemic lupus erythematosus; IVIG, intravenous immunoglobulin; BMT, bone marrow transplantation; OR, overall response; and CR, complete response. Table 5 Comparison of initial treatment outcomes in primary and secondary TTP patients Median time to CR, daysa (range) OR, number of patientsa (%) CR, number of patientsa (%) Mortality ratea (%) Median no. TPE sessionsb (range) Median follow-up timeb, months (range)

Primary TTP (n D 35)

Secondary TTP (n D 17)

p

11 (5–49) 29 (82.8%) 26 (74.2%) 8 (22.9%) 7 (1–45) 20 (3d–73m)

9 (7–17) 11 (64.7%) 5 (29.4%) 7 (41.2%) 5 (1–13) 10 (3d–49m)

0.45 0.17 0.005 0.3 0.52 0.36

OR, overall response; CR, complete response; d, days; and m, months. a Pearson’s chi-squared test was used. b Mann–Whitney U-test was used.

passed away (one with BMT was on steroids). Three (33.3%) out of nine patients achieved CR; two were on cyclophosphamide for SLE and one on antibiotic for brucellosis (Table 4). Of the other six patients, three remained PR and three were unresponsive to treatments. Five out of these seven patients who did not achieved a CR died. Characteristics of the patients with primary and secondary TTP are shown in Table 5. Five of seven pregnant women had CR with TPE alone. Two other pregnant patients died in the early

stages of TPE therapy, due to intracranial bleeding. None of six patients who presented with the TTP secondary to BMT and/or CsA and malignancy achieved CR with TPE + prednisolone or TPE alone as initial therapy. Also, these patients did not show a signiWcant response to other treatment modalities including cyclophosphamide, high dose methylprednisolone, IVIG and splenectomy. Only one of these patients is still alive with PR. Three patients with SLE achieved a PR with TPE + prednisolone. Although two patients had CR after cyclophospha-

62

F. Altuntas et al. / Transfusion and Apheresis Science 36 (2007) 57–67

mide, the third patient died in PR status due to sepsis after high dose methylprednisolone and cyclophosphamide. One patient with brucellosis had CR with TPE and antibiotic treatment.

1.0

0.8

In one of the primary TTP patient who had CR after daily TPE therapy for 12 days, exacerbation of the disease symptoms, increased LDH level and decreased platelet level occurred during FFP maintenance therapy, TPE was reintroduced twice a day and a CR was achieved following eight session of TPE. Three (8.1%) of 37 complete responders experienced a relapse. All three patients relapsed were primary TTP. One presented with a combination of thrombocytopenia, MAHA and renal failure within 39 months after discharge and achieved a CR after seven sessions of TPE + prednisolone. Other two patients presented with thrombocytopenia and MAHA within 12 and 34 months after discharge: One achieved a CR after 12 sessions of TPE + prednisolone; another achieved a CR after FFP infusion + prednisolone at another center. 3.6. Follow up characteristics The median follow-up period was 40 months (range: 3 days–73 months). Currently, 37/52 (71.1%) patients are still alive; 15/52 (28.8%) patients died. The causes of death were related to multiple factors: sepsis § disseminated intravascular coagulation (DIC) § multiple organ failure § GVHD § primary disease D 5, DIC D 1, hemorrhage D 2, cardiac reason D 3, sepsis D 2 and stroke D 1. There were no statistical diVerences in terms of mortality rate between patients with secondary and primary TTP [41.2% (7/17) vs. 22.9% (8/35); p D 0.3]. 3/7 (46.6%) with primary TTP and 4/7 with secondary TTP (two were pregnant and two had malignancy) passed away during the Wrst acute episode before completing the course of TPE. Four out of eight patients with primary TTP and 4/8 with secondary TTP (two received BMT, CsA and steroid, one had malignancy, one had SLE) passed away at 3 days–72 months after initial treatment. No statistical diVerences in terms of mortality rate were noted between patients on TPE alone and TPE + prednisolone [26.3% (5/19) vs. 30.3% (10/33), p D 0.1] and patients on TPE using replacement products of FFP and CSP [35% (14/40) vs. 8.3% (1/12); p D 0.14]. Although a 30-day mortality rate was

Cum Survival

3.5. Relapse and exacerbation

0.6

0.4

0.2

primary secondary 1.00-censored 2.00-censored

0.0

0.00

20.00

40.00 60.00 Time (months)

80.00

Fig. 1. OS in primary and secondary TTP (OS D overall survival).

13.4% (7/52), the overall mortality rate was 28.8%. Overall survival (OS) curve of patients is shown in Figs. 1, 2 and 3. The median estimated OS was 72 months (95% CI: 27.2–116.8). Although the mean estimated OS was higher in patients with primary TTP compared to secondary TTP, there were no statistical diVerences between groups [59.4 § 5.15 (95% CI: 49.3–69.6) vs. 29.5 § 5.6 (95% CI: 18.4–40.5), p D 0.07)]. Additionally, we could not demonstrate any association in terms of the mean estimated OS between patients on TPE and TPE + prednisolone [57.6 § 7.6 (95% CI: 42.7–72.6) vs. 48.5 § 6.9 (95% CI: 35.0–62.0), p D 0.35)]. Although the mean estimated OS was higher in patients receiving FFP as the replacement products, compared to CSP there were no statistical diVerences between these groups [50.6 § 5.5 (95% CI: 39.3–61.3) vs. 38.5 § 3.2 (95% CI: 31.9–45.0), p D 0.2)]. 3.7. Factors related to response and survival A univariate analyses with logistic regression were performed to evaluate whether there was any association between response and age, sex, type of TTP (primary and secondary), anemia, thrombocy-

F. Altuntas et al. / Transfusion and Apheresis Science 36 (2007) 57–67

PE

1.0

PE+steroid 1.00-censored 2.00-censored

Cum Survival

0.8

0.6

0.4

0.2

0.0 0.00

20.00

40.00

60.00

80.00

Time (month)

Fig. 2. OS in patients on TPE and TPE + prednisolone (OS D overall survival).

CSP

1.0

FFP .00-censored 1.00-censored

0.8

63

therapy (TPE alone or TPE + prednisolone), number of TPE, initial serum Cr, BUN, LDH, Hb level and platelet count. In multivariate analysis with logistic regression (backward stepwise procedure), there was nearly a 24.9-fold increased response probability in patients without fever compared to patients with fever [odds ratio (OR) 0.040, 95% CI: 0.004–0.367, p < 0.01]. As the number of TPE was increased, the response probability increased [OR 1.794, 95% CI: 1.158–2.778; p < 0.01]. None of the other parameters were associated with the probability of achieving response. A univariate analysis with Cox’s regression was used to determine whether there was any association between survival and age, sex, type of TTP, anemia, thrombocytopenia, neurological manifestations, renal dysfunction, fever, replacement products, therapy, number of TPE, initial serum Cr, BUN, LDH, Hb level, and platelet count. Fever, LDH level and response status [unresponsive and responsive (PR + CR)] were found to be associated with the probability of survival. However, in multivariate analysis with Cox’s regression, there was nearly a 32.3-fold increased probability of survival in patients who were responsive to treatment compared to patients who were unresponsive [hazard ratio 0.031, 95% CI: 0.007–0.141, p < 0.001]. None of other parameters had statistical signiWcance regarding the probability of survival in multivariate Cox’s regression analysis.

Cum Survival

4. Discussion 0.6

0.4

0.2

0.0 0.00

20.00

40.00

60.00

80.00

Time (month)

Fig. 3. OS in patients on TPE with CSP and FFP (OS D overall survival).

topenia, neurological manifestations, renal dysfunction, fever, replacement products (FFP and CSP),

TTP typically aVects women more than men, with a ratio of 2:1 [1,31–34]. The most commonly aVected individuals are between 20 and 60 years of age with a reported incidence of 3.7 cases per million adult [22,32,33]. In our study, 65% of the patients were females, with an age range of 17–73 years (median 34 years). It is reported that the most frequently observed abnormalities are MAHA (100%) and thrombocytopenia (100%), neurological manifestations (60–88%), renal dysfunction (18–76%) and fever (22–86%) [18–20,31–36]. The presence of the complete pentad only occurs in a few cases at presentation [15]. In our study, the classical pentad picture was present in only 23% of the cases. Additionally, all patients had anemia and thrombocytopenia on presentation. Neurological manifestations were the chief presenting symptom in 65.4% of the patients. Renal dysfunction was detected in 52% of the patients. Fever was present in 30.8% of the cases.

64

F. Altuntas et al. / Transfusion and Apheresis Science 36 (2007) 57–67

It is reported that an excess of unusually large von Willebrand factor (vWF) multimers have been linked to TTP [9,37]. Recent studies suggest that the presence of auto-antibodies against VWF-CPase may be responsible for the presence of these multimers in adult TTP patients [5,7,27]. Therefore, TPE is considered to be the therapy of choice in adult TTP patients. It removes antibodies against VWF-CPase and replaces fresh proteases. Response rates to TPE were 56–90% of acute TTP [15,19,20,31,34,38]. In the present study, OR rate to initial therapy was 77%, with a 60% rate of CR. Although there are no well-conducted randomized trials regarding the use of corticosteroids in TTP patients, corticosteroids are often used in combination with TPE as a frontline therapy [1,39,40]. Some studies report that TTP might be controlled with high dose corticosteroid therapy [29,41]. However, Gurkan E revealed that there was no overall beneWt in using high-dose corticosteroids in adjunct to TPE [42]. In our study, there was no advantage of TPE + prednisolone compared to TPE alone in terms of OR (75.8% vs. 79%; p D 1) and CR rates (60.6% vs. 57.9%; p D 0.8). Additionally, the median time to a CR was longer in patients on TPE + prednisolone compared with TPE alone (11 days vs. 9 days); however, there were no statistical diVerences between groups (p D 0.3). On the basis of the possible involvement of large VWF multimers in the pathogenesis of TTP [9,43], the use of CSP seems to be reasonable due to the fact that it is relatively deWcient of VWF multimers [44,45]. Some studies reported that TPE with CSP was eVective in unresponsive patients or who had incomplete response to TPE with FFP [44,46,47]. Other retrospective studies revealed that TPE with CSP showed an improved response rate and survival in newly diagnosed TTP patients [45,48]. However, North American TTP Group’s retrospective randomized study revealed that FFP and CSP are both acceptable replacement products in the treatment of TTP and provide similar results in the acute management of newly diagnosed primary TTP [49]. In the present study, OR rate was higher in patients on TPE with FFP compared to CSP (91.6% vs. 72.5%, respectively). However, there were no statistical diVerences between the two groups (p D 0.25). In contrast to OR, TPE with CSP resulted in a higher CR rate compared to TPE with FFP (83.3% vs. 52.5%). However, the diVerence was not statistically signiWcant (p D 0.16). Additionally, there were no

statistical diVerences between patients on TPE with CSP and FFP in terms of median time to a CR (11 days vs. 10 days; p D 0.8). Some patients do not respond well to TPE and will need alternative and/or adjunct therapy with steroids, vincristine, cyclophosphamide, rituximab or other medications that can suppress inhibitor production [25,27–29,50,51]. If all these treatments fail, then the removal of the spleen may be considered as a means to reach sustainable remission or to reduce/prevent future relapses [15,26,52]. Because TTP is a rare disorder, demonstration of the eYcacy of these alternate and/or adjunct therapies has been limited to small studies. Often, several treatment approaches may be required to treat unresponsive cases [15,53]. In this study, OR and CR rates 55.5% and 33.3%, respectively, were achieved with other treatment regimens. Complete response was achieved in 100% with rituximab, 50% with vincristine and 28.5% with cyclophosphamide. There was no response to high dose methylprednisolone, IVIG and splenectomy. Most TTPs are called primary TTP because no underlying cause is detected. However, when TTP is found in association with certain diseases like malignancy, chemotherapy, BMT, autoimmune disorders, pregnancy, drugs and infections, then it is called secondary TTP [10–18,54,55]. In the present study, secondary TTP is identiWed in 32.7% of the patients. The response to TPE in primary TTP is excellent. When TTP is secondary to some other underlying disorder, the responses may be minimal and unsustainable, especially if the causative ailment or agent cannot be eradicated. In our study, OR and CR rates to initial treatment were 64.7% and 29.4% in patients with secondary TTP, respectively. 29.4% of secondary TTP had CR to initial treatment and 33.3% (3/9) achieved CR with cyclophosphamide for SLE and antibiotic for brucellosis. None of the patients presented with TTP secondary to CsA, BMT and malignancy were assessed to have any signiWcant response. This is consistent with the experience of TPE in this group, where the utility of TPE is questionable [13,55,56]. TTP is rarely seen as complicating SLE [12,17]. There is scarce data regarding optimal treatment of TTP patients complicated with SLE [24,57,58]. In our patient population, we observed that all of the SLE patients were unresponsive to TPE + steroid. Complete response could be achieved after cyclophosphamide therapy. Our Wndings suggest that the earlier addition of immunosup-

F. Altuntas et al. / Transfusion and Apheresis Science 36 (2007) 57–67

pressive agents to TPE may improve treatment outcome in patients with SLE. TPE has reduced the overall mortality rate from 90% in untreated cases to less than 20% [1,18,19,25,38,59]. Although the 30-day mortality rate (13.4%) in the present study is comparable to that in the literature [21,45], the overall mortality of 28.8% in this study was relatively higher in comparison with others in the literature [1,18,19,31,32,38]. The relatively high overall mortality rate may be attributed to the increased number of secondary TTP patients, where the mortality rate was higher compared with primary TTP patients (41.2% vs. 22.9%; p D 0.3) and the CR rate was lower compared to primary TTP patients (74.2% vs. 29.4%; p D 0.005). Although, the mean estimated OS was higher in patients with primary TTP compared to secondary TTP, no statistical diVerences were noted between the groups (59.4 § 5.15 vs. 29.5 § 5.6; p D 0.07)). Additionally, we could not demonstrate any association, in terms of the estimated OS, between patients on TPE and TPE + prednisolone (p D 0.35) and on TPE + FFP and TPE + CSP (p D 0.2). However, there was nearly a 32.3-fold increased probability of survival in patients who were responsive to treatment compared to patients who were unresponsive (p < 0.001). Additionally, there was nearly a 24.9-fold increased response probability in patients with fever compared to patients without fever (p < 0.01). In the present study, as the number of TPE was increased, the response probability increased proportionately (p < 0.01). Therefore, TPE should be performed immediately after TTP diagnosis; it should then be more slowly tapered in TTP patients with fever compare to patients without fever. We conclude that TPE is extremely eVective for primary TTP. However, it may be used as an adjunctive therapy for secondary TTP, until the primary disorder is successfully controlled. The addition of steroids to TPE had no advantage in terms of response rate, time to response and survival compare to TPE alone. Additionally, CSP as a replacement product is not superior compared to FFP in terms of response rate, time to response and survival. However, the roles of steroids and CSP need to be further investigated by randomized prospective clinical trials conducted with a larger series of patients. Additionally, fever appears to be a poor prognostic indicator; further, prolonged

65

treatment with TPE may be needed in patients with fever. References [1] Bell WR, Braine HG, Ness PM, Kickler TS. Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. N Engl J Med 1991;325:398–403. [2] Moake JL. Thrombotic microangiopathies. N Engl J Med 2002;347:589–600. [3] Drew MJ. Therapeutic plasma exchange in hematologic diseases and dysproteinemias. In: McLeod BC, Price TH, Weinstein R, editors. Apheresis: principles and practice. 2nd ed. Bethasda, MD: AABB Press; 2003. p. 345–73. [4] Chow TW, Turner NA, Chintagumpala M, McPherson PD, Nolasco LH, Rice L, et al. Increased von Willebrand factor binding to platelets in single episode and recurrent types of thrombotic thrombocytopenic purpura. Am J Hematol 1998;57:293–302. [5] Tsai HM, Lian EC. Antibodies to von Willebrand factor – cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998;339:1585–94. [6] Furlan M, Robles R, Solenthaler M, Wassmer M, Sandoz P, Lammle B. DeWcient activity of von Willebrand factor-cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura. Blood 1997;89:3097–103. [7] Furlan M, Robles R, Galbusera M, Remuzzi G, Kyrle PA, Brenner B, et al. Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome. N Engl J Med 1998;339:1578–84. [8] Levy GG, Nichols WC, Lian EC, Foroud T, McClintick JN, McGee BM, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001;413:488–94. [9] Moake JL, Turner NA, Stathopulos NA, Nolasco L, Hellums JD. Involvement of large plasma von Willebrand factor (vWF) multimers and unusually large vWF forms derived from endothelial cells in shear stress-induced platelet aggregation. J Clin Invest 1986;78:1456–61. [10] Altuntas F, Eser B, Sar I, Yildiz O, Cetin M, Unal A. Severe thrombotic microangiopathy associated with brucellosis: successful treatment with plasmapheresis. Clin Appl Thromb Hemost 2005;11(1):105–8. [11] Bennett CL, Connors JM, Carwile JM, Moake JL, Bell WR, Tarantolo SR, et al. Thrombotic thrombocytopenic purpura associated with clopidogrel. New Engl J Med 2000;342:1773– 7. [12] Nesher G, Hanna VE, Moore TL, Hersh M, Osborn TG. Thrombotic microangiopathic hemolytic anemia in systemic lupus erythematosus. Semin Arthritis Rheum 1994;24:165–72. [13] Roy V, Rizvi MA, Vesely SK, George JN. Thrombotic thrombocytopenic purpura-like syndromes following bone marrow transplantation: an analysis of associated conditions and clinical outcomes. Bone Marrow Transplant 2001;27:641–6. [14] Shamseddine A, Chehal A, Usta I, Salem Z, El Saghir N, Taher A. Thrombotic thrombocytopenic purpura and pregnancy: report of 4 cases and literature review. J Clin Apher 2004;19:5–10.

66

F. Altuntas et al. / Transfusion and Apheresis Science 36 (2007) 57–67

[15] Thompson CE, Damon LE, Ries CA, Linker CS. Thrombotic microangiopathies in the 1980s: clinical features, response to treatment, and the impact of the human immunodeWciency virus epidemic. Blood 1992;80:1890–5. [16] Tsai HM, Rice L, Sarode R, Chow TW, Moake JL. Antibody inhibitors to von Willebrand factor metalloproteinase and increased von Willebrand factor-platelet binding inticlopidine-associated thrombotic thrombocytopenic purpura. Ann Int Med 2000;132:794–9. [17] Vaidya S, Abulezz S, Lipsmeyer E. Thrombotic thrombocytopenic purpura and systemic lupus erythematosus. Scand J Rheumatol 2001;30(5):308–10. [18] Lara PN, Coe TL, Zhou H, Fernando L, Holland PV, Wun T. Improved survival with plasma exchange in patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Am J Med 1999;107:573–9. [19] Rock GA, Shumak KH, Buskard NA, Blanchette VS, Kelton JG, Nair RC, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. N Engl J Med 1991;325:393–7. [20] Sarode R, Gottschall JL, Aster RH, McFarland JG. Thrombotic thrombocytopenic purpura: early and late responders. Am J Hematol 1997;54:102–7. [21] Hayward CP, Sutton DM, Carter Jr WH, Campbell ED, Scott JG, Francombe WH, et al. Treatment outcomes in patients with adult thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Arch Int Med 1994;154: 982–7. [22] Torok TJ, Holman RC, Chorba TL. Increasing mortality from thrombotic thrombocytopenic purpura in the United States: analysis of national mortality data ,1968–1991. Am J Hematol 1995;50:84–90. [23] Ahmad A, Aggarwal A, Sharma D, Dave HP, Kinsella V, Rick ME, et al. Rituximab for treatment of refractory/relapsing thrombotic thrombocytopenic purpura. Am J Hematol 2004;77(2):171–6. [24] Akaogi J, Akasaka N, Yamada H, Hama N, Satoh M, Nichols C, et al. Intravenous cyclophosphamide therapy in a case with refractory thrombotic microangiopathic hemolytic anemia and SLE. Clin Rheumatol 2004;23(6):541–3. [25] Allan DS, Kovacs MJ, Clark WF. Frequently relapsing thrombotic thrombocytopenic purpura treated with cytotoxic immunosuppressive therapy. Haematologica 2001;86(8):844–50. [26] Kappers-Klunne MC, Wijermans P, Fijnheer R, Croockewit AJ, van der Holt B, de Wolf JT, et al. Splenectomy for the treatment of thrombotic thrombocytopenic purpura. Br J Haematol 2005;130(5):768–76. [27] Bohm M, Betz C, Miesbach W, Krause M, von Auer C, Geiger H, et al. The course of ADAMTS-13 activity and inhibitor titre in the treatment of thrombotic thrombocytopenic purpura with plasma exchange and vincristine. Br J Haematol 2005;129(5):644–52. [28] Stein GY, Zeidman A, Fradin Z, Varon M, Cohen A, Mittelman M. Treatment of resistant thrombotic thrombocytopenic purpura with rituximab and cyclophosphamide. Int J Hematol 2004;80(1):94–6. [29] Toyoshige M, Zaitsu Y, Okafuji K, Inoue Y, Hiroshige Y, Matsumoto N, et al. Successful treatment of thrombotic thrombocytopenic purpura with high-dose corticosteroid. Am J Hematol 1992;41:69.

[30] Dervenoulas J, Tsirigotis P, Bollas G, Koumarianou AA, Pappa V, Mantzios G, et al. EYcacy of intravenous immunoglobulin in the treatment of thrombotic thrombocytopaenic purpura. A study of 44 cases. Acta Haematol 2001;105(4):204–8. [31] Dervenoulas J, Tsirigotis P, Bollas G, Pappa V, Xiros N, Economopoulos T, et al. Thrombotic thrombocytopenic purpura/haemolytic uremic syndrome (TTP/HUS): treatment outcome, relapses, prognostic factors. A single-center experience of 48 cases. Ann Hematol 2000;79:66–72. [32] Ramanan AS, Thirumala S, Chandrasekaran V. Thrombotic thrombocytopenic purpura: a single institution experience. J Clin Apher 1999;14:9–13. [33] Rock G, Kelton JG, Shumak KH, Buskard NA, Sutton DM, Benny WB. Laboratory abnormalities in thrombotic thrombocytopenic purpura. Br J Haematol 1998;103:1031–6. [34] Shamseddine A, Saliba T, Aoun E, Chahal A, El-Saghir N, Salem Z, et al. Thrombotic thrombocytopenic purpura: 24 years of experience at the American University of Beirut Medical Center. J Clin Apher 2004;19(3):119–24. [35] Gasparovic V, Radonic R, Mejic S, Pisl Z, Radman I. Possibilities and limits of treatment in patients with thrombotic thrombocytopenic purpura. Intensive Care Med 2000;26:1690–3. [36] RidolW RL, Bell WR. Thrombotic thrombocytopenic purpura. Report of 25 cases and review of the literature. Medicine 1981;60:413–28. [37] Moake JL, Rudy CK, Troll JH, Weinstein MJ, Colannino NM, Azocar J, et al. Unusually large plasma factor VIII: von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med 1982;307:1432–5. [38] Bandarenko N, Brecher ME. United States Thrombotic Thrombocytopenic Purpura Apheresis Study Group (US TTP ASG): multicenter survey and retrospective analysis of current eYcacy of therapeutic plasma exchange. J Clin Apher 1998;13(3):133–41. [39] De la Rubia J, Lopez A, Arriaga F, Cid AR, Vicente AI, Marty ML, et al. Response to plasma exchange and steroids as combined therapy for patients with thrombotic thrombocytopenic purpura. Acta Haematol 1999;102:12–6. [40] Yang CW, Chen YC, Dunn P, Chang MY, Fang JT, Huang CC. Thrombotic thrombocytopenic purpura: initial treatment with plasma exchange plus steroids and immunosuppressive agents for relapsing cases. Renal Fail 2003;25:21–30. [41] Ozsoylu S. High-dose intravenous methylprednisolone for thrombotic thrombocytopenic purpura. Acta Haematol 1990;84:110. [42] Gurkan E, Baslamisli F, Guvenc B, Kilic NB, Unsal C, Karakoc E. Thrombotic thrombocytopenic purpura in southern Turkey: a single-center experience of 29 cases. Clin Lab Haematol 2005;27(2):121–5. [43] Moake JL, McPherson PD. Abnormalities of von Willebrand factor multimers in thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome. Am J Med 1989;87:9–15. [44] Byrnes JJ, Moake JL, Klug P, Periman P. EVectivenss of the cryosupernatant fraction of plasma in the treatment of refractory thrombotic thrombocytopenic purpura. Am J Hematol 1990;34:169–74. [45] Rock G, Shumak KH, Sutton DM, Buskard NA, Nair RC. Cryosupernatant as replacement Xuid for plasma exchange

F. Altuntas et al. / Transfusion and Apheresis Science 36 (2007) 57–67

[46]

[47]

[48]

[49]

[50]

[51]

[52]

in thrombotic thrombocytopenic purpura. Br J Haematol 1996;94:383–6. Obrador GT, Zeigler ZR, Shadduck RK, Rosenfeld CS, Hanrahan JB. EVectiveness of cryosupernatant therapy in refractory and chronic relapsing thrombotic thrombocytopenic purpura. Am J Hematol 1993;42:217–20. Sgarabotto D, Vianello F, Scano F, Stefani PM, Sartori R, Girolami A. Clinical and laboratoristic remission after cryosupernatant plasma exchange in thrombotic thrombocytopenic purpura. Hematologica 1998;83:569–76. Owens MR, Sweeney JD, Tahhan RH, Fortkolt P. InXuence of type of exchange Xuid on survival in therapeutic apheresis for thrombotic thrombocytopenic purpura. J Clin Apher 1995;10:178–82. Zeigler ZR, Shadduck RK, Gryn JF, Rintels PB, George JN, Besa EC, et al. Cryoprecipitate poor plasma does not improve early response in primary adult thrombotic thrombocytopenic purpura. J Clin Apher 2001;16(1):19–22. Gutterman LA, Kloster B, Tsai HM. Rituximab therapy for refractory thrombotic thrombocytopenic purpura. Blood Cells Mol Dis 2002;28(3):385–91. Yomtovian R, Niklinski W, Silver B, Sarode R, Tsai HM. Rituximab for chronic recurring thrombotic thrombocytopenic purpura: a case report and review of the literature. Br J Haematol 2004;124(6):787–95. Aqui NA, Stein SH, Konkle BA, Abrams CS, Strobl FJ. Role of splenectomy in patients with refractory or relapsed thrombotic thrombocytopenic purpura. J Clin Apher 2003;18(2):51–4.

67

[53] George JN. How I treat patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Blood 2000;96:1223–9. [54] Mach-Pascual S, Samii K, Beris P. Microangiopathic hemolytic anemia complicating FK506 (tacrolimus) therapy. Am J Hematol 1996;52:310–2. [55] Moake JL, Byrnes JJ. Thrombotic microangiopathies associated with drugs and bone marrow transplantation. Hematol Oncol Clin North Am 1996;10:485–97. [56] Sarode R, McFarland JG, Flomenberg N, Casper JT, Cohen EP, Drobyski WR, et al. Therapeutic plasma exchange does not appear to be eVective in the management of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome following bone marrow transplantation. Bone Marrow Transplant 1995;16(2):271–5. [57] Perez-Sanchez I, Anguita J, Pintado T. Use of cyclophosphamide in the treatment of thrombotic thrombocytopenic purpura complicating systemic lupus erythematosus: report of two cases. Ann Hematol 1999;78(6):285–7. [58] Vasoo S, Thumboo J, Fong KY. Thrombotic thrombocytopenic purpura in systemic lupus erythematosus: disease activity and the use of cytotoxic drugs. Lupus 2002;11:443– 50. [59] Amorosi EL, Ultman JE. Thrombotic thrombocytopenic purpura: report of 16 cases and review of literature. Medicine 1966;45:139–59.