Abbreviations used in this article: HD-PI, high-dose plasma infusion, HIV, human immunodeficiency virus, HUS, hemolytic-uremic syndrome, IVIG, intravenous immunoglobulins, LDH, lactate dehydrogenase, RBC, red blood cells, TPE, therapeutic plasma exchange, TTP, thrombotic thrombocytopenic purpura, vWF, von Willebrand factor
Thrombotic thrombocytopenic purpura (TTP) and adult hemolytic uremic syndrome (HUS) are uncommon diseases with a high spontaneous mortality rate. Symptoms are characterized by microangiopathic hemolytic anemia with fragmented red cells (schistocytes), and peripheral thrombocytopenia. In TTP, typical clinical pathologic features include fever and neurologic manifestations, whereas in HUS acute renal failure is the prominent abnormality (22). However, it is widely assumed that these 2 entities are similar and difficult to distinguish, and consequently the term TTP/HUS is commonly used to define them (11,28).
The implication of von Willebrand factor (vWF) in the pathogenesis of TTP/HUS has been recognized for many years (16,17). Indeed, there is a body of evidence suggesting that TTP/HUS is triggered by various conditions that may induce endothelial cell injury and the subsequent release of high-molecular weight vWF polymers into the plasma (17,32,33). In 1998, Furlan and colleagues (9) and Tsaï and coworkers (29) found that in TTP, high-molecular weight vWF polymers were associated with a deficiency in vWF-cleaving protease activity. This deficiency may be congenital and related to mutations of the protease gene (13), or acquired and due to a plasma IgG inhibitor (9,29). Within the context of endothelial cell injury, this deficiency may favor the accumulation of large amounts of high-molecular weight vWF polymers, which may lead to platelet activation and aggregation. These findings also account for the efficiency of plasma manipulation in the treatment of TTP, which may be related to plasma intrinsic vWF-cleaving protease activity.
TTP/HUS represents a medical emergency, the prognosis of which has been outstandingly improved by the administration of large volumes of plasma, either associated with plasmapheresis or not. The efficacy of other agents, such as steroids and antiplatelet agents, has not been validated in randomized studies and remains widely debated (11). Indeed, their use is empirical and depends on the clinician’s experience (24,25,27,28). Large volumes of plasma are required for the management of TTP/HUS, and therapeutic plasma exchanges are usually recommended to avoid fluid overload (24,25). However, when compared with high-dose plasma infusion, therapeutic plasma exchange is a cumbersome (8) and invasive (23) procedure that may not be available easily, especially in emergency settings. Few studies have attempted to compare these 2 therapeutic modalities (18,24). The authors of a large prospective study (24) reported therapeutic plasma exchange to be superior to plasma infusion. In this study, however, the volumes of plasma administered in the plasma infusion group were low compared with those of the therapeutic plasma exchange group (15 versus 45 mL/kg per day, respectively), and therefore the clear effectiveness of high-dose plasma infusion could not be tested. Here, we report our 13-year experience in managing patients with TTP/HUS with high-dose plasma infusion and therapeutic plasma exchange. In this retrospective analysis, we compared the relative efficacy of high-dose plasma infusion (25–30 mL/kg per day) and therapeutic plasma exchange to assess if high-dose plasma infusion could be used as an efficient and safe first-line therapy for TTP/HUS in emergency settings.
Patients and Methods
All adult (>18 yr) patients admitted to Hôpital Saint-Louis (Paris, France) from 1989 to 2001 for TTP/HUS were retrospectively included. Specific eligibility criteria were the presence of acute thrombocytopenia (defined as a platelet count <100 × 109/L), microangiopathic hemolytic anemia (as indicated by the presence of schistocytes and a negative Coomb test), and no identifiable cause for the thrombocytopenia and microangiopathic hemolytic anemia: eclampsia, disseminated intravascular coagulation (normal plasma fibrinogen), valvular and/or vascular prosthesis, or disseminated carcinoma. Patients with TTP/HUS whose outcome directly depended on underlying diseases with poor prognosis, and usually nonresponsive to conventional treatment (bone marrow or peripheral hematopoietic stem cell transplantation, metastatic carcinoma, CDC stage C human immunodeficiency virus [HIV] disease) were excluded. Physical examination and routine laboratory tests (hemoglobin, hematocrit value, platelets, serum lactate dehydrogenase [LDH], urea, and creatinine clearance) were evaluated daily in all patients from admission. Schistocytes were investigated every day for the first week and then 3 times weekly.
Patients were managed nonrandomly by 2 different groups of physicians. According to the experience of each of the 2 groups, patients were preferentially treated with high-dose plasma infusion (HD-PI, Group 1) or therapeutic plasma exchange (TPE, Group 2), independent of the initial clinical symptoms or biologic disturbances.
Treatment with high-dose plasma infusion consisted of daily infusions of large volumes (25–30 mL/kg) of solvent/detergent-treated plasma (Etablissement de Transfusion Sanguine d’Aquitaine) (21), in 4 fractionated doses until complete remission, as defined below. After 2 consecutive days of complete remission, a gradual stepwise reduction was begun until plasma administration was stopped. Patients were switched to therapeutic plasma exchange if complete remission could not be reached, or if patients experienced fluid overload.
Apheresis was performed with a COBE Spectra (Gambro BCT, Lakewood, CO). Fluid replacement consisted of daily 30 mL/kg solvent/detergent-treated plasma infusion associated with 15 mL/kg 4% albumin and 15 mL/kg hydroxyethylamidon (Elohès 4%, Laboratoire Fresenius, Louvier, France) until complete remission. Therapeutic plasma exchange procedures were then progressively tapered and stopped.
Steroids and acetylsalicylate were administered to both treatment groups. Methylprednisolone was given 1 mg/kg per day intravenously in patients who had no evidence of infection until complete remission or for a maximum duration of 3 weeks, and then was decreased and stopped. Acetylsalicylate 300 mg was administered orally and daily until complete remission. Patients with refractory TTP/HUS (defined below) received intravenous immunoglobulins (IVIG) (0.5 g/kg per day, 5 days) associated with immunosuppressive drugs, such as vincristine (1.5 mg weekly, 3 pulses) and/or cyclophosphamide (800 mg monthly, 6 pulses).
Hemoglobin levels of >8 g/dL were maintained with red blood cells (RBC) infusion. Platelet transfusions were not encouraged because they are likely to worsen TTP/HUS, with exceptions for patients who required an invasive procedure or experienced a life-threatening hemorrhage.
Complete remission was defined as total reversal of clinical manifestations and thrombocytopenia. Relapse was defined as the reappearance of clinical disturbances and/or thrombocytopenia after 7 consecutive days of complete remission. Patients with platelet counts below 20 × 109/L after 3 days of therapeutic plasma exchange were considered as having refractory TTP/HUS. Exacerbation was defined as a worsening of clinical symptoms and/or laboratory values during treatment or during the 7 consecutive days following complete remission. Endpoints for comparison between the 2 groups were the duration of platelet counts below 150 × 109/L and LDH levels over 190 U/L; the daily volumes of plasma administered and the duration of treatment before withdrawal of plasma dose; complete remission, relapse, and mortality rates; and therapy-related complications.
Data were expressed as median and range. Statistical analyses were performed using the Student t-test. A chi-square test was performed to compare complete remission, mortality, and complications between the 2 groups. Median time to platelet count and LDH level recovery was calculated from the data on admission, using the Kaplan-Meier method (12). Tests of difference between populations were made using Log-rank or Mantel-Haenszel tests (14). Characteristics of patients on admission (that is, fever, renal and/or neurologic involvement, platelet count, and LDH level) were associated with complete remission rate and mortality using univariate analysis. Statistical significance was set at p < 0.05.
Clinical and laboratory data (
Sixty-six adult patients fulfilling the diagnosis criteria for TTP/HUS were referred to our institution over a 13-year period. Twenty-nine patients were excluded because TTP/HUS was associated with bone marrow or peripheral hematopoietic stem cell transplantation (8 patients), CDC stage C HIV disease (13 patients), and metastatic cancer (8 patients). Thirty-seven patients were therefore retrospectively included in the study.
Twenty-five patients were women and 12 were men, with a median age of 39 years (range, 19–71 yr). Associated medical conditions were identified in 19 patients: microbiologically documented infections (14 patients), systemic lupus erythematosus (5 patients), postpartum (1 patient), and drug intake (3 patients). In 3 patients, 2 or 3 medical conditions were associated. Fourteen patients presented with temperatures over 38 °C. Fluctuating neurologic abnormalities were present in 31 patients on admission, ranging from headache (13/31) to seizure (5/31), including confusion (9/31) and focal deficiency (7/31). Twenty-seven patients had acute renal involvement. Five patients had only proteinuria. Serum urea and creatinine clearance on admission, as well as hemoglobin, platelets, and LDH level, did not significantly differ between the 2 groups (see Table 1).
High-dose plasma infusion group (Group 1) (
Tables 2 and 3)
Nineteen patients were initially treated with high-dose plasma infusion alone. Median daily plasma dose was 27.5 mL/kg (range, 15–37 mL/kg). Eight of these patients were switched to therapeutic plasma exchange within a median of 10.5 days (range, 4–26 d), for persistent moderate thrombocytopenia (Patient 60), unresponsiveness to high-dose plasma infusion treatment (Patient 58), fluid overload that occurred during full-dose plasma treatment (Patients 11, 36, 55, 62) or while plasma dose was tapered (Patients 53 and 66). These patients subsequently had a median number of 6 therapeutic plasma exchanges (range, 2–24 exchanges), with a median plasma dose of 38.7 mL/kg (range, 25–60 mL/kg) per procedure. Median duration of total high-dose plasma treatment in the HD-PI group (including possible therapeutic plasma exchange procedures) was 12 days (range, 1–36 d). Thirteen patients received steroids; 13 patients took acetylsalicylate, and 6 patients were treated with antibiotics. RBC and platelets were transfused in 11 patients and 1 patient, respectively.
Sixteen patients reached complete remission. Median time to platelet count and LDH level recovery was 8 days (range, 1–27 d) and 14 days (range, 1–62 d), respectively (Figure 1). Of the 8 patients who were switched to therapeutic plasma exchange, 7 had improved (Patients 11, 36, 55, 60, 62) or even recovered (Patients 53 and 66) platelet count with only plasma infusion.
Four patients died 1–27 days (median, 7d) after start of therapy. They had a median daily plasma dose of 30 mL/kg (range, 15–37 mL/kg). In 2 patients (Patients 27, 31), death was caused by multiorgan failure related to TTP/HUS. In Patient 58, high-dose plasma infusion was ineffective, and therapeutic plasma exchanges were performed from day 3. However, the patient remained thrombocytopenic despite 4 therapeutic plasma exchange sessions and 1 pulse of vincristine, and died of a cerebromeningeal hemorrhage on day 8 in the context of refractory TTP/HUS. Patient 53 died of a gastrointestinal hemorrhage when TTP/HUS had been in complete remission for 3 weeks.
Eight patients experienced an episode of fluid overload. All patients were treated successfully with loop-acting diuretics associated with therapeutic plasma exchange (Patients 11, 36, 53, 55, 62, 66) or not (Patients 15, 64). In 5 patients (Patients 11, 15, 63, 64, 65), proteinuria (median, 8.85 g/24 h; range, 4.6–35 g/24 h) occurred during high-dose plasma infusion treatment. Two of these patients (Patients 15, 64) had mild proteinuria and acute renal failure before treatment. However, while clinical and laboratory values (including renal function) improved with plasma, proteinuria increased from 3.6 to 18.4 g daily (Patient 15), and from 4 to 12 g daily (Patient 64). In all patients, this urinary protein loss was glomerular and tubular. It was transient, and resolved completely in all patients when high-dose plasma infusion dose was tapered. Remarkably, in Patient 11, proteinuria rapidly decreased after she was switched to therapeutic plasma exchange for fluid overload. None of these patients experienced chronic renal failure, and therefore renal histopathologic examination was not performed.
Two patients (Patients 60, 62) developed chronic renal failure related to TTP/HUS, requiring chronic dialysis.
Three patients (Patients 11, 60, 65) experienced a first relapse 13 days–25 months (median, 9 mo) following complete remission. Relapse was treated with high-dose plasma infusion and steroids (Patients 11, 65), or therapeutic plasma exchange (Patient 60). In Patient 11, relapse was related to pregnancy, and treatment also consisted of child extraction. All patients reached complete remission. However, all 3 experienced a second relapse within a median of 20 months (range, 16 mo-4 yr) after first complete remission, which was successfully treated with therapeutic plasma exchange in association with vincristine (Patient 60) and steroids (Patient 11), or with high-dose plasma infusion and steroids (Patient 65) (Figure 2). Plasma vWF-cleaving protease activity was investigated in all 3 patients and was found to be normal (Patient 60) or persistently undetectable (Patients 11, 65), both on admission and during complete remission. In Patient 11, plasma inhibitor was consistently undetectable. It is noteworthy that in Patient 65, vWF-cleaving protease deficiency was systematically associated with a persistent low-titer plasma inhibitor that was detected during the acute episode of TTP/HUS, but also during complete remission (data not shown). The median follow-up was 39 months (range, 8–149 mo).
Therapeutic plasma exchange group (Group 2) (
Tables 4 and 5)
Eighteen patients were initially managed with therapeutic plasma exchange. Median daily plasma dose was 32 mL/kg (range, 17.6–50.0 mL/kg), over a median period of 7 days (range, 2–50 d). Nine patients received steroids, acetylsalicylate was given to 15 patients, and 7 patients also were treated with antibiotics. Fifteen patients required RBC transfusion. Two patients received platelets for a surgical procedure in emergency, that is, a necrotizing cholecystitis (Patient 24) and a splenectomy in the context of severe thrombocytopenia (Patient 59). Both had a favorable postoperative outcome, with no bleeding complications and no worsening of TTP/HUS (3). Although this procedure was discouraged except in the case of life-threatening hemorrhage or invasive procedures, 5 other patients (Patients 1, 3, 5, 9, 54) received platelet transfusions, with no apparent side effects.
Sixteen patients reached complete remission (see Table 5). Median time to platelet count and LDH level recovery was 12 (range, 2–162 d) and 17 (range, 0–73 d) days, respectively (see Figure 1). In Patient 59, therapeutic plasma exchange and steroids were ineffective, and IVIG and vincristine were added, with no efficacy. A splenectomy permitted a transient improvement of platelet count and LDH level. The patient was subsequently treated with 6 pulses of cyclophosphamide, leading to complete and lasting remission. Two patients (Patients 48, 50) experienced an exacerbation of the disease at day 5 and day 7, respectively. Patient 48 was treated effectively with 12 therapeutic plasma exchanges and 3 pulses of vincristine, whereas Patient 50 died before therapy could be undertaken.
Three patients died within a median of 16 days (range, 4–19 d). Two patients (Patients 1, 43) died of multiorgan failure related to refractory TTP/HUS. Vincristine was administered to Patient 1, with no improvement. Median daily plasma dose was 28.6 mL/kg (range, 17.8–39.4 mL/kg). Patient 50 achieved complete remission at day 11, but experienced a fatal exacerbation of the disease 5 days later.
One patient (Patient 20) experienced an allergy related to hydroxyethylamidon with favorable outcome after symptomatic measures. One patient (Patient 24) had an episode of collapse that required macromolecules during a therapeutic plasma exchange procedure. The central venous catheter had to be removed in 2 patients because of thrombosis (Patient 24) or infection (Patients 24, 59).
Three patients (Patients 3, 37, 54) relapsed within a median of 14 days (range, 11–18 d). They all achieved complete remission with therapeutic plasma exchange, associated with 1 pulse of vincristine (Patient 3) or not (Patient 54), or with only steroids (Patient 37). The median follow-up was 83 months (range, 29–152 mo).
Comparison of the 2 groups and prognostic factors (
Median duration of high-dose plasma treatment was comparable in the 2 groups (p = 0.74). Daily plasma dose was slightly higher in the TPE group than in the HD-PI group (p < 0.02). The difference in time to platelet count and LDH level recovery was not statistically significant between the 2 groups (p = 0.2 and 0.49, respectively). Moreover complete remission, mortality, and relapse rates did not significantly differ (p = 0.95, 0.94, and 0.71, respectively), and in both groups, death occurred within the first 30 days. However, the incidence of complications related to treatment was higher in the HD-PI group (fluid overload: 8 cases, overload proteinuria: 5 cases) than in the TPE group (catheter infection: 2 cases, catheter thrombosis, collapse during therapeutic plasma exchange, hydroxyethylamidon allergy: 1 case each) (13 episodes of complication versus 5, respectively, p = 0.03).
No characteristic at the time of admission (that is, associated diseases, neurologic involvement, acute renal failure, fever, platelet count, and LDH level) could be associated with complete remission rate or mortality. Particularly, platelet count and LDH level on admission were not statistically different between survivors (13 × 109/L [range, 2–94], and 1,189 U/L [range, 284–4,700], respectively), and nonsurvivors (24.5 × 109/L [range, 9–73], and 694 U/L [range, 51–1,590], p = 0.79 and 0.13, respectively).
TTP/HUS is a severe life-threatening systemic disorder requiring prompt treatment. High-dose plasma therapy has improved the prognosis dramatically, permitting complete remission in 70%-80% of cases (1,18,24). Since it allows the infusion of larger volumes of plasma, therapeutic plasma exchange has been reported to be the treatment of choice, compared with plasma infusion alone, in a comparative trial (24). It also has been suggested that therapeutic plasma exchange may remove toxic factors from plasma and restore normal plasma viscosity (25). However, therapeutic plasma exchange imposes a heavy demand on available resources (6,8), which may be difficult to obtain, especially in an emergency. Furthermore, the efficiency of plasma infusion alone has been largely reported, especially when large volumes of plasma are delivered (2,18,26). Indeed, high-dose plasma infusion represents an interesting alternative therapy for TTP/HUS in emergency settings.
We herein report 1 of the largest retrospective studies comparing plasma infusion and therapeutic plasma exchange in adult patients with TTP/HUS. In this singlecenter study, 37 adult patients were treated initially with high-dose plasma infusion (19/37 patients) or with therapeutic plasma exchange (18/37 patients), according to the experience of 2 different groups of physicians, regardless of the initial clinical or laboratory manifestations of the patients. This approach was influenced at least in part by the fact that in previous studies (5,19,24), clinical and standard biologic parameters on admission were reported to have a poor prognostic value, particularly in terms of response to treatment. Despite the retrospective nature of our study and the fact that therapeutic decisions were not randomized, neurologic involvement was represented equally in both groups, including the more severe variants, and laboratory values on admission were comparable in the 2 groups. Importantly, patients with TTP/HUS associated with bone marrow or hematopoietic stem cell transplantation, metastatic cancer, or CDC stage C HIV disease were excluded because the disease course was determined by the primary underlying disease, regardless of initial treatment.
In both groups, patients received large volumes of plasma daily, with similar treatment duration. We found that complete remission and mortality rates in the HD-PI group were comparable to those of the TPE group. Moreover, median time to platelet count and LDH level recovery did not differ significantly between the 2 groups. We note that 7 patients in the HD-PI group had to be switched to therapeutic plasma exchange for fluid overload or for persistent though moderate thrombocytopenia, and had a favorable outcome. In regard to this procedure, it could be argued that patients who were switched to therapeutic plasma exchange may have a more severe disease than the other patients in the HD-PI group, and that the switch to therapeutic plasma exchange may have prevented potentially adverse outcomes. However, it is important to consider that in these patients, the sequential treatment consisting of high-dose plasma infusion and then therapeutic plasma exchange led finally to complete remission in all cases. This suggests that high-dose plasma infusion used as first-line therapy did not alter complete remission rates, and that far from being opposed, high-dose plasma infusion and therapeutic plasma exchange may be considered as complementary treatments for TTP/HUS. One patient in the HD-PI group had severe TTP/HUS unresponsive to high-dose plasma infusion, and was promptly switched to therapeutic plasma exchange. However, 4 therapeutic plasma exchange procedures and 1 pulse of vincristine also failed to improve the disease, and the patient rapidly died.
In 5 patients in the HD-PI group, transient nephrotic-range proteinuria occurred during treatment. Two of these patients had acute renal failure and mild proteinuria before treatment. The latter dramatically increased during plasma infusions, while renal function and other clinical and biologic disturbances rapidly improved with plasma. Proteinuria rapidly resolved in all patients after treatment was stopped. We note that in 1 patient, proteinuria decreased when she was switched to therapeutic plasma exchange for fluid overload. This “overload proteinuria” may be a complication of high-dose plasma infusion performed for several days, whether there is renal involvement on admission or not. The pathophysiology of overload proteinuria remains controversial, and could be genetically determined (34). However, the parenteral administration of large doses of protein (protein content of infused plasma is at least 5 g/dL, with 60% albumin) (21) is believed to enhance the glomerular epithelial cell absorption of albumin (7,15,20). Studies on experimental rat models of overload proteinuria induced by infusion of bovine serum albumin have shown that increased transcapillary movement of proteins causes degenerative changes of glomerular epithelial cells. These lesions are characterized by swelling, vacuolization, increased reabsorption droplets, and detachment of glomerular epithelium from the underlying glomerular basement membrane, which lead to large pore defects. In these studies, however, changes were completely reversible (34). In our patients, the possibility that preexisting glomerular lesions related to TTP/HUS may have facilitated an alteration in glomerular membrane pore structure cannot be ruled out.
All patients received solvent/detergent-treated plasma, in which vWF-cleaving protease activity was not altered by the method of inactivation, as shown by Furlan et al (9). In both groups, steroids were administered inconsistently compared with others (4,6,18), largely because in both groups of our study, infectious diseases hampered the use of steroids in many patients (8 patients in the HD-PI group and 6 in the TPE group). Eight patients received platelet transfusions, with no apparent side effects since all patients but 1 (Patient 1) are alive and achieved complete remission. This may be, at least in part, because all transfusions were performed along with therapeutic plasma exchange, which may have prevented an eventual worsening of TTP/HUS, as previously suggested (3).
The incidence of complete remission in patients treated with plasma infusion was higher than that reported by other groups (18,24) (Table 7). Particularly, Rock et al (24) conducted a prospective and randomized study that compared therapeutic plasma exchange (45–60 mL/kg daily) with plasma infusion (15 mL/kg per day). The outcomes in the 2 groups were compared 9 days and again 6 months after entry into the trial. At both 9 days and 6 months, response rates were significantly higher in the TPE group than in the plasma infusion group (TPE group: 24/51 and 40/51, respectively; plasma infusion group: 13/51 and 25/51, respectively). However, one may hypothesize that higher volumes of plasma in the plasma infusion group may have improved the response rate in this group. In a retrospective study, Novitzky et al (18) compared 10 patients treated with plasma infusion (25.9 mL/kg per day) as first-line therapy with 9 others treated with therapeutic plasma exchange. They found that with plasma infusion, 6 patients responded while 4 others did not and died. Three of these patients were switched to therapeutic plasma exchange with no efficacy. Half of the patients in the HD-PI group experienced fluid overload with favorable outcome. Proteinuria was not reported (see Table 7).
As in other studies (5,19,24), no prognostic factors could be defined on admission, which emphasizes that specific therapies based on initial clinical and standard biologic parameters remain challenging in TTP/HUS. This point is important considering that in our study, death always occurred before day 30 in both the HD-PI and the TPE groups, and within the first 3 days for 50% of patients. Recent biologic parameters, such as vWF-cleaving protease activity and its inhibitor, may represent original early prognostic factors to adapt the schedule of treatment in TTP/HUS, or to evaluate the risk of relapse (10,30,31). We note that, in 2 patients who both experienced 2 episodes of relapse, vWF-cleaving protease activity was persistently undetectable far from complete remission. In 1 patient, this deficiency may have been congenital (not associated with a plasma inhibitor), whereas in the second patient the decreased activity was due to a persistently low titer of inhibitor. This finding suggests that a plasma inhibitor may persist in some patients and therefore may increase the risk of chronic relapse, as observed in the context of a congenital deficiency (9). In such patients, the follow-up may systematically include evaluating the vWF-cleaving protease activity and its inhibitor titer. Concerning patients in the TPE group, relapses occurred early after complete remission, with no late relapse. This finding suggests that those patients with a vWF-cleaving protease deficiency had rather a plasma inhibitor, which disappeared following the TTP/HUS episode. However, this hypothesis could not be investigated.
Our results suggest that high-dose plasma infusion (25–30 mL/kg per day) is an efficient treatment of TTP/HUS in an emergency, especially when therapeutic plasma exchange is not available, since neither complete remission and mortality rates, nor median duration of clinical and biologic abnormalities are worsened. Moreover, high-dose plasma infusion may reduce the duration of central catheter use, which may prevent complications such as thrombosis or infections (23). However, high-dose plasma infusion may be rapidly hampered by fluid overload, and may thus require a switch to therapeutic plasma exchange until complete remission. Other side effects such as transient proteinuria may also be observed in prolonged high-dose plasma infusion treatment. Therefore, the occurrence of proteinuria or the exacerbation of preexisting proteinuria during high-dose plasma infusion treatment may not systematically indicate a renal manifestation of TTP/HUS, and should not warrant a renal biopsy. The determination of vWF-cleaving protease activity and the search for its inhibitor before treatment and during complete remission may predict long-term outcome. Further studies are required to specify a vWF-cleaving protease inhibitor titer value to predict TTP/HUS of poor prognosis and to determine the schedule of therapy for management of such forms.
We thank Professor K. Lassoued, Professor E. Rondeau, and Doctor A. Hertig for their many suggestions, and S. Malot for technical assistance in the preparation of the manuscript.
1. Bell WR, Braine HG, Ness PM, Kichler TS. Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. N Engl J Med 325: 398–403, 1991.
2. Byrnes JJ, Khurana M. Treatment of thrombotic thrombocytopenic purpura with plasma. N Engl J Med 297: 1386–9, 1977.
3. Coppo P, Lassoued K, Mariette X, Gossot D, Oksenhendler E, Adrie C, Azoulay E, Schlemmer B, Clauvel JP, Bussel A. Effectiveness of platelet transfusion after plasma exchange in adult thrombotic thrombocytopenic purpura: A report of two cases. Am J Hematol 68: 198–201, 2001.
4. De la Rubia J, Lopez A, Arriaga F, Cid AR, Vicente AI, Marty ML, Sanz MA. Response to plasma exchange and steroids as combined therapy for patients with thrombotic thrombocytopenic purpura. Acta Haematol 102: 12–6, 1999.
5. Dervenoulas J, Tsirigotis P, Bollas G, Pappa V, Xiros N, Economopoulos T, Pappa M, Mellou S, Kostourou A, Papageorgiou E, Raptis SA. Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS): Treatment outcome, relapses, prognostic factors. A single-center experience of 48 cases. Ann Hematol 79: 66–72, 2000.
6. Dundas S, Murphy J, Soutar RL, Jones GA, Hutchinson SJ, Todd WTA. Effectiveness of therapeutic plasma exchange in the 1996 Lanarkshire Escherichia coli O 157:H7 outbreak. Lancet 354: 1327–30, 1999.
7. Eddy AA, Geary DF, Balfe JW, Clark WF, Baumal R. Prolongation of acute renal failure in two patients with hemolytic-uremic syndrome due to excessive plasma infusion therapy. Pediatr Nephrol 3: 420–3, 1989.
8. Fakhouri F, Vincent F, Legendre C. Pathological and therapeutic distinction in HUS/TTP [Correspondence]. Lancet 355: 497–8, 2000.
9. Furlan M, Robles R, Galbusera M, Remuzzi G, Kyrle PA, Brenner B, Krause M, Scharrer I, Aumann V, Mittler U, Solenthaler M, Lammle B. Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med 339: 1578–84, 1998.
10. Furlan M, Robles R, Morselli B, Sandoz P, Lammle B. Recovery and half-life of von Willebrand factor-cleaving protease after plasma therapy in patients with thrombocytic thrombocytopenic purpura. Thromb Haemost 81: 8–13, 1999.
11. George JN. How I treat patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Blood 96: 1223–9, 2000.
12. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457–81, 1958.
13. Levy GG, Nichols WC, Lian EC, Foroud T, McClintick JN, McGee BM, Yang AY, Siemieniak DR, Stark KR, Gruppo R, Sarode R, Shurin SB, Chandrasekaran V, Stabler SP, Sabio H, Bouhassira EE, Upshaw Jr, JD Ginsburg D, Tsai HM. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 413: 488–94, 2001.
14. Mantel N, Haenszel W. Statistical aspect of the analysis of data from retrospective studies of disease. J Natl Cancer Instit 22: 719–48, 1959.
15. McLaine PN, Marks MI, Baliah T, Drummond KN. Hyperproteinemic proteinuria induced by plasma infusion. Pediatr Res 3: 597–603, 1969.
16. Moake JL, Rudy CK, Troll JH, Schafer AI, Weinstein MJ, Colannino NM, Hong SL. Unusually large plasma factor VIII: von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med 307: 1432–5, 1982.
17. Moake JL, Turner NA, Stathopoulos NA, Nolasco LH, 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 78: 1456–61, 1986.
18. Novitzky N, Jacobs P, Rosenstrauch W. The treatment of thrombotic thrombocytopenic purpura: Plasma infusion or exchange? Br J Haematol 87: 317–20, 1994.
19. Patton JF, Manning KR, Case D, Owen J. Serum lactate deshydrogenase and platelet count predict survival in thrombotic thrombocytopenic purpura. Am J Hematol 47: 94–9, 1994.
20. Petrie JJ, Cleland JF, MacLean PR, Robson JS. Glomerular permeability during proteinuria induced by plasma infusion. Clin Sci 39: 383–9, 1970.
21. Piquet Y, Janvier G, Selosse P, Doutremepuich C, Jouneau J, Nicolle G, Platel D, Vezon G. Virus inactivation of fresh frozen plasma by a solvent detergent procedure: Biological results. Vox Sang 63: 251–6, 1992.
22. Remuzzi G, Ruggenenti P. The hemolytic uremic syndrome. Kidney Int 47: 2–19, 1995.
23. Rizvi MA, Vesely SK, George JN, Chandler L, Duvall D, Smith JW, Gilcher RO. Plasma exchange complications in 71 consecutive patients treated for clinically suspected thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Transfusion 40: 896–901, 2000.
24. Rock GA, Shumak KH, Buskard NA, Blanchette VS, Kelton JG, Nair RC, Spasoff RA, and the Canadian Apheresis Group. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. N Engl J Med 325: 393–7, 1991.
25. Rock GA. Management of thrombotic thrombocytopenic purpura. Br J Haematol 109: 496–507, 2000.
26. Ruggenenti P, Galbusera M, Plata Cornejo R, Bellevita P, Remuzzi G. Thrombotic thrombocytopenic purpura: Evidence that infusion rather than plasma exchanges induces remission of the disease. Am J Kidney Dis 21: 314–8, 1993.
27. Ruggenenti P, Remuzzi G. The pathophysiology and management of thrombotic thrombocytopenic purpura. Eur J Haematol 56: 191–207, 1996.
28. Ruggenenti P, Noris M, Remuzzi G. Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Kidney Int 60: 831–46, 2001.
29. Tsai H-M, Lian EC-Y. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 339: 1585–94, 1998.
30. Tsai HM. High titers of inhibitors of von Willebrand factor-cleaving metalloproteinase in a fatal case of acute thrombotic thrombocytopenic purpura. Am J Hematol 65: 251–5, 2000.
31. Tsai HM, Li A, Rock G. Inhibitors of von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura. Clin Lab 47: 387–92, 2001.
32. Veyradier A, Obert B, Houllier A, Meyer D, Girma JP. Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: A study of 111 cases. Blood 98: 1765–72, 2001.
33. Wada H, Kaneko T, Ohiwa M, Tanigawa M, Hayashi T, Tamaki S, Minami N, Deguchi K, Suzuki K, Nakano T. Increased levels of vascular endothelial cell markers in thrombotic thrombocytopenic purpura. Am J Hematol 44: 101–5, 1993.
34. Weening JJ, van Guldener C, Daha MR, Klar N, van der Wal A, Prins FA. The pathophysiology of protein-overload proteinuria. Am J Pathol 129: 64–73, 1987.