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.
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