SEARCH

SEARCH BY CITATION

Keywords:

  • autoimmune thrombocytopenic purpura;
  • intravenous immunoglobulin;
  • thrombocytopenia

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

Since the first reports demonstrating the ability of a total dose of 2 g/kg body weight (b.w.) of intravenous immunoglobulin (IVIg) to increase the platelet count in patients with autoimmune thrombocytopenic purpura (AITP), the optimal dose has remained controversial. We report the results of a randomized study which compared two low doses of IVIg (0.5 g/kg b.w., group A, n = 19, and 1 g/kg b.w., group B, n = 18) in 37 adults with AITP and platelet count <50 × 109/l, in preparation for surgery or in a situation with a risk of bleeding. On day 4 the proportion of responses, defined by a platelet count > 80 × 109/l and at least twice the initial platelet count, was significantly higher in the group receiving 1 g/kg b.w. (12/18 in group B versus 4/19 in group A, P = 0.005). All but one of the day 4 responders had already responded on day 3. The daily changes in the platelet count from the beginning of IVIg treatment were larger in group B, with a significant difference relative to group A on day 3 (92 × 109/l in group B versus 50 × 109/l in group A, P = 0.03) and on day 4 (106 × 109/l in group B versus 55 × 109/l in group A, P = 0.03). Patients who had not responded by day 4 subsequently received 1.5 g IVIg/kg b.w. (group A) or 1 g IVIg/kg b.w. (group B). A response was observed in 11/13 initial non-responders in group A, and in 2/6 initial non-responders in group B. Finally, on day 8, the proportion of responders was 78% (29/37) in the entire group and was similar in the two subgroups. In conclusion, (1) initial treatment with 1 g/kg b.w. of IVIg appeared to be more effective than 0.5 g/kg b.w. in adults with AITP; (2) infusion of a low dose of IVIg did not jeopardize the efficacy of IVIg reinfusion; (3) some adults who did not respond to 1 g IVIg/kg b.w. responded to a higher dose.

Autoimmune thrombocytopenic purpura (AITP) is due to platelet antibodies that opsonize the platelet membrane, leading to platelet destruction by the reticulo-endothelial system (George et al, 1994). Given the risk of life-threatening bleeding, patients with severe thrombocytopenia require a treatment that should ideally be rapidly, reliably and durably effective. It should be inexpensive and simple to administer. Steroids are generally used but their effects are inconsistent and often transient (George et al, 1996). The ability of intravenous immunoglobulin (IVIg) infusions to transiently increase the platelet count in patients with AITP was first reported by Imbach et al (1981), who observed platelet responses in children receiving 0.4 g/kg body weight (b.w.) daily for 5 d. These results were confirmed in adults, and IVIg infusions are now used for initial treatment of patients with severe thrombocytopenia, and also when surgery (particularly splenectomy) is planned, in order to reduce the risk of peri- and postoperative bleeding (George et al, 1996). The optimal dose of IVIg is controversial, particularly for adults. Most teams still use the original dose of 0.4 g/kg b.w. daily for 5 consecutive days, or the dose of 1 g/kg b.w. daily for 2 consecutive days (Bussel & Pham, 1987). However, reduced doses might be effective (Godeau et al, 1993; Blanchette et al, 1994) and would reduce the cost of treatment. Other arguments in favour of a lower dose include the need to shorten the infusion time and to reduce the incidence and severity of side-effects. We report the results of a randomized study which compared two weak doses of IVIg (0.5 g/kg b.w. and 1 g/kg b.w.) in adults with AITP.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

Patients

40 consecutive adults with AITP were included in a prospective multicentre, randomized, open study. The study was approved by the ethics committee of Centre Hospitalier Universitaire Ambroise Paré (Boulogne, France). It was performed according to the Helsinki Declaration, and to the Good Clinical Practices. AITP was diagnosed according to standard criteria, i.e. isolated thrombocytopenia, a normal or increased megakaryocyte count in an otherwise normal bone marrow aspirate, and absence of other causes of thrombocytopenia. The eligibility criteria were as follows: preparation of surgery, delivery or a clinical condition with a risk of bleeding, no treatment for at least 2 weeks before the study, a stable platelet count <50 × 109/l, and no life-threatening bleeding.

IVIg preparation and treatment schedules

Initial treatment. Batches of a registered IVIg (Tegeline®, Laboratoire Français du Fractionnement et des Biotechnologies, Courtaboeuf, France) were used. They contained >97% of unmodified human IgG and were obtained by Cohn ethanol fractionation and treatment at pH 4 in the presence of trace amounts of pepsin. The patients were randomized to receive an initial total dose of 0.5 g/kg b.w. (group A) or 1 g/kg b.w. (group B). IVIg infusions were administered over a period of 4–12 h according to tolerability. Platelet counts were determined on days 1 (pretreatment), 2, 3, 4, 5, 6, 7, 8 and 10, and then every 5 days for 2 weeks. The response was analysed on day 4 and patients were considered as responders if the platelet count increased >80 × 109/l and was at least twice the initial platelet count (this cut-off is usually considered as safe for surgery or delivery).

IVIg reinfusions. Non-responders received IVIg reinfusions of a total dose of 1.5 g/kg b.w. (group A) or 1 g/kg b.w. (group B) as two divided doses on day 4 and day 5 (thus, in both groups, the non-responders on day 4 received a total of 2 g/kg b.w.). The response of IVIg reinfusions was analysed on day 8 as described above, according to the same platelet criteria.

Statistical analysis

Nominal qualitative variables were compared using Chi2 test or direct calculation of the degree of significance using Fisher's exact test. Ordinal qualitative variables were compared using Wilcoxon's test. Quantitative variables were compared using Student's t-test in the event of normal distribution in each of the two treatment groups; otherwise Wilcoxon's test was used. A difference was considered statistically significant when the significance level of the bilateral test was leqslant R: less-than-or-eq, slant0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

Forty patients were randomized in the study; three were excluded for major protocol violations (mistaken diagnosis, n = 1; no treatment or wrong dose of IVIg, n = 2). Among the 37 evaluable patients, 19 were randomized to group A and 18 to group B. The mean platelet count at inclusion was 26 ± 15 × 109/l and the duration of AITP was >6 months in all the patients but six (five in group A and one in group B). All patients but one had not been splenectomized and they had no disease known to be associated with AITP (i.e. human immunodeficiency virus infection, systemic lupus erythematosus and other connective tissue disorders, lymphoproliferative disorders, thyroid or liver diseases). The patients' characteristics were comparable in the two groups (Table I). Transient and reversible intolerance requiring immediate interruption of the IVIg infusion was observed in two group A patients (hypertension and headache in one, and chills, vomiting and hypotension in the other). These two patients received a total IVIg dose of 0.06 g/kg b.w. and 0.4 g/kg b.w., respectively; no platelet response was observed and they were classified as non-responders.

Table 1. Table I. Patients' characteristics. * Most of the patients received IVIg infusions to increase the platelet count prior to planned splenectomy or delivery; miscellaneous indications included preparation for endoscopy (n = 2), tooth extraction (n = 1), in vitro fertilization (n = 1), umbilical cord blood sampling (n = 1), platelet survival study (n = 1) and preparation for a retro-orbital haematoma surgery (n = 1). NS, not significant.Thumbnail image of

A significant difference in the number of responders was observed on day 4 between the two groups (12/18 in group B versus 4/19 in group A, P = 0.005). The proportion of responders was also significantly different when the two group A patients who did not receive the planned dose of IVIg were excluded from the analysis (Table II). All but one responders on day 4 had already responded on day 3 (Table II). The daily changes in platelet counts after IVIg infusion are shown in Fig 1; platelet counts were observed to be higher in group B than in group A [the difference was statistically significant on day 3 and day 4 (P = 0.03)].

Table II. Responders on days 1, 2.  , 3 and 4.* Numbers within parentheses are confidence intervals [CI 95%].* A response was defined as in increase of the platelet count to geqslant R: gt-or-equal, slanted80 × 109/l and at least twice the initial platelet count. Results were analysed in the group of evaluable patients (the two group A patients who did not receive the planned dose of IVIg were excluded from analysis).† Before initial IVIg infusion.Thumbnail image of
image

Figure 1. . Median platelet counts (×109/l) on days 1, 2, 3 and 4. Numbers within parentheses are quartile values [Q1–Q3].

Download figure to PowerPoint

3Table III shows the results of IVIg reinfusions on day 4 in the non-responders (the two non-tolerant patients who did not receive IVIg reinfusions were not taken into account in the statistical analysis). A response was observed in 11/13 initial non-responders in group A, but in only two of the six initial non-responders in group B. Finally, on day 8, the per-centage of responders was 78% (29/37) for the entire patient population and was similar in the two subgroups (Table III).

Table 3. Table III. IVIg re-administration to non-responders after initial IVIg infusion.* Numbers within parentheses are confidence intervals [CI 95%].* A response was defined as an increase in the platelet count to geqslant R: gt-or-equal, slanted80 ×109/l and at least twice the initial platelet count. Results were analysed in the group of evaluable patients (the two group A patients who did not receive the planned dose of IVIg were excluded from the analysis).† IVIg reinfusions on day 4 and day 5 of 0.75 g/kg b.w. for group A patients and 0.5 g/kg b.w. for group B patients.Thumbnail image of

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

A recent review of the literature underlined the lack of rigorous clinical trial data on which to base recommendations for the care of AITP patients (George et al, 1996). Our randomized study was designed to help to define the optimal IVIg dose for adults with AITP. Since the original reports, which demonstrated the ability of 0.4 g/kg b.w. of IVIg administered daily for 5 consecutive days to transiently increase the platelet count in these patients (Imbach et al, 1981; Bussel et al, 1983), the optimal dose of IVIg has been the subject of controversy. Paediatric studies suggested that 1 g/kg b.w. for 1 d (Bussel et al, 1985) or 0.4 g/kg b.w./d for 2 d (Imbach et al, 1985) may be sufficient, and a randomized trial showed that 0.8 g/kg b.w. of IVIg achieved short-term platelet responses equivalent to those observed with 2 g/kg b.w. (Blanchette et al, 1994). However, these results cannot be extended to adults because the course of the disease and the response to treatment are different (George et al, 1994, 1996). There are few published data on the optimal dose of IVIg for adults with AITP. In a previous randomized study (Godeau et al, 1993) we found no difference in the platelet response between a total dose of 1 g/kg b.w. or 2 g/kg b.w. of IVIg given on 2 consecutive days in a small group of adults with chronic AITP; Bussel et al (1990) also failed to find a significant difference between the platelet count increment and the amount of IVIg infused in retrospective studies. However, others have reported conflicting results. For example, Uchino et al (1984) reported that, although a regimen of 0.4 g/kg/b.w. was suitable for some patients, the wide range of individual responses meant that the optimal dose should be determined for each patient.

The present randomized study clearly demonstrated that initial treatment with 1 g/kg b.w. of IVIg was more effective than 0.5 g/kg b.w. in adults with AITP, because a significantly higher proportion of responders and larger daily changes in the platelet count were observed in the patients who received the higher dose. We confirm, however, that a low dose is suitable for some patients, as a platelet response was observed in almost one-fifth (4/19; 21%) of the patients who initially received 0.5 g/kg b.w. of IVIg. Another important result was that an initial infusion of a low dose of IVIg did not jeopardize the efficacy of subsequent IVIg infusions. Indeed, a platelet response after IVIg reinfusions was observed in the majority of group A patients who did not initially respond to 0.5 g/kg b.w. of IVIg, and the total number of responders after the total dose of 2 g/kg b.w. of IVIg was comparable to published data (George et al, 1996). Finally, our results also demonstrated (1) that the final response to IVIg could be evaluated as early as day 3, as a positive response was observed at this time in all but one day 4 responders (Table II), and (2) that some adults did not respond to 1 g/kg b.w. of IVIg, whereas higher doses could provoke an increase in the platelet count that is usually moderate and incomplete but sometimes enough to stop bleeding or to permit surgery (Bierling & Godeau, 1997).

Taken together, our results support, in adults, the recommendation by American haematologists (George et al, 1996) that children could receive lower doses, and demonstrate that the ideal initial dose of IVIg seems, as in children, to be between 0.5 and 1 g/kg b.w. IVIg reinfusions should be given up to a maximum of 2 g/kg b.w. if no response is observed on day 3. However, contrary to that proposed for children, patients with severe life-threatening conditions should, in our view, receive 2 g/kg b.w. administered over 36–48 h.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

We thank the physicians Professor J. F. Abgrall (Brest), Dr J. Beyloune (Le Kremlin Bicêtre), Professor P. Bierling (Créteil), Dr M. T. Caulier (Lille et Arras), Dr C. Decervens (Caen), Dr B. Dupriez (Lens), Professor B. Godeau (Créteil), Professor J. L. Harousseau (Nantes), Dr F. Lefrère (Paris), Dr E. Legouffe (Montpellier), Professor M. Leporrier (Caen), Professor M. Navarro (Montpellier), Dr C. Rose (Lille), Professor F. Rossi (Montpellier), Professor G. Tchernia (Le Kremlin Bicêtre) and Professor B. Varet (Paris) of the Groupe d'Etude du Traitement du PTAI, and Dr F. Roudot-Thoraval (Créteil) for statistical analysis.

This work was supported by grants from Laboratoire Français du Fractionnement et des Biotechnologies, Courtaboeuf, France.

References

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References
  • 1
    Bierling, P. & Godeau, B. (1997) Antibodies in the therapy of autoimmune thrombocytopenia: practical recommendations. Biological Drugs, 2, 99106.
  • 2
    Blanchette, V., Imbach, P., Andrew, M., Adams, M., McMillan, J., Wang, E., Milner, R., Ali, K., Barnard, D. & Bernstein, M. (1994) Randomised trial of intravenous immunoglobulin G, intravenous anti-D, and oral prednisone in childhood acute immune thrombocytopenic purpura. Lancet, 334, 703707.
  • 3
    Bussel, J., Kimberly, R.P., Inman, R.D., Schulman, I., Cunningham-Rundles, C., Cheung, N., Smithwick, E.M., O'malley, J., Barandun, S. & Hilgartner, M.W. (1983) Intravenous gammaglobulin treatment of chronic idiopathic thrombocytopenic purpura. Blood, 62, 480486.
  • 4
    Bussel, J.B., Fitzgeral-Pedersen, J. & Feldman, C. (1990) Alternation of two doses of intravenous gammaglobulin in the maintenance treatment of patients with immune thrombocytopenic purpura: more is not always better. American Journal of Hematology, 33, 184188.
  • 5
    Bussel, J.B., Goldman, A., Imbach, P., Schuman, I. & Hilgartner, M.W. (1985) Treatment of acute thrombocytopenia of childhood with intravenous infusions of gammaglobulin. Journal of Pediatrics, 106, 886890.
  • 6
    Bussel, J.B. & Pham, L.C. (1987) Intravenous treatment with gammaglobulin in adults with immune thrombocytopenic purpura: review of the literature. Vox Sanguinis, 52, 206211.
  • 7
    George, J.N., El-Harake, M.A. & Raskob, G.E. (1994) Chronic idiopathic thrombocytopenic purpura. New England Journal of Medicine, 331, 12071211.DOI: 10.1056/NEJM199411033311807
  • 8
    George, J.N., Woolf, S.H., Raskob, G.E., Wasser, J.S., Aldedort, L.M., Ballem, P.J., Blanchette, V.S., Bussel, J.B., Cines, D.B., Kelton, J.G., Lichtin, A.E., McMillan, R., Okerbloom, J.A., Regan, D.H. & Warrier, I. (1996) Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood, 88, 240.
  • 9
    Godeau, B., Lesage, S., Divine, M., Wirquin, V., Farcet, J.P. & Bielring, P. (1993) Treatment of adult chronic autoimmune thrombocytopenic purpura with repeated high-dose intravenous immunoglobulin. Blood, 82, 14151421.
  • 10
    Imbach, P., Barandum, S., D'apuzzo, V., Baumgartner, C., Hirt, A., Morell, A., Rossi, E., Schoni, M., Vest, M. & Wagner, H.P. (1981) High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet, i, 12281230.DOI: 10.1016/S0140-6736(81)92400-4
  • 11
    Imbach, P., Wagner, H.P., Berchtold, W., Gaedicke, G., Hirt, A., Joller, P., Mueller-Eckhardt, C., Muller, B., Rossdi, E. & Barandun, S. (1985) Intravenous immunoglobulin versus oral corticosteroids in acute immune thrombocytopenic purpura in childhood. Lancet, ii, 464468.DOI: 10.1016/S0140-6736(85)90400-3
  • 12
    Uchino, H., Yasunaga, K. & Akatsuka, J.I. (1984) A cooperative clinical trial of high-dose immunoglobulin therapy in 177 cases of idiopathic thrombocytopenic purpura. Thrombosis and Haemostasis, 51, 182185.