High-dose intravenous IgG for chronic idiopathic thrombocytopenic purpura in adults

Summary Sixteen adult patients of mean age 48 years with chronic ITP were studied for platelet response to high-dose (0.4 g/kg body weight per day for five consecutive days) intravenous polyvalent intact IgG in the absence of any concurrent treatment. The platelet count returned to normal values in nine patients, a partial response (rise in the platelet count between 50 and 150 ×10⁹/l) was observed in three cases. One patient refractory to any other treatment went into a sustained remission. In the other responsive patients the response was only transient. Among seven splenectomised patients only three responded to IgG infusions versus nine in the non-splenectomised group. The length of ITP history appeared as a more critical factor for the response to IgG than previous splenectomy.     

High-dose intravenous methylprednisolone for acute childhood idiopathic thrombocytopenic purpura

49 children with acute idiopathic thrombocytopenic purpura (ITP) were divided into non-treatment, oral prednisone (2 mg/kg), and high-dose intravenous methylprednisolone (HIVMP) treatment groups which consisted of 17, 16 and 16 children respectively. Platelet counts rose above 150,000/microliters over a 2-week period in 5 (29.4%) children in the first group, 5 (31.2%) in the second group and 15 (93.7%) children in the third group. Platelet counts reached the normal level in only 3 days in 11 (68.7%) children treated with HIVMP. Initially, antiplatelet antibodies (APA) were shown by the Handin and Stossel method in every patient. With normalization of platelet counts, the antibodies decreased but could still be detected in every case; antibody decrease was greater in the HIVMP group. With the exception of mild cushingoid appearance, none of the major corticosteroid side effects was observed in the treated children.     

Platelet associated IgG, platelet mean life span and treatment with intravenous immunoglobulin in idiopathic thrombocytopenic purpura

The clinical significance of platelet associated IgG in ITP detected by direct platelet suspension immunofluorescence test (PSIFT) was studied. The platelet mean life span (MLS) was measured with 111In-labelled platelets in 17 adult patients. All the patients had shortened platelet MLS. The direct PSIFT was positive in 14 patients. Patients were initially treated with prednisone; 12 patients with poor response to the drug were splenectomised. 8 of these 12 patients were treated with intravenous immunoglobulin (IvIg) before splenectomy. The response to IvIg was as good or better in the 3 patients with negative PSIFT, than in the 5 patients with positive PSIFT.     

Low fetal morbidity in pregnancy associated with acute and chronic idiopathic thrombocytopenic purpura

Forty-six mothers with immune thrombocytopenic purpura (ITP) gave birth to 72 babies. Sixty-two babies were delivered vaginally and 10 babies by cesarean section. There was no mortality among mothers or babies. Eighteen infants were born thrombocytopenic (PLT < 100 ± 10⁹/l). Eleven infants had a platelet count of less than 50 ± 10⁹/l. All the severely thrombocytopenic babies (except 1) were born to post splenectomy thrombocytopenic mothers, regardless of steroid treatment during pregnancy. Five babies had clinical manifestations of bleeding; 3 had mild purpura, 1 severe gastrointestinal bleeding, and 1 intracranial bleeding. The latter 2 babies were born prematurely to the same mother who was severely thrombocytopenic despite splenectomy in childhood. In view of very low morbidity in babies of ITP mothers, we suggest that they be delivered vaginally. Cesarean delivery should be performed in selected cases where the mother is severely thrombocytopenic despite splenectomy or where prematurity or obstetrical complications are encountered. © 1994 Wiley-Liss, Inc.     

Treatment of idiopathic thrombocytic purpura in pregnancy by high-dose intravenous immunoglobulin

Summary ITP in pregnancy may lead to fetal thrombocytopenia caused by the transplacental passage of maternal antiplatelet antibody. The most hazardous complication in the infant is intracranial hemorrhage. In addition ITP in pregnancy is reported to be associated with an increased abortion rate and an elevated fetal morbidity and mortality. Therefore obstetric management must aim at increasing maternal and fetal platelets. Severel therapeutic approaches to the treatment of ITP in pregnancy are evaluated. Two cases of ITP in pregnancy are reported. Administration of high-dose intravenous immunoglobulin is introduced as a new therapy for ITP in pregnancy. The rapid reversal of thrombocytopenia following immunoglobulin G administration suggests that it is useful especially as emergency treatment for ITP in pregnancy.     

Red cell sequestration during high dose intravenous immunoglobulin in idiopathic thrombocytopenic purpura

Summary The cellular interactions involved in the platelet response after immunoglobulin infusion in acute and chronic idiopathic thrombocytopenic purpura (ITP) are unknown. There have been a number of theories including the competitive inhibition of platelet-binding to macrophages by the preferential sequestration of immunoglobulin coated red cells. We report a study to examine this hypothesis. Adult acute and chronic patients were given infusions of immunoglobulin at a rate of 0.4 g/kg body weight, daily for 5 days. Serum haptoglobin, lactate dehydrogenase and the absolute reticulocyte counts were monitored and no significant change in any value was seen during the period of study. A red cell survival was performed on four of the patients and no increase in the rate of red cell clearance occurred during the infusion period. We conclude from this that in these patients no significant degree of haemolysis was provoked by the infusion although this does not preclude this as a mechanism of action in some individuals.     

Treatment of refractory chronic idiopathic thrombocytopenic purpura with high dose intravenous immunoglobulin

Summary Three patients with a history of chronic idiopathic thrombocytopenic purpura stretching back over 20 years are reported. Despite splenectomy and immunosuppressive therapy satisfactory control of their disease has not been achieved. They had remained refractory to all therapeutic manoeuvres with corticosteroids and immunosuppressives for years with thrombocyte counts between 5,000 and 25,000/l and the concommitant risk of bleeding.This report describes the treatment of bleeding complications in these patients with high dose intravenous immunoglobulin; the peripheral blood thrombocyte count increased in all three patients from subnormal towards normal, but 2 to 4 weeks later returned to its initial low value.During the therapeutically induced raised thrombocyte count a normal bleeding time and only a moderate inhibition of thrombocyte adhesion and aggregation was observed resulting in reasonable haemostasis. High dose intravenous immunoglobulin is therefore a practical method for the control of bleeding complications in patients with refractory chronic idiopathic thrombocytopenic purpura. A clear explanation for its mode of action has not been found — the lymphocyte subpopulations remained unchanged and immunoglobulin production in vitro during the course of treatment was only minimally decreased.     

Idiopathic thrombocytopenic purpura in pregnancy and neonatal period

Summary In pregnancy and neonatal period both mother and child are endangered by bleeding complications due to maternal idiopathic thrombocytopenic purpura. Obstetrical and perinatal management therefore must aim at increasing maternal and fetal platelet count.In our paper six patients in nine pregnancies are reported. Two of them (five pregnancies) were treated with corticosteroids, four of the patients were successfully treated with i.v. immunoglobulins (IgG).Longterm steroid application and splenectomy during pregnancy may be hazardous for mother and fetus. IgG i.v. administration in contrast offers a new and safe way to control maternal and fetal platelet counts during pregnancy, delivery and the neonatal period.     

Antiplatelet antibodies in childhood idiopathic thrombocytopenic purpura

Antiplatelet antibodies were shown by the Handin and Stossel method in the sera of all 103 patients with acute idiopathic thrombocytopenic purpura (ITP) and in 100 cases following recovery from it. These antibodies were also shown in the sera of all 46 patients with chronic ITP and 32 cases after recovery. The decrease in level of antiplatelet antibodies was significant in all these children following recovery (P less than 0.001 for acute ITP, P less than 0.05 for chronic ITP). Antiplatelet antibodies could be determined in 67 acute and 21 chronic ITP cases in thrombocytopenic phase and following recovery, which showed very significant decreases in levels in each case in a later period. Antiplatelet antibody levels corresponding to the thrombocytopenic phase and recovery in acute and chronic ITP were significantly higher than normal and thrombocytopenic control values (P less than 0.001 for each).     

Detection of platelet-associated IgG in chronic immune thrombocytopenic purpura using antibody-coated polyacrylamide beads

Summary Platelet-associated IgG (PAIgG) was detected by means of anti-human IgG coated polyacrylamide beads (Immunobeads) technique in 32 patients with chronic ITP. Both a direct test (with in vivo sensitized platelets) and an indirect test (with in vitro loaded platelets) were carried out. The percent of rosette forming beads was both in the direct test (41.2%) and in the indirect test (32.6%) significantly higher in the cases of chronic ITP patients than in the controls (2.5% and 3.2%, respectively). These results confirm the diagnostic value of this new, relatively simple and rapid method in routine clinical practice.     

Perinatal management of idiopathic thrombocytopenic purpura in pregnancy: risk factors for passive immune thrombocytopenia

Summary Thirty-nine pregnant women with idiopathic thrombocytopenic purpura (ITP) were studied in order to evaluate the influence of therapies for maternal ITP on fetal passive immune thrombocytopenia (PIT). Neonatal platelet counts were also compared with platelet counts, amount of PAIgG, and presence of circulating antiplatelet antibody in maternal blood. Eight of 41 neonates (19.5%) presented PIT without neonatal mortality. A higher incidence of PIT was observed in women with prior splenectomy than in women without splenectomy (66.7% vs 11.4%). Neither a therapeutic effect nor an increased risk of PIT was observed with steroids or gammaglobulin administration. No correlation was found between neonatal platelet counts and maternal platelet counts or maternal PAIgG, while positive cases for circulating antiplatelet antibody assay presented a higher incidence of PIT than negative cases. Additionally, a higher incidence of PIT was observed in women with a history of previous PIT than in women with a history of normal delivery. Prior splenectomy, presence of antiplatelet antibody in maternal blood, and a history of previous PIT seem to be risk factors for fetal PIT.     

Specific and nonspecific mechanisms of action of immunoglobulin G in therapy of idiopathic thrombocytopenic purpura (ITP)

Summary The efficacy of IgG infusion therapy in ITP is now established even in cases resistant to other forms of therapy. However, the mechanism of action is still speculative. We assume that a correction of the elevated thrombocyte clearance is brought about at several levels. First, antibodies specific for an inciting antigen (and for which the patient is deficient) may remove free antigen and/or immune complexes which adhere to platelet surfaces, thereby rendering platelets less susceptible to clearance. Second, IgG may act nonspecifically by protecting the platelet surface from becoming covered with immune complexes. Third, monomeric IgG may display a nonspecific inhibitory effect at the level of the interaction of immunologically altered platelets with Fc receptors of mononuclear phagocytes. For the latter effect, good in vivo evidence exists. However, it must be born in mind that interaction of antibodies with Fc receptors is but one mechanisms for triggering adherence and endocytosis. A variety of other receptors and binding sites exists which may interact with immunologically altered thrombocytes. These may either trigger phagocytes on their own or facilitate the interaction of antibodies and Fc receptors. How IgG infusion influences such interactions remains to be determinded.Supported by the Swiss National Science Foundation and the Stanley Thomas Johnson Foundation     

Intravenous immunoglobulin (i.v. IgG) for previously treated acute or for chronic idiopathic thrombocytopenic purpura (ITP) in childhood: a prospective multicenter study

Summary In a prospective multicenter study 42 thrombocytopenic (<30×10⁹ platelets/l) children with chronic idiopathic thrombocytopenic purpura (ITP) or with acute ITP, dependent on or refractory to corticosteroids, were given 0.4 g i.v. IgG/kg body weight/day on 5 consecutive days and thereafter once a week if the platelet count fell to <20×10⁹/l or if the patient bled. After the initial 5 days of i.v. IgG the platelets rose within a mean of 7–8 days to >30×10⁹/l in all and to >150×10⁹/l in 33 of 42 patients (79%). After a mean observation time of 26.6 months 26 of 42 patients (62%) showed a satisfactory long-term effect, i.e. no need for treatment for at least 6 months without bleeding and with no platelet counts below 20×10⁹/l. No difference in response rate was found between children with chronic and those with previously treated acute ITP. These results indicate that i.v. IgG could be used to control emergency situations, e.g. to stop bleeding or to prepare a patient for surgery. I.v. IgG also represents a good alternative to treatment modalities, such as splenectomy and/or the administration of cytostatic immunosuppressants with potentially serious side effects. In addition to the expected transient rise in serum IgG levels, i.v. IgG induced a more prolonged elevation of serum IgM. Platelet associated IgG, elevated before therapy, was correlated with the clinical long-term outcome.This paper is part of the doctoral thesis of B. I. Responsible physicians of hospitals: see Appendix     

Magnetic resonance imaging of reticulo-endothelial system in patients with idiopathic thrombocytopenic purpura

Idiopathic thrombocytopenic purpura (ITP) is characterized by accelerated platelet destruction in the reticulo-endothelial system (RES). We performed magnetic resonance imaging (MRI) to estimate the degree of activated RES. MRI was performed with a Gyroscan S-15 (1.5 tesla) in 7 healthy volunteers and 22 patients with ITP. The 22 patients included 19 who were at initial diagnosis or were nonresponders to the therapy (non-DX group), and 3 who were responders. For the non-DX group, the T1 relaxation time of the spleen was initially significantly shorter than for healthy volunteers, but normalized after responding to the therapy. The initially shorter T1 values of the spleen for ITP patients correlated with a low platelet count (P < 0.05). This condition may indicate foam cells or fatty components due to platelet destruction. There was no significant relationship between the sequestration in ¹¹¹In-scan and T1 values of the liver or spleen. However, MRI is a noninvasive method, and it may be a clinically useful tool in the evaluation of RES in patients with ITP. Am. J. Hematol. 56:52–58, 1997. © 1997 Wiley-Liss, Inc.     

Successful treatment of severe refractory idiopathic thrombocytopenic purpura with liposomal doxorubicin

Idiopathic thrombocytopenic purpura (ITP) is refractory to initial treatment (steroids and splenectomy) in 25 to 30% of patients. These patients have a significant risk of fatal hemorrhage. Two patients with ITP refractory to multiple interventions and severe depression of platelet counts responded to treatment with liposomal doxorubicin with a return of platelet counts to normal. The drug is easily administered and was well tolerated. Use of this drug in refractory ITP merits further study. Am. J. Hematol. 57:85–86, 1998. © 1998 Wiley-Liss, Inc.     

Failure of repeated courses of high-dose intravenous immunoglobulin to induce stable remission in patients with chronic idiopathic thrombocytopenic purpura

Repeated courses of HD IVIg are reported to induce stable remission in a significant proportion of adults with chronic refractory ITP. We have treated 14 such patients obtaining a remission rate quite comparable to the 5–10% of spontaneous remission.     

Flow cytometry detection of platelets autoantibodies in children with idiopathic thrombocytopenic purpura

Abstract  

Immune thrombocytopenic purpura is an acquired disorder, in which accelerated platelet consumption is due to platelet autoantibodies. The aim of this study was to investigate the clinical value of platelet autoantibodies assay in children with ITP and to evaluate flow cytometry in the detection of platelet autoantibodies in comparison with monoclonal antibody specific immobilization of platelet antigen (MAIPA) assay. We measured platelet autoantibodies by flow cytometry and MAIPA in 18 children with ITP (6 acute, 7 chronic and 5 in remission), in addition to 5 healthy children with matched age and sex as a control group. Significant elevation of platelet-associated immunoglobulin G (PAIgG), PAIgM and PAIgA was demonstrated in children with acute ITP compared to controls and children with chronic ITP (P < 0.05). There was significant elevation of PAIgG and PAIgM in children with acute ITP compared to children with ITP in remission (P < 0.05). There was significant negative correlation between platelet count and PAIgG levels in ITP children (r = −0.717; P = 0.001). Flow cytometry found PAIgG in 94.4% of ITP children. MAIPA has detected platelet specific IgG autoantibodies in 83.3% of ITP children. ROC analysis revealed sensitivity of 94%, specificity of 57% with overall accuracy of 83% for detection of PAIgG by flow cytometry compared to MAIPA.     

Efficacy and safety of a nanofiltered liquid intravenous immunoglobulin product in patients with primary immunodeficiency and idiopathic thrombocytopenic purpura

Background and Objectives In the production process of a new 5% liquid intravenous immunoglobulin (IVIG‐L) product (Nanogam^®), a combined pepsin/pH 4·4 treatment/15‐nm filtration (pH 4·4/15NF) step and a solvent‐detergent (SD) treatment step were incorporated to improve the virus inactivating/reducing capacity of the manufacturing process. Two prospective uncontrolled multicentre studies were performed to evaluate the safety and efficacy of this product. Materials and Methods Efficacy, including pharmacokinetics, of IVIG‐L was studied for 6 months in 18 primary immunodeficiency (PID) patients, succeeded by a long‐term follow‐up study (mean 2·2 years, n = 17). Second, in 24 patients with idiopathic thrombocytopenic purpura (ITP), IVIG‐L was studied for efficacy for 14 days. In both studies, adverse events and vital signs were recorded to study safety. Results In PID patients treated with IVIG‐L, 0·60 and 0·38 severe infections per patient per year were reported during, respectively, the short‐term and long‐term follow‐up. Pharmacokinetic studies resulted in an IgG half‐life of 30·9 ± 11·3 days and a mean IgG trough level of 6·8 ± 1·2 g/l. In the ITP study, all patients showed an increase in platelet counts after infusion with IVIG‐L, and 20/24 patients responded with a platelet count > 50 × 10⁹/l (83·3%) within 1 week. IVIG‐L infusions did not cause clinical relevant changes in laboratory parameters or vital signs. Conclusions In clinical studies, IVIG‐L (Nanogam^®) demonstrated to be efficacious, well tolerated and safe.     

High-dose dexamethasone therapy in chronic idiopathic thrombocytopenic purpura

 A high-dose pulse of dexamethasone has been described as a current option for the treatment of refractory idiopathic thrombocytopenic purpura (ITP), but the results are controversial. Here we describe the use of a high dose of dexamethasone (40 mg per day for 4 days every month) in 18 patients with chronic ITP. The median age of the patients was 42.5 years (range, 16–77 years); 13 were female and five male. The duration of the disease ranged from 5 to 480 months, and splenectomy was carried out in six of the 18 patients.The overall results obtained revealed a satisfactory response (platelet counts higher than 50×10⁹/l) in eight of the 18 patients. However, a long-term remisson was achieved in only three of the eight patients with a follow up of 7–16 months. We were not able to identify any clinical or laboratory prognostic parameters or previous treatment which would allow one to predict a successful outcome of this treatment. These results suggest that a high dose of dexamethasone may provide an alternative, be it a poor one, for the treatment of refractory IPT, in which the use of a low-cost drug with limited side effects is an important consideration. Received: 18 March 1996 / Accepted: 2 July 1996     

Multiple cerebral infarctions in a patient with refractory idiopathic thrombocytopenic purpura

Multiple cerebral infarctions were observed in a patient with refractory idiopathic thrombocytopenic purpura who was positive for lupus anticoagulant (LAC) when her platelet counts were 2000 μL⁻¹. It is suspected that LAC may have played an important role in the pathogenesis of this patient's cerebral infarctions, although she had severe thrombocytopenia.