High-dose IgG Research Articles

Neonatal allo-immune thrombocytopenia due to fetomaternal HPA-1 incompatibility of a homozygous HPA-1a mother and a homozygous HPA-1b father

We report a case of neonatal allo-immune thrombocytopenia due to fetomaternal human platelet antigen (HPA)-1 incompatibility. Anit-HPA-1b antibodies were detectable in maternal serum. Repeated treatment of the infant with high-dose IgG effectively raised platelet counts transiently, but the patient remained thrombocytopenic for more than 6 weeks. Serological and DNA analysis revealed that the mother was homozygous HPA-1a and the father homozygous HPA-1b.

Severe thrombocytopenia in an acquired immunodeficiency syndrome patient associated with pentamidine-dependent antibodies specific for glycoprotein IIb/IIIa

Severe thrombocytopenia developed in a patient with acquired immunodeficiency syndrome during treatment with intravenous pentamidine for Pneumocystis carinii pneumonia. The patient's bone marrow contained adequate numbers of megakaryocytes, suggesting peripheral platelet destruction. Platelet counts ranged between less than 3 and 20 x 10(9)/L for 2 weeks despite cessation of pentamidine, platelet transfusions, high-dose intravenous IgG, and 2 mg/kg/d prednisone. Thereafter, the platelet count increased to prepentamidine levels (95 x 10(9)/L0, permitting rapid withdrawal of steroids. Testing by immunofluorescence disclosed a high-titer, pentamidine-dependent IgG antibody in the patient's acute-phase serum that almost entirely disappeared by the time the patient's platelet count returned to baseline levels. This antibody reacted only with platelet glycoprotein (GP) IIb/IIIa as shown by antigen-capture enzyme-linked immunosorbent assay using monoclonal antibodies specific for various GPs, and was absorbable by normal, but not by GPIIb/IIIa-deficient platelets (from a patient with Glanzmann's thrombasthenia). The pentamidine-dependent antibody could not be demonstrated by immunoprecipitation using the patient's serum and 125I-labeled normal platelets, although a separate pentamidine-independent antibody was detected by this method. This latter antibody reacted with two GPs having molecular weights consistent with GPIIb/IIIa, and was present in postrecovery as well as acute-phase sera. However, only the pentamidine-dependent antibody was temporally associated with the severe thrombocytopenia. Therefore, we believe that these studies demonstrate, for the first time, that intravenous pentamidine therapy can provoke formation of drug-dependent antibodies that induce immunologic thrombocytopenia.

Severe Thrombocytopenia in an Acquired Immunodeficiency Syndrome Patient Associated With Pentamidine-Dependent Antibodies Specific for Glycoprotein IIb/IIIa

Severe thrombocytopenia developed in a patient with acquired immunodeficiency syndrome during treatment with intravenous pentamidine for Pneumocystis carinii pneumonia. The patient's bone marrow contained adequate numbers of megakaryocytes, suggesting peripheral platelet destruction. Platelet counts ranged between less than 3 and 20 x 10(9)/L for 2 weeks despite cessation of pentamidine, platelet transfusions, high-dose intravenous IgG, and 2 mg/kg/d prednisone. Thereafter, the platelet count increased to prepentamidine levels (95 x 10(9)/L0, permitting rapid withdrawal of steroids. Testing by immunofluorescence disclosed a high-titer, pentamidine-dependent IgG antibody in the patient's acute-phase serum that almost entirely disappeared by the time the patient's platelet count returned to baseline levels. This antibody reacted only with platelet glycoprotein (GP) IIb/IIIa as shown by antigen-capture enzyme-linked immunosorbent assay using monoclonal antibodies specific for various GPs, and was absorbable by normal, but not by GPIIb/IIIa-deficient platelets (from a patient with Glanzmann's thrombasthenia). The pentamidine-dependent antibody could not be demonstrated by immunoprecipitation using the patient's serum and 125I-labeled normal platelets, although a separate pentamidine-independent antibody was detected by this method. This latter antibody reacted with two GPs having molecular weights consistent with GPIIb/IIIa, and was present in postrecovery as well as acute-phase sera. However, only the pentamidine-dependent antibody was temporally associated with the severe thrombocytopenia. Therefore, we believe that these studies demonstrate, for the first time, that intravenous pentamidine therapy can provoke formation of drug-dependent antibodies that induce immunologic thrombocytopenia.

Thrombotic Thrombocytopenic Purpura Resistant to Plasma-exchange: Salvage Treatment with High-dose IgG or Vincristine

Even though plasmaexchange (PE), either alone or combined with cortisone or platelet anti-aggregating substances is the treatment of choice for TTP, 10-15% of patients is resistant to treatment. Since immunoglobulin (IgG) infusion was reported to cure the clinical symptoms of PE-resistant TTP, and vincristine (VCR) has been recently successful in treating TTP, we reviewed the results obtained with both drugs in 20 PE-resistant patients. Of 12 patients receiving IgG and 8 receiving VCR, 3 (25%) and 4 (50%), respectively, achieved complete remission. Even though no conclusions can be drawn from such results, if complete remission can be achieved in a however small number of PE-resistant patients, the use of these drugs is suggested as a salvage treatment for TTP.

Surgical treatment of immune thrombocytopenic purpura

The role of surgery in the treatment of immune thrombocytopenic purpura (ITP) is still discussed. The aim of this study was to verify our criteria of patient selection for splenectomy, to analyze the results of a protocol for the evaluation of the hemorrhagic risk, and to discuss long-term results of 70 patients with ITP who underwent surgical treatment from 1984 to 1990. All patients received steroid therapy. Sixty-two patients were given high doses of IgG (600 mg/kg/iv bolus) pre-operatively in order to obviate the need for intra-operative platelet transfusions. Forty-three patients showed a significant increase in the platelet count, 8 a moderate increase, while 11 patients did not respond. No operative mortality was observed, however postoperative minor complications occurred in 14 (20%) patients. Accessory spleens were found in 11 (15.7%) patients. Mean follow-up was 21 months. Response to splenectomy was considered as complete (platelets greater than 150,000 mm3 with no need for medical treatment) in 63 (90%) patients. No response was observed in 7 patients. In 2 of the non-responders postoperative indium-111 scan revealed accessory spleens and ITP remitted after accessory splenectomy. All non-responders were in the group of patients who did not respond to the pre-operative infusion of high dose IgG. It can be concluded that splenectomy is a safe and effective treatment for ITP and that response to pre-operative infusion of IgG may be considered as predictive for the outcome after splenectomy.

Therapeutic approach with IVIG in patients affected by connective tissue disease

The infusion of high-dose intravenous IgG (IVIG) may result in clinical improvement and immunological changes in patients affected by connective tissue diseases. In our experience patients affected by severe rheumatoid arthritis derive a limited benefit from IVIG therapy, namely when this treatment is followed by a drop in CD8+ cell number. When IVIG infusion fails to induce a decrease in the number of CD8+ cells, the outcome seems to be better but the clinical remission is usually temporary in such severely affected patients. In patients affected by systemic lupus erythematosus, manifestations of the disease sensitive to IVIG included encephalitis, cytopenias and anti-cardiolipin-related recurrent fetal loss. Severe renal involvement should be considered as a counterindication to IVIG therapy, since renal function may rapidly deteriorate. Some cases of necrotizing vasculitis may also benefit from IVIG therapy. Despite the uncertain therapeutic value of IVIG in patients affected by connective tissue diseases, this regimen showed clinical efficacy in some cases and proved to interfere with the immunological mechanisms thought to sustain these diseases.

Effects of high-dose IgG on survival of surgical patients with sepsis scores of 20 or greater: Dominioni L, Diorigi R, et al. Arch Surg 126:236, 1991

Effects of high-dose IgG on survival of surgical patients with sepsis scores of 20 or greater: Dominioni L, Diorigi R, et al. Arch Surg 126:236, 1991

High-dose IgG for neutropenic patients with acquired immunodeficiency syndrome (AIDS)

Leukocytopenia and bacterial infections are common and serious complications in patients with AIDS. We report here on three patients in whom the administration of high IgG doses led to gradual (two patients) or prompt (one patient) increases in circulating leukocyte counts (from 200-600 to 2500-5900/microliters), inducing definite improvement in two patients; one patient died from Pneumocystis carinii pneumonia. Although the rise in leukocyte counts lasted for only approximately 3 weeks, high-dose IgG might be a useful therapeutic adjunct in such patients.

Post-transfusion purpura as the main manifestation of a trilineal transfusion reaction, responsive to steroids: flow-cytometric investigation of granulocyte and platelet antibodies

We report a typical case of post-transfusion purpura (PTP) due to anti-PlA1 in a 65-year-old woman. Serological studies were carried out using flow cytometry (FCM). The patient also developed red cell alloantibodies that produced a delayed hemolytic transfusion reaction (DHTR) and broad HLA antibodies. Treatment with high-dose intravenous IgG (HDIgG; a first-generation preparation) was ineffective, but a course of steroids resulted in a rapid increase in the the platelet count.

Stimulation of B and T cells by in vivo high dose immunoglobulin administration in normal mice

Adult BALB c mice were injected intravenously with a preparation of pooled normal murine IgG (400 mg/kg/day, on five consecutive days) and studied 8, 15, and 60 days later. High dose IgG administration increased the total numbers of splenic activated B and CD4 + (but not CD8 +) T cells, as well as the numbers of splenic Ig-secreting cells, particularly in the IgG isotypes. Reactivities to some autoantigens, but not to bacterial or other heteroantigens, were selectively amplified amongst IgM-secreting cells. IgG administration did not alter the specific primary immune response to heterologous erythrocytes or bacterial dextran. No cellular alterations were detected in the lymph nodes or peritoneal cavity of treated animals. Most of these effects subsided with time, but some autoantibody reactivities remained elevated 60 days later. The present results suggest that the therapeutic effects of high dose IgG administration which have been reported in human diseases might be associated with the immunostimulatory activities of such treatment.

Effects of High-Dose IgG on Survival of Surgical Patients With Sepsis Scores of 20 or Greater

Sixty-two consecutive septic surgical patients receiving standard multimodal intensive care unit treatment who developed a sepsis score of 20 or greater (day 0) were randomized to receive 0.4 g/kg of either intravenous IgG (29 patients) or human albumin (controls; 33 patients), repeated on days +1 and +5, in a prospective, double-blind, multicenter study. The two groups were similar in age, initial sepsis scores, and acute physiology and chronic health evaluation II score. A significantly lower mortality was recorded in the IgG-treated group (38%) than in controls (67%). Septic shock was the cause of death in 7% of IgG-treated patients and in 33% of controls. The results of this study indicate that high-dose IgG improves survival and decreases death from septic shock in surgical patients with a sepsis score of 20 or greater.

High-Dose Intravenous IgG for the Treatment of Severe Rhesus Alloimmunization

High-Dose Intravenous IgG for the Treatment of Severe Rhesus Alloimmunization

Thrombotic Thrombocytopenic Purpura Treated With High-Dose Intravenous Gamma Globulin

Plasma infusion and/or plasma exchange has become standard therapy in the treatment of thrombotic thrombocytopenic purpura (TTP). The management of patients in whom such primary therapy fails is difficult and uncertain. We have described a patient who obtained a sustained remission with the use of high-dose IV gamma globulin after an initial response to aggressive plasma exchange was followed by prompt relapse. Our case and others suggest that high-dose IV IgG may induce remission in patients with TTP who do not respond to standard plasma infusion and/or exchange.

Behçet's syndrome treated with high-dose intravenous IgG and low-dose aspirin

Behçet's syndrome treated with high-dose intravenous IgG and low-dose aspirin

Noncoagulation Inhibitory Factor VIII Antibodies After Induction of Tolerance to Factor VIII in Hemophilia A Patients

We recently described tolerance induction with factor VIII/IX, cyclophosphamide, and high-dose intravenous IgG in hemophilia A or B patients with coagulation inhibitory antibodies. Circulating noninhibitory antibodies complexed with factor IX have been demonstrated in tolerant hemophilia B patients. Similar findings are now described in six tolerant hemophilia A patients. Complexes between factor VIII and the 'tolerant' antibody were demonstrated by subjecting plasma to gel filtration chromatography, void fractions containing factor VIII/vWF complexes being collected and adsorbed to protein A. Using 125I-labeled F(ab')2 fragments against IgG subclass and factor VIII antigen, complexes between an IgG4 antibody and factor VIII were found to adsorb to protein A. After infusion of factor VIII to tolerant patients, all factor VIII circulated in complex with IgG4 antibody. In three of the patients, the 'tolerant' antibodies inhibited an ELISA specific for factor VIII light chain but, unlike the pretolerant antibodies, did not bind radiolabeled factor VIII heavy chain. Although after induction of tolerance the patients still have circulating IgG4 antibodies against factor VIII, the antibodies differ in specificity, lack coagulation inhibitory activity, and do not enhance the rate of elimination of factor VIII.

Noncoagulation inhibitory factor VIII antibodies after induction of tolerance to factor VIII in hemophilia A patients

We recently described tolerance induction with factor VIII/IX, cyclophosphamide, and high-dose intravenous IgG in hemophilia A or B patients with coagulation inhibitory antibodies. Circulating noninhibitory antibodies complexed with factor IX have been demonstrated in tolerant hemophilia B patients. Similar findings are now described in six tolerant hemophilia A patients. Complexes between factor VIII and the ‘tolerant’ antibody were demonstrated by subjecting plasma to gel filtration chromatography, void fractions containing factor VIII/vWF complexes being collected and adsorbed to protein A. Using 125I-labeled F(ab')2 fragments against IgG subclass and factor VIII antigen, complexes between an IgG4 antibody and factor VIII were found to adsorb to protein A. After infusion of factor VIII to tolerant patients, all factor VIII circulated in complex with IgG4 antibody. In three of the patients, the ‘tolerant’ antibodies inhibited an ELISA specific for factor VIII light chain but, unlike the pretolerant antibodies, did not bind radiolabeled factor VIII heavy chain. Although after induction of tolerance the patients still have circulating IgG4 antibodies against factor VIII, the antibodies differ in specificity, lack coagulation inhibitory activity, and do not enhance the rate of elimination of factor VIII.

High-dose IgG treatment for neonatal alloimmune thrombocytopenia.

Twelve children with neonatal alloimmune thrombocytopenia (NAT) due to Zwa incompatibility were treated with intravenous IgG (IVIG). Total doses ranged between 1 and 9 g. Ten out of 12 infants had a favorable response. It is concluded that IVIG can serve as an emergency treatment in NAT if material (or compatible) platelets are not available.

Posttransfusion Purpura Associated with an Anti‐Bakb

We describe a 46-year-old white woman with typical clinical features of posttransfusion purpura (PTP) whose serum held a platelet-specific alloantibody reactive with an antigen antithetical to Baka, i.e. anti-Bakb. The specificity of the antibody was confirmed by family analysis, a population study (expected versus observed gene frequency: 0.3651 versus 0.3984; n = 105) and localization of the antigen on glycoprotein IIb in radioimmunoprecipitation. Typing of family members and blood donors for platelet antigens disclosed that the patient had been preimmunized by two blood transfusions in 1981, while fetomaternal incompatibility for Bakb was ruled out (her three children and their father were Bakb negative). Treatment of PTP with corticosteroids and platelet transfusions was ineffective, but infusion of high-dose intravenous IgG resulted in a rapid increase in the platelet count.

High-dose IgG for post-transfusion purpura-revisited.

Therapy for post-transfusion purpura (PTP) is controversial. We have evaluated the effect of high-dose IgG (HDIgG) in 11 PTP cases investigated in our institution and summarized the clinical data of 8 additional cases reported in the literature. Two of these 19 cases had to be eliminated from the analysis (1 patient received a total dose of less than 30 g of IgG; 1 patient died 2 days after starting HDIgG therapy from congestive heart failure). Out of a total of 17 cases, 16 had good or excellent response reaching normal platelet values within few days; only one failure was observed. Five patients relapsed, but attained complete remission after a second course (dose) of IgG. Total doses per course ranged between 52 and 180 g of IgG. Five different IgG preparations were used and seemed similarly effective. No adverse reactions were observed. We conclude that HDIgG is the treatment of choice for PTP.

Induction of immune tolerance in patients with hemophilia and antibodies to factor VIII by combined treatment with intravenous IgG, cyclophosphamide, and factor VIII.

The development of antibodies to factor VIII is a serious complication of the treatment of patients with hemophilia A. We successfully induced immune tolerance in patients with such antibodies with a new treatment protocol, which combined factor VIII, cyclophosphamide, and high-dose intravenous IgG, followed by regular prophylactic treatment with factor VIII. This protocol has now been used in 11 patients with hemophilia A, of whom 9 had a strong antibody response. When the initial concentration of antibodies exceeded 3 Malmö inhibitor units (corresponding to about 10 Bethesda units) per milliliter, treatment was preceded by adsorption of antibody to protein A. After two to three weeks of the combined treatment, factor VIII coagulant antibodies had disappeared in 9 of the 11 patients; in 8 of these 9 patients the half-life of infused factor VIII had normalized. The tolerant state appears to be stable after a median of 30 months. Two patients did not respond to the treatment. Because earlier treatment with factor VIII and cyclophosphamide or with factor VIII and IgG had been ineffective in these patients, our experience suggests that all three components of the protocol are required for the successful induction of tolerance to factor VIII.