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

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/microliters 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.     

Cellular changes during the infusion of high dose intravenous immunoglobulin

With the ever widening group of autoimmune conditions that are beneficially affected by infusions of high dose immunoglobulin the possible mechanisms of action of such therapy appear increasingly complex. Fc mediated blockade of the mononuclear phagocyte system is an acknowledged early effect. This is, however, accompanied by a decrease of neutrophil counts which suggests that IgG binding to the neutrophil may be a mechanism of action. The decrease of neutrophil counts is transient but in immune thrombocytopenia is inversely proportional to the platelet response observed. In parallel to the effect on the neutrophil there are changes in the lymphocyte subsets with reversal of the T helper/suppressor ratio and alterations in the individual cellular constituents of each subset that correlate with the clinical response. The observed changes in B cell numbers and function suggest that T dependent and independent antibody production is effected by intravenous immunoglobulin. It is increasingly clear that in ITP at least the clinical response to IV IgG is a summation of several cellular events and their balance reflects the ultimate outcome. It may eventually be possible to use these observations to predict the likely outcome in the individual patient of this mode of therapy.     

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

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.     

Post-transfusion purpura following open heart surgery: management by high dose intravenous immunoglobulin infusion

We present three cases of post-transfusion purpura (PTP) developing in the immediate post operative period after open heart surgery. All had developed platelet specific antibodies and severe anaphylactoid reactions occurred to platelet transfusion in two cases. Treatment with high dose intravenous immunoglobulin (IV IgG) led to complete recovery in two patients one of whom demonstrated a marked biphasic response pattern to therapy. The other died from congestive cardiac failure. PTP is a potentially fatal complication which may well become more frequent with increasing blood product usage.     

Functional integrity of intravenous immunoglobulin following irradiation with a virucidal dose of gamma radiation.

Although intravenous immunoglobulins (IVIG) and other plasma therapeutics have had a relatively good safety record, improved methods for viral clearance are constantly being evaluated and incorporated into new manufacturing processes. Gamma irradiation has been used routinely to assure sterility of healthcare products and medical devices, but it has not been applied successfully as a viral inactivation method for biologics. We examine whether virucidal doses of gamma irradiation (50 kGy) can be delivered to a manufacturing intermediate form of IVIG, a fractionated plasma paste, with negligible effect on structural and functional integrity of purified IgG product. Immunoglobulins from paste were examined for radiation-induced damage by SDS-PAGE and ELISAs utilizing viral antigens specific for rubella, CMV and mumps. Fc domain integrity was assessed by immunoblotting, quantitatively comparing the binding of irradiated and non-irradiated materials to cell surface Fcgamma receptors, and by employing quantitative RT-PCR to study the kinetics of accumulation of mRNA for the immune modulatory cytokines IL-1alpha, IL-1beta, IL-4, IL-8, IFNgamma, and TNFalpha. The results demonstrate that Fab and Fc domains of IVIG remain essentially intact and functional after gamma irradiation to virucidal doses, suggesting that this method could be used to enhance the safety of IVIG products.     

High dose intravenous immunoglobulin repertoire versus anti-D. Disproportions in quantity and quality.

Here we consider certain therapeutic effects that intravenous administration of pooled high dose immunoglobulin and anti-D IgG share. Despite million-fold difference in doses such an effect occurs at least in idiopathic thrombocytopenic purpura (ITP). We postulate that spontaneous bleeding events may remit even when platelet numbers show refractoriness. We also mention the possible sparing of anti-D antibody-coated red blood cell (RBC) destruction and, finally, an acceleration of fibrotic involution. Fc receptors (FcRs) play a central role; beyond the well-established interactions with the immunoglobulin Fc fragment, FcRs are supposed to display special cognitive properties that enable them to pick out the therapeutic molecules from the recipient's IgG pool. Such subtle selection suggests some disarray in the host. On the other hand it may explain why the often-encouraging outcome of IVIG therapy remains unpredictable.     

Human intravenous immunoglobulin preparation and virus inactivation by pasteurization and solvent detergent treatment

Human intravenous immunoglobulin (IVIG) solutions were prepared by two different methods and compared to each other. The crude immunoglobulin fraction obtained from Cohn-Oncley fractionation of plasma was further purified and subjected to virus inactivation, either by polyethylene glycol precipitation and pasteurization at 60 degrees C for 10 hours, or by ion exchange chromatography and solvent/detergent treatment. The final preparations, formulated in 5% immunoglobulin solutions were characterized by in vitro analyses of biochemical and biological properties and compared with the samples of other manufacturer's IVIG solution products. The critical properties evaluated in this study were purity, molecular intactness, and the biological functions such as Fc function and anticomplementary activity. Virus inactivation and removal by processing steps and by deliberate virucidal steps, as described above, were tested on various human pathogenic viruses, such as human immunodeficiency and experimental model viruses. The tested viruses were successfully inactivated and removed. We conclude that the intravenous immunoglobulins prepared by two different methods, as described above, provide an equivalent viral safety and quality.     

Equivalent inhibition of in vivo platelet function by low dose and high dose aspirin treatment

In vitro platelet function was inhibited in healthy volunteers by two different doses of aspirin, as confirmed by measurement of maximum serum production of thromboxane B2 (TXB2) by platelets. 75 mg aspirin did not fully inhibit serum TXB2 production after 24 hours, whereas 300 mg aspirin did. Inhibition of platelet function in vitro was maintained by both 75 mg/day aspirin or 300 mg/alternate day aspirin. In contrast, in vivo production of TXB2, measured as urinary levels of the 11-keto-TXB2 metabolite, was inhibited similarly by both doses of aspirin throughout the study. These findings suggest that 75 mg/day aspirin may be sufficient adequately to inhibit platelet aggregation in vivo.     

Hypotension with intravenous immunoglobulin therapy: importance of pH and dimer formation

Therapy with intravenous immunoglobulin preparations has been used effectively in a wide range of conditions. Although generally well tolerated, intravenous immunoglobulin preparations may be associated with transient hypotension in some patients. This study examined the role of different immunoglobulin G fractions in the development of intravenous immunoglobulin-induced hypotension in an anaesthetized rat model and assessed the effects of a new liquid immunoglobulin prepared at a low pH on both the formation of immunoglobulin G dimers and the development of hypotension. The effects of this new preparation in an experimental autoimmune encephalomyelitis model were also evaluated.Results from the haemodynamic studies indicated that immunoglobulin G dimers in polyclonal immunoglobulin G are responsible for the hypotensive events associated with some immunoglobulin preparations. They also showed that adjustment to an acidic pH results in the rapid dissociation of immunoglobulin G dimers and prevents the development of hypotension. Additional experiments demonstrated that only immunoglobulin G dimers with a functional Fc fragment can bind to Fcgamma receptors on macrophages to induce the release of blood pressure-lowering mediators. Moreover, essentially monomeric Fc fragments can block the blood pressure-lowering effects of immunoglobulin G dimers.Preparation of a new liquid intravenous immunoglobulin with the pH adjusted to 4.3 prevents the formation of immunoglobulin G dimers even over long-term storage and does not significantly affect blood pressure in a rat model. This preparation is as effective as other intravenous immunoglobulin preparations in ameliorating symptoms of experimental autoimmune encephalomyelitis. These results, like those from previous studies, indicate that preparation of intravenous immunoglobulin at a low pH substantially reduces immunoglobulin G dimerization; this effect significantly decreases the potential for intravenous immunoglobulin to induce hypotension without reducing its clinically relevant biological activity.     

Haemophilia due to factor VIII inhibitors in a patient suffering from an autoimmune disease: treatment with intravenous immunoglobulin. A case report

This paper describes a case of haemophilia due to factor VIII inhibitors occurring in a 13-year-old boy suffering from an autoimmune disease. The patient had autoantibodies to factor VIII. The haemophilia was controlled by vincristine and steroids, but this regimen had to be discontinued because of side effects, whereupon the haemophilia recurred. Treatment with intravenous immunoglobulin (IgG i.v.) produced a slow rise in factor VIII, and the factor VIII inhibitors disappeared. Although factor VIII activity was raised for only a few months and factor VIII inhibitors reappeared, immunoglobulin treatment was continued and the patient remained free of clinical symptoms. The mechanism of action of treatment with IgG is discussed.