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The treatment of chronic idiopathic thrombocytopenia with anti-D (Rho) immunoglobulin: Its effectiveness, safety and mechanism of action
Abstract
Twenty-three courses of i.v. anti-D (Rho) immunoglobulin were administered to 13 Rh D-positive patients with chronic idiopathic thrombocytopenia (ITP). Clinically significant responses were seen in a proportion of patients treated with 500-2500 i.u. anti-D, but all those treated with 12,500 i.u. (180 i.u./kg) responded. Patients refractory to other forms of treatment responded well to anti-D, and previous splenectomy did not influence the clinical response. No adverse reactions were observed. The anti-D response was preceded by a lag period of 3-16 days and was maintained for 14-145 days. Platelet-associated IgG was increased after treatment, due to improved survival of immunosensitized platelets or platelet Fc receptor binding of high molecular weight IgG in the therapeutic material. There was no clinical or biochemical evidence of haemolysis. The erythrocyte direct Coombs' test remained positive for 3-45 days, and histological examination of splenic material showed no erythrophagocytosis. We conclude that anti-D (Rho) immunoglobulin is a safe and effective treatment for chronic ITP and that the therapeutic dose is now established in standardized units. The mechanism of action appears to be complex and is probably not due to macrophage Fc receptor blockade with immunosensitized red cells.
... Boughton et al reported a study of 13 Rh-positive adult patients with chronic ITP who received varying intravenous doses of anti-D. 21 Signifi cant increases in platelet counts were seen in all patients, especially those who received 12,500 IU of anti-D. No adverse effects were observed in the patient groups. ...
Immune thrombocytopenia (ITP) is an acquired bleeding autoimmune disorder characterized by a markedly decreased blood platelet count. The disorder is variable, frequently having an acute onset of limited duration in children and a more chronic course in adults. A number of therapeutic agents have demonstrated efficacy in increasing the platelet counts in both children and adults. Anti-RhD immunoglobulin (anti-D) is one such agent, and has been successfully used in the setting of both acute and chronic immune thrombocytopenia. In this report we review the use of anti-D in the management of ITP. While the FDA-approved dose of 50 mg/kg has documented efficacy in increasing platelet counts in approximately 80% of children and 70% of adults, a higher dose of 75 μg/kg has been shown to result in a more rapid increase in platelet count without a greater reduction in hemoglobin. Anti-D is generally ineffective in patients who have failed splenectomy. Anti-RhD therapy has been shown capable of delaying splenectomy in adult patients, but does not significantly increase the total number of patients in whom the procedure can be avoided. Anti-D therapy appears to inhibit macrophage phagocytosis by a combination of both FcR blockade and inflammatory cytokine inhibition of platelet phagocytosis within the spleen. Anti-RhD treatment is associated with mild to moderate infusion toxicities. Rare life-threatening toxicities such as hemoglobinuria, acute renal failure and disseminated intravascular coagulation have been reported. Recommendations have been proposed to reduce the risk of these complications. Anti-D immunoglobulin can be an effective option for rapidly increasing platelet counts in patients with symptomatic ITP.
... 27 Several studies have confirmed that anti-RhD is an effective and safe treatment option in ITP. 28,29 Moreover, similar to IVIG, this agent has the benefit of inducing a more rapid increase in platelet count than oral corticosteroids; however, it also requires intravenous infusion and usually demonstrates a infection did not influence the response to the treatment among the adults. The response rate in the adult group was 72% and was significantly higher in patients with hemoglobin levels ≥12 g/dL. ...
Immune thrombocytopenia (ITP) is an autoimmune disease characterized by platelet destruction and reduced platelet production resulting in decreased platelet level and an increased risk of bleeding. Based on the immunologic mechanism of ITP, front‐line standard therapy consists of corticosteroids and intravenous immunoglobulins (IVIG). If patients do not respond to the first‐line treatment, or if continuous therapy is required, the disorder is called refractory ITP, and second‐line therapy is indicated. This treatment may consist of rituximab, thrombopoietin receptor agonists, splenectomy, or cytotoxic drugs. Despite significant advances, many patients do not respond to any the treatments listed below, and new treatment options need to be developed for this relapsed and refractory group. Recent clinical studies have indicated promising outcomes for novel drugs, either as single agents or in combination with traditional drugs. This review discusses the latest and the most promising novel drugs for ITP in adults.
... High doses of methylpredisolone are considered to be as effective as IVIg. In some reports, a synergistic effect was suggested when IVIg and methylprednisolone were used together (28,29). Anti-D immunoglobulin may transiently increase the platelet count in rhesus-D-positive patients (30), but in one trial the response rate to anti-D was significantly lower than to IVIg (13). ...
In the last decade large amounts of intravenous immunoglobulin (i.v.Ig) have been used worldwide. Doubts exist as to whether this increased use is paralleled by a comparable growth of reliable data on the therapeutic effectiveness of i.v.Ig. We performed a literature search using MEDLINE from January 1981 to January 1997 and analysed articles on the use of i.v.Ig in hematological disorders and searched for published guidelines. For most hematological disorders, evidence to use i.v.Ig as first line therapy is not very strong. For many disorders no controlled trials have been performed. In published guidelines, i.v.Ig is only recommended, with a few exceptions, when other treatments have failed or are contraindicated. Therefore the increase of consumption of i.v.Ig can not be explained by an increase in established indications in hematology.
... Boughton et al reported a study of 13 Rh-positive adult patients with chronic ITP who received varying intravenous doses of anti-D.21 Significant increases in platelet counts were seen in all patients, especially those who received 12,500 IU of anti-D. ...
Immune thrombocytopenia (ITP) is an acquired bleeding autoimmune disorder characterized by a markedly decreased blood platelet count. The disorder is variable, frequently having an acute onset of limited duration in children and a more chronic course in adults. A number of therapeutic agents have demonstrated efficacy in increasing the platelet counts in both children and adults. Anti-RhD immunoglobulin (anti-D) is one such agent, and has been successfully used in the setting of both acute and chronic immune thrombocytopenia. In this report we review the use of anti-D in the management of ITP. While the FDA-approved dose of 50 mg/kg has documented efficacy in increasing platelet counts in approximately 80% of children and 70% of adults, a higher dose of 75 microg/kg has been shown to result in a more rapid increase in platelet count without a greater reduction in hemoglobin. Anti-D is generally ineffective in patients who have failed splenectomy. Anti-RhD therapy has been shown capable of delaying splenectomy in adult patients, but does not significantly increase the total number of patients in whom the procedure can be avoided. Anti-D therapy appears to inhibit macrophage phagocytosis by a combination of both FcR blockade and inflammatory cytokine inhibition of platelet phagocytosis within the spleen. Anti-RhD treatment is associated with mild to moderate infusion toxicities. Rare life-threatening toxicities such as hemoglobinuria, acute renal failure and disseminated intravascular coagulation have been reported. Recommendations have been proposed to reduce the risk of these complications. Anti-D immunoglobulin can be an effective option for rapidly increasing platelet counts in patients with symptomatic ITP.
... 88 "" 93 Other investigators reported similar results. [94][95][96][97][98][99][100] The same approach has been used for treating HIV-related thrombocytopenia in D+ patients. 98 < 10°-i°3 In about 25% of D+ patients, Rh(D) IVIgG therapy does not seem effective. ...
The problem of passively acquired alloantibodies is an old one. Since group O blood was first transfused to patients who were not group O, clinicians and immunohematologists have had to deal with the passive transfer of anti-A, anti-B, and anti-A,B to group A, B, or AB recipients. As more plasma products (eg, platelets, fresh frozen plasma, coagulation factors) were used for recipients who were sometimes not ABO identical, the problems grew. With the advent of bone marrow transplantation (BMT), the increasing use of intravenous immune gamma globulin (IVIgG), and, more recently, the use of intravenous (TV) anti-D, an Rh (D) immune globulin, in Rh+ recipients, new problems have arisen. The last problem initiated this review.
... 2,3,[5][6][7] Several reports have suggested that anti-D immunoglobulin is superior to ''normal'' immunoglobulin for treatment of ITP, at least in some cases. [8][9][10][11] The usual mechanism of action proposed for this is more e#icient blockade of the reticuloendothelial system by immunoglobulin sensitised erythrocytes. 12 On the basis of this some reports recommend the use of much lower doses of intramuscular anti-D rather than high doses of intravenous Ig (IVIG) for treatment of ITP patients. ...
Several reports have suggested that low dose anti-D immunoglobulin is superior to high dose immunoglobulin for treatment of idiopathic thrombocytopenia purpura (ITP). However, some findings suggest that it is not the anti-D activity per se that is responsible for efficacy for treatment of ITP with anti-D immunoglobulin. Amongst alternative explanations for the mechanism of action is a relatively higher immunoglobulin polymer content of anti-D compared to other immunoglobulin products, which is more efficient in causing reticuloendothelial Fc receptor blockade. In order to investigate this we have evaluated the polymeric IgG content of anti-D and other immunoglobulin products. Different products showed considerable variation in immunoglobulin polymer content. There was no clear correlation between aggregate or dimer content and product type and anti-D as a class of product did not contain higher amounts of either dimer or aggregate compared to other products. Some manufacturers' products increased in polymer content on storage, but others did not show this effect. Therefore, higher immunoglobulin dimer and/or aggregate content cannot explain the increased efficacy of anti-D immunoglobulin for treatment of ITP. The role of polymeric Ig in efficacy for treatment of ITP is unclear.
Tissue plasminogen activator (tPA) is the only US Food and Drug Administration (FDA)-approved drug for ischemic stroke. However, delayed tPA administration is associated with increased risk of blood-brain barrier (BBB) disruption and hemorrhagic transformation (HT). Interferon-β (IFNβ), an FDA-approved drug for the treatment of multiple sclerosis, is a cytokine with immunomodulatory properties. Previous studies, including ours, demonstrated that IFNβ or type I IFN receptor signaling conferred protection against ischemic stroke in preclinical models, suggesting IFNβ might have translational therapeutic potential for the treatment of ischemic stroke. Currently, whether IFNβ could be coadministered with tPA to alleviate delayed tPA-induced adverse effects remains unknown. To elucidate that, IFNβ was coadministered with delayed tPA to ischemic stroke animals, and the severity and pathology of ischemic brain injury were assessed. We found delayed tPA treatment exacerbated ischemic brain injury, manifested by aggravated BBB disruption and HT. Notably, IFNβ ameliorated delayed tPA-exacerbated brain injury and alleviated adverse effects. Mechanistic studies revealed IFNβ suppressed tPA-enhanced neuroinflammation and MMP3/9 production in the ischemic brain. Furthermore, we identified IFNβ suppressed MMP9 production in microglia and attenuated tight junction protein degradation in brain endothelial cells. Moreover, we observed that peripheral immune cells may participate to a lesser extent in delayed tPA-exacerbated brain injury during the early phase of ischemic stroke. In conclusion, we provide the first evidence that IFNβ can be coadministered with tPA to mitigate delayed tPA-induced adverse effects of BBB disruption and HT that could potentially extend the tPA therapeutic window for the treatment of ischemic stroke.
Five patients with ITP were treated with 2 gram intravenous infusions of intramuscular human non specific immunoglobulin (IMIg). Increased platelet counts similar to those achieved with intravenous Rhesus anti D immunoglobulin were observed in four patients. 5000 iu anti D immunoglobulin contain up to 2 g of IMIg, and the clinical responses seen in ITP patients treated with anti D may therefore be attributed to this non specific fraction. This was supported by the in vitro finding that adsorption of the rhesus specific IgG from anti D immunoglobulin did not reduce its inhibitory effect on monocyte Fc receptor function. The dose of intravenous IMIg which produced a response in ITP was less than 2% of the recommended standard dose of intravenous immunoglobulin. This correlated with the higher concentration of IgG polymers in IMIg, and we suggest therefore that the mechanism of action of this material is due to the inhibitory effect of its polymeric IgG fraction on low affinity monocyte/phagocyte Fc receptors.
Pathophysiology: Chronic idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by platelet destruction due to an antiplatelet autoantibody, usually of the IgG class, which coats autologue platelets and leads to their elimination by the reticuloendothelial system (RES). While in childhood ITP is more usually an acute and self-limiting problem which needs no drug treatment, adult ITP is a relatively common chronic hematological disease. Treatment: Treatment aimes at inhibition of antibody-production and binding on thrombocytes and thrombocyte phagocytosis by the RES. Therapy should result in a platelet count of > 100,000/mu l or at least in stabilization of the platelet count without bleeding. Therapeutic approaches were divided into emergency and long-term treatment. In patients who require non-emergency treatment conventional-dose corticoids (1 to 2 mg/kg/d prednisone) are recommended as initial treatment, whereas pulsed high-dose dexamethason is recently reported to be effective in refractory ITP. After unsuccessful splenectomy or if treatment with gammaglobulins fails alternative and partly experimental therapies may have to be used. Conclusion: Treatment of adult ITP includes established medical, immunological and surgical measurements. Their application depends on disease progression as well as imminent or manifest complications. Remissions is achieved in up to 75% of all patients. Alternative treatments remain for refractory cases.
Maternal ThrombocytopeniaOther CausesFetal ThrombocytopeniaAlloimmune ThrombocytopeniaCase Presentation 1Case Presentation 2References
The antepartum diagnosis of maternal thrombocytopenia has become more common because platelet counts are now routinely obtained as part of prenatal screening. Although thrombocytopenia is classically defined as a platelet count of less than 150,000/μL, there is a physiologic drop in platelet count during pregnancy of 10-30% secondary to hemodilution and increased consumption. The most common causes of maternal thrombocytopenia include gestational thrombocytopenia, preeclampsia/hemolysis, elevated liver enzymes, and low platelet count syndrome, and autoimmune thrombocytopenia. These conditions have implications for both mother and fetus. Thus, it is important to consider both maternal and fetal thrombocytopenia.
Hemolytic Disease of the Fetus and Newborn and the RH-Antigen Treatment of HDFN Immune Thrombocytopoenic Purpura Manufacturing Process Future Trends References
Seventy-nine cases of autoimmune thrombocytopenia seen by the Baylor Hematology section of The Methodist Hospital between 1991 and 1996 were retrospectively reviewed to assess the effectiveness of danazol in the treatment of autoimmune thrombocytopenia. Among the 42 patients who received danazol, the mean initial platelet count prior to treatment was 24.3 ± 17.4 (SD) × 109/L with a mean duration of disease of 53 months. Most cases were idiopathic, but some patients had underlying secondary disorders (rheumatoid arthritis, systemic lupus erythematosus, HIV, and/or Evans' syndrome). Overall 57% of the patients treated with danazol had an excellent or a good response with three patients who had unmaintained remission for >11 months. Minimal side effects were noted. Fifty percent of the patients with associated secondary disorders achieved an excellent or good response. The hemolytic component of all three Evans' syndrome cases was well controlled with danazol. In two cases, danazol was effective where a variety of other treatment regimens were not. An excellent or a good response was found in 58%, 62%, and 53% in patients >65 years old, between 45 and 65 years old, and
Summary Anti-Rho(D) immunoglobulin (anti-D) contained more high molecular weight (HMW) IgG polymers than intravenous non-specific immunoglobulin (i.v. Ig). The low-dose anti-D and high-dose i.v. Ig regimens used to treat idiopathic thrombocytopenic purpura (ITP) therefore contained similar total amounts of HMW IgG. In vitro, the HMW IgG polymers were more effective competitive inhibitors of monocyte phagocyte Fc receptors than monomeric IgG. The IgG subclass composition of anti-D and i.v. Ig were both similar to normal human plasma. We conclude that the HMW IgG content but not the IgG subclass composition of anti-D may explain its low-dose therapeutic efficacy in ITP.
Pathophysiology
Chronic idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by platelet destruction due to an antiplatelet autoantibody, usually of the IgG class, which coats autologue platelets and leads to their elimination by the reticuloendothelial system (RES). While in childhood ITP is more usually an acute and self-limiting problem which needs no drug treatment, adult ITP is a relatively common chronic hematological disease.
□ Treatment
Treatment aimes at inhibition of antibody-production and binding on thrombocytes and thrombocyte phagocytosis by the RES. Therapy should result in a platelet count of >100,000/μl or at least in stabilization of the platelet count without bleeding. Therapeutic approaches were divided into emergency and long-term treatment. In patients who require non-emergency treatment conventional-dose corticoids (1 to 2 mg/kg/d prednisone) are recommended as initial treatment, whereas pulsed high-dose dexamethason is recently reported to be effective in refractory ITP. After unsuccessful splenectomy or if treatment with gammaglobulins fails alternative and partly experimental therapies may have to be used.
□ Conclusion
Treatment of adult ITP includes established medical, immunological and surgical measurements. Their application depends on diseases progression as well as imminent or manifest complications. Remission is achieved in up to 75% of all patients. Alternative treatments remain for refractory cases.
IVIG has been shown to be useful in the treatment of acute and chronic ITP, immune neutropenia, and in some cases of AIHA.
The mechanism of action of IVIG is owing to a number of factors, which include Fc blockade, immune modulation of T- and B-cell
number and function, alterations in NK activity, and direct effects on autoantibody binding and production via the antiidiotypic
antibody network. Current research efforts are directed toward elucidation of these modalities and determination of their
relative importance in treating patients with immune-mediated cytopenias.
Significant advances have been made in the understanding of organ specific autoimmune disorders and parallels can now be drawn with autoimmune thrombocytopenia (AITP). In AITP, the platelet surface glycoprotein target antigen epitopes are now well characterised and reliable autoantibody assays are available. Most patients can be treated effectively, and in refractory patients, experimental treatment has given new insights into the pathogenesis of the disorder. This article reviews the immunological aspects of AITP and suggests a diagnostic and therapeutic strategy in responsive and refractory patients.
Hematologic disorders in pregnancy are relatively common and encompass a wide spectrum of clinical conditions. The treatment and obstetric management of the majority of these diseases are well established, although controversy exists in areas such as sickle cell disease and ITP. Once the diagnosis of a specific disorder is confirmed, therapy is directed toward improved perinatal outcome. Recent advances in prenatal diagnostic techniques make in utero diagnosis feasible for most of the inherited disorders and aid in genetic counseling.
To assess the efficacy of home treatment with intramuscular anti-D immunoglobulins (anti-D IgG) in patients with idiopathic or HIV-related chronic immune thrombocytopenic purpura (ITP), we conducted an open label, non-controlled, prospective study with a follow-up of 6 months in 51 consecutive patients with HIV-related (n = 24) or idiopathic ITP (n = 27). Anti-D IgG (13 micrograms/kg) were infused intravenously for three consecutive days (induction therapy). Patients whose platelet counts failed to increase above 50 x 10(9)/l were given a second course of the same therapy. If their platelet counts remained lower than 50 x 10(9)/l, they were considered non-responsive. Patients who responded to induction therapy were injected intramuscularly with 6 micrograms/kg/week anti-D IgG if platelets were between 50 and 100 x 10(9)/l or 13 micrograms/kg/week if they dropped to less than 50 x 10(9)/l. After induction therapy, responses occurred in 20/24 HIV-related chronic ITP patients (83%) and in 14/27 idiopathic chronic ITP patients (52%). During follow-up, platelets remained above 50 x 10(9)/l in 17/20 HIV-related chronic ITP patients (85%) and in 8/14 (57%) idiopathic chronic ITP patients. We conclude that anti-D IgG are a valid therapeutic option for treatment of idiopathic and HIV-related chronic ITP, since they are safe, cheap and can be given intramuscularly at home.
IVIG has been shown to be useful in the treatment of acute and chronic ITP, immune neutropenia, and in some cases of AIHA. The mechanism of action of IVIG is owing to a number of factors, which include Fc blockade, immune modulation of T- and B-cell number and function, alterations in NK activity, and direct effects on autoantibody binding and production via the antiidiotypic antibody network. Current research efforts are directed toward elucidation of these modalities and determination of their relative importance in treating patients with immune-mediated cytopenias.
Intravenous immunoglobulin (IVIgG) has many potential applications in haematology both as antibody replacement therapy and as an immune-modulater in autoimmune disorders. Antibody replacement appears to be of value in the prophylaxis of infection in low-grade B-cell malignancies, in bone marrow transplant recipients and in children with AIDS, although optimal treatment strategies have not been assessed and determining which patients are likely to derive greatest benefit has been problematic. IVIgG appears to be effective in the prevention or amelioration of CMV-related pathology if given frequently and has also dramatically improved the survival of patients with established interstitial pneumonia when used in combination with ganciclovir. Intriguingly, IVIgG appears to moderate the severity of GVHD in adult transplant recipients. IVIgG has short term efficacy in most patients with ITP but, as long term remissions are uncommon, it has become necessary to be more selective in the use of IVIgG in this disorder. The response to IVIgG in other immune-mediated cytopenias is similar with generally transient improvement but also with occasional spectacular cures. The treatment of the acquired haemophilias with IVIgG has yielded in vivo and vitro evidence to support the idiotype-antiidiotype theory of IVIgG immune-modulation and has also demonstrated significant differences in the sensitivity of coagulation factor autoantibodies and alloantibodies to IVIgG therapy. IVIgG has several roles in pregnancy related disorders, including the management of both mother and fetus in ITP during pregnancy, the antenatal and postnatal management of platelet alloimmunisation and also in the management of severe rhesus isoimmunisation. IVIgG is safe and well tolerated. The expense of this therapy should be balanced against the likely gains and the overall costs of alternative approaches.
25 patients with confirmed chronic autoimmune thrombocytopenia (AITP) (20 women, 5 men; mean age 42 [17-75] years) were treated with anti-erythrocytic rhesus (D) antibodies. In the course of 5 days they each received three doses of 1200 micrograms of anti-D IgG antiserum by short-duration infusion. No adverse effects were noted. In 19 out of 25 (76%) the platelet counts (determined on the 6th day after the last infusion) rose by more than 30,000/microliters, in some by over 200,000/microliters. In 6 patients the maximal rise in platelets was below 30,000/microliters. There was little or no fall in haemoglobin concentration in 24 of the patients, although the direct antiglobulin test was clearly positive in all cases. Moderate transitory anaemia occurred in one case only (haemoglobin fell from 12.4 to 8.4 g/dl). The platelet counts gradually declined after treatment, taking several weeks or months to reach their original levels. The mechanism of anti-D therapy in AITP is not fully understood, but it probably depends on competitive inhibition of Fc receptors on phagocytic cells in the reticuloendothelial system.
Platelet destruction by antibodies is a common cause of thrombocytopenia. In this review, various treatments for immune thrombocytopenia are discussed, with emphasis on corticosteroids, splenectomy, danazol, high-dose immunoglobulin G, anti-Rhesus globulin, colchicine and cytotoxic, immunosuppressive agents such as cyclophosphamide and azathioprine. An approach to the treatment of adult idiopathic thrombocytopenic purpura (ITP) is reviewed in detail and the treatments for several other immune thrombocytopenic disorders are summarised.
Five patients with ITP were treated with 2 gram intravenous infusions of intramuscular human non specific immunoglobulin (IMIg). Increased platelet counts similar to those achieved with intravenous Rhesus anti D immunoglobulin were observed in four patients. 5000 iu anti D immunoglobulin contain up to 2 g of IMIg, and the clinical responses seen in ITP patients treated with anti D may therefore be attributed to this non specific fraction. This was supported by the in vitro finding that adsorption of the rhesus specific IgG from anti D immunoglobulin did not reduce its inhibitory effect on monocyte Fc receptor function. The dose of intravenous IMIg which produced a response in ITP was less than 2% of the recommended standard dose of intravenous immunoglobulin. This correlated with the higher concentration of IgG polymers in IMIg, and we suggest therefore that the mechanism of action of this material is due to the inhibitory effect of its polymeric IgG fraction on low affinity monocyte/phagocyte Fc receptors.
Treatment with 120 micrograms of intravenous rhesus immune globulin at 29 1/2 weeks' gestation resulted in an elevation of the platelet count from 38,000/mm3 to 73,000/mm3 in a patient with rhesus-negative blood with autoimmune thrombocytopenic purpura. Red blood cell immune blockade of the reticuloendothelial system is probably not the primary mechanism by which rhesus immune globulin elevates the platelet count.
A patient with chronic ITP relapsed after conventional therapy but following an infusion with low dose anti D (Rho) immunoglobulin, she entered a remission which has now lasted 10 months. This is difficult to explain on the basis of long term macrophage Fc receptor blockade and suggests an alternative mechanism of action.
In chronic autoimmune thrombocytopenic purpura (AITP), an indirect monoclonal antibody immobilised platelet antigen (MAIPA) assay detected serum glycoprotein (GP) IIb/IIIa antibodies in 16/39 (41%) cases. In patients with clinically active AITP, a direct MAIPA assay detected platelet-associated GP IIb/IIIa kantibodies in 8/13 (62%) cases. Platelet bound and serum antibody concentrations suggested a high antibody affinity for platelet membrane glycoprotein IIb/IIIa. Five AITP patients with platelet associated glycoprotein IIb/IIIa antibodies were treated with intravenous anti D immunoglobulin. All showed an increase in platelet counts and a decrease in platelet associated autoantibody. These responses could be due to immunosuppressive anti-idiotype antibodies in anti D immunoglobulin.
Seven patients with chronic immune thrombocytopenic purpura (ITP) were treated with intramuscular anti-D (anti-D IgG) five times, on an alternate-day basis, or until a platelet count of 100 x 10(9)/l was achieved, and, subsequently, when necessary to maintain platelet counts above 50 x 10(9)/l. Five patients responded to therapy, two of whom entered long-term remission. Although signs of haemolysis were present in all patients, anaemia was never a problem. No patient developed haematomas at the site of injection. We suggest that intramuscular anti-D represents a safe and relatively inexpensive alternative to intravenous gamma globulins (IVGG) for children with severe chronic ITP.
Anti-D was evaluated in 8 RhD positive patients (6 males, 2 females) aged 2-21 years (mean 10 years) with Idiopathic Thrombocytopenic Purpura (ITP). Five patients with chronic ITP and 3 patients with acute ITP were administered Anti-D in the dosage of 50 micrograms/kg intramuscularly (IM) for 3 consecutive days. One patient of chronic ITP received two courses of Anti-D. Patients were followed up for 7 to 16 months (mean 9 months). All three cases of acute ITP had a complete response and are in remission between 3 to 12 months of follow up. Two of five cases of chronic ITP had a partial response. Rise in platelet count was observed within 72-124 hours, and duration of response varied between 10 to 15 days. None of these patients had any significant side effects of anti-D immunoglobulin therapy. Intramuscular administration of Anti-D is safe, effective and low cost alternative to IVIgG in the treatment of acute ITP.
We report the results of intravenous anti-D (WinRho, WinRho SD) therapy in 261 non-splenectomized patients treated at the New York Hospital-Cornell Medical Center over the period from 1987 to 1994. Children (n = 124) and adult patients (n = 137) with classic immune thrombocytopenic purpura (ITP; n = 156) or human immunodeficiency virus (HIV) related thrombocytopenia (n = 105) and acute (n = 75) or chronic (n = 186) disease at the time of the initial anti-D treatment were studied. In addition, 11 previously splenectomized patients were treated as a separate group. Our objectives were to evaluate the following. (1) Efficacy of anti-D: The response after the initial infusion was analyzed according to clinical parameters, such as patient's age, HIV status, gender, disease duration, pretreatment platelet count, and hemoglobin value, as well as treatment-related factors, including the dose of anti-D, the solvent detergent treatment of the preparation, and the type of administration. (2) Use of anti-D as maintenance therapy: The duration of response after the initial infusion and the results of subsequent treatments were evaluated. (3) Safety/toxicity of anti-D: Postinfusion reactions and hemoglobin decrease after treatment were studied. Anti-D is a safe treatment providing a hemostatic platelet increase in greater than 70% of the Rh+ non-splenectomized patients. The group with the best results is HIV- children, but all patient groups respond and the effect lasts more than 21 days in 50% of the responders. Duration of response is not influenced by HIV status; furthermore, HIV+ patients show no adverse effects on hemoglobin decrease or HIV disease progression. Patients with chronic ITP after splenectomy have minimal or no response to intravenous anti-D.
Twenty-one patients with autoimmune thrombocytopaenic purpura (AITP) were treated with anti-D immunoglobulin. There was no significant difference with low and high dose anti-D treatment in the platelet count response between homozygous and heterozygous Rh(D) positive patients. The heterogeneous responses seen in Rh(D) positive AITP patients treated with anti-D immunoglobulin cannot therefore be explained by differences in Rh(D) phenotypes.
Approximately 70% to 80% of Rh-positive adults and children with acute or chronic immune thrombocytopenic purpura or HIV-related thrombocytopenia respond to infusions of anti-D immunoglobulin. The speed of onset of response is slower than that seen with intravenous immunoglobulin. Anti-D immunoglobulin is well tolerated, with occasional adverse reactions similar to those seen in treatment with polyclonal intravenous immunoglobulin, but anemia requiring blood transfusion can occur. Response is generally better in younger patients and those who have responded to other forms of treatment. Inhibition of Fc receptor-mediated platelet destruction by anti-D immunoglobulin-opsonized erythrocytes is the most likely mechanism of action, although the relative ineffectiveness of a monoclonal anti-D immunoglobulin preparation in treatment of immune thrombocytopenic purpura suggests that other mechanisms may exist. Hepatitis C has been transmitted by intravenous anti-D immunoglobulin preparations when used in the prevention of Rh immunization, prior to the introduction of screening donor plasma for hepatitis C virus antibodies. However, an intravenous solvent-detergent-treated preparation is now available.
Idiopathic thrombocytopenic purpura (ITP), an autoimmune disease of children and adults, is characterized by low platelet counts and bleeding through mucous membranes. While not uncommon among otherwise healthy adults and children, ITP is a frequent complication of human immunodeficiency virus (HIV) infection. Anti-D is a gamma globulin (IgG) fraction containing a high proportion of antibodies to the Rh0 (D) antigen of the red blood cells. Clinical studies over the past 10 years have shown intravenous anti-D to be a safe and effective treatment for Rh-positive, nonsplenectomized patients with ITP (classic or HIV-related). While it is unlikely that anti-D is a curative treatment for ITP, repeated infusions can be used to maintain the platelet count at a level sufficient to provide adequate hemostasis (>30,000/microL) and may enable patients to postpone or even avoid splenectomy.
Chronic idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by platelet destruction due to an antiplatelet autoantibody, usually of the IgG class, which coats autologue platelets and leads to their elimination by the reticuloendothelial system (RES). While in childhood ITP is more usually an acute and self-limiting problem which needs no drug treatment, adult ITP is a relatively common chronic hematological disease.
Treatment aimes at inhibition of antibody-production and binding on thrombocytes and thrombocyte phagocytosis by the RES. Therapy should result in a platelet count of > 100,000/microliter or at least in stabilization of the platelet count without bleeding. Therapeutic approaches were divided into emergency and long-term treatment. In patients who require non-emergency treatment conventional-dose corticoids (1 to 2 mg/kg/d prednisone) are recommended as initial treatment, whereas pulsed high-dose dexamethason is recently reported to be effective in refractory ITP. After unsuccessful splenectomy or if treatment with gammaglobulins fails alternative and partly experimental therapies may have to be used.
Treatment of adult ITP includes established medical, immunological and surgical measurements. Their application depends on diseases progression as well as imminent or manifest complications. Remission is achieved in up to 75% of all patients. Alternative treatments remain for refractory cases.
The use of i.v. anti-Rh(D) IgG for conditions other than prevention of Rh(D) sensitization is discussed. Besides highlighting the platelet response in ATP, a putative distinctive effect on the hemorrhagic threshold is suggested. Accordingly, we have included discussion of cases of aplastic anemia, myelodysplasia, heavy chemotherapy, coagulation deficiency, and senile vascular atrophy. We have also considered attempts to replace the high-dose pooled i.v. IgG (IVIG) with the much smaller amounts of IgG present in anti-Rh(D) preparations used to prevent Rh-sensitization in pregnancy. Both Fc and variable fragments of the IgG molecule may play a role, the former potentiated by manufacture-induced IgG aggregation and the latter by donor hypersensitization. A role for IgG-anti-F(ab')2 molecules cannot be ruled out.
N 1981, IMBACH and colleagues ~ reported the first clinical trial using intravenous immune globulin (IV1G) to treat immune (idiopathic) thrombocytopenic purpura (ITP).~ This study was initiated after the publication of a report that 2 patients with congenital agammaglobulinemia and thrombocytopenia had increased platelet counts after treatment with IVIG, as well as a report of increased platelet counts in a child with ITP after "desensitization" with IVIG. 2 Imbach and colleagues ~ reported favorable outcomes in 7 children with chronic ITP and 6 with acute ITP who were treated with IVIG (Immunoglobuline SKR, Swiss Red Cross, Berne, Switzerland). They suggested that the mode of action of the effect of IVIG in ITP may be "overloading and blocking of the reticuloendothelial system by IgG catabolism, m These findings in children with ITP were confirmed by other investigators, for children and adults with
Intravenous Rh [corrected] immune globulin was licensed by the U. S. Food and Drug administration in 1995 for the treatment of acute and chronic immune thrombocytopenic purpura in children and chronic immune thrombocytopenic purpura in adults. In 1996, the American Society of Hematology published a practice guideline for immune thrombocytopenic purpura, but treatment recommendations of necessity were formulated using only results of early clinical trials with intravenous Rh immune globulin. To date, there are no published results of large-scale clinical trials comparing conventional doses of intravenous immune globulin with the most promising dose range for intravenous Rh immune globulin (50-75 microg/kg). However, clinical experience is accumulating to indicate that intravenous Rh immune globulin is as effective, probably safer, and easier to administer than intravenous immune globulin. Acute intravascular hemolysis after infusions of intravenous Rh immune globulin for immune thrombocytopenic purpura has been reported with an estimated incidence of 1 in 1,115 patients. The risk factors for this adverse event have not been defined.
To review our experience of anti-D immunoglobulin for immune thrombocytopenia (ITP) in patients with primary antibody deficiency.
A retrospective case notes review of four Rhesus positive patients with ITP and primary antibody deficiency, treated with anti-D. Patients were refractory to steroids and high dose intravenous immunoglobulin (IVIG). Two patients were previously splenectomised.
All patients responded to anti-D immunoglobulin. Improved platelet counts were sustained for at least three months. Side effects included a fall in haemoglobin in all cases; one patient required red blood cell transfusion. Two patients had transient neutropenia (< 1 x 10(9)/litre).
Anti-D immunoglobulin may be an effective treatment for antibody deficiency associated thrombocytopenia, even after splenectomy. Anti-D immunoglobulin may have considerable clinical advantages in this group of patients, where treatments resulting in further immunosuppression are relatively contraindicated.
This Phase III study examined the efficacy and safety of Rhophylac (CSL Behring AG, Bern, Switzerland), a highly pure, liquid-stable anti-D preparation, in chronic immune thrombocytopenic purpura (ITP).
Ninety-eight patients (96 adults, two adolescents) with chronic ITP and platelet counts < 30 x 10(9)/l received a single intravenous injection of 50 microg/kg bodyweight Rhophylac.
A response (defined as an increase in platelet count by >or= 20 x 10(9)/l to >or= 30 x 10(9)/l in the first 15 days after treatment) was seen in 66% of patients. Mean time to response was 3.1 +/- 3.0 days, and mean duration of response was 19.2 +/- 1.1 days for responders. The most frequent drug-related adverse events were chills, pyrexia, an increase in bilirubin, and headache; events were mainly mild or moderate. there was no severe hemolysis or renal failure.
rhophylac is well tolerated and efficacious in chronic itp.
To determine quantitatively the number and avidity of receptors for the Fc portion of IgG on human platelets, we have measured the binding to platelets of human monomeric monoclonal IgG, and of small covalently crosslinked polymers of IgG1 labeled with 125I. The binding of labeled IgG1 monomers to platelets is too weak to permit quantitation. The binding of dimers or larger polymers of IgG1 is much more avid (greater at 4 degrees C than 37 degrees C), is readily reversible, and is saturable. The number of receptor sites ranges from 400 to 2000 per platelet and the mean equilibrium association constant (Ka) for the binding of dimers at 4 degrees C is 2.2 x 10(7) M-1 +/- 0.9 x 10(7) M- 1. The binding is specific for the Fc portion of IgG, and IgG1 and IgG3 bind to the receptors much more avidly than IgG2 or IgG4. Unlabeled IgG1 dimers are about 7--8-fold more potent in inhibiting binding than are IgG1 monomers, and larger polymers are even more potent than dimers. Thus, the Fc receptors on platelets bind human IgG1 with the same specificity and similar avidity as Fc receptors on polymorphonuclear leukocytes (PMNs), but PMNs have about 300-fold more receptors per unit of surface area than platelets.
We have recently reported that a rise of platelet numbers in ITP can be induced by blockade of the RES with antibody-coated red blood cells. We now present a collaborative study in which 15 Rhesus-positive children with ITP (nine boys and six girls aged 1-15 years) were treated with low-dose anti-D. Ten patients had chronic ITP (duration 6-47 months), five had acute ITP. Doses of 28-50 micrograms anti-D/kg bodyweight per course were given intravenously. In all patients clinical signs of bleeding ceased and platelet counts were elevated. An excellent, good or fair response with platelet increments of greater than 100, 50-100, or 20-50 X 10(9)/l, respectively, was observed in 19, 7, and 12 out of 45 courses in chronic ITP, and in 4, 1, and 2 out of 8 courses in acute ITP. The platelet increase (greater than 40 X 10(9)/l) persisted for 10 to over 360 days in chronic ITP. There were no untoward side reactions. Haemoglobin values remained stable in all patients but laboratory signs of mild, compensated haemolysis ensued. The direct antiglobulin test became positive in all cases due to anti-D IgG. Previous therapy of patients with chronic ITP included high-dose immunoglobulins and prednisone. These regimens were both effective but remissions were short. We conclude that anti-D therapy is an effective and safe form of treatment in childhood ITP.
Seven children with chronic or intermittent and six with acute idiopathic thrombocytopenic purpura (ITP) were treated with large intravenous doses of polyvalent, intact immunoglobulin (Ig). In all patients the platelet count rose sharply within 5 days, but the initial response and the subsequent course varied from patient to patient. Among children with chronic ITP the initial response was more marked in splenectomised than in non-splenectomised patients. Among those with acute ITP the two who remained Ig dependent had a smaller initial response than the four patients who required no maintenance treatment. During the 90-110 days of observation five of six patients with chronic ITP could be maintained with Ig alone. No untoward effects of Ig therapy were observed.
The rapid rise in platelet count after immunoglobulin treatment in acute and chronic forms of idiopathic thrombocytopenic purpura (ITP), autoimmune neutropenia, and post-transfusion purpura is well documented. It is suggested that the rise in platelet count is due to competitive inhibition of the macrophage binding of platelets by preferential sequestration of immunoglobulin-coated red blood cells. Measurement of haptoglobin levels, a sensitive indicator of haemolysis, suggests that clinically inapparent haemolysis occurs during immunoglobulin therapy of ITP patients. In-vitro experiments confirm that there is immunoglobulin coating of red blood cells. The hypothesis is further supported by the findings that immunoglobulin treatment in autoimmune haemolytic anaemia is ineffective, and that platelet counts rise in some ITP patients after induction of a mild haemolytic syndrome by injection of anti-Rho (D).
To determine quantitatively the number and avidity of receptors for the Fc portion of IgG on human platelets, we have measured the binding to platelets of human monomeric monoclonal IgG, and of small covalently crosslinked polymers of IgG1 labeled with 125I. The binding of labeled IgG1 monomers to platelets is too weak to permit quantitation. The binding of dimers or larger polymers of IgG1 is much more avid (greater at 4 degrees C than 37 degrees C), is readily reversible, and is saturable. The number of receptor sites ranges from 400 to 2000 per platelet and the mean equilibrium association constant (Ka) for the binding of dimers at 4 degrees C is 2.2 x 10(7) M-1 +/- 0.9 x 10(7) M-1. The binding is specific for the Fc portion of IgG, and IgG1 and IgG3 bind to the receptors much more avidly than IgG2 or IgG4. Unlabeled IgG1 dimers are about 7--8-fold more potent in inhibiting binding than are IgG1 monomers, and larger polymers are even more potent than dimers. Thus, the Fc receptors on platelets bind human IgG1 with the same specificity and similar avidity as Fc receptors on polymorphonuclear leukocytes (PMNs), but PMNs have about 300-fold more receptors per unit of surface area than platelets.
There is considerable controversy as to whether antigens of the Rh, Duffy, Kidd, Kell, or Lutheran red cell systems are present on human platelets. The majority of previous investigators of this topic have reported them to be present. We have used a sensitive two-stage radioimmunoassay to examine human platelets for the presence of antigens of these five red cell systems. Platelets from donors of appropriate red cell phenotype were incubated with monospecific anti-erythrocyte IgG, followed by a second-stage incubation with 125I-labeled mouse IgG monoclonal anti-human IgG (Fc). Analysis of ligand bound per cell demonstrated no significant difference in binding of erythrocyte antibodies to platelets from donors homozygous, heterozygous, or negative for D, C, c, E, e, Fya, Fyb, Jka, Jkb , K, k, and Lub antigens. These findings indicate that major antigens of the Rh, Duffy, Kidd, Kell, and Lutheran systems are not expressed on the surface of human platelets.
There is evidence that blockade of the reticuloendothelial system (RES) by sequestration of autologous red blood cells (RBC) leads to an elevation of platelet counts in immune thrombocytopenia. To substantiate this hypothesis, 10 Rh0(D)-positive adult patients (9 female, 1 male) with chronic autoimmune thrombocytopenic purpura (ITP) (1 to 21 years duration) were treated with low doses of intravenous IgG-anti-Rh0(D) (200 to 1,000 micrograms per dose; 300 to 3,600 micrograms per course; administration within 1 to 5 days). All patients improved clinically as indicated by cessation of bleeding. In eight out of ten patients there was a rise in platelet count. Platelet increments were excellent (greater than 100 X 10(9)/l) in one, good (50-100 X 10(9)/l) in three, fair (20-50 X 10(9)/1) in two and low (10-20 X 10(9)/1) in two patients. Splenectomized patients (N = 4) had a poorer response than non-splenectomized patients (N = 6) with mean increments of 16 X 10(9)/l (range 5-43 X 10(9)/l) versus 60 X 10(9)/l (range 10-110 X 10(9)/l). The increase in platelet counts persisted for seven to over 150 days. Transient and slight signs of haemolysis developed in seven out of ten patients (haemoglobin remained stable; increase of lactate dehydrogenase (greater than 250 IU/l) in four, decrease of haptoglobin (less than 60 mg/dl) in five patients). The direct antiglobulin test became positive in all cases due to IgG1 without complement fixation. We conclude that the interaction of antibody-coated RBC with macrophages (and, probably, other means of RBC alteration) is a feasible therapeutic approach in selected cases of ITP and related conditions.
A simple and rapid enzyme-linked immunosorbent assay (ELISA) for factor VIII related antigen has been developed using a commercially prepared enzyme conjugate. Levels as low as 0.01 units/ml can be measured and there is a CV of less than 5%. The advantages of the ELISA technique over electro-immunoassay are discussed.
Intravenous gammaglobulin treatment of chronic ITP
- Bussel