Intravenous Anti-D treatment of immune thrombocytopenic purpura: Analysis of efficacy, toxicity, and mechanism of effect

Department of Pediatrics, New York Hospital, New York, NY.
Blood (Impact Factor: 10.45). 06/1991; 77(9):1884-93.
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The efficacy, toxicity, and mechanism of effect of intravenous Anti-D (Winrho) were studied in 43 Rh+ patients with immune thrombocytopenia purpura (ITP) who had not undergone splenectomy and in three already splenectomized patients. The mean platelet increase for the 43 nonsplenectomized patients was 95,000/microL (median 43,000/microL). Children had greater acute platelet responses than did adults. Human immunodeficiency virus status and duration of thrombocytopenia did not affect response. Maintenance treatment was given to patients as needed: the average interval between infusions was 24 days. The three splenectomized patients had no platelet response whatsoever. Toxicity was minimal; infusions were completed in less than 5 minutes. The generally accepted mechanism of effect of Anti-D has been Fc receptor blockade by substitution of antibody-coated red blood cells for antibody-coated platelets. Evidence is presented suggesting that the effect of IV Anti-D is not limited to Fc receptor blockade, including: (1) no correlation of parameters of hemolysis with platelet increase; (2) a 48- to 72-hour delay before platelet increase; (3) a tendency of the change in monocyte Fc receptor I expression to correlate with platelet increase; and (4) increased in vitro production of antibodies to sheep red blood cells following IV Anti-D infusion.

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    • "For example, OVA-anti-OVA conjugates, aggregated intravenous immunoglobulin (IVIG) products, and antibody-coated liposomes are therapeutically efficacious in murine models of idiopathic thrombocytopenic purpura (ITP) and rheumatoid arthritis [2-5]. The translational relevance of these animal findings is supported by clinical studies in ITP, in which the therapeutic effects of IVIG directly correlate with the presence of immune aggregates in the sera [6], and intramuscular (IM) administration of anti-D immunoglobulin, containing a high aggregate percentage, improves platelet counts even in Rh-negative patients [7]. Despite data supporting the therapeutic potential of IgG containing Fc multimers, to the best of our knowledge, no one has generated and evaluated the antiinflammatory and antiautoimmune properties of fully recombinant IgG Fc multimers for potential clinical application. "
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    ABSTRACT: Introduction Soluble immune aggregates bearing intact Fc fragments are effective treatment for a variety of autoimmune disorders in mice. The better to understand the mechanisms by which Fc-bearing immune complexes suppress autoimmunity, and to develop a platform for clinical translation, we created a series of fully recombinant forms of polyvalent IgG2a Fc, termed stradomers, and tested their efficacy in a therapeutic model of collagen-induced arthritis (CIA) and preventive models of both idiopathic thrombocytopenic purpura (ITP) and graft-versus-host disease (GVHD). Methods Stradomers were created by engineering either the human IgG2 hinge sequence (IgG2H) or the isoleucine zipper (ILZ) onto either the carboxy or amino termini of murine IgG2a Fc. Multimerization and binding to the canonical Fc receptors and the C-type lectin SIGN-RI were evaluated by using sodium dodecylsulfate-polymerase chain reaction (SDS-PAGE) and Biacore/Octet assays. The efficacy of stradomers in alleviating CIA and preventing ITP and GVHD was compared with "gold standard" therapies, including prednisolone and intravenous immune globulin (IVIG). Results Stradomers exist as both homodimeric and highly ordered sequential multimers. Higher-order multimers demonstrate increasingly stable associations with the canonic Fcγ receptors (FcγRs), and SIGN-R1, and are more effective than Fc homodimers in treating CIA. Furthermore, stradomers confer partial protection against platelet loss in a murine model ITP, but do not prevent GVHD. Conclusion These data suggest that fully human stradomers might serve as valuable tools for the treatment of selected autoimmune disorders and as reagents to study the function of Fc:FcR interactions in vivo.
    Full-text · Article · Aug 2012 · Arthritis research & therapy
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    • "These investigators documented platelet responses in Rhesus-positive ITP patients following the intravenous administration of an anti-D product and introduced the concept of macrophage blockade (Salama et al, 1983). James Bussel and his group later expanded the knowledge about the modalities of treatment with anti-D in various settings (Bussel et al, 1991; Scaradavou et al, 1997; Newman et al, 2001; Cooper et al, 2002; Michel et al, 2003; Kane et al, 2010). With advances in molecular biology and pharmacological technologies, targeted therapy has been investigated since the 1980s. "
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    ABSTRACT: A clinical syndrome of bleeding and purpura consistent with a diagnosis of immune thrombocytopenia (ITP) was described by Werlhof long before platelets were identified as the cellular component of blood playing an essential role in primary haemostasis. Although a role for the spleen was suggested nearly a century ago, the pathophysiology of ITP has remained elusive for many decades. During this time Werlhof's disease was renamed idiopathic thrombocytopenic purpura, from which the acronym ITP originally derives. The second half of the 20th century brought recognition of the autoimmune components of ITP, and hence the need for a new standard nomenclature, which has recently been accepted. ITP currently stands for Immune Thrombocytopenia, a name that more appropriately reflects the low platelet count rather than purpura as the main feature of the disease, as well as to defining its underlying nature. Advances in our knowledge of the disease have paralleled the availability of new therapeutic agents, and we are now entering an era of pathophysiologically-based treatment options.
    Full-text · Article · Apr 2011 · British Journal of Haematology
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    • "IVIg administered at a dose of 1–2 g/kg causes a rapid transient increases in platelet counts (within 1–2 d) in over 80% of patients (Godeau et al, 1999); however platelet counts generally return to pretreatment levels within 4 weeks. Rhesus immune globulin (RhIg/ anti-D) is felt to be less effective for patients post-splenectomy (Bussel et al, 1991). Repeated doses of IVIg at regular intervals may be useful as maintenance therapy for patients who require ongoing treatment because of bleeding. "
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    ABSTRACT: Immune thrombocytopenia (ITP) is a common autoimmune disease characterized by low platelet counts and an increased risk of bleeding. Antibody-mediated platelet destruction has been the prevailing hypothesis to explain ITP pathogenesis, supported by the efficacy of B-cell depletion therapy; however, the recent success of thrombopoietin receptor agonists lends support to the notion that platelet production is also insufficient. Best practice for the management of chronic ITP has not yet been established because data from comparative trials are lacking. Despite renewed interest in novel drugs capable of increasing platelet counts, ultimate treatment goals for ITP patients must be kept in mind: to improve patients' health and well-being. In this article, the pathophysiology of ITP is reviewed and key remaining questions about mechanism are explored. A rational approach to the management of ITP in adults is outlined, acknowledging evidence and evidence gaps, and highlighting the need for clinically important endpoints in future clinical trials.
    Preview · Article · Nov 2010 · British Journal of Haematology
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