To determine the mechanisms of an increase in the platelet count after therapy for autoimmune thrombocytopenic purpura, we determined the survival time and localization of radiolabeled autologous platelets and measured platelet-associated immunoglobulin levels before and after prednisone therapy or splenectomy in 19 patients with the disease. Eleven of 12 patients (92 percent) responded to prednisone with a mean threefold increase in the platelet count, resulting from increased platelet production (P less than 0.005); platelet survival was unchanged. Treatment with steroids failed in only one patient, whose pretreatment platelet production was already above normal. After splenectomy, 6 of 10 patients had a mean fourfold rise in the platelet count that correlated with increased platelet survival (P less than 0.005), together with improved platelet recovery (the percentage of platelets circulating in the blood immediately after the injection). Platelet production was unchanged. Base-line 111In-labeled platelet localization in the liver was normal in five patients in whom splenectomy was effective and increased to above normal in two of three in whom it was ineffective. Total platelet localization in the liver and spleen decreased by more than half after successful splenectomy (P less than 0.001), whereas it decreased by less than 25 percent after unsuccessful splenectomy. Platelet-associated immunoglobulin levels neither predicted nor correlated with treatment responses to prednisone or splenectomy. We conclude that prednisone improves platelet counts primarily by increasing platelet production, whereas the effect of splenectomy is to prolong platelet survival. Baseline measurements of platelet turnover and of platelet localization in the liver may be helpful in predicting the response to prednisone or splenectomy, respectively.
"For patients with a bleeding history or <20,000 platelets/μL a therapeutic intervention is usually warranted. Steroids are thought to increase platelet counts through their immunosuppressive action; however, recent data suggest that they may also work by increasing platelet production.28,29 Steroids are still considered to be the first line of therapy. "
[Show abstract][Hide abstract] ABSTRACT: Traditionally, anti-platelet autoantibodies accelerating platelet clearance from the peripheral circulation have been recognized as the primary pathopysiological mechanism in chronic immune thrombocytopenia (ITP). Recently, increasing evidence supports the co-existence of insufficient megakaryopoiesis. Inadequate low thrombopoietin (TPO) levels are associated with insufficient proliferation and differentiation of megakaryocytes, decreased proplatelet formation, and subsequent platelet release. Recently two novel activators of TPO receptors have been made available: romiplostim and eltrombopag. In several phase III studies, both agents demonstrated increase of platelet counts in about 80% of chronic ITP patients within 2 to 3 weeks. These agents substantially broaden the therapeutic options for patients with chronic ITP although long-term results are still pending. This review will provide an update on the current conception of underlying mechanisms in ITP and novel, pathophysiologically based treatment options.
"With the use of 111 Indium-labeled platelets, it was observed that the platelet life-span was not as short as previously thought,20 and that the majority of patients with ITP did not have an increase in platelet production.21 This has led investigators to conclude that despite the hyperplasia of megakaryocytes in the bone marrow, “the predominant cause of thrombocytopenia is ineffective marrow platelet production rather than accelerated platelet removal”.22 It should be noted that many patients enrolled in this trial had very mild ITP, and the few patients with severe ITP, who were studied by this method did have markedly shortened platelet survival. "
[Show abstract][Hide abstract] ABSTRACT: Decades of basic science and clinical research have led to an increased understanding of the pathophysiology of immune thrombocytopenic purpura (ITP), the processes underlying thrombopoiesis, and the treatment of chronic ITP. Now, new agents are available to treat ITP in a nonimmunosuppressive fashion. Lessons learned from the clinical trials of recombinant human thrombopoietin (TPO) have led to the development of a novel class of compounds: nonimmunogenic agonists of the thrombopoietin receptor. Representing the first nonimmunosuppressive agents to treat chronic refractory ITP in decades, medications such as romiplostim and eltrombopag were recently approved by the US Food and Drug Administration. These new agents offer physicians a new tool for treating difficult cases of ITP in their medical armamentarium. Additional TPO mimetics are also being developed that show promise in vitro, and await future development.
"Clinical response of ITP patients to therapy that inhibits phagocytosis The importance of platelet destruction in ITP is further supported by the demonstration that splenectomy results in a complete, unmaintained remission in about two-thirds of ITP patients (Branehog, 1975; Gernsheimer et al, 1989; Louwes et al, 2001). In addition, agents such as intravenous IgG, anti- D and corticosteroids, which work, in part, by interfering with phagocytosis, may result in a temporary normalization of the platelet count (Cines & McMillan, 2005). "
[Show abstract][Hide abstract] ABSTRACT: Chronic immune thrombocytopenia (ITP) is a haematological disorder in which patients predominantly develop skin and mucosal bleeding. Early studies suggested ITP was primarily due to immune-mediated peripheral platelet destruction. However, increasing evidence indicates that an additional component of this disorder is immune-mediated decreased platelet production that cannot keep pace with platelet destruction. Evidence for increased platelet destruction is thrombocytopenia following ITP plasma infusions in normal subjects, in vitro platelet phagocytosis, and decreased platelet survivals in ITP patients that respond to therapies that prevent in vivo platelet phagocytosis; e.g., intravenous immunoglobulin G, anti-D, corticosteroids, and splenectomy. The cause of platelet destruction in most ITP patients appears to be autoantibody-mediated. However, cytotoxic T lymphocyte-mediated platelet (and possibly megakaryocyte) lysis, may also be important. Studies supporting suppressed platelet production include: reduced platelet turnover in over 80% of ITP patients, morphological evidence of megakaryocyte damage, autoantibody-induced suppression of in vitro megakaryocytopoiesis, and increased platelet counts in most ITP patients following treatment with thrombopoietin receptor agonists. This review summarizes data that indicates that the pathogenesis of chronic ITP may be due to both immune-mediated platelet destruction and/or suppressed platelet production. The relative importance of these two mechanisms undoubtedly varies among patients.
British Journal of Haematology 06/2009; 146(6):585-96. DOI:10.1111/j.1365-2141.2009.07717.x · 4.71 Impact Factor
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