The immunopathogenesis of immune thrombocytopenia: T cells still take center-stage.
ABSTRACT Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder in which T and B cells recognize platelet antigens and initiate antiplatelet destructive mechanisms such as peripheral Fc receptor-mediated phagocytosis in the spleen or megakaryocyte destruction/inhibition within the bone marrow. The purpose of this review is to report on the ITP pathophysiology literature published from January 2011 to early in 2012.
The underlying stimulus of platelet autoimmunity is not known; however, in 2011, as in previous years, there has been a significant contribution of published studies addressing the pathophysiology of ITP. At least half of the 2011 ITP pathophysiology literature was associated with T-cell dysregulation particularly with respect to T-helper 17 cell and related cytokine and genetic studies. There were also studies related to B-cell responses, human spleen cells and the potential role of oxidative stress in ITP. With respect to therapeutic research, the mechanisms of action of intravenous gammaglobulin relating to Fc inhibitory receptors and sialylation have been challenged.
The overall landscape of pathophysiological research into ITP still is overwhelmed by studies on abnormal T-cell responses and these studies are beginning to clarify the underlying immune mechanisms that are responsible for the disorder.
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ABSTRACT: Antiphospholipid antibodies (aPL) have been detected in various proportions of patients with primary immune thrombocytopenia (ITP), but the clinical significance of this is debatable. The present study aimed to determine the frequency and clinical implications of elevated aPL in adult patients with ITP. We prospectively studied newly diagnosed adult patients with ITP who were enrolled between January 2003 and December 2008 at Chungnam National University Hospital. They were evaluated for the presence of lupus anticoagulant (LA) and anticardiolipin antibodies (aCL) at diagnosis and were followed for the development of thrombosis. Seventy consecutive patients with ITP (median age, 48 years; range, 18 to 79) were enrolled. Twenty patients (28.5%) were positive for aPL at the time of diagnosis: aCL alone in 15 (75%), aCL and LA in two (10%), and LA alone in three (15%). Patients who had platelet counts < 50,000/µL were administered oral prednisolone with or without intravenous immune globulin. No difference was found between the aPL-positive and -negative groups regarding gender, initial platelet count, and response to the therapy. After a median follow-up of 20 months (range, 2 to 68), two of 20 patients who were aPL-positive (10%) developed thrombosis, whereas no thrombotic event was found among those who were aPL-negative. Our data suggest that aPL levels should be determined at the initial presentation of ITP and that patients found to be aPL-positive should receive closer follow-up for thrombotic events.The Korean Journal of Internal Medicine 12/2011; 26(4):449-54.
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ABSTRACT: We previously showed that platelet aggregation and thrombus formation occurred in mice lacking both fibrinogen (Fg) and von Willebrand factor (VWF) and that plasma fibronectin (pFn) promoted thrombus growth and stability in injured arterioles in wild-type mice. To examine whether pFn is required for Fg/VWF-independent thrombosis, we generated Fg/VWF/conditional pFn triple-deficient (TKO; Cre(+), Fn(flox/flox), Fg/VWF(-/-)) mice and littermate control (Cre(-), Fn(flox/flox), Fg/VWF(-/-)) mice. Surprisingly, TKO platelet aggregation was not abolished, but instead was enhanced in both heparinized platelet-rich plasma and gel-filtered platelets. This enhancement was diminished when TKO platelets were aggregated in pFn-positive control platelet-poor plasma (PPP), whereas aggregation was enhanced when control platelets were aggregated in pFn-depleted TKO PPP. The TKO platelet aggregation can be completely inhibited by our newly developed mouse anti-mouse beta(3) integrin antibodies but was not affected by anti-mouse GPIbalpha antibodies. Enhanced platelet aggregation was also observed when heparinized TKO blood was perfused in collagen-coated perfusion chambers. Using intravital microscopy, we further showed that thrombogenesis in TKO mice was enhanced in both FeCl(3)-injured mesenteric arterioles and laser-injured cremaster arterioles. Our data indicate that pFn is not essential for Fg/VWF-independent thrombosis and that soluble pFn is probably an important inhibitory factor for platelet aggregation.Blood 12/2008; 113(8):1809-17. · 9.06 Impact Factor
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ABSTRACT: Immune thrombocytopenia (ITP) is mediated by platelet autoantibodies that accelerate platelet destruction and inhibit their production. Most cases are considered idiopathic, whereas others are secondary to coexisting conditions. Insights from secondary forms suggest that the proclivity to develop platelet-reactive antibodies arises through diverse mechanisms. Variability in natural history and response to therapy suggests that primary ITP is also heterogeneous. Certain cases may be secondary to persistent, sometimes inapparent, infections, accompanied by coexisting antibodies that influence outcome. Alternatively, underlying immune deficiencies may emerge. In addition, environmental and genetic factors may impact platelet turnover, propensity to bleed, and response to ITP-directed therapy. We review the pathophysiology of several common secondary forms of ITP. We suggest that primary ITP is also best thought of as an autoimmune syndrome. Better understanding of pathogenesis and tolerance checkpoint defects leading to autoantibody formation may facilitate patient-specific approaches to diagnosis and management.Blood 05/2009; 113(26):6511-21. · 9.06 Impact Factor