New concepts in pathogenesis of primary immune thrombocytopenia (original) (raw)
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Pathophysiological Mechanisms Leading to Low Platelet Count in Immune Thrombocytopenia
Journal of Immunological Sciences, 2020
Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by the decrease in peripheral blood platelet count below 100 x 10 9 /L, and an increased bleeding risk when thrombocytopenia drops below 30 x 10 9 /L. The mechanisms leading to ITP in adults, although not completely elucidated, involves an imbalance between effector and regulatory cells that results in a breakdown of the immune tolerance. Autoantibodies are considered the main responsible for thrombocytopenia, although direct T-cell cytotoxic effect and lysis by Complement attachment and activation could also contribute to platelet elimination from circulation. In addition to increased peripheral clearance, abnormalities in platelet production also favors platelet count reduction. This review is intended to describe some specific knowledge about peripheral and bone marrow mechanisms leading to thrombocytopenia in adult ITP.
Scientific Reports
Mechanisms leading to low platelet count in immune thrombocytopenia (ITP) involves both decreased production and increased destruction of platelet. However, the contribution of these pathologic mechanisms to clinical outcome of individual patients is uncertain. Here we evaluated different pathogenic mechanisms including in vitro megakaryopoiesis, platelet/megakaryocyte (MK) desialylation and MK apoptosis, and compared these effects with thrombopoyesis and platelet apoptosis in the same cohort of ITP patients. Normal umbilical cord blood-CD34+ cells, mature MK derived cells or platelets were incubated with plasma from ITP patients. Despite inhibition of thrombopoiesis previously observed, megakaryopoiesis was normal or even increased. Plasma from ITP patients affected the sialylation pattern of control platelets and this effect occurred concomitantly with apoptosis in 35% ITP samples. However, none of these abnormalities were observed in control MKs incubated with ITP plasma. Addition of mononuclear cells as immune effectors did not lead to phosphatidylserine exposure in MK, ruling out an antibody-mediated cytotoxic effect. These results suggest that both desialylation and apoptosis may be relevant mechanisms leading to platelet destruction although, they do not interfere with MK function. Analysis of these thrombocytopenic factors in individual patients showed no specific distribution pattern. However, the presence of circulating antiplatelet autoantibodies was associated with higher incidence of abnormalities. In conclusion, the causes of thrombocytopenia are multifactorial and may occur together, providing a rational basis for the use of combination therapies targeting concomitant ITP mechanisms in patients with refractory disease. Primary immune thrombocytopenia (ITP) is defined as a megakaryocytic/platelet-specific autoimmune disorder characterized by isolated platelet count < 100 × 10 9 /L with or without bleeding manifestations, in the absence of other disorders that may be associated with thrombocytopenia 1. Mechanisms leading to low platelet count in ITP are multifactorial involving both, increased peripheral platelet destruction and decreased platelet production. Platelet destruction was classically described in the spleen through Fc-FcγR interactions in macrophages. In addition, Li and colleagues 2 reported clearance of desialylated platelets
Scandinavian journal of haematology, 2009
A two-stage radioactive antiglobulin test-using unlabelled antisera specific for IgG, IgA, IgM and C3 followed by binding of '251-staphyloccocal protein A-was applied to determine platelet-associated immunoglobulins (PAIg) and complement (PAC3) in thrombocytopenias of various etiologies. One hundred and one patients with immune thrombocytopenia (chronic autoimmune, 48; acute autoimmune, 37; Evans syndrome, nine; connective tissue diseases, seven) and 20 patients with presumed nonimmune thrombocytopenia (bone marrow aplasia or malignancy, six; septicemia, five; hypersplenism, five; cirrhosis of liver, three; others, one) were studied. Increased levels of PAIgK3 were found in 76% of patients with immune thrombocytopenia. PAIgG was raised in 66%, PAIgM in 57 % , PAIgA in 44%, and PAC3 in 29 %. Isolated elevation of PAIgG and of PAIgM was found in four and three cases, respectively; PAIgA and PAC3 were elevated in one case each. PAIgG was associated with PAIgM in 56%, with PAIgA in 34%, and with PAC3 in 27%. Both patients with Evans' syndrome and patients with connective tissue diseases had significantly higher PAIgM levels than the other patients with immune thrombocytopenia. In patients with nonimmune thrombocytopenia, increased rates of PAIg/C3 were also encountered. Positive test results were found in 88 % (PAIgG 88 % , PAIgM 47 % , PAIgA 35 % , and PAC3 24 %). In immune-mediated thrombocytopenia, we observed a significant inverse correlation between platelet counts and PAIgG, PAIgA, and PAC3, but not with PAIgM. In contrast, no such correlation was found in patients with nonimmune thrombocytopenia. Our data indicate that the evaluation of neither parameter alone nor the combination of PAIg/C3 will discriminate between immune and nonimmune thrombocytopenia. Preferential coating with certain immunoglobulins, however, may be present in some subgroups of immune thrombocytopenias.
Journal of Clinical Investigation, 1987
Mechanisms of thrombocytopenia were studied in 38 patients with mild to moderately severe chronic autoimmune thrombocytopenia (AITP). 5"Cr and "'In-labeled autologous platelet turnover studies and in vitro analysis of committed megakaryocyte progenitors (CFU-Meg) were used as independent measures of platelet production. Autologous "'In-labeled platelet localization studies were performed to assess platelet clearance. Although there was no increase in the frequency of marrow CFU-Meg, a specific increase in the CFU-Meg [3HJTdR suicide rate was seen which was inversely correlated with the platelet count (P < 0.001). Platelet turnover studies showed significant numbers of patients had inappropriate thrombopoietic responses to their reduced platelet counts. Platelet-associated antibody levels correlated inversely with platelet turnover suggesting that antiplatelet antibody impairs platelet production. The circulating platelet count was best predicted by an index relating platelet production (i.e., turnover) to the spleen-liver platelet clearance that correlated directly with platelet survival (P < 0.001). In summary, both depressed platelet production and increased platelet clearance by the liver and spleen contribute to the thrombocytopenia of AITP.
The Immune Thrombocytopenia Syndrome: A Disorder of Diverse Pathogenesis and Clinical Presentation
Hematology/Oncology Clinics of North America, 2009
Two young girls with symptoms of epistaxis and purpura are seen by a German physician. Later, one young patient has a spontaneous remission while the second suffers from repeated relapses. This report by Paul Gottlieb Werlhof 1 in 1735 is believed to be the first clinical description of a patient with immune thrombocytopenia (ITP). Nearly 150 years passed before this disorder was determined to be due to a deficiency in blood platelets. 2 Controversy soon emerged regarding the pathologic mechanisms responsible for the thrombocytopenia. In 1915, Frank 3 proposed that the thrombocytopenia resulted from toxic suppression of the megakaryocyte by a substance produced in the spleen. A year later, Kaznelson, 4 a Viennese medical student, reported on the beneficial effect of splenectomy in this disorder. In contrast to Frank, he proposed that thrombocytopenia resulted from increased platelet destruction in the spleen. The controversy continued as to whether this disorder, now termed idiopathic thrombocytopenia purpura, resulted from increased platelet destruction, defective production, or both. Dameshek and Miller, 5 in a study of bone marrow specimens from patients with ITP, found an increase in the total number of megakaryocytes in the bone marrows, but the majority of cells appeared not to be producing platelets. Effective platelet production appeared to increase after splenectomy. In 1951, a series of reports appeared to firmly document an immunologic role for accelerated platelet
Clinical Significance of Positive Platelet Immunofluorescence Assay in Adult Immune Thrombocytopenia
Indian Journal of Hematology and Blood Transfusion, 2014
Immune thrombocytopenia (ITP) is a relatively common hematologic disorder manifested by low platelet count due to immune-mediated platelet destruction and/or suppression of platelet production. This study aim was to evaluate characteristics and clinical presentation of adult patients with ITP and exploring the clinical value of platelet antibodies assay in proposed cases in Iranian population. In this prospective case series 46 adult patients with ITP and platelet count of \100 9 10 9 /L, referred to the Taleghani Medical Center, Tehran, Iran between 2007 and 2009 were evaluated. There were 26 females and 20 males (1.3:1) with mean age of 38.9 ± 19.7 years. The platelet autoantibodies were measured by means of indirect platelet suspension immunofluorescence test. According to our results, 7 patients (15.2 %) displayed a positive platelet antibody assay. There was a significant negative correlation between platelet count and antibody level (r =-0 0.59; p \ 0.001). Additionally, a positive correlation between platelet count and patients' age (r = 0.302; p = 0.042) was detected. 20 patients (56.5 %) were symptomatic at presentation and the most common bleeding signs were petechia, purpura and epistaxis. Results indicated no significant correlation between increased platelet antibody level and bleeding manifestations except for hematuria (r = 0.435; p = 0.02) and epistaxis (r = 0.382; p = 0.015). Disclosure of platelet autoantibodies and the consequential thrombocytopenia associated to some extent but not completely with the propensity to bleed which necessitates more factors to be evaluated.
American Journal of Hematology, 1986
A two-stage radioactive antiglobulin test-using unlabelled antisera specific for IgG, IgA, IgM and C3 followed by binding of '251-staphyloccocal protein A-was applied to determine platelet-associated immunoglobulins (PAIg) and complement (PAC3) in thrombocytopenias of various etiologies. One hundred and one patients with immune thrombocytopenia (chronic autoimmune, 48; acute autoimmune, 37; Evans syndrome, nine; connective tissue diseases, seven) and 20 patients with presumed nonimmune thrombocytopenia (bone marrow aplasia or malignancy, six; septicemia, five; hypersplenism, five; cirrhosis of liver, three; others, one) were studied. Increased levels of PAIgK3 were found in 76% of patients with immune thrombocytopenia. PAIgG was raised in 66%, PAIgM in 57 % , PAIgA in 44%, and PAC3 in 29 %. Isolated elevation of PAIgG and of PAIgM was found in four and three cases, respectively; PAIgA and PAC3 were elevated in one case each. PAIgG was associated with PAIgM in 56%, with PAIgA in 34%, and with PAC3 in 27%. Both patients with Evans' syndrome and patients with connective tissue diseases had significantly higher PAIgM levels than the other patients with immune thrombocytopenia. In patients with nonimmune thrombocytopenia, increased rates of PAIg/C3 were also encountered. Positive test results were found in 88 % (PAIgG 88 % , PAIgM 47 % , PAIgA 35 % , and PAC3 24 %). In immune-mediated thrombocytopenia, we observed a significant inverse correlation between platelet counts and PAIgG, PAIgA, and PAC3, but not with PAIgM. In contrast, no such correlation was found in patients with nonimmune thrombocytopenia. Our data indicate that the evaluation of neither parameter alone nor the combination of PAIg/C3 will discriminate between immune and nonimmune thrombocytopenia. Preferential coating with certain immunoglobulins, however, may be present in some subgroups of immune thrombocytopenias.
The cellular immunology associated with autoimmune thrombocytopenic purpura: an update
Transfusion science, 1998
Chronic autoimmune thrombocytopenic purpura (AITP) is an organ specific autoimmune bleeding disease in which autoantibodies are directed against the individual's own platelets, resulting in increased Fc-mediated platelet destruction by macrophages in the reticuloendothelial system. Although AITP is primarily mediated by IgG auto-antibodies, their production is regulated by the influence of T lymphocytes and antigen presenting cells (APC). This review argues that enhanced T helper cell/antigen presenting cell interactions in patients with AITP may be responsible for IgG anti-platelet auto-antibody production. Understanding these cellular immune responses in AITP may lead to the development of more immune specific therapies for the management of this disease.