Kinetics and sites of destruction of <sup>111</sup>indium‐oxine‐labeled platelets in idiopathic thrombocytopenic purpura: A quantitative study

Heyns, A. du P.; Mg, Lötter; Badenhorst, P. N.; Kock, F. de; Pieters, H; Herbst, C.P.; Reenen, O.R. Van; Kotzé, Harry F.; Minnaar, P.C.

doi:10.1002/ajh.2830120209

Cited by 81 publications

(18 citation statements)

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“…However, autologous platelet survival studies in the 1980s, showing that most ITP patients had normal or decreased platelet turnover, suggested that platelet production in chronic ITP may also be impaired. [3][4][5][6] This hypothesis is supported by early morphologic studies of ITP bone marrow showing normal or increased numbers of megakaryocytes with a shift to younger forms that lacked evidence of cytoplasmic granularity or platelet formation and manifested degenerative changes in the nucleus and cytoplasm. 13,14 Subsequent studies, using electron microscopy, showed 50% to 75% of ITP megakaryocytes had extensive damage consisting primarily of abnormalities of the demarcation membrane system.…”

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confidence: 49%

“…[3][4][5][6] Because megakaryocytes express GPIIb-IIIa and GPIb-IX on their surfaces during maturation 7 and because most ITP autoantibodies react with one or both of these glycoprotein complexes, 8,9 it follows that autoantibody binding to megakaryocytes could interfere with platelet production and release from the bone marrow either by causing intramedullary megakaryocyte or platelet destruction or by interfering with megakaryocyte maturation.…”

Section: Introductionmentioning

confidence: 99%

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Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP

McMillan

Wang²,

Tomer³

et al. 2004

Blood

488

319

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Chronic immune thrombocytopenic purpura (ITP) is manifested by autoantibodyinduced platelet destruction. Platelet turnover studies suggest that autoantibody may also affect platelet production. To evaluate this, we studied the effect of plasma from adult patients with chronic ITP on in vitro megakaryocyte production. CD34 ؉ cells, obtained from healthy donors, were cultured in medium containing PEG-rHuMGDF and 10% plasma from either ITP patients or healthy subjects. Cultures containing plasma from 12 of 18 ITP patients showed a significant decrease (26%-95%) in megakaryocyte production when compared with control cultures. Positive ITP plasmas not only reduced the total number of megakaryocytes produced during the culture period but also inhibited megakaryocyte maturation, resulting in fewer 4N, 8N, and 16N cells. The role of antibody in this suppression is supported by 2 factors: (1) immunoglobulin G (IgG) from ITP patients inhibited megakaryocyte production when compared with control IgG; and (2) adsorption of autoantibody, using immobilized antigen, resulted in significantly less inhibition of megakaryocyte production when compared with unadsorbed plasma. These results show that plasma autoantibody from some adult patients with ITP inhibits in vitro megakaryocyte production, suggesting that a similar effect may occur in vivo. IntroductionIn 1950, Dr William Harrington was infused with blood from a patient with chronic immune thrombocytopenic purpura (ITP), resulting in the rapid onset of severe thrombocytopenia. He recovered within the next few days. Further studies by Harrington et al 1 and Shulman et al 2 showed clearly that patients with chronic ITP have a circulating factor capable of destroying homologous and autologous platelets. The severity of the thrombocytopenia was dose dependent, and the plasma factor could be adsorbed by platelets and was present in the immunoglobulin G (IgG)-rich fraction after ion-exchange chromatography. For the next several years, it was concluded that thrombocytopenia in patients with chronic ITP was caused solely by autoantibody-induced platelet destruction.However, in the early 1980s, autologous platelet survival studies from several laboratories showed that in approximately two thirds of ITP patients, platelet turnover is either reduced or normal, not increased, as would be expected if platelet destruction were the only mechanism causing thrombocytpenia. [3][4][5][6] Because megakaryocytes express GPIIb-IIIa and GPIb-IX on their surfaces during maturation 7 and because most ITP autoantibodies react with one or both of these glycoprotein complexes, 8,9 it follows that autoantibody binding to megakaryocytes could interfere with platelet production and release from the bone marrow either by causing intramedullary megakaryocyte or platelet destruction or by interfering with megakaryocyte maturation.Recently, Chang et al 10 evaluated the effect of plasma, from patients with childhood ITP (44 with acute ITP and 9 with chronic ITP), on thrombopoietin-induced production of megaka...

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mentioning

confidence: 49%

Section: Introductionmentioning

confidence: 99%

Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP

McMillan

Wang²,

Tomer³

et al. 2004

Blood

488

319

View full text Add to dashboard Cite

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“…5,9 The modulation of PLTs, however, is less characterized. The splenic MPS plays important roles in the phagocytic clearance of PLT during ITP, 1,10,11 suggesting that the severity of ITP is associated with PLT-phagocyte engagements. Thus, we established a flow cytometry-based PLT-splenic CD14 ϩ leukocyte (PLT-CD14 ϩ LC) engagement analysis to investigate the roles of PLTs and phagocytes in IVIg-primed DCs (IVIg-DCs)-mediated modulations.…”

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confidence: 99%

Dendritic cells modulate platelet activity in IVIg-mediated amelioration of ITP in mice

Huang

Sun

Lien³

et al. 2010

Blood

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Intravenous immunoglobulin (IVIg) is an effective treatment against immune thrombocytopenia (ITP). Previous studies suggested that IVIg exerts this ame IntroductionImmune thrombocytopenia (ITP) is a disorder manifested by immune-mediated low platelet (PLT) counts. 1-3 Treatment with high-dose intravenous immunoglobulin (IVIg), a human IgG fraction prepared from pools of plasma of thousands of donors, can rapidly relieve the symptoms of thrombocytopenia. 2,4 The PLT clearance is mainly mediated through IgG Fc receptors (Fc␥R) bearing macrophages in the mononuclear phagocytic system (MPS). 5 In mice, both inhibitory and activating Fc␥Rs, the Fc␥RIIB and Fc␥RIII (encoded by Fcgr2b and Fcgr3, respectively) are important for IVIg-mediated amelioration. [6][7][8] IVIg treatment was shown to induce macrophages expressing Fc␥RIIB, by which it reduced the phagocytic activity of the macrophages. 5,7,8 In addition, Fc␥RIII on CD11c ϩ dendritic cells (DCs) is important for IVIg-mediated amelioration of ITP in a 2-step priming model, in which IVIg could modulate effector leukocytes indirectly through initiator DCs. 5,9 The modulation of PLTs, however, is less characterized. The splenic MPS plays important roles in the phagocytic clearance of PLT during ITP, 1,10,11 suggesting that the severity of ITP is associated with PLT-phagocyte engagements. Thus, we established a flow cytometry-based PLT-splenic CD14 ϩ leukocyte (PLT-CD14 ϩ LC) engagement analysis to investigate the roles of PLTs and phagocytes in IVIg-primed DCs (IVIg-DCs)-mediated modulations. The involvements of P-selectin, Fc␥RIIB, and Fc␥RIII in the amelioration of ITP are discussed. Methods IVIg and miceIVIg was purchased from Bayer (Gamimune N) and CSL Limited Inc. The C57BL/6J mice (males, 7-10 weeks old) were purchased from the National Laboratory Animal Center (NLAC). C57BL/6J mice deficient in Fc␥RIII (B6;129P2-Fcgr3 tm1Sjv /J), Fc␥RIIB (B6;129S4-Fcgr2b tm1Rav /J), and Pselectin (B6;129S2-Selp tm1Hyn /J), were purchased from The Jackson Laboratory. Mice were housed in the Laboratory Animal Center of Tzu Chi University. The research methods were approved by the Animal Care and Use Committee of Tzu-Chi University. Induction and reversal of murine ITPITP was induced and treated as previously described. 7 Mice were intravenously injected with 0.1 mg/kg body weight of anti-PLT monoclonal antibody (mAb, rat anti-mouse integrin ␣ IIb /CD41 Ig, clone MWReg30; BD Biosciences) to induce ITP in all experiments, except for the low-dose treatments of MWReg30 (0.03 mg/kg) described in supplemental Figure 1 (available on the Blood web site; see the Supplemental Materials link at the top of the online article). To analyze PLT counts, whole blood samples (50-100 L) of mice were collected from the retro-orbital venous plexus and mixed with anticoagulant ACD solution (38mM citric acid, 75mM sodium citrate, 100mM dextrose) in Eppendorf tubes. PLT counts were then measured with a hematology analyzer (KX-21N; Sysmex) at various time intervals (0, 2, 4, and 24 hours after anti-CD41...

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“…In autoimmune hemolytic anemia, the compensatory reaction is much more pronounced, except when circulating antibodies are directed to normoblasts [31]. Previous studies have shown that, in the majority of ITP patients, the PPR is either reduced or normal [28,30,[32][33][34][35][36]. Additional support for a suppressed platelet production in ITP comes from in vitro studies showing that megakaryocyte production and maturation can be inhibited by antiplatelet antibodies [1,2,37].…”

Section: Discussionmentioning

confidence: 99%

Platelet production rate predicts the response to prednisone therapy in patients with idiopathic thrombocytopenic purpura

et al. 2008

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The predictive value of clinical and platelet kinetic parameters for treatment outcome in idiopathic thrombocytopenic purpura (ITP) was investigated in 75 patients with platelets ≤20×10 9 /L. The platelet kinetic studies showed that the platelet production rate (PPR) was decreased (<100×10 9 /day), normal, or increased (>355×10 9 /day) in 33%, 48%, and 19% of patients, respectively. All patients started with prednisone at diagnosis (1 mg/kg/day). Initial complete and partial response (CR/PR) rate was 84% and a durable CR/PR (≥6 months without treatment) was attained in 44% of the patients. Durable CR/PR was noticed in 64% of the patients with decreased PPR during a median followup time without treatment of 81 (range 18-92) months, compared to 34% of the patients with normal or increased PPR during a median follow-up time without treatment of 141 (range 10-284) months (p=0.03). Splenectomy was performed in 32% of patients with decreased PPR and in 62% of patients with normal or increased PPR (p=0.03). In conclusion, ITP patients with suppressed PPR have a significant higher durable CR/PR rate to prednisone therapy and are less frequently exposed to splenectomy than those with a normal or increased PPR.

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Kinetics and sites of destruction of ¹¹¹indium‐oxine‐labeled platelets in idiopathic thrombocytopenic purpura: A quantitative study

Cited by 81 publications

References 19 publications

Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP

Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP

Dendritic cells modulate platelet activity in IVIg-mediated amelioration of ITP in mice

Platelet production rate predicts the response to prednisone therapy in patients with idiopathic thrombocytopenic purpura

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Kinetics and sites of destruction of 111indium‐oxine‐labeled platelets in idiopathic thrombocytopenic purpura: A quantitative study

Cited by 81 publications

References 19 publications

Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP

Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP

Dendritic cells modulate platelet activity in IVIg-mediated amelioration of ITP in mice

Platelet production rate predicts the response to prednisone therapy in patients with idiopathic thrombocytopenic purpura

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Kinetics and sites of destruction of ¹¹¹indium‐oxine‐labeled platelets in idiopathic thrombocytopenic purpura: A quantitative study