Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired platelet production and increased platelet clearance.

Ballem, Penny; Segal, Gerald M.; Stratton, John R.; Gernsheimer, Terry; Adamson, John W.; Slichter, Sherrill J.

doi:10.1172/jci113060

Cited by 380 publications

(222 citation statements)

References 47 publications

Supporting

Mentioning

217

Contrasting

Unclassified

Order By: Relevance

“…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.…”

Section: Discussionmentioning

confidence: 98%

“…[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%

See 1 more Smart Citation

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

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...

show abstract

Section: Discussionmentioning

confidence: 98%

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

show abstract

“…In addition, platelet kinetic studies have identified large subgroups of ITP patients with a decreased or normal platelet turnover. 40,41 Figure 2 The ultrastructure of megakaryocytes. ITP megakaryocyte showing features of apoptosis (a; Â 5000) and apoptosis-like cell death (paraapoptosis) (b; Â 7000).…”

Section: Is Platelet Production Impaired In Itp?mentioning

confidence: 99%

Megakaryocytic dysfunction in myelodysplastic syndromes and idiopathic thrombocytopenic purpura is in part due to different forms of cell death

et al. 2006

View full text Add to dashboard Cite

Platelet production requires compartmentalized caspase activation within megakaryocytes. This eventually results in platelet release in conjunction with apoptosis of the remaining megakaryocyte. Recent studies have indicated that in low-risk myelodysplastic syndromes (MDS) and idiopathic thrombocytopenic purpura (ITP), premature cell death of megakaryocytes may contribute to thrombocytopenia. Different cell death patterns have been identified in megakaryocytes in these disorders. Growing evidence suggests that, besides apoptosis, necrosis and autophagic cell death, may also be programmed. Therefore, programmed cell death (PCD) can be classified in apoptosis, a caspase-dependent process, apoptosis-like, autophagic and necrosis-like PCD, which are predominantly caspase-independent processes. In MDS, megakaryocytes show features of necrosis-like PCD, whereas ITP megakaryocytes demonstrate predominantly characteristics of apoptosis-like PCD (para-apoptosis). Triggers for these death pathways are largely unknown. In MDS, the interaction of Fas/Fas-ligand might be of importance, whereas in ITP antiplatelet autoantibodies recognizing common antigens on megakaryocytes and platelets might be involved. These findings illustrate that cellular death pathways in megakaryocytes are recruited in both physiological and pathological settings, and that different forms of cell death can occur in the same cell depending on the stimulus and the cellular context. Elucidation of the underlying mechanisms might lead to novel therapeutic interventions.

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired platelet production and increased platelet clearance.

Cited by 380 publications

References 47 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

Megakaryocytic dysfunction in myelodysplastic syndromes and idiopathic thrombocytopenic purpura is in part due to different forms of cell death

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

Contact Info

Product

Resources

About