An Antibody Cytotoxic to Megakaryocyte Progenitor Cells in a Patient with Immune Thrombocytopenic Purpura

Hoffman, Ronald; Zaknoen, Sara; Yang, Hsin-Hsin; Bruno, Edward; LoBuglio, Albert F.; Arrowsmith, Janet B.; Prchal, JT

doi:10.1056/nejm198505023121807

Cited by 77 publications

(36 citation statements)

References 24 publications

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“…During maturation, MK express CD41/CD61 and CD42b/CD42a on their surfaces, 6,7,26 so it is likely that the binding of antiplatelet autoantibodies could inhibit MK maturation [27][28][29] and interfere with platelet release. During endomitosis, the ploidy of diploid (2N) MK precursors increases 30 and each of these mature MK is able to release thousands of platelets 31 by extending proplatelets.…”

Section: Discussionmentioning

confidence: 99%

Immune thrombocytopenia: antiplatelet autoantibodies inhibit proplatelet formation by megakaryocytes and impair platelet production in vitro

et al. 2015

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ABSTRACTdecreased the number of proplatelet-bearing MK and hence the number of platelets released in culture, without altering MK proliferation, differentiation or apoptosis. A small subset of sera decreased MK numbers, inhibited maturation and enhanced caspase activation, but the corresponding patients' IgG did not recapitulate these effects. Notably, TPO-R agonists were able to overcome the inhibitory effect of several ITP antibodies on MK by enhancing their capacity to form proplatelets.

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Section: Discussionmentioning

confidence: 99%

Immune thrombocytopenia: antiplatelet autoantibodies inhibit proplatelet formation by megakaryocytes and impair platelet production in vitro

et al. 2015

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“…[4][5][6] The reduced platelet production rate might be mediated by the action of antiplatelet antibodies, which can bind to megakaryocytes in the bone marrow. [7][8][9] Recent in vitro studies support this concept showing that human megakaryocyte colony formation and proplatelet formation is inhibited 10 and that a reduced expansion of megakaryocytic progenitors can be observed especially in the presence of certain antiplatelet glycoprotein antibodies. 11 However, despite the evidence of a reduced platelet production in several ITP patients, numbers of megakaryocytes in the bone marrow are usually normal or increased.…”

Section: Introductionmentioning

confidence: 99%

Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura

Houwerzijl

Blom

Want

et al. 2004

Blood

259

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To investigate whether altered megakaryocyte morphology contributes to reduced platelet production in idiopathic thrombocytopenic purpura (ITP), ultrastructural analysis of megakaryocytes was performed in 11 ITP patients. Ultrastructural abnormalities compatible with (para-)apoptosis were present in 78% ؎ 14% of ITP megakaryocytes, which could be reversed by in vivo treatment with prednisone and intravenous immunoglobulin. Immunohistochemistry of bone marrow biopsies of ITP patients with extensive apoptosis showed an increased number of megakaryocytes with activated caspase-3 com- IntroductionIdiopathic, or immune, thrombocytopenic purpura (ITP) is an autoimmune disease characterized by isolated thrombocytopenia in an otherwise healthy person. The thrombocytopenia in ITP is caused by accelerated platelet destruction due to the action of antiplatelet immunoglobulin G (IgG) autoantibodies that bind to antigens on the platelet cell membrane. The platelets are subsequently destroyed by tissue macrophages, predominantly in the spleen. 1 As a result of the accelerated destruction, platelet survival is usually greatly shortened and platelet production is thought to be compensatorily increased. 2,3 However, there is also evidence that platelet production can be impaired in ITP. This was demonstrated in platelet kinetic studies using radiolabeled platelets. [4][5][6] The reduced platelet production rate might be mediated by the action of antiplatelet antibodies, which can bind to megakaryocytes in the bone marrow. [7][8][9] Recent in vitro studies support this concept showing that human megakaryocyte colony formation and proplatelet formation is inhibited 10 and that a reduced expansion of megakaryocytic progenitors can be observed especially in the presence of certain antiplatelet glycoprotein antibodies. 11 However, despite the evidence of a reduced platelet production in several ITP patients, numbers of megakaryocytes in the bone marrow are usually normal or increased. 6 This is compatible with the finding that plasma thrombopoietin (TPO) levels in ITP patients are not significantly different from healthy controls, indicating that the total megakaryocytic mass has not been changed in ITP. Investigating the relationship between thrombokinetic parameters and the glycocalicin index (GCI), a parameter of platelet destruction, 12 we recently demonstrated that there is an inverse correlation between the platelet production rate and the GCI. 13 These results suggest that despite the normal number of megakaryocytes in the bone marrow an increased destruction of platelets and/or megakaryocytes might occur. These findings support the concept of ineffective thrombopoiesis in the bone marrow. To investigate whether apoptosis or other forms of programmed cell death are responsible for this ineffective thrombopoiesis, we examined the ultrastructure of bone marrow megakaryocytes from ITP patients with electron microscopy. The results demonstrate that, independent of the refractoriness of ITP to therapy, in all patients most bone ma...

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“…In addition to an immune mechanism, therefore, other factors likely contributed to the severe thrombocytopenia observed in this case including splenic platelet sequestration, sepsis-associated marrow suppression and hemophagocytosis. The marked reduction in bone marrow megakaryocytes may be consistent with an autoimmune syndrome in view of the fact that cytotoxic autoantibodies directed against megakaryocyte precursors have been demonstrated in patients with acquired pure megakaryocytic aplasia [26,27] and immunosuppressive treatment has been successful in this disorder [28]. The lack of response to prednisone and IVIg argues against an immune mediated mechanism; however, up to 30% of ITP patients are refractory to steroids [29] and up to 25% have an inadequate response to IVIg [30,31].…”

Section: Discussionmentioning

confidence: 96%

Cardiobacterium hominis endocarditis associated with very severe thrombocytopenia and platelet autoantibodies

et al. 2004

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Severe thrombocytopenia is a life-threatening condition. It is often associated with immune-mediated platelet destruction or myeloablative chemotherapy. Infective endocarditis has been associated with thrombocytopenia, which, as in sepsis, tends to be mild and is often the result of several pathological mechanisms. We report a case of Cardiobacterium hominis endocarditis associated with very severe thrombocytopenia and bleeding in a patient who refused platelet transfusion. Platelet autoantibodies directed against glycoprotein (Gp) IIb/IIIa and Gp Ib/IX were detected during active infection using a glycoprotein-specific assay. Successful treatment of C. hominis endocarditis was associated with loss of platelet autoantibodies and recovery of the platelet count. This report illustrates that the development of platelet autoantibodies can contribute to very severe thrombocytopenia in occasional patients with infective endocarditis. Am.

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An Antibody Cytotoxic to Megakaryocyte Progenitor Cells in a Patient with Immune Thrombocytopenic Purpura

Cited by 77 publications

References 24 publications

Immune thrombocytopenia: antiplatelet autoantibodies inhibit proplatelet formation by megakaryocytes and impair platelet production in vitro

Immune thrombocytopenia: antiplatelet autoantibodies inhibit proplatelet formation by megakaryocytes and impair platelet production in vitro

Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura

Cardiobacterium hominis endocarditis associated with very severe thrombocytopenia and platelet autoantibodies

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