title: Immune thrombocytopenia: antiplatelet autoantibodies inhibit proplatelet formation by megakaryocytes and impair platelet production in vitro.
abstract: Primary immune thrombocytopenia is an autoimmune disease mediated by antiplatelet autoantibodies that cause platelet destruction and suppression of platelet production. In vitro effects of autoantibodies on megakaryocyte production and maturation have been reported recently. However, the impact of these autoantibodies on crucial megakaryocyte functions, proplatelet formation and subsequent platelet release, has not been evaluated. We examined the effects of serum and IgG from 19 patients with immune thrombocytopenia using day 8 or 9 megakaryocytes (66.3 ± 10.6% CD41(+)), derived from cord blood hematopoietic stem cells (CD34(+)). The number of proplatelet-bearing megakaryocytes, the number of platelets released in the culture, total megakaryocyte numbers, ploidy pattern and caspase activation were measured at various times after treatment. After 5 days of treatment the number of proplatelet-bearing megakaryocytes was significantly decreased by 13 immune thrombocytopenia autoantibodies relative to the control group (P<0.0001) and this decrease was accompanied by a corresponding reduction of platelet release. Other features, including total megakaryocyte numbers, maturation and apoptosis, were not affected by immune thrombocytopenia antibodies. Treating the megakaryocytes with the thrombopoietin receptor agonists romiplostim and eltrombopag reversed the effect of the autoantibodies on megakaryocytes by restoring their capacity to form proplatelets. We conclude that antiplatelet antibodies in immune thrombocytopenia inhibit proplatelet formation by megakaryocytes and hence the ability of the megakaryocytes to release platelets. Treatment with either romiplostim or eltrombopag regenerates proplatelet formation from the megakaryocytes.
authors: Department of Medicine, St George and Sutherland Clinical School, University of New South Wales, Australia Centre for Vascular Research, University of New South Wales, Australia.
authors: Muna
authors: M
authors: Iraqi
authors: Department of Medicine, St George and Sutherland Clinical School, University of New South Wales, Australia Centre for Vascular Research, University of New South Wales, Australia j.perdomo@unsw.edu.au.
authors: Jose
authors: J
authors: Perdomo
authors: Department of Medicine, St George and Sutherland Clinical School, University of New South Wales, Australia Centre for Vascular Research, University of New South Wales, Australia Haematology Department, St George and Sutherland Hospitals, Sydney, Australia.
authors: Feng
authors: F
authors: Yan
authors: Department of Medicine, St George and Sutherland Clinical School, University of New South Wales, Australia Centre for Vascular Research, University of New South Wales, Australia.
authors: Philip Y-I
authors: PY
authors: Choi
authors: Department of Medicine, St George and Sutherland Clinical School, University of New South Wales, Australia Centre for Vascular Research, University of New South Wales, Australia Haematology Department, St George and Sutherland Hospitals, Sydney, Australia.
authors: Beng H
authors: BH
authors: Chong
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001323:Autoantibodies / Q000097:blood / Q000276:immunology* / Q000494:pharmacology; D001792:Blood Platelets / Q000166:cytology* / Q000276:immunology*; D016022:Case-Control Studies; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology / Q000494:pharmacology; D007958:Leukocyte Count; D008297:Male; D008533:Megakaryocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D010976:Platelet Count; D011003:Ploidies; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000097:blood* / Q000276:immunology*; D053628:Receptors, Thrombopoietin / Q000819:agonists; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D053628:Receptors, Thrombopoietin; D020169:Caspases