Circulating levels of thrombopoietic and inflammatory cytokines in patients with clonal and reactive thrombocytosis

Hsu, Hui‐Chi; Tsai, Wen‐Hui; Jiang, Mei-Lan; Ho, Chau-Hung; Hsu, Ming-Ling; Ho, Chi-Kuan; Wang, Shengyuan

doi:10.1016/s0022-2143(99)90154-3

Cited by 84 publications

(70 citation statements)

References 35 publications

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“…37 However, TPO levels increased in secondary thrombocytosis, perhaps as an acute-phase reactant. 38,39 We observed normal c-Mpl expression in patients with RT; hence, the increased TPO levels observed in these patients might be the cause of their thrombocytosis. We found no prognostic significance, at least as can be determined by the current duration of follow-up, to the degree of c-Mpl expression in ET, similar to the lack of prognostic value for c-Mpl in PV.…”

Section: Discussionmentioning

confidence: 66%

Diagnostic and prognostic value of bone marrow angiogenesis and megakaryocyte c-Mpl expression in essential thrombocythemia

Mesa

Hanson

et al. 2002

Blood

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The lack of diagnostic certainty in some patients makes it difficult to distinguish between primary and secondary forms of thrombocytosis. To augment current diagnostic studies for thrombocytosis, we retrospectively evaluated clinical records and bone marrow trephine specimens of 183 patients with thrombocytosis-164 with essential thrombocythemia (ET), 19 with reactive thrombocytosis (RT)-for bone marrow angiogenesis, bone marrow megakaryocyte c-Mpl staining, and morphologic evidence of megakaryocyte proliferation. Angiogenesis was increased in patients with ET compared with healthy controls (P < .0001) and patients with RT (P ‫؍‬ .006). In addition, an increase in angiogenesis was associated with certain disease features such as splenomegaly (P ‫؍‬ .004) and reticulin fibrosis (P ‫؍‬ .005). Decreased megakaryocyte c-Mpl staining was observed in a heterogeneous pattern in ET compared with healthy controls (P < .0001) and RT (P < .0001). Histologic stratifying criteria incorporating increased angiogenesis, decreased megakaryocyte c-Mpl expression, and marked megakaryocyte proliferation in the bone marrow was highly sensitive (97%) and specific (95%) for distinguishing ET from RT (P < .0001

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Section: Discussionmentioning

confidence: 66%

Diagnostic and prognostic value of bone marrow angiogenesis and megakaryocyte c-Mpl expression in essential thrombocythemia

Mesa

Hanson

et al. 2002

Blood

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“…Activation was maximal in the range of 0.125 to 1.25 pmol/L IL-8, and similar levels have been reported in human serum. 19 Moreover, Arepally et al 20 also recently showed that antibodies from HIT patients induced IL-8 synthesis and secretion by monocytes. A decrease in platelet response was observed at higher concentrations of IL-8 ( Figures 1B and 2A), supporting the hypothesis of formation of immune complexes in the fluid phase that may prevent the binding of antibodies to surface-bound IL-8, as previously reported.…”

Section: Resultsmentioning

confidence: 99%

Platelet activation induced by human antibodies to interleukin-8

Régnault

Maistre

Carteaux

et al. 2003

Blood

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Some cases of heparin-induced thrombocytopenia (HIT) have been reported to be associated with antibodies against interleukin-8 (IL-8), a chemokine related to platelet factor 4. We found that sera from 5 HIT patients containing immunoglobulin G (IgG) or IgM antibodies to IL-8, as evidenced using surface plasmon resonance spectroscopy, were able to trigger IL-8-dependent activation of washed platelets, leading to procoagulant activity. This activation occurred at IL-8 concentrations achievable in vivo and was facilitated by heparin (0.1 U/mL). Activation was also induced by affinity-purified anti-IL-8 IgG and involved Fc␥RIIa. In the 2 patients who could be followed up, antibodies were no longer detectable 4 months after heparin withdrawal. One additional patient with paraneoplastic recurrent thrombosis without thrombocytopenia was found to have platelet-activating anti-IL-8 IgM, but in this case heparin was inhibitory. This is another example of potentially pathogenic platelet activation by antibodies. IntroductionIn most patients with heparin-induced thrombocytopenia (HIT), antibodies bind to complexes of heparin and platelet factor 4 (PF4). If these antibodies are immunoglobulin G (IgG), they interact with Fc␥RIIa receptors and trigger platelet activation. 1,2 However, previous investigators using enzyme-linked immunosorbent assay (ELISA) have reported that a few HIT patients have antibodies specific to another, PF4-related ␣-chemokine-interleukin-8 (IL-8), alone 3,4 or in combination with antibodies to heparin-PF4 complexes. 5 These antibodies were infrequently detected in patients with heparin exposure but no thrombocytopenia and in patients with thrombocytopenia from another etiology. 3 The main known property of IL-8 is to induce neutrophil activation, and anti-IL-8 autoantibodies have been shown to inhibit IL-8 interaction with its specific receptors on neutrophils. 6 IL-8 also binds to heparin, 7 and there may be IL-8 receptors on platelets. [8][9][10] This study was undertaken to investigate whether antibodies to IL-8 are able to induce platelet activation in vitro and whether they are dependent on heparin. Study designSera were obtained from 5 selected patients (P1-P5) who fulfilled the diagnostic criteria for HIT 1,11 (suggestive temporal pattern of platelet counts in relation to heparin therapy and evidence for heparin-dependent platelet-activating antibodies) but without IgG to heparin-PF4 complexes. 3 Patient 6 had typical HIT with IgG to heparin-PF4 only. One additional patient (P7), who had experienced fatal recurrent paraneoplastic thromboses while on heparin therapy without thrombocytopenia, 12 was also studied. Small volumes of blood were collected from samples required for routine patient management and were withdrawn after heparin therapy was stopped; heparin was no longer detectable with anti-Xa assay. ELISA (Asserachrom HPIA; Diagnostica Stago, Asnières, France) was used to detect antibodies to heparin-PF4. 13 IgG was purified by affinity chromatography on protein G-Sepharose (Pharmacia Bi...

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“…Thus, megakaryocytopoiesis is regulated by plasma levels of unbound TPO, which reflects the balance between constitutive production and rate of destruction that is generally dictated by the overall platelet production. Exceptions to steady state platelet production occur during essential thrombocythaemia (ET) (Akiyama et al, 2005;Harrison, 2005) and in acute inflammation when circulating TPO levels are increased (Cerutti et al, 1997;Kaushansky, 1997;Hsu et al, 1999) due to enhanced hepatic expression driven by the acute phase protein, interleukin 6 (IL-6) (Wolber et al, 2001). Mice in which either TPO or its ligand c-Mpl genes have been knocked out have severe thrombocytopenia with 10-20% residual platelet counts and small numbers of functionally normal MKs (Alexander et al, 1996).…”

Section: Thrombopoietinmentioning

confidence: 99%

Megakaryocyte development and platelet production

2006

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SummaryMegakaryocytopoiesis involves the commitment of haematopoietic stem cells, and the proliferation, maturation and terminal differentiation of the megakaryocytic progenitors. Circulating levels of thrombopoietin (TPO), the primary growth-factor for the megakaryocyte (MK) lineage, induce concentration-dependent proliferation and maturation of MK progenitors by binding to the c-Mpl receptor and signalling induction. Decreased platelet turnover rates results in increased concentration of free TPO, enabling the compensatory response of marrow MKs to increased platelet production. C-Mpl activity is orchestrated by a complex cascade of signalling molecules that induces the action of specific transcription factors to drive MK proliferation and maturation. Mature MKs form proplatelet projections that are fragmented into circulating particles. Newly developed thrombopoietic agents operating via c-Mpl receptor may prove useful in supporting platelet production in thrombocytopenic state. Herein, we review the regulation of megakaryocytopoiesis and platelet production in normal and disease state, and the new approaches to thrombopoietic therapy.

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Circulating levels of thrombopoietic and inflammatory cytokines in patients with clonal and reactive thrombocytosis

Cited by 84 publications

References 35 publications

Diagnostic and prognostic value of bone marrow angiogenesis and megakaryocyte c-Mpl expression in essential thrombocythemia

Diagnostic and prognostic value of bone marrow angiogenesis and megakaryocyte c-Mpl expression in essential thrombocythemia

Platelet activation induced by human antibodies to interleukin-8

Megakaryocyte development and platelet production

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