Enhanced platelet turnover after acute myocardial infarction in thrombocytopenic mice and GPVI-deficient mice

Introduction: Side effects of acute myocardial infarction (AMI) include thrombocytopenia and increased mean platelet volume. Thrombopoietin (TPO), the main regulator of platelet production, is increased at early time points after AMI. TPO production is regulated by the hepatic Ashwell-Morell receptor (AMR), which removes desialylated platelets and thus regulates TPO hemostasis [1]. The aim of the study was to analyze the platelet turnover after AMI in wild-type mice, in mice with acute thrombocytopenia and in GPVI-deficient mice.

Method: A closed-chest model of experimental myocardial infarction was used following ischemia and reperfusion. Experimentswere conducted using mice with a GPVI ablation (Gp6 ^-/- ), C57BL/6J WT (wild-type) and acute thrombocytopenic mice [2] [3]. Thrombocytopenia was induced by injection of a GPIbα or adequate IgG antibody (control) 24 hours before left anterior descending artery ligation.

Results: At early time points after AMI, we detected reduced platelet counts, an enhanced fraction of senescent desialylated platelets as well as an increase in the number of thiazole orange-positive cells in wildtype mice. Upregulation of hepatic TPO gene expression and increased TPO plasma accumulation were also observed. Enhanced TPO production was mediated by an increase in the IL-6 receptor mediated signaling cascade, including elevated phosphorylation of STAT3 at early time points. In line with an increased number of aged desialylated platelets, we detected enhanced gene expression of AMR subunits such as Asgr1 and Asgr2 in hepatic tissue. Restoration of platelet counts after AMI is associated with increased splenic megakaryopoiesis. In thrombocytopenic mice, we found reduced gene expression of AMR subunits after 24 h compared to control mice that was paralleled by reduced phosphorylation of STAT3. GPVI deficient mice show no differences in gene expression of AMR receptor subunits or TPO production. However, 6 h after AMI reduced desialylated platelets were detected in GPVI deficient mice that was paralleled by significantly reduced splenic megakaryopoiesis. These results indicate that GPVI is important for platelet turnover and TPO hemostasis after AMI.

Conclusion: AMI induced short-term thrombocytopenia is associated with an increase in platelet desialylation and hepatic AMR and IL-6 receptor signaling in the liver leading to the up-regulation of TPO mRNA expression in hepatic tissue and TPO release into the circulation.

Publikationsverlauf

Artikel online veröffentlicht:
13. Februar 2025

• References

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