Moderate Platelet Defects but Efficiently Restored Thrombopoietin Production Early after Partial Hepatectomy via JAK2-STAT3 Signaling in Mice

F. Reusswig¹, N. Fazel Modares², M. Brechtenkamp³, I. Krueger³, D. Herebian⁴, D. Häussinger⁵, J. Scheller², M. Elvers³

¹University Clinic of the Heinrich-Heine University, Clinic for Vascular and Endovascular Surgery, Duesseldorf, Germany, ²Heinrich-Heine-University Duesseldorf, Medical Faculty, Institute of Biochemistry and Molecular Biology II, Duesseldorf, Germany, ³University Clinic of the Heinrich-Heine University, Duesseldorf, Germany, Clinic for Vascular and Endovascular Surgery, Duesseldorf, Germany, ⁴Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany, ⁵University Clinic of the Heinrich-Heine-University Düsseldorf, Clinic for Gastroenterology, Hepatology and Infectiology, Duesseldorf, Germany

Abstract Number: OC 04.1

Meeting: ISTH 2020 Congress

Theme: Platelets and Megakaryocytes » Platelet Function and Interactions

Background: Side effects of liver injury are characterized by alterations in primary hemostasis including thrombocytopenia and platelet function defects. However, the consequences of liver resection on platelet function are not well defined.

Aims: The aim of this study is to analyze platelet activity, hemostasis and thrombopoietin (TPO) signaling up to 14 days after partial hepatectomy in mice.

Methods: In vitro and in vivo experiments using partial hepatectomy (PHx) in wildtype and interleukin-6 receptor (IL-6R) knockout mice.

Results: Significantly decreased platelet counts following PHx operation increase to normal levels within 3 days. Simultaneously, intrinsic platelet activation was strongly reduced, due to high plasma levels of nitric oxide, prostaglandin I₂ and bile acids. These factors cause an increased endogenous phosphorylation of VASP resulting in functional platelet inhibition after liver dissection. The activation defects resulted in strongly reduced thrombus formation under flow and prolonged bleeding time in the first 3 days after PHx. Increasing TPO expression in liver tissue and plasma TPO levels were measured in the early phase of regeneration mediated through activation of the Ashwell Morell (AMR) and IL-6 receptor, leading to a JAK2-STAT3 downstream signaling. Interestingly, genetic deletion of IL-6R leads to a compensatory upregulation of the AMR in naive and PHx operated mice resulting in higher TPO expression and plasma levels in knockout compared to wildtype mice. Enhanced TPO production in wildtype mice leads to splenic megakaryopoiesis and moderate splenomegaly of PHx operated animals indicating high platelet turn-over as compensatory event after PHx to overcome decreased platelet counts, defective platelet activation and platelet infiltration into the regenerating liver tissue.

Conclusions: These results indicate that liver dissection affects primary hemostasis and highlights the regulatory mechanisms behind TPO expression in an inflammatory and regenerative in vivo model that might contribute to prevent bleeding complications in patients after liver resection.

To cite this abstract in AMA style:

Reusswig F, Fazel Modares N, Brechtenkamp M, Krueger I, Herebian D, Häussinger D, Scheller J, Elvers M. Moderate Platelet Defects but Efficiently Restored Thrombopoietin Production Early after Partial Hepatectomy via JAK2-STAT3 Signaling in Mice [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/moderate-platelet-defects-but-efficiently-restored-thrombopoietin-production-early-after-partial-hepatectomy-via-jak2-stat3-signaling-in-mice/. Accessed November 28, 2023.

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