GPIbα is the driving force of hepatic thrombopoietin generation

Abstract

Thrombopoietin (TPO), a glycoprotein hormone produced predominantly in the liver, plays important roles in the hematopoietic stem cell (HSC) niche, and is essential for megakaryopoiesis and platelet generation. Long-standing understanding proposes that TPO is constitutively produced by hepatocytes, and levels are fine-tuned through platelet and megakaryocyte internalization/degradation via the c-Mpl receptor. However, in immune thrombocytopenia (ITP) and several other diseases, TPO levels are inconsistent with this theory. Recent studies showed that platelets, besides their TPO clearance, can induce TPO production in the liver. Our group also accidentally discovered that platelet glycoprotein (GP) Ibα is required for platelet-mediated TPO generation, which is underscored in both GPIbα^-/- mice and patients with Bernard-Soulier syndrome. This review will introduce platelet versatilities and several new findings in hemostasis and platelet consumption but focus on its roles in TPO regulation. The implications of these new discoveries in hematopoiesis and the HSC niche, particularly in ITP, will be discussed.

Keywords: Antibodies; GPIbα and GPIIbIIIa; Platelet; Thrombocytopenia; Thrombopoietin; Thrombosis.

FIGURE 1

Glycoprotein Ibα (GPIbα) is the driving force of hepatic thrombopoietin (TPO) generation. TPO is constitutively produced by liver hepatocytes and internalized and degraded by platelet and megakaryocytes via the c‐Mpl receptor. Although the detailed mechanism is currently unknown, GPIbα is required for platelet‐mediated TPO generation. The interactions between platelet GPIbα and hepatocyte protrusions and Kupffer cells may contribute to this process. Following phagocytosis of GPIbα‐positive platelets, Kupffer cells may interact with hepatocyte protrusions or release of soluble factors, such as interleukin‐6 that directly or indirectly stimulate TPO generation