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. 2021 Jan 22;10(3):427. doi: 10.3390/jcm10030427

Figure 3.

Figure 3

Heme activates cellular components of hemostasis. The main investigated pathways and consequences that result in the activation of cellular components of hemostasis and, thus, prothrombotic reactions by heme are depicted. On cellular level, hemostasis results from an interplay of RBCs (red, Section 4.3), platelets (yellow; Section 4.1), leukocytes (violet; Section 4.4) and endothelial cells (ECs, grey; Section 4.2). RBCs contribute to heme-induced hemostasis through the release of heme upon hemolysis, which can be further strengthened by heme itself (Section 4.3). Moreover, erythrocyte membrane particles (MP) incorporate and accumulate heme within the membrane, and allow for the transfer of heme to ECs (Section 4.2). These, in turn, become activated by heme in a TLR-4 -dependent manner (turquoise), which can lead either to the secretion of the contents of Weibel Palade bodies (WPBs; pink) (Section 4.2), among them VWF, or to ROS generation that triggers the increase of surface expression of adhesion proteins, such as P-selectin and VCAM-1 (orange) (Section 4.2). The exposure of those adhesion molecules as well as the secretion of VWF leads to the adhesion of platelets and leukocytes onto the endothelium. In contrast, activation of TLR-4 in leukocytes promotes the rolling and adhesion to ECs (Section 4.4). In addition, heme-induced NADPH oxidase (NOx; green)-dependent ROS generation in neutrophils can lead to NET formation, forming the scaffold for the adhesion of platelets and RBCs (Section 4.4). Finally, heme can also directly activate platelets. Two main mechanisms have been proposed. On the one hand, heme binding to CLEC2 was shown, leading to the phosphorylation of Syk (P-Syk) and PLCγ2 (P-PLCγ2) and eventually to the activation of platelets (Section 4.1). On the other hand, a ROS-dependent activation of the inflammasome via NLRP-3 has been demonstrated, which culminates in the expression of for example P-selectin, which again allows for the adhesion and activation of platelets (Section 4.1). Furthermore, the induction of ferroptosis (platelets) as well as apoptosis and necroptosis (endothelial cells) by heme has been demonstrated, which further might support the activation of endothelial cells and platelets (not shown; Section 4.1 and Section 4.2).