Proposed scheme of the KHE/KMP impact on patient platelets. (A) KHE pathogenesis is mostly based on aberrant VEGFR signaling in LECs.9 These LECs are constitutively proliferating and subsequently intervene in the blood vessel endothelium, thus causing blood endothelium activation, disruption, and extracellular matrix exposure to the blood flow (Ai).9,10 Exposed collagen causes the initiation of platelet thrombus formation and subsequent thrombocytopenia due to platelet consumption. Thrombi are heterogenous in nature; although platelets in the thrombus core are highly activated by a combination of collagen, thrombin, and platelet granule contents, platelets in the thrombus shell are stimulated mostly by ADP and thromboxane.50 Here, platelets in the outer layers of the thrombus can leave the thrombus shell and return to the circulation.50,56 Meanwhile, even moderate platelet activation can cause platelet GPVI receptor shedding.57 Thus, these preactivated platelets (orange platelets on the scheme) become less responsive to further GPVI-mediated activation (Ai). In the meantime, pathologically proliferating LECs also intrude the blood flow and, via the podoplanin-CLEC-2 axis, initiate platelet adhesion and activation (Aii-iii).9,10 Active platelets secrete growth factors stored in their granules, which causes additional LEC and EC activation and proliferation, thus acting as a positive feedback loop (Aii).9,58 Finally, platelets are heterogenous because of the mechanisms of their production: platelets are “ripped” from the megakaryocytes, and thus, platelet membrane receptor expression is not uniform.54 Hereby, it can be expected that some of the platelets in the blood flow have higher CLEC-2 levels (green platelets on the scheme) and some have lesser CLEC-2 levels (white platelets on the scheme). LECs, by exposing podoplanin to the blood flow, capture platelets with higher CLEC-2 levels, acting like filters. Hence, only platelets with lesser CLEC-2 on the surface, those cannot be effectively captured by the LECs, remain in circulation (Aiii). (B) Upon HR, proliferation of the LECs is abrogated because chemotherapy inhibits their VEGF signaling. This allows the blood vessel endothelial cells to cover the exposed extracellular matrix and thus significantly reduce pathological thrombus formation. However, despite being inhibited, LECs still remain in the blood vasculature and still filter platelets with higher CLEC-2 levels (Biii). These platelets secrete growth factors from their granules and thus activate remaining LECs, which maintain LECs’ presence in the blood flow (Bii). (C) Finally, upon recovery, no LECs are exposed to blood flow.
