Introduction

Vascular neoplasms are tumors arising from blood vessel endothelial cells. Kaposiform hemangioendothelioma (KHE) is a rare (incidence 0.07 : 100 000 per year 1) vascular tumor of infancy with locally aggressive behavior 2. The most common KHE tumor sites are limbs and the trunk, followed by the head and neck3. KHE is commonly (71% cases 1) associated with the Kasabach-Merritt phenomenon (KMP), a potentially life-threatening hematologic complication 4 with reported mortality of up to 30% 1. KMP refers to severe thrombocytopenia, consumptive coagulation dysfunction, secondary fibrinogen reduction, and microangiopathic hemolytic anemia5. Histologically, KHE is composed of infiltrating nodules with slit-like or crescentic vessels lined by spindled endothelial cells 6. When they are dilated, also lymphatic channels are observed, this is called «kaposiform lymphangiomatosis» 7. KHE is primarily positive for endothelial markers CD31 and CD34 and lymphatic markers LYVE1, PROX1, and podoplanin 8. KMP causes platelet «trapping» and activation within abnormal tumor vessels, which results in formation of platelet thrombi and initiaton of plasma coagulation9. The subsequent hyper‐activation of the fibrinolytic system may cause intratumoral hemorrhage 6,10. Unlike DIC (disseminated intravascular coagulation), KMP causes localized coagulation disorder. However, DIC may be eventually induced in severe cases of KMP 10.
Despite these findings, the etiology of KMP and the initial molecular mechanisms of platelet activation in KHE are not fully characterized. KHE cells are known to express podoplanin, the only known endogenous ligand for the platelet receptor CLEC-2 11. The critical physiological function of podoplanin-induced platelet aggregation is the embryological separation of blood and lymphatic circulations 11,12. CLEC-2 also contributes to vascular integrity during inflammation 13,14 and plays a role in thrombosis and wound healing 15,16. Thus, in patients with podoplanin-expressing KHE, the long-term platelet exposure to podoplanin might potentially affect platelet functionality.
Upon activation in KHE, platelets secrete their granule content, which can cause tumor growth and progression 17. Clinical findings support the critical role of platelets in KHE progression and development, namely, platelet transfusions in patients with KMP can lead not only to rapid tumor growth but also to severe deterioration of the coagulopathy 18,19. While platelet activation is considered to be one of the critical pathogenic mechanisms in KMP, antiplatelet therapy for patients with KMP did not give positive results20. Moreover, usage of antiplatelet agents for patients with severe thrombocytopenia is controversial21,22. Therefore, understanding platelet functioning in KHE/KMP is critically important in therapeutic management of these conditions.
In this study, we examined platelets from 7 patients with KHE/KMP. We found that in KHE, platelets are less responsive to weak stimulation, while platelet responsiveness to strong stimulation is mostly unimpaired.