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.