Prior research has demonstrated that platelets are involved in the pathogenesis of kaposiform hemangioendothelioma (KHE) and Kasabach-Merritt phenomenon (KMP). The results of a comprehensive evaluation of platelet function for patients with podoplanin-expressing KHE show that platelet aggregation is diminished in patients with KHE.
Specifically, researchers, led by Dr. Alexey A. Martynov, of Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology in Moscow, found that in the main circulation of patients with KHE, the platelets had a decreased number of C-type lectin-like receptor-2 (CLEC-2) during active KMP, and the number of receptors returned to normal when patients achieved hematologic response. The results of the study were published in Blood Advances.
Ionela Iacobas, MD, associate professor of pediatric hematology-oncology at Baylor College of Medicine in Houston, called this observation an “important finding.”
“While many theories have been explored in the study of KHE, they mainly focused on identification of a potential somatic genetic alteration that would explain tumor formation,” Dr. Iacobas said. “It is well reported during clinical observation that the KHE tumor size increases with platelet transfusion administration, and this study may offer a plausible explanation.”
The study included 13 patients; the median age was 6 months. Eleven of the 13 patients had KHE (one patient had kaposiform lymphangiomatosis, and one had rapidly involuting congenital hemangioma; both were excluded from the final analysis). Platelet functionality using continuous and endpoint flow cytometry, low-angle light scattering aggregometry, fluorescent microscopy of blood smears, and ex vivo thrombi formation was assessed in three groups: those with KHE/KMP without hematologic response to therapy, those with KHE/KMP with hematologic response, and a group of healthy controls.
Both groups of patients with KHE had diminished platelet integrin activation in response to a combination of collagen-related peptide (CRP) – a glycoprotein VI (GPVI) agonist – and thrombin receptor-activating peptide-6 (TRAP-6) – a protease-activated receptor-1 (PAR-1) agonist – as well as calcium mobilization and integrin activation in response to CRP or rhodocytin, a CLEC-2 agonist, alone. However, platelet responses to adenosine 5’-diphosphate (ADP) with or without TRAP-6 were not altered.
Additionally, all patients with KHE had decreased thrombi formation from collagen in parallel plate flow chambers. Diminished amounts of CLEC-2 on the platelet surface were found in all patients with KHE, and patients with KHE/KMP without hematologic response also had decreased GPVI levels on platelets. The researchers noted the dysfunction of platelet GPVI, and to some extent CLEC-2, resolved when patients achieved hematologic response.
Dr. Iacobas explained there are two coagulopathy phenomena in the vascular field that have overlapping clinical features – thrombocytopenia, decreased fibrinogen, high D-dimer – but completely different pathophysiology: KMP in KHE and localized intravascular coagulopathy (LIC) in venous malformations.
“Understanding the two phenomena at the molecular level will hopefully reduce the number of misdiagnoses,” Dr. Iacobas said. “While KMP initiation is completely dependent on abnormal lymphatic endothelial cell proliferation, LIC is the result of abnormal venous blood flow in venous malformations without a required lymphatic component.”
Dr. Iacobas hopes that increased understanding of the mechanism underlying KHE will result in less platelet transfusion administration – outside of life-threatening situations.
“Recognizing the pathophysiology difference between KMP and LIC has direct implication in management: KMP is treated with tumor-targeted therapy, while LIC responds to anticoagulation,” Dr. Iacobas said. “Switching the therapies due to misunderstanding of underlying pathophysiology will have not only a lack of efficacy, but a high risk of complications for the patients.
“While administration of blood products in LIC may not help but also will not cause significant problems, in KMP it will ‘fuel the fire’ and result in significant increase in severity,” she added.
The researchers noted several limitations to be considered, including that not all the patients in the study were treatment-naïve and the receipt of doxorubicin could affect platelets. In addition, patients with KHE/KMP without hematologic response had thrombocytopenia, so platelet aggregometry could not be used to investigate these patients’ platelets.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Martyanov A, Tesakov I, Khachatryan L, et al. Platelet functional abnormalities in pediatric patients with kaposiform hemangioendothelioma/Kasabach-Merritt phenomenon [published online ahead of print, 2023 Jun 12]. Blood Advances. doi: 10.1182/bloodadvances.2022009590.