MET somatic activating mutations are responsible for lymphovenous malformation and can be identified using cell-free DNA next generation sequencing liquid biopsy.

OBJECTIVE: Germline mutations of either the endothelial cell-specific tyrosine kinase receptor TIE2 or the glomulin (GLMN) gene are responsible for rare inherited venous malformations. Both genes affect the hepatocyte growth factor receptor c-Met, inducing vascular smooth muscle cell migration. Germline mutations of hepatocyte growth factor are responsible for lymphatic malformations, leading to lymphedema. The molecular alteration leading to the abnormal mixed vascular anomaly defined as lymphovenous malformation has remained unknown. METHODS: A group of 4 patients with lymphovenous malformations were selected. Plasma was obtained from both peripheral and efferent vein samples at the vascular malformation site for cell-free DNA extraction. When possible, we analyzed tissue biopsy samples from the vascular lesion. RESULTS: We have demonstrated that in all four patients, an activating MET mutation was present. In three of the four patients, the same pathogenic activating mutation, T1010I, was identified. The mutation was found at the tissue level for the patient with tissue samples available, confirming its causative role in the lymphovenous malformations. CONCLUSIONS: In the present study, we have demonstrated that cell-free DNA next generation sequencing liquid biopsy is able to identify the MET mutations in affected tissues. Although a wider cohort of patients is necessary to confirm its causative role in lymphovenous malformations, these data suggest that lymphovenous malformations could result from postzygotic somatic mutations in genes that are key regulators of lymphatic development. The noninvasiveness of the method avoids any risk of bleeding and can be easily performed in children. We are confident that the present pioneering results have provided a viable alternative in the future for lymphovenous malformation diagnosis, allowing for subsequent therapy tailored to the genetic defect.

Characteristics of Venous Thromboembolism in COVID-19 Patients: A Multicenter Experience from Northern Italy.

BACKGROUND: The liability of patients affected by novel coronavirus disease (COVID-19) to develop venous thromboembolic events is widely acknowledged. However, many particulars of the interactions between the two diseases are still unknown. This study aims to outline the main characteristics of deep venous thrombosis (DVT) and pulmonary embolism (PE) in COVID-19 patients, based on the experience of four high-volume COVID-19 hospitals in Northern Italy. METHODS: All cases of COVID-19 in-hospital patients undergoing duplex ultrasound (DUS) for clinically suspected DVT between March 1st and April 25th, 2020, were reviewed. Demographics and clinical data of all patients with confirmed DVT were recorded. Computed tomography pulmonary angiographies of the same population were also examined looking for signs of PE. RESULTS: Of 101 DUS performed, 42 were positive for DVT, 7 for superficial thrombophlebitis, and 24 for PE, 8 of which associated with a DVT. Most had a moderate (43.9%) or mild (16.9%) pneumonia. All venous districts were involved. Time of onset varied greatly, but diagnosis was more frequent in the first two weeks since in-hospital acceptance (73.8%). Most PEs involved the most distal pulmonary vessels, and two-thirds occurred in absence of a recognizable DVT. CONCLUSIONS: DVT, thrombophlebitis, and PE are different aspects of COVID-19 procoagulant activity and they can arise regardless of severity of respiratory impairment. All venous districts can be involved, including the pulmonary arteries, where the high number and distribution of the thrombotic lesions without signs of DVT could hint a primitive thrombosis rather than embolism.