Vascular anomalies (VA), comprised of tumors and malformations, are a spectrum of disorders including benign and malignant lesions characterized by abnormal growth or development of vascular and/or lymphatic vessels that can affect any organ. If left untreated VA can be associated with substantial morbidity and mortality through disfiguration, organ dysfunction, hemorrhage, infection, and/or thrombosis. Correct diagnosis is critical to provide optimal management recommendations but is often challenging due to the phenotypic heterogeneity of these lesions. The biomarker angiopoietin-2 (ang-2), a member of a family of growth factors that regulate blood vessel growth and development, has previously been reported to be elevated in certain VA associated with coagulopathy, including Kaposiform hemangioendotheliomas (KHE) and Kaposiform lymphangiomatosis (KLA) (Le Cras TD, Angiogenesis 2017). Ang-2 levels have been reported to decrease in some patients in response to treatment with sirolimus (Le Cras TD, Angiogenesis 2017; Crane J, Pediatr Blood Cancer 2020). Based upon the published methodology, a clinical serum ang-2 assay was developed that employs a quantitative sandwich enzyme immunoassay technique using a monoclonal antibody specific for human ang-2. Age specific normal ranges for serum ang-2 were determined and were congruent with those first reported for the research assay (range: 1,434-4,141 pg/mL). Here we describe two VA cases in which the clinical ang-2 assay was utilized to aid diagnosis and to detect treatment response, replacing or limiting more invasive, expensive, and high-risk evaluations such as sedated imaging or surgical biopsy.

Patient 1 presented at birth with a large purpuric tumor of the right leg associated with thrombocytopenia and hypofibrinogenemia concerning for Kasabach-Merritt phenomenon (KMP). MRI imaging was suggestive of KHE, and the diagnosis was confirmed by biopsy. He was started on methylprednisolone 0.8mg/kg q12h for 1 week and then tapered over 2 months. He was also started on sirolimus 0.4mg/m 2 q12h. His ang-2 serum level was elevated at diagnosis (23,674 pg/mL) and showed reductions over time (graph 1). His ang-2 level continued to decrease as steroids were weaned despite initially having increased swelling and discoloration of the tumor. His steroid wean was slowed; however, therapy was not escalated due to continued decreases in ang-2 levels. Clinically the patient is doing well 1-year post-diagnosis, with improvement in appearance of the tumor and without recurrence of KMP.

Patient 2 is a 13-year-old male initially diagnosed at 5 years of age with generalized lymphatic anomaly (GLA) after presenting with acute respiratory failure secondary to significant pleural effusions, bony lesions, and splenic involvement. Prior attempts to classify his diagnosis by histology were inconclusive. He was treated with sirolimus, intermittent pulse steroids, celecoxib, and zoledronic acid, with suboptimal response to therapy. During puberty he presented with significantly increased coagulopathy (D-dimer 32,815 ng/mL and fibrinogen 62 mg/dL: ranges <500ng/mL and 150-400mg/dL respectively) and worsening pericardial and pleural effusions. The lesion was not clinically behaving as expected for GLA, with features suggestive of KLA. Serum ang-2 was measured as an additional diagnostic aid and was elevated at 8,903 pg/mL. GLA has not been reported to be associated with elevations in ang-2. Based on this new information his diagnosis was re-classified as KLA. He was started on weekly vincristine and trametinib, a mitogen activated protein kinase (MEK) inhibitor, with reported efficacy in treatment of KLA, replacing his sirolimus. After 2 months, there were improvement in coagulopathy (D-Dimer 23,306ng/mL and fibrinogen 154mg/dL) and decreasing ang-2 levels (graph 2).

These cases demonstrate the potential utility of serum ang-2 as a diagnostic tool and biomarker to monitor response to treatment in selected patients with VA. Next steps are to evaluate ang-2 levels in an expanded group of VA to understand which diagnoses can be distinguished by elevated levels at baseline and how treatment impacts ang-2 over time.

Figure 1
Figure 1.
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Disclosures

No relevant conflicts of interest to declare.

© 2021 by The American Society of Hematology
2021
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