{"doi":"10.1002/ajmg.a.61861","title":"Prophylactic anticoagulation of individuals with Proteus syndrome and <scp>COVID</scp>‐19","abstract":"To the Editor Proteus syndrome is a rare mosaic segmental overgrowth disorder associated with activating variants in AKT1. Individuals with Proteus syndrome have an increased risk of venous thromboembolism (VTE), which can be fatal. These events may occur without provocation or can be associated with additional risk factors such as postsurgical convalescence or acute infectious illnesses. Prior publications recommended that prophylactic anticoagulation should be considered when additional risk factors are present. Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulting in symptomatic coronavirus disease 2019 (COVID-19) is also associated with an increased risk of VTE. This has prompted recommendations for the diagnosis, prevention, and treatment of VTE in hospitalized adults with COVID-19. Given the underlying risk of VTE in Proteus syndrome and hypercoagulability associated with COVID-19, we reviewed the evidence for both of these clinical scenarios to determine if a general recommendation for Proteus syndrome anticoagulation is warranted. The association of VTE and Proteus syndrome has been described in multiple clinical reports and series (Eberhard, 1994; Papadimitriou et al., 2002; Slavotinek et al., 2000). These reports included thrombotic events that occurred postsurgically, during inpatient treatment for sinusitis and otitis media, and without known provocation. The largest review, which included 57 individuals with Proteus syndrome, showed that 12 (21%) had a history of deep venous thrombosis (DVT) and/or pulmonary embolism (PE). Of these 12 individuals, six had thrombotic events which resulted in death. The remaining individuals developed a postoperative thrombosis in an overgrown limb at a median age of 17 years (Keppler-Noreuil et al., 2017). Pulmonary embolism is the primary contributor to premature mortality in Proteus syndrome—a survival analysis of 64 individuals found that PE was the leading cause of death. Of the 11 deceased individuals, confirmed or suspected PE was the cause of death in seven, six of whom were <22 years old. The cause of death was either unknown or due to respiratory failure in the remainder (Sapp et al., 2017). It is possible that some of the unknown causes of death were in fact related to VTE. The clinical features and laboratory findings that predict thrombotic risk in Proteus syndrome have not been completely elucidated. A prospective study of 22 individuals found a baseline elevation in D-dimer, range of 0.6–3.77 mcg/ml, in 45% of individuals with Proteus syndrome, irrespective of the presence of a detectable thrombus (Keppler-Noreuil et al., 2019). The pathophysiology of the elevated risk of VTE in Proteus syndrome remains unknown. It is hypothesized that venous stasis from vascular malformations or ectasias lead to thrombosis in Proteus syndrome but additional factors likely participate in the overall risk. These factors may be both intrinsic, related to increased AKT1 activity in the endothelium, or extrinsic additive factors, such as immobility, postsurgical convalescence, infection, and inflammation. While more research is needed to understand the cause of thrombosis in Proteus syndrome, the abnormal baseline D-dimer and high incidence of VTE demonstrate a convincing increased underlying risk of VTE. As noted above, prior recommendations included VTE prophylaxis when there are risk factors beyond that of Proteus syndrome itself. There has not been a recommendation for routine prophylactic anticoagulation because of the risk of life-threatening hemorrhage in children from minor trauma. COVID-19 is associated with an increased risk of VTE. Although data from pediatric populations are lacking, thrombotic events have been observed in 31–49% of adults with COVID-19 requiring intensive care (Klok et al., 2020). The experience in pediatrics includes reports of thrombosis in SARS-CoV-2 associated multisystem inflammatory syndrome (Feldstein et al., 2020). 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Biesecker","orcid":null,"position":1,"is_corresponding":false},{"id":549894,"name":"Christopher Ours","orcid":"0000-0002-7831-1621","position":0,"is_corresponding":true}],"reference_count":15,"raw_metadata":null,"created_at":"2026-07-18T23:13:58.531532Z","pmid":"32914583","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}