Increased risk of thromboembolism has been recognized in individuals with mosaic overgrowth disorders, Proteus syndrome (PS) and PIK3CA-related overgrowth spectrum (PROS), including Klippel-Trenaunay syndrome and CLOVES syndrome. PS and PROS have distinct, yet overlapping clinical findings and are caused by somatic pathogenic variants in the PI3K/AKT gene signaling pathway. PS is caused by a single somatic activating AKT1 c.49G > A p.E17K variant while PROS can be caused one of multiple variants in PIK3CA. The role of prothrombotic factors, endothelial cell adhesion molecules, and vascular malformations in both PS and PROS have not been previously investigated. A pilot study of prospective clinical and laboratory evaluations with the purposes of identifying potential risk factors for thrombosis was conducted. Doppler ultrasounds and magnetic resonance angiogram/ venography (MRA/MRV) scans identified vascular malformations in PS and PROS that were not appreciated on physical examination. Abnormal D-dimers (0.60-2.0 mcg/ml) occurred in half of individuals, many having vascular malformations, but no thromboses. Soluble vascular endothelial markers, including thrombomodulin, soluble vascular adhesion molecule (sVCAM), soluble intercellular adhesion molecule (sICAM), E-selectin, and P-selectin were significantly higher in PS and PROS compared to controls. However, no single attribute was identified that explained the risk of thrombosis. Predisposition to thrombosis is likely multifactorial with risk factors including chronic stasis within vascular malformations, stasis from impaired mobility (e.g., following surgery), decreased anticoagulant proteins, and effects of AKT1 and PIK3CA variants on vascular endothelium. Based on our findings, we propose clinical recommendations for surveillance of thrombosis in PS and PROS.

中文翻译：

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PIK3CA 相关过度生长谱和变形杆菌综合征中的血栓形成危险因素。

在患有马赛克过度生长障碍、变形杆菌综合征 (PS) 和 PIK3CA 相关过度生长谱 (PROS) （包括 Klippel-Trenaunay 综合征和 CLOVES 综合征）的个体中，血栓栓塞的风险增加已得到认可。PS 和 PROS 具有不同但重叠的临床表现，是由 PI3K/AKT 基因信号通路中的体细胞致病变异引起的。PS 是由单个体细胞激活 AKT1 c.49G > A p.E17K 变体引起的，而 PROS 可能是 PIK3CA 中的多个变体之一引起的。以前没有研究过促血栓因子、内皮细胞粘附分子和血管畸形在 PS 和 PROS 中的作用。进行了一项前瞻性临床和实验室评估的初步研究，目的是确定血栓形成的潜在危险因素。多普勒超声和磁共振血管造影/静脉造影 (MRA/MRV) 扫描确定了 PS 和 PROS 中的血管畸形，这些畸形在体格检查中未被发现。半数个体出现异常 D-二聚体 (0.60-2.0 mcg/ml)，许多人患有血管畸形，但没有血栓形成。与对照组相比，PS 和 PROS 中的可溶性血管内皮标志物，包括血栓调节蛋白、可溶性血管粘附分子 (sVCAM)、可溶性细胞间粘附分子 (sICAM)、E-选择素和 P-选择素显着升高。然而，没有发现单一的属性可以解释血栓形成的风险。血栓形成的易感性可能与多种风险因素有关，包括血管畸形内的慢性淤滞、活动受限（例如，手术后）引起的淤滞、抗凝蛋白减少、以及 AKT1 和 PIK3CA 变体对血管内皮的影响。根据我们的研究结果，我们提出了监测 PS 和 PROS 血栓形成的临床建议。