Thrombosis risk factors in PIK3CA-related overgrowth spectrum and Proteus syndrome

Abstract

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.

Keywords: PIK3CA-related overgrowth spectrum (PROS); Proteus syndrome; deep vein thrombosis (DVT); pulmonary embolism (PE); thrombosis.

FIGURE 1

MRA/MRV scans on two individuals with Proteus syndrome (a) PS47 (42 year old woman): Multiple findings including 1) A large varicosity in the right gluteal region, 2) multiple dilated superficial vein in the left subcutaneous tissue posteriorly in the upper thigh, 3) A prominent large anterior vein in the left thigh, draining to the left iliac vessels, 4) prominent hepatic vein varicosity in the liver below the level of the portal vein, 5) large cervical mass—No high flow arterial involvement, just evidence of low-flow state. (b) PS38 (29-year-old man) multiple findings including: 1) diffusely enlarged inferior vena cava, 2) portal vein focally dilated at confluence with superior mesenteric vein and splenic vein, and 3) left renal vein also slightly enlarged. MRA/MRV, magnetic resonance angiogram/ venography

FIGURE 2

MRA/MRV scan on two individuals with PROS (a) PS113, 48-year-old woman. Abnormalities include a varix of the right iliac vein and abnormal superficial vessels in the posterior thoracic and abdominal wall. (b) PS138, 16-year-old girl. Abnormalities include a dilated IVC and left renal vein. IVC, inferior vena cavae; MRA/MRV, magnetic resonance angiogram/ venography; PROS, PIK3CA-related overgrowth spectrum

FIGURE 3

Box and whisker plot of soluble cellular endothelial marker levels with t-test p-values. (a) Thrombomodulin levels were significantly increased in Proteus syndrome and PROS compared to normal controls. (b) sVCAM levels were significantly increased in Proteus syndrome and PROS compared to normal controls. (c) sICAM levels were significantly increased in PROS compared to normal controls. (d) E-selectin levels were significantly increased in PROS compared to normal controls. (e) P-selectin levels were significantly increased in Proteus syndrome compared to normal controls. PROS, PIK3CA-related overgrowth spectrum; sICAM, soluble intercellular adhesion molecule; sVCAM, soluble vascular adhesion molecule

FIGURE 4

Contributing risk factors for thrombosis in Proteus syndrome and PIK3CA-related overgrowth spectrum