PROS1 and Rare hereditary thrombophilia: In addition to environmental factors such as aging, life style, high altitude travel and smoking, macrothrombosis may be upregulated by genetic factors, especially thrombophilia affecting TF pathway (e.g., gene mutation of protein C and protein S, and factor V Leiden) [41], and microthrombosis can be upregulated by thrombophilia affecting ULVWF pathway (e.g., ADAMTS13 polymorphism) [23].