Fibronectin orchestrates thrombosis and hemostasis

Fibronectin (Fn) is an essential extracellular matrix protein involved in cell adhesion, migration, differentiation and proliferation. Fn is required for embryogenesis, and is intricately involved in malignant transformation, angiogenesis, inflammation, fibrosis, wound healing, thrombosis and hemostasis [1]. Fn is a dimer consisting of two 250 kDa subunits. Alternative splicing of Fn pre-mRNA at extra domain (ED)-A, ED-B, and variable region results in up to 20 Fn variants in humans, which are categorized into two major groups, cellular fibronectin (cFn) and plasma fibronectin (pFn). cFn contains at least one of the EDs and is expressed by various cell types. In contrast, pFn is secreted specifically by hepatocytes to the blood circulation and excludes both ED-A and ED-B. Since pFn is an abundant protein in the blood plasma and contains integrin binding motif Arg-Gly-Asp (RGD) as well as N-terminal fibrin and collagen binding sites, it has long been suspected to play a role in thrombosis and hemostasis [2]. Thrombosis is the pathological occlusion or stenosis of blood vessels by platelets and fibrin clots, which often results in heart attack, stroke, and deep vein thrombosis (DVT), the leading causes of mortality and morbidity worldwide [3]. Cancer associated thrombosis is also one of the leading causes of mortality in cancer patients. Recent advances in treatment and prevention of thrombotic diseases have greatly improved patient survival and quality of life. However, many of these therapeutic modalities risk impairing hemostasis (i.e., the physiological process to stop bleeding), leading to life-threatening hemorrhage. On the other hand, therapies to control bleeding can sometimes lead to thrombosis. It is therefore crucial to study the factors involved in the regulation of thrombosis/hemostasis. In a recent report, we demonstrated that pFn is a vital factor in keeping the balance between thrombosis and hemostasis [4]. We found that pFn is crucial for hemostasis and survival of mice deficient in fibrinogen (a key coagulation factor and the precursor of fibrin) or treated with anticoagulants. Conventional theory states that platelet accumulation is the first wave of hemostatic response to vascular injury. Using our state-of-the-art intravital microscopy models, we found, surprisingly, pFn deposits at the site of injury to support hemostasis even prior to platelet accumulation, and the deposition is independent of platelet, fibrinogen, β3 integrin, or anticoagulants. In addition, we revealed that pFn enhances the mechanical strength of the blood clot by actively incorporating into the fibrin network and markedly increasing the diameter of …