Plasma fibronectin supports hemostasis and regulates thrombosis
Yiming Wang, … , John Freedman, Heyu Ni
Yiming Wang, … , John Freedman, Heyu Ni
Published September 2, 2014
Citation Information: J Clin Invest. 2014;124(10):4281-4293. https://doi.org/10.1172/JCI74630.
View: Text | PDF
Research Article Hematology

Plasma fibronectin supports hemostasis and regulates thrombosis

Abstract

Plasma fibronectin (pFn) has long been suspected to be involved in hemostasis; however, direct evidence has been lacking. Here, we demonstrated that pFn is vital to control bleeding in fibrinogen-deficient mice and in WT mice given anticoagulants. At the site of vessel injury, pFn was rapidly deposited and initiated hemostasis, even before platelet accumulation, which is considered the first wave of hemostasis. This pFn deposition was independent of fibrinogen, von Willebrand factor, β3 integrin, and platelets. Confocal and scanning electron microscopy revealed pFn integration into fibrin, which increased fibrin fiber diameter and enhanced the mechanical strength of clots, as determined by thromboelastography. Interestingly, pFn promoted platelet aggregation when linked with fibrin but inhibited this process when fibrin was absent. Therefore, pFn may gradually switch from supporting hemostasis to inhibiting thrombosis and vessel occlusion following the fibrin gradient that decreases farther from the injured endothelium. Our data indicate that pFn is a supportive factor in hemostasis, which is vital under both genetic and therapeutic conditions of coagulation deficiency. By interacting with fibrin and platelet β3 integrin, pFn plays a self-limiting regulatory role in thrombosis, suggesting pFn transfusion may be a potential therapy for bleeding disorders, particularly in association with anticoagulant therapy.

Authors

Yiming Wang, Adili Reheman, Christopher M. Spring, Jalil Kalantari, Alexandra H. Marshall, Alisa S. Wolberg, Peter L. Gross, Jeffrey I. Weitz, Margaret L. Rand, Deane F. Mosher, John Freedman, Heyu Ni

×

Figure 7

pFn is a self-limiting factor for hemostasis and thrombosis.

Options: View larger image (or click on image) Download as PowerPoint
pFn is a self-limiting factor for hemostasis and thrombosis. (A) Platele...
(A) Platelet accumulation and fibrin formation in WT mice in the laser-induced cremaster arterial thrombosis model. Fibrin forms at the bottom of the platelet thrombi, while at the top of the growing thrombi, fibrin is nearly undetectable. Scale bar: 10 μm. (B) Illustration of the self-limiting role of pFn for thrombosis after vascular injury. pFn deposited at the base of the hemostatic plug likely cross-links with fibrin to support platelet aggregation. The soluble pFn at the top of the thrombi is associated with platelets but not with fibrin. These pFn molecules play a solely inhibitory role, stabilizing the thrombus and suppressing excessive thrombus buildup, thus helping to form a restricted local hemostatic plug that maintains hemostasis without causing downstream ischemia. (C) Illustration of pFn promoting efficient hemostasis after severe vascular injury. After severe trauma to a vessel, a large amount of thrombin is generated from multiple sites of the injured vessel wall, so that even at the top of the growing thrombi, there is a sufficient amount of thrombin to initiate fibrin formation. Under this condition, pFn is continuously incorporated onto the top of the growing thrombus through fibrin. This fibrin cross-linked pFn promotes the formation of an occlusive thrombus and helps to stop blood loss efficiently after severe vascular injuries. Blue arrows indicate fibrin concentration change from high level (H, red) to low level (L, yellow) as the hemostatic plug extends from the vessel wall into to the vessel lumen.