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.
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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

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Figure 1

pFn is a key hemostatic factor in deficiencies of Fg and blood coagulation.

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pFn is a key hemostatic factor in deficiencies of Fg and blood coagulati...
(A) Representative images of abdominal and subcutaneous bleeding in TKO mice. Red arrows show the bleeding site. (B) Tail bleeding time in WT, FG–/– Vwf–/–, and TKO mice. (C) Tail bleeding time in FG–/– and FG–/– pFn–/– mice. (D) Tail bleeding time in FG–/– pFn–/– mice transfused with 200 μl PBS, 1.5 mg/ml purified pFn, or BSA. (E) Tail bleeding time in pFn–/– mice and their WT (pFn+/+) littermates treated with i.p. injection of PBS, 20 U heparin, or 0.5 mg/kg recombinant hirudin (r-hirudin). Tail bleeding assay was performed 30 minutes after the injection. (F) Tail bleeding time in WT mice given high-dose heparin (200 U) and then transfused with PBS or pFn. For all tail bleeding assays, 2 mm of the tip of the tail was severed. Bleeding time assay was terminated at 20 or 30 minutes, as indicated, and mice that bled beyond this end point were counted as 20 or 30 minutes, respectively. Data are presented as mean ± SEM. Individual symbols represent individual mice.