A Sequential Mechanism for Exosite-mediated Factor IX Activation by Factor XIa

Geng, Yipeng; Verhamme, Ingrid M.; Messer, Amanda S.; Sun, Mao-fu; Smith, Stephen B.; Bajaj, S. Paul; Gailani, David

doi:10.1074/jbc.m112.376343

Cited by 28 publications

(94 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…13,32 O1A6 reduces systemic TAT levels by $80%, and significantly reduces platelet and fibrin accumulation within the collagencoated segments of grafts. Platelets adhere to collagen in the presence of O1A6, but there is a defect in 3-dimensional thrombus growth, 13 consistent with the thrombus instability observed in fXI-and fXIIdeficient mice.…”

Section: Discussionmentioning

confidence: 99%

“…32 Sequence encoding individual domains from the fXII homolog hepatocyte growth factor activator (HGFA) were amplified from the human HGFA cDNA by polymerase chain reaction (PCR), 33 and used to replace corresponding sequence in the fXII cDNA (Figure 1A and supplemental Tables 1-2, available on the Blood Web site). HEK293 fibroblasts (ATCC-CRL1573) were transfected with pJVCMV/fXII-HGFA constructs as described.…”

Section: Expression Of Recombinant Fxii and Antibody Mappingmentioning

confidence: 99%

“…HEK293 fibroblasts (ATCC-CRL1573) were transfected with pJVCMV/fXII-HGFA constructs as described. 32 Conditioned serum-free media (Cellgro Complete; Mediatech) from expressing clones were size-fractionated on 10% polyacrylamide-sodium dodecyl sulfate gels, and chemiluminescent western blots were prepared using 9A2, 15H8, or goat polyclonal-anti-human fXII immunoglobulin G (IgG) for detection.…”

Section: Expression Of Recombinant Fxii and Antibody Mappingmentioning

confidence: 99%

See 2 more Smart Citations

Factor XII inhibition reduces thrombus formation in a primate thrombosis model

Matafonov

Leung

Gailani

et al. 2014

Blood

Self Cite

200

167

View full text Add to dashboard Cite

• Factor XII can contribute to thrombus formation in human and nonhuman primate blood.• An antibody that blocks factor XII activation (15H8) produces an antithrombotic effect in a primate thrombosis model.The plasma zymogens factor XII (fXII) and factor XI (fXI) contribute to thrombosis in a variety of mouse models. These proteins serve a limited role in hemostasis, suggesting that antithrombotic therapies targeting them may be associated with low bleeding risks.Although there is substantial epidemiologic evidence supporting a role for fXI in human thrombosis, the situation is not as clear for fXII. We generated monoclonal antibodies (9A2 and 15H8) against the human fXII heavy chain that interfere with fXII conversion to the protease factor XIIa (fXIIa). The anti-fXII antibodies were tested in models in which anti-fXI antibodies are known to have antithrombotic effects. Both anti-fXII antibodies reduced fibrin formation in human blood perfused through collagen-coated tubes. fXII-deficient mice are resistant to ferric chloride-induced arterial thrombosis, and this resistance can be reversed by infusion of human fXII. 9A2 partially blocks, and 15H8 completely blocks, the prothrombotic effect of fXII in this model. 15H8 prolonged the activated partial thromboplastin time of baboon and human plasmas. 15H8 reduced fibrin formation in collagen-coated vascular grafts inserted into arteriovenous shunts in baboons, and reduced fibrin and platelet accumulation downstream of the graft. These findings support a role for fXII in

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Expression Of Recombinant Fxii and Antibody Mappingmentioning

confidence: 99%

Section: Expression Of Recombinant Fxii and Antibody Mappingmentioning

confidence: 99%

See 1 more Smart Citation

Factor XII inhibition reduces thrombus formation in a primate thrombosis model

Matafonov

Leung

Gailani

et al. 2014

Blood

Self Cite

200

167

View full text Add to dashboard Cite

show abstract

“…fIX can be activated by fXIa (Figure 1a, yellow arrows) [2,5,10]. This reaction appears to serve a relatively minor role in hemostasis, because patients lacking fXI have, at most, a moderate bleeding disorder.…”

Section: Factor XI and Thrombin Generationmentioning

confidence: 99%

“…IgG O1A6 (aXIMAb) was raised against human fXI in wild-type mice [10,22], and binds to the third ‘apple’ (A3) domain of fXI–fXIa [1,2] (Figure 2). The antibody inhibits fIX activation by fXIa by blocking a fIX-binding exosite on the A3 domain [10,24] (indicated in yellow in Figure 2). In our experience, O1A6 is more potent in plasma than are antibodies that block the fXIa active site [25], probably because it interferes with initial fIX recognition by fXIa.…”

Section: Monoclonal Antibodies To Factor XImentioning

confidence: 99%

Factor XI as a target for antithrombotic therapy

Bane

Gailani

2014

Drug Discovery Today

Self Cite

View full text Add to dashboard Cite

Anticoagulants currently used in clinical practice to treat thromboembolic disorders are effective but increase the risk of severe bleeding because they target proteins that are essential for normal coagulation (hemostasis). Drugs with better safety profiles are required for prevention and treatment of thromboembolic disease. Coagulation factor XIa has emerged as a novel target for safer anticoagulant therapy because of its role in thrombosis and its relatively small contribution to hemostasis.

show abstract

Interactions Between Platelets and the Coagulation System

Smith

Morrissey

2019

Platelets

View full text Add to dashboard Cite

A Sequential Mechanism for Exosite-mediated Factor IX Activation by Factor XIa

Cited by 28 publications

References 34 publications

Factor XII inhibition reduces thrombus formation in a primate thrombosis model

Factor XII inhibition reduces thrombus formation in a primate thrombosis model

Factor XI as a target for antithrombotic therapy

Interactions Between Platelets and the Coagulation System

Contact Info

Product

Resources

About