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• W4309705384 abstract "Factor XIa (FXIa), the activated form of the plasma zymogen FXI, is a trypsin‐like protease that contributes to thrombin generation and hemostasis primarily by activating factor IX (FIX).1.Mohammed B.M. Matafonov A. Ivanov I. et al.An update on factor XI structure and function.Thromb Res. 2018; 161: 94-105Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar In humans, severe FXI deficiency may cause excessive bleeding with trauma or surgery, particularly when injury involves the mouth, nasopharynx, or urinary tract.2.James P. Salomon O. Mikovic D. Peyvandi F. Rare bleeding disorders ‐ bleeding assessment tools, laboratory aspects and phenotype and therapy of FXI deficiency.Haemophilia. 2014; 20: 71-75Crossref PubMed Scopus (61) Google Scholar, 3.Gailani D. Wheeler A.P. Neff A.T. Rare coagulation factor deficiencies.in: Hoffman R Benz EJ Silberstein LE Hematology: Basic Principles and Practice. 7th ed. Elsevier, 2018: 2034-2050Crossref Scopus (0) Google Scholar Bleeding severity varies, and many individuals who are FXI deficient do not experience abnormal hemostasis. A variable trauma‐induced bleeding disorder has also been reported in FXI‐deficient dogs,4.Knowler C. Giger U. Dodds W.J. Brooks M. Factor XI deficiency in Kerry blue terriers.J Am Vet Med Assoc. 1994; 205: 1557-1561PubMed Google Scholar cats,5.Kuder H. Dickeson S.K. Brooks M.B. et al.A common missense variant causing factor XI deficiency and increased bleeding tendency in Maine coon cats.Genes (Basel). 2022; 13: 792Crossref PubMed Scopus (1) Google Scholar and cattle.6.Marron B.M. Robinson J.L. Gentry P.A. Beever J.E. Identification of a mutations associated with factor XI deficiency in Holstein cattle.Anim Genet. 2004; 35: 454-456Crossref PubMed Scopus (54) Google Scholar Bleeding associated with FXI deficiency is considerably milder than with FIX deficiency (hemophilia B), supporting the premise that FIX is primarily activated by the factor VIIa/tissue factor complex in vivo.7.Smith S.A. Travers R.J. Morrissey J.H. How it all starts: initiation of the coagulation cascade.Crit Rev Biochem Mol Biol. 2015; 50: 326-336Crossref PubMed Scopus (207) Google Scholar, 8.Grover S.P. Mackman N. Tissue factor: an essential mediator of hemostasis and trigger of thrombosis.Arterioscler Thromb Vasc Biol. 2018; 38: 709-725Crossref PubMed Scopus (317) Google Scholar In the cascade/waterfall hypotheses of thrombin generation, FXI is activated by the protease factor XIIa (FXIIa).1.Mohammed B.M. Matafonov A. Ivanov I. et al.An update on factor XI structure and function.Thromb Res. 2018; 161: 94-105Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar However, the absence of an obvious hemostatic abnormality in humans and other animals lacking FXII (the zymogen of FXIIa) implies that other proteases activate FXI during hemostasis.3.Gailani D. Wheeler A.P. Neff A.T. Rare coagulation factor deficiencies.in: Hoffman R Benz EJ Silberstein LE Hematology: Basic Principles and Practice. 7th ed. Elsevier, 2018: 2034-2050Crossref Scopus (0) Google Scholar For example, thrombin activates FXI in purified protein and plasma‐based systems.9.Naito K. Fujikawa F. Activation of human blood coagulation factor XI independent of factor XII. Factor XI is activated by thrombin and factor XIa in the presence of negatively charged surfaces.J Biol Chem. 1991; 266: 7353-7358Abstract Full Text PDF PubMed Google Scholar, 10.Gailani D. Broze Jr, G.J. Factor XI activation in a revised model of blood coagulation.Science. 1991; 253: 909-912Crossref PubMed Scopus (642) Google Scholar, 11.von dem Borne P.A. Meijers J.C. Bouma B.N. Feedback activation of factor XI by thrombin in plasma results in additional formation of thrombin that protects fibrin clots from fibrinolysis.Blood. 1995; 86: 3035-3042Crossref PubMed Google Scholar, 12.Kravtsov D.V. Matafonov A. Tucker E.I. et al.Factor XI contributes to thrombin generation in the absence of factor XII.Blood. 2009; 114: 452-458Crossref PubMed Scopus (107) Google Scholar However, to our knowledge, there has not been a demonstration of FXI contributing to hemostasis in the absence of FXII. Mice lacking FXI (F11−/− mice), in contrast to humans who are FXI deficient, do not appear to bleed excessively with trauma.13.Gailani D. Lasky N.M. Broze Jr, G.J. A murine model of factor XI deficiency.Blood Coagul Fibrinolysis. 1997; 8: 134-144Crossref PubMed Scopus (114) Google Scholar, 14.Mohammed B.M. Cheng Q. Matafonov A. Monroe D.M. Meijers J.C.M. Gailani D. Factor XI promotes hemostasis in factor IX‐deficient mice.J Thromb Haemost. 2018; 16: 2044-2049Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Furthermore, murine FXI is primarily bound to blood vessel endothelium rather than circulating in plasma, as in humans.15.Mohammed B.M. Cheng Q. Matafonov A. et al.A non‐circulating pool of factor XI associated with glycosaminoglycans in mice.J Thromb Haemost. 2019; 17: 1449-1460Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar These features would seem to make mice unsuitable for studying the impact of FXI on hemostasis. However, we showed that intravenous infusion of human FXI, or inducing expression of human FXI by hydrodynamic tail vein injection (HTI), decreased the severity of bleeding in male mice lacking FIX (F9−) in a saphenous vein bleeding (SVB) model.14.Mohammed B.M. Cheng Q. Matafonov A. Monroe D.M. Meijers J.C.M. Gailani D. Factor XI promotes hemostasis in factor IX‐deficient mice.J Thromb Haemost. 2018; 16: 2044-2049Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Human FXIa, in addition to activating FIX, activates factors V, VIII, and X, which may explain the beneficial effect in the absence of FIX.16.Whelihan M.F. Orfeo T. Gissel M.T. Mann K.G. Coagulation procofactor activation by factor XIa.J Thromb Haemost. 2010; 8: 1532-1539Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 17.Matafonov A. Cheng Q. Geng Y. et al.Evidence for factor IX‐independent roles for factor XIa in blood coagulation.J Thromb Haemost. 2013; 11: 2118-2127Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Now, using mice deficient in both FIX and FXII, this model provides us with a system to specifically address the hypothesis that FXI can contribute to hemostasis in vivo in the absence of FXII. C57Bl/6 F9−/− female mice18.Lin H.F. Maeda N. Smithies O. Straight D.L. Stafford D.W. A coagulation factor IX‐deficient mouse model for human hemophilia B.Blood. 1997; 90: 3962-3966Crossref PubMed Google Scholar were crossed with C57Bl/6 male mice lacking FXII (F12−/−).19.Pauer H.U. Renné T. Hemmerlein B. et al.Targeted deletion of murine coagulation factor XII gene‐a model for contact phase activation in vivo.Thromb Haemost. 2004; 92: 503-508Crossref PubMed Scopus (103) Google Scholar Female offspring were heterozygous for FIX and FXII null alleles (F9+/−/F12+/−), while males were heterozygous null for FXII and null for FIX. F9+/−/F12+/− females were crossed with F9−/F12+/− males, and offspring homozygous null for both genes (F9−/−/F12−/− females and F9−/F12−/− males) were identified (Figure 1A). Western blots of plasma confirmed that the mice with hemophilia also lack FXII (Figure 1B). The animals were crossed to generate sufficient F9−/F12−/− males for testing. In the SVB model, the saphenous vein is exposed and punctured with a needle.14.Mohammed B.M. Cheng Q. Matafonov A. Monroe D.M. Meijers J.C.M. Gailani D. Factor XI promotes hemostasis in factor IX‐deficient mice.J Thromb Haemost. 2018; 16: 2044-2049Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 20.Monroe D.M. Hoffman M. A mouse bleeding model to study oral anticoagulants.Thromb Res. 2014; 133: S6-S8Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, 21.Mohammed B.M. Cheng Q. Ivanov I.S. Gailani D. Murine models in the evaluation of heparan sulfate‐based anticoagulants.in: Balagurunathan K Nakato H Desai U Saijoh Y Glycosaminoglycans: Methods and Protocols, Methods in Molecular Biology. 2303. Springer Nature, 2022: 789-805Google Scholar After bleeding stops, clot is gently removed to restart bleeding. The number of clots forming over 30 min and the duration of each bleeding episode are recorded (Figure 1C). C57Bl/6 wild‐type (WT) and F12−/− mice formed 20.2 ± 3.1 and 18.7 ± 3.6 (p = 0.26) clots over 30 min, with bleeding times of 75 ± 14 and 79 ± 19 s (p = 0.65), respectively. In contrast, F9− mice formed 1.8 ± 1.0 clots, with bleeding times of 1333 ± 589 s (p < 0.001 for both parameters compared with WT mice), demonstrating the severe hemostatic defect caused by FIX deficiency. Results with F9−/F12−/− mice were comparable to F9− mice (2.0 ± 1.5 clots, bleeding times 1165 ± 622 s). Human FXI was infused into F9−/F12−/− mice through a tail vein to achieve plasma concentrations twice the normal level in human plasma (approximately 60 nM).14.Mohammed B.M. Cheng Q. Matafonov A. Monroe D.M. Meijers J.C.M. Gailani D. Factor XI promotes hemostasis in factor IX‐deficient mice.J Thromb Haemost. 2018; 16: 2044-2049Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar As in our prior work with F9− mice, human FXI was superimposed on endogenous murine FXI in all mouse lines. The infusions resulted in an increase in the number of clots formed over 30 min (5.8 ± 3.3) and a decrease in bleeding time (393 ± 233 s) compared to F9−/F12−/− control mice (Figure 1C, p < 0.01 for both parameters), consistent with our earlier experience with F9− mice.14.Mohammed B.M. Cheng Q. Matafonov A. Monroe D.M. Meijers J.C.M. Gailani D. Factor XI promotes hemostasis in factor IX‐deficient mice.J Thromb Haemost. 2018; 16: 2044-2049Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Because infused FXI could contain FXIa that may influence hemostasis, we expressed human FXI in F9−/F12−/− mice by HTI.14.Mohammed B.M. Cheng Q. Matafonov A. Monroe D.M. Meijers J.C.M. Gailani D. Factor XI promotes hemostasis in factor IX‐deficient mice.J Thromb Haemost. 2018; 16: 2044-2049Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar HTI resulted in sustained expression of human FXI for at least 6 weeks, with an average plasma concentration approximately 65% of that achieved with FXI infusion (a concentration slightly above the upper end of the normal plasma FXI concentration range in humans). The number of clots in mice expressing human FXI (7.2 ± 4.5) was significantly greater, and the bleeding times (380 ± 307 s) significantly shorter, than for untreated F9−/F12−/− mice (p < 0.01 for both parameters). Some comments on the model used in these experiments are required. Human FXI was used rather than increasing endogenous expression of murine FXI for two reasons. First, most mouse FXI is bound to blood vessel endothelium, making it difficult to determine the effect of infusing or expressing additional protein.15.Mohammed B.M. Cheng Q. Matafonov A. et al.A non‐circulating pool of factor XI associated with glycosaminoglycans in mice.J Thromb Haemost. 2019; 17: 1449-1460Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Second, given the absence of a bleeding disorder in FXI‐deficient mice, murine FXI may not be a hemostatic protease.10.Gailani D. Broze Jr, G.J. Factor XI activation in a revised model of blood coagulation.Science. 1991; 253: 909-912Crossref PubMed Scopus (642) Google Scholar, 14.Mohammed B.M. Cheng Q. Matafonov A. Monroe D.M. Meijers J.C.M. Gailani D. Factor XI promotes hemostasis in factor IX‐deficient mice.J Thromb Haemost. 2018; 16: 2044-2049Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Indeed, FXI may not be involved in hemostasis in all mammal species. We also used a relatively high plasma concentration of human FXI. This was necessary to get a hemostatic signal in the absence of FIX. While these features of the model raise legitimate concerns regarding the physiologic relevance of FXIa activating targets other than FIX, our sole purpose in this study was to demonstrate that FXI can have an impact on hemostasis in the absence of FXII. The results shown here imply that FXI is being converted to FXIa in this model independently of FXII. The F11 gene arose early in the evolution of mammals from a duplication of the Klkb1 gene encoding the contact protease prekallikrein, a substrate of FXIIa.22.Ponczek M.B. Shamanaev A. LaPlace A. et al.The evolution of factor XI and the kallikrein‐kinin system.Blood Adv. 2020; 4: 6135-6147Crossref PubMed Scopus (13) Google Scholar FXI combines features of prekallikrein with a mechanism for efficient FIX activation, allowing it to form a bridge between FXIIa‐initiated contact activation and thrombin generation.1.Mohammed B.M. Matafonov A. Ivanov I. et al.An update on factor XI structure and function.Thromb Res. 2018; 161: 94-105Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar This bridge is required for normal FXII‐initiated clotting in the activated partial thromboplastin time assay used in clinical practice. However, while complete deficiency of FXII does not compromise hemostasis in humans, FXI deficiency does.2.James P. Salomon O. Mikovic D. Peyvandi F. Rare bleeding disorders ‐ bleeding assessment tools, laboratory aspects and phenotype and therapy of FXI deficiency.Haemophilia. 2014; 20: 71-75Crossref PubMed Scopus (61) Google Scholar, 3.Gailani D. Wheeler A.P. Neff A.T. Rare coagulation factor deficiencies.in: Hoffman R Benz EJ Silberstein LE Hematology: Basic Principles and Practice. 7th ed. Elsevier, 2018: 2034-2050Crossref Scopus (0) Google Scholar This suggests that there are FXII‐independent mechanisms for FXI activation operating in vivo. The data shown here demonstrate that human FXI can contribute to hemostasis in mice in the absence of FXII, supporting this hypothesis. The findings are also in line with the observation that members of the mammalian infraorder Cetacea (whales, porpoises, and dolphins) have FXI in their plasmas, despite lacking FXII.22.Ponczek M.B. Shamanaev A. LaPlace A. et al.The evolution of factor XI and the kallikrein‐kinin system.Blood Adv. 2020; 4: 6135-6147Crossref PubMed Scopus (13) Google Scholar It is important to note that we have not demonstrated that thrombin is the sole, or even the major, FXI activator in the SVB model. In most placental mammals, the P2′ residing at the FXI activation cleavage site is proline, which is a common feature in thrombin substrates.23.Matafonov A. Sarilla S. Sun M.F. et al.Activation of factor XI by products of prothrombin activation.Blood. 2011; 118: 437-445Crossref PubMed Scopus (55) Google Scholar FXI differs in this regard from prekallikrein, which is not activated by thrombin.23.Matafonov A. Sarilla S. Sun M.F. et al.Activation of factor XI by products of prothrombin activation.Blood. 2011; 118: 437-445Crossref PubMed Scopus (55) Google Scholar However, it is possible that proteases other than thrombin activate FXI in our system. On a more controversial point, our observations should not be construed as a demonstration that FXII does not contribute to hemostasis. Patients who are FXII deficient and FXII‐deficient mice do not bleed abnormally during surgery,3.Gailani D. Wheeler A.P. Neff A.T. Rare coagulation factor deficiencies.in: Hoffman R Benz EJ Silberstein LE Hematology: Basic Principles and Practice. 7th ed. Elsevier, 2018: 2034-2050Crossref Scopus (0) Google Scholar, 19.Pauer H.U. Renné T. Hemmerlein B. et al.Targeted deletion of murine coagulation factor XII gene‐a model for contact phase activation in vivo.Thromb Haemost. 2004; 92: 503-508Crossref PubMed Scopus (103) Google Scholar which usually involves clean wounds. However, Juang and colleagues24.Juang L.J. Mazinani N. Novakowski S.K. et al.Coagulation factor XII contributes to hemostasis when activated by soil in wounds.Blood Adv. 2020; 4: 1737-1745Crossref PubMed Scopus (12) Google Scholar showed that exposing wounds to silicate‐containing earth (as may occur often in nature) shortens the duration of bleeding in WT mice but not in FXII‐deficient mice. Thus, depending on circumstances, FXI may be activated by different proteases, including FXIIa, at a wound site, consistent with FXI's dual nature as a contact factor and a hemostatic protein. BMM and QC generated the mice and performed experiments, and contributed to the preparation of the manuscript. DG oversaw the project and writing of the final manuscript. BMM and QC have no conflicts to declare. DG is a consultant for pharmaceutical companies (Anthos Therapeutics; Aronora, Inc.; Bayer Pharma; Bristol‐Myers Squibb; Ionis Pharmaceuticals; Janssen Pharmaceuticals) with interests in targeting factor XI, factor XII, and prekallikrein for therapeutic purposes. The authors wish to acknowledge the generous support for this work from the Ernest W. Goodpasture chair in Experimental Pathology for Translational Research, and award R35 HL140025 from the National Heart, Lung, and Blood Institute.David GailaniBiochemistry and Pathophysiology of factor XINational Heart, Lung, and Blood InstituteR35 HL140025" @default.
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• W4309705384 title "A demonstration of factor XI contributing to hemostasis in the absence of factor XII" @default.
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