作者
Alejandro Lova,Javier Pagán,Gonzalo de la Morena,D. Vazquez,Juan José Cerezo-Manchado,Carlos Bravo-Pérez,Antonia Miñano,Ana Tomas,Vicente Vicente,Marı́a Luisa Lozano,Javier Corral,María Eugenia de la Morena‐Barrio
摘要
Factor (F)XI is a procoagulant zymogen that is activated by FXIIa (contact pathway) and thrombin [ [1] Matafonov A. Sarilla S. Sun M. Sheehan J.P. Serebrov V. Verhamme I.M. Gailani D. Activation of factor XI by products of prothrombin activation. Blood. 2011; 118: 437-445 Crossref PubMed Scopus (61) Google Scholar ]. However, FXI-deficient animals had no evident hemostatic phenotype, and only a moderate coagulopathy has been reported in patients with severe FXI deficiency [ [2] Duga S. Salomon O. Factor XI deficiency. Semin Thromb Hemost. 2009; 35: 416-425 Crossref PubMed Scopus (58) Google Scholar ]. Indeed, the main interest in FXI during the last century was raised from the increased risk of thrombosis observed in patients with high FXI levels [ [3] Meijers J.C. Tekelenburg W.L. Bouma B.N. Bertina R.M. Rosendaal F.R. High levels of coagulation factor XI as a risk factor for venous thrombosis. N Engl J Med. 2000; 342: 696-701 Crossref PubMed Scopus (607) Google Scholar ]. Nevertheless, in 2005 and onward, FXI has emerged as probably the most revolutionary hemostatic molecule. The findings obtained from a diverse range of animal models employing various strategies targeting FXI and from epidemiologic studies conducted on large cohorts of patients with congenital FXI deficiency strongly support that decreased FXI levels provide antithrombotic protection, with minimal bleeding side effects [ [4] Gailani D. Making anticoagulation safer. Lancet. 2022; 399: 1360-1361 Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar ]. These observations have encouraged the development of novel drugs that specifically target FXI activation or FXIa activity, including antisense oligonucleotides, antibodies, and small inhibitory molecules [ [5] Cave B.E. Shah S.P. Turning up to eleven: factor XI inhibitors as novel agents to maximize safety and maintain efficacy in thromboembolic disease. Curr Probl Cardiol. 2021; 46100696 Crossref Scopus (7) Google Scholar ]. Favorable preclinical results with these pioneering drugs [ [6] Srivastava P. Gailani D. The rebirth of the contact pathway: a new therapeutic target. Curr Opin Hematol. 2020; 27: 311-319 Crossref PubMed Scopus (28) Google Scholar ] have paved the way for clinical trials encompassing different scenarios and diseases, ranging from highly prothrombotic surgical procedures like total knee replacement to chronic antithrombotic prophylaxis in patients with conditions such as atrial fibrillation, stroke, or cancer [ 7 Fredenburgh J.C. Weitz J.I. News at XI: moving beyond factor Xa inhibitors. J Thromb Haemost. 2023; 21: 1692-1702 Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar , 8 Greco A. Laudani C. Spagnolo M. Agnello F. Faro D.C. Finocchiaro S. Legnazzi M. Mauro M.S. Mazzone P.M. Occhipinti G. Rochira C. Scalia L. Capodanno D. Pharmacology and clinical development of factor XI inhibitors. Circulation. 2023; 147: 897-913 Crossref PubMed Scopus (19) Google Scholar , 9 Harrington J. Piccini J.P. Alexander J.H. Granger C.B. Patel M.R. Clinical evaluation of factor XIa inhibitor drugs: JACC review topic of the week. J Am Coll Cardiol. 2023; 81: 771-779 Crossref PubMed Scopus (5) Google Scholar ]. Although the scientific community is still reviewing the results of these clinical trials, which have enrolled thousands of patients, many of whom are elderly and possess cardiovascular risk factors, concerns have recently emerged regarding the potential unexpected side effects of these treatments that could also impact individuals with severe congenital FXI deficiency. An elegant study by Cao et al. [ [10] Cao Y. Wang Y. Zhou Z. Pan C. Jiang L. Zhou Z. Meng Y. Charugundla S. Li T. Allayee H. Seldin M.M. Lusis A.J. Liver-heart cross-talk mediated by coagulation factor XI protects against heart failure. Science. 2022; 377: 1399-1406 Crossref PubMed Scopus (26) Google Scholar ] evaluating the liver–heart cross-talk revealed compelling evidence suggesting that FXI plays a protective role against diastolic dysfunction, cardiac inflammation, and fibrosis in a mouse model of heart failure with preserved ejection fraction (HFpEF). Moreover, gain- and loss-of-function studies also performed in mice models confirmed this new FXI function and suggested a potential mechanism: FXIa may activate the bone morphogenetic protein–SMAD1/5 pathway and cause activation of extracellular matrix–associated bone morphogenetic protein 7 in the heart, thus inhibiting genes involved in inflammation and fibrosis [ [10] Cao Y. Wang Y. Zhou Z. Pan C. Jiang L. Zhou Z. Meng Y. Charugundla S. Li T. Allayee H. Seldin M.M. Lusis A.J. Liver-heart cross-talk mediated by coagulation factor XI protects against heart failure. Science. 2022; 377: 1399-1406 Crossref PubMed Scopus (26) Google Scholar ]. Interestingly, this study also tried to find evidence supporting a similar role in humans, but they evaluated FXI levels in a small case-control study that included few patients with HFpEF (N = 21) and non-HFpEF controls (N = 20). Although plasma FXI levels were not significantly different between groups, the inverse correlation of FXI levels with the echocardiographic parameter E/e′ ratio, a surrogate parameter of left ventricular function in the diagnostic workup of HFpEF, encouraged the authors to conclude that FXI protects against diastolic dysfunction in HFpEF [ [10] Cao Y. Wang Y. Zhou Z. Pan C. Jiang L. Zhou Z. Meng Y. Charugundla S. Li T. Allayee H. Seldin M.M. Lusis A.J. Liver-heart cross-talk mediated by coagulation factor XI protects against heart failure. Science. 2022; 377: 1399-1406 Crossref PubMed Scopus (26) Google Scholar ]. This parameter is used to estimate left ventricular filling pressure. The weak association found in humans, together with the relevance that it could have in these new antithrombotic treatments and congenital FXI deficiency, encouraged us to address this question using a different approach.