Congenital Factor XI Deficiency: An Update

Stefano Duga; Ophira Salomon

doi:10.1055/s-0033-1353420

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2013; 39(06): 621-631
DOI: 10.1055/s-0033-1353420

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Congenital Factor XI Deficiency: An Update

Stefano Duga

¹Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy

,

Ophira Salomon

²The Amalia Biron Research Institute of Thrombosis and Hemostasis, Chaim Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

› Author Affiliations

Abstract

Severe factor XI (FXI) deficiency is an injury-related bleeding disorder, common in Ashkenazi Jews (with two mutations prevailing), but rare worldwide (with heterogeneous mutations). In the past two decades, more than 220 mutations in the FXI gene have been reported in patients with FXI deficiency, of which 7 showed a founder effect. Inhibitors to FXI were described in patients with null-allele mutations, following exposure to plasma, FXI concentrates, or anti-RhD immunoglobulin. Treatment of patients with severe FXI deficiency remains challenging because factors influencing bleeding risks are still unknown. The use of lower doses of recombinant activated factor VII in comparison with the doses commonly applied in hemophilia A or B seems promising also when assessed in vitro by thrombin generation test. Recently, FXI has been shown to have a separate role in hemostasis and in thrombosis. In animal models, targeting FXI by knocking out the gene or by using FXI-neutralizing antibodies, antisense oligonucleotides, and peptidomimetic inhibitors, prevents arterial and vein thrombosis. The homology between human and murine FXI and the significant antithrombotic effect of FXI deficiency in animal models resulted in the development of a novel approach of targeting FXI for prevention of thrombosis without impairing hemostasis in high-risk patients. The acceptance of FXI as a risk factor for thrombosis is a new concept, and patients with severe FXI deficiency might gain profit during life course.

Keywords

factor XI - inhibitors - bleeding - thrombosis - antithrombosis - animal models - global coagulation test - genetics - molecular diagnosis

Full Text

References

References
1 Emsley J, McEwan PA, Gailani D. Structure and function of factor XI. Blood 2010; 115 (13) 2569-2577
2 Rosenthal RL, Dreskin OH, Rosenthal N. New hemophilia-like disease caused by deficiency of a third plasma thromboplastin factor. Proc Soc Exp Biol Med 1953; 82 (1) 171-174
3 Salomon O, Steinberg DM, Seligshon U. Variable bleeding manifestations characterize different types of surgery in patients with severe factor XI deficiency enabling parsimonious use of replacement therapy. Haemophilia 2006; 12 (5) 490-493
4 Bolton-Maggs PH. Factor XI deficiency—resolving the enigma?. Hematology (Am Soc Hematol Educ Program) 2009; 97-105
5 Kravtsov DV, Wu W, Meijers JC , et al. Dominant factor XI deficiency caused by mutations in the factor XI catalytic domain. Blood 2004; 104 (1) 128-134
6 Kravtsov DV, Monahan PE, Gailani D. A classification system for cross-reactive material-negative factor XI deficiency. Blood 2005; 105 (12) 4671-4673
7 Dai L, Rangarajan S, Mitchell M. Three dominant-negative mutations in factor XI-deficient patients. Haemophilia 2011; 17 (5) e919-e922
8 Mitchell M, Mountford R, Butler R , et al. Spectrum of factor XI (F11) mutations in the UK population—116 index cases and 140 mutations. Hum Mutat 2006; 27 (8) 829
9 Shpilberg O, Peretz H, Zivelin A , et al. One of the two common mutations causing factor XI deficiency in Ashkenazi Jews (type II) is also prevalent in Iraqi Jews, who represent the ancient gene pool of Jews. Blood 1995; 85 (2) 429-432
10 Zadra G, Asselta R, Tenchini ML , et al. Simultaneous genotyping of coagulation factor XI type II and type III mutations by multiplex real-time polymerase chain reaction to determine their prevalence in healthy and factor XI-deficient Italians. Haematologica 2008; 93 (5) 715-721
11 Salomon O, Seligsohn U. New observations on factor XI deficiency. Haemophilia 2004; 10 (Suppl. 04) 184-187
12 Bouma BN, Meijers JC. Role of blood coagulation factor XI in downregulation of fibrinolysis. Curr Opin Hematol 2000; 7 (5) 266-272
13 Bolton-Maggs PH, Patterson DA, Wensley RT, Tuddenham EG. Definition of the bleeding tendency in factor XI-deficient kindreds—a clinical and laboratory study. Thromb Haemost 1995; 73 (2) 194-202
14 Kadir RA, Economides DL, Sabin CA, Owens D, Lee CA. Frequency of inherited bleeding disorders in women with menorrhagia. Lancet 1998; 351 (9101) 485-489
15 Salomon O, Zivelin A, Livnat T , et al. Prevalence, causes, and characterization of factor XI inhibitors in patients with inherited factor XI deficiency. Blood 2003; 101 (12) 4783-4788
16 Salomon O, Zivelin A, Livnat T, Seligsohn U. Inhibitors to Factor XI in patients with severe Factor XI deficiency. Semin Hematol 2006; 43 (1) (Suppl. 01) S10-S12
17 Zucker M, Zivelin A, Teitel J, Seligsohn U. Induction of an inhibitor antibody to factor XI in a patient with severe inherited factor XI deficiency by Rh immune globulin. Blood 2008; 111 (3) 1306-1308
18 Quélin F, Trossaërt M, Sigaud M, Mazancourt PD, Fressinaud E. Molecular basis of severe factor XI deficiency in seven families from the west of France. Seven novel mutations, including an ancient Q88X mutation. J Thromb Haemost 2004; 2 (1) 71-76
19 Salomon O, Steinberg DM, Koren-Morag N, Tanne D, Seligsohn U. Reduced incidence of ischemic stroke in patients with severe factor XI deficiency. Blood 2008; 111 (8) 4113-4117
20 Yang DT, Flanders MM, Kim H, Rodgers GM. Elevated factor XI activity levels are associated with an increased odds ratio for cerebrovascular events. Am J Clin Pathol 2006; 126 (3) 411-415
21 Davis J, Wagner MR, Zhang W, Xu F, Van Nostrand WE. Amyloid beta-protein stimulates the expression of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) in human cerebrovascular smooth muscle cells. J Biol Chem 2003; 278 (21) 19054-19061
22 Bolton-Maggs PH, Peretz H, Butler R , et al. A common ancestral mutation (C128X) occurring in 11 non-Jewish families from the UK with factor XI deficiency. J Thromb Haemost 2004; 2 (6) 918-924
23 Umeda T, Hiramaru M, Nishino T, Onchi K, Matsuda T. A case of congenital factor XI (plasma thromboplastin antecedent) deficiency with large organized thrombus in the vena cava inferior . [in Japanese]. Nippon Ketsueki Gakkai Zasshi 1968; 31 (3) 325-333
24 Brodsky JB, Burgess III GE. Pulmonary embolism with factor XI deficiency. JAMA 1975; 234 (11) 1156-1157
25 Evans G, Pasi KJ, Mehta A, Lee CA, Perry DJ. Recurrent venous thromboembolic disease and factor XI concentrate in a patient with severe factor XI deficiency, chronic myelomonocytic leukaemia, factor V Leiden and heterozygous plasminogen deficiency. Blood Coagul Fibrinolysis 1997; 8 (7) 437-440
26 Salomon O, Steinberg DM, Zucker M, Varon D, Zivelin A, Seligsohn U. Patients with severe factor XI deficiency have a reduced incidence of deep-vein thrombosis. Thromb Haemost 2011; 105 (2) 269-273
27 Meijers JC, Tekelenburg WL, Bouma BN, Bertina RM, Rosendaal FR. High levels of coagulation factor XI as a risk factor for venous thrombosis. N Engl J Med 2000; 342 (10) 696-701
28 Etscheid M, Breitner-Ruddock S, Gross S, Hunfeld A, Seitz R, Dodt J. Identification of kallikrein and FXIa as impurities in therapeutic immunoglobulins: implications for the safety and control of intravenous blood products. Vox Sang 2012; 102 (1) 40-46
29 Tucker EI, Gailani D, Hurst S, Cheng Q, Hanson SR, Gruber A. Survival advantage of coagulation factor XI-deficient mice during peritoneal sepsis. J Infect Dis 2008; 198 (2) 271-274
30 Tucker EI, Verbout NG, Leung PY , et al. Inhibition of factor XI activation attenuates inflammation and coagulopathy while improving the survival of mouse polymicrobial sepsis. Blood 2012; 119 (20) 4762-4768
31 Luo D, Szaba FM, Kummer LW , et al. Factor XI-deficient mice display reduced inflammation, coagulopathy, and bacterial growth during listeriosis. Infect Immun 2012; 80 (1) 91-99
32 Itakura A, Verbout NG, Phillips KG , et al. Activated factor XI inhibits chemotaxis of polymorphonuclear leukocytes. J Leukoc Biol 2011; 90 (5) 923-927
33 Salomon O, Steinberg DM, Tamarin I, Zivelin A, Seligsohn U. Plasma replacement therapy during labor is not mandatory for women with severe factor XI deficiency. Blood Coagul Fibrinolysis 2005; 16 (1) 37-41
34 Myers B, Pavord S, Kean L, Hill M, Dolan G. Pregnancy outcome in Factor XI deficiency: incidence of miscarriage, antenatal and postnatal haemorrhage in 33 women with Factor XI deficiency. BJOG 2007; 114 (5) 643-646
35 Tarantino MD, Gupta SL, Brusky RM. The incidence and outcome of intracranial haemorrhage in newborns with haemophilia: analysis of the Nationwide Inpatient Sample database. Haemophilia 2007; 13 (4) 380-382
36 Singh A, Harnett MJ, Connors JM, Camann WR. Factor XI deficiency and obstetrical anesthesia. Anesth Analg 2009; 108 (6) 1882-1885
37 Setty S, Reddell A, England A, Gomez K, Kadir R. The role of recombinant factor VIIa for obstetric block in women with severe factor XI deficiency. Haemophilia 2011; 17 (6) 906-909
38 Peretz H, Mulai A, Usher S , et al. The two common mutations causing factor XI deficiency in Jews stem from distinct founders: one of ancient Middle Eastern origin and another of more recent European origin. Blood 1997; 90 (7) 2654-2659
39 Zivelin A, Bauduer F, Ducout L , et al. Factor XI deficiency in French Basques is caused predominantly by an ancestral Cys38Arg mutation in the factor XI gene. Blood 2002; 99 (7) 2448-2454
40 Bolton-Maggs PHB, Young Wan-Yin B, McCraw AH, Slack J, Kernoff PB. Inheritance and bleeding in factor XI deficiency. Br J Haematol 1988; 69 (4) 521-528
41 Wu W, Li H, Navaneetham D, Reichenbach ZW, Tuma RF, Walsh PN. The kunitz protease inhibitor domain of protease nexin-2 inhibits factor XIa and murine carotid artery and middle cerebral artery thrombosis. Blood 2012; 120 (3) 671-677
42 Younis HS, Crosby J, Huh JI , et al. Antisense inhibition of coagulation factor XI prolongs APTT without increased bleeding risk in cynomolgus monkeys. Blood 2012; 119 (10) 2401-2408
43 Minnema MC, Friederich PW, Levi M , et al. Enhancement of rabbit jugular vein thrombolysis by neutralization of factor XI. In vivo evidence for a role of factor XI as an anti-fibrinolytic factor. J Clin Invest 1998; 101 (1) 10-14
44 Kleinschnitz C, Stoll G, Bendszus M , et al. Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis. J Exp Med 2006; 203 (3) 513-518
45 Rosen ED, Gailani D, Castellino FJ. FXI is essential for thrombus formation following FeCl3-induced injury of the carotid artery in the mouse. Thromb Haemost 2002; 87 (4) 774-776
46 Yamashita A, Nishihira K, Kitazawa T , et al. Factor XI contributes to thrombus propagation on injured neointima of the rabbit iliac artery. J Thromb Haemost 2006; 4 (7) 1496-1501
47 Rugonyi S, McCarty OJ, Gailani D, Gruber A, Hanson SR. Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI. Blood 2009; 113 (4) 936-944
48 Mannucci PM, Duga S, Peyvandi F. Recessively inherited coagulation disorders. Blood 2004; 104 (5) 1243-1252
49 Zadra G, Asselta R, Malcovati M , et al. Molecular genetic analysis of severe coagulation factor XI deficiency in six Italian patients. Haematologica 2004; 89 (11) 1332-1340
50 Cheng Q, Kantz J, Poffenberger G, Powers AC, Gailani D. Factor XI protein in human pancreas and kidney. Thromb Haemost 2008; 100 (1) 158-160
51 Tarumi T, Kravtsov DV, Zhao M, Williams SM, Gailani D. Cloning and characterization of the human factor XI gene promoter: transcription factor hepatocyte nuclear factor 4alpha (HNF-4alpha ) is required for hepatocyte-specific expression of factor XI. J Biol Chem 2002; 277 (21) 18510-18516
52 Asselta R, Rimoldi V, Guella I , et al. Molecular characterization of in-frame and out-of-frame alternative splicings in coagulation factor XI pre-mRNA. Blood 2010; 115 (10) 2065-2072
53 Lejeune F, Maquat LE. Mechanistic links between nonsense-mediated mRNA decay and pre-mRNA splicing in mammalian cells. Curr Opin Cell Biol 2005; 17 (3) 309-315
54 Thompson RE, Mandle Jr R, Kaplan AP. Association of factor XI and high molecular weight kininogen in human plasma. J Clin Invest 1977; 60 (6) 1376-1380
55 Fujikawa K, Chung DW, Hendrickson LE, Davie EW. Amino acid sequence of human factor XI, a blood coagulation factor with four tandem repeats that are highly homologous with plasma prekallikrein. Biochemistry 1986; 25 (9) 2417-2424
56 McMullen BA, Fujikawa K, Davie EW. Location of the disulfide bonds in human coagulation factor XI: the presence of tandem apple domains. Biochemistry 1991; 30 (8) 2056-2060
57 Papagrigoriou E, McEwan PA, Walsh PN, Emsley J. Crystal structure of the factor XI zymogen reveals a pathway for transactivation. Nat Struct Mol Biol 2006; 13 (6) 557-558
58 Sinha D, Marcinkiewicz M, Gailani D, Walsh PN. Molecular cloning and biochemical characterization of rabbit factor XI. Biochem J 2002; 367 (Pt 1) 49-56
59 Wu W, Sinha D, Shikov S , et al. Factor XI homodimer structure is essential for normal proteolytic activation by factor XIIa, thrombin, and factor XIa. J Biol Chem 2008; 283 (27) 18655-18664
60 Gailani D, Broze Jr GJ. Factor XI activation in a revised model of blood coagulation. Science 1991; 253 (5022) 909-912
61 Di Scipio RG, Kurachi K, Davie EW. Activation of human factor IX (Christmas factor). J Clin Invest 1978; 61 (6) 1528-1538
62 von dem Borne PAK, Meijers JCM, Bouma BN. Feedback activation of factor XI by thrombin in plasma results in additional formation of thrombin that protects fibrin clots from fibrinolysis. Blood 1995; 86 (8) 3035-3042
63 Matafonov A, Sarilla S, Sun MF , et al. Activation of factor XI by products of prothrombin activation. Blood 2011; 118 (2) 437-445
64 Kannemeier C, Shibamiya A, Nakazawa F , et al. Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci U S A 2007; 104 (15) 6388-6393
65 Smith SA, Mutch NJ, Baskar D, Rohloff P, Docampo R, Morrissey JH. Polyphosphate modulates blood coagulation and fibrinolysis. Proc Natl Acad Sci U S A 2006; 103 (4) 903-908
66 Maas C, Meijers JC, Marquart JA , et al. Activated factor V is a cofactor for the activation of factor XI by thrombin in plasma. Proc Natl Acad Sci U S A 2010; 107 (20) 9083-9087
67 Choi SH, Smith SA, Morrissey JH. Polyphosphate is a cofactor for the activation of factor XI by thrombin. Blood 2011; 118 (26) 6963-6970
68 Whelihan MF, Orfeo T, Gissel MT, Mann KG. Coagulation procofactor activation by factor XIa. J Thromb Haemost 2010; 8 (7) 1532-1539
69 Saunders RE, O'Connell NM, Lee CA, Perry DJ, Perkins SJ. Factor XI deficiency database: an interactive web database of mutations, phenotypes, and structural analysis tools. Hum Mutat 2005; 26 (3) 192-198
70 Saunders RE, Shiltagh N, Gomez K , et al. Structural analysis of eight novel and 112 previously reported missense mutations in the interactive FXI mutation database reveals new insight on FXI deficiency. Thromb Haemost 2009; 102 (2) 287-301
71 O'Connell NM, Saunders RE, Lee CA, Perry DJ, Perkins SJ. Structural interpretation of 42 mutations causing factor XI deficiency using homology modeling. J Thromb Haemost 2005; 3 (1) 127-138
72 Sun MF, Ho D, Martincic D, Ware RE, Walsh PN, Gailani D. Defective binding of factor XI-N248 to activated human platelets. Blood 2007; 110 (13) 4164
73 Guella I, Soldà G, Spena S , et al. Molecular characterization of two novel mutations causing factor XI deficiency: A splicing defect and a missense mutation responsible for a CRM+ defect. Thromb Haemost 2008; 99 (3) 523-530
74 Zivelin A, Ogawa T, Bulvik S , et al. Severe factor XI deficiency caused by a Gly555 to Glu mutation (factor XI-Glu555): a cross-reactive material positive variant defective in factor IX activation. J Thromb Haemost 2004; 2 (10) 1782-1789
75 Germanos-Haddad M, de Moerloose P, Boehlen F, Peyvandi F, Neerman-Arbez M. Homozygosity for a Thr575Met missense mutation in the catalytic domain associated with factor XI deficiency. Haematologica 2005; 90 (3) 418-419
76 Sun MF, Ho D, Martincic D, Ware RE, Walsh PN, Gailani D. Defective binding of factor XI-N248 to activated human platelets. Blood 2007; 110 (13) 4164
77 Gailani D, Schmidt A, Sun MF, Bolton-Maggs PH, Bajaj SP. A cross-reactive material positive variant of coagulation factor XI (FXIP520L) with a catalytic defect. J Thromb Haemost 2007; 5 (4) 781-787
78 Bozzao C, Rimoldi V, Asselta R , et al. A novel factor XI missense mutation (Val371Ile) in the activation loop is responsible for a case of mild type II factor XI deficiency. FEBS J 2007; 274 (23) 6128-6138
79 Mitchell M, Cutler J, Thompson S , et al. Heterozygous factor XI deficiency associated with three novel mutations. Br J Haematol 1999; 107 (4) 763-765
80 Mitchell MJ, Dai L, Clarke JB, Bolton-Maggs PH, Savidge GF, Alhaq A. Characterisation of five factor XI mutations. Thromb Haemost 2007; 97 (6) 884-889
81 Mitchell M, Dai L, Savidge G, Alhaq A. An Alu-mediated 31.5-kb deletion as the cause of factor XI deficiency in 2 unrelated patients. Blood 2004; 104 (8) 2394-2396
82 Asakai R, Chung DW, Ratnoff OD, Davie EW. Factor XI (plasma thromboplastin antecedent) deficiency in Ashkenazi Jews is a bleeding disorder that can result from three types of point mutations. Proc Natl Acad Sci U S A 1989; 86 (20) 7667-7671
83 Peretz H, Zivelin A, Usher S, Seligsohn U. A 14-bp deletion (codon 554 del AAGgtaacagagtg) at exon 14/intron N junction of the coagulation factor XI gene disrupts splicing and causes severe factor XI deficiency. Hum Mutat 1996; 8 (1) 77-78
84 Asakai R, Chung DW, Davie EW, Seligsohn U. Factor XI deficiency in Ashkenazi Jews in Israel. N Engl J Med 1991; 325 (3) 153-158
85 Peretz H, Salomon O, Mor-Cohen R , et al. Type I mutation in the F11 gene is a third ancestral mutation which causes factor XI deficiency in Ashkenazi Jews. J Thromb Haemost 2013; 11 (4) 724-730
86 Girolami A, Scarparo P, Bonamigo E , et al. A cluster of factor XI-deficient patients due to a new mutation (Ile 436 Lys) in northeastern Italy. Eur J Haematol 2012; 88 (3) 229-236
87 Kim J, Song J, Lyu CJ , et al. Population-specific spectrum of the F11 mutations in Koreans: evidence for a founder effect. Clin Genet 2012; 82 (2) 180-186
88 Meijers JC, Davie EW, Chung DW. Expression of human blood coagulation factor XI: characterization of the defect in factor XI type III deficiency. Blood 1992; 79 (6) 1435-1440
89 Soldà G, Asselta R, Ghiotto R, Tenchini ML, Castaman G, Duga S. A type II mutation (Glu117stop), induction of allele-specific mRNA degradation and factor XI deficiency. Haematologica 2005; 90: 1716-1718
90 Zucker M, Rosenberg N, Peretz H , et al. Point mutations regarded as missense mutations cause splicing defects in the factor XI gene. J Thromb Haemost 2011; 9 (10) 1977-1984
91 Mitchell M, Harrington P, Cutler J, Rangarajan S, Savidge G, Alhaq A. Eighteen unrelated patients with factor XI deficiency, four novel mutations and a 100% detection rate by denaturing high-performance liquid chromatography. Br J Haematol 2003; 121 (3) 500-502
92 Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 2002; 30 (12) e57
93 Weaver JM, Edwards PA. Targeted next-generation sequencing for routine clinical screening of mutations. Genome Med 2011; 3 (9) 58
94 Rugeri L, Quélin F, Chatard B, De Mazancourt P, Negrier C, Dargaud Y. Thrombin generation in patients with factor XI deficiency and clinical bleeding risk. Haemophilia 2010; 16 (5) 771-777
95 Riddell A, Abdul-Kadir R, Pollard D, Tuddenham E, Gomez K. Monitoring low dose recombinant factor VIIa therapy in patients with severe factor XI deficiency undergoing surgery. Thromb Haemost 2011; 106 (3) 521-527
96 Guéguen P, Galinat H, Blouch MT , et al. Biological determinants of bleeding in patients with heterozygous factor XI deficiency. Br J Haematol 2012; 156 (2) 245-251
97 Livnat T, Tamarin I, Mor Y , et al. Recombinant activated factor VII and tranexamic acid are haemostatically effective during major surgery in factor XI-deficient patients with inhibitor antibodies. Thromb Haemost 2009; 102 (3) 487-492
98 Gomez K, Bolton-Maggs P. Factor XI deficiency. Haemophilia 2008; 14 (6) 1183-1189
99 Duga S, Asselta R. Mutations in disguise. J Thromb Haemost 2011; 9 (10) 1973-1976
100 Bell J, Bodmer D, Sistermans E, Ramsden SC. Practice guidelines for the interpretation and reporting of unclassified variants (UVs) in clinical molecular genetics. Available at: http://cmgsweb.shared.hosting.zen.co.uk/BPGs/pdfs%20current%20bpgs/UV%20GUIDELINES%20ratified.pdf. 2007. Accessed XX.
101 Fabian ID, Sachs D, Moisseiev J , et al. Cataract extraction without prophylactic treatment in patients with severe factor XI deficiency. Am J Ophthalmol 2009; 148 (6) 920-924 , e1
102 Mannucci PM, Bauer KA, Santagostino E , et al. Activation of the coagulation cascade after infusion of a factor XI concentrate in congenitally deficient patients. Blood 1994; 84 (4) 1314-1319
103 O'Connell NM, Riddell AF, Pascoe G, Perry DJ, Lee CA. Recombinant factor VIIa to prevent surgical bleeding in factor XI deficiency. Haemophilia 2008; 14 (4) 775-781
104 Schulman S, Németh G. An illustrative case and a review on the dosing of recombinant factor VIIa in congenital factor XI deficiency. Haemophilia 2006; 12 (3) 223-227
105 Livnat T, Zivelin A, Martinowitz U, Salomon O, Seligsohn U. Prerequisites for recombinant factor VIIa-induced thrombin generation in plasmas deficient in factors VIII, IX or XI. J Thromb Haemost 2006; 4 (1) 192-200
106 Mannucci PM, Levi M. Prevention and treatment of major blood loss. N Engl J Med 2007; 356 (22) 2301-2311
107 Zhang H, Löwenberg EC, Crosby JR , et al. Inhibition of the intrinsic coagulation pathway factor XI by antisense oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk. Blood 2010; 116 (22) 4684-4692
108 Lin J, Deng H, Jin L , et al. Design, synthesis, and biological evaluation of peptidomimetic inhibitors of factor XIa as novel anticoagulants. J Med Chem 2006; 49 (26) 7781-7791