Tissue Factor-Independent Coagulation Correlates with Clinical Phenotype in Factor XI Deficiency and Replacement TherapyFunding This study was supported by the annual research grant of Swiss Hemophilia Network (Switzerland), unrestricted research grants from CSL-Behring AG (Switzerland), Novo Nordisk Pharma SA (Switzerland), Roche Pharma SA (Switzerland), Swedish Orphan Biovitrum AG (Switzerland), and an investigator initiated research grant from Shire International GmbH, Switzerland, now a Takeda company (grant id # IIR-CHE-001695). The authors confirm that all the indicated funders were used to support the current study.
Background In factor XI (FXI) deficiency, bleeding cannot be predicted by routine analyses. Since FXI is involved in tissue factor (TF)-independent propagation loop of coagulation, we hypothesized that investigating the spatiotemporal separated phases of coagulation (TF-dependent and -independent) could improve diagnostics.
Objectives This article investigates the correlation of parameters describing TF-dependent and -independent coagulation with the clinical phenotype of FXI deficiency and their ability to assess hemostasis after FXI replacement.
Methods We analyzed: (1) plasma from healthy controls (n = 53); (2) normal plasma (n = 4) spiked with increasing concentrations of a specific FXI inhibitor (C7P); (3) plasma from FXI-deficient patients (n = 24) with different clinical phenotypes (13 bleeders, 8 non-bleeders, 3 prothrombotics); (4) FXI-deficient plasma spiked with FXI concentrate (n = 6); and (5) plasma from FXI-deficient patients after FXI replacement (n = 7). Thrombin generation was measured with the reference method calibrated automated thrombogram and with Thrombodynamics (TD), a novel global assay differentiating TF-dependent and -independent coagulation.
Results C7P dose-dependently decreased FXI activity, prolonged activated partial thromboplastin time, and hampered TF-independent coagulation. In FXI-deficient bleeders, TD parameters describing TF-independent propagation of coagulation and fibrin clot formation were reduced compared with controls and FXI-deficient nonbleeders and increased in FXI-deficient patients with prothrombotic phenotype. Receiver operating characteristic analysis indicated that TF-independent parameters were useful for discriminating FXI-deficient bleeders from non-bleeders. In FXI-deficient plasma spiked with FXI concentrate and in patients receiving FXI replacement, TD parameters were shifted toward hypercoagulation already at plasma FXI levels around 20%.
Conclusion TF-independent coagulation parameters assessed by TD have the potential to identify the clinical phenotype in FXI-deficient patients and to monitor FXI replacement therapy.
D.B.C. contributed to the design and the implementation of the research, performed research, analyzed results, wrote and edited the manuscript; M.G.Z. performed research and critically revised the manuscript. A.A. and A.-P.B.M.S. contributed to research and critically revised the manuscript. V.C. and C.H. developed and made available for this study the specific FXI inhibitor and critically revised the manuscript. L.A. conceived the original idea, supervised the research, wrote and edited the manuscript.
Eingereicht: 17. April 2020
Angenommen: 23. Juli 2020
13. September 2020 (online)
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- 1 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 (07) 2654-2659
- 2 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 (02) 429-432
- 3 Asselta R, Paraboschi EM, Rimoldi V. et al. Exploring the global landscape of genetic variation in coagulation factor XI deficiency. Blood 2017; 130 (04) e1-e6
- 4 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 (05) 490-493
- 5 Bolton-Maggs PH. Factor XI deficiency--resolving the enigma?. Hematology (Am Soc Hematol Educ Program) 2009; •••: 97-105
- 6 Duga S, Salomon O. Congenital factor XI deficiency: an update. Semin Thromb Hemost 2013; 39 (06) 621-631
- 7 Bolton-Maggs PH, Young Wan-Yin B, McCraw AH, Slack J, Kernoff PB. Inheritance and bleeding in factor XI deficiency. Br J Haematol 1988; 69 (04) 521-528
- 8 Bauduer F, de Raucourt E, Boyer-Neumann C. et al; French Postmarketing Study Group. Factor XI replacement for inherited factor XI deficiency in routine clinical practice: results of the HEMOLEVEN prospective 3-year postmarketing study. Haemophilia 2015; 21 (04) 481-489
- 9 Santoro C, Di Mauro R, Baldacci E. et al. Bleeding phenotype and correlation with factor XI (FXI) activity in congenital FXI deficiency: results of a retrospective study from a single centre. Haemophilia 2015; 21 (04) 496-501
- 10 Wheeler AP, Gailani D. Why factor XI deficiency is a clinical concern. Expert Rev Hematol 2016; 9 (07) 629-637
- 11 Menegatti M, Peyvandi F. Treatment of rare factor deficiencies other than hemophilia. Blood 2019; 133 (05) 415-424
- 12 Bolton-Maggs P, Goudemand J, Hermans C, Makris M, de Moerloose P. FXI concentrate use and risk of thrombosis. Haemophilia 2014; 20 (04) e349-e351
- 13 Bolton-Maggs PH, Colvin BT, Satchi BT, Lee CA, Lucas GS. Thrombogenic potential of factor XI concentrate. Lancet 1994; 344 (8924): 748-749
- 14 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 (04) 1314-1319
- 15 Naito K, Fujikawa K. 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 (12) 7353-7358
- 16 Gailani D, Broze Jr GJ. Factor XI activation in a revised model of blood coagulation. Science 1991; 253 (5022): 909-912
- 17 Ratnoff OD, Colopy JE. A familial hemorrhagic trait associated with a deficiency of a clot-promoting fraction of plasma. J Clin Invest 1955; 34 (04) 602-613
- 18 Choi SH, Smith SA, Morrissey JH. Polyphosphate is a cofactor for the activation of factor XI by thrombin. Blood 2011; 118 (26) 6963-6970
- 19 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 (12) 2118-2127
- 20 Puy C, Tucker EI, Matafonov A. et al. Activated factor XI increases the procoagulant activity of the extrinsic pathway by inactivating tissue factor pathway inhibitor. Blood 2015; 125 (09) 1488-1496
- 21 Whelihan MF, Orfeo T, Gissel MT, Mann KG. Coagulation procofactor activation by factor XIa. J Thromb Haemost 2010; 8 (07) 1532-1539
- 22 Von dem Borne PA, Bajzar L, Meijers JC, Nesheim ME, Bouma BN. Thrombin-mediated activation of factor XI results in a thrombin-activatable fibrinolysis inhibitor-dependent inhibition of fibrinolysis. J Clin Invest 1997; 99 (10) 2323-2327
- 23 Pike GN, Cumming AM, Thachil J, Hay CRM, Bolton-Maggs PHB, Burthem J. Evaluation of the use of rotational thromboelastometry in the assessment of FXI deficiency. Haemophilia 2017; 23 (03) 449-457
- 24 Livnat T, Shenkman B, Martinowitz U. et al. The impact of thrombin generation and rotation thromboelastometry on assessment of severity of factor XI deficiency. Thromb Res 2015; 136 (02) 465-473
- 25 Guéguen P, Galinat H, Blouch MT. et al. Biological determinants of bleeding in patients with heterozygous factor XI deficiency. Br J Haematol 2012; 156 (02) 245-251
- 26 Zucker M, Seligsohn U, Salomon O, Wolberg AS. Abnormal plasma clot structure and stability distinguish bleeding risk in patients with severe factor XI deficiency. J Thromb Haemost 2014; 12 (07) 1121-1130
- 27 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 (05) 771-777
- 28 Pike GN, Cumming AM, Hay CR, Bolton-Maggs PH, Burthem J. Sample conditions determine the ability of thrombin generation parameters to identify bleeding phenotype in FXI deficiency. Blood 2015; 126 (03) 397-405
- 29 Gidley GN, Holle LA, Burthem J, Bolton-Maggs PHB, Lin FC, Wolberg AS. Abnormal plasma clot formation and fibrinolysis reveal bleeding tendency in patients with partial factor XI deficiency. Blood Adv 2018; 2 (10) 1076-1088
- 30 Hemker HC, Wielders S, Kessels H, Béguin S. Continuous registration of thrombin generation in plasma, its use for the determination of the thrombin potential. Thromb Haemost 1993; 70 (04) 617-624
- 31 Dashkevich NM, Ovanesov MV, Balandina AN. et al. Thrombin activity propagates in space during blood coagulation as an excitation wave. Biophys J 2012; 103 (10) 2233-2240
- 32 Dashkevich NM, Vuimo TA, Ovsepyan RA. et al. Effect of pre-analytical conditions on the thrombodynamics assay. Thromb Res 2014; 133 (03) 472-476
- 33 Bertaggia Calderara D, Aliotta A, Zermatten MG, Kröll D, Stirnimann G, Alberio L. Hyper-coagulability in obese patients accurately identified by combinations of global coagulation assay parameters. Thromb Res 2020; 187: 91-102
- 34 Hemker HC, Giesen P, AlDieri R. et al. The calibrated automated thrombogram (CAT): a universal routine test for hyper- and hypocoagulability. Pathophysiol Haemost Thromb 2002; 32 (5-6): 249-253
- 35 Sinauridze EI, Vuimo TA, Tarandovskiy ID. et al. Thrombodynamics, a new global coagulation test: measurement of heparin efficiency. Talanta 2018; 180: 282-291
- 36 Shibeko AM, Panteleev MA. Untangling the complexity of blood coagulation network: use of computational modelling in pharmacology and diagnostics. Brief Bioinform 2016; 17 (03) 429-439
- 37 Mazzara S, Rossi RL, Grifantini R, Donizetti S, Abrignani S, Bombaci M. CombiROC: an interactive web tool for selecting accurate marker combinations of omics data. Sci Rep 2017; 7: 45477
- 38 Kuprash AD, Shibeko AM, Vijay R. et al. Sensitivity and robustness of spatially dependent thrombin generation and fibrin clot propagation. Biophys J 2018; 115 (12) 2461-2473
- 39 Bolton-Maggs PH, Perry DJ, Chalmers EA. et al. The rare coagulation disorders--review with guidelines for management from the United Kingdom Haemophilia Centre Doctors' Organisation. Haemophilia 2004; 10 (05) 593-628
- 40 Mumford AD, Ackroyd S, Alikhan R. et al; BCSH Committee. Guideline for the diagnosis and management of the rare coagulation disorders: a United Kingdom Haemophilia Centre Doctors' Organization guideline on behalf of the British Committee for Standards in Haematology. Br J Haematol 2014; 167 (03) 304-326
- 41 Mann KG, Brummel K, Butenas S. What is all that thrombin for?. J Thromb Haemost 2003; 1 (07) 1504-1514
- 42 Palla R, Peyvandi F, Shapiro AD. Rare bleeding disorders: diagnosis and treatment. Blood 2015; 125 (13) 2052-2061
- 43 Batty P, Honke A, Bowles L. et al. Ongoing risk of thrombosis with factor XI concentrate: 5 years experience in two centres. Haemophilia 2015; 21 (04) 490-495
- 44 Hoffman M, Monroe III DM. A cell-based model of hemostasis. Thromb Haemost 2001; 85 (06) 958-965
- 45 Panteleev MA, Dashkevich NM, Ataullakhanov FI. Hemostasis and thrombosis beyond biochemistry: roles of geometry, flow and diffusion. Thromb Res 2015; 136 (04) 699-711
- 46 Ataullakhanov FI, Dashkevich NM, Negrier C, Panteleev MA. Factor XI and traveling waves: the key to understanding coagulation in hemophilia?. Expert Rev Hematol 2013; 6 (02) 111-113
- 47 Aghighi S, Riddell A, Lee CA, Brown SA, Tuddenham E, Chowdary P. Global coagulation assays in hemophilia A: a comparison to conventional assays. Res Pract Thromb Haemost 2019; 4 (02) 298-308
- 48 Parunov LA, Surov SS, Tucker E, Ovanesov MV. The effect of corn trypsin inhibitor and inhibiting antibodies for FXIa and FXIIa on coagulation of plasma and whole blood: comment. J Thromb Haemost 2015; 13 (08) 1527-1530
- 49 Al Dieri R, Peyvandi F, Santagostino E. et al. The thrombogram in rare inherited coagulation disorders: its relation to clinical bleeding. Thromb Haemost 2002; 88 (04) 576-582
- 50 Fadeeva OA, Panteleev MA, Karamzin SS, Balandina AN, Smirnov IV, Ataullakhanov FI. Thromboplastin immobilized on polystyrene surface exhibits kinetic characteristics close to those for the native protein and activates in vitro blood coagulation similarly to thromboplastin on fibroblasts. Biochemistry (Mosc) 2010; 75 (06) 734-743
- 51 Pike GN, Cumming AM, Hay CR. et al. In vitro comparison of the effect of two factor XI (FXI) concentrates on thrombin generation in major FXI deficiency. Haemophilia 2016; 22 (03) 403-410