Reversal Agents for the Direct Factor Xa Inhibitors: Biochemical Mechanisms of Current and Newly Emerging Therapies

Mark Schreuder; Pieter H. Reitsma; Mettine H. A. Bos

doi:10.1055/s-0040-1709134

Seminars in Thrombosis and Hemostasis, Inhaltsverzeichnis

Semin Thromb Hemost 2020; 46(08): 986-998
DOI: 10.1055/s-0040-1709134

Review Article

Reversal Agents for the Direct Factor Xa Inhibitors: Biochemical Mechanisms of Current and Newly Emerging Therapies

Mark Schreuder

¹Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands

,

Pieter H. Reitsma

¹Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands

,

Mettine H. A. Bos

¹Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands

› Institutsangaben

Abstract

The direct oral anticoagulants targeting coagulation factor Xa or thrombin are widely used as alternatives to vitamin K antagonists in the management of venous thromboembolism and nonvalvular atrial fibrillation. In case of bleeding or emergency surgery, reversal agents are helpful to counteract the anticoagulant therapy and restore hemostasis. While idarucizumab has been established as an antidote for the direct thrombin inhibitor dabigatran, reversal strategies for the direct factor Xa inhibitors have been a focal point in clinical care over the past years. In the absence of specific reversal agents, the off-label use of (activated) prothrombin complex concentrate and recombinant factor VIIa have been suggested as effective treatment options during inhibitor-induced bleeding complications. Meanwhile, several specific reversal agents have been developed. In this review, an overview of the current state of nonspecific and specific reversal agents for the direct factor Xa inhibitors is provided, focusing on the biochemistry and mechanism of action and the preclinical assessment of newly emerging therapies.

Keywords

factor Xa inhibitors - hemorrhage - anticoagulants - antidotes

Volltext

Referenzen

References
1 Cuker A, Siegal D. Monitoring and reversal of direct oral anticoagulants. Hematology (Am Soc Hematol Educ Program) 2015; 2015: 117-124
2 Barnes GD, Lucas E, Alexander GC, Goldberger ZD. National trends in ambulatory oral anticoagulant use. Am J Med 2015; 128 (12) 1300-5.e2
3 Pollack Jr CV, Reilly PA, van Ryn J. et al. Idarucizumab for dabigatran reversal - full cohort analysis. N Engl J Med 2017; 377 (05) 431-441
4 Loo SY, Dell'Aniello S, Huiart L, Renoux C. Trends in the prescription of novel oral anticoagulants in UK primary care. Br J Clin Pharmacol 2017; 83 (09) 2096-2106
5 Roehrig S, Straub A, Pohlmann J. et al. Discovery of the novel antithrombotic agent 5-chloro-N-((5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-ylmethyl)thiophene- 2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor. J Med Chem 2005; 48 (19) 5900-5908
6 Pinto DJ, Orwat MJ, Koch S. et al. Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa. J Med Chem 2007; 50 (22) 5339-5356
7 Furugohri T, Isobe K, Honda Y. et al. DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles. J Thromb Haemost 2008; 6 (09) 1542-1549
8 Hedstrom L. Serine protease mechanism and specificity. Chem Rev 2002; 102 (12) 4501-4524
9 Wong PC, Pinto DJ, Zhang D. Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor. J Thromb Thrombolysis 2011; 31 (04) 478-492
10 Padmanabhan K, Padmanabhan KP, Tulinsky A. et al. Structure of human des(1-45) factor Xa at 2.2 A resolution. J Mol Biol 1993; 232 (03) 947-966
11 Zhang P, Huang W, Wang L. et al. Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor. Bioorg Med Chem Lett 2009; 19 (08) 2179-2185
12 Samama MM. The mechanism of action of rivaroxaban--an oral, direct Factor Xa inhibitor--compared with other anticoagulants. Thromb Res 2011; 127 (06) 497-504
13 Masotti L, Campanini M. Pharmacology of new oral anticoagulants: mechanism of action, pharmacokinetics, pharmacodynamics. Ital J Med 2013; 7 (08) 1-7
14 Gómez-Outes A, Suárez-Gea ML, Lecumberri R, Terleira-Fernández AI, Vargas-Castrillón E. Direct-acting oral anticoagulants: pharmacology, indications, management, and future perspectives. Eur J Haematol 2015; 95 (05) 389-404
15 Connolly SJ, Ezekowitz MD, Yusuf S. et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
16 Patel MR, Mahaffey KW, Garg J. et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
17 Agnelli G, Buller HR, Cohen A. et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369 (09) 799-808
18 Deitelzweig SB, Johnson BH, Lin J, Schulman KL. Prevalence of clinical venous thromboembolism in the USA: current trends and future projections. Am J Hematol 2011; 86 (02) 217-220
19 Chugh SS, Havmoeller R, Narayanan K. et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 2014; 129 (08) 837-847
20 Connolly SJ, Crowther M, Eikelboom JW. et al; ANNEXA-4 Investigators. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med 2019; 380 (14) 1326-1335
21 Lu G, DeGuzman FR, Hollenbach SJ. et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013; 19 (04) 446-451
22 Hellstern P. Production and composition of prothrombin complex concentrates: correlation between composition and therapeutic efficiency. Thromb Res 1999; 95 (4, Suppl 1): S7-S12
23 Franchini M, Lippi G. Prothrombin complex concentrates: an update. Blood Transfus 2010; 8 (03) 149-154
24 Cada DJ, Levien TL, Baker DE. Prothrombin complex concentrate. Hosp Pharm 2013; 48 (11) 951-957
25 Sarode R, Milling Jr TJ, Refaai MA. et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 2013; 128 (11) 1234-1243
26 Godier A, Miclot A, Le Bonniec B. et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology 2012; 116 (01) 94-102
27 Martin AC, Le Bonniec B, Fischer AM. et al. Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixaban in a rabbit model of bleeding and thrombosis. Int J Cardiol 2013; 168 (04) 4228-4233
28 Perzborn E, Gruber A, Tinel H. et al. Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates. Thromb Haemost 2013; 110 (01) 162-172
29 Zhou W, Zorn M, Nawroth P. et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with rivaroxaban. Stroke 2013; 44 (03) 771-778
30 Herrmann R, Thom J, Wood A, Phillips M, Muhammad S, Baker R. Thrombin generation using the calibrated automated thrombinoscope to assess reversibility of dabigatran and rivaroxaban. Thromb Haemost 2014; 111 (05) 989-995
31 Levi M, Moore KT, Castillejos CF. et al. Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost 2014; 12 (09) 1428-1436
32 Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011; 124 (14) 1573-1579
33 Barco S, Whitney Cheung Y, Coppens M, Hutten BA, Meijers JC, Middeldorp S. In vivo reversal of the anticoagulant effect of rivaroxaban with four-factor prothrombin complex concentrate. Br J Haematol 2016; 172 (02) 255-261
34 Song Y, Wang Z, Perlstein I. et al. Reversal of apixaban anticoagulation by four-factor prothrombin complex concentrates in healthy subjects: a randomized three-period crossover study. J Thromb Haemost 2017; 15 (11) 2125-2137
35 Brown KS, Wickremasingha P, Parasrampuria DA. et al. The impact of a three-factor prothrombin complex concentrate on the anticoagulatory effects of the factor Xa inhibitor edoxaban. Thromb Res 2015; 136 (04) 825-831
36 Nagalla S, Thomson L, Oppong Y, Bachman B, Chervoneva I, Kraft WK. Reversibility of apixaban anticoagulation with a four-factor prothrombin complex concentrate in healthy volunteers. Clin Transl Sci 2016; 9 (03) 176-180
37 Cheung YW, Barco S, Hutten BA, Meijers JC, Middeldorp S, Coppens M. In vivo increase in thrombin generation by four-factor prothrombin complex concentrate in apixaban-treated healthy volunteers. J Thromb Haemost 2015; 13 (10) 1799-1805
38 Zahir H, Brown KS, Vandell AG. et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation 2015; 131 (01) 82-90
39 Schulman S, Gross PL, Ritchie B. et al; Study Investigators. Prothrombin complex concentrate for major bleeding on factor Xa inhibitors: a prospective cohort study. Thromb Haemost 2018; 118 (05) 842-851
40 Majeed A, Ågren A, Holmström M. et al. Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood 2017; 130 (15) 1706-1712
41 Arachchillage DRJ, Alavian S, Griffin J. et al. Efficacy and safety of prothrombin complex concentrate in patients treated with rivaroxaban or apixaban compared to warfarin presenting with major bleeding. Br J Haematol 2019; 184 (05) 808-816
42 Gerner ST, Kuramatsu JB, Sembill JA. et al; RETRACE II (German-Wide Multicenter Analysis of Oral Anticoagulation-Associated Intracerebral Hemorrhage II) Investigators. Association of prothrombin complex concentrate administration and hematoma enlargement in non-vitamin K antagonist oral anticoagulant-related intracerebral hemorrhage. Ann Neurol 2018; 83 (01) 186-196
43 Tomaselli GF, Mahaffey KW, Cuker A. et al. 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol 2017; 70 (24) 3042-3067
44 Sjamsoedin LJ, Heijnen L, Mauser-Bunschoten EP. et al. The effect of activated prothrombin-complex concentrate (FEIBA) on joint and muscle bleeding in patients with hemophilia A and antibodies to factor VIII. A double-blind clinical trial. N Engl J Med 1981; 305 (13) 717-721
45 Hilgartner MW, Knatterud GL. The use of factor eight inhibitor by-passing activity (FEIBA immuno) product for treatment of bleeding episodes in hemophiliacs with inhibitors. Blood 1983; 61 (01) 36-40
46 Hilgartner M, Aledort L, Andes A, Gill J. ; FEIBA Study Group. Efficacy and safety of vapor-heated anti-inhibitor coagulant complex in hemophilia patients. Transfusion 1990; 30 (07) 626-630
47 Fukuda T, Honda Y, Kamisato C, Morishima Y, Shibano T. Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents. Thromb Haemost 2012; 107 (02) 253-259
48 Halim AB, Samama MM, Mendell J. Ex vivo reversal of the anticoagulant effects of edoxaban. Thromb Res 2014; 134 (04) 909-913
49 Schultz NH, Tran HTT, Bjørnsen S, Henriksson CE, Sandset PM, Holme PA. The reversal effect of prothrombin complex concentrate (PCC), activated PCC and recombinant activated factor VII against anticoagulation of Xa inhibitor. Thromb J 2017; 15: 6
50 Perzborn E, Heitmeier S, Laux V, Buchmüller A. Reversal of rivaroxaban-induced anticoagulation with prothrombin complex concentrate, activated prothrombin complex concentrate and recombinant activated factor VII in vitro. Thromb Res 2014; 133 (04) 671-681
51 Marlu R, Hodaj E, Paris A, Albaladejo P, Cracowski JL, Pernod G. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 2012; 108 (02) 217-224
52 Mao G, King L, Young S, Kaplan R. Factor eight inhibitor bypassing agent (FEIBA) for reversal of target-specific oral anticoagulants in life-threatening intracranial bleeding. J Emerg Med 2017; 52 (05) 731-737
53 Dibu JR, Weimer JM, Ahrens C, Manno E, Frontera JA. The role of FEIBA in reversing novel oral anticoagulants in intracerebral hemorrhage. Neurocrit Care 2016; 24 (03) 413-419
54 Dager WE, Roberts AJ, Nishijima DK. Effect of low and moderate dose FEIBA to reverse major bleeding in patients on direct oral anticoagulants. Thromb Res 2019; 173: 71-76
55 Engelbart JM, Zepeski A, Galet C, Policeni B, Skeete DA, Faine BA. Safety and effectiveness of Factor Eight Inhibitor Bypassing Activity for direct oral anticoagulant-related hemorrhage reversal. Am J Emerg Med 2019; 37 (02) 214-219
56 Lentz SR, Ehrenforth S, Karim FA. et al; adept™2 investigators. Recombinant factor VIIa analog in the management of hemophilia with inhibitors: results from a multicenter, randomized, controlled trial of vatreptacog alfa. J Thromb Haemost 2014; 12 (08) 1244-1253
57 Lusher JM, Roberts HR, Davignon G. et al. A randomized, double-blind comparison of two dosage levels of recombinant factor VIIa in the treatment of joint, muscle and mucocutaneous haemorrhages in persons with haemophilia A and B, with and without inhibitors. rFVIIa Study Group. Haemophilia 1998; 4 (06) 790-798
58 Goodnough LT, Levy JH. The judicious use of recombinant factor VIIa. Semin Thromb Hemost 2016; 42 (02) 125-132
59 Schmidt K, Krüger K, Langer E. et al. Reversal of apixaban induced alterations in haemostasis by different coagulation factor concentrates in patients after hip or knee replacement surgery. Blood Transfus 2019; 17 (02) 157-162
60 Hemphill III JC, Greenberg SM, Anderson CS. et al; American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2015; 46 (07) 2032-2060
61 Turecek PL, Váradi K, Gritsch H, Schwarz HP. FEIBA: mode of action. Haemophilia 2004; 10 (Suppl. 02) 3-9
62 Turecek PL, Varadi K, Gritsch H. et al. Factor Xa and prothrombin: mechanism of action of FEIBA. Vox Sang 1999; 77 (Suppl. 01) 72-79
63 Himmelspach M, Richter G, Muhr E. et al. A fully recombinant partial prothrombin complex effectively bypasses fVIII in vitro and in vivo. Thromb Haemost 2002; 88 (06) 1003-1011
64 Schuijt TJ, Bakhtiari K, Daffre S. et al. Factor Xa activation of factor V is of paramount importance in initiating the coagulation system: lessons from a tick salivary protein. Circulation 2013; 128 (03) 254-266
65 Schreuder M, Reitsma PH, Bos MHA. Blood coagulation factor Va's key interactive residues and regions for prothrombinase assembly and prothrombin binding. J Thromb Haemost 2019; 17 (08) 1229-1239
66 Johnson DJ, Li W, Adams TE, Huntington JA. Antithrombin-S195A factor Xa-heparin structure reveals the allosteric mechanism of antithrombin activation. EMBO J 2006; 25 (09) 2029-2037
67 Li W, Johnson DJ, Esmon CT, Huntington JA. Structure of the antithrombin-thrombin-heparin ternary complex reveals the antithrombotic mechanism of heparin. Nat Struct Mol Biol 2004; 11 (09) 857-862
68 Thalji NK, Ivanciu L, Davidson R, Gimotty PA, Krishnaswamy S, Camire RM. A rapid pro-hemostatic approach to overcome direct oral anticoagulants. Nat Med 2016; 22 (08) 924-932
69 Monroe DM, Hoffman M, Oliver JA, Roberts HR. Platelet activity of high-dose factor VIIa is independent of tissue factor. Br J Haematol 1997; 99 (03) 542-547
70 Lu G, Pine P, Leeds JM. et al. Andexanet alfa effectively reverses edoxaban anticoagulation effects and associated bleeding in a rabbit acute hemorrhage model. PLoS One 2018; 13 (03) e0195122
71 Lu G, Hollenbach SJ, Baker DC. et al. Preclinical safety and efficacy of andexanet alfa in animal models. J Thromb Haemost 2017; 15 (09) 1747-1756
72 Siegal DM, Curnutte JT, Connolly SJ. et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015; 373 (25) 2413-2424
73 Siegal D, Lu G, Leeds JM. et al. Safety, pharmacokinetics, and reversal of apixaban anticoagulation with andexanet alfa. Blood Adv 2017; 1 (21) 1827-1838
74 Goldstein JN, Refaai MA, Milling Jr TJ. et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet 2015; 385 (9982): 2077-2087
75 Ersayin A, Thomas A, Seyve L. et al. Catalytically inactive Gla-domainless factor Xa binds to TFPI and restores ex vivo coagulation in hemophilia plasma. Haematologica 2017; 102 (12) e483-e485
76 Marlu R, Polack B. Gla-domainless factor Xa: molecular bait to bypass a blocked tenase complex. Haematologica 2012; 97 (08) 1165-1172
77 Lu G, Lin JP, Curnutte JT, Conley PB. Effect of andexanet-TFPI interaction on in vitro thrombin formation and coagulation markers in the TF-pathway [Abstract]. Blood 2017; 130 (629) 629
78 Ansell JE, Bakhru SH, Laulicht BE. et al. Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban. Thromb Haemost 2017; 117 (02) 238-245
79 Weitz JI, Eikelboom JW. Ciraparantag for enoxaparin reversal: adding to the evidence. Thromb Res 2016; 146: 106-107
80 Ansell JE, Laulicht BE, Bakhru SH, Hoffman M, Steiner SS, Costin JC. Ciraparantag safely and completely reverses the anticoagulant effects of low molecular weight heparin. Thromb Res 2016; 146: 113-118
81 Laulicht BE, Bakhru SH, Jiang X. et al. Antidote for new oral anticoagulants: mechanism of action and binding specificity of PER977 [Abstract]. J Thromb Haemost 2013; 11: 75
82 Laulicht BE, Bakhru SH, Lee C. et al. Small molecule antidote for anticoagulants [Abstract]. Circulation 2018; 126 (Suppl. 21) A11395
83 Bakhru SH, Laulicht BE, Jiang X. et al. Reversal of anticoagulant-induced bleeding in external and internal bleeding models by PER977, a small molecule anticoagulant antidote [Abstract]. Circulation 2018; 130 (Suppl 2): A19361
84 Hollenbach SJ, Lu G, DeGuzman F. et al. Andexanet-alfa and PER977 (arapazine) correct blood loss in a rabbit liver laceration model - only andexanet reverses markers of fXa-mediated anticoagulation [Abstract]. Circulation 2018; 130 (Suppl 2): A14657
85 Sullivan Jr DW, Gad SC, Laulicht B, Bakhru S, Steiner S. Nonclinical safety assessment of PER977: a small molecule reversal agent for new oral anticoagulants and heparins. Int J Toxicol 2015; 34 (04) 308-317
86 Ansell JE, Bakhru SH, Laulicht BE. et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014; 371 (22) 2141-2142
87 Kalathottukaren MT, Creagh AL, Abbina S. et al. Comparison of reversal activity and mechanism of action of UHRA, andexanet, and PER977 on heparin and oral FXa inhibitors. Blood Adv 2018; 2 (16) 2104-2114
88 Lu G, Kotha J, Cardenas JM. et al. Abstract 18218: In vitro characterization of andexanet alfa (PRT064445), a specific fXa Inhibitor antidote versus aripazine (PER977), a non-specific reversal agent. Circulation 2018;130(02):
89 Jourdi G, Gouin-Thibault I, Siguret V, Gandrille S, Gaussem P, Le Bonniec B. FXa-α2-macroglobulin complex neutralizes direct oral anticoagulants targeting FXa in vitro and in vivo. Thromb Haemost 2018; 118 (09) 1535-1544
90 Qazi U, Kolodziej SJ, Gettins PG, Stoops JK. The structure of the C949S mutant human alpha(2)-macroglobulin demonstrates the critical role of the internal thiol esters in its proteinase-entrapping structural transformation. J Struct Biol 2000; 131 (01) 19-26
91 Rehman AA, Ahsan H, Khan FH. α-2-Macroglobulin: a physiological guardian. J Cell Physiol 2013; 228 (08) 1665-1675
92 Jourdi G, Siguret V, Martin AC. et al. Association rate constants rationalise the pharmacodynamics of apixaban and rivaroxaban. Thromb Haemost 2015; 114 (01) 78-86
93 Toso R, Zhu H, Camire RM. The conformational switch from the factor X zymogen to protease state mediates exosite expression and prothrombinase assembly. J Biol Chem 2008; 283 (27) 18627-18635
94 Huber R, Bode W. Structural basis of the activation and action of trypsin. Acc Chem Res 1978; 11 (11) 114-122
95 Bunce MW, Toso R, Camire RM. Zymogen-like factor Xa variants restore thrombin generation and effectively bypass the intrinsic pathway in vitro. Blood 2011; 117 (01) 290-298
96 Ivanciu L, Camire RM. Hemostatic agents of broad applicability produced by selective tuning of factor Xa zymogenicity. Blood 2015; 126 (01) 94-102
97 Ivanciu L, Toso R, Margaritis P. et al. A zymogen-like factor Xa variant corrects the coagulation defect in hemophilia. Nat Biotechnol 2011; 29 (11) 1028-1033
98 Greene LA, Thalji NK, Raffini LJ, Camire RM. Abstract: Zymogen-like FXa variant as a short-acting warfarin reversal agent: pre-clinical evaluation and mechanism of action. Blood 2014;124(4262):
99 Parng C, Markiewicz V, Chen J. et al. Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and interspecies scaling of recombinant human coagulation factor Xa^I16L . J Pharm Sci 2017; 106 (08) 2136-2143
100 Parsons-Rich D, Hua F, Li G, Kantaridis C, Pittman DD, Arkin S. Phase 1 dose-escalating study to evaluate the safety, pharmacokinetics, and pharmacodynamics of a recombinant factor Xa variant (FXa^I16L ). J Thromb Haemost 2017; 15 (05) 931-937
101 Verhoef D, Visscher KM, Vosmeer CR. et al. Engineered factor Xa variants retain procoagulant activity independent of direct factor Xa inhibitors. Nat Commun 2017; 8 (01) 528
102 Schreuder M, Verhoef D, Cheung KL. et al. Abstract: Phe174-mutated human factor X as bypassing agent to the direct FXa inhibitors. Blood 2017;130(363):