Download PDF
Semin Thromb Hemost 2024; 50(07): 989-997
DOI: 10.1055/s-0043-57011
Review Article

Targeting the Contact Pathway of Coagulation for the Prevention and Management of Medical Device-Associated Thrombosis

Abhishek Goel
1   Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon
,
Harsha Tathireddy
1   Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon
,
Si-Han Wang
2   Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon
,
Helen H. Vu
2   Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon
,
Cristina Puy
2   Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon
,
Monica T. Hinds
2   Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon
,
David Zonies
3   Department of Surgery, Oregon Health and Science University, Portland, Oregon
,
Owen J.T. McCarty
1   Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon
2   Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon
,
Joseph J. Shatzel
1   Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon
2   Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon
› Author Affiliations Funding This work was supported by the National Institutes of Health (R01HL151367 to J.J.S, R01HL101972 and R01HL144113 to O.J.T.M).
› Further Information
    Permissions and Reprints

Abstract

Hemorrhage remains a major complication of anticoagulants, with bleeding leading to serious and even life-threatening outcomes in rare settings. Currently available anticoagulants target either multiple coagulation factors or specifically coagulation factor (F) Xa or thrombin; however, inhibiting these pathways universally impairs hemostasis. Bleeding complications are especially salient in the medically complex population who benefit from medical devices. Extracorporeal devices—such as extracorporeal membrane oxygenation, hemodialysis, and cardiac bypass—require anticoagulation for optimal use. Nonetheless, bleeding complications are common, and with certain devices, highly morbid. Likewise, pharmacologic prophylaxis to prevent thrombosis is not commonly used with many medical devices like central venous catheters due to high rates of bleeding. The contact pathway members FXI, FXII, and prekallikrein serve as a nexus, connecting biomaterial surface-mediated thrombin generation and inflammation, and may represent safe, druggable targets to improve medical device hemocompatibility and thrombogenicity. Recent in vivo and clinical data suggest that selectively targeting the contact pathway of coagulation through the inhibition of FXI and FXII can reduce the incidence of medical device-associated thrombotic events, and potentially systemic inflammation, without impairing hemostasis. In the following review, we will outline the current in vivo and clinical data encompassing the mechanism of action of drugs targeting the contact pathway. This new class of inhibitors has the potential to herald a new era of effective and low-risk anticoagulation for the management of patients requiring the use of medical devices.

Keywords

medical device - anticoagulation - thrombosis - contact pathway - factor XI


Publication History

Article published online:
12 April 2023

© 2023. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Revenko AS, Gao D, Crosby JR. et al. Selective depletion of plasma prekallikrein or coagulation factor XII inhibits thrombosis in mice without increased risk of bleeding. Blood 2011; 118 (19) 5302-5311
    CrossrefPubMedSearch in Google Scholar
  • 2 DeLoughery EP, Olson SR, Puy C, McCarty OJT, Shatzel JJ. The safety and efficacy of novel agents targeting factors XI and XII in early phase human trials. Semin Thromb Hemost 2019; 45 (05) 502-508
    Thieme ConnectPubMedSearch in Google Scholar
  • 3 Eikelboom JW, Connolly SJ, Brueckmann M. et al; RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013; 369 (13) 1206-1214
    CrossrefPubMedSearch in Google Scholar
  • 4 Kato C, Oakes M, Kim M. et al. Anticoagulation strategies in extracorporeal circulatory devices in adult populations. Eur J Haematol 2021; 106 (01) 19-31
    CrossrefPubMedSearch in Google Scholar
  • 5 Jawitz OK, Wang TY, Lopes RD. et al. Rationale and design of PROACT Xa: a randomized, multicenter, open-label, clinical trial to evaluate the efficacy and safety of apixaban versus warfarin in patients with a mechanical On-X Aortic Heart Valve. Am Heart J 2020; 227: 91-99
    CrossrefPubMedSearch in Google Scholar
  • 6 Andreas M, Moayedifar R, Wieselthaler G. et al. Increased thromboembolic events with dabigatran compared with vitamin K antagonism in left ventricular assist device patients: a randomized controlled pilot trial. Circ Heart Fail 2017; 10 (05) e003709
    CrossrefPubMedSearch in Google Scholar
  • 7 Lorentz CU, Verbout NG, Wallisch M. et al. Contact activation inhibitor and factor XI antibody, AB023, produces safe, dose-dependent anticoagulation in a phase 1 first-in-human trial. Arterioscler Thromb Vasc Biol 2019; 39 (04) 799-809
    CrossrefPubMedSearch in Google Scholar
  • 8 Puy C, Rigg RA, McCarty OJ. The hemostatic role of factor XI. Thromb Res 2016; 141 (Suppl. 02) S8-S11
    CrossrefPubMedSearch in Google Scholar
  • 9 Raghunathan V, Zilberman-Rudenko J, Olson SR, Lupu F, McCarty OJT, Shatzel JJ. The contact pathway and sepsis. Res Pract Thromb Haemost 2019; 3 (03) 331-339
    CrossrefPubMedSearch in Google Scholar
  • 10 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
    CrossrefPubMedSearch in Google Scholar
  • 11 Merlo C, Wuillemin WA, Redondo M. et al. Elevated levels of plasma prekallikrein, high molecular weight kininogen and factor XI in coronary heart disease. Atherosclerosis 2002; 161 (02) 261-267
    CrossrefPubMedSearch in Google Scholar
  • 12 Adenaeuer A, Barco S, Trinchero A, Lackner KJ, Lämmle B, Rossmann H. Definite diagnosis of plasma prekallikrein deficiency should not be based exclusively on shortening of the aPTT upon prolonged pre-incubation. Int J Lab Hematol 2022; 44 (04) e179-e180
    CrossrefPubMedSearch in Google Scholar
  • 13 Abraham R, Viswanathan GK, Dass J. et al. Prekallikrein deficiency: challenges in laboratory testing. Int J Lab Hematol 2022; 44 (04) e185-e186
    CrossrefPubMedSearch in Google Scholar
  • 14 Deroux A, Boccon-Gibod I, Fain O. et al. Hereditary angioedema with normal C1 inhibitor and factor XII mutation: a series of 57 patients from the French National Center of Reference for Angioedema. Clin Exp Immunol 2016; 185 (03) 332-337
    CrossrefPubMedSearch in Google Scholar
  • 15 Labarrere CA, Dabiri AE, Kassab GS. Thrombogenic and inflammatory reactions to biomaterials in medical devices. Front Bioeng Biotechnol 2020; 8: 123
    CrossrefPubMedSearch in Google Scholar
  • 16 Annich GM. Extracorporeal life support: the precarious balance of hemostasis. J Thromb Haemost 2015; 13 (Suppl. 01) S336-S342
    CrossrefPubMedSearch in Google Scholar
  • 17 Wong TE, Nguyen T, Shah SS, Brogan TV, Witmer CM. Antithrombin concentrate use in pediatric extracorporeal membrane oxygenation: a multicenter cohort study. Pediatr Crit Care Med 2016; 17 (12) 1170-1178
    CrossrefPubMedSearch in Google Scholar
  • 18 Jaffer IH, Fredenburgh JC, Hirsh J, Weitz JI. Medical device-induced thrombosis: what causes it and how can we prevent it?. J Thromb Haemost 2015; 13 (Suppl. 01) S72-S81
    CrossrefPubMedSearch in Google Scholar
  • 19 Byrnes JR, Wolberg AS. Red blood cells in thrombosis. Blood 2017; 130 (16) 1795-1799
    CrossrefPubMedSearch in Google Scholar
  • 20 Palta S, Saroa R, Palta A. Overview of the coagulation system. Indian J Anaesth 2014; 58 (05) 515-523
    CrossrefPubMedSearch in Google Scholar
  • 21 Aleman MM, Walton BL, Byrnes JR, Wolberg AS. Fibrinogen and red blood cells in venous thrombosis. Thromb Res 2014; 133 (0 1, Suppl 1): S38-S40
    CrossrefPubMedSearch in Google Scholar
  • 22 Jaffer IH, Weitz JI. The blood compatibility challenge. Part 1: Blood-contacting medical devices: the scope of the problem. Acta Biomater 2019; 94: 2-10
    CrossrefPubMedSearch in Google Scholar
  • 23 Vogler EA, Siedlecki CA. Contact activation of blood-plasma coagulation. Biomaterials 2009; 30 (10) 1857-1869
    CrossrefPubMedSearch in Google Scholar
  • 24 Badv M, Bayat F, Weitz JI, Didar TF. Single and multi-functional coating strategies for enhancing the biocompatibility and tissue integration of blood-contacting medical implants. Biomaterials 2020; 258: 120291
    CrossrefPubMedSearch in Google Scholar
  • 25 Dal Sasso E, Bagno A, Scuri STG, Gerosa G, Iop L. The biocompatibility challenges in the total artificial heart evolution. Annu Rev Biomed Eng 2019; 21: 85-110
    CrossrefPubMedSearch in Google Scholar
  • 26 Manivasagam VK, Sabino RM, Kantam P, Popat K. Surface modification strategies to improve titanium hemocompatibility: a comprehensive review. Mater Adv 2021; 2 (18) 5824-5842
    CrossrefPubMedSearch in Google Scholar
  • 27 Spijker HT, Graaff R, Boonstra PW, Busscher HJ, van Oeveren W. On the influence of flow conditions and wettability on blood material interactions. Biomaterials 2003; 24 (26) 4717-4727
    CrossrefPubMedSearch in Google Scholar
  • 28 Douglass M, Garren M, Devine R, Mondal A, Handa H. Bio-inspired hemocompatible surface modifications for biomedical applications. Prog Mater Sci 2022; 130: 100997
    CrossrefPubMedSearch in Google Scholar
  • 29 Fisher C, Shao H, Ho CH. Improved hemocompatibility of polysulfone hemodialyzers with Endexo® surface modifying molecules. J Biomed Mater Res B Appl Biomater 2022; 110 (06) 1335-1343
    CrossrefPubMedSearch in Google Scholar
  • 30 Fallon ME, Le HH, Bates NM. et al. Hemocompatibility of micropatterned biomaterial surfaces is dependent on topographical feature size. Front Physiol 2022; 13: 983187
    CrossrefPubMedSearch in Google Scholar
  • 31 Ngo BKD, Grunlan MA. Protein resistant polymeric biomaterials. ACS Macro Lett 2017; 6 (09) 992-1000
    CrossrefPubMedSearch in Google Scholar
  • 32 Gifford R, Kehoe JJ, Barnes SL, Kornilayev BA, Alterman MA, Wilson GS. Protein interactions with subcutaneously implanted biosensors. Biomaterials 2006; 27 (12) 2587-2598
    CrossrefPubMedSearch in Google Scholar
  • 33 Wolberg AS, Campbell RA. Thrombin generation, fibrin clot formation and hemostasis. Transfus Apheresis Sci 2008; 38 (01) 15-23
    CrossrefPubMedSearch in Google Scholar
  • 34 Klopfleisch R, Jung F. The pathology of the foreign body reaction against biomaterials. J Biomed Mater Res A 2017; 105 (03) 927-940
    CrossrefPubMedSearch in Google Scholar
  • 35 Richenbacher WE. Complications of mechanical ventricular assistance. In: Mechanical Circulatory Support. CRC Press; 2020: 183-198
    CrossrefSearch in Google Scholar
  • 36 Bazzan M, Vaccarino A, Marletto F. Systemic lupus erythematosus and thrombosis. Thromb J 2015; 13 (01) 16
    CrossrefPubMedSearch in Google Scholar
  • 37 Hong JK, Gao L, Singh J. et al. Evaluating medical device and material thrombosis under flow: current and emerging technologies. Biomater Sci 2020; 8 (21) 5824-5845
    CrossrefPubMedSearch in Google Scholar
  • 38 Kohs TCL, Lorentz CU, Johnson J. et al. Development of coagulation factor XII antibodies for inhibiting vascular device-related thrombosis. Cell Mol Bioeng 2020; 14 (02) 161-175
    CrossrefPubMedSearch in Google Scholar
  • 39 Wu Y. Contact pathway of coagulation and inflammation. Thromb J 2015; 13: 17
    CrossrefPubMedSearch in Google Scholar
  • 40 Grover SP, Mackman N. Intrinsic pathway of coagulation and thrombosis: insights from animal models. Arterioscler Thromb Vasc Biol 2019; 39 (03) 331-338
    CrossrefPubMedSearch in Google Scholar
  • 41 de Maat S, Maas C. Factor XII: form determines function. J Thromb Haemost 2016; 14 (08) 1498-1506
    CrossrefPubMedSearch in Google Scholar
  • 42 Shamanaev A, Ivanov I, Sun M-F. et al. Model for surface-dependent factor XII activation: the roles of factor XII heavy chain domains. Blood Adv 2022; 6 (10) 3142-3154
    CrossrefPubMedSearch in Google Scholar
  • 43 Wu W, Roder H, Walsh PN. Conformational changes facilitate FXI autoactivation to FXIa. Blood 2010; 116 (21) 19
    CrossrefPubMedSearch in Google Scholar
  • 44 Shamanaev A, Litvak M, Gailani D. Recent advances in factor XII structure and function. Curr Opin Hematol 2022; 29 (05) 233-243
    CrossrefPubMedSearch in Google Scholar
  • 45 Naudin C, Burillo E, Blankenberg S, Butler L, Renné T. Factor XII contact activation. Semin Thromb Hemost 2017; 43 (08) 814-826
    Thieme ConnectPubMedSearch in Google Scholar
  • 46 Ivanov I, Matafonov A, Gailani D. Single-chain factor XII: a new form of activated factor XII. Curr Opin Hematol 2017; 24 (05) 411-418
    CrossrefPubMedSearch in Google Scholar
  • 47 Tillman BF, Gruber A, McCarty OJT, Gailani D. Plasma contact factors as therapeutic targets. Blood Rev 2018; 32 (06) 433-448
    CrossrefPubMedSearch in Google Scholar
  • 48 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 (03) 513-518
    CrossrefPubMedSearch in Google Scholar
  • 49 Renné T, Stavrou EX. Roles of factor XII in Innate Immunity. Front Immunol 2019; 10: 2011
    CrossrefPubMedSearch in Google Scholar
  • 50 Barbieri CM, Wang X, Wu W. et al. Factor XIIa as a novel target for thrombosis: target engagement requirement and efficacy in a rabbit model of microembolic signals. J Pharmacol Exp Ther 2017; 360 (03) 466-475
    CrossrefPubMedSearch in Google Scholar
  • 51 Kenne E, Nickel KF, Long AT. et al. Factor XII: a novel target for safe prevention of thrombosis and inflammation. J Intern Med 2015; 278 (06) 571-585
    CrossrefPubMedSearch in Google Scholar
  • 52 Larsson M, Rayzman V, Nolte MW. et al. A factor XIIa inhibitory antibody provides thromboprotection in extracorporeal circulation without increasing bleeding risk. Sci Transl Med 2014; 6 (222) 222ra17
    CrossrefPubMedSearch in Google Scholar
  • 53 Wallisch M, Lorentz CU, Lakshmanan HHS. et al. Antibody inhibition of contact factor XII reduces platelet deposition in a model of extracorporeal membrane oxygenator perfusion in nonhuman primates. Res Pract Thromb Haemost 2020; 4 (02) 205-216
    CrossrefPubMedSearch in Google Scholar
  • 54 Wilbs J, Kong XD, Middendorp SJ. et al. Cyclic peptide FXII inhibitor provides safe anticoagulation in a thrombosis model and in artificial lungs. Nat Commun 2020; 11 (01) 3890
    CrossrefPubMedSearch in Google Scholar
  • 55 Matafonov A, Leung PY, Gailani AE. et al. Factor XII inhibition reduces thrombus formation in a primate thrombosis model. Blood 2014; 123 (11) 1739-1746
    CrossrefPubMedSearch in Google Scholar
  • 56 Pollack Jr CV, Kurz MA, Hayward NJ. EP-7041, a factor XIa inhibitor as a potential antithrombotic strategy in extracorporeal membrane oxygenation: a brief report. Crit Care Explor 2020; 2 (09) e0196
    CrossrefPubMedSearch in Google Scholar
  • 57 Schumacher WA, Seiler SE, Steinbacher TE. et al. Antithrombotic and hemostatic effects of a small molecule factor XIa inhibitor in rats. Eur J Pharmacol 2007; 570 (1-3): 167-174
    CrossrefPubMedSearch in Google Scholar
  • 58 Cheng Q, Tucker EI, Pine MS. et al. A role for factor XIIa-mediated factor XI activation in thrombus formation in vivo. Blood 2010; 116 (19) 3981-3989
    CrossrefPubMedSearch in Google Scholar
  • 59 Gruber A, Hanson SR. Factor XI-dependence of surface- and tissue factor-initiated thrombus propagation in primates. Blood 2003; 102 (03) 953-955
    CrossrefPubMedSearch in Google Scholar
  • 60 Schultze AE, Walker DB, Turk JR, Tarrant JM, Brooks MB, Pettit SD. Current practices in preclinical drug development: gaps in hemostasis testing to assess risk of thromboembolic injury. Toxicol Pathol 2013; 41 (03) 445-453
    CrossrefPubMedSearch in Google Scholar
  • 61 Fredenburgh JC, Weitz JI. Factor XI as a target for new anticoagulants. Hamostaseologie 2021; 41 (02) 104-110
    Thieme ConnectPubMedSearch in Google Scholar
  • 62 Büller HR, Bethune C, Bhanot S. et al; FXI-ASO TKA Investigators. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med 2015; 372 (03) 232-240
    CrossrefPubMedSearch in Google Scholar
  • 63 Lippi G, Harenberg J, Mattiuzzi C, Favaloro EJ. Next generation antithrombotic therapy: focus on antisense therapy against coagulation factor XI. Semin Thromb Hemost 2015; 41 (02) 255-262
    Thieme ConnectPubMedSearch in Google Scholar
  • 64 Geary RS, Norris D, Yu R, Bennett CF. Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides. Adv Drug Deliv Rev 2015; 87: 46-51
    CrossrefPubMedSearch in Google Scholar
  • 65 Salomon O, Gailani D. A proposal for managing bleeding in patients on therapeutic factor XI(a) inhibitors. J Thromb Haemost 2022; 20 (01) 32-38
    CrossrefPubMedSearch in Google Scholar
  • 66 Wang X, Li Q, Du F. et al. Reversal of antithrombotic effects of FXIa inhibitor milvexian (BMS-986177/JNJ-70033093) by non-specific agents in a rabbit AV-shunt model of thrombosis. In: Proceedings of the ISTH 2021 Congress, Philadelphia, PA; 2021:17–21
    PubMed
  • 67 Fischer PM. Design of small-molecule active-site inhibitors of the S1A family proteases as procoagulant and anticoagulant drugs. J Med Chem 2018; 61 (09) 3799-3822
    CrossrefPubMedSearch in Google Scholar
  • 68 Walsh M, Bethune C, Smyth A. et al; CS4 Investigators. Phase 2 study of the factor XI antisense inhibitor IONIS-FXIRx in patients with ESRD. Kidney Int Rep 2021; 7 (02) 200-209
    CrossrefPubMedSearch in Google Scholar
  • 69 Lorentz CU, Tucker EI, Verbout NG. et al. The contact activation inhibitor AB023 in heparin-free hemodialysis: results of a randomized phase 2 clinical trial. Blood 2021; 138 (22) 2173-2184
    CrossrefPubMedSearch in Google Scholar
  • 70 Gailani D, Broze Jr GJ. Factor XI activation in a revised model of blood coagulation. Science 1991; 253 (5022): 909-912
    CrossrefPubMedSearch in Google Scholar
  • 71 Lewandowska MD, Connors JM. Factor XI deficiency. Hematol Oncol Clin North Am 2021; 35 (06) 1157-1169
    CrossrefPubMedSearch in Google Scholar
  • 72 Preis M, Hirsch J, Kotler A. et al. Factor XI deficiency is associated with lower risk for cardiovascular and venous thromboembolism events. Blood 2017; 129 (09) 1210-1215
    CrossrefPubMedSearch in Google Scholar
  • 73 Georgi B, Mielke J, Chaffin M. et al. Leveraging human genetics to estimate clinical risk reductions achievable by inhibiting factor XI. Stroke 2019; 50 (11) 3004-3012
    CrossrefPubMedSearch in Google Scholar
  • 74 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 (03) 411-415
    CrossrefPubMedSearch in Google Scholar
  • 75 Meijers JCM, Tekelenburg WLH, 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
    CrossrefPubMedSearch in Google Scholar
  • 76 Berliner JI, Rybicki AC, Kaplan RC, Monrad ES, Freeman R, Billett HH. Elevated levels of factor XI are associated with cardiovascular disease in women. Thromb Res 2002; 107 (1-2): 55-60
    CrossrefPubMedSearch in Google Scholar
  • 77 Kalinin DV. Factor XII(a) inhibitors: a review of the patent literature. Expert Opin Ther Pat 2021; 31 (12) 1155-1176
    CrossrefPubMedSearch in Google Scholar
  • 78 Craig T, Magerl M, Levy DS. et al. Prophylactic use of an anti-activated factor XII monoclonal antibody, garadacimab, for patients with C1-esterase inhibitor-deficient hereditary angioedema: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2022; 399 (10328): 945-955
    CrossrefPubMedSearch in Google Scholar
  • 79 Naito N, Ukita R, Wilbs J. et al. Combination of polycarboxybetaine coating and factor XII inhibitor reduces clot formation while preserving normal tissue coagulation during extracorporeal life support. Biomaterials 2021; 272: 120778
    CrossrefPubMedSearch in Google Scholar
  • 80 Yau JW, Liao P, Fredenburgh JC. et al. Selective depletion of factor XI or factor XII with antisense oligonucleotides attenuates catheter thrombosis in rabbits. Blood 2014; 123 (13) 2102-2107
    CrossrefPubMedSearch in Google Scholar
  • 81 Tucker EI, Marzec UM, White TC. et al. Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI. Blood 2009; 113 (04) 936-944
    CrossrefPubMedSearch in Google Scholar