Download PDF
Hamostaseologie 2022; 42(01): 065-072
DOI: 10.1055/a-1717-7958
Review Article

An Update on Safe Anticoagulation

Reiner K. Mailer
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany
,
Piotr Kuta
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany
,
Thomas Renné
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany
2   Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
3   Center for Thrombosis and Hemostasis (CTH), Johannes Gutenberg University Medical Center, Mainz, Germany
› Author Affiliations
› Further Information
Also available at
   Permissions and Reprints

Abstract

Blood coagulation is essential to maintain the integrity of a closed circulatory system (hemostasis), but also contributes to thromboembolic occlusion of vessels (thrombosis). Thrombosis may cause deep vein thrombosis, pulmonary embolism, myocardial infarction, peripheral artery disease, and ischemic stroke, collectively the most common causes of death and disability in the developed world. Treatment for the prevention of thromboembolic diseases using anticoagulants such as heparin, coumarins, thrombin inhibitors, or antiplatelet drugs increase the risk of bleeding and are associated with an increase in potentially life-threatening hemorrhage, partially offsetting the benefits of reduced coagulation. Thus, drug development aiming at novel targets is needed to provide efficient and safe anticoagulation. Within the last decade, experimental and preclinical data have shown that some coagulation mechanisms principally differ in thrombosis and hemostasis. The plasma contact system protein factors XII and XI, high-molecular-weight kininogen, and plasma kallikrein specifically contribute to thrombosis, however, have minor, if any, role in hemostatic coagulation mechanisms. Inherited deficiency in contact system proteins is not associated with increased bleeding in humans and animal models. Therefore, targeting contact system proteins provides the exciting opportunity to interfere specifically with thromboembolic diseases without increasing the bleeding risk. Recent studies that investigated pharmacologic inhibition of contact system proteins have shown that this approach provides efficient and safe thrombo-protection that in contrast to classical anticoagulants is not associated with increased bleeding risk. This review summarizes therapeutic and conceptual developments for selective interference with pathological thrombus formation, while sparing physiologic hemostasis, that enables safe anticoagulation treatment.

Keywords

coagulation - thrombosis - contact activation - polyphosphate - factor XII


Publication History

Received: 04 November 2021

Accepted: 08 December 2021

Article published online:
23 February 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Shevchuk O, Begonja AJ, Gambaryan S. et al. Proteomics: a tool to study platelet function. Int J Mol Sci 2021; 22 (09) 4776
    CrossrefPubMedGoogle Scholar
  • 2 Vara D, Mailer RK, Tarafdar A. et al. NADPH oxidases are required for full platelet activation in vitro and thrombosis in vivo but dispensable for plasma coagulation and hemostasis. Arterioscler Thromb Vasc Biol 2021; 41 (02) 683-697
    CrossrefPubMedGoogle Scholar
  • 3 Schulman S, Shrum J, Majeed A. Management of bleeding complications in patients with cancer on DOACs. Thromb Res 2016; 140 (Suppl. 01) S142-S147
    CrossrefPubMedGoogle Scholar
  • 4 Long AT, Kenne E, Jung R, Fuchs TA, Renné T. Contact system revisited: an interface between inflammation, coagulation, and innate immunity. J Thromb Haemost 2016; 14 (03) 427-437
    CrossrefPubMedGoogle Scholar
  • 5 Nickel KF, Long AT, Fuchs TA, Butler LM, Renné T. Factor XII as a therapeutic target in thromboembolic and inflammatory diseases. Arterioscler Thromb Vasc Biol 2017; 37 (01) 13-20
    CrossrefPubMedGoogle Scholar
  • 6 Björkqvist J, Nickel KF, Stavrou E, Renné T. In vivo activation and functions of the protease factor XII. Thromb Haemost 2014; 112 (05) 868-875
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Noubouossie DF, Henderson MW, Mooberry M. et al. Red blood cell microvesicles activate the contact system, leading to factor IX activation via 2 independent pathways. Blood 2020; 135 (10) 755-765
    CrossrefPubMedGoogle Scholar
  • 8 Renné T, Schuh K, Müller-Esterl W. Local bradykinin formation is controlled by glycosaminoglycans. J Immunol 2005; 175 (05) 3377-3385
    CrossrefPubMedGoogle Scholar
  • 9 Hofman Z, de Maat S, Hack CE, Maas C. Bradykinin: inflammatory product of the coagulation system. Clin Rev Allergy Immunol 2016; 51 (02) 152-161
    CrossrefPubMedGoogle Scholar
  • 10 Renné T, Gailani D, Meijers JC, Müller-Esterl W. Characterization of the H-kininogen-binding site on factor XI: a comparison of factor XI and plasma prekallikrein. J Biol Chem 2002; 277 (07) 4892-4899
    CrossrefPubMedGoogle Scholar
  • 11 Renné T, Dedio J, Meijers JC, Chung D, Müller-Esterl W. Mapping of the discontinuous H-kininogen binding site of plasma prekallikrein. Evidence for a critical role of apple domain-2. J Biol Chem 1999; 274 (36) 25777-25784
    CrossrefPubMedGoogle Scholar
  • 12 Renné T. The procoagulant and proinflammatory plasma contact system. Semin Immunopathol 2012; 34 (01) 31-41
    CrossrefPubMedGoogle Scholar
  • 13 Björkqvist J, Sala-Cunill A, Renné T. Hereditary angioedema: a bradykinin-mediated swelling disorder. Thromb Haemost 2013; 109 (03) 368-374
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Renné T, Nieswandt B, Gailani D. The intrinsic pathway of coagulation is essential for thrombus stability in mice. Blood Cells Mol Dis 2006; 36 (02) 148-151
    CrossrefPubMedGoogle Scholar
  • 15 Renné T, Pozgajová M, Grüner S. et al. Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med 2005; 202 (02) 271-281
    CrossrefPubMedGoogle Scholar
  • 16 Kenne E, Renné T. Factor XII: a drug target for safe interference with thrombosis and inflammation. Drug Discov Today 2014; 19 (09) 1459-1464
    CrossrefPubMedGoogle Scholar
  • 17 Kuijpers MJ, van der Meijden PE, Feijge MA. et al. Factor XII regulates the pathological process of thrombus formation on ruptured plaques. Arterioscler Thromb Vasc Biol 2014; 34 (08) 1674-1680
    CrossrefPubMedGoogle Scholar
  • 18 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
    CrossrefPubMedGoogle Scholar
  • 19 Xu Y, Cai TQ, Castriota G. et al. Factor XIIa inhibition by infestin-4: in vitro mode of action and in vivo antithrombotic benefit. Thromb Haemost 2014; 111 (04) 694-704
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 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
    CrossrefPubMedGoogle Scholar
  • 21 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
    CrossrefPubMedGoogle Scholar
  • 22 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
    CrossrefPubMedGoogle Scholar
  • 23 May F, Krupka J, Fries M. et al. FXIIa inhibitor rHA-infestin-4: safe thromboprotection in experimental venous, arterial and foreign surface-induced thrombosis. Br J Haematol 2016; 173 (05) 769-778
    CrossrefPubMedGoogle Scholar
  • 24 Hagedorn I, Schmidbauer S, Pleines I. et al. Factor XIIa inhibitor recombinant human albumin infestin-4 abolishes occlusive arterial thrombus formation without affecting bleeding. Circulation 2010; 121 (13) 1510-1517
    CrossrefPubMedGoogle Scholar
  • 25 Chen JW, Figueiredo JL, Wojtkiewicz GR. et al. Selective factor XIIa inhibition attenuates silent brain ischemia: application of molecular imaging targeting coagulation pathway. JACC Cardiovasc Imaging 2012; 5 (11) 1127-1138
    CrossrefPubMedGoogle Scholar
  • 26 Decrem Y, Rath G, Blasioli V. et al. Ir-CPI, a coagulation contact phase inhibitor from the tick Ixodes ricinus, inhibits thrombus formation without impairing hemostasis. J Exp Med 2009; 206 (11) 2381-2395
    CrossrefPubMedGoogle Scholar
  • 27 von Brühl ML, Stark K, Steinhart A. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209 (04) 819-835
    CrossrefPubMedGoogle Scholar
  • 28 Müller F, Mutch NJ, Schenk WA. et al. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell 2009; 139 (06) 1143-1156
    CrossrefPubMedGoogle Scholar
  • 29 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
    CrossrefPubMedGoogle Scholar
  • 30 Bird JE, Smith PL, Wang X. et al. Effects of plasma kallikrein deficiency on haemostasis and thrombosis in mice: murine ortholog of the Fletcher trait. Thromb Haemost 2012; 107 (06) 1141-1150
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Göb E, Reymann S, Langhauser F. et al. Blocking of plasma kallikrein ameliorates stroke by reducing thromboinflammation. Ann Neurol 2015; 77 (05) 784-803
    CrossrefPubMedGoogle Scholar
  • 32 Merkulov S, Zhang WM, Komar AA. et al. Deletion of murine kininogen gene 1 (mKng1) causes loss of plasma kininogen and delays thrombosis. Blood 2008; 111 (03) 1274-1281
    CrossrefPubMedGoogle Scholar
  • 33 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
    CrossrefPubMedGoogle Scholar
  • 34 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 (04) 774-776
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 Iglesias MJ, Kruse LD, Sanchez-Rivera L. et al. Identification of endothelial proteins in plasma associated with cardiovascular risk factors. Arterioscler Thromb Vasc Biol 2021; 41 (12) 2990-3004
    CrossrefPubMedGoogle Scholar
  • 36 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
    CrossrefPubMedGoogle Scholar
  • 37 Mailer RK, Rangaswamy C, Konrath S, Emsley J, Renné T. An update on factor XII-driven vascular inflammation. Biochim Biophys Acta Mol Cell Res 2022; 1869 (01) 119166
    CrossrefPubMedGoogle Scholar
  • 38 Oschatz C, Maas C, Lecher B. et al. Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo. Immunity 2011; 34 (02) 258-268
    CrossrefPubMedGoogle Scholar
  • 39 Zink J, Frye M, Frömel T. et al. EVL regulates VEGF receptor-2 internalization and signaling in developmental angiogenesis. EMBO Rep 2021; 22 (02) e48961
    CrossrefPubMedGoogle Scholar
  • 40 Englert H, Rangaswamy C, Deppermann C. et al. Defective NET clearance contributes to sustained FXII activation in COVID-19-associated pulmonary thrombo-inflammation. EBioMedicine 2021; 67: 103382
    CrossrefPubMedGoogle Scholar
  • 41 Fogarty H, Townsend L, Morrin H. et al; Irish COVID-19 Vasculopathy Study (iCVS) Investigators. Persistent endotheliopathy in the pathogenesis of long COVID syndrome. J Thromb Haemost 2021; 19 (10) 2546-2553
    CrossrefPubMedGoogle Scholar
  • 42 Henderson MW, Sparkenbaugh EM, Wang S. et al. Plasmin-mediated cleavage of high-molecular-weight kininogen contributes to acetaminophen-induced acute liver failure. Blood 2021; 138 (03) 259-272
    CrossrefPubMedGoogle Scholar
  • 43 Rangaswamy C, Mailer RK, Englert H, Konrath S, Renné T. The contact system in liver injury. Semin Immunopathol 2021; 43 (04) 507-517
    CrossrefPubMedGoogle Scholar
  • 44 Sanrattana W, Smits S, Barendrecht AD. et al. Targeted SERPIN (TaSER): a dual-action antithrombotic agent that targets platelets for SERPIN delivery. J Thromb Haemost 2021; DOI: 10.1111/jth.15554.
    CrossrefPubMedGoogle Scholar
  • 45 Göbel K, Pankratz S, Asaridou CM. et al. Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells. Nat Commun 2016; 7: 11626
    CrossrefPubMedGoogle Scholar
  • 46 Sala-Cunill A, Björkqvist J, Senter R. et al. Plasma contact system activation drives anaphylaxis in severe mast cell-mediated allergic reactions. J Allergy Clin Immunol 2015; 135 (04) 1031-1043.e6 , e6
    CrossrefPubMedGoogle Scholar
  • 47 Rangaswamy C, Englert H, Deppermann C, Renné T. Polyanions in coagulation and thrombosis: focus on polyphosphate and neutrophils extracellular traps. Thromb Haemost 2021; 121 (08) 1021-1030
    Article in Thieme ConnectPubMedGoogle Scholar
  • 48 Johne J, Blume C, Benz PM. et al. Platelets promote coagulation factor XII-mediated proteolytic cascade systems in plasma. Biol Chem 2006; 387 (02) 173-178
    CrossrefPubMedGoogle Scholar
  • 49 Maas C, Renné T. Coagulation factor XII in thrombosis and inflammation. Blood 2018; 131 (17) 1903-1909
    CrossrefPubMedGoogle Scholar
  • 50 Baker CJ, Smith SA, Morrissey JH. Polyphosphate in thrombosis, hemostasis, and inflammation. Res Pract Thromb Haemost 2018; 3 (01) 18-25
    CrossrefPubMedGoogle Scholar
  • 51 Verhoef JJ, Barendrecht AD, Nickel KF. et al. Polyphosphate nanoparticles on the platelet surface trigger contact system activation. Blood 2017; 129 (12) 1707-1717
    CrossrefPubMedGoogle Scholar
  • 52 Labberton L, Kenne E, Long AT. et al. Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection. Nat Commun 2016; 7: 12616
    CrossrefPubMedGoogle Scholar
  • 53 Greinacher A, Selleng K, Palankar R. et al. Insights in ChAdOx1 nCoV-19 vaccine-induced immune thrombotic thrombocytopenia. Blood 2021; 138 (22) 2256-2268
    CrossrefPubMedGoogle Scholar
  • 54 Mailer RK, Allende M, Heestermans M. et al. Xenotropic and polytropic retrovirus receptor 1 regulates procoagulant platelet polyphosphate. Blood 2021; 137 (10) 1392-1405
    CrossrefPubMedGoogle Scholar
  • 55 Heestermans M, Naudin C, Mailer RK. et al. Identification of the factor XII contact activation site enables sensitive coagulation diagnostics. Nat Commun 2021; 12 (01) 5596
    Google Scholar