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Semin Thromb Hemost 2022; 48(01): 093-099
DOI: 10.1055/s-0041-1732372
Review Article

Involvement of Inflammation in Venous Thromboembolic Disease: An Update in the Age of COVID-19

Peter Poredos
1   Department of Anesthesiology and Perioperative Intensive Care, University Medical Centre Ljubljana, Ljubljana, Slovenia
,
Pavel Poredos
2   Department of Vascular Disease, University Medical Centre Ljubljana, Ljubljana, Slovenia
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Abstract

The inflammatory process is strongly involved in the pathophysiology of venous thromboembolism (VTE) and has a significant role in disease prediction. Inflammation most probably represents a common denominator through which classical and nonclassical risk factors stimulate thrombotic process. Inflammation of the venous wall promotes the release of tissue factor, inhibits the release of anticoagulant factors, and hampers endogenous fibrinolysis. Systemic inflammatory response also inhibits restoration of blood flow in the occluded vessel. Recent studies indicate that increased inflammatory response (“cytokine storm”) is related to prothrombotic state and thromboembolic events in patients with coronavirus disease 2019 (COVID-19). The growing evidence of involvement of inflammation in the pathogenesis of VTE indicates the importance of anti-inflammatory treatment and prevention of VTE. While aspirin was shown to be effective in prevention of recurrent venous thrombosis after treatment with anticoagulant drugs, some other anti-inflammatory drugs like nonsteroidal anti-inflammatory agents may have prothrombotic effect, thus potentially increasing the risk of VTE. Recently, new specific anti-inflammatory drug inhibitors of inflammatory markers that have been shown to be involved in the pathogenesis of VTE are being searched. As thrombogenesis is based on activation of coagulation provoked by inflammation, then prevention and treatment of VTE should include both anticoagulant and anti-inflammatory agents. Combined treatment is related to increased risk of bleeding complications, therefore subtherapeutic doses of both drugs should be used to improve the efficacy of management of VTE without increasing the risk of bleeding.

Keywords

inflammation - venous thromboembolism - risk factors - COVID-19 - anti-inflammatory treatment


Publication History

Article published online:
13 August 2021

© 2021. Thieme. All rights reserved.

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  • References

  • 1 Aksu K, Donmez A, Keser G. Inflammation-induced thrombosis: mechanisms, disease associations and management. Curr Pharm Des 2012; 18 (11) 1478-1493
    CrossrefPubMedGoogle Scholar
  • 2 Poredos P, Jezovnik MK. The role of inflammation in venous thromboembolism and the link between arterial and venous thrombosis. Int Angiol 2007; 26 (04) 306-311
    PubMedGoogle Scholar
  • 3 Tieken C, Versteeg HH. Anticoagulants versus cancer. Thromb Res 2016; 140 (Suppl. 01) S148-S153
    CrossrefPubMedGoogle Scholar
  • 4 Rodger M, Versteeg HH. An inflammatory fascination for thrombosis. Thromb Res 2016; 144: 224-225
    CrossrefPubMedGoogle Scholar
  • 5 Lippi G, Plebani M. Cytokine “storm”, cytokine “breeze”, or both in COVID-19?. Clin Chem Lab Med 2021; 59: 637-639
    CrossrefPubMedGoogle Scholar
  • 6 Kyrle PA, Eichinger S. Deep vein thrombosis. Lancet 2005; 365 (9465): 1163-1174
    CrossrefPubMedGoogle Scholar
  • 7 Wakefield TW, Myers DD, Henke PK. Mechanisms of venous thrombosis and resolution. Arterioscler Thromb Vasc Biol 2008; 28 (03) 387-391
    CrossrefPubMedGoogle Scholar
  • 8 Laridan E, Martinod K, De Meyer SF. Neutrophil extracellular traps in arterial and venous thrombosis. Semin Thromb Hemost 2019; 45 (01) 86-93
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Badimon L, Vilahur G. Neutrophil extracellular traps: a new source of tissue factor in atherothrombosis. Eur Heart J 2015; 36 (22) 1364-1366
    CrossrefPubMedGoogle Scholar
  • 10 Massberg S, Grahl L, von Bruehl ML. et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 2010; 16 (08) 887-896
    CrossrefPubMedGoogle Scholar
  • 11 Branchford BR, Carpenter SL. The role of inflammation in venous thromboembolism. Front Pediatr 2018; 6: 142
    CrossrefPubMedGoogle Scholar
  • 12 Esmon CT. The interactions between inflammation and coagulation. Br J Haematol 2005; 131 (04) 417-430
    CrossrefPubMedGoogle Scholar
  • 13 Gao Q, Zhang P, Wang W. et al. The correlation analysis of tumor necrosis factor-alpha-308G/A polymorphism and venous thromboembolism risk: a meta-analysis. Phlebology 2016; 31 (09) 625-631
    CrossrefPubMedGoogle Scholar
  • 14 Saghazadeh A, Hafizi S, Rezaei N. Inflammation in venous thromboembolism: cause or consequence?. Int Immunopharmacol 2015; 28 (01) 655-665
    CrossrefPubMedGoogle Scholar
  • 15 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
  • 16 Folsom AR, Lutsey PL, Astor BC, Cushman M. C-reactive protein and venous thromboembolism. A prospective investigation in the ARIC cohort. Thromb Haemost 2009; 102 (04) 615-619
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Mahemuti A, Abudureheman K, Aihemaiti X. et al. Association of interleukin-6 and C-reactive protein genetic polymorphisms levels with venous thromboembolism. Chin Med J (Engl) 2012; 125 (22) 3997-4002
    PubMedGoogle Scholar
  • 18 Jezovnik MK, Poredos P. Idiopathic venous thrombosis is related to systemic inflammatory response and to increased levels of circulating markers of endothelial dysfunction. Int Angiol 2010; 29 (03) 226-231
    PubMedGoogle Scholar
  • 19 Jezovnik MK, Fareed J, Poredos P. Patients with a history of idiopathic deep venous thrombosis have long-term increased levels of inflammatory markers and markers of endothelial damage. Clin Appl Thromb Hemost 2017; 23 (02) 124-131
    CrossrefPubMedGoogle Scholar
  • 20 Foley JH, Conway EM. Cross talk pathways between coagulation and inflammation. Circ Res 2016; 118 (09) 1392-1408
    CrossrefPubMedGoogle Scholar
  • 21 Sower LE, Froelich CJ, Carney DH, Fenton II JW, Klimpel GR. Thrombin induces IL-6 production in fibroblasts and epithelial cells. Evidence for the involvement of the seven-transmembrane domain (STD) receptor for alpha-thrombin. J Immunol 1995; 155 (02) 895-901
    CrossrefPubMedGoogle Scholar
  • 22 O'Brien M. The reciprocal relationship between inflammation and coagulation. Top Companion Anim Med 2012; 27 (02) 46-52
    CrossrefPubMedGoogle Scholar
  • 23 Maas C, Renné T. Coagulation factor XII in thrombosis and inflammation. Blood 2018; 131 (17) 1903-1909
    CrossrefPubMedGoogle Scholar
  • 24 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
  • 25 Renné T, Schuh K, Müller-Esterl W. Local bradykinin formation is controlled by glycosaminoglycans. J Immunol 2005; 175 (05) 3377-3385
    CrossrefPubMedGoogle Scholar
  • 26 Ortega-Gómez A, Perretti M, Soehnlein O. Resolution of inflammation: an integrated view. EMBO Mol Med 2013; 5 (05) 661-674
    CrossrefPubMedGoogle Scholar
  • 27 Mackman N. New insights into the mechanisms of venous thrombosis. J Clin Invest 2012; 122 (07) 2331-2336
    CrossrefPubMedGoogle Scholar
  • 28 Nosaka M, Ishida Y, Kimura A. et al. Contribution of the TNF-α (Tumor Necrosis Factor-α)-TNF-Rp55 (tumor necrosis factor receptor p55) axis in the resolution of venous thrombus. Arterioscler Thromb Vasc Biol 2018; 38 (11) 2638-2650
    CrossrefPubMedGoogle Scholar
  • 29 Poredoš P, Spirkoska A, Ježovnik MK. In patients with superficial vein thrombosis the inflammatory response is increased and related to the recanalization rate. Arch Med Sci 2019; 15 (02) 393-401
    CrossrefPubMedGoogle Scholar
  • 30 Schuliga M. The inflammatory actions of coagulant and fibrinolytic proteases in disease. Mediators Inflamm 2015; 2015: 437695
    CrossrefPubMedGoogle Scholar
  • 31 Larsson P, Ulfhammer E, Karlsson L, Bokarewa M, Wåhlander K, Jern S. Effects of IL-1beta and IL-6 on tissue-type plasminogen activator expression in vascular endothelial cells. Thromb Res 2008; 123 (02) 342-351
    CrossrefPubMedGoogle Scholar
  • 32 Lin H, Xu L, Yu S, Hong W, Huang M, Xu P. Therapeutics targeting the fibrinolytic system. Exp Mol Med 2020; 52 (03) 367-379
    CrossrefPubMedGoogle Scholar
  • 33 Malas MB, Naazie IN, Elsayed N, Mathlouthi A, Marmor R, Clary B. Thromboembolism risk of COVID-19 is high and associated with a higher risk of mortality: a systematic review and meta-analysis. EClinicalMedicine 2020; 29: 100639
    CrossrefPubMedGoogle Scholar
  • 34 Di Minno A, Ambrosino P, Calcaterra I, Di Minno MND. COVID-19 and venous thromboembolism: a meta-analysis of literature studies. Semin Thromb Hemost 2020; 46 (07) 763-771
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 Fernández-Capitán C, Barba R, Díaz-Pedroche MDC. et al. Presenting characteristics, treatment patterns, and outcomes among patients with venous thromboembolism during hospitalization for COVID-19. Semin Thromb Hemost 2021; 47 (04) 351-361
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Engelen MM, Vandenbriele C, Balthazar T. et al. Venous thromboembolism in patients discharged after COVID-19 hospitalization. Semin Thromb Hemost 2021; 47 (04) 362-371
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Huang C, Wang Y, Li X. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395 (10223): 497-506
    CrossrefPubMedGoogle Scholar
  • 38 Gao Y, Li T, Han M. et al. Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19. J Med Virol 2020; 92 (07) 791-796
    CrossrefPubMedGoogle Scholar
  • 39 Henry BM, Vikse J, Benoit S, Favaloro EJ, Lippi G. Hyperinflammation and derangement of renin-angiotensin-aldosterone system in COVID-19: a novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis. Clin Chim Acta 2020; 507: 167-173
    CrossrefPubMedGoogle Scholar
  • 40 Rapkiewicz AV, Mai X, Carsons SE. et al. Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: a case series. EClinicalMedicine 2020; 24: 100434
    CrossrefPubMedGoogle Scholar
  • 41 Lippi G, Sanchis-Gomar F, Favaloro EJ, Lavie CJ, Henry BM. Coronavirus disease 2019-associated coagulopathy. Mayo Clin Proc 2021; 96 (01) 203-217
    CrossrefPubMedGoogle Scholar
  • 42 Bunce PE, High SM, Nadjafi M, Stanley K, Liles WC, Christian MD. Pandemic H1N1 influenza infection and vascular thrombosis. Clin Infect Dis 2011; 52 (02) e14-e17
    CrossrefPubMedGoogle Scholar
  • 43 Vadasz Z, Brenner B, Toubi E. Immune-mediated coagulopathy in COVID-19 infection. Semin Thromb Hemost 2020; 46 (07) 838-840
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood 2020; 135 (23) 2033-2040
    CrossrefPubMedGoogle Scholar
  • 45 Benati M, Salvagno GL, Nitto S. et al. Thrombin generation in patients with coronavirus disease 2019. Semin Thromb Hemost 2021; 47 (04) 447-450
    Article in Thieme ConnectPubMedGoogle Scholar
  • 46 Zuo Y, Yalavarthi S, Shi H. et al. Neutrophil extracellular traps in COVID-19. JCI Insight 2020; 5 (11) e138999
    PubMedGoogle Scholar
  • 47 Poredoš P, Poredoš P, Jezovnik MK. Factors influencing recanalization of thrombotic venous occlusions. Vasa 2020; 49 (01) 17-22
    CrossrefPubMedGoogle Scholar
  • 48 Lippi G, Favaloro EJ. Venous and arterial thromboses: two sides of the same coin?. Semin Thromb Hemost 2018; 44 (03) 239-248
    Article in Thieme ConnectPubMedGoogle Scholar
  • 49 Becattini C, Agnelli G. Aspirin for prevention and treatment of venous thromboembolism. Blood Rev 2014; 28 (03) 103-108
    CrossrefPubMedGoogle Scholar
  • 50 Simes J, Becattini C, Agnelli G. et al; INSPIRE Study Investigators (International Collaboration of Aspirin Trials for Recurrent Venous Thromboembolism). Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration. Circulation 2014; 130 (13) 1062-1071
    CrossrefPubMedGoogle Scholar
  • 51 Brighton TA, Eikelboom JW, Mann K. et al; ASPIRE Investigators. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med 2012; 367 (21) 1979-1987
    CrossrefPubMedGoogle Scholar
  • 52 Schmidt M, Christiansen CF, Horváth-Puhó E, Glynn RJ, Rothman KJ, Sørensen HT. Non-steroidal anti-inflammatory drug use and risk of venous thromboembolism. J Thromb Haemost 2011; 9 (07) 1326-1333
    CrossrefPubMedGoogle Scholar
  • 53 Ungprasert P, Srivali N, Wijarnpreecha K, Charoenpong P, Knight EL. Non-steroidal anti-inflammatory drugs and risk of venous thromboembolism: a systematic review and meta-analysis. Rheumatology (Oxford) 2015; 54 (04) 736-742
    CrossrefPubMedGoogle Scholar
  • 54 Diaz JA, Wrobleski SK, Alvarado CM. et al. P-selectin inhibition therapeutically promotes thrombus resolution and prevents vein wall fibrosis better than enoxaparin and an inhibitor to von Willebrand factor. Arterioscler Thromb Vasc Biol 2015; 35 (04) 829-837
    CrossrefPubMedGoogle Scholar
  • 55 Kosmas CE, Silverio D, Sourlas A, Montan PD, Guzman E, Garcia MJ. Anti-inflammatory therapy for cardiovascular disease. Ann Transl Med 2019; 7 (07) 147
    CrossrefPubMedGoogle Scholar
  • 56 Yuan S, Chen P, Li H, Chen C, Wang F, Wang DW. Mortality and pre-hospitalization use of low-dose aspirin in COVID-19 patients with coronary artery disease. J Cell Mol Med 2020
    PubMedGoogle Scholar
  • 57 Glynn RJ, Danielson E, Fonseca FA. et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med 2009; 360 (18) 1851-1861
    CrossrefPubMedGoogle Scholar
  • 58 Onorato D, Pucci M, Carpene G, Henry BM, Sanchis-Gomar F, Lippi G. Protective effects of statins administration in European and North American patients infected with COVID-19: a meta-analysis. Semin Thromb Hemost 2021; 47 (04) 392-399
    Article in Thieme ConnectPubMedGoogle Scholar
  • 59 Feng Y, Lei B, Zhang F, Niu L, Zhang H, Zhang M. Anti-inflammatory effects of simvastatin during the resolution phase of experimentally formed venous thrombi. J Investig Med 2017; 65 (06) 999-1007
    CrossrefPubMedGoogle Scholar
  • 60 Poterucha TJ, Libby P, Goldhaber SZ. More than an anticoagulant: Do heparins have direct anti-inflammatory effects?. Thromb Haemost 2017; 117 (03) 437-444
    Article in Thieme ConnectPubMedGoogle Scholar
  • 61 Esmon CT. Targeting factor Xa and thrombin: impact on coagulation and beyond. Thromb Haemost 2014; 111 (04) 625-633
    Article in Thieme ConnectPubMedGoogle Scholar
  • 62 Borissoff JI, Otten JJ, Heeneman S. et al. Genetic and pharmacological modifications of thrombin formation in apolipoprotein e-deficient mice determine atherosclerosis severity and atherothrombosis onset in a neutrophil-dependent manner. PLoS One 2013; 8 (02) e55784
    CrossrefPubMedGoogle Scholar
  • 63 Jeraj L, Jezovnik MK, Poredos P. Rivaroxaban versus warfarin in the prevention of post-thrombotic syndrome. Thromb Res 2017; 157: 46-48
    CrossrefPubMedGoogle Scholar