More than an anticoagulant: Do heparins have direct anti-inflammatory effects?

Timothy J. Poterucha; Peter Libby; Samuel Z. Goldhaber

doi:10.1160/TH16-08-0620

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2017; 117(03): 437-444
DOI: 10.1160/TH16-08-0620

Coagulation and Fibrinolysis

Schattauer GmbH

More than an anticoagulant: Do heparins have direct anti-inflammatory effects?

Timothy J. Poterucha

¹Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

,

Peter Libby

²Cardiovascular Medicine Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

,

Samuel Z. Goldhaber

²Cardiovascular Medicine Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

› Author Affiliations

Abstract

Summary

The heparins, well-known for their anticoagulant properties, may also have anti-inflammatory effects that could contribute to their effectiveness in the treatment of venous thromboembolism and other vascular diseases. This review focuses on the inflammatory pathophysiology that underlies the development of thrombosis and the putative effects of heparin on these pathways. We present evidence supporting the use of heparin for other indications, including autoimmune disease, malignancy, and disseminated intravascular coagulation. These considerations highlight the need for further research to elucidate the mechanisms of the possible pleiotropic effects of the heparins, with a view to advancing treatments based upon heparin derivatives.

Keywords

Heparin - Coagulation - inflammation

Full Text

References

References
1 McLean J.. The discovery of heparin. Circulation 1959; 19: 75-78.
2 Wardrop D, Keeling D.. The story of the discovery of heparin and warfarin. Br J Haematol 2008; 141: 757-763.
3 Dougherty TF, Dolowitz DA.. Physiologic Actions of Heparin Not Related to Blood Clotting. Am J Cardiol 1964; 14: 18-24.
4 Libby P. et al. Leukocytes Link Local and Systemic Inflammation in Ischemic Cardiovascular Disease: An Expanded „Cardiovascular Continuum“. J Am Coll Cardiol 2016; 67: 1091-1103.
5 Croce K, Libby P.. Intertwining of thrombosis and inflammation in atherosclerosis. Curr Opin Hematol 2007; 14: 55-61.
6 Riva N. et al. Epidemiology and pathophysiology of venous thromboembolism: similarities with atherothrombosis and the role of inflammation. Thromb Haemost 2015; 113: 1176-1183.
7 Watt J. et al. The effect of reactive oxygen species on whole blood aggregation and the endothelial cell-platelet interaction in patients with coronary heart disease. Thromb Res 2012; 130: 210-215.
8 Eltzschig HK, Carmeliet P.. Hypoxia and inflammation. N Engl J Med 2011; 364: 656-665.
9 Rius J. et al. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature 2008; 453: 807-811.
10 Cummins EP. et al. Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc Natl Acad Sci USA 2006; 103: 18154-18159.
11 Markiewski MM, Lambris JD.. The role of complement in inflammatory diseases from behind the scenes into the spotlight. Am J Pathol 2007; 171: 715-727.
12 Semeraro F. et al. Histones induce phosphatidylserine exposure and a procoagulant phenotype in human red blood cells. J Thromb Haemost 2014; 12: 1697-1702.
13 Owens AP 3rd, Mackman N.. Microparticles in haemostasis and thrombosis. Circ Res 2011; 108: 1284-1297.
14 Quillard T. et al. TLR2 and neutrophils potentiate endothelial stress, apoptosis and detachment: implications for superficial erosion. Eur Heart J 2015; 36: 1394-1404.
15 Shim K. et al. Platelet-VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress. Blood 2008; 111: 651-657.
16 Chatzizisis YS. et al. Augmented expression and activity of extracellular matrix-degrading enzymes in regions of low endothelial shear stress colocalize with coronary atheromata with thin fibrous caps in pigs. Circulation 2011; 123: 621-630.
17 Koskinas KC. et al. Thin-capped atheromata with reduced collagen content in pigs develop in coronary arterial regions exposed to persistently low endothelial shear stress. Arterioscler Thromb Vasc Biol 2013; 33: 1494-1504.
18 Gimbrone Jr MA, Garcia-Cardena G.. Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis. Circ Res 2016; 118: 620-636.
19 Jain MK. et al. Regulation of an inflammatory disease: Kruppel-like factors and atherosclerosis. Arterioscler Thromb Vasc Biol 2014; 34: 499-508.
20 Everett BM. et al. Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis. Am Heart J 2013; 166 (199) 207 e15.
21 Ridker PM. et al. Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J 2011; 162: 597-605.
22 Dvorak M. et al. Heparin and its derivatives in the treatment of arterial thrombosis: a review. Veterinarni Medicina 2010; 55: 523.
23 Aksu K. et al. Inflammation-induced thrombosis: mechanisms, disease associations and management. Curr Pharm Des 2012; 18: 1478-1493.
24 Tichelaar YI. et al. Infections and inflammatory diseases as risk factors for venous thrombosis. A systematic review. Thromb Haemost 2012; 107: 827-837.
25 Wakefield TW. et al. Inflammatory and procoagulant mediator interactions in an experimental baboon model of venous thrombosis. Thromb Haemost 1993; 69: 164-172.
26 Etulain J. et al. P-selectin promotes neutrophil extracellular trap formation in mice. Blood 2015; 126: 242-246.
27 Demers M, Wagner DD.. NETosis: a new factor in tumour progression and cancer-associated thrombosis. Semin Thromb Haemost 2014; 40: 277-283.
28 Brinkmann V, Zychlinsky A.. Neutrophil extracellular traps: is immunity the second function of chromatin?. J Cell Biol 2012; 198: 773-783.
29 Fuchs TA. et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci USA 2010; 107: 15880-15885.
30 Stakos DA. et al. Expression of functional tissue factor by neutrophil extracellular traps in culprit artery of acute myocardial infarction. Eur Heart J 2015; 36: 1405-1414.
31 Marin V. et al. The IL-6-soluble IL-6Ralpha autocrine loop of endothelial activation as an intermediate between acute and chronic inflammation: an experimental model involving thrombin. J Immunol 2001; 167: 3435-3442.
32 Schonbeck U, Libby P.. The CD40/CD154 receptor/ligand dyad. Cell Mol Life Sci 2001; 58: 4-43.
33 Kranzhofer R. et al. Thrombin potently stimulates cytokine production in human vascular smooth muscle cells but not in mononuclear phagocytes. Circ Res 1996; 79: 286-294.
34 McNamara CA. et al. Thrombin stimulates proliferation of cultured rat aortic smooth muscle cells by a proteolytically activated receptor. J Clin Invest 1993; 91: 94-98.
35 Marutsuka K. et al. Protease-activated receptor 2 (PAR2) mediates vascular smooth muscle cell migration induced by tissue factor/factor VIIa complex. Thromb Res 2002; 107: 271-276.
36 Libby P, Simon DI.. Inflammation and thrombosis: the clot thickens. Circulation 2001; 103: 1718-1720.
37 Mertens G. et al. Cell surface heparan sulfate proteoglycans from human vascular endothelial cells. Core protein characterisation and antithrombin III binding properties J Biol Chem 1992; 267: 20435-20443.
38 Li JP, Vlodavsky I.. Heparin, heparan sulfate and heparanase in inflammatory reactions. Thromb Haemost 2009; 102: 823-828.
39 Wang L. et al. Heparin’s anti-inflammatory effects require glucosamine 6-O-sulfation and are mediated by blockade of L- and P-selectins. J Clin Invest 2002; 110: 127-136.
40 Najjam S. et al. Further characterisation of the binding of human recombinant interleukin 2 to heparin and identification of putative binding sites. Glycobiology 1998; 08: 509-516.
41 Spillmann D. et al. Defining the interleukin-8-binding domain of heparan sulfate. J Biol Chem 1998; 273: 15487-15493.
42 Salek-Ardakani S. et al. Heparin and heparan sulfate bind interleukin-10 and modulate its activity. Blood 2000; 96: 1879-1888.
43 Salas A. et al. Heparin attenuates TNF-alpha induced inflammatory response through a CD11b dependent mechanism. Gut 2000; 47: 88-96.
44 Rao NV. et al. Low anticoagulant heparin targets multiple sites of inflammation, suppresses heparin-induced thrombocytopenia, and inhibits interaction of RAGE with its ligands. Am J Physiol Cell Physiol 2010; 299: C97-110.
45 Gonzales JN. et al. Low anticoagulant heparin blocks thrombin-induced endothelial permeability in a PAR-dependent manner. Vascul Pharmacol 2014; 62: 63-71.
46 Gao Y, Li N, Fei R. et al. P-Selectin-mediated acute inflammation can be blocked by chemically modified heparin, RO-heparin. Mol Cells 2005; 19: 350-355.
47 Hochart H. et al. Low-molecular weight and unfractionated heparins induce a downregulation of inflammation: decreased levels of proinflammatory cytokines and nuclear factor-kappaB in LPS-stimulated human monocytes. Br J Haematol 2006; 133: 62-67.
48 Downing LJ. et al. Low-dose low-molecular-weight heparin is anti-inflammatory during venous thrombosis. J Vasc Surg 1998; 28: 848-854.
49 Poyrazoglu OK. et al. Acute effect of standard heparin versus low molecular weight heparin on oxidative stress and inflammation in haemodialysis patients. Ren Fail 2006; 28: 723-727.
50 Frank RD. et al. The synthetic pentasaccharide fondaparinux reduces coagulation, inflammation and neutrophil accumulation in kidney ischemia-reperfusion injury. J Thromb Haemost 2005; 03: 531-540.
51 Frank RD. et al. A non-anticoagulant synthetic pentasaccharide reduces inflammation in a murine model of kidney ischemia-reperfusion injury. Thromb Haemost 2006; 96: 802-806.
52 Callander NS. et al. Immunohistochemical identification of tissue factor in solid tumours. Cancer 1992; 70: 1194-1201.
53 Zwicker JI. et al. Tumour-derived tissue factor-bearing microparticles are associated with venous thromboembolic events in malignancy. Clin Cancer Res 2009; 15: 6830-6840.
54 Zwicker JI. et al. Prediction and prevention of thromboembolic events with enoxaparin in cancer patients with elevated tissue factor-bearing microparticles: a randomized-controlled phase II trial (the Microtec study). Br J Haematol 2013; 160: 530-537.
55 Ettelaie C. et al. Low molecular weight heparin downregulates tissue factor expression and activity by modulating growth factor receptor-mediated induction of nuclear factor-kappaB. Biochim Biophys Acta 2011; 1812: 1591-1600.
56 Lupu C. et al. Cellular effects of heparin on the production and release of tissue factor pathway inhibitor in human endothelial cells in culture. Arterioscler Thromb Vasc Biol 1999; 19: 2251-2262.
57 Demers M. et al. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc Natl Acad Sci USA 2012; 109: 13076-13081.
58 Van Den Berg YW, Reitsma PH.. Not exclusively tissue factor: neutrophil extracellular traps provide another link between chaemotherapy and thrombosis. J Thromb Haemost 2011; 09: 2311-2312.
59 Lee AY. et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349: 146-153.
60 Agnelli G. et al. Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chaemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol 2009; 10: 943-949.
61 Barni S. et al. The effect of low-molecular-weight heparin in cancer patients: the mirror image of survival? Blood. 2014; 124: 155-156.
62 Mousa SA, Petersen LJ.. Anti-cancer properties of low-molecular-weight heparin: preclinical evidence. Thromb Haemost 2009; 102: 258-267.
63 Borsig L. et al. Synergistic effects of L- and P-selectin in facilitating tumour metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis. Proc Natl Acad Sci USA 2002; 99: 2193-2198.
64 Stevenson JL. et al. Differential metastasis inhibition by clinically relevant levels of heparins--correlation with selectin inhibition, not antithrombotic activity. Clin Cancer Res 2005; 11: 7003-7011.
65 Ludwig RJ. et al. Endothelial P-selectin as a target of heparin action in experimental melanoma lung metastasis. Cancer Res 2004; 64: 2743-2750.
66 Ludwig RJ. et al. The ability of different forms of heparins to suppress P-selectin function in vitro correlates to their inhibitory capacity on bloodborne metastasis in vivo. Thromb Haemost 2006; 95: 535-540.
67 Alyahya R. et al. Anti-metastasis efficacy and safety of non-anticoagulant heparin derivative versus low molecular weight heparin in surgical pancreatic cancer models. Int J Oncol 2015; 46: 1225-1231.
68 Mousavi S. et al. Anti-Inflammatory Effects of Heparin and Its Derivatives: A Systematic Review. Adv Pharmacol Sci 2015; 2015: 507151.
69 Stelmach I. et al. The effect of inhaled heparin on post-leukotriene bronchoconstriction in children with bronchial asthma. Pol Merkur Lekarski 2002; 12: 95-98.
70 Ahmed T. et al. Preventing bronchoconstriction in exercise-induced asthma with inhaled heparin. N Engl J Med 1993; 329: 90-95.
71 Brown RA. et al. Additional clinical benefit of enoxaparin in COPD patients receiving salmeterol and fluticasone propionate in combination. Pulm Pharmacol Ther 2006; 19: 419-424.
72 Shen J. et al. Meta-analysis: The utility and safety of heparin in the treatment of active ulcerative colitis. Aliment Pharmacol Ther 2007; 26: 653-663.
73 Pellequer Y. et al. Epithelial heparin delivery via microspheres mitigates experimental colitis in mice. J Pharmacol Exp Ther 2007; 321: 726-733.
74 Cui HF, Jiang XL.. Treatment of corticosteroid-resistant ulcerative colitis with oral low molecular weight heparin. World J Gastroenterol 1999; 05: 448-450.
75 Hull RD. et al. Long-term low-molecular-weight heparin and the post-thrombotic syndrome: a systematic review. Am J Med 2011; 124: 756-765.
76 van Dongen CJ. et al. Relation between quality of anticoagulant treatment and the development of the postthrombotic syndrome. J Thromb Haemost 2005; 03: 939-942.
77 Schulte W. et al. Cytokines in sepsis: potent immunoregulators and potential therapeutic targets--an updated view. Mediators Inflamm 2013; 2013: 165974.
78 Fiusa MM. et al. Causes and consequences of coagulation activation in sepsis: an evolutionary medicine perspective. BMC Med 2015; 13 (105)
79 Ding R. et al. Treatment with unfractionated heparin attenuates coagulation and inflammation in endotoxemic mice. Thromb Res 2011; 128: e160-165.
80 Pernerstorfer T. et al. Heparin blunts endotoxin-induced coagulation activation. Circulation 1999; 100: 2485-2490.
81 Levi M. et al. Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated). Am J Respir Crit Care Med 2007; 176: 483-490.
82 Alfonso F, Angiolillo DJ.. Targeting p-selectin during coronary interventions: the elusive link between inflammation and platelets to prevent myocardial damage. J Am Coll Cardiol 2013; 61: 2056-2059.
83 Wang HB. et al. P-selectin primes leukocyte integrin activation during inflammation. Nat Immunol 2007; 08: 882-892.
84 Gotoh R. et al. E-selectin blockade decreases adventitial inflammation and attenuates intimal hyperplasia in rat carotid arteries after balloon injury. Arterioscler Thromb Vasc Biol 2004; 24: 2063-2068.
85 Ma S. et al. E-selectin-targeting delivery of microRNAs by microparticles ameliorates endothelial inflammation and atherosclerosis. Sci Rep 2016; 06: 22910.
86 Hajishengallis G, Chavakis T.. Endogenous modulators of inflammatory cell recruitment. Trends Immunol 2013; 34: 1-6.
87 Gros A. et al. Platelets in inflammation: regulation of leukocyte activities and vascular repair. Front Immunol 2015; 05: 678.
88 Thourani VH. et al. Nonanticoagulant heparin inhibits NF-kappaB activation and attenuates myocardial reperfusion injury. Am J Physiol Heart Circ Physiol 2000; 278: H2084-2093.
89 Gilotti AC. et al. Heparin responses in vascular smooth muscle cells involve cGMP-dependent protein kinase (PKG). J Cell Physiol 2014; 229: 2142-2152.
90 van Es N. et al. Edoxaban for treatment of venous thromboembolism in patients with cancer. Rationale and design of the Hokusai VTE-cancer study Thromb Haemost 2015; 114: 1268-1276.