Heparin, Low Molecular Weight Heparin, and Derivatives in Thrombosis, Angiogenesis, and Inflammation: Emerging Links

ABSTRACT

The key reason behind the success of heparin in thrombosis and beyond is its polypharmacological sites of action for the prevention and treatment of multifactorial diseases that will only benefit slightly with single pharmacological mechanism-based agents. Thromboembolic disorders are driven by hypercoagulable, hyperactive platelet, proinflammatory, endothelial dysfunction, and proangiogenesis states. Heparin can effectively modulate all of those multifactorial components, as well as the interface among those components.

KEYWORDS

Heparin - low molecular weight heparin - glycosaminoglycans - thrombosis - angiogenesis - inflamation - tissue factor - tissue factor pathway inhibitor - anti-factor Xa - anti-factor IIa

REFERENCES

• 1 Weitz J I. Low-molecular-weight heparin.  N Engl J Med. 1997;  337 688-698
• 2 Aguilar D, Goldhaber S Z. Clinical uses of low molecular weight heparin.  Chest. 1999;  115 1418-1423
• 3 Mousa S A, Fareed J. Overview: from heparin to low molecular weight heparin: beyond anticoagulation.  Curr Opin Investig Drugs. 2001;  2(8) 1077-1080
• 4 Mousa S A. Comparative efficacy of different low-molecular-weight heparins (LMWHs) and drug interactions with LMWH: implications for management of vascular disorders.  Semin Thromb Hemost. 2000;  26(suppl 1) 39-46
• 5 Taheri S A, Lazar L, Haddad G, Castaldo R, Wilson M, Mousa S. Diagnosis of deep venous thrombosis by use of soluble necrosis factor receptor.  Angiology. 1998;  49 537-541
• 6 Nelson R M, Cecconi O, Roberts W G, Aruffo A, Linhardt R J, Bevilacqua M P. Heparin oligosaccharides bind L- and P-selectin and inhibit acute inflammation.  Blood. 1993;  82 3253-3258
• 7 Lantz M, Thysell H, Nilsson E, Olsson I. On the binding of tumor necrosis factor (TNF) to heparin and the release in vivo of the TNF-binding protein I by heparin.  J Clin Invest. 1991;  88 2026-2031
• 8 Tyrell D J, Kilfeather S, Page C P. Therapeutic uses of heparin beyond its traditional role as an anticoagulant.  Trends Pharmacol Sci. 1995;  16 198-204
• 9 Hocking D, Ferro T J, Johnson A. Dextran sulfate and heparin sulfate inhibit platelet-activating factor-induced pulmonary edema.  J Appl Physiol. 1992;  72 179-185
• 10 Darien B J, Fareed J, Centgraf K S et al.. Low molecular weight heparin prevents the pulmonary hemodynamic and pathomorphologic effects of endotoxin in a porcine acute lung injury model.  Shock. 1998;  9 274-281
• 11 Meyer J, Cox C S, Herndon D N et al.. Heparin in experimental hyperdynamic sepsis.  Crit Care Med. 1993;  21 84-89
• 12 Hiebert L M, Liu J M. Heparin protects cultured arterial endothelial cells from damage by toxic oxygen metabolites.  Atherosclerosis. 1990;  83 47-51
• 13 Matzner Y, Marx G, Drexler R, Eldor A. The inhibitory effect of heparin and related glycosaminoglycans on neutrophil chemotaxis.  Thromb Haemost. 1984;  52 134-137
• 14 Bazzoni G, Beltran Nunez A, Mascellani G, Bianchini P, Dejana E, Del Maschio A. Effect of heparin, dermatan sulfate, and related oligo-derivatives on human polymorphonuclear leukocyte functions.  J Lab Clin Med. 1993;  121 268-275
• 15 Buller H R, Agnelli G, Hull R D, Hyers T M, Prins M H, Raskob G E. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.  Chest. 2004;  126 401S-428S
• 16 Hutten B A, Prins M H, Gent M et al.. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis.  J Clin Oncol. 2000;  18 3078-3083
• 17 Palareti G, Legnani C, Lee A et al.. A comparison of the safety and efficacy of oral anticoagulation for the treatment of venous thromboembolic disease in patients with or without malignancy.  Thromb Haemost. 2000;  84 805-810
• 18 Prandoni P, Lensing A WA, Piccioli A et al.. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis.  Blood. 2002;  100 3484-3488
• 19 Lee A Y, Levine M N, Baker R I et al.. Randomized comparison of low-molecular-weight heparin versus oral anticoagulant therapy for the prevention of recurrent venous thromboembolism in patients with cancer.  N Engl J Med. 2003;  349 146-153
• 20 Meyer G, Marjanovic Z, Valcke J et al.. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer.  Arch Intern Med. 2002;  162 1729-1735
• 21 The Columbus Investigators . Low-molecular-weight heparin in the treatment of patients with venous thromboembolism.  N Engl J Med. 1997;  337 657-662
• 22 Simonneau G, Sors H, Charbonnier B et al.. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism.  N Engl J Med. 1997;  337 663-669
• 23 Quinlan D J, McQuillan A, Eikelboom J W. Low-molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta-analysis of randomized, controlled trials.  Ann Intern Med. 2004;  140 175-183
• 24 Goldhaber S Z, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER).  Lancet. 1999;  353 1386-1389
• 25 Grifoni S, Olivotto I, Cecchini P et al.. Short-term clinical outcome of patients with acute pulmonary embolism, normal blood pressure, and echocardiographic right ventricular dysfunction.  Circulation. 2000;  101 2817-2822
• 26 Agnelli G, Becattini C, Kirschstein T. Thrombolysis vs heparin in the treatment of pulmonary embolism.  Arch Intern Med. 2002;  162 2537-2541
• 27 Thabut G, Thabut D, Myers R P et al.. Thrombolytic therapy of pulmonary embolism: a meta-analysis.  J Am Coll Cardiol. 2002;  40 1660-1667
• 28 Konstantinides S, Gebel A, Heusel G et al.. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism.  N Engl J Med. 2002;  347 1143-1150
• 29 Ten Wolde M, Sohne M, Quak E, Mac Gillavry M R, Buller H R. Prognostic value of echocardiographically assessed right ventricular dysfunction in patients with pulmonary embolism.  Arch Intern Med. 2004;  164 1685-1689
• 30 Prandoni P, Lensing A WA, Cogo A et al.. The long-term clinical course of acute deep venous thrombosis.  Ann Intern Med. 1996;  125 1-7
• 31 Prandoni P, Villalta S, Bagatella P et al.. The clinical course of deep-vein thrombosis. Prospective long-term follow-up of 528 symptomatic patients.  Haematologica. 1997;  82 423-428
• 32 Hansson P O, Sorbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors.  Arch Intern Med. 2000;  160 769-774
• 33 Heit J A, Mohr D N, Silverstein M D, Petterson T M, O'Fallon W M, Melton III L J. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study.  Arch Intern Med. 2000;  160 761-768
• 34 Schulman S, Rhedin A S, Lindmarker P et al.. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism.  N Engl J Med. 1995;  332 1661-1665
• 35 Kearon C, Gent M, Hirsh J et al.. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism.  N Engl J Med. 1999;  340 901-907
• 36 Agnelli G, Prandoni P, Santamaria M G et al.. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis.  N Engl J Med. 2001;  345 165-169
• 37 Pinede L, Ninet J, Duhaut P et al.. Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis.  Circulation. 2001;  103 2453-2460
• 38 Agnelli G, Prandoni P, Becattini C et al.. Extended oral anticoagulant therapy after a first episode of pulmonary embolism.  Ann Intern Med. 2003;  139 19-25
• 39 Schulman S, Granqvist S, Holmstrom M et al.. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism.  N Engl J Med. 1997;  336 393-398
• 40 Ridker P M, Goldhaber S Z, Danielson E et al.. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism.  N Engl J Med. 2003;  348 1425-1434
• 41 Kearon C, Ginsberg J S, Anderson D R et al.. Comparison of 1 month with 3 months of anticoagulation for a first episode of venous thromboembolism associated with a transient risk factor.  J Thromb Haemost. 2004;  2 743-749
• 42 Vancheri C, Mastruzzo C, Armato F et al.. Intranasal heparin reduces eosinophil recruitment after nasal allergen challenge in patients with allergic rhinitis.  J Allergy Clin Immunol. 2001;  108 703-708
• 43 Diamant Z, Timmers M C, van der Veen H, Page C P, van der Meer F J, Sterk P J. Effect of inhaled heparin on allergen-induced early and late asthmatic responses in patients with atopic asthma.  Am J Respir Crit Care Med. 1996;  153 1790-1795
• 44 Garrigo J, Danta I, Ahmed T. Time course of the protective effect of inhaled heparin on exercise-induced asthma.  Am J Respir Crit Care Med. 1996;  153 1702-1707
• 45 Gaffney A, Gaffney P. Rheumatoid arthritis and heparin.  Br J Rheumatol. 1996;  35 808-809
• 46 Bowler S D, Smith S M, Lavercombe P S. Heparin inhibits the immediate response to antigen in the skin and lungs of allergic subjects.  Am Rev Respir Dis. 1993;  147 160-163
• 47 Dwarakanath A D, Yu L G, Brookes C, Pryce D, Rhodes J M. Sticky neutrophils, pathergic arthritis, and response to heparin in pyoderma gangrenosum complicating ulcerative colitis.  Gut. 1995;  37 585-588
• 48 Petitou M, Hérault J-P, Bernat A et al.. Synthesis of thrombin-inhibiting heparin mimetics without side effects.  Nature. 1999;  398 417-422
• 49 Tyrrel D J, Horne A P, Holme K R, Preuss J MH, Page C P. Heparin in inflammation: potential therapeutic applications beyond anticoagulation.  Adv Pharmacol. 1999;  46 151-208
• 50 Salas A, Sans M, Soriano A et al.. Heparin attenuates TNF-induced inflammatory response through a CD11b dependent mechanism.  Gut. 2000;  47 88-96
• 51 Panés J, Perry M, Granger D N. Leukocyte-endothelial cell adhesion: avenues for therapeutic intervention.  Br J Pharmacol. 1999;  126 537-550
• 52 Lever R, Hoult J RS, Page C P. The effects of heparin and related molecules upon the adhesion of human polymorphonuclear leukocytes to vascular endothelium in vitro.  Br J Pharmacol. 2000;  129 533-540
• 53 Gaffney P R, Doyle C T, Gaffney A, Hogan J, Hayes D P, Annis P. Paradoxical response to heparin in 10 patients with ulcerative colitis.  Am J Gastroenterol. 1995;  90 220-223
• 54 Gaffney P, Gaffney A. Heparin therapy in refractory ulcerative colitis-an update.  Gastroenterology. 1996;  110 A913 , (abst)
• 55 Evans R C, Rhodes J M. Treatment of corticosteroid-resistant ulcerative colitis with heparin. A report of nine cases.  Gut. 1995;  37 A49 , (abst)
• 56 Brazier F, Yzet T, Duchmann J C et al.. Effect of heparin treatment on extra intestinal manifestations associated with inflammatory bowel diseases.  Gastroenterology. 1996;  110 A872 , (abst)
• 57 Brazier F, Yzet T, Boruchowicz A et al.. Treatment of ulcerative colitis with heparin.  Gastroenterology. 1996;  110 A872 , (abst)
• 58 Dupas J L, Brazier F, Yzet T et al.. Treatment of active Crohn's disease with heparin.  Gastroenterology. 1996;  110 A900 , (abst)
• 59 Folwaczny C, Spannagl M, Wiebecke W et al.. Heparin in the treatment of highly active inflammatory bowel disease (IBD).  Gastroenterology. 1996;  110 A908 , (abst)
• 60 Dwarakanath A D, Yu L G, Brookes C, Pryce D, Rhodes J M. “Sticky” neutrophils, pathergic arthritis, and response to heparin in pyoderma gangrenosum complicating ulcerative colitis.  Gut. 1995;  37 585-588
• 61 Teixeira M M, Hellewell P G. Suppression by intradermal administration of heparin of eosinophil accumulation but not edema formation in inflammatory reactions in guinea-pig skin.  Br J Pharmacol. 1993;  110 1496-1500
• 62 Carr J. The anti-inflammatory action of heparin: heparin as an antagonist to histamine, bradykinin and prostaglandin E1.  Thromb Res. 1979;  16 507-516
• 63 Koenig A, Norgard-Sumnicht K, Linhardt R, Varki A. Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins: implications for the use of unfractionated and low molecular weight heparins as therapeutic agents.  J Clin Invest. 1998;  101 877-889
• 64 Diamond M S, Alon R, Parkos C A, Quinn M T, Springer T A. Heparin is an adhesive ligand for the leukocyte integrin Mac-1 (CD11b/CD18).  J Cell Biol. 1995;  130 1473-1482
• 65 Benimetskaya L, Loike J D, Khaled Z et al.. Mac-1 (CD11b/CD18) is an oligodeoxy-nucleotide-binding protein.  Nat Med. 1997;  3 414-420
• 66 Emanuele R M, Fareed J. The effect of molecular weight on the bioavailability of heparin.  Thromb Res. 1987;  48 591-596
• 67 Brieger D, Dawes J. Production method affects the pharmacokinetic and ex vivo biological properties of low molecular weight heparins.  Thromb Haemost. 1997;  77 317-322
• 68 Mousa S A, Mohamed S. Inhibition of endothelial cell tube formation by the low molecular weight heparin, tinzaparin, is mediated by tissue factor pathway inhibitor.  Thromb Haemost. 2004;  92 627-633
• 69 Mousa S A, Kaiser B. Tissue factor pathway inhibitor in thrombosis and beyond: role of heparin.  Drugs Future. 2004;  29 751-766
• 70 Boneu B, Caranobe C, Cadroy Y et al.. Pharmacokinetic studies of standard unfractionated heparin, and low molecular weight heparins in the rabbit.  Semin Thromb Hemost. 1988;  14 18-27
• 71 Sutor A H, Massicotte P, Leaker M, Andrew M. Heparin therapy in pediatric patients.  Semin Thromb Hemost. 1997;  23 303-319
• 72 Majerus P, Broze J G, Miletich J. Anticoagulant, thrombolytic and antiplatelet drugs. In: Hardman J, Limbird L, Molinoff P, Ruddon R, Goodman A Goodman & Gilman's, The Pharmacological Basis of Therapeutics. 9th ed. New York; McGraw-Hill 1996: 1341-1359
• 73 Silverstein R. Drugs affecting hemostosis. In: Munson P, Mueller R, Breeze G Munson's Principles of Pharmacology. New York; Chapman & Hall 1995: 1123-1143
• 74 Theroux P, Waters D, Qiu S, McCans J, de Guise P, Juneau M. Aspirin versus heparin to prevent myocardial infarction during the acute phase of unstable angina.  Circulation. 1993;  88 2045-2048
• 75 Itoh K, Nakao A, Kishimoto W, Takagi H. Heparin effects on superoxide production by neutrophils.  Eur Surg Res. 1995;  27 184-188
• 76 Attanasio M, Gori A M, Giusti B et al.. Cytokine gene expression in human LPS- and IFNgamma-stimulated mononuclear cells is inhibited by heparin.  Thromb Haemost. 1998;  79 959-962
• 77 Dandona P, Qutob T, Hamouda W, Bakri F, Aljada A, Kumbkarni Y. Heparin inhibits reactive oxygen species generation by polymorphonuclear and mononuclear leucocytes.  Thromb Res. 1999;  96 437-443
• 78 Friedrichs G S, Kilgore K S, Manley P J, Gralinski M R, Lucchesi B R. Effects of heparin and N-acetyl heparin on ischemia/reperfusion-induced alterations in myocardial function in the rabbit isolated heart.  Circ Res. 1994;  75 701-710
• 79 Black S C, Gralinski M R, Friedrichs G S, Kilgore K S, Driscoll E M, Lucchesi B R. Cardioprotective effects of heparin or N-acetylheparin in an in vivo model of myocardial ischaemic and reperfusion injury.  Cardiovasc Res. 1995;  29 629-636
• 80 Lucchesi B R, Kilgore K S. Complement inhibitors in myocardial ischemia/reperfusion injury.  Immunopharmacology. 1997;  38 27-42
• 81 Hawari F I, Shykoff B E, Izzo Jr J L. Heparin attenuates norepinephrine-induced venoconstriction.  Vasc Med. 1998;  3 95-100
• 82 De Caterina R, Libby P, Peng H B et al.. Nitric oxide decreases cytokine-induced endothelial activation: nitric oxide selectively reduces endothelial expression of adhesion molecules and pro-inflammatory cytokines.  J Clin Invest. 1995;  96 60-68
• 83 Merwin R M, Algire G H. Induction of plasma-cell neoplasms and fibrosarcomas in BALB/c mice carrying diffusion chambers.  Proc Soc Exp Biol Med. 1959;  101(3) 437-439
• 84 Kerbel R S. Tumor angiogenesis: past, present and the near future.  Carcinogenesis. 2000;  21 505-515
• 85 Folkman J. Proceedings: tumor angiogenesis factor.  Cancer Res. 1974;  34(8) 2109-2113
• 86 Folkman J, Langer R, Linhardt R, Haudenschild C, Taylor S. Angiogenesis inhibition and tumor regression caused by heparin or a heparin fragment in the presence of cortisone.  Science. 1983;  221 719-725
• 87 Folkman J, Shing Y. Control of angiogenesis by heparin and other sulfated polysaccharides.  Adv Exp Med Biol. 1992;  313 355-364
• 88 Mousa S A, Mohamed S. Anti-angiogenic mechanisms and efficacy of the low molecular weight heparin, tinzaparin: anti-cancer efficacy.  Oncol Rep. 2004;  12 683-688
• 89 Hull R D, Raskob G E, Pineo G F et al.. Subcutaneous LMWH compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis.  N Engl J Med. 1992;  326 975-982
• 90 Simonneau G, Sors H, Charbonnier B et al.. A comparison of LMWH with unfractionated heparin for acute pulmonary embolism.  N Engl J Med. 1997;  337 663-669
• 91 Dahlback B. Blood coagulation.  Lancet. 2000;  355 1627-1632
• 92 Bajaj M S, Bajaj S P. Tissue factor pathway inhibitor: potential therapeutic applications.  Thromb Haemost. 1997;  78 471-477
• 93 Von Tempelhoff G-F, Hareberg J, Niemann F, Hommel G, Kirkpatrik C J, Heilmann L. Subcutaneous heparin treatment increases survival in small cell lung cancer.  Int J Oncol. 2000;  16 815-824
• 94 Kakkar A K, Williamson R C. Antithrombotic therapy in cancer.  BMJ. 1999;  318(7198) 1571-1572
• 95 Kohanna F H, Sweeny J, Hussey S, Zacharski L, Salzman E W. Effect of perioperative low-dose heparin on the course of colon cancer.  Surgery. 1983;  93 433-438
• 96 Leonard W J, Lin J X. Cytokine receptor signaling pathways.  J Allergy Clin Immunol. 2000;  105 877-888
• 97 Mousa S A, Linhardt R, Francis J L, Amirkhosravi A. Anti-metastatic effect of a non-anticoagulant low-molecular-weight heparin versus the standard low-molecular-weight heparin, enoxaparin.  Thromb Haemost. 2006;  96 816-821