Therapeutic use of heparin beyond anticoagulation

Current Drug Discovery Technologies

Volumn 6, Issue 4, 2009, Pages 281-289

  Ludwig, Ralf J ^a  

^a UNIVERSITY OF LÜBECK   (Germany)

Author keywords

Adverse events; Angiogenesis; Chemokines; Complement; Glycosaminoglycans; Heparin; Inflammation; Lymphocyte homing; Metastasis

Indexed keywords

ANTINEOPLASTIC AGENT; ANTIVITAMIN K; ARDEPARIN; BEMIPARIN; CELL ADHESION MOLECULE; CERTOPARIN; CYTOKINE; DALTEPARIN; ENOXAPARIN; FONDAPARINUX; GLUCAN; HEPARIN; HYDROCORTISONE; LOW MOLECULAR WEIGHT HEPARIN; NADROPARIN; PARNAPARIN; PLACEBO; PS3; REVIPARIN; SALICYLIC ACID; SODIUM CHLORIDE; SULFATE; TINZAPARIN; UNCLASSIFIED DRUG;

ALLERGIC ENCEPHALOMYELITIS; ALLERGIC RHINITIS; ANGIOGENESIS; ANTICOAGULATION; ARTHRITIS; ASTHMA; BLEEDING; BRONCHOSPASM; CLINICAL TRIAL; COLITIS; COMPLEMENT ACTIVATION; DELAYED HYPERSENSITIVITY; DRUG ACTIVITY; DRUG INHIBITION; DRUG USE; ENTERITIS; HAIR LOSS; HEART INFARCTION; HOUSE DUST ALLERGY; HUMAN; LUNG EMBOLISM; LUNG SMALL CELL CANCER; NONHUMAN; OSTEOPOROSIS; PERITONITIS; PRIORITY JOURNAL; REVIEW; SKIN DEFECT; SKIN DISEASE; SOLID TUMOR; THROMBOCYTOPENIA; THROMBOSIS; THROMBOSIS PREVENTION;

ANGIOGENESIS INHIBITORS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; ANTICOAGULANTS; CELL ADHESION MOLECULES; CLINICAL TRIALS AS TOPIC; COMPLEMENT ACTIVATION; CYTOKINES; GLUCANS; HEPARIN; HUMANS; INFLAMMATION; NEOPLASM METASTASIS; POLYSACCHARIDES;

EID: 70449701596     PISSN: 15701638     EISSN: None     Source Type: Journal    
DOI: 10.2174/157016309789869001     Document Type: Review

References (112)

1. Jorpes E. The chemistry of heparin. Biochem J 1935; 29(8): 1817-1830
2. Crafoord C. Preliminary report on postoperative treatment with heparin as a preventive of thrombosis. Acta Chir Scand 1937; 79: 407-426
3. Björg I, Olson ST, Shore JD. Molecular mechanisms of the accelerating effect on the reactions between antithrombin and clotting proteases. In: Lane DA, Lindahl U, Eds. Heparin, chemical and biological properties, clinical applications. Boca Raton, Fl: CRC Press 1989. pp. 229-256
4. Alban S. From heparins to factor Xa inhibitors and beyond. Eur J Clin Invest 2005; 35(Supp I): 12-20.
5. Andersson LO, Barrowcliffe TW, Holmer E, Johnson EA, Sims GE. Anticoagulant properties of heparin fractionated by affinity chromatography on matrix-bound antithrombin iii and by gel filtration. Thromb Res 1976; 9(6): 575-583 (Pubitemid 8010572)
6. Alban S. Carbohydrates with anticoagulant and antithrombotic properties. In: Witczak ZJ, Nieforth KA, Eds. Carbohydrates in drug design. New York: Marcel Dekker, 1997, pp. 209-276
7. Kishimoto TK, Viswanathan K, Ganguly T, et al. Contaminated heparin associated with adverse clinical events and activation of the contact system. N Engl J Med 2008; 358(23): 2457-2467 (Pubitemid 351793019)
8. Demir M, Iqbal O, Dietrich CP, et al. Anticoagulant and antiprotease effects of a novel heparinlike compound from shrimp (Penaeus brasiliensis) and its neutralization by heparinase I. Clin Appl Thromb Hemost 2001; 7(1): 44-52. (Pubitemid 32112602)
9. Bauer KA, Hawkins DW, Peters PC, et al. Fondaparinux, a synthetic pentasaccharide: The first in a new class of antithrombotic agents - the selective factor Xa inhibitors. Cardiovasc Drug Rev 2002; 20(1): 37-52. (Pubitemid 34657226)
10. Eriksson BI, Bauer KA, Lassen MR, Turpie AG. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med 2001; 345(18): 1298-1304 (Pubitemid 34940741)
11. Bauer KA, Eriksson BI, Lassen MR, Turpie AG. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001; 345(18): 1305-1310 (Pubitemid 34940742)
12. Lassen MR, Bauer KA, Eriksson BI, Turpie AG. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: A randomised double-blind comparison. Lancet 2002; 359(9319): 1715-1720 (Pubitemid 34607083)
13. th ed. Chest 2008; 133: 71S-109S.
14. Sculpher MJ, Lozano-Ortega G, Sambrook J, et al. Fondaparinux versus Enoxaparin in non-ST-elevation acute coronary syndromes: Short-term cost and long-term cost-effectiveness using data from the Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators (OASIS-5) trial. Am Heart J 2009; 157(5): 845-852
15. Cohen AT, Davidson BL, Gallus AS, et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006; 332(7537): 325-329
16. Agnelli G, Bergqvist D, Cohen AT, Gallus AS, Gent M. Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in hig-hrisk abdominal surgery. Br J Surg 2005; 92(10): 1212-1220 (Pubitemid 41475229)
17. Menard R, Alban S, de RP, et al. Beta-1,3 glucan sulfate, but not beta-1,3 glucan, induces the salicylic acid signaling pathway in tobacco and Arabidopsis. Plant Cell 2004; 16(11): 3020-3032 (Pubitemid 41075749)
18. Ludwig RJ, Alban S, Boehncke WH. Structural requirements of heparin and related molecules to exert a multitude of antiinflammatory activities. Mini Rev Med Chem 2006; 6: 1009-1023 (Pubitemid 44383187)
19. Fritzsche J, Alban S, Ludwig RJ, Boehncke WH, Schuhmacher G, Bendas G. Influence of structural parameters of sulphated polysaccharides on P-selectin inhibition. Biochem Pharmacol 2006; 72(4): 474-485
20. Kuschert GS, Coulin F, Power CA, et al. Glycosaminoglycans interact selectively with chemokines and modulate receptor binding and cellular responses. Biochemistry 1999; 38(39): 12959-12968 (Pubitemid 129515595)
21. Shaw JP, Johnson Z, Borlat F, et al. The X-Ray structure of RANTES: heparin-derived disaccharides allows the rational design of chemokine inhibitors. Structure (Camb ) 2004; 12(11): 2081-2093 (Pubitemid 39469405)
22. Schön M, Ludwig RJ. Leukocyte trafficking to inflamed skin - molecular mechanisms and implications for therapeutic target molecules. Expert Opin Ther Targets 2005; 9(2): 225-243 (Pubitemid 40613865)
23. Radeke HH, Ludwig RJ, Boehncke WH. Experimental approaches to lymphocyte migration in dermatology in vitro and in vivo. Exp Dermatol 2005; 14(9): 641-666
24. Butcher EC, Picker LJ. Lymphocyte homing and homeostasis. Science 1996; 272(5258): 60-66
25. Anderson DC, Springer TA. Leukocyte adhesion deficiency: An inherited defect in the Mac-1, LFA-1, and p150,95 glycoproteins. Annu Rev Med 1987; 38: 175-194
26. Weninger W, Ulfman LH, Cheng G, et al. Specialized contributions by alpha(1,3)-fucosyltransferase-IV and FucT-VII during leukocyte rolling in dermal microvessels. Immunity 2000; 12(6): 665-676
27. Carr MW, Alon R, Springer TA. The C-C chemokine MCP-1 differentially modulates the avidity of beta 1 and beta 2 integrins on T lymphocytes. Immunity 1996; 4(2): 179-187 (Pubitemid 26093777)
28. Chavakis T, Preissner KT, Santoso S. Leukocyte trans-endothelial migration: JAMs add new pieces to the puzzle. Thromb Haemost 2003; 89(1): 13-17 (Pubitemid 36149787)
29. Muller WA. Migration of leukocytes across endothelial junctions: some concepts and controversies. Microcirculation 2001; 8: 181-193
30. Ludwig RJ, Zollner TM, Santoso S, et al. Junctional Adhesion Molecules (JAM)-B and -C contribute to leukocyte extravasation to the skin and mediate cutaneous inflammation. J Invest Dermatol 2005; 125(5): 969-976
31. Fritzsche J, Simonis D, Bendas G. Melanoma cell adhesion can be blocked by heparin in vitro: Suggestion of VLA-4 as a novel target for antimetastatic approaches. Thromb Haemost 2008; 100(6): 1166-1175
32. Ludwig RJ, Schön MP, Boehncke WH. P-selectin: a common therapeutic target for cardiovascular disorders, infl ammation and tumour metastasis. Expert Opin Ther Targets 2007; 11(8): 1-15.
33. Borsig L. Antimetastatic activities of modified heparins: Selectin inhibition by heparin attenuates metastasis. Semin Thromb Hemost 2007; 33(5): 540-546
34. nd ed. UK, Academic Press Inc 2000.
35. Hecht I, Hershkoviz R, Shivtiel S, et al. Heparin-disaccharide affects T cells: inhibition of NF-kappaB activation, cell migration, and modulation of intracellular signaling. J Leukoc Biol 2004; 75(6): 1139-1146 (Pubitemid 38720658)
36. Lider O, Cahalon L, Gilat D, et al. A disaccharide that inhibits tumor necrosis factor alpha is formed from the extracellular matrix by the enzyme heparanase. Proc Natl Acad Sci USA 1995; 92(11): 5037-5041
37. Cahalon L, Lider O, Schor H, et al. Heparin disaccharides inhibit tumor necrosis factor-alpha production by macrophages and arrest immune inflammation in rodents. Int Immunol 1997; 9(10): 1517-1522 (Pubitemid 27434683)
38. Proudfoot AE, Fritchley S, Borlat F, et al. The BBXB motif of RANTES is the principal site for heparin binding and controls receptor selectivity. J Biol Chem 2001; 276(14): 10620-10626 (Pubitemid 38089230)
39. Walport MJ. Complement. First of two parts. N Engl J Med 2001; 344(14): 1058-1066
40. Walport MJ. Complement. Second of two parts. N Engl J Med 2001; 344(15): 1140-1144
41. Bieber K, Sun S, Ishii N, et al. Animal models for autoimmune bullous dermatoses. Exp Dermatol 2009; in press - DOI: 10.1111/j.1600-0625.2009.00948.x.
42. Mihai S, Chiriac MT, Takahashi K, et al. The alternative pathway of complement activation is critical for blister induction in experimental epidermolysis bullosa acquisita. J Immunol 2007; 178(10): 6514-6521 (Pubitemid 46717435)
43. Liu Z, Giudice GJ, Swartz SJ, et al. The role of complement in experimental bullous pemphigoid. J Clin Invest 1995; 95(4): 1539-1544 (Pubitemid 27386312)
44. Truedsson L, Bengtsson AA, Sturfelt G. Complement deficiencies and systemic lupus erythematosus. Autoimmunity 2007; 40(8): 560-566 (Pubitemid 350302182)
45. Watson WC, Brown PS, Pitcock JA, Townes AS. Passive transfer studies with type II collagen antibody in B10.D2/old and new line and C57Bl/6 normal and beige (Chediak-Higashi) strains: evidence of important roles for C5 and multiple inflammatory cell types in the development of erosive arthritis. Arthritis Rheum 1987; 30(4): 460-465
46. Karp CL, Grupe A, Schadt E, et al. Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma. Nat Immunol 2000; 1(3): 221-226
47. Ecker EE, Gross P. Anticomplementary power of heparin. J Infect Dis 1929; 44: 250-253
48. Linhardt RJ, Rice KG, Kim YS, Engelken JD, Weiler JM. Homogeneous, structurally defined heparin-oligosaccharides with low anticoagulant activity inhibit the generation of the amplification pathway C3 convertase in vitro. J Biol Chem 1988; 263(26): 13090-13096
49. Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993; 362(6423): 841-844 (Pubitemid 23132159)
50. Gerritsen ME. Genetic variations in vascular endothelial growth factor and endothelial nitric oxide synthase and their contributions to human disease. Microcirculation 2005; 12(1): 129-140 (Pubitemid 40450624)
51. Lee CG, Link H, Baluk P, et al. Vascular endothelial growth factor (VEGF) induces remodeling and enhances TH2-mediated sensitization and inflammation in the lung. Nat Med 2004; 10(10): 1095-1103 (Pubitemid 39424871)
52. Castelli R, Porro F, Tarsia P. The heparins and cancer: review of clinical trials and biological properties. Vasc Med 2004; 9(3): 205-213. (Pubitemid 40124086)
53. Colin S, Jeanny JC, Mascarelli F, et al. In vivo involvement of heparan sulfate proteoglycan in the bioavailability, internalization, and catabolism of exogenous basic fibroblast growth factor. Mol Pharmacol 1999; 55(1): 74-82.
54. Schlessinger J, Lax I, Lemmon M. Regulation of growth factor activation by proteoglycans: what is the role of the low affinity receptors? Cell 1995; 83(3): 357-360
55. Soker S, Goldstaub D, Svahn CM, Vlodavsky I, Levi BZ, Neufeld G. Variations in the size and sulfation of heparin modulate the effect of heparin on the binding of VEGF165 to its receptors. Biochem Biophys Res Commun 1994; 203(2): 1339-1347 (Pubitemid 24304976)
56. Pisano C, Aulicino C, Vesci L, et al. Undersulfated, low-molecular-weight glycol-split heparin as an antiangiogenic VEGF antagonist. Glycobiology 2005; 15(2): 1C-6C. (Pubitemid 40227915)
57. Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002; 347(12): 911-920
58. Schön M, Boehncke WH. Psoriasis - immunopathogenesis, genetics and therapeutic perspectives. N Engl J Med 2005; 352(18): 1899-1912
59. Joly P, Roujeau JC, Benichou J, et al. A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N Engl J Med 2002; 346(5): 321-327 (Pubitemid 34438839)
60. Joly P, Roujeau JC, Benichou J, et al. A comparison of two regimens of topical corticosteroids in the treatment of patients with bullous pemphigoid: a multicenter randomized study. J Invest Dermatol 2009; 129(7): 1681-1687
61. Ludwig RJ, Herzog C, Rostock A, et al. Psoriasis: a possible risk factor for development of coronary artery calcification. Br J Dermatol 2007; 156(2): 271-276 (Pubitemid 46095954)
62. Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA 2006; 296(14): 1735-1741 (Pubitemid 44547793)
63. Roman MJ, Shanker BA, Davis A, et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003; 349(25): 2399-2406 (Pubitemid 37542988)
64. Wan MX, Liu Q, Wang Y, Thorlacius H. Protective effect of low molecular weight heparin on experimental colitis: role of neutrophil recruitment and TNF-alpha production. Inflamm Res 2002; 51(4): 182-187 (Pubitemid 34457531)
65. Lider O, Baharav E, Mekori YA, et al. Suppression of experimental autoimmune diseases and prolongation of allograft survival by treatment of animals with low doses of heparins. J Clin Invest 1989; 83(3): 752-756 (Pubitemid 19080602)
66. Wang L, Brown JR, Varki A, Esko JD. 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(1): 127-136 (Pubitemid 34743473)
67. Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2002; 2(8): 563-572 (Pubitemid 37328923)
68. Zacharski LR, Ornstein DL. Heparin and cancer. Thromb Haemost 1998; 80(1): 10-23.
69. Ornstein DL, Zacharski LR. Cancer, thrombosis, and anticoagulants. Curr Opin Pulm Med 2000; 6(4): 301-308
70. Ludwig RJ, Boehme B, Podda M, et al. Endothelial P-selectin as a target of heparin action in experimental melanoma lung metastasis. Cancer Res 2004; 64: 2743-2750 (Pubitemid 38500611)
71. Ludwig RJ, Alban S, Bislian R, et al. The ability of different forms of heparins to suppress P-selectin function in vitro correlates to their inhibitory capacity on blood-borne metastasis in vivo. Thromb Haemost 2006; 95(3): 535-540
72. Stevenson JL, Choi SH, Varki A. Differential metastasis inhibition by clinically relevant levels of heparins - correlation with selectin inhibition, not antithrombotic activity. Clin Cancer Res 2005; 11: 7003-7011 (Pubitemid 41428760)
73. Borsig L, Wong R, Hynes RO, Varki NM, Varki A. Synergistic effects of L- and P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis. Proc Natl Acad Sci USA 2002; 99 (4): 2193-2198 (Pubitemid 34169037)
74. Ludwig RJ, Schon MP, Boehncke WH. P-selectin: a common therapeutic target for cardiovascular disorders, inflammation and tumour metastasis. Expert Opin Ther Targets 2007; 11(8): 1103-1117
75. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 311S-37S. (Pubitemid 39297959)
76. th ed. Chest 2008; 133: 340S-80S.
77. Warkentin TE, Sheppard JA, Sigouin CS, Kohlmann T, Eichler P, Greinacher A. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood 2006; 108(9): 2937-2941 (Pubitemid 44776929)
78. Warkentin TE, Roberts RS, Hirsh J, Kelton JG. Heparin-induced skin lesions and other unusual sequelae of the heparin-induced thrombocytopenia syndrome: a nested cohort study. Chest 2005; 127(5): 1857-1861 (Pubitemid 46218820)
79. Ludwig RJ, Schindewolf M, Alban S, Kaufmann R, Lindhoff-Last E, Boehncke WH. Molecular weight determines the frequency of delayed type hypersensitivity reactions to heparin and synthetic oligosaccharides. Thromb Haemost 2005; 94: 1265-1269 (Pubitemid 41819625)
80. Ludwig RJ, Schindewolf M, Utikal J, Lindhoff-Last E, Boehncke WH. Management of cutaneous type IV hypersensitivity reactions induced by heparin. Thromb Haemost 2006; 96(5): 611-617 (Pubitemid 44782541)
81. Bircher AJ, Harr T, Hohenstein L, Tsakiris DA. Hypersensitivity reactions to anticoagulant drugs: Diagnosis and management options. Allergy 2006; 61(12): 1432-1440 (Pubitemid 44665308)
82. Schindewolf M, Schwaner S, Wolter M, et al. Incidence and causes of heparin-induced skin lesions. CMAJ 2009; 181(8): 477-481
83. Schindewolf M, Ludwig RJ, Wolter M, et al. Tolerance of fondaparinux in patients with generalized contact dermatitis to heparin. J Eur Acad Dermatol Venereol 2008; 22: 378-380 (Pubitemid 351247440)
84. Ludwig RJ, Beier C, Lindhoff-Last E, Kaufmann R, Boehncke WH. Tolerance of fondaparinux in a patient allergic to heparins and other glycosaminoglycans. Contact Dermatitis 2003; 49(3): 158-159 (Pubitemid 38021667)
85. Jappe U, Juschka U, Kuner N, Hausen BM, Krohn K. Fondaparinux: A suitable alternative in cases of delayed-type allergy to heparins and semisynthetic heparinoids? A study of 7 cases. Contact Dermatitis 2004; 51(2): 67-72. (Pubitemid 39331598)
86. Maetzke J, Hinrichs R, Staib G, Scharffetter-Kochanek K. Fondaparinux as a novel therapeutic alternative in a patient with heparin allergy. Allergy 2004; 59(2): 237-238 (Pubitemid 38250789)
87. O'Meara AC, Demarmels BF, Heizmann M. Fondaparinux as an alternative therapy in heparin-induced delayed-type hypersensitivity skin lesions. Thromb Haemost 2007; 98(6): 1389-1391 (Pubitemid 350239120)
88. Parody R, Oliver A, Souto JC, Fontcuberta J. Fondaparinux (ARIXTRA) as an alternative anti-thrombotic prophylaxis when there is hypersensitivity to low molecular weight and unfractionated heparins. Haematologica 2003; 88(11): ECR32.
89. Hirsch K, Ludwig RJ, Lindhoff-Last E, Kaufmann R, Boehncke WH. Intolerance of fondaparinux in a patient allercig to heparins. Contact Dermatitis 2004; 50(6): 383-384 (Pubitemid 39070773)
90. Hohenstein E, Tsakiris D, Bircher AJ. Delayed-type hypersensitivity to the ultra-low-molecular-weight heparin fondaparinux. Contact Dermatitis 2004; 51(3): 149-151 (Pubitemid 39423061)
91. Maetzke J, Hinrichs R, Schneider LA, Scharffetter-Kochanek K. Unexpected delayed-type hypersensitivity skin reactions to the ultra-low-molecular-weight heparin fondaparinux. Allergy 2005; 60(3): 413-415 (Pubitemid 40293368)
92. Alban S, Ludwig RJ, Bendas G, et al. PS3, A semisynthetic beta-1,3-glucan sulfate, diminishes contact hypersensitivity responses through inhibition of L- and P-selectin functions. J Invest Dermatol 2009; 129(5): 1192-1202
93. Diamond MS, Alon R, Parkos CA, Quinn MT, Springer TA. Heparin is an adhesive ligand for the leukocyte integrin Mac-1 (CD11b/CD1). J Cell Biol 1995; 130(6): 1473-1482
94. Sun QH, Paddock C, Visentin GP, Zukowski MM, Muller WA, Newman PJ. Cell surface glycosaminoglycans do not serve as ligands for PECAM-1. PECAM-1 is not a heparin-binding protein. J Biol Chem 1998; 273(19): 11483-11490 (Pubitemid 28272042)
95. Ang YS, Mahmud N, White B, et al. Randomized comparison of unfractionated heparin with corticosteroids in severe active inflammatory bowel disease. Aliment Pharmacol Ther 2000; 14(8): 1015-1122 (Pubitemid 30618162)
96. Bloom S, Kiilerich S, Lassen MR, et al. Low molecular weight heparin (tinzaparin) vs. placebo in the treatment of mild to moderately active ulcerative colitis. Aliment Pharmacol Ther 2004; 19(8): 871-878 (Pubitemid 38534816)
97. de Bievre MA, Vrij AA, Schoon EJ, et al. Randomized, placebo-controlled trial of low molecular weight heparin in active ulcerative colitis. Inflamm Bowel Dis 2007; 13(6): 753-758
98. Torkvist L, Thorlacius H, Sjoqvist U, et al. Low molecular weight heparin as adjuvant therapy in active ulcerative colitis. Aliment Pharmacol Ther 1999; 13(10): 1323-1338 (Pubitemid 29462307)
99. Ingber A, Trattner A, Cohen IR, Mekori YA. Low doses of low molecular weight heparin in vivo inhibits the elicitation of contact hypersensitivity. Acta Derm Venereol 1994; 74(6): 454-456
100. Bowler SD, Smith SM, Lavercombe PS. Heparin inhibits the immediate response to antigen in the skin and lungs of allergic subjects. Am Rev Respir Dis 1993; 147(1): 160-163
101. Ahmed T, Garrigo J, Danta I. Preventing bronchoconstriction in exercise-induced asthma with inhaled heparin. N Engl J Med 1993; 329(2): 90-95. (Pubitemid 23188822)
102. Ceyhan B, Celikel T. Effect of inhaled heparin on methacholine-induced bronchial hyperreactivity. Chest 1995; 107(4): 1009-1012
103. 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(5): 703-708 (Pubitemid 33096198)
104. Lebeau B, Chastang C, Brechot JM, et al. Subcutaneous heparin treatment increases survival in small cell lung cancer. "Petites Cellules" Group. Cancer 1994; 74(1): 38-45.
105. Altinbas M, Coskun HS, Er O, et al. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost 2004; 2(8): 1266-1271 (Pubitemid 40186120)
106. Klerk CPW, Smorenburg SM, Otten HM, et al. The effect of low molecular weight heparin on ssurvival in patients with advanced malignancy. J Clin Oncol 2005; 23(10): 2130-2135 (Pubitemid 46218704)
107. Lee AY, Rickles FR, Julian JF, et al. Randomized comparison of low molecular weight heparin and coumarin derivates on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 2005; 23(10): 2123-2129 (Pubitemid 46218703)
108. Kakkar AK, Levine MN, Kadziola Z, et al. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol 2004; (10) 1944-1948.
109. Icli F, Akbulut H, Utkan G, et al. Low molecular weight heparin (LMWH) increases the efficacy of cisplatinum plus gemcitabine combination in advanced pancreatic cancer. J Surg Oncol 2007; 95(6): 507-512 (Pubitemid 46709395)
110. Gerdsen F, Luxembourg B, Langer F, Bauersachs R, Lindhoff-Last E. A prospective analysis of heparin-platelet factor 4 antibodies in pregnant women treated with the low-molecular-weight heparin, dalteparin. Blood Coagul Fibrinolysis 2008; 19(6): 477-481
111. Pouplard C, May MA, Iochmann S, et al. Antibodies to platelet factor 4-heparin after cardiopulmonary bypass in patient's anticoagulated with unfractionated heparin or a low-molecular-weight heparin: clinical implications for heparin-induced thrombocytopenia. Circulation 1999; 99(19): 2530-2536 (Pubitemid 29228283)
112. Rota E, Bazzan M, Fantino G. Fondaparinux-related thrombocytopenia in a previous low-molecular-weight heparin (LMWH)-induced heparin-induced thrombocytopenia (HIT). Thromb Haemost 2008; 99(4): 779-781