Heparin-induced skin lesions

The Lancet

Volumn 380, Issue 9856, 2012, Pages 1867-1879

  Schindewolf, Marc ^a   Lindhoff Last, Edelgard ^a   Ludwig, Ralf J ^b   Boehncke, Wolf Henning ^a,b  

^a UNIVERSITY HOSPITAL FRANKFURT   (Germany)

^b UNIVERSITY OF LÜBECK   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ANTITHROMBIN; APIXABAN; CERTOPARIN; DABIGATRAN; DALTEPARIN; DANAPAROID; ENOXAPARIN; FONDAPARINUX; HEPARIN; LOW MOLECULAR WEIGHT HEPARIN; NADROPARIN; REVIPARIN; RIVAROXABAN; TINZAPARIN;

ACUTE CORONARY SYNDROME; ALLERGIC RHINITIS; ANGIONEUROTIC EDEMA; ARTHUS PHENOMENON; BRONCHOSPASM; CARDIOVASCULAR RISK; CELL ASSAY; CLINICAL FEATURE; DEEP VEIN THROMBOSIS; DIFFERENTIAL DIAGNOSIS; DRUG HYPERSENSITIVITY; EPIDERMOLYSIS BULLOSA HEREDITARIA; HEART ATRIUM FIBRILLATION; HISTOLOGY; HUMAN; HYPEREOSINOPHILIA; HYPOTENSION; LUNG EMBOLISM; LYMPHOCYTE PROLIFERATION; NECROSIS; PATHOGENESIS; PREGNANCY; PRIORITY JOURNAL; PRURITUS; PUSTULOSIS; REVIEW; SEX DIFFERENCE; SKIN ALLERGY; SKIN CALCIFICATION; SKIN DEFECT; TACHYCARDIA; THROMBOCYTOPENIA; THROMBOPHILIA; URTICARIA;

EID: 84869505861     PISSN: 01406736     EISSN: 1474547X     Source Type: Journal    
DOI: 10.1016/S0140-6736(12)60409-7     Document Type: Review

References (101)

1. Alban S. From heparins to factor Xa inhibitors and beyond. Eur J Clin Invest 2005; 35 (suppl 1): 12-20.
2. Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001; 119 (suppl): 64S-94S.
3. Hirsh J, Bauer KA, Donati MB, Gould M, Samama MM, Weitz JI. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008; 133: 141S-59S.
4. van Boeckel CA, Petitou M. The unique antithrombin III binding domain of heparin: a lead to new synthetic antithrombotics. Angew Chem Int Ed Engl 1993; 32: 1671-90.
5. 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: 611-17.
6. Grassegger A, Fritsch P, Reider N. Delayed-type hypersensitivity and cross-reactivity to heparins and danaparoid: a prospective study. Dermatol Surg 2001; 27: 47-52.
7. Harenberg J, Schulze F, Sheikh H, Zimmermann R, Weber E. Allergische Hautreaktionen auf Heparin. Phlebol Proktol 1982; 11: 195-96 (in German).
8. Sanson BJ, Lensing AW, Prins MH, et al. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost 1999; 81: 668-72.
9. Ensom MH, Stephenson MD. Low-molecular-weight heparins in pregnancy. Pharmacotherapy 1999; 19: 1013-25.
10. Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 2005; 106: 401-07.
11. Deruelle P, Denervaud M, Hachulla E, et al. Use of low-molecular-weight heparin from the first trimester of pregnancy: a retrospective study of 111 consecutive pregnancies. Eur J Obstet Gynecol Reprod Biol 2006; 127: 73-78.
12. Brenner B, Hoffman R, Carp H, Dulitsky M, Younis J, and the LIVE-ENOX Investigators. Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss: the LIVE-ENOX study. J Thromb Haemost 2005; 3: 227-29.
13. Kaandorp SP, Goddijn M, van der Post JA, et al. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med 2010; 362: 1586-96.
14. Bank I, Libourel EJ, Middeldorp S, Van Der Meer J, Büller HR. High rate of skin complications due to low-molecular-weight heparins in pregnant women. J Thromb Haemost 2003; 1: 859-61.
15. Schindewolf M, Gobst C, Kroll H, et al. Pregnant women have an increased risk for heparin-induced allergic skin reactions-results of a prospective investigation. Vasa 2010; 39: 61-62 (abstract).
16. Schindewolf M, Schwaner S, Wolter M, et al. Incidence and causes of heparin-induced skin lesions. CMAJ 2009; 181: 477-81.
17. Schindewolf M, Scheuermann J, Kroll H, et al. Low allergenic potential with fondaparinux: results of a prospective investigation. Mayo Clin Proc 2010; 85: 913-19.
18. Jappe U. Allergy to heparins and anticoagulants with a similar pharmacological profile: an update. Blood Coagul Fibrinolysis 2006; 17: 605-13.
19. Schindewolf M, Kroll H, Ackermann H, et al. Heparin-induced non-necrotizing skin lesions: rarely associated with heparin-induced thrombocytopenia. J Thromb Haemost 2010; 8: 1486-91.
20. 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: 1857-61.
21. Bertrand PM, Perbet S, Sapin AF, et al. Heparin-induced skin necrosis: HIT-2 without thrombocytopenia. Intensive Care Med 2011; 37: 172-73.
22. Harenberg J, Huhle G, Wang L, Hoffmann U, Bayerl C, Kerowgan M. Association of heparin-induced skin lesions, intracutaneous tests, and heparin-induced IgG. Allergy 1999; 54: 473-77.
23. Warkentin TE. Heparin-induced skin lesions. Br J Haematol 1996; 92: 494-97.
24. Warkentin TE, Greinacher A, Koster A, Lincoff AM. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008; 133: 340S-80S.
25. Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006; 4: 759-65.
26. Warkentin TE, Linkins LA. Non-necrotizing heparin-induced skin lesions and the 4T's score. J Thromb Haemost 2010; 8: 1483-85.
27. Schindewolf M, Ludwig RJ, Wolter M, et al. Diagnosis of heparin-induced delayed-type hypersensitivity. Phlebologie 2010; 39: 226-31.
28. 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: 1265-69.
29. 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: 378-80.
30. Boehncke WH, Weber L, Gall H. Tolerance to intravenous administration of heparin and heparinoid in a patient with delayed-type hypersensitivity to heparins and heparinoids. Contact Dermat 1996; 35: 73-75.
31. Bircher AJ, Itin PH, Tsakiris DA, Surber C. Delayed hypersensitivity to one low-molecular-weight heparin with tolerance of other low-molecular-weight heparins. Br J Dermatol 1995; 132: 461-63.
32. Greinacher A, Pötzsch B, Amiral J, Dummel V, Eichner A, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen. Thromb Haemost 1994; 71: 247-51.
33. Warkentin TE. Clinical picture of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, eds. Heparin-induced thrombocytopenia, 3rd edn. New York: Marcel Dekker, 2004: 53-106.
34. Warkentin TE, Kelton JG. Delayed-onset heparin-induced thrombocytopenia and thrombosis. Ann Intern Med 2001; 135: 502-06.
35. Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996; 101: 502-07.
36. Warkentin TE, Greinacher A. Heparin-induced anaphylactic and anaphylactoid reactions: two distinct but overlapping syndromes. Expert Opin Drug Saf 2009; 8: 129-44.
37. Peitsch WK, Glorer E, Dempfle CE, Back W, Bayerl C, Goerdt S. Cutaneous necrosis mainly on the extremities. Hautarzt 2004; 55: 410-13 (in German).
38. Gröger M, Sarmay G, Fiebiger E, Wolff K, Petzelbauer P. Dermal microvascular endothelial cells express CD32 receptors in vivo and in vitro. J Immunol 1996; 156: 1549-56.
39. Greinacher A, Warkentin TE. Treatment of heparin-induced thrombocytopenia: an overview. In: Warkentin TE, Greinacher A, eds. Heparin-induced thrombocytopenia, 3rd edn. New York: Marcel Dekker, 2004: 335-370.
40. Dux S, Pitlik S, Perry G, Rosenfeld JB. Hypersensitivity reaction to chlorbutol-preserved heparin. Lancet 1981; 1: 149.
41. Hochart H, Jenkins PV, Smith OP, White B. 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.
42. Berkun Y, Haviv YS, Schwartz LB, Shalit M. Heparin-induced recurrent anaphylaxis. Clin Exp Allergy 2004; 34: 1916-18.
43. Bernstein IL. Anaphylaxis to heparin sodium; report of a case, with immunologic studies. J Am Med Assoc 1956; 161: 1379-81.
44. Harr T, Scherer K, Tsakiris DA, Bircher AJ. Immediate type hypersensitivity to low molecular weight heparins and tolerance of unfractioned heparin and fondaparinux. Allergy 2006; 61: 787-88.
45. Patriarca G, Rossi M, Schiavino D, et al. Rush desensitization in heparin hypersensitivity: a case report. Allergy 1994; 49: 292-94.
46. Caliskaner Z, Karaayvaz M, Oztürk S. Recurrent urticaria lesions in a heparin-allergic patient: most likely another form of "recall urticaria". J Investig Allergol Clin Immunol 2005; 15: 78-80.
47. Weber HO, Fischer J, Kneilling M, Caroli U, Rocken M, Biedermann T. Recall urticaria induced by skin tests with heparin. Br J Dermatol 2009; 161: 187-89.
48. 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: 2457-67.
49. Beltraminelli H, Itin P, Cerroni L. Intraepidermal bullous haemorrhage during anticoagulation with low-molecular-weight heparin: two cases. Br J Dermatol 2009; 161: 191-93.
50. Komericki P, Grims R, Kränke B, Aberer W. Acute generalized exanthematous pustulosis from dalteparin. J Am Acad Dermatol 2007; 57: 718-21.
51. Giorgini S, Martinelli C, Massi D, Lumini A, Mannucci M, Giglioli L. Iatrogenic calcinosis cutis following nadroparin injection. Int J Dermatol 2005; 44: 855-57.
52. Nadir Y, Mazor Y, Reuven B, Sarig G, Brenner B, Krivoy N. A fatal case of enoxaparin induced skin necrosis and thrombophilia. Eur J Haematol 2006; 77: 166-68.
53. Singh S, Verma M, Bahekar A, et al. Enoxaparin-induced skin necrosis: a fatal outcome. Am J Ther 2007; 14: 408-10.
54. Taylor AA. Successful use of heparinoids in a pregnancy complicated by allergy to heparin. BJOG 2001; 108: 1011-12.
55. Thuillier D, Chaby G, Dadban A, et al. [Low-molecular-weight heparin-induced bullous haemorrhagic dermatosis associated with cell-mediated hypersensitivity]. Ann Dermatol Venereol 2009; 136: 705-08 (in French).
56. Perrinaud A, Jacobi D, Machet MC, Grodet C, Gruel Y, Machet L. Bullous hemorrhagic dermatosis occurring at sites distant from subcutaneous injections of heparin: three cases. J Am Acad Dermatol 2006; 54 (suppl): S5-7.
57. Gallais V, Bredoux H, Rancourt MF, Dallot A, Salama J, Laroche L. [Toxic dermatitis caused by heparin]. Presse Med 1996; 25: 1040 (in French).
58. Leung A. Toxic epidermal necrolysis associated with maternal use of heparin. JAMA 1985; 253: 201.
59. Jackson AM, Pollock AV. Skin necrosis after heparin injection. BMJ (Clin Res Ed) 1981; 283: 1087-88.
60. Phillips JK, Majumdar G, Hunt BJ, Savidge GF. Heparin-induced skin reaction due to two different preparations of low molecular weight heparin (LMWH). Br J Haematol 1993; 84: 349-50.
61. Pfeiff B, Pullmann H. Baboon's syndrome due to heparin. Deutsch Dermatologe 1991; 39: 559-60 (in German).
62. Giustolisi R, Guglielmo P, di Raimondo F, Cacciola E, Stagno F. Hypereosinophilia and subcutaneous heparin. Lancet 1993; 342: 1371.
63. Bircher AJ, Itin PH, Büchner SA. Skin lesions, hypereosinophilia, and subcutaneous heparin. Lancet 1994; 343: 861.
64. Boccara O, Prost-Squarcioni C, Battistella M, Brousse N, Rongioletti F, Fraitag S. Calcinosis cutis: a rare reaction to subcutaneous injections of calcium-containing heparin in patients with renal failure. Am J Dermatopathol 2010; 32: 52-55.
65. Bonnecarrère L, Templier I, Carron PL, et al. [Two cases of iatrogenic cutis and subcutis calcinosis after calcium-containing heparin injection]. J Mal Vasc 2009; 34: 366-71 (in French).
66. Eich D, Scharffetter-Kochanek K, Weihrauch J, Krieg T, Hunzelmann N. Calcinosis of the cutis and subcutis: an unusual nonimmunologic adverse reaction to subcutaneous injections of low-molecular-weight calcium-containing heparins. J Am Acad Dermatol 2004; 50: 210-14.
67. Campanelli A, Kaya G, Masouyé I, Borradori L. Calcifying panniculitis following subcutaneous injections of nadroparin-calcium in a patient with osteomalacia. Br J Dermatol 2005; 153: 657-60.
68. van Haren FM, Ruiter DJ, Hilbrands LB. Nadroparin-induced calcinosis cutis in renal transplant recipients. Nephron 2001; 87: 279-82.
69. Grims RH, Weger W, Reiter H, Arbab E, Kränke B, Aberer W. Delayed-type hypersensitivity to low molecular weight heparins and heparinoids: cross-reactivity does not depend on molecular weight. Br J Dermatol 2007; 157: 514-17.
70. Greinacher A, Farner B, Kroll H, Kohlmann T, Warkentin TE, Eichler P. Clinical features of heparin-induced thrombocytopenia including risk factors for thrombosis. A retrospective analysis of 408 patients. Thromb Haemost 2005; 94: 132-35.
71. 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: 2937-41.
72. Posadas SJ, Pichler WJ. Delayed drug hypersensitivity reactions-new concepts. Clin Exp Allergy 2007; 37: 989-99.
73. Gaigl Z, Pfeuffer P, Raith P, Bröcker EB, Trautmann A. Tolerance to intravenous heparin in patients with delayed-type hypersensitivity to heparins: a prospective study. Br J Haematol 2005; 128: 389-92.
74. Bircher AJ, Harr T, Hohenstein L, Tsakiris DA. Hypersensitivity reactions to anticoagulant drugs: diagnosis and management options. Allergy 2006; 61: 1432-40.
75. Koch P, Münssinger T, Rupp-John C, Uhl K. Delayed-type hypersensitivity skin reactions caused by subcutaneous unfractionated and low-molecular-weight heparins: tolerance of a new recombinant hirudin. J Am Acad Dermatol 2000; 42: 612-19.
76. Ludwig RJ, Beier C, Lindhoff-Last E, Kaufmann R, Boehncke WH. Tolerance of fondaparinux in a patient allergic to heparins and other glycosaminoglycans. Contact Dermat 2003; 49: 158-59.
77. Lopez S, Torres MJ, Rodríguez-Pena R, et al. Lymphocyte proliferation response in patients with delayed hypersensitivity reactions to heparins. Br J Dermatol 2009; 160: 259-65.
78. Garcia-Ortega P, Asencio J. Dabigatran offers the simplest solution for thromboprophylaxis after orthopaedic surgery in patients allergic to low-molecular-weight heparins. Br J Haematol 2010; 151: 84-85.
79. Trautmann A, Bröcker EB, Klein CE. Intravenous challenge with heparins in patients with delayed-type skin reactions after subcutaneous administration of the drug. Contact Dermat 1998; 39: 43-44.
80. Schiffner R, Glässl A, Landthaler M, Stolz W. Tolerance of desirudin in a patient with generalized eczema after intravenous challenge with heparin and a delayed-type skin reaction to high and low molecular weight heparins and heparinoids. Contact Dermat 2000; 42: 49.
81. Ojukwu C, Jenkinson SD, Obeid D. Deep vein thrombosis in pregnancy and heparin hypersensitivity. Br J Obstet Gynaecol 1996; 103: 934-36.
82. Liew G, Campbell C, Thursby P. Delayed-type hypersensitivity to subcutaneous heparin with tolerance of i.v. administration. Aust N Z J Surg 2004; 74: 1020-21.
83. Schindewolf M, Magnani HN, Lindhoff-Last E. [Danaparoid in pregnancy in cases of heparin intolerance-use in 59 cases]. Hamostaseologie 2007; 27: 89-97 (in German).
84. Koch P, Reinhold S, Busch C. Delayed allergic skin reactions to subcutaneous heparins. Tolerance of 2 recombinant hirudins. Contact Dermat 2000; 42: 278-79.
85. Smith KJ, Rosario-Collazo J, Skelton H. Delayed cutaneous hypersensitivity reactions to hirudin. Arch Pathol Lab Med 2001; 125: 1585-87.
86. Koch P, Bahmer FA, Schäfer H. Tolerance of intravenous low-molecular-weight heparin after eczematous reaction to subcutaneous heparin. Contact Dermat 1991; 25: 205-06.
87. Dave S, Park M.A. Successful heparin desensitization: a case report and review of the literature. J Card Surg 2008; 23: 394-97.
88. al-Eryani AY, al-Momen AK, Fayed DF, Allam AK. Successful heparin desensitization after heparin-induced anaphylactic shock. Thromb Res 1995; 79: 523-26.
89. Parekh K, Burkhart HM, Hatab A, Ross A, Muller BA. Heparin allergy: successful desensitization for cardiopulmonary bypass. J Thorac Cardiovasc Surg 2005; 130: 1455-56.
90. Verdonkschot AE, Vasmel WL, Middeldorp S, van der Schoot JT. Skin reactions due to low molecular weight heparin in pregnancy: a strategic dilemma. Arch Gynecol Obstet 2005; 271: 163-65.
91. Sanders MN, Bernhisel-Broadbent J, Staker LV. Delayed hypersensitivity reaction to heparin in a pregnant woman. Int J Dermatol 1995; 34: 443-44.
92. Aberer W, Bircher A, Romano A, et al, and the European Network for Drug Allergy (ENDA), and the EAACI interest group on drug hypersensitivity. Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations. Allergy 2003; 58: 854-63.
93. Bates SM, Greer IA, Pabinger I, Sofaer S, Hirsh J. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008; 133: 844S-86S.
94. Gerhardt A, Zotz RB, Stockschlaeder M, Scharf RE. Fondaparinux is an effective alternative anticoagulant in pregnant women with high risk of venous thromboembolism and intolerance to low-molecular-weight heparins and heparinoids. Thromb Haemost 2007; 97: 496-97.
95. Lagrange F, Vergnes C, Brun JL, et al. Absence of placental transfer of pentasaccharide (Fondaparinux, Arixtra) in the dually perfused human cotyledon in vitro. Thromb Haemost 2002; 87: 831-35.
96. Dempfle CE. Minor transplacental passage of fondaparinux in vivo. N Engl J Med 2004; 350: 1914-15.
97. Handschin AE, Trentz OA, Hoerstrup SP, Kock HJ, Wanner GA, Trentz O. Effect of low molecular weight heparin (dalteparin) and fondaparinux (Arixtra) on human osteoblasts in vitro. Br J Surg 2005; 92: 177-83.
98. Akl EA, Gunukula S, Barba M, et al. Parenteral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation. Cochrane Database Syst Rev 2011; CD006652.
99. Ludwig RJ, Alban S, Bistrian R, 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: 535-40.
100. Erpenbeck L, Schön MP. Deadly allies: the fatal interplay between platelets and metastasizing cancer cells. Blood 2010; 115: 3427-36.
101. Ludwig RJ. Therapeutic use of heparin beyond anticoagulation. Curr Drug Discov Technol 2009; 6: 281-89.