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Abstract

The adverse cutaneous reactions associated with injectable anticoagulants such as unfractionated (standard) heparin, low molecular weight heparins (LMWHs) (enoxaparin, nadroparin [fraxiparin], certoparin, ardeparin, dalteparin, tinzaparin, bemiparin), direct thrombin inhibitors (argatroban), hirudins (desirudin, lepirudin, bivalirudin), synthetic pentasaccharides fondaparinux and idraparinux, heparinoids (danaparoid, pentosan polysulfate); and oral anticoagulants such as warfarin, acenocoumarol, fluindione, phenindione, direct thrombin inhibitor (dabigatran), and factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) are reviewed in this section.

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References

  1. Maldonado Cid P, de Alonso Celada RM, Noguera Morel L, Feito-Rodríguez M, Gómez-Fernández C, Herranz Pinto P. Cutaneous adverse events associated with heparin. Clin Exp Dermatol. 2012;37:707–11.

    Article  CAS  PubMed  Google Scholar 

  2. Frishman WH, Brosnan BD, Grossman M, Dasgupta D, Sun DK. Adverse dermatologic effects of cardiovascular drug therapy: part III. Cardiol Rev. 2002;10:337–48.

    Article  PubMed  Google Scholar 

  3. Patel GK, Knight AG. Generalised cutaneous necrosis: a complication of low-molecular-weight heparin. Int Wound J. 2005;2:267–70.

    Article  PubMed  Google Scholar 

  4. Toll A, Gallardo F, Abella ME, Fontcuberta J, Barranco C, Pujol RM. Low-molecular-weight heparin-induced skin necrosis: a potential association with pre-existent hypercoagulable states. Int J Dermatol. 2005;44:964–6.

    Article  PubMed  Google Scholar 

  5. Shelley WB, Sayen JJ. Heparin necrosis: an anticoagulant-induced cutaneous infarct. J Am Acad Dermatol. 1982;7:674–7.

    Article  CAS  PubMed  Google Scholar 

  6. Byrne JS, Abdul Razak AR, Patchett S, Murphy GM. Warfarin skin necrosis associated with protein S deficiency and a mutation in the methylenetetrahydrofolate reductase gene. Clin Exp Dermatol. 2004;29:35–6.

    Article  CAS  PubMed  Google Scholar 

  7. Valdivielso M, Longo I, Lecona M, Lázaro P. Cutaneous necrosis induced by acenocoumarol. J Eur Acad Dermatol Venereol. 2004;18:211–5.

    Article  CAS  PubMed  Google Scholar 

  8. Merklen-Djafri C, Mazurier I, Samama MM, Alhenc-Gelas M, Tortel MC, Cribier B, et al. Skin necrosis during long-term fluindione treatment revealing protein C deficiency. Ann Dermatol Venereol. 2012;139:199–203.

    Google Scholar 

  9. Beqqal K, Horellou MH, Philippe A, Alhene Gelas M, Flaujac C, Gorin I, et al. Skin necrosis due to fluindione treatment: a rare but serious complication. J Wound Care. 2014;23(2 Suppl):S16–9.

    Google Scholar 

  10. Warkentin TE, Whitlock RP, Teoh KH. Warfarin-associated multiple digital necrosis complicating heparin-induced thrombocytopenia and Raynaud’s phenomenon after aortic valve replacement for adenocarcinoma-associated thrombotic endocarditis. Am J Hematol. 2004;75:56–62.

    Article  PubMed  Google Scholar 

  11. Klein L, Galvez A, Klein O, Chediak J. Warfarin-induced limb gangrene in the setting of lung adenocarcinoma. Am J Hematol. 2004;76:176–9.

    Article  PubMed  Google Scholar 

  12. Jappe U, Reinhold D, Bonnekoh B. Arthus reaction to lepirudin, a new recombinant hirudin, and delayed-type hypersensitivity to several heparins and heparinoids, with tolerance to its intravenous administration. Contact Dermatitis. 2002;46:29–32.

    Article  CAS  PubMed  Google Scholar 

  13. Klein GF, Kofler H, Wolf H, Fritsch PO. Eczema-like, erythematous, infiltrated plaques: a common side effect of subcutaneous heparin therapy. J Am Acad Dermatol. 1989;21:703–7.

    Article  CAS  PubMed  Google Scholar 

  14. Gupta S, Mishra P, Palaian S, Prabhu S, Bista D, Prabhu M. Probable cutaneous allergic response to subcutaneous heparin - a case report. Acta Dermatovenerol Alp Panonica Adriat. 2006;15:98–101.

    CAS  Google Scholar 

  15. Méndez J, Sanchís ME, de la Fuente R, Stolle R, Vega JM, Martínez C, et al. Delayed-type hypersensitivity to subcutaneous enoxaparin. Allergy. 1998;53:999–1003.

    Google Scholar 

  16. Bircher AJ, Harr T, Hohenstein L, Tsakiris DA. Hypersensitivity reactions to anticoagulant drugs: diagnosis and management options. Allergy. 2006;61:1432–40.

    Article  CAS  PubMed  Google Scholar 

  17. Enrique E, Alijotas J, Cistero A, san Miguel MM, Bartra J, Tresserra F. Patch-test positivity in cutaneous reactions to enoxaparin. Contact Dermatitis. 2000;42:43.

    CAS  PubMed  Google Scholar 

  18. White JM, Munn SE, Seet JE, Adams N, Clement M. Eczema-like plaques secondary to enoxaparin. Contact Dermatitis. 2006;54:18–20.

    Article  CAS  PubMed  Google Scholar 

  19. 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 Dermatitis. 2000;42:49.

    CAS  PubMed  Google Scholar 

  20. Koch P, Munssinger 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;42:612–9.

    Article  CAS  PubMed  Google Scholar 

  21. 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.

    CAS  PubMed  Google Scholar 

  22. Koch P. Delayed-type hypersensitivity skin reactions due to heparins and heparinoids. Tolerance of recombinant hirudins and of the new synthetic anticoagulant fondaparinux. Contact Dermatitis. 2004;49:276–80.

    Article  Google Scholar 

  23. 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;51:67–72.

    Article  CAS  PubMed  Google Scholar 

  24. Jappe U, Gollnick H. Allergy to heparin, heparinoids, and recombinant hirudin. Diagnostic and therapeutic alternatives. Hautarzt. 1999;50:406–11.

    Article  CAS  PubMed  Google Scholar 

  25. Zollner TM, Gall H, Völpel H, Kaufmann R. Type IV allergy to natural hirudin confirmed by in vitro stimulation with recombinant hirudin. Contact Dermatitis. 1996;35:59–60.

    Article  CAS  PubMed  Google Scholar 

  26. Koutsojannis CM, Kounis NG. Lepirudin anaphylaxis and Kounis syndrome. Circulation. 2004;109:315.

    Article  Google Scholar 

  27. Greinacher A, Lubenow N, Eichler P. Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia. Circulation. 2003;108:2062–5.

    Article  CAS  PubMed  Google Scholar 

  28. Hohenstein E, Tsakiris D, Bircher AJ. Delayed-type hypersensitivity to the ultra-low-molecular-weight heparin fondaparinux. Contact Dermatitis. 2004;51:149–51.

    Article  CAS  PubMed  Google Scholar 

  29. Berkun Y, Haviv YS, Schwartz LB, Shalit M. Heparin-induced recurrent anaphylaxis. Clin Exp Allergy. 2004;34:1916–8.

    Article  CAS  PubMed  Google Scholar 

  30. Tejedor Alonso MA, Lopez Revuelta K, Garcia Bueno MJ, Casas Losada ML, Rosado Ingelmo A, Gruss Vergara E, et al. Thrombocytopenia and anaphylaxis secondary to heparin in a hemodialysis patient. Clin Nephrol. 2005;63:236–40.

    Article  CAS  PubMed  Google Scholar 

  31. 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;61:787–8.

    Article  CAS  PubMed  Google Scholar 

  32. Peña ZG, Suszko JW, Morrison LH. Hemorrhagic bullae in a 73-year-old man. Bullous hemorrhagic dermatosis related to enoxaparin use. JAMA Dermatol. 2013;149:871–2.

    Article  PubMed  Google Scholar 

  33. Dixit S, Fischer G, Lim A. Haemorrhagic purpura in an elderly man. BHD. Australas J Dermatol. 2013;54:228–9.

    Article  PubMed  Google Scholar 

  34. Villanueva CA, Nájera L, Espinosa P, Borbujo J. Bullous hemorrhagic dermatosis at distant sites: a report of 2 new cases due to enoxaparin injection and a review of the literature. Actas Dermosifiliogr. 2012;103:816–9.

    Article  CAS  PubMed  Google Scholar 

  35. Maldonado Cid P, de Moreno Alonso Celada R, Herranz Pinto P, Noguera Morel L, Feltes Ochoa R, Beato Merino MJ, et al. Bullous hemorrhagic dermatosis at sites distant from subcutaneous injections of heparin: a report of 5 cases. J Am Acad Dermatol. 2012;67:e220–2.

    Article  PubMed  Google Scholar 

  36. 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(2 Suppl):S5–7.

    Article  PubMed  Google Scholar 

  37. Beltraminelli H, Itin P, Cerroni L. Intraepidermal bullous haemorrhage during anticoagulation with low-molecular-weight heparin: two cases. Br J Dermatol. 2009;161:191–3.

    Article  CAS  PubMed  Google Scholar 

  38. Benatar J, Stewart RA. Cutaneous blood-filled vesicles on idraparinux. Lancet. 2008;372:1949.

    Article  CAS  PubMed  Google Scholar 

  39. Dyson SW, Lin C, Jaworsky C. Enoxaparin sodium-induced bullous pemphigoid-like eruption: a report of 2 cases. J Am Acad Dermatol. 2004;51:141–2.

    Article  PubMed  Google Scholar 

  40. Greiner D, Schofer H. Allergic drug exanthema to heparin. Cutaneous reactions to high molecular and fractionated heparin. Hautarzt. 1994;45:569–72.

    Article  CAS  PubMed  Google Scholar 

  41. Figarella I, Barbaud A, Lecompte T, De Maistre E, Reichert-Penetrat S, Schmutz JL. Cutaneous delayed hypersensitivity reactions to heparins and heparinoids. Ann Dermatol Venereol. 2001;128:25–30.

    CAS  PubMed  Google Scholar 

  42. To K, Reynolds C, Spinler SA. Rash associated with dabigatran etexilate. Pharmacotherapy. 2013;33:e23–7.

    Article  PubMed  Google Scholar 

  43. Winkle RA, Mead RH, Engel G, Kong MH, Patrawala RA. The use of dabigatran immediately after atrial fibrillation ablation. J Cardiovasc Electrophysiol. 2012;23:264–8.

    Article  PubMed  Google Scholar 

  44. de Bats B, Rivard L, Bellemin B, Duflo F, Allaouchiche B, Chassard D. Leukocytoclastic vasculitis after injection of low-molecular-weight heparin (letter). Presse Med. 2000;29:1604.

    PubMed  Google Scholar 

  45. Humeau-Commin A, Chatap G, Giraud K, Vincent JP. IgA vasculitis induced by low molecular weight heparin. Ann Dermatol Venereol. 2005;132:705–6.

    Article  CAS  PubMed  Google Scholar 

  46. Jiménez-Gonzalo FJ, Medina-Pérez M, Marín-Martín J. Acenocoumarol-induced leukocytoclastic vasculitis. Haematologica. 1999;84:462–3.

    PubMed  Google Scholar 

  47. Aouam K, Gassab A, Khorchani H, Bel Hadj Ali H, Amri M, Boughattas NA, Zili JE. Acenocoumarol and vasculitis: a case report. Pharmacoepidemiol Drug Saf. 2007;16:113–4.

    Article  PubMed  Google Scholar 

  48. Hsu CY, Chen WS, Sung SH. Warfarin-induced leukocytoclastic vasculitis: a case report and review of literature. Intern Med. 2012;51:601–6.

    Article  CAS  PubMed  Google Scholar 

  49. Wang YY, Po HL. Enoxaparin-induced alopecia in patients with cerebral venous thrombosis. J Clin Pharm Ther. 2006;31:513–7.

    Article  PubMed  Google Scholar 

  50. Sarris E, Tsele E, Bagiatoudi G, Salpigidis K, Stavrianaki D, Kaklamanis L, Siakotos M. Diffuse alopecia in a hemodialysis patient caused by a low-molecular-weight heparin, tinzaparin. Am J Kidney Dis. 2003;41:E15.

    Article  PubMed  Google Scholar 

  51. Apsner R, Horl WH, Sunder-Plassmann G. Dalteparin-induced alopecia in hemodialysis patients: reversal by regional citrate anticoagulation. Blood. 2001;97:2914–5.

    Article  CAS  PubMed  Google Scholar 

  52. Umlas J, Harken DE. Warfarin-induced alopecia. Cutis. 1988;42:63–4.

    CAS  PubMed  Google Scholar 

  53. Nagao T, Ibayashi S, Fujii K, Sugimori H, Sadoshima S, Fujishima M. Treatment of warfarin-induced hair loss with ubidecarenone. Lancet. 1995;346:1104–5.

    Article  CAS  PubMed  Google Scholar 

  54. 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;50:210–4.

    Article  PubMed  Google Scholar 

  55. 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;32:52–5.

    Article  PubMed  Google Scholar 

  56. 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.

    Article  CAS  PubMed  Google Scholar 

  57. Al-Niaimi F, Clark C. A case of unilateral purple toes due to warfarin. Clin Exp Dermatol. 2009;34:527–8.

    Article  CAS  PubMed  Google Scholar 

  58. Dulíček P, Bártová J, Beránek M, Malý J, Pecka M. The purple toe syndrome in female with Factor V Leiden mutation successfully treated with enoxaparin. Clin Appl Thromb Hemost. 2013;19:100–2.

    Article  PubMed  Google Scholar 

  59. Talmadge DB, Spyropoulos AC. Purple toes syndrome associated with warfarin therapy in a patient with antiphospholipid syndrome. Pharmacotherapy. 2003;23:674–7.

    Article  PubMed  Google Scholar 

  60. Piñero-Saavedra M, Castaño MP, Camarero MO, Milla SL. DRESS syndrome induced by acenocoumarol with tolerance to warfarin and dabigatran: a case report. Blood Coagul Fibrinolysis. 2013;24:576–8.

    Article  PubMed  Google Scholar 

  61. Sparsa A, Bédane C, Benazahary H, De Vencay P, Gauthier ML, Le Brun V, et al. Drug hypersensitive syndrome caused by fluindione. Ann Dermatol Venereol. 2001;128:1014–8.

    CAS  PubMed  Google Scholar 

  62. Frouin E, Roth B, Grange A, Grange F, Tortel MC, Guillaume JC. Hypersensitivity to fluindione (Previscan). Positive skin patch tests. Ann Dermatol Venereol. 2005;132:1000–2.

    Article  CAS  PubMed  Google Scholar 

  63. Ronceray S, Dinulescu M, Le Gall F, Polard E, Dupuy A, Adamski H. Enoxaparin-induced DRESS syndrome. Case Rep Dermatol. 2012;4:233–7.

    Article  PubMed Central  PubMed  Google Scholar 

  64. Katoh S, Terashima S, Nakahara Y, Yamada H, Tatsukawa H, Ida K, Nakagawa M. Hypersensitivity to heparin; a case report. Nihon Jinzo Gakkai Shi. 1993;35:411–4.

    CAS  PubMed  Google Scholar 

  65. Mohamed SD. Sensitivity reaction to phenindione with urticaria, hepatitis, and pancytopenia. Br Med J. 1965;2:1475–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Naisbitt DJ, Farrell J, Chamberlain PJ, Hopkins JE, Berry NG, Pirmohamed M, Park BK. Characterization of the T-cell response in a patient with phenindione hypersensitivity. J Pharmacol Exp Ther. 2005;313:1058–65.

    Article  CAS  PubMed  Google Scholar 

  67. Wright JS. Phenindione sensitivity with leukaemoid reaction and hepato-renal damage. Postgrad Med J. 1970;46:452–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Garnett ES, Pegrum GD, McDonald SJ. A fatal case of phenindione sensitivity. Br Med J. 1962;2:1032–3.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Komericki P, Grims R, Kränke B, Aberer W. Acute generalized exanthematous pustulosis from dalteparin. J Am Acad Dermatol. 2007;57:718–21.

    Article  PubMed  Google Scholar 

  70. Chtioui M, Cousin-Testard F, Zimmermann U, Amar A, Saiag P, Mahé E. Fluindione-induced acute generalised exanthematous pustulosis confirmed by patch testing. Ann Dermatol Venereol. 2008;135:295–8.

    Article  CAS  PubMed  Google Scholar 

  71. Thurot C, Reymond JL, Bourrain JL, Pinel N, Beani JC. Fluindione-induced acute exanthematous pustulosis with renal involvement. Ann Dermatol Venereol. 2003;130(12 Pt 1):1146–9.

    CAS  PubMed  Google Scholar 

  72. Smith KJ, Rosario-Collazo J, Skelton H. Delayed cutaneous hypersensitivity reactions to hirudin. Arch Pathol Lab Med. 2001;125:1585–7.

    CAS  PubMed  Google Scholar 

  73. Mohammed KN. Symmetric fixed eruption to heparin. Dermatology. 1995;190:91.

    Article  CAS  PubMed  Google Scholar 

  74. Shaheen S, Akhtar S. Fixed drug eruption due to heparin injection. JPMI. 2008;22:340–1.

    Google Scholar 

  75. Tsoumpris A, Tzimas T, Gkabrelas K, Akritidis N. Iron complex, dabigatran and toxic epidermal necrolysis syndrome: a case-report. J Clin Pharm Ther. 2013;38:177–8.

    Article  CAS  PubMed  Google Scholar 

  76. Pfeiff B, Pullmann H. Baboon-artiges Arzneiexanthem auf heparin. Dtsch Dermatologe. 1991;39:559–60.

    Google Scholar 

  77. Silverton NH. Skin pigmentation by phenindione. Br Med J. 1966;1:675.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Özkaya, E., Yazganoğlu, K.D. (2014). Anticoagulants. In: Adverse Cutaneous Drug Reactions to Cardiovascular Drugs. Springer, London. https://doi.org/10.1007/978-1-4471-6536-1_14

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