Warfarin and heparin-induced skin necrosis and the purple toe syndrome: Infrequent complications of anticoagulant treatment

Thrombosis and Haemostasis

Volumn 78, Issue 2, 1997, Pages 785-790

  Sallah, Sabah ^a   Thomas, Duncan P ^a   Roberts, Harold R ^a  

^a UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTICOAGULANT AGENT; BLOOD CLOTTING FACTOR 5; HEPARIN; PROTEIN C; PROTEIN S; WARFARIN;

ARTERY OCCLUSION; PRIORITY JOURNAL; PROTEIN C DEFICIENCY; PROTEIN S DEFICIENCY; REVIEW; SKIN NECROSIS;

EID: 0030859905     PISSN: 03406245     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-0038-1657628     Document Type: Review

References (96)

1. Verhagen H. Local haemorrhage and necrosis of the skin and underlying tissues during anticoagulant therapy with dicumorol or dicumocyl. Acta Med Scand 1954; 48: 433-62.
2. Nalbandian RM, Mader IJ, Barrett JL, Peavee JF, Rupp EC. Petechiae, ecchymoses and necrosis of skin induced by coumarin congeners. JAMA 1965; 192: 107-12.
3. van Amstel WJ, Boekhout-Mussert MJ, Loeliger EA. Successful prevention of skin necrosis by timely administration of vitamin K. Blut 1978; 36: 89-93.
4. Eby CS. Warfarin-induced skin necrosis. Hem One Clin N Am 1993; 7: 1291-301.
5. Koch-Weser J. Coumarin necrosis: Editorial notes. Ann Intern Med 1968; 68: 1365-7.
6. Horn JR, Danziger LH, Davis RJ. Warfarin-induced skin necrosis: Report of four cases. Am J Hosp Pharm 1981; 38: 1763-8.
7. Torngren S, Somell A. Warfarin skin necrosis of the breast. Acta Chir Scand 1982; 148: 471-2.
8. Kagan RJ. Glassford GH. Coumadin-induced breast necrosis. Am J Surg 1981; 47: 509-10.
9. Kuntz HD, Straub H, May B. Coumarin necrosis at the upper leg. Münch Med Wochenschr 1982; 124: 73-4.
10. Barkley C, Badalament RA, Metz EN, Nesbitt J, Drago JR. Coumarin necrosis of the penis. J Urol 1989; 141: 946-8.
11. Vaughan ED, Moore RA, Warren H, Moler DN, Gillenwater JY. Skin necrosis of the genital organs and warfarin therapy. JAMA 1969; 210: 2282-3.
12. Loeliger EA, Paul LC, van Brummelan P, Bieger R. Is coumarin-induced haemorrhagic necrosis of the skin the result of hypoproconvertinaemic bleeding in non-specifically inflamed skin patches. Neth Med J 1975; 18: 12-7.
13. Loeliger EA, Broekmans AW. Drugs affecting blood clotting fibrinolysis, and haemostasis, Westerholm B (ed): Meyler's Side Effects of Drugs, 10th edition. Elsevier Science Publishers, Amsterdam, The Netherlands, 1984; pp 59-60.
14. Sternberg ML, Pettyjohn FS. Warfarin sodium- induced skin necrosis. Ann Emerg Med 1995; 26: 94-7.
15. Cole MS, Minifee PK, Wolma FJ. Coumarin necrosis: A review of the literature. Surgery 1988; 103: 271-7.
16. Goldberg SL, Orthner CL, Yalisove BL, Elgart ML, Kessler CM. Skin necrosis following prolonged administration of coumarin in a patient with inherited protein C deficiency. Am J Hematol 1991; 38: 64-6.
17. Bahadir I, James EC, Fedde CW. Soft tissue necrosis and gangrene complicating treatment with the coumarin derivatives. Surg Gynecol Obstet 1977; 145: 497-500.
18. Berkompas DC. Coumarin skin necrosis in a patient with a free protein S deficiency. Indiana Med 1991; 81: 788-91.
19. Teepe RGC, Broekmans AW, Veronoer BJ, Nienhuis Am, Loeliger EA. Recurrent Protein C deficiency. Recurrent Coumarin-induced skin necrosis in a patient with an acquired functional protein C deficiency. Arch Dermatol 1986; 122: 1408-12.
20. Hofmann V, Frick PG. Repeated occurrence of skin necrosis twice following coumarin intake and subsequently during decrease of Vitamin K dependent coagulation factors associated with cholestasis. Thromb Haemost 1982; 48: 254-6.
21. Humphries JE, Gardner JH, Connely JE. Warfarin skin necrosis: Recurrence in the absence of Anticoagulant therapy. Am J Hematol 1991; 37: 197-200.
22. Renich Jr AM. Anticoagulant-induced necrosis of the skin and subcutaneous tissues. Report of two cases and review of English literature. South Med J 1976; 69: 755-8.
23. Faraci PA, Deterling RA, Stein AM, Rheinlander HF, Cleveland RJ. Warfarin induced necrosis of the skin. Surg Gynecol Obstet 1978; 146: 695-700.
24. Von Haam E, Seidensticker JF, Hatfield GE: Coumarin-related breast necrosis: A case report and review of the literature. Ohio State Med J 1974; 70: 38-42.
25. Martin BF, Phillips JD. Gangrene of the female breast with anticoagulant therapy: Report of two cases. Am J Clin Pathol 1970; 53: 622-6.
26. Ibels LS, Alfrey LC, Huffer WE, Craswell DW, Anderson JT, Weil R III. Arterial calcification and pathology in uremic patients undergoing dialysis. Am J Med 1979; 66: 790-6.
27. Gipstein RM, Coburn JW, Adams DA, Lee DB, Parsa KP, Sellers A, Sukiw N, Massry SG. Calciphylaxis in man: A syndrome of tissue necrosis and vascular calcification in 11 patients with chronic renal failure. Arch Intern Med 1976; 136: 1273-80.
28. Metha LR, Scott G, Sloand J, Francis CW. Skin necrosis associated with acquired protein C deficiency in patients with renal failure and calciphylaxis. Am J Med 1990; 88: 252-7.
29. Grob JJ, Legre R, Bertocchio P, Payan MJ, Andrac L, Bonerandi JJ. Calcifying panniculitis and kidney failure: Consideration on pathogenesis and treatment of calciphylaxis. Internat J Dermatol 1989; 28: 129-31.
30. Fine MJ, Kapoor W, Falanga V. Cholesterol crystal embolization: A review of 221 cases in the English literature. Angiology 1987; 38: 769-84.
31. Goldgraber MB, Kirsner JB. Gangrenous skin lesions associated with chronic ulcerative colitis: A case study. Gasteroenterology 1960; 39: 94-103.
32. Wattiaux MJ, Herve R, Robert A, Cabane J, Hausset B, Imbert JC. Coumarin-induced skin necrosis associated with acquired protein S deficiency and antiphospholipid antibody syndrome. Arthritis and Rheumatism 1994; 37: 1096-100.
33. Moreb J, Kitchens CS. Acquired functional protein S deficiency, central venous thrombosis, and coumarin necrosis in association with antiphospholipid antibody syndrome. Report of two cases. Am J Med 1989; 87: 207-10.
34. Grob JJ, Bonerandi JJ. Cutaneous manifestations associated with the presence of the lupus anticoagulant. J Am Acad Dermatol 1986; 15: 211-9.
35. Alegre VA, Winkelmann RK. Histopathologic and immunofluorescence study of skin lesions associated with circulating lupus anticoagulant. J Am Acad Dermatol 1988; 19: 117-24.
36. Esmon CT. Regulatory mechanisms in hemostasis: Natural anticoagulants, in Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE (eds): Hematology, basic principles and practice. 2nd Ed. New York, Churchill Livingstone, Inc 1995, pp. 1598-604.
37. Esmon CT. The role of protein C and thrombomodulin in the regulation of blood coagulation. J Biol Chem 1989; 264: 4743-6.
38. Miletich J, Sherman L, Broze G Jr. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Eng J Med 1987; 317: 991-6.
39. Vigano S, Mannucci PM, Solinas S, Botosso B, Mariani G. Decrease in protein C antigen and formation of an abnormal protein soon after starting oral anticoagulant therapy. Br J Haematol 1984; 57: 213-7.
40. Rose VL, Kwaan HC, Williamson K, Hoppensteadt D, Walenga J, Fareed J. Protein C antigen deficiency and warfarin necrosis. Am J Clin Pathol 1986; 86: 653-5.
41. McGehee WG, Klotz TA, Epstein DJ, Rapaport SI. Coumarin necrosis associated with hereditary protein C deficiency. Ann Intern Med 1984; 100: 59-60.
42. Weiss P, Soff GA, Halkin H, Seligsohn U. Decline of proteins C and S and factors II, VII, IX and X during the initiation of warfarin therapy. Thromb Res 1987; 45: 783-90.
43. Vigano-D'Angelo S, Comp PC, Esmon CT, D'Angelo A. Relationship between protein C antigen and anticoagulant activity during oral anticoagulation and in selected disease stages. J Clin Invest 1986; 77: 416-25.
44. Bauer KA, Rosenberg RD. The pathophysiology of the prothrombotic state in humans: Insights gained from studies using markers of hemostatic system activation. Blood 1987; 70: 343-50.
45. Bauer KA. Hypercoagulable states, in: Hematology: basic principles and practice. Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE (Eds). 2 Ed. New York: Churchill Livingstone, Inc. 1995 pp. 1786-92.
46. Broekmans AW, Bertina RM, Loeliger EA, Hofmann V, Klingemann HG. Protein C and the development of skin necrosis during anticoagulant therapy. Thromb Haemost 1983; 49: 251 (letter).
47. Broekmans AW, Teepe RG, van der Meer FJ, Briet E, Bertina RM. Protein C and coumarin induced skin necrosis. Thromb Res Suppl VI 1986; 137. (abstract)
48. Comp PC, Elrod JP, Karzenski S. Warfarin-induced skin necrosis. Semin Thromb Hemost 1990; 16: 293-8.
49. Rick ME. Protein C and protein S- vitamin K-dependent inhibitors of blood coagulation. JAMA 1990; 263: 701-3.
50. Dahlback B. Purification of human C4 b binding protein and formation of it's complex with vitamin K-dependent protein S. Biochem J 1983; 209: 852-6.
51. Anderson DR, Edwards PB, Walker I. Warfarin-induced skin necrosis in 2 patients with protein S deficiency: Successful reinstatement of warfarin therapy. Haemost 1992; 22: 124-8.
52. Grimaudo V, Gueissaz F, Hauert T, Sarraj A, Kiuithof E, Bachmann F. Necrosis of skin induced by coumarin in a patient deficient in protein S. Br Med J 1989; 298: 233-4.
53. Kant KS, Glueck H, Coats MC, Tonne VA, Brubaker K, Penn I. Protein S deficiency and skin necrosis associated with continous peritoneal dialysis. Am J Kid Dis 1992; 19: 264-71.
54. Dulaney JT, Hatch FE. Peritoneal dialysis and loss of proteins: A review. Kidney Internat 1984; 26: 253-62.
55. Dahlback B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: Prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004-8.
56. Bertina RM, Koeleman BPC, Koster T, Rosendal FR, Driven RJ, de Ronde H, van der Velden PA, Reitsma PH: Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
57. Dahlbäck B. New molecular insights into the genetics of thrombophilia. Resistance to activated protein C caused by Arg 506-Gln mutation in factor V as a pathogenic risk factor for venous thrombosis. Thromb Haemost 1995; 74: 139-48.
58. Kiehl R, Hellstern P, Wenzel E. Hereditary antithrombin III deficiency and atypical localization of coumarin necrosis. Thromb Res 1987; 45: 191-3.
59. Colman RW, Rao AK, Rubin RN. Warfarin skin necrosis in a 33-year-old woman. Am J Hematol 1993; 43: 300-3.
60. Nudelman HL, Kempson RL. Necrosis of the breast: A rare complication of anticoagulant therapy. Am J Surg 1966; 111: 728-33.
61. Weinberg AC, Lieskovsky G, McGehee WG, Skinner D. Warfarin necrosis of the skin and subcutaneous tissue of the male external genitalia. J Urol 1983; 130: 352-4.
62. Lewandowski K, Zawilska K. Protein C concentrate in the treatment of warfarin-induced skin necrosis in protein C deficiency. Thromb Haemost 1994; 71: 395.
63. Nalbandian RM, Beller FK, Kamp AK, Henry RL, Wolf PL. Coumarin necrosis of skin treated successfuly with heparin. Obstet Gynecol 1971; 38: 395-9.
64. Enzenauer RJ, Bernberg JL, Campbell J. Progressive warfarin anticoagulation in protein C deficiency: A therapeutic strategy. Am J Med 1990; 88: 697-8.
65. Zauber NP, Stark MW. Successful warfarin anticoagulation despite protein C deficiency and a history of warfarin necrosis. Ann Intern Med 1986; 104: 659-60.
66. Samama M, Horellou MH, Soria J, Conrad J, Nicoles G. Successful progressive anticoagulation in a severe protein C deficiency and previous skin necrosis at the initiation of oral anticoagulant treatment. Thromb Haemost 1984; 51: 132-3.
67. Jillella AP, Lutcher LC. Reinstituting warfarin in patients who develop warfarin skin necrosis. Am J Hematol 1996; 52: 117-9.
68. Chang J. White clot syndrome associated with heparin-induced thrombocytopenia: a review of 23 cases. Heart Lung 1987; 16: 403-7.
69. Kelly RA, Gelfand JA, Pincus SH. Cutaneous necrosis caused by systemically administered heparin. JAMA 1981; 246: 1582.
70. Mayou JC, Kelly SE, McGibbon DH. Local cutaneous sensitivity to subcutaneous heparin. Br J Dermatol 1987; 117: 664-5.
71. Rongioletti F, Pisani M, Ciaccio M, Rebora A. Skin necrosis due to intravenous heparin. Dermatologica 1989; 178: 47-50.
72. White PW, Sadd JR, Nensel RE. Thrombotic complications of heparin therapy, including 6 cases of heparin-induced skin necrosis. Ann Surg 1979; 190: 595-608.
73. Platell CF, Tan EG. Hypersensitivity reactions to heparin. Delayed onset thrombocytopenia and necrotizing skin lesions: Aust and NZ J Surg 1986; 56: 621-3.
74. Silver D, Kapsch DN, Tsoi EKM. Heparin-induced thrombocytopenia, thrombosis and hemorrhage. Ann Surg 1983; 198: 301-5.
75. Hartman AR, Hood RM, Anagnostopoulos CE. Phenomenon of heparin-induced thrombocytopenia associated with skin necrosis. J Vasc Surg 1988; 7:781-4.
76. Kapsch DN, Silver D. Heparin induced thrombocytopenia: Life and limb threatening complication of heparin therapy. Mo Med 1979; 76: 274-8.
77. Baird RA, Convery FR. Arterial thromboembolism in patients recieving systemic heparin therapy - a complication associated with heparin-induced thrombocytopenia. J Bone Joint Surg (Am) 1977; 59: 1061.
78. Pabinger I, Karnik R, Slany J, Niessner H. Coumarin induced acral skin necrosis associated with hereditary protein C. Blut 1986; 52: 365.
79. Levine LE, Bernestein JE, Soltani K, Medenica MM, Yung CW. Heparin-induced cutaneous necrosis unrelated to injection site: A sign of a potentially lethal complication. Arch Dermatol 1983; 119: 400-3.
80. Yates P, Jones S. Heparin skin necrosis: An important indicator of potentially fatal heparin sensitivity. Clin Exp Dermatol 1993; 18: 138-41.
81. Battey PM, Atef AS. Venous gangrene associated with heparin-induced thromboyctopenia. Surgery 1985; 97: 116-8.
82. Feder W, Auerbach R. "Purple toes": An uncommon sequela of oral coumarin drug therapy. Ann Intern Med 1961; 55: 911-7.
83. Soisson A, Kenneth M. An unusual cutaneous reaction to anticoagulant therapy. Military Med 1994; 159: 252-3.
84. Di Cato MA. "Purple toes" syndrome: An uncommon complication of oral anticoagulant therapy. Postgrad Med 1975; 58: 133-4.
85. Akle CA, Joiner CL. Purple toe syndrome. J R Soc Med 1981; 74: 219.
86. Kwaan HC, Peterson CE. Current concepts of warfarin therapy. Arch Intern Med 1986; 146: 581-4.
87. Weibert R, Lebsack C. "Purple toe syndrome". Postgrad Med 1982; 71: 81.
88. Karmody AM, Powens SR, Monaco VJ, Lather RP. "Blue toe" syndrome: an indication for limb salvage therapy. Surg 1976; 111: 1263-5.
89. Lopez P, Gonzalez B, Serrano C, Alvarez A, Ortega N, Cornejo B. A cholesterol embolism during heparin treatment. Revista Espanola de Cardiologia 1993; 46: 758-60.
90. Bols A, Nevelsteen A, Verhaeghe R. Atheromatous embolization precipitated by oral anticoagulants. International Angiology 1994; 13: 271-4.
91. Geraets D, Hoehns J, Burke T, Grover-McKay M. Thrombolytic-associated cholesterol emboli syndrome: Case report and literature review. Pharmacotherapy 1995; 15: 441-50.
92. Zautcke JL, Propp DA, Cook D. Atheromatous embolism: An unusual case of acute lower extremity ischemia. J Emerg Med 1995; 13: 639-41.
93. Nasser T, Mohler ER III, Wilensky R, Hathaway D. Peripheral vascular complications following coronary interventional procedures. Clin Cardiol 1995; 18: 609-14.
94. Badawi G, Jebara VA, el Rassi I, Tabet G, el Ayle N, Ashoush R, el Asmar B, Sarkis A. Spontaneous cholesterol embolization: A rarely reported entity. Texas Heart Institute J 1994; 21: 228-30.
95. O'Keeffe ST, Woods Bo, Breslin DJ, Tsapatsarins NP. Blue toe syndrome: causes and management. Arch Int Med 1992; 152: 2197-202.
96. Abdelmalek MF, Spittell PC. 79 year old women with blue toes. Mayo Clin Proc 1995; 70: 292-5.