Download PDF
Thromb Haemost 1997; 78(02): 785-790
DOI: 10.1055/s-0038-1657628
Review Article
Schattauer GmbH Stuttgart

Warfarin and Heparin-Induced Skin Necrosis and the Purple Toe Syndrome: Infrequent Complications of Anticoagulant Treatment

Sabah Sallah
The Center for Thrombosis and Hemostasis and the Division of Hematology/Oncology University of North Carolina at Chapel Hill Chapel Hill NC, USA
,
Duncan P Thomas
The Center for Thrombosis and Hemostasis and the Division of Hematology/Oncology University of North Carolina at Chapel Hill Chapel Hill NC, USA
,
Harold R Roberts
The Center for Thrombosis and Hemostasis and the Division of Hematology/Oncology University of North Carolina at Chapel Hill Chapel Hill NC, USA
› Author Affiliations
Further Information

Publication History

Received 10 1997

Accepted after revision 08 April 1997

Publication Date:
30 July 2018 (online)

Also available at
  PDF Download  Permissions and Reprints
 

  • References

  • 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: 433-462
    PubMedGoogle Scholar
  • 2 Nalbandian RM, Mader IJ, Barrett JL, Peavee JF, Rupp EC. Petechiae, ecchymoses and necrosis of skin induced by coumarin congeners. JAMA 1965; 192: 107-112
    CrossrefPubMedGoogle Scholar
  • 3 van AmstelWJ, Boekhout-Mussert MJ, Loeliger EA. Successful prevention of skin necrosis by timely administration of vitamin K. Blut 1978; 36: 189-193
    CrossrefPubMedGoogle Scholar
  • 4 Eby CS. Warfarin-induced skin necrosis. Hem One Clin N Am 1993; 07: 1291-1301
    PubMedGoogle Scholar
  • 5 Koch-Weser J. Coumarin necrosis: Editorial notes. Ann Intern Med 1968; 68: 1365-1367
    CrossrefPubMedGoogle Scholar
  • 6 Horn JR, Danziger LH, Davis RJ. Warfarin-induced skin necrosis: Report of four cases. Am J Hosp Pharm 1981; 38: 1763-1768
    PubMedGoogle Scholar
  • 7 Tomgren S, Somell A. Warfarin skin necrosis of the breast. Acta Chir Scand 1982; 148: 471-472
    PubMedGoogle Scholar
  • 8 Kagan RJ, Glassford GH. Coumadin-induced breast necrosis. Am J Surg 1981; 47: 509-510
    PubMedGoogle Scholar
  • 9 Kuntz HD, Straub H, May B. Coumarin necrosis at the upper leg. Munch Med Wochenschr 1982; 124: 73-74
    PubMedGoogle Scholar
  • 10 Barkley C, Badalament RA, Metz EN, Nesbitt J, Drago JR. Coumarin necrosis of the penis. J Urol 1989; 141: 946-948
    CrossrefPubMedGoogle Scholar
  • 11 Vaughan ED, Moore RA, Warren H, Moler DN, Gillenwater JY. Skin necrosis of the genital organs and warfarin therapy. JAMA 1969; 210: 2282-2283
    PubMedGoogle Scholar
  • 12 Loeliger EA, Paul LC, van BrummelanP, 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: 12-17
    PubMedGoogle Scholar
  • 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
    Google Scholar
  • 14 Sternberg ML, Pettyjohn FS. Warfarin sodium-induced skin necrosis. Ann Emerg Med 1995; 26: 94-97
    CrossrefPubMedGoogle Scholar
  • 15 Cole MS, Minifee PK, Wolma FJ. Coumarin necrosis: A review of the literature. Surgery 1988; 103: 271-277
    PubMedGoogle Scholar
  • 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: 64-66
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 18 Berkompas DC. Coumarin skin necrosis in a patient with a free protein S deficiency. Indiana Med 1991; 81: 788-791
    PubMedGoogle Scholar
  • 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: 1408-1412
    CrossrefPubMedGoogle Scholar
  • 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: 254-256
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Humphries JE, Gardner JH, Connely JE. Warfarin skin necrosis: Recurrence in the absence of Anticoagulant therapy. Am J Hematol 1991; 37: 197-200
    CrossrefPubMedGoogle Scholar
  • 22 Renich JrAM. Anticoagulant-induced necrosis of the skin and subcutaneous tissues. Report of two cases and review of English literature. South Med J 1976; 69: 755-758
    CrossrefPubMedGoogle Scholar
  • 23 Faraci PA, Deterling RA, Stein AM, Rheinlander HF, Cleveland RJ. Warfarin induced necrosis of the skin. Surg Gynecol Obstet 1978; 146: 695-700
    PubMedGoogle Scholar
  • 24 Von HaamE, Seidensticker JF, Hatfield GE. Coumarin-related breast necrosis: A case report and review of the literature. Ohio State Med J 1974; 70: 38-42
    PubMedGoogle Scholar
  • 25 Martin BF, Phillips JD. Gangrene of the female breast with anticoagulant therapy: Report of two cases. Am J Clin Pathol 1970; 53: 622-626
    CrossrefPubMedGoogle Scholar
  • 26 Ibels LS, Alfrey LC, Huffer WE, Craswell DW, Anderson JT, Weil III R. Arterial calcification and pathology in uremic patients undergoing dialysis. Am J Med 1979; 66: 790-796
    CrossrefPubMedGoogle Scholar
  • 27 Gipstein RM, Cobum 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: 1273-1280
    CrossrefPubMedGoogle Scholar
  • 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: 252-257
    CrossrefPubMedGoogle Scholar
  • 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. Intemat J Dermatol 1989; 28: 129-131
    PubMedGoogle Scholar
  • 30 Fine MJ, Kapoor W, Falanga V. Cholesterol crystal embolization: A review of 221 cases in the English literature. Angiology 1987; 38: 769-784
    CrossrefPubMedGoogle Scholar
  • 31 Goldgraber MB, Kirsner JB. Gangrenous skin lesions associated with chronic ulcerative colitis: A case study. Gasteroenterology 1960; 39: 94-103
    PubMedGoogle Scholar
  • 32 Wattiaux MJ, Herve R, Robert A, Cabane J, Hausset B, Imbert JC. Coumar-in-induced skin necrosis associated with acquired protein S deficiency and antiphospholipid antibody syndrome. Arthritis and Rheumatism 1994; 37: 1096-1100
    CrossrefPubMedGoogle Scholar
  • 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: 207-210
    CrossrefPubMedGoogle Scholar
  • 34 Grob JJ, Bonerandi JJ. Cutaneous manifestations associated with the presence of the lupus anticoagulant. J Am Acad Dermatol 1986; 15: 211-219
    CrossrefPubMedGoogle Scholar
  • 35 Alegre VA, Winkelmann RK. Histopathologic and immunofluorescence study of skin lesions associated with circulating lupus anticoagulant. J Am Acad Dermatol 1988; 19: 117-124
    CrossrefPubMedGoogle Scholar
  • 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
    Google Scholar
  • 37 Esmon CT. The role of protein C and thrombomodulin in the regulation of blood coagulation. J Biol Chem 1989; 264: 4743-4746
    PubMedGoogle Scholar
  • 38 Miletich J, Sherman L, Broze Jr G. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Eng J Med 1987; 317: 991-996
    CrossrefPubMedGoogle Scholar
  • 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: 213-217
    CrossrefPubMedGoogle Scholar
  • 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: 653-655
    CrossrefPubMedGoogle Scholar
  • 41 McGehee WG, Klotz TA, Epstein DJ, Rapaport SI. Coumarin necrosis associated with hereditary protein C deficiency. Ann Intern Med 1984; 100: 59-60
    CrossrefPubMedGoogle Scholar
  • 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: 783-790
    CrossrefPubMedGoogle Scholar
  • 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: 416-425
    CrossrefPubMedGoogle Scholar
  • 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: 343-350
    PubMedGoogle Scholar
  • 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. 1786-1792
    Google Scholar
  • 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).
    Article in Thieme ConnectPubMedGoogle Scholar
  • 47 Broekmans AW, Teepe RG, van derMeer FJ, Briet E, Bertina RM. Protein C and coumarin induced skin necrosis. Thromb Res Suppl VI. 1986: 137 (abstract)
    PubMedGoogle Scholar
  • 48 Comp PC, Elrod JP, Karzenski S. Warfarin-induced skin necrosis. Semin Thromb Hemost 1990; 16: 293-298
    Article in Thieme ConnectPubMedGoogle Scholar
  • 49 Rick ME. Protein C and protein S-vitamin K-dependent inhibitors of blood coagulation. JAMA 1990; 263: 701-703
    CrossrefPubMedGoogle Scholar
  • 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: 852-856
    PubMedGoogle Scholar
  • 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: 124-128
    CrossrefPubMedGoogle Scholar
  • 52 Grimaudo V, Gueissaz F, Hauert T, Sarraj A, Kruithof E, Bachmann F. Necrosis of skin induced by coumarin in a patient deficient in protein S. Br Med J 1989; 298: 233-234
    CrossrefPubMedGoogle Scholar
  • 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: 264-271
    CrossrefPubMedGoogle Scholar
  • 54 Dulaney JT, Hatch FE. Peritoneal dialysis and loss of proteins: A review. Kidney Intemat 1984; 26: 253-262
    PubMedGoogle Scholar
  • 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: 1004-1008
    CrossrefPubMedGoogle Scholar
  • 56 Bertina RM, Koeleman BPC, Koster T, Rosendal FR, Driven RJ, de RondeH, van derVelden PA, Reitsma P. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67
    CrossrefPubMedGoogle Scholar
  • 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: 139-148
    Article in Thieme ConnectPubMedGoogle Scholar
  • 58 Kiehl R, Hellstem P, Wenzel E. Hereditary antithrombin III deficiency and atypical localization of coumarin necrosis. Thromb Res 1987; 45: 191-193
    CrossrefPubMedGoogle Scholar
  • 59 Colman RW, Rao AK, Rubin RN. Warfarin skin necrosis in a 33-year-old woman. Am J Hematol 1993; 43: 300-303
    CrossrefPubMedGoogle Scholar
  • 60 Nudelman HL, Kempson RL. Necrosis of the breast: A rare complication of anticoagulant therapy. Am J Surg 1966; 111: 728-733
    CrossrefPubMedGoogle Scholar
  • 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: 352-354
    CrossrefPubMedGoogle Scholar
  • 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 63 Nalbandian RM, Beller FK, Kamp AK, Henry RL, Wolf PL. Coumarin necrosis of skin treated successfuly with heparin. Obstet Gynecol 1971; 38: 395-399
    PubMedGoogle Scholar
  • 64 Enzenauer RJ, Bemberg JL, Campbell J. Progressive warfarin anticoagulation in protein C deficiency: A therapeutic strategy. Am J Med 1990; 88: 697-698
    CrossrefPubMedGoogle Scholar
  • 65 Zauber NP, Stark MW. Successful warfarin anticoagulation despite protein C deficiency and a history of warfarin necrosis. Ann Intern Med 1986; 104: 659-660
    CrossrefPubMedGoogle Scholar
  • 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: 132-133
    Article in Thieme ConnectPubMedGoogle Scholar
  • 67 Jillella AP, Lutcher LC. Reinstituting warfarin in patients who develop warfarin skin necrosis. Am J Hematol 1996; 52: 117-119
    CrossrefPubMedGoogle Scholar
  • 68 Chang J. White clot syndrome associated with heparin-induced thrombocytopenia: a review of 23 cases. Heart Lung 1987; 16: 403-407
    PubMedGoogle Scholar
  • 69 Kelly RA, Gelfand JA, Pincus SH. Cutaneous necrosis caused by systemically administered heparin. JAMA 1981; 246: 1582
    CrossrefPubMedGoogle Scholar
  • 70 Mayou JC, Kelly SE, McGibbon DH. Local cutaneous sensitivity to subcutaneous heparin. Br J Dermatol 1987; 117: 664-665
    CrossrefPubMedGoogle Scholar
  • 71 Rongioletti F, Pisani M, Ciaccio M, Rebora A. Skin necrosis due to intravenous heparin. Dermatologica 1989; 178: 47-50
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 73 Platell CF, Tan EG. Hypersensitivity reactions to heparin. Delayed onset thrombocytopenia and necrotizing skin lesions: Aust and NZ J Surg 1986; 56: 621-623
    PubMedGoogle Scholar
  • 74 Silver D, Kapsch DN, Tsoi EKM. Heparin-induced thrombocytopenia, thrombosis and hemorrhage. Ann Surg 1983; 198: 301-305
    CrossrefPubMedGoogle Scholar
  • 75 Hartman AR, Hood RM, Anagnostopoulos CE. Phenomenon of heparin-induced thrombocytopenia associated with skin necrosis. J Vase Surg 1988; 7: 781-784
    CrossrefPubMedGoogle Scholar
  • 76 Kapsch DN, Silver D. Heparin induced thrombocytopenia: Life and limb threatening complication of heparin therapy. Mo Med 1979; 76: 274-278
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 78 Pabinger I, Kamik R, Slany J, Niessner H. Coumarin induced acral skin necrosis associated with hereditary protein C. Blut 1986; 52: 365
    CrossrefPubMedGoogle Scholar
  • 79 Levine LE, Bemestein 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: 400-403
    CrossrefPubMedGoogle Scholar
  • 80 Yates P, Jones S. Heparin skin necrosis: An important indicator of potentially fatal heparin sensitivity. Clin Exp Dermatol 1993; 18: 138-141
    CrossrefPubMedGoogle Scholar
  • 81 Battey PM, Atef AS. Venous gangrene associated with heparin-induced thromboyctopenia. Surgery 1985; 97: 116-118
    PubMedGoogle Scholar
  • 82 Feder W, Auerbach R. “Purple toes”: An uncommon sequela of oral coumarin drug therapy. Ann Intern Med 1961; 55: 911-917
    CrossrefPubMedGoogle Scholar
  • 83 Soisson A, Kenneth M. An unusual cutaneous reaction to anticoagulant therapy. Military Med 1994; 159: 252-253
    PubMedGoogle Scholar
  • 84 Di CatoMA. “Purple toes” syndrome: An uncommon complication of oral anticoagulant therapy. Postgrad Med 1975; 58: 133-134
    PubMedGoogle Scholar
  • 85 Akle CA, Joiner CL. Purple toe syndrome. J R Soc Med 1981; 74: 219
    CrossrefPubMedGoogle Scholar
  • 86 Kwaan HC, Peterson CE. Current concepts of warfarin therapy. Arch Intern Med 1986; 146: 581-584
    CrossrefPubMedGoogle Scholar
  • 87 Weibert R, Lebsack C. “Purple toe syndrome”. Postgrad Med 1982; 71: 81
    PubMedGoogle Scholar
  • 88 Karmody AM, Powens SR, Monaco VJ, Lather RP. “Blue toe” syndrome: an indication for limb salvage therapy. Surg 1976; 111: 1263-1265
    PubMedGoogle Scholar
  • 89 Lopez P, Gonzalez B, Serrano C, Alvarez A, Ortega N, Cornejo B. A cholesterol embolism during heparin treatment. Revista Espanola de Cardi-ologia 1993; 46: 758-760
    PubMedGoogle Scholar
  • 90 Bols A, Nevelsteen A, Verhaeghe R. Atheromatous embolization precipitated by oral anticoagulants. International Angiology 1994; 13: 271-274
    PubMedGoogle Scholar
  • 91 Geraets D, Hoehns J, Burke T, Grover-McKay M. Thrombolytic-associated cholesterol emboli syndrome: Case report and literature review. Pharmacotherapy 1995; 15: 441-450
    PubMedGoogle Scholar
  • 92 Zautcke JL, Propp DA, Cook D. Atheromatous embolism: An unusual case of acute lower extremity ischemia. J Emerg Med 1995; 13: 639-641
    CrossrefPubMedGoogle Scholar
  • 93 Nasser T, Mohler III E, Wilensky R, Hathaway D. Peripheral vascular complications following coronary interventional procedures. Clin Cardiol 1995; 18: 609-614
    CrossrefPubMedGoogle Scholar
  • 94 Badawi G, Jebara VA, el RassiI, Tabet G, el AyleN, Ashoush R, el AsmarB, Sarkis A. Spontaneous cholesterol embolization: A rarely reported entity. Texas Heart Institute J 1994; 21: 228-230
    PubMedGoogle Scholar
  • 95 O’Keeffe ST, Woods Bo, Breslin DJ, Tsapatsarins NP. Blue toe syndrome: causes and management. Arch Int Med 1992; 152: 2197-202
    CrossrefPubMedGoogle Scholar
  • 96 Abdelmalek MF, Spittell PC. 79 year old women with blue toes. Mayo Clin Proc 1995; 70: 292-295
    CrossrefPubMedGoogle Scholar