Coumarin-induced skin necrosis

LLOYD W. BROOKS, JR, DO FRANCIS X. BLAIS, DO

Coumarin skin necrosis is a tin time. The patients initial course was uncom- rare and usually unpredictable compli- plicated. On the seventh hospital day, heparin ther- cation of coumarin therapy, occasionally apy was discontinued; 10 mg of sodium warfarin leading to death. Onset is usually between was given orally, followed thereafter with 2.5 mg the third and sixth day of coumarin daily, maintaining the prothrombin time at 27.8 therapy. The patient most commonly com- seconds (control, 12.5 seconds). On the ninth day plains of pain in a region of abundant of hospitalization, the patient was discharged on subcutaneous fat, with progression to a daily regimen of warfarin (2.5 mg orally). erythema, petechiae, and gangrenous ne- Two days after discharge, the patient was read- mitted when nursing home personnel noticed a crosis. Thrombosis of the dermal and the bright erythematous spot on the lateral aspect of subcutaneous veins is demonstrated pa- the patients right hip early in the morning, which thologically. We describe a case and re- enlarged, turned purple, and began to spread down view the pathogenesis, treatment, and pre- the leg. A second area of erythema was noticed on vention of this lesion. the patients left shoulder. The patient denied hav- (Key words: Coumarin therapy, skin ing suffered any trauma. Prothrombin time on ad- necrosis, anticoagulation therapy) mission was 22.8 seconds (control, 11.2 seconds; nor- mal, < 14 seconds), partial thrompoplastin time Coumarin skin necrosis is a rare and usu- was 30 seconds (normal, < 40 seconds), and throm- bocytopenia was now present (platelet count, 50 ally unpredictable complication of coumarin x 109/L; normal, 150 to 400 x 10 9/L). Findings congener anticoagulant therapy (Table 1). Occa- were consistent with coumarin-induced skin ne- sionally, this complication leads to death. The crosis. more common complications of coumarin ther- Warfarin therapy was stopped and heparin ther- apy, such as subcutaneous hemorrhage, intra- apy was initiated after a bone marrow aspirate was muscular hematoma, visceral intramural bleed- obtained from the posterior iliac crest, and a bi- ing, and cutaneous reactions are directly re- opsy specimen was obtained from the margin of lated to anticoagulation, while coumarin-in- the lesion on the thigh. Results of a bone marrow duced skin necrosis has well-defined histopa- and peripheral smear were normal, and the throm- thologic changes consistent with thrombosis bocytopenia was considered consumptive. Histolo- and infarction (Table 2). gic study of the lesional biopsy specimen showed a scattering of mononuclear inflammatory cells and Report of a case extravasation of erythrocytes in the papillary der- mis. A large number of vessels within the subcutis An 81-year-old woman with chronic dementia was showed evidence of thrombosis, with focal areas of admitted to the hospital from a nursing home, with hemorrhagic fat necrosis. deep venous thrombosis of the left thigh that was The patient continued to deteriorate and died confirmed by venogram. Constant infusion of hepa- of cardiac arrest on the ninth hospital day. No rin was instituted, and anticoagulation was main- postmortem examination was obtained. tained at two times the control partial thromboplas- Discussion At the time this article was written, Dr Brooks was a cardiology fellow, Riverside Hospital, Trenton, Mich; and Coumarin-congener-associated skin necrosis Dr Blais is an associate professor, Medicine Department, was first reported by Flood and coworkers3 in Texas College of Osteopathic Medicine, Fort Worth. Dr 1943 as thrombophlebitis migrans disseminata Brooks is currently in private practice of cardiology, Fort Worth. with breast involvement. Verhagen 4 more ac- Reprint requests to Lloyd W. Brooks, Jr, DO, PO Box curately described the entity in 1954. In a se- 470097, Fort Worth, TX 76147-0097. ries of 13 patients with diagnoses including

Case report • Brooks and Blais JAOA • Vol 91 • No 6 • June 1991 • 601 Table 1 Coumarin Congeners Implicated in Production of Hemorrhagic Skin Lesions as a Complication of Anticoagulant Therapyl

No. of reported Agent cases

Bishydroxycoumarin (Dicoumarol) 27

Phenprocoumon (Marcumar, foreign trade name; Liquamar, United States) 20 Phenindoione (Danilone, Hedulin) 3 Acenocoumarol (Sintrom) 8

Ethyl biscoumacetate (Tromexan ethyl acetate, Dicoumacyl [available outside United States]) 7

3,3-Ethyl-bis-(4-oxycumarin) (Pertromben and Thromboton [available outside United States]) 1

Sodium warfarin (Coumadin sodium) 3 fractures, postpartum state, thyroidectomy, motic discoloration surrounded by an erythe- and thrombosis, he concluded that "any dis- matous halo. Bullae may occur that contain ease, when complicated by a thrombosis and sterile serosanguineous fluid, and are often fol- treated with dicumarol . . . can lead to the dis- lowed by hemorrhagic infarcts and gangrenous cussed haemorrhagic complications." Kipen5 necrosis that involve deeper tissues, produc- was the first to prop erly ascribe the gangre- ing sloughing that may require acute surgical nous changes to anticoagulant therapy. Since debridement, skin grafting, or amputation. Usu- Kipens description in 1961, approximately 200 ally, no extension of the lesion occurs.1,8,9 cases have been reported in the literature. Numerous cases of full recovery without se- Skin necrosis occurs in approximately 0.1% quelae have been reported. 6 Clinical differen- of patients receiving anticoagulant therapy tiation between subcutaneous hemorrhage and with a coumarin derivative. 6 Most patients skin necrosis is paramount, because the treat- (90%) are middle-aged, obese women 1 who are ment and prognosis are different. Nudelman being treated for thrombophlebitis of the lower and Kempson9 have summarized the differ- extremities, pulmonary embolus, or cerebrovas- ences (Table 3). cular or coronary thrombosis. The onset and Histologically, the lesions demonstrate oc- course of skin necrosis occur in a consistent clusion of dermal and subcutaneous veins, pattern.? Onset is between the third and sixth with fibrin thrombi and, occasionally, with neu- day of coumarin therapy, with the patient com- trophilic vasculitis 10; arteries appear to be plaining of pain in a region of abundant subcu- spared while thrombosis is the inciting factor. taneous fat. Sites of involvement are most com- Hypersensitivity vasculitis is unlikely because monly the buttocks, breasts, thighs, anterior the lesion appears too late to be an immediate- aspect of the calves, and dorsum of the feet. type reaction and too soon to be an allergic- The patch is typically erythematous, with mediated reaction. 4 Skin tests for allergic vas- poor demarcation and often edema. Petechiae culitis have been negative,8 as have histologic develop, followed within a few hours by ecchy- studies."

602 • JAOA • Vol 91 • No 6 • June 1991 Case report • Brooks and Blais Table 2 Some Uncommon Adverse Reactions to Coumarin Drugs2

Hemorrhagic reactions Other reactions

Central nervous system hemorrhage Urticaria Bleeding from eardrum Extensive dermatitis Hemarthrosis "Purple toes" Carpal tunnel syndrome Drug interactions Intramuscular hematoma Intestinal necrosis Hemopericardium Alopecia Hemorrhagic pancreatitis Orange-red staining of hands and urine Hemorrhage from surreptitious self-administration Intestinal obstruction Adrenal hemorrhage Maculopapular, purpuric, or vesicular skin lesions Hemorrhage into pituitary adenoma Retroperitoneal and intramural intestinal bleeding

Table 3 Comparison of Hemorrhage and Necrosis in Patients Receiving Coumarin Therapyl

Hemorrhage Necrosis

Affects men and women equally Female predominance Onset unrelated to initiation of therapy Onset 3 to 6 days after initiation of therapy Corrected with administration of vitamin K Progresses despite administration of vitamin K Continuance of coumarin worsens complication Continuance of coumarin has no effect on degree of Heparin worsens complication complication Necrosis absent Heparin may be beneficial Surgery not indicated Necrosis present Surgery often necessary

In their pathogenic explanation, based on extensive necrosis and sloughing of the sub- serial biopsy specimens, Nalbandian and co- cutaneous adipose tissue. workers1 proposed two stages to the disorder. The coumarin congeners alter the hepatic The first stage occurs at the junction of the synthesis of coagulation factors II, VII, IX, and capillary and precapillary arteriole in the X by interference with vitamin K utilization dermovascular loop. The clinical changes can in the carboxylation of the glutamic acid resi- be correlated with this localization, such as the dues of the precursors of these coagulation fac- initial erythematous flush with capillary dila- tors, resulting in dysfunctional factors. Be- tion in the loop, followed by petechial forma- cause coumarin derivatives alter only the pro- tion when the capillary walls rupture. Ecchy- duction of the vitamin K–dependent factors, moses represent coalescence of hemorrhage not preformed factors or their catabolism, de- from the petechiae secondary to the previously pletion of the preformed factors must occur be- administered anticoagulant. fore full anticoagulation occurs. The second stage—hemorrhagic infarct or The concentration of functional factor VII gangrenous necrosis—correlates with stasis (plasma half-life, 5 to 6 hours) first decreases, and subsequent thrombosis in the venules im- then factor IX (half-life, 20 to 24 hours), X (half- mediately distal to the dermovascular loop, life, 40 hours), and II (half-life, 60 hours). An- where thrombotic occlusion of the larger veins tithrombogenic effects occur only after func- of the dermis and subcutaneous tissue causes tional concentrations of factors IX and X are

Case report • Brooks and Blais JAOA • Vol 91 • No 6 • June 1991 • 603 sufficiently diminished, usually in 2 to 7 will not prevent the occurrence of the necro- days.12 sis. Recent biochemical studies have defined a Zauber and Stark19 report that they pre- correlation between protein C deficiency and vented skin necrosis in a patient who had pre- coumarin-induced skin necrosis. Protein C is viously had coumarin necrosis and who re- a vitamin K–dependent protein that, along quired reinitiation of coumarin anticoagula- with protein S and factors II, VII, IX, and X, tion by the infusion of fresh frozen plasma is a -y-carboxyglutamic acid protein.° In con- (which is rich in protein C) along with hepa- trast with the vitamin K–dependent coagula- rin for 3 to 5 days to maintain protein C levels tion factors, protein C, with the aid of protein until all vitamin K–dependent factors were de- S, induces a fibrinolytic state, with a decrease pleted. Continuation of coumarin therapy dur- in whole blood clot lysis time but without sys- ing the episode did not appear to hamper re- temic plasminogen activation." Activated pro- covery or to cause further morbidity. Recur- tein C (protein C a) selectively inactivates ac- rence of skin necrosis on rechallenge, however, tive cofactors Va and Villa, while inhibiting appears to be the exception rather than the platelet coagulant activity by inactivation of rule. platelet factor X and Va.8 Absence or deficiency of proteins C and S Summary is strongly associated with congenital throm- Coumarin-congener necrosis may be precipi- botic disease15 and recurrent venous throm- tated by decreased levels of protein C, either boembolism.° The ability of protein C a to pro- inherently or iatrogenically, allowing forma- mote clot lysis by enzymatically binding to, tion or extension of clots by other remaining or degrading, an inhibitor of tissue plasmi- clotting factors. This clotting leads to infarc- nogen activator (TPA) may herald a synergis- tion and necrosis of the dermis and subcuta- tic use of protein C a in TPA-induced throm- neous adipose tissue. bolysis.17 Concomitant heparin therapy during initia- Functionally, when coumarin therapy is in- tion of low-dose coumarin therapy or therapy itiated, protein C levels drop rapidly, parallel- with coumarin congeners on day 1 of heparin ing factor VII levels; however, factor X and administration may prevent the occurrence of prothrombin are not depleted for 3 to 9 days. the associated skin necrosis. The necrosis may Therefore, with decreased protein C levels, the also be prevented if the early signs (erythema, risk of thrombosis or extension of existing clots pain, and edema) are recognized and heparin may increase until factor X and prothrombin therapy is initiated. Once infarction has oc- are sufficiently depleted to achieve anticoagu- curred, surgical management may be the only lation. Concurrent administration of heparin available treatment. and warfarin during initial anticoagulation may prevent this clotting process. At the on- set of coumarin therapy, however, large doses 1.Nalbandian RM, Litman RE, Farberow NL, et al: Petechiae, of coumarin should be avoided. Measurement ecchymoses, and necrosis of skin induced by coumarin conge- of proteins C and S functional levels prior to ners. JAMA 1965;192:107-112. initiation of coumarin therapy is ideal but im- 2. Renick AM: Anticoagulant-induced necrosis of skin and sub- cutaneous tissue: Report of two cases and review of the English practical and not cost-efficient.3 literature. South Med J 1976;69:775-778. Numerous regimens have been used to treat 3. Flood EP, Redish MH, Bociek S, et al: Thrombophlebitis mi- coumarin-induced skin necrosis, including lo- grans disseminata: Report of a case in which gangrene of breast occurred (observations on therapeutic use of Dicumarol). NY cal hypothermia, lumbar sympathectomy, vaso- State J Med 1943;43:1121-1124. dilators, vitamin K, and vitamin C, all with- 4. Verhagen H: Local hemorrhage and necrosis of skin and un- out success. Nalbandian and associates 18 re- derlying tissues during anticoagulant therapy with Dicumarol port a successful regimen of heparin and vita- or Dicumacyl. Acta Med Scand 1954;148:453. 5. Kipen CS: Gangrene of the breast: A complication of antico- min Kl , but only if initiated before the occur- agulant therapy. N Engl J Med 1961;265:638-640. rence of infarcts. They also state that heparin 6. Kahn S, Stern HD, Rhodes GA: Cutaneous and subcutane-

604 • JAOA • Vol 91 • No 6 • June 1991 Case report • Brooks and Blais ous necrosis as a complication of coumadin-congener therapy. al: Activated protein C decreases plasminogen activator-in- Plast Reconstr Surg 1971;48:160. hibitor activity in endothelial cell conditioned medium. Blood 7. Caldwell EH, Stewart S: Skin necrosis as a consequence of 1985;65:444-451. coumadin therapy. Plast Reconstr Surg 1983;72:231-232. 15.Griffin JH, Evatt B, Zimmerman TS, et al: Deficiency of 8. Esmon CT: Protein C: Biochemistry, physiology and clinical protein C in congenital thrombotic disease. J Clin Invest implications. Blood 1983;62:1155-1158. 1981;68:1370-1373. 9. Nudelman HL, Kempson RL: Necrosis of the breast: A rare 16.Comp PC, Esmon CT: Recurrent venous thromboembolism complication of anticoagulant therapy. Am J Surg 1966;111:731. in patients with a partial deficiency of protein S. N Engl J Med 10.Faraci PA, Dieterling RA, Stein AM, et al: Warfarin in- 1985;311:1525-1528. duced necrosis of skin. Surg Gynecol Obstet 1978;146:1121-1124. 17.Sakata Y, Curriden S, Lawrence D, et al: Activated protein 11. Koch-Weser J: Coumarin necrosis. Ann Intern Med C stimulates the fibrinolytic activity of cultured endothelial 1968;68:1365-1367. cells and decreases antiactivator activity. Proc Natl Acad Sci 12.Gilman AG, Rall TW, Nies AS, et al: Goodman and Gil- USA 1985;82:1121-1125. man's The Pharmacological Basis of Therapeutics, ed 8. New 18.Nalbandian RM, Beller AK, Kamp AK, et al: Coumarin York, Pergamon Press, Inc, 1990, pp 1319-1322. necrosis of skin treated successfully with heparin. Obstet Gyne- 13.Griffin JH, Mosher DF, Zimmerman TS, et al: Protein C, col 1971;38:395-399. an antithrombotic protein, is reduced in hospitalized patients 19.Zauber NP, Stark MW: Successful warfarin anticoagulation with intravascular coagulation. Blood 1982;60:261-264. despite protein C deficiency and a history of warfarin necrosis: 14.Van Hinsbergh VWM, Bertina RM, von Wijngaarden A, et Brief report. Ann Intern Med 1986;104:659-660.

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