Acral purpura: An unusual sign of coumarin necrosis

Adverse reactions Acral purpura: An unusual sign of coumarin . necrOSIS Mary Seabury Stone, M.D., and Ted Rosen, M.D. Houston, TX Coumarin necrosis, a rare complication of coumarin anticoagulation, typically presents with well-defined purpuric patches that progress to bullae formation and necrosis. The vast majority of those affected are women, and most commonly affected sites are the breasts, buttocks, thighs, and abdomen. We present a male patient who manifested a unique reticulated purpura that progressed to bullae formation on the toes of one foot in addition to more classic lesions on the thigh and calf. (J AM ACAD DERMATOL 14:797-802, 1986.)

Coumarin necrosis is a well-recognized, although rare, complication of coumarin anticoagulant therapy. Lesions appear between days 3 and 10 of coumarin loading and consist initially of well-defined purpuric patches that progress to bullae formation with underlying necrosis. We recently have seen a patient with typical warfarin sodium (Coumadin) necrosis associated with a reticulated purpura involving the toes and one foot. This lesion, although clinically atypical for coumarin necrosis, was classic both histopathologically and in its ultimate clinical evolution. CASE REPORT A 47-year-old black man was admitted to the Houston Veterans Administration Medical Center on June 21, 1985, complaining that for the preceding 3 days he had a tender, swollen left lower extremity. The patient's medical history was remarkable for widely metastatic adenocarcinoma of the lung diagnosed in March 1985, hypertension, and chronic schizophrenia. Therapy for his adenocarcinoma had consisted only of radiation to bony metastases. At the time of admission, the patient was on no medications. On physical examination, he From the Department of Dermatology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Reprint requests to: Dr. Ted Rosen, Department of Dermatology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.

was noted to be afebrile and mildly hyperpneic. The left calf was 2 em greater in diameter than the right calf and was tender to palpation. There were no purpuric, ecchymotic, or discolored areas on either the left leg or the left foot at this time. Complete blood count showed a hemoglobin of 8.3 gm, hematocrit of 24.6%, and white blood count of 11,700. Platelets were reported as adequate. Admission chemistries were within normal limits except for a calcium level of 10.4 mgl dl, alanine transaminase (AST; SGOT) of 61 mID, alkaline phosphatase of 321 mID, and lactate dehydrogenase (LDH) of 330 mIU. Venogram performed on admission revealed deep venous thrombosis of the left femoral vein. Heparin was administered intravenously in a 10,000-U loading dose, followed by an infusion of 50 Ulhr. On June 23, 1985, warfarin sodium loading was begun. The heparin was discontinued on the morning of June 27, 1985. That evening (day 4 of warfarin sodium therapy), the patient complained of pain in his left calf. Within 24 hours, a 1.5 x L5-cm dark purple patch, surrounded by ecchymosis, was present on the left inner aspect of the thigh and a lOX 4-cm dark purple, slightly indurated plaque with a peau d'orange texture and surrounding ecchymosis was present on the left calf (Fig. 1). All of the toes on the left foot were palpably cooler than those on the right and manifested a reticulated purple discoloration. Although the lesions of the leg were typical of coumarin necrosis, the toes suggested possible arterial occlusion, sepsis, cryoglobulinemia, cryofibrinogenemia, disseminated in;ravascular coagulation, or a livedo vasculitis. However, the

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Fig. 1. Purple indurated plaque on the left calf with a peau d'orange texture present on

day 1 of the eruption.

Fig. 2. Flaccid, necrotic bulla on the left calf on day 3. patient had strong dorsalis pedis pulses, was afebrile, and his prothrombin time and partial thromobplastin time remained in the therapeutic range with a normal platelet count. The diagnosis of coumarin necrosis was made and it was decided to continue warfarin sodium therapy. None of the lesions enlarged despite the continuation of warfarin sodium, and no new lesions appeared. By day 3 of the eruption, bullae formation was evident on the calf and thigh (Fig. 2) and the purpura on the toes was sharply demarcated, demonstrating sparing of most ofthe tips of the toes (Figs. 3 and 4). A biopsy specimen from a purpuric area on the great toe showed plugging of the superficial dermal capillaries with fibrin thrombi and extravasation of red blood cells with minimal inflammation (Fig. 5). By 7 days after the appearance of

the eruption, bullae had also formed over the toes and reepithelialization was evident at the base of the thigh and calf lesions. The patient expired because of respiratory failure on day 21 of hospitalization. Autopsy was not performed. DISCUSSION

Two chemical classes with similar pharmacologic mechanisms have been responsible for' 'coumarin necrosis." They are the coumarin (or warfarin) derivatives, of which warfarin sodium (Coumadin) and bishydroxycoumarin (Dicumarol) are the most commonly used, and the indanedione derivatives. Heparin, which has been reported to cause lesions clinically identical to those caused

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Fig. 3. Anterior view of the left foot with distal purple discoloration.

Fig. 4. Plantar surface of the left foot. with reticulated purpura of the toes. The tip of the great toe is spared.

by the coumarin derivatives, will be discussed later. The coumarin and indanedione derivatives act as antimetabolites of vitamin K. Thus, they cause decreased levels of vitamin K-dependent clotting factors: II, VII, IX, and X. Because these drugs act on synthesis of the clotting factors, their effect is delayed because existing levels of the clotting factors must fall before an anticoagulant effect is obtained. The effect of these drugs can be reversed by vitamin K infusion. The first reported case of coumarin necrosis (1943) is attributed to Flood and co-workers,' although they implicated thrombophlebitis for the necrosis of the breast in their patient. Verhagen2 in 1954 reported eight cases of the entity, which he attributed to the drug itself. This complication of the coumarin derivatives is rare, with only just over 150 cases having been reported in the English literature by 1976 despite widespread use of these drugs. 3 The typical presentation of coumarin necrosis is the sudden onset of pain followed by purpura, bullae formation, and necrosis. The onset is on day 3 to day 10 of coumarin loading. The vast majority of the patients, over 90%, are women, usually obese and middle-aged. The necrotic areas generally occur in areas with significant subcutaneous adipose tissue, such as the breasts, buttocks, abdomen, or thighs. The necrosis may extend deeply into the subcutaneous fat

or remain more superficial. Coumarin necrosis does not necessarily recur on subsequent courses of treatment. 4.5 The major differential consideration in the classical lesions of coumarin necrosis is that of hemorrhage caused by excessive anticoagulation. This can be readily eliminated as a possibility by coagulation studies. A biopsy specimen from an area of coumarin necrosis shows extensive occlusion of the dermal and subcutaneous capillaries with fibrin thrombi. There is no vasculitis and little inflammation. Reports of direct immunofluorescence have ranged from negative6 •7 to C3 deposition at the dermoepidermal junction. 8 In a case of coumarin necrosis associated with mononucleosis, deposition of IgM in the vessel walls and upper dermal IgG deposition were reported. 9 Necrosis of toes or fingers is very rare in coumarin necrosis. Reviewing the English literature, we were unable to find a report similar to the reticulated pattern of purpura seen on the toes in this patient. Had it not been for the more typical lesions on the leg, coumarin necrosis would have been less likely considered in our differential diagnosis. Acral reticulated purpura and necrosis suggest embolic phenomenon, sepsis with disseminated intravascular coagulation, vasculitis, or vascular compromise from cryoglobulins or cryofi-

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Fig. 5. The papillary dermis contains capillaries occluded by fibrin thrombi, many extravasated red blood cells, and very little inflammation: The arrow indicates an ocCluded dermal vessel. (Hematoxylin-eosin stain; X300.)-

brinogenemia. The evolution of the eruption on his toes was identical to that of his more classic lesions, although slower, and the histology was typical for coumarin necrosis. Suggested pathogenetic mechanisms for this disorder have included hemorrhage and a hypersensitivity phenomenon,s neither of which is supported by clinical or laboratory evidence. 3 The more widely accepted theory is that of a direct toxic effect of the drug on the vascular endothelium. 4 In 1979, lones-and Cunningham6 proposed a new mechanism for the cutaneous necrosis from these drugs. As mentioned previously, coumarin derivatives work by decreasing the levels of the vitamin K-dependent liver":derived clotting factors: II, VII, IX, and X. After institution of coumarin therapy, the level of these clotting factors decreases in accordance: with their half-lives. Since factor VII has the shortest half-life at 4 hours, it disappears first. Citing reports of factor VII defi-

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ciency and thromboembolic phenomena, Jones and Cunningham6 proposed intravascular thrombosis associated with transient isolated deficiency of factor VII as the mechanism of this eruption. Several recent reports of deficient protein C levels in patients with coumarin necrosis suggest that low levels of this substance may prove to be an important factor predisposing to coumarin necrosis. 10-12 Protein C is a potent anticoagulant that functions through inactivation of clotting factors Va and VIIIa, as well as platelet factor V. Deficiency of protein C is inherited as an autosomal trait. Individuals heterozygous for factor C deficiency have an increased incidence of thrombosis; while homozygous individuals may die in the neonatal period from massive venous thrombosis. II After institution of coumarin, protein C declines rapidly, paralleling the fall in factor VII. In patients with low levels of factor C prior to therapy, this further drop -may initiate thrombosis. Since coumarin necrosis is a discrete eruption, with the tendency to occur over fatty areas, local factors also must be involved in its pathogenesis. It is very interesting that all of the lesions in our patient were confined to his phlebitic leg, suggesting the possibility that the compromised vasculature in the leg increased its susceptibility to coumarin necrosis. Heparin has repeatedly been reported to cause lesions at the sites of subcutaneous injections which are identical in appearance and histology to those seen with coumarin necrosis. 13-16 There have been only a very few reports of lesions similar to coumarin necrosis occurring at distant sites during intravenous heparin administration. Kelly et ail? reported two· patients with necrotic skin lesions that developed during heparin infusion. In one patient the lesions were on the nose, dorsal aspect of the hand, and right lateral malleolus, all sites that would· be unusual for coumarin-induced necrosis. The second patient developed two necrotic bullae on the forearm. In neither case were fibrin thrombi, ~ypical of coumarin necrosis, found on biopsy examination. White et aIlS reported two patients with necrotic lesions that developed during heparin therapy; however, these patients were also receiving warfarin. Levine et all& reported a patient receiving intravenous as well as subcutaneous heparin during

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dialysis. This patient developed thrombocytopenia and hemorrhagic bullae on the lateral aspect of her thighs. Biopsy examination revealed a necrotic epidermis and necrotic, thrombosed dermal vessels, extravasated red blood cells, and minimal inflamf1'ation. Necrosis of vessel walls is not typical of coumarin necrosis. Although our patient received intravenous heparin until the day prior to the appearance of skin lesions, we believe that the clinical presentation and histology suggest warfarin sodium as the. etiology of his skin lesions. If heparin is capableof causing lesions clinically and histologically identical to coumarin necrosis at sites distant to administration, it must be an exceedingly rare occurrence. Other coumarin-induced cutaneous manifestations have been reported. Hemorrhagic complications are the most common; however, macular, papular, purpuric, or vesicular eruptions,19-21 urticaria,22 alopecia, 5 and the "purple toe syndrome"23 have been attributed to coumarin therapy. The "purple toe syndrome" consists of bilateral, tender, blue-purple discoloration of the feet, especially affecting the plantar surface and the lateral aspect· of the great and second toes. These "purple toes" present 3 to 8 weeks after coumarin initiation, blanch on pressure, and fade with elevation of the feet. Toes so affected do not progress to bullae formation and necrosis. Biopsy examination reveals no abnormalities. The etiology of this uncommon complication is unclear. Thus, while our patient had purple toes, he certainly did not have the "purple toe syndrome." The therapy of coumarin necrosis is primarily supportive. Lesions do not progress with continued coumarin therapy and neither vasodilators, vitamin K, nor steroids appear to change the course of the disease. 2.4 Nalbandian et aF4 reported beneficial results with heparin therapy, but other authors disagree as to its usefulness. 7 •25 Appropriate management of the damaged sites varies with the depth of the necrosis. In some instances skin grafting or amputation may be necessary. The coumarin derivatives are responsible for various types of cutaneous reactions, the most dramatic being coumarin necrosis. The typical presentation of coumarin necrosis is the development of one or several necrotic plaques over fatty areas

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in middle-aged women occurring 3 to 10 days after initiation of coumarin therapy. As our patient demonstrates, however, the spectrum of the disease includes a reticulated purpura of the distal extremities progressing to bulla formation. The case described represents a unique variant of the classic coumarin necrosis. Additional patients with coumarin necrosis might be expected to present solely with reticulated acral purpura. Therefore, coumarin necrosis should be considered in the differential diagnosis of purple toes in patients undergoing anticoagulation therapy with a coumarin derivative. REFERENCES 1. Flood EP, Redish MH, Bociek Sl, Shapiro S: Thrombophlebitis migrans disseminata: Report of a case in which gangrene of a breast occurred. NY State 1 Med 43:1121-1124, 1943. 2. Verhagen H: Local haemorrhage and necrosis of the skin and underlying tissues, during anti-coagulant therapy with Dicumarol or Dicumacyl. Acta Med Scand 148:453467, 1954. 3. Renick AM: Anticoagulant-induced necrosis of skin and subcutaneous tissues: Report of two cases and review of the English literature. South Med J 69:775-778, 1976. 4. Nalbandian RM, Mader Il, Barrett JL, et al: Petechiae, ecchymoses, and necrosis of skin induced by coumarin congeners. JAMA 192:107-112, 1965. 5. Baker H, Levene GM: Quarterly review: Drug reactions. V. Br 1 Dermatol 81:236-238,. 1969. 6. Jones RR, Cunningham 1: Warfarin skin necrosis: Role of factor VII. Br J Dermatoll00:561-565, 1979. 7. Schleicher SM, Fricker MP: Coumarin necrosis. Arch DermatoI116:444-445, 1980. 8. Hislop IG, Zilko PJ, Petersen M, Ahmed N: Dermal necrosis following coumarin: Is it immunologically induced? Aust NZ Med 10:51-53, 1980. 9. Franson TR, Rose HD, Spivey MR, et al: Late-onset, warfarin-caused necrosis occurring in a patient with infectious mononucleosis. Arch Dermatol 120:927-931, 1984. 10. Broekmans AW, Bertina RM, Loeliger EA, et al: Protein C and the development of skin necrosis during anticoagulant therapy. Thromb Haemost 49:251, 1983. (Letter to Editor.) 11. McGehee WG, Klotz TA, Epstein DJ, Rapaport SI: Coumarin necrosis associated with hereditary protein C deficiency. Ann Intern Med 100:59-60, 1984. 12. Kazmier FI: Thromboembolism, coumarin necrosis, and protein C. Mayo Clin Proc 60:673-674, 1985. 13. O'Toole RD: Heparin: Adverse reaction. Ann Intern Med 79:759, 1973. 14. Hall JC, McConahay D, Gibson D, et al: Heparin necrosis: An anticoagulation syndrome. lAMA 244:18311832, 1980. 15. White PW, Sadd JR, Nense! RE: Thrombotic compli-

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19. 20.

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cations of heparin therapy: Including six cases of heparininduced necrosis. Ann Surg 190:595-608, 1979. Shelley WB, Sayen JJ: Heparin necrosis: An anticoagulant-induced cutaneous infarct. 1 AM ACAD DERMATOL 7:674-677, 1982. Kelly RA, Gelfand lA, Pincus SH: Cutaneous necrosis caused by systemically administered heparin. lAMA 246:1582-1583, 1981. Levine LE, Bernstein lE, Soltani K, et al: Heparin-induced necrosis unrelated to injection sites: A sign of potentially lethal complications. Arch DermatoI119:400403, 1983. Schiff BL, Pawtucket RI, Kern AB: Cutaneous reactions to anticoagulants. Arch DermatoI98:136-137, 1968. Adams CW, Pass Bl: Extensive dermatitis due to warfarin sodium (Coumadin). Circulation 22:947-948, 1960.

21. Kwong P, Roberts P, Prescott SM, Tikoff G: Dermatitis induced by warfarin. JAMA 239:1884-1885, 1978. 22. Sheps ES, Gifford RW: Urticaria after administration of warfarin sodium. Am J CardioI3:118-120, 1959. 23. Feder W, Auerbach R: "Purple toes": An uncommon sequela of oral coumarin drug therapy. Ann Intern Med 55:911-917, 1961. 24. Nalbandian RM, Beller FK, Kamp AK, et a1: Coumarin necrosis of skin treated successfully with heparin. Obstet GynecoI38:395-399, 1971. . 25. Kahn S, Stern HD, Rhodes GA: Cutaneous and subcutaneous necrosis as a complication of coumarin-congener therapy. Plast Reconstr Surg 48:160-166, 1971.

ABSTRACTS Transdermal nitrate, penile erection, and spousal headache Talley JD, Crawley IS: Ann Intern Med 103:804, 1985 A male patient rubbed a previously used transdermal nitrate patch on his penis. He developed an erection and became sexually aroused within 5 minutes. Following sexual intercourse with his wife, she wondered why she had the worst headache she had ever had in her life. J. Graham Smith, Jr., M.D.

Computer searching of the medical literature Haynes RB, McKibbon KA, Walker CJ, et al: Ann Intern Med 103:812-816, 1985 The retrieval quantity and quality, user and on-line search time, and cost for randomly ordered standardized searches on common clinical problems were compared on 14 access routes to the MEDLINE data base ofjournal literature. On-line time fOf the same searches varied from 5.15 to 18.72 minutes, total search time, 8.37 to 20.55 minutes, and cost, $3.38 to $11.62. The proportion of articles relevant to the topic varied from 98% to 75%. Ignoring "user friendliness," results, in general, showed that the higher the cost, the worse the product. Search systems requiring the least amount of total time were the National Library of Medicine (night), SearchMaster-NLM, NLM (day), SearchMaster-dialog, and SearchMaster-BRS.

J. Graham Smith, Jr.. M.D.

Link between recurrent urticaria and migraine DuPont C; Br Med J 291: 1172, 1985 Sixty-four of 136 patients with recurrent attacks of urticaria and angioneurotic edema gave a history of migraine compared

with only nine age- and sex-matched controls suffering from warts, acne, eczema or psoriasis.

J. Graham Smith, Jr., M.D.

Prospects of therapy for infections with human T-Iymphotropic virus type III syndrome Hirsch MS, Kaplan Je: Ann Intern Med 103:750755, 1985 Suramin, antimoniotungstate (HPA-23), and trisodium phosphonoformate, inhibitors of reverse transcriptase activity, have shown in vitro activity against human T-lymphotropic virus type III (HTLV -1lI). Other antiviral agents include recombinant interferon alpha-A, ribavirin, and ansamycin. Clinical trials of interferon alpha are underway.

J. Graham Smith, Jr., M.D.

Antibody to hepatitis B surface antigen and screening before hepatitis B vaccination Kane MA, Hadler SC, Maynard JE: Ann Intern Med 103:791-793, 1985 Antibodies to hepatitis B SUrface antigen (anti-HBs) detected by radioimmunoassay at levels of 2.1 to 10 ratio units probably are not indicative of immunity to hepatitis B infection. Persons with higher titers of anti-HBs (10 ratio units or more) are more likely to have persistence of antibody and up to 45% will show an anamnestic response to hepatitis B vaccine. It is probable that immunity occurs in those individuals with 10 ratio units or more to anti-HBs and also antihepatitis core antigen positivity (HBc). Anti-HBc has not been studied as extensively as anti-HBs; it also is usually associated with hepatitis surface antigen carriers and therefore cannot be used alone as a test for immunity. J. Graham Smith, Jr., M.D.