بسم الله الرحمن الرحيم

Warfarin Induced Skin

NecrosisA Case Report and Review of the

Literature

Dr Mohamad Taha YousufConsultant of Vascular Surgery

Mataria Teaching Hospital

Warfarin is the standard oral anticoagulant used in a variety of clinical conditions. Warfarin inhibits the vitamin-K dependent gamma-carboxylation of coagulation factors II, VII, IX, X and the anticoagulant proteins C and S.

Rarely (0.01 to 0.1 percent of warfarin-treated patients), skin necrosis occurs when the resultant initial procoagulant state in the first few days of starting Warfarin leads to thrombosis in the dermal capillaries, leading to skin necrosis.

Kumar M, Abrina V, Chittimireddy S. Coumadin-induced skin necrosis in a 64 year-old female despite LMWH

bridging therapy. Am J Case Rep. 2012;13:157-159.

Skin necrosis affects areas of the body with a high fat content, such as breasts, thighs, buttocks, and abdomen. It is more common in females.

Onset of skin changes may begin from day one to day ten, with a peak incidence on days three to seven after initiating Warfarin.

The condition is most often unilateral, but 30 percent of cases occur bilaterally with multiple lesions.

Early recognition of this complication is very important because a delay in the diagnosis may lead to serious complications such as limb amputation.

Brooks LW, Blais FX. Coumadin-induced skin necrosis. J Am Osteopath Assoc 1991;91(6):601-5. Eby CS. Warfarin-induced skin necrosis. Hematol Oncol Clin North Am 1993;7(6):1291-300.

Case Report

Our patient is a 52 year old Egyptian female with PMH of diabetes and hypertension with a history of a cerebrovascular accident 2 months ago with residual aphasia and bulbar symptoms.

The patient presented to the emergency department with a few days history of left lower limb edema.

Duplex ultrasound revealed left ileo-femoral DVT.

The patient was not admitted due to family refusal, so Tinzaparin 0.7 ml once daily s.c. and Warfarin 5 mg tab. once daily were prescribed with follow up at outpatient department to check her INR after 1 week.

The patient returned to the emergency department after 8 days by disturbed conscious level (GCS 10/15), chest infection and urinary tract infection.

The left lower limb was swollen but less than before with ecchymosis in the left thigh and left foot with blackish discoloration.

The patient was admitted in the medical ICU.

CBC showed leukocytosis of 34000, severe anemia with a hemoglobin of 6.6 mg/dL, and thrombocytopenia with a platelet count 111000.INR was 5.1 Creat. 1.2

Warfarin-induced skin necrosis was suspected based on presentation, time since initiation of warfarin therapy and supratherapeutic INR.

Warfarin was stopped.

The patient received vit. K 10 mg I.V. amp.,2 units PRBCs, 4 units FFP and broad spectrum antibiotic.

Subsequent lab. results were as follows:-

2nd day 3rd day 4th day 5th day

Hb 7.7 8.3 8.6 10.2

WBCs 30400 28900 27200 23100

Platelets 152000 153000 182000 207000

INR 12.9 9.1 5 3.2

Other investigations• Duplex ultrasound revealed subacute left ileo-

femoral DVT.

• Abdominal ultrasound revealed fatty liver and grade II nephropathy.

We put a plan of local wound care, waiting for improvement of the general condition of the patient for the definitive care.

After improvement of the INR, Fondaparinux 2.5 mg once daily was started.

Unfortunately the patient died suddenly without any surgical intervention in the 6th day of admission.

Warfarin Induced Skin Necrosis

(WISN)

The clinical use of the coumarin anticoagulants began with the discovery of an anticoagulant substance formed in spoiled sweet clover silage which caused hemorrhagic disease in cattle.

At the behest of local farmers, a chemist at the University of Wisconsin identified the toxic agent as bishydroxycoumarin.

A synthesized derivative, dicumarol and its congeners, most notably warfarin (Wisconsin Alumni Research Foundation, with "arin" from coumarin added; were initially used as rodenticides.

Warfarin (Bristol-Myers Squibb, New York, NY) was first introduced in 1941 and now it is a frequently used oral anticoagulant that is approved by the US Food and Drug Administration (FDA) in 1955 for the treatment and prevention of various medical conditions.

Warfarin inhibits the vitamin-K dependent gammam carboxylation of coagulation factors II, VII, IX, X and the anticoagulant proteins C and S. The blockade results in incomplete coagulation factor molecules that are biologically inactive.

The protein carboxylation reaction is coupled to the oxidation of vitamin K. The vitamin must then be reduced to reactivate it. Warfarin prevents reductive metabolism of the inactive vitamin K epoxide back to its active form.

After starting Warfarin therapy, there is a delay in its action. Its anticoagulant effect results from a balance between partially inhibited synthesis and unaltered degradation of the four vitamin K dependent clotting factors.

The resulting inhibition of coagulation is dependent on their degradation half-lives in the circulation. These half-lives are 6, 24, 40, and 60 hours for factors VII, IX, X, and II, respectively.

The initial procoagulant effect of Warfarin Half the activated Protein C disappears within 6 hours (its half-life). So,

Protein C runs out during the first few days of warfarin therapy, before Factor X and II disappear, which have half-lives of 2-3 days. In some circumstances this leads to excessive clotting.

Warfarin-induced skin necrosis was described by Flood and colleagues who reported a case of a gangrenous breast but erroneously believed it was due to an underlying coagulopathy and not the drug therapy.

In 1954, Verhagen described a series of 13 patients on dicumarol who developed necrosis, but he incorrectly suggested the necrosis was associated with the underlying disease being treated when in fact it was complicated by a thrombosis and dicumarol therapy.

In 1961 Kipen first correctly ascribed the gangrenous skin changes to anticoagulant therapy.

Flood EP, Redish MH, Bociek S, et al. Thrombophlebitis migrans disseminata. NY State J Med 1943;43:1121-4.Berkompas DC. Coumadin skin necrosis in a patient with a free Protein S deficiency. India Med 1991;84(11):788-91

Verhagen H. Necrosis of skin and underlying tissues during anticoagulant therapy with dicumarol Acta Medica Scandinavica 1954;148:453.Kipen CS. Gangrene of the breast: A complication of anticoagulant therapy. N Engl J Med 1961;265:638-40.

What are the clinical features?

The condition remains a major diagnostic and therapeutic challenge.

The first sign is usually parathesia, pain and purpura , which over a few days becomes bluish-black with a red rim.

Hemorrhagic bullae and full thickness skin necrosis follows.

Who is affected by warfarin necrosis?

Warfarin induced skin necrosis is more common in women than men. It usually occurs between the age of 50 and 70 years. It is more common in obese patients and perimenopausal women.

Warfarin induced skin necrosis is more likely if warfarin is given without heparin or if a higher loading dose of warfarin is given in the first day or two of treatment.

WISN is a complication of the drug therapy rather than the result of simple over-anticoagulation.

Coumadin-Induced Skin Necrosis Janice M. Beitz, PhD, RN, CS, CNOR, CWOCNWounds. 2002;14(6)

What are the risk factors?

Inherited deficiency of Protein C, Protein S or Factor V Leiden

Hyperhomocysteinaemia

Antithrombin deficiency

Antiphospholipid antibodies.

Etiology The exact aetiology of Warfarin-induced skin necrosis is still

unknown, but is often associated with a hypercoagulable state.

Protein C or protein S deficiencies have been reported in patients with Warfarin-induced skin necrosis as well as in those with Factor V Leiden, mutation of the prothrombin gene, lupus anticoagulants and antiphospholipid syndrome.

ANDERSON DR, BRILL-EDWARDS P, WALKER I:. Haemostasis (1992) 22:124-128.

Pathogenesis The pathogenesis is believed to be secondary to

a more rapid initial reduction in blood levels of vitamin K-dependent anticoagulants (proteins C and S) than the procoagulants (factors II, IX, X) during the warfarin anticoagulation, this would paradoxically render a temporary hypercoagulable especially In those patients already deficient in the natural anticoagulants, i.e., protein C, protein S and Antithrombin.

The transient hypercoagulability leads to local thrombotic occlusions in the small vessels of the skin followed by skin necrosis.

ROSE VL, KWAAN HC, WILLIAMSON K, HOPPENSTEADT D, WALENGA J, FAREED J: Am. J. Clin. Pathol. (1986) 86:653-635.

Differential diagnosis• Acute necrotizing fasciitis

• Calciphylaxis (in patients undergoing renal dialysis)

• Cellulitis

• Decubitus ulcer

• Disseminated intravascular coagulopathy with purpura fulminans

• Fournier’s gangrene

• Hematoma

• Heparin-induced thrombocytopenia

• Inflammatory breast cancer

• Lupus anticoagulation–associated skin necrosis

• Microembolization

• Cholesterol emboli syndrome

• Pyoderma gangrenosum

DiagnosisThe diagnosis of warfarin induced skin necrosis is made

clinically. Clinical history and cutaneous distribution may be of major

assistance in distinguishing WISN from other conditions, because WISN lesions are difficult to distinguish histologically by biopsy.

Biopsy results suggestive of WISN usually show fibrin and thrombi in small dermal vessels with no evidence of inflammatory infiltration.

Blood tests for protein C and protein S levels are important to assess the likely predisposing causes.

Comp PC, Elrod JP, Karzenski S. Warfarin-induced skin necrosis. Semin Thromb Hemost 1990;16(4):293-8.

Prevention Recognition of the population at risk is crucial.

According to The American College of Chest Physicians Guidelines, a bridge therapy for at least 5 days and until the INR is stable and therapeutic for at least 24 hours in patients receiving warfarin for treatment of a DVT.

Standard or low-dose warfarin should be used instead of initial large loading-doses.

A clinician should be cautious when advancing the dosage of warfarin.

Chest. 2012;141(2)(Suppl):e152S–e184S.

In high risk patients full heparinization should be achieved before starting warfarin.

Clinicians should be aware of the syndrome and especially attuned to patients with early complaints of localized skin discomfort especially in the breast, buttocks, and thighs even in the absence of overt signs.

A high level of suspicion may allow rapid reversal of warfarin and full heparinization before the syndrome processes begin.

Treatment No current consensus exists regarding how to best treat WISN. Current

treatment options are based on previously published case reports and include the following:-

Immediate discontinuation of warfarin to prevent further necrosis, reversal of warfarin effects by the administration of vitamin K and FFP or PCC.

Protein C concentrate in patients with an underlying deficiency.

Anticoagulation should be continued with a parenteral agent once appropriate.

Wound care.

Viegas GV. Coumadin skin necrosis: Pedal manifestations. J Am Podiatr Med Assoc 1992;82(9):463-8.

For the necrotic areas topical therapy may include use of local antibiotics, such as silver sulfadiazine, or special dressings including foams, special impregnated gauzes, and hydrogels.

Surgical treatment is required in more than 50 percent of cases, with mastectomies and amputations necessary in advanced cases.

Skin grafting may be required. Myocutaneous flaps are sometimes needed to close large defects.

Timmons J. Dressing selection for the treatment of coumarin necrosis. Nurs Stand 2000;14(49):66-8, 70.Miura Y, Ardenghy M, Ramasastry S, et al. Coumadin necrosis of the skin: Report of four patients. Ann Plast Surg 1996;37:332-7

Sustained anticoagulation is vital for some patients' conditions but remains a challenge. Long-term heparin is inconvenient and may be associated with osteoporosis. An alternative is enoxaparin, a low-molecular-weight heparin.

Cases have been reported in which WISN sufferers have been restarted on Warfarin without any further sequelae (warfarin was started at 1 mg/day with a very slow increase in the dose). Others have developed signs of impending recurrence.

Jillella AP, Lutcher CL. Reinstituting warfarin in patients who develop warfarin skin necrosis. Am J Hematol 1996;52:117-9.

Development of new oral anticoagulants offers the possibility of treating these patients effectively due to the high thrombophilic diathesis in such patients.

After the acute event is resolved ,the patient and family members may need to consider testing for Protein C and S or Antithrombin deficiencies.

Arch Turk Soc Cardiol 2014;42(8):787

Take Home Message

WISN is a rare but serious complication of Warfarin therapy, associated with high morbidity and mortality rates, and often requires surgical intervention.

WISN usually appears 3 - 7 days after initiating warfarin treatment in susceptible individuals, although it may appear later.

It is more common in females and frequently affects areas with abundant subcutaneous fatty tissue such as breasts, thighs, and buttocks.

A bridge therapy for at least 5 days and until the INR is stable and therapeutic is important.

Standard or low-dose warfarin should be used instead of initial large loading-doses.

Once it is suspected, Warfarin should be stopped and the patient should be given Vitamin K and FFP to reverse the effects of Warfarin.

The novel anti-coagulants can be safely used in this relatively rare but serious clinical situation.

Thank You

Dr Mohamad Taha