Dr. Maher Hashem AL-khateeb, MD, JBS (Corresponding author)
Department of Plastic Surgery,
Royal Medical Services,
Amman,
Jordan
Email: mbdooor@yahoo.com

Dr. Maher Hashem AL-khateeb, MD, JBS
Jordanian Board of Surgery

Dr. Mohammed Nayef AL-Bdour, MD, JBS
Jordanian Board of Surgery

Dr. Waleed Ziad Haddadin, MD, JBS
Jordanian Board of Surgery

 

INTRODUCTION

Warfarin-induced skin necrosis (WISN) is a rare, unusual, and unpredictable complication of anticoagulant therapy. It occurs in 0.01 to 0.1 percent of warfarin-treated patients.
Anticoagulants are used frequently in the management of wide variety of medical diseases, so awareness and early detection and management of this rare complication are essential.

Case 1:
A 23-year-old female, previously healthy, with family history of DVT (deep vein thrombosis), two weeks post normal vaginal delivery she developed right leg swelling and pain, diagnosed to have popliteal and femoral vein thrombosis proved by Doppler ultrasound, she was started on clexan ( low molecular weight heparin) and warfarin.

One week later she developed skin eruptions and discoloration on the dorsum of the right foot. Here INR was within the therapeutic range, arterial Doppler ultrasound was free, and coagulation profile studies showed protein C and protein S deficiency.

The clinical impression was warfarin induced skin necrosis. Warfarin was discontinued and she was started on low molecular weight heparin.

She was referred to the plastic surgery department for wound care, underwent frequent debridement and dressings, and her wound was covered with split thickness skin graft.

Case 2:
A 19-year old female, previously healthy, with family history of DVT, one week post normal vaginal delivery started to complain of right leg pain and swelling. Doppler ultrasound showed extensive deep vein thrombosis.

She was started on heparin; two days later warfarin was added, five days later she had right loin skin discoloration and necrosis, her INR was within therapeutic range, abdominal and pelvic ultrasound and CT was free.

Coagulation profile studies showed Activated protein C resistance (Factor V Leiden). Warfarin was discontinued and she was started on low molecular weight heparin; also vitamin K and fresh frozen plasma was given.


Skin necrosis continued to progress and involved necrosis of subcutaneous tissue; plastic surgeon was consulted, patient under went excision of necrotic skin and subcutaneous tissue with frequent dressings. Here the wound was closed primarily with small raw areas healed by secondary intention.

The mechanism of action of warfarin involves inhibition of vitamin K-dependent coagulation factors. Inhibition of protein C and Factor VII is stronger than inhibition of the other vitamin K-dependent coagulation factors II, IX and X. This results from the fact that protein C and Factor VII have shorter half lives. This difference in effect is proportional to the initial dose of vitamin K-antagonist [1, 2].

As a result of this imbalance in coagulation factors inhibition, paradoxical activation of coagulation occurs, resulting in a hypercoagulable state and thrombosis. This results in blood clots that interrupt the blood supply to the skin, causing necrosis. Protein C is an innate anticoagulant, and as warfarin further decreases protein C levels, it can lead to massive thrombosis with necrosis and gangrene of limbs [1, 2].
Development of the syndrome is associated with the use of large loading doses at the start of treatment [3].

The prothrombin time (or international normalized ratio, INR) is highly dependent on factor VII, which explains why patients can have a therapeutic INR (indicating good anticoagulant effect) but still be in a hypercoagulable state [1, 2].

In one third of cases, warfarin necrosis occurs in patients with an underlying, innate and previously unknown deficiency of protein C. There have also been cases in patients with other deficiencies, including protein S deficiency, activated protein C resistance (Factor V Leiden) and antithrombin III deficiency[3,4].

Although the above mentioned explanation is the most accepted theory of pathogenesis, others believe that it is a hypersensitivity reaction or a direct toxic effect [3].

This syndrome is more often in obese, middle aged woman. The median age is around 54 years with male to female ratio 1:3 [5]. The onset of the drug eruption usually occurs between the third and tenth days of therapy with warfarin derivatives [6].

Initial presentation involves pain and redness in the affected area. As they progress, lesions develop a sharp border and become petechial, then hard and purpuric. They may then resolve or progress to form large, irregular, bloody bullae with eventual necrosis and slow-healing eschar formation [6, 7, 8]. This syndrome can involve any area in the skin but more often in: breasts, thighs, buttocks and penis. In rare cases it can involve the fascia and muscles [7].

The differential diagnosis includes many conditions such as pyoderma gangrenosum or necrotizing fasciitis [9].

Treatment includes: discontinuation of warfarin, Vitamin K as an antidote to warfarin action, heparin or low molecular weight heparin (LMWH) can be used to prevent further clotting, fresh frozen plasma or pure activated protein C also has been used [9,10,11].

Heparin and LMWH act by a different mechanism than warfarin, so these drugs can also be used to prevent clotting during the first few days of warfarin therapy and thus prevent warfarin necrosis (this is called 'bridging') [9].

The necrotic skin areas need proper wound care with frequent proper dressings. Healing can occur spontaneously with or without scarring. In severe cases surgical debridement and skin grafting are required. The leading cause of death is related to underlying disorders for which anticoagulation is started, for example, recurrent pulmonary embolism. [12].