What are the other Names for this Condition? (Also known as/Synonyms)

• WISN (Warfarin-Induced Skin Necrosis)

What is Warfarin-Induced Skin Necrosis? (Definition/Background Information)

• Warfarin is a blood-thinner (anticoagulant) medication that is administered in the treatment of thromboembolic disorders (clotting disorders such as deep vein thrombosis and pulmonary embolism). Warfarin is also prescribed as a prophylaxis towards preventing stroke, especially in individuals with certain heart conditions
• Warfarin-Induced Skin Necrosis (WISN) is a rare adverse reaction of the body to warfarin injections, administered intravenously or subcutaneously, resulting in severe skin signs and symptoms. The skin turns red at the injection site with the formation of inflammatory blisters that later necrotize (leading to cell death)
• Discontinuation of warfarin immediately on recognizing/diagnosing condition can help in a complete resolution. In such cases, the prognosis of Warfarin-Induced Skin Necrosis is generally excellent. Nevertheless, individuals may need to be prescribed an alternative anticoagulant medication to prevent blood clots from forming

Who gets Warfarin-Induced Skin Necrosis? (Age and Sex Distribution)

• Individuals of all ages may be affected, although most cases of Warfarin-Induced Skin Necrosis are noted in adults. The incidence rate of WISN is 1 in 10,000
• Both males and females may be affected; for some reason, the condition is noted in middle-aged women at a higher incidence rate (women-men ratio is 3:1)
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Warfarin-Induced Skin Necrosis? (Predisposing Factors)

The key risk factor for Warfarin-Induced Skin Necrosis (WISN) is the use of warfarin (to treat coagulation disorders) that results in the skin condition as a side effect. However, the following factors are associated with an increased risk for the occurrence of WISN:

• Antiphospholipid antibody syndrome
• Antithrombin III deficiency disorder
• Factor V Leiden disorder
• Hyperhomocysteinaemia (HHcy) caused by MTHFR gene mutations
• Protein C and protein S deficiency disorders

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Warfarin-Induced Skin Necrosis? (Etiology)

Warfarin-Induced Skin Necrosis (WISN) develops from warfarin administration via injection or intravenous infusion usually within 3-5 days of therapy with this anticoagulant. The condition may be described as an uncommon complication of warfarin treatment.

• The signs and symptoms are due to blood clots that obstruct blood vessels leading to necrosis (death) of skin and subcutaneous cells and tissues
• The signs and symptoms may be also observed due to a condition called calciphylaxis, which may develop from warfarin usage. In calciphylaxis, an abnormal accumulation of calcium is observed in the small blood vessels resulting in its obstruction

Sometimes, WISN develops weeks to months following warfarin therapy, which may be due to:

• Missed doses
• Increased warfarin dosage
• Drug interactions that occur from multiple drugs reacting with each other (or with other substances in the body)
• The individual has a liver condition (liver disease)

The proposed mechanisms to explain WISN include:

• Nearly 33% of the cases are reported in individuals with protein C deficiency (in some, the deficiency status may remain unknown/undiagnosed)
• Hypersensitivity reaction (immune-mediated response) of the body
• Toxic effect of drug on the body

In cases where the individual is already sensitized to warfarin, the skin signs and symptoms may develop almost immediately (within a few hours). In rare cases, a delayed onset of the condition (after several months) is seen.

It is important to note that a vast majority of individuals who are administered the warfarin anticoagulant are not affected by the drug.

What are the Signs and Symptoms of Warfarin-Induced Skin Necrosis?

The signs and symptoms of Warfarin-Induced Skin Necrosis may vary from one individual to another. It may be mild or severe and related to the usage (dose) of the drug. The condition is known to get better after stoppage of the offending medication.

The signs and symptoms may include:

• Pain and purple-red bruise like rash on skin
• After a few days, the lesions turn blue-black with a red border
• The affected area may be the site of warfarin injection; or, the rash can appear anywhere in the body, if warfarin is administered intravenously
• The preferred sites include lower limbs (thighs) and buttocks, hips, abdomen, penis, and breasts. Sometimes, extensive areas of skin may be involved
• When one or more toes are affected, which may happen during early drug reaction, the condition is known as blue toe syndrome
• Further progression of the blue-black lesions leads to necrosis of the superficial and deep layers of skin; rarely, the deeper tissues and even muscles may be affected
• Following necrosis, scar formation (resembling a burn scar) is noted

How is Warfarin-Induced Skin Necrosis Diagnosed?

It may be difficult and challenging to diagnose Warfarin-Induced Skin Necrosis (WISN), especially if other medications are being taken by the individual and if the skin lesions site is away from the warfarin administration site.

WISN is diagnosed on the basis of the following information:

• Complete physical examination and thorough medical history evaluation (including evaluating for warfarin administration, current medications in use, etc.)
• Assessment of the presenting signs and symptoms
• Imaging studies, if necessary
• Laboratory blood tests, such as protein C and protein S, and other coagulation studies
• Dermoscopy: It is a diagnostic tool where a dermatologist examines the skin using a special magnified lens
• Wood’s lamp examination: In this procedure, the healthcare provider examines the skin using ultraviolet light. It is performed to examine the change in skin pigmentation
• Skin biopsy: A skin tissue biopsy is performed and sent to a laboratory for a pathological examination. The pathologist examines the biopsy under a microscope. After putting together clinical findings, special studies on tissues (if needed) and with microscope findings, the pathologist arrives at a definitive diagnosis

A differential diagnosis may be necessary to eliminate other conditions that present similar signs and symptoms. This may include:

• Cholesterol embolism
• Necrotizing fasciitis
• Pyoderma gangrenosum

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Warfarin-Induced Skin Necrosis?

The complications of Warfarin-Induced Skin Necrosis (WISN) may include:

• Anaphylactoid reactions causing fever, low blood pressure, chest pain, and labored breathing
• Severe WISN due to extensive involvement of the skin
• Permanent scarring following healing of the skin lesions may take place
• Delayed recognition of WISN resulting in a more severe condition

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Warfarin-Induced Skin Necrosis Treated?

The treatment for Warfarin-Induced Skin Necrosis (WISN) may include one or more of the following measures, depending on the severity of signs and symptoms:

• Immediate discontinuation of warfarin
• In some, administration of vitamin K is necessary for symptom reversal
• If an anticoagulant medication is deemed necessary; then, the use of alternate medications, such as heparin or lepirudin, may be considered
• Protein C concentrates (pure activated protein C) for severe cases of blood coagulation, if decreased protein C levels are involved in WISN
• Wound care, which includes cleaning and dressing the skin lesion sites
• Surgical debridement of necrotic tissue, if necessary, especially when large skin areas are noted
• Skin grafting if a large skin area was involved

How can Warfarin-Induced Skin Necrosis be Prevented?

• Warfarin-Induced Skin Necrosis may be preventable, by avoiding anticoagulation medication containing warfarin in some individuals
• A healthcare expert guidance is necessary in restarting warfarin in individuals who are required to use the medication for long periods

What is the Prognosis of Warfarin-Induced Skin Necrosis? (Outcomes/Resolutions)

The prognosis of Warfarin-Induced Skin Necrosis is dependent upon the severity of the signs and symptoms and associated complications.

• However, in most cases, following stoppage of the offending medication, the condition tends to resolve completely. In many, the skin may heal without any permanent scarring
• Rarely, due to extensive involvement of the skin and a delayed diagnosis/treatment of warfarin, the condition may be life-threatening

Additional and Relevant Useful Information for Warfarin-Induced Skin Necrosis:

The following DoveMed website link is a useful resource for additional information:

https://www.dovemed.com/healthy-living/skin-disorders/