Treating Warfarin-Induced Tissue Necrosis With a Hypothermically Stored Amniotic Tissue Graft

Amniotic tissue grafts continue to show potential in the wound clinic for healing recalcitrant wounds. Offering a case study, these authors explore how an innovative amniotic tissue graft successfully treated a patient with warfarin-induced tissue necrosis.

Warfarin is one of the most widely prescribed oral anticoagulant medications. Many of the patients we see in our wound care practices are taking warfarin for various reasons. There are many indications for warfarin including prophylaxis and/or treatment of thrombolytic complications caused by venous thrombosis, atrial fibrillation, and pulmonary embolism. The use of warfarin can reduce the risk of death in patients prone to myocardial infarcts and other thrombolytic events such as stroke.

Herein the author presents a case of warfarin-induced tissue necrosis that presented at the wound care center as a lower extremity wound. Successful treatment included surgical debridement followed by weekly applications of a hypothermically stored amniotic tissue graft.

Case Report

A 69-year-old female was originally seen in the emergency department of a suburban hospital with a three-day history of pain and edema in her left lower leg. She had noticed a rapidly appearing area of necrosis overlying the area of pain (Figure 1). Her work-up in the emergency room consisted of a duplex venous ultrasound that was negative for deep vein thrombosis (DVT), non-invasive vascular studies without evidence of arterial stenosis, and tissue cultures that resulted in the growth of normal flora. The patient was placed on oral Keflex 500 mg BID and was told to soak the leg and apply antibiotic ointment to the wound with a bandage daily and follow up with wound care.

The patient presented to the wound care clinic located within the hospital heart and vascular department 1 week after being seen in the emergency department. The patient related increasing pain and worsening of the wound on the left leg. Upon examination the wound measured 5.4 cm x 2.2 cm x 0.1 cm and was covered in thick, fibrinous tissue with a necrotic border (Figure 2). The peri-wound tissue exhibited erythema and inflammation and there was a slight malodor present. A complete patient evaluation was performed. Past medical history consists of non-insulin dependent diabetes, chronic obstructive pulmonary disease (COPD), aortic stenosis, heart murmur, pulmonary hypertension, degenerative joint disease (DJD), and obesity.

The patient was recently seen in the heart and vascular center by her cardiologist and diagnosed with atrial fibrillation. She was placed on 5 mg warfarin daily therapy without initial co-administration of heparin. She related no history of trauma and did not have a history of previous ulcerations. Based on her history and wound presentation, a 3 mm punch biopsy was obtained. The patient was sent for labs including chemistry panel, complete blood cell count (CBC), international normalized ratio (INR), and prothrombin time test (PT). She was given a prescription to apply collagenase ointment to the wound daily and cover with a bordered foam bandage.

The patient was seen in the wound center the following week. Upon exam the wound was still covered with adherent fibrotic tissue. The histopathology report showed evidence of dermal necrosis, fibrin deposits, intervascular thrombi of the capillaries and venules. Lab values were as follows: WBC 8.0, INR 3.0, PT 33.9, glucose 283, HA1c 9. Based on clinical, laboratory, and histological findings, the diagnosis of warfarin-induced skin necrosis was made.

After collaborating with the patient’s cardiologist, it was decided to stop warfarin therapy and implement vitamin K to normalize the patient’s INR. The care plan was discussed with the patient and based on the characteristics of the wound and the patient’s significant pain, it was decided that patient would undergo surgical debridement of the wound in the OR once her INR normalized. Surgical intervention included low-frequency ultrasonic debridement of all devitalized tissue. Post-debridement the wound base was noted to extend through the deep subcutaneous tissue layer.

Taking into account the depth of the wound, a hypothermically stored amniotic tissue graft (Affinity, Organogenesis) was used to augment healing. It was determined that the placental graft was a better option than a split-thickness skin graft, considering the patient’s comorbidities. The wound was bandaged with a non-adherent contact layer, foam and a compression bandage.

The patient presented to the wound clinic 3 days post-op for her first bandage change. Upon exam it was noted that the wound base was free of clinical signs of infection and there were robust granulation buds throughout (Figure 3). The patient was seen at the wound care center weekly for wound assessments and re-application of Affinity. By post-op visit 3 the patient related minimal pain and the wound had reduced by 40% total area. At this time the cardiologist put her on apixaban (Eliquis, Bristol-Myers Squibb) 5 mg BID. The wound resolved 7 weeks post-op with 6 weekly applications of Affinity (Figure 4).

What You Should Know About Warfarin-Induced Skin Necrosis

Warfarin-induced skin necrosis (WISN) is a rare condition that is reported to occur in 0.01–0.1% of people taking the medication.¹ This complication commonly occurs within 5–10 days of warfarin use. However, longer time intervals have also been observed. This complication is more prevalent in middle aged women of perimenopausal age who have been treated for pulmonary emboli, DVT or heart valve replacement. In women, these lesions are most commonly located in areas of subcutaneous fat such as breasts, buttocks, thighs, and feet.²

The characteristic presentation of WISN includes the development of painful erythematous macules within days of warfarin administration. These macules quickly develop into purpuric lesions with multiple zones of necrosis. Clinical diagnosis takes precedence over biopsy. However, cutaneous necrosis, fibrin deposits in post-capillary venules and arterioalar thrombosis with lack of perivascular inflammation are some of the hallmarks of WISN.³ Conditions that mimic WISN include heparin-induced thrombocytopenia (HIT), calciphylaxis, necrotizing fasciitis, and disseminated intravascular coagulation.³

The pathophysiology of WISN is still not well understood. Warfarin causes a transient  hypercoagulable state, which causes vascular occlusions and in the end, extravasation of vessels. Warfarin administration causes an inhibition of clotting factors 2, 7, 9, and 10, as well as protein C and S.⁴ However, the levels of protein C have been seen to be lower in the early administration of warfarin.⁵ Along with protein C deficiency, heparin-induced thrombocytopenia, lupus, and psoriasis have been found to be underlying risk factors.^3,6–8

Although the disease has been recognized since the 1940s, due to WISN’s rarity, there is a lack of standardized treatment. Treatments differ from case to case; the discontinuation of warfarin is the immediate protocol. Patients are immediately treated with IV heparin as well as fresh frozen plasma and vitamin K to reverse the effects of warfarin. For long-term therapy, oral anticoagulants such as dabigatran (Pradaxa, Boehringer Ingelheim), argibatran, and rivaroxaban (Xarelto, Janssen Pharmaceuticals) have been shown to be successful.^7,9 In most cases, surgical debridement often follows. However, if the limb is unsalvageable, amputation and flap closure is a more viable option.⁷

Due to a lack of published studies on the optimum wound care treatment, physician preference and the nature of the wound guide further treatment of WISN. A wide variety of wound care treatments have been used in the past. Chittoria et al reported a case of a surgically unfit patient due to severe anemia and ongoing infection.¹ The wound was treated with a combination of negative pressure wound therapy (NPWT), autologous protein rich plasma (PRP) injections, collagen granules and collagen sheet. The authors also used an external tissue expansion wound closure using hooks and rubber bands. At 8 weeks, the wound was completely healed.

Murad and colleagues report a case of an abdominal wound that was successfully treated without grafts.¹⁰ The main component of their therapy was NPWT, which was applied after 3 weeks of surgical debridement and antibiotics. At 10 weeks post-treatment, complete closure of the wound was achieved.

Biscoe and colleagues took a different approach to a complicated case.¹¹ Their patient presented with extensively necrotic wounds which were ungraftable. The authors tried multiple surgical debridement and NPWT dressings before applying maggot larvae. Maggot larvae are sterile larvae that secrete proteolytic enzymes and digest the necrotic tissue. The species used in this case were blow flies of the species Phaenicia sericata. The maggots were applied for 7 days with special dressing. Post-maggot treatment, the wound was treated with Manuka honey dressing and NPWT until the wound site was appropriate for grafting.

To the authors’ knowledge this is the first case of WISN successfully treated with surgical debridement paired with wound care consisting of hypothermically stored amniotic tissue graft application.

Conclusion

Pathophysiology of atypical wounds, such as those caused by warfarin-induced tissue necrosis, have an unpredictable progression and are often refractory to standard of wound care therapies. No gold standard treatment exists due to the low incidence of occurrence. By utilizing a multidisciplinary approach, which included medical management, aggressive surgical intervention and advanced wound therapy with a hypothermically stored amniotic tissue graft, this case resulted in positive outcome with minimal patient morbidity.

Windy Cole, DPM, CWSP, is an Adjunct Professor and the Director of Wound Care at Kent State University College of Podiatric Medicine in Independence, Ohio.

Asad Sohail, DPM, is a 2020 graduate of Dr. William Scholl College of Podiatric Medicine and a first-year resident at University Hospitals Regional Hospital, Foot and Ankle Surgery.

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