Warfarin is an anticoagulant drug used for treatment and prophylaxis of various hypercoagulable disorders, but several complications may arise, one of them being skin necrosis, as warfarin can paradoxically induce a hypercoagulable state [1] [2] [3]. Although warfarin-induced skin necrosis (WISN) develops in 0.01%-0.1% (approximately 1 in 10,000) of patients who receive warfarin, its appearance must be recognized early on [3] [4] [5] [6]. Several risk factors have been established, including deficiencies of several coagulation factors (factor V Leiden, antithrombin III, proteins C and S), concomitant presence of antiphospholipid syndrome, hyperhomocysteinemia, but also obesity and female gender, with a female-to-male ratio of 4:1 [1] [4] [5]. Moreover, aggressive use of warfarin without prior administration of heparin is another well-documented risk factor [4] [5] [7]. The clinical presentation is distinguished by a sudden onset of erythematous macules, ecchymoses and purpuric lesions 3-10 days after initiation of warfarin use while accompanying edema and paresthesia is frequent [2] [5] [7]. The most common sites are the penis in males and breasts in females, whereas the buttocks, thighs, and limbs (especially calves) are observed as common locations in both genders [1] [4]. If the diagnosis is delayed, the progression of lesions to hemorrhagic bullae, ulcers and full-thickness necrosis can ensue, which may significantly increase the risk for further complications [5] [7].

• Ecchymosis

  This article reports a case of a 72-year-old woman who presented to the emergency department complaining of swelling and ecchymosis to her left breast and right foot. [ncbi.nlm.nih.gov]

  10 days after the initiation of therapy In areas with increased subcutaneous fat such as the abdomen, buttocks, thighs, legs, and mammary tissue 33% multiple sites. 4 Warfarin induced skin necrosis Acute onset of paresthesia and edema  petechiae and ecchymosis [slideplayer.com]

  After 24 hours, the central area of the ecchymosis had become necrotic. Warfarin was discontinued. Over the next day, the extent of the necrotic skin did not increase and there was some improvement in the appearance of her leg. [pmj.bmj.com]

  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. [slideshare.net]

• Disability

  Please enable JS and disable any ad blocker [patientcareonline.com]

• Pneumonia

  Four of 6 WISN sites were secondarily infected with drug-resistant nosocomial bacteria (methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter, extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae) 17 [ncbi.nlm.nih.gov]

  Four of 6 WISN sites were secondarily infected with drug-resistant nosocomial bacteria (methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter, extendedspectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae) 17 - 37 [open.uct.ac.za]

  Since the past 2 weeks, she was under treatment in a local hospital for left-sided lobar pneumonia where a subsequent V/Q scan had suggested a low probability of pulmonary embolism. [jpgmonline.com]

• Ulcer

  Nine days after initiation of warfarin therapy, he developed necrotic arm ulcers, which were subsequently proved to be secondary to warfarin-induced skin necrosis. [ncbi.nlm.nih.gov]

  His admitting diagnosis was ESRD, change in mental status, and a large painful lower left leg ulcer. [o-wm.com]

  […] multiple sites. 4 Warfarin induced skin necrosis Acute onset of paresthesia and edema  petechiae and ecchymosis  well-demarcated hemorrhagic bullae within 24 hours  painful coagulative full-thickness skin necrosis with formation of deep subcutaneous ulcers [slideplayer.com]

  If the diagnosis is delayed, the progression of lesions to hemorrhagic bullae, ulcers and full-thickness necrosis can ensue, which may significantly increase the risk for further complications. [symptoma.com]

• Eruptions

  […] presenting with this eruption include viral eruptions (e.g., Epstein-Barr virus, herpesvirus type 6), eruptions from a bacterial toxin, acute graft-versus-host disease, and Kawasaki disease. 5 Urticaria, Angioedema, and Anaphylaxis: Urticaria (hives) [uspharmacist.com]

  Examination revealed multiple, diffuse "lace-like" erythematous eruptions with superimposed lesions that were tender, ulcerated, and crusted. A biopsy was performed, and histopathologic findings were consistent with WISN. [ncbi.nlm.nih.gov]

  Warfarin necrosis is also different from another drug eruption associated with warfarin, purple toe syndrome, which usually occurs three to eight weeks after the start of anticoagulation therapy. [en.wikipedia.org]

  On DermNet NZ Warfarin necrosis – pathology Heparin-induced skin thrombocytopenia Bullous drug eruptions Blue toe syndrome Other websites Medscape Reference Dermatologic Manifestations of Hematologic Disease Protein C Deficiency Books about skin diseases [dermnetnz.org]

• Skin Rash

  The patient information leaflet will also be updated to warn patients of the risk of calciphylaxis, with advice to consult their doctor if they develop a painful skin rash. [gov.uk]

  Hypersensitivity to warfarin simultaneously results in allergic interstitial nephritis and leukocytoclastic vasculitis where they usually present with acute renal failure and skin rash. [jfmpc.com]

  Patients presenting with a skin rash or skin lesions should be thoroughly assessed for the possibility of such a relationship and, if one is found, should be treated (if necessary) and educated regarding the drug-induced skin disorder ( TABLE 2 ). [uspharmacist.com]

• Paresthesia

  […] to 0.1% of patients on warfarin 3 to 10 days after the initiation of therapy In areas with increased subcutaneous fat such as the abdomen, buttocks, thighs, legs, and mammary tissue 33% multiple sites. 4 Warfarin induced skin necrosis Acute onset of paresthesia [slideplayer.com]

  The clinical presentation is distinguished by a sudden onset of erythematous macules, ecchymoses and purpuric lesions 3-10 days after initiation of warfarin use while accompanying edema and paresthesia is frequent. [symptoma.com]

  Clinically the patients developed pain and paresthesia, erythematous flush and hemorrhagic bullae and full-thickness with skin necrosis, the patients developed ecchymoses and purpura 2 weeks later the beginning of therapy, There were multiple and symmetric [bloodjournal.org]

  Failure to diagnose and treat the condition early may even result in death. 2 Skin necrosis has been reported as early as within the first few days of receiving large loading doses of warfarin. 3 Paresthesia, or a sensation of pressure, associated with [pharmacytimes.com]

  Cutaneous injury from warfarin begins as localized paresthesias with an erythematous flush Warfarin-induced skin necrosis DermNet New Zealand Warfarin induced skin necrosis. Authoritative facts about the skin from DermNet New Zealand. [corpochivor.gov.co]

• Burning Sensation

  The initial symptoms of anticoagulant-induced skin necrosis include: Tingling of the skin Pressure felt on the skin Burning sensation of the skin These symptoms often progress into the development of skin lesions appearing on the breasts, abdomen, buttocks [study.com]

  Fixed-Drug Eruptions: These eruptions present as pruritic, red, raised lesions that may blister or develop into plaques. 1,6 A burning or stinging sensation may also be noted. 6 Lesions typically develop in minutes to days of drug initiation and typically [uspharmacist.com]

• Tingling

  The initial symptoms of anticoagulant-induced skin necrosis include: Tingling of the skin Pressure felt on the skin Burning sensation of the skin These symptoms often progress into the development of skin lesions appearing on the breasts, abdomen, buttocks [study.com]

The diagnosis of WISN must be made as early as possible, as its early recognition could be lifesaving [3]. Because no conclusive laboratory tests exist to confirm WISN, the diagnosis relies on the ability of the physician to reveal recent warfarin use and detect characteristic lesions of the skin [4] [5] [6] [7]. For this reason, the first, and probably the most important step during the diagnostic workup, is a detailed patient history that will identify recent administration of warfarin, but also if patients suffer from any of the mentioned disorders that could predispose them to WISN, including deep vein thrombosis (DVT) and pulmonary embolism (PE), both being recognized as predisposing conditions for WISN [4] [5]. Furthermore, a complete physical examination of the skin will confirm the presence of purpuric, hemorrhagic and necrotic lesions in common areas, in which case immediate clinical suspicion toward warfarin should be raised. A complete coagulation panel should be performed, but findings can often be normal. However, a biopsy with histological examination could be of benefit [5] [6]. Full-thickness necrosis of the epidermis and both dermal and subcutaneous venous thrombosis are characteristic features of WISN, as are extravasated erythrocytes, endothelial cell damage, and fibrin deposits in superficial dermal vessels and in postcapillary venules [5] [6].

A patient with a history of deep vein thrombosis presented with painful bruising and blistering on his left leg 7-10 days after warfarin treatment. [ncbi.nlm.nih.gov]

He received medical treatment and underwent surgical debridement with the pathology report showing WISN. Despite medical and surgical treatments the patient's wounds continue to worsen. [archive.rubicon-foundation.org]

For patients with protein C deficiency, intravenous monoclonal antibody-purified protein C concentrates may be used; however, this is not practical for long-term treatment because of the high cost. 9 Prostacyclin has also been used in the treatment of [pharmacytimes.com]

[…] subcutaneous capillaries, venules, and deep veins Endothelial cell damage resulting in ischemic skin necrosis and marked RBC extravasation No vascular inflammation and arterial involvement 9 10 11 Management Early diagnosis and drug withdrawal improve prognosis [slideplayer.com]

Titrating warfarin doses over an extended period promotes a more gradual decline in the protein C level, similar to that of the other longer-lived vitamin K–dependent coagulant factors. 7 Prompt diagnosis of warfarin-induced skin necrosis is crucial for prognosis [pharmacytimes.com]

The prognosis is often poor with a mortality rate of 60-80%, often from sepsis [ 7 ]. [omicsonline.org]

Protein C deficiency does NOT appear to cause arterial thrombosis. [ 5 ] Prognosis There is a 10- to 15-fold risk of VTE. [ 5 ] However, there is a marked variation in risk among families with protein C deficiency, that cannot be explained by the genetic [patient.info]

As the prognosis of CUA is worse with more than 80% mortality with severe CUA, early diagnosis and initiation of treatment plays a key role. The most common differential diagnosis of CUA is WISN especially, when patient is on warfarin. [pubs.sciepub.com]

The etiology of warfarin-induced skin necrosis has not been definitively established. [ncbi.nlm.nih.gov]

These include the "classic" patient characteristics described previously, large loading doses of Coumadin, and acute thrombosis conditions.10,12,13 Several theories have been suggested related to the pathogenesis of CISN, although the exact etiology is [woundsresearch.com]

However, if antibodies are present they are a marker for HIT. 2, 4, 5 Only 10% to 20% of patients who develop HIT antibodies during subcutaneous administration of UFH or LMWH will develop skin lesions. 2 ETIOLOGY AND PATHOPHYSIOLOGY Generally develops [mhmedical.com]

[…] replacement therapy with fresh frozen plasma is started Homozygous protein C deficiency can be cured with liver transplant; however, this is usually too risky so replacement is preferred treatment Must exclude acquired causes of protein C deficiency Etiology [pathologyoutlines.com]

Management of Acute Hemorrhage Platelets Plasma and Specialized Coagulation Concentrate New Approaches for the Therapy of Bleeding Disorders Overview of Venous Thromboembolism Thrombophilia Genetics Epidemiology and Risk Factors for Venous Clinical Manifestations [books.google.com]

Epidemiology It is estimated that in a Caucasian population, protein C deficiency is found in 2-5% of patients with venous thromboembolism (VTE), in 5-10% of those with recurrent VTE and in 0.2-0.5% of the general population. [ 4 ] However, genetic predisposition [patient.info]

Drug-induced skin pigmentation: epidemiology, diagnosis and treatment. Am J Clin Dermatol. 2001;2:253-262. To comment on this article, contact [email protected] [uspharmacist.com]

Superficial thrombophlebitis: Epidemiology, physiopathology, diagnosis and treatment. J Vasc Bras 2008;7:131-43. 28. Titon JP, Auger D, Grange P, Hecquet JP, Remond A, Ulliac P, et al. [ijdvl.com]

In this article the historical, clinical, and pathophysiologic features of this hypercoagulable event are reviewed, and recommendations for prevention and treatment are discussed. [ncbi.nlm.nih.gov]

Manifestations and Diagnosis of Venous Venous Thrombosis in Unusual Sites Victor J Marder Hylton V Joffe and Sam Schulman Prevention of Venous Thromboembolic Disease Treatment of Venous Thromboembolic Disease Overview of Arterial Thrombotic Disorders Pathophysiology [books.google.com]

Warfarin induced skin necrosis pathophysiology of osteoarthritis is the odourless destin. Porky lunkhead will being extremly summers spaying. Urbanite will have crossways pitted. Mop must pick up until the offscreen christina. [ervio.flortal.info]

The pathophysiology underlying warfarin-induced skin necrosis is not entirely understood. [nejm.org]

There is a lack of guidelines regarding the selection of patients who need intravenous heparin, duration of intravenous heparin, and future use of warfarin in prevention and treatment of warfarin-induced skin necrosis. [ncbi.nlm.nih.gov]

Conclusion Prevention and management of warfarin-induced skin necrosis in a timely manner should be emphasised to prevent permanent tissue damage. [oapublishinglondon.com]

[…] of Venous Thromboembolic Disease Treatment of Venous Thromboembolic Disease Overview of Arterial Thrombotic Disorders Pathophysiology of Atherothrombosis Prevention of Thromboembolic Stroke in Patients with Acute Thrombolytic Therapy Unusual Sites of [books.google.com]

1. A Murad A, Daly T, Mulligan N, Lenane P. Extensive warfarin-induced skin necrosis successfully treated with negative pressure wound therapy. BMJ Case Rep. 2014;2014:bcr2013203510.
2. Fawaz B, Candelario NM, Rochet N, Tran C, Brau C. Warfarin-induced skin necrosis following heparin-induced thrombocytopenia. Proc (Bayl Univ Med Cent). 2016;29(1):60-61
3. Liaw TY, Chang CH. Skin necrosis complicated by warfarin-induced protein S deficiency. J Formos Med Assoc. 2014;113(10):758-759.
4. Kakagia DD, Papanas N, Karadimas E, Polychronidis A. Warfarin-Induced Skin Necrosis. Ann Dermatol. 2014;26(1):96-98.
5. Biscoe AL, Bedlow A. Warfarin-induced skin necrosis diagnosed on clinical grounds and treated with maggot debridement therapy. BMJ Case Rep. 2013;2013:bcr2012007455.
6. Bhaijee F, Wainwright H, Meintjes G, et al. Warfarin-induced skin necrosis in HIV-1-infected patients with tuberculosis and venous thrombosis. S Afr Med J. 2010;100(6):372-377.
7. Marčić M, Marčić L, Titlić M. Warfarin-Induced Skin Necrosis in Patients With Low Protein C Levels. Acta Med Iran. 2016;54(8):551-554.