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].

• Sepsis

  Wound and associated systemic sepsis followed, and the patient was transferred to our burn unit. [ncbi.nlm.nih.gov]

  Vascular Complications Differential Diagnosis of Thrombocytopenia Developmental Hemostasis Bleeding in Neonates and Children Venous and Arterial Thromboembolism in Children Thrombotic Complications of Sickle Cell Disease Thrombohemorrhagic Complications of Sepsis [books.google.com]

  The patient developed overwhelming cardiopulmonary failure and sepsis and subsequently died. [o-wm.com]

  The condition is related to purpura fulminans, a complication in infants with sepsis which also involves skin necrosis. These infants often have protein C deficiency as well. [en.wikipedia.org]

  FDA for treating severe sepsis. [wikivisually.com]

• Asymptomatic

  Heparin should be started in high-doses and vitamin K and fresh frozen plasma (FFP) should be administered to restore protein C and S levels. [2], [3] A 29-year-old female patient, referred from general medicine department was presented with asymptomatic [ijstd.org]

  The eruptions may be asymptomatic or associated with itching, burning, or edema. [jfmpc.com]

  Antiphospholipid syndrome and asymptomatic carriers of antiphospholipid antibody: Prospective analysis of 404 individuals. J Rheumatol 2004;31:1560-7. 65. Ginsburg KS, Liang MH, Newcomer L, Goldhaber SZ, Schur PH, Hennekens CH, et al. [ijdvl.com]

  Asymptomatic patients with protein C deficiency, ie those without VTE: Long-term primary prophylaxis (anticoagulants) is not indicated (the risk of haemorrhage outweighs the benefits). [patient.info]

  Patients with underlying partial protein C deficiency could be asymptomatic, but hold a higher risk of skin necrosis following treatment with warfarin. [omicsonline.org]

• Chills

  There was no fever, chills, joints pain, or headache. There was no nausea, vomiting, hematuria, or urinary symptoms. No over-the-counter or nonsteroidal anti-inflammatory drugs (NSAIDs) medications used. His vital signs were normal. [jfmpc.com]

• Osteoporosis

  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 CISN sufferers have been restarted on Coumadin without any further sequelae. [woundsresearch.com]

  Long-term heparin is inconvenient and may be associated with osteoporosis. An alternative is enoxaparin, a low- molecular-weight heparin. [slideshare.net]

  […] unfractionated heparin and low molecular weight heparins are used, the latter are currently preferred for livedoid vasculopathy because of their advantages although there still are concerns related to cost, need for parenteral administration and the risk of osteoporosis [ijdvl.com]

• Skin Lesion

  The skin lesions in the patient were associated with acquired deficiency of protein C and protein S and abnormal liver function. [ncbi.nlm.nih.gov]

• Erythema

  Seven days after the initiation of warfarin therapy, an area of erythema surrounded by a halo was noted on the left thigh of a 79-year-old woman. [ncbi.nlm.nih.gov]

  It presents as an area of erythema, which quickly progresses to purpura, hemorrhage, and necrosis. Most of these patients do not develop thrombocytopenia. [usmleforum.com]

  On the seventh postoperative day, when her INR was 3.1, she developed an area of extremely tender erythema on her left calf, surrounded by bruising. [pmj.bmj.com]

  Deep vein thrombosis most commonly involves the deeper venous system of the lower extremities and is characterized clinically by erythema, edema, warmth, pain and tenderness. [ijdvl.com]

  Skin over right knee revealed black eschar surrounded by ecchymotic patch and erythema [Figure 3]. She also had resolving grouped vesicular lesions involving right L3, 4 dermatome, and clinically, suggestive of Herpes zoster. [ijstd.org]

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.