Warfarin-induced skin necrosis: a narrative review of clinical features, risk factors, and treatment strategies

Abstract

Warfarin-induced skin necrosis (WSN) is a rare but potentially life-threatening complication of anticoagulation therapy, typically emerging within the first few days of warfarin initiation. It is characterized by painful, hemorrhagic skin lesions that can rapidly progress to full-thickness tissue necrosis. This review, designed as a narrative review, provides a comprehensive and updated overview of WSN, emphasizing its clinical presentation, underlying pathophysiology, risk factors, diagnostic challenges, treatment options, and prevention strategies. A broad literature search was conducted using PubMed, Google Scholar, ScienceDirect, and Scopus, including case reports, retrospective studies, and review articles published between 1943 and 2023. Articles were selected for their relevance to the etiology, clinical features, diagnosis, management, and outcomes of WSN. The review highlights that WSN predominantly affects middle-aged women and is often associated with protein C or S deficiency, initiation of high-dose warfarin without appropriate heparin bridging, and other thrombophilic disorders. Clinical outcomes vary depending on the timing of diagnosis and intervention; early recognition is often associated with complete recovery, whereas delayed treatment may lead to extensive tissue necrosis requiring surgical intervention in up to 40% of cases, with reported mortality rates as high as 15%. Prevention through risk stratification, cautious warfarin dosing, and early recognition remains critical. By consolidating current knowledge, this review aims to support clinicians in identifying patients at risk and implementing timely interventions to improve clinical outcomes.

Introduction

Warfarin (Coumadin), a coumarin-derived oral anticoagulant, is widely used for preventing thromboembolic events such as deep vein thrombosis (DVT), pulmonary embolism (PE), atrial fibrillation-related embolism, and prosthetic valve complications^[1]. Despite its clinical utility, warfarin has a narrow therapeutic index and is associated with adverse effects, primarily bleeding^[2–5]. Dermatologic reactions are rare but include urticaria, alopecia, and the potentially life-threatening warfarin-induced skin necrosis (WSN)^[6].

HIGHLIGHTS

• Comprehensive review covering 80 years (1943–2023) of warfarin-induced skin necrosis (WSN) literature.

• Identification of late-onset WSN cases occurring years after warfarin initiation.

• Introduction of AI applications for early risk prediction and management of WSN.

• Proposal of a practical clinical algorithm addressing the lack of formal guidelines.

• Expansion of rare risk factors beyond protein C/S deficiency, including human immunodeficiency virus, heparin-induced thrombocytopenia, and prothrombin complex concentrate -related cases.

WSN is a serious complication that rarely develops among warfarin users^[2]. WSN was first described by Flood et al in 1943, who reported a case of breast necrosis misdiagnosed as migratory thrombophlebitis. It was not until the early 1950s that the link to warfarin was recognized. By 2000, over 300 cases had been reported globally, though only one originated from the Middle East^[1,7,8]. While bleeding is the primary and most well-known adverse effect of warfarin, WSN remains a rare but serious complication^[2–5]. While the bleeding risks of warfarin are well recognized by clinicians, WSN and other interchangeability-related complications are often underdiagnosed or misattributed to other conditions, such as cellulitis, vasculitis, or necrotizing infections, especially in the early stages, as highlighted in multiple retrospective case series^[2,9–13]. Research of 111 cases reported common diagnostic delays, with many cases confirmed only after biopsy^[10]. One study noted that up to 40% of similar ulcerative skin conditions are initially misdiagnosed, underscoring the need for early recognition of WSN to avoid serious complications^[13].

Furthermore, although the pathogenesis and predisposing factors of WSN are described in the literature, there is limited consolidated guidance on its clinical management and prognosis. This gap presents a challenge for healthcare professionals seeking evidence-based strategies for diagnosis and treatment.

This narrative review aims to bridge this gap by providing a comprehensive and practical summary of the current literature on WSN. By consolidating available evidence, this review seeks to support early recognition and improve outcomes in patients at risk of or affected by WSN.

Methods

This article is a narrative review that aims to provide an updated and comprehensive overview of WSN, focusing on its clinical presentation, pathophysiology, risk factors, diagnosis, treatment, prognosis, and prevention strategies.

A systematic search of the literature was conducted using four electronic databases: PubMed, Google Scholar, ScienceDirect, and Scopus. The search covered publications from 1943 to 2023 and used the following search terms in various combinations: “warfarin-induced skin necrosis,” “warfarin skin necrosis,” “coumarin necrosis,” “anticoagulant complications,” “protein C deficiency,” “protein S deficiency,” “warfarin complications,” “cutaneous necrosis,” “warfarin-induced tissue damage,” and “warfarin-induced coagulopathy.” The search strategy included Boolean operators and truncation to maximize relevant yield.

Inclusion criteria encompassed

• Case reports, case series, retrospective studies, review articles, and systematic reviews focused on the clinical aspects, risk factors, management, or prognosis of WSN.

• Articles published in English or translated by certified academic or professional means.

• Human studies with available abstracts or full texts.

Exclusion criteria included

• Non-English publications not translated by certified academic or professional means.

• Studies with limited access to full texts or unverifiable sources.

• Animal studies, in vitro studies, or editorials without clinical relevance.

• Articles lacking sufficient detail on diagnosis or treatment of WSN.

A total of 210 articles were initially retrieved. After screening titles and abstracts for relevance and removing duplicates, 66 articles were selected for full-text review and inclusion in this study (Table 1). The final selection was based on their relevance to WSN’s etiology, presentation, pathogenesis, diagnostic process, treatment strategies, and clinical outcomes (Fig. 1).

Table 1.

Characteristics of the articles included in the study

Author	Publication year	Type of article	Key elements
McKnight JT et al	1992	Review article	History of WSN, its clinical presentation, pathogenesis, and possible treatments.
Morán-Mariños C et al	2021	Systematic review	SR of case reports, presenting the clinical characteristics and mortality-related factors.
Nazarian RM et al	2009	Case and review	Case reports a 79-year-old patient who developed WSN, was on warfarin, and had acquired protein C and antithrombin III deficiency.
Cole MS et al	1988	Cases and review
Chan YC et al	2000	Review article	The article reviews the history of WSN, its clinical presentation, histopathology, predisposing factors, treatment, and prevention.
Zhang L et al	2022	Case report	Case reports a 62-year-old patient who developed WSN following recommencement of warfarin and the use of Prothrombinex-VF.
Alves DW and Chen IA	2002	Case report	Case reports a 73-year-old patient who developed WSN following administration of warfarin.
Flood EP	1943	Case report	Case reports a 49-year-old patient taking coumarin-derived anticoagulant (dicumarol) who developed WSN but falsely attributed to thrombophlebitis migrans disseminate.
Verhagen H	1954	Case series	Case reports patients develop warfarin skin necrosis while on dicumacyl or dicumarol.
Eby CS	1993	Review article	The article reviews clinical presentation, histopathology, pathophysiology, and treatment.
Scandling J and Walker BK	1980	Case report	Case reports a 66-year-old Patient developed WSN while following administration of warfarin
Nalbandian RM et al	1971	Case report	Case reports a 44-year-old patient developing ischemic lesions following warfarin therapy, followed by spontaneous resolution with heparin.
Teepe RG	1986	Case report	Case reports a 57-year-old patient with acquired protein C deficiency who developed coumarin-induced skin necrosis while on coumarin-derived anticoagulant.
Pourdeyhimi N and Bullard Z	2014	Case report	Case reports a 52-year-old patient who developed warfarin skin necrosis while on warfarin due to DVT.
Barkley C et al	1989	Case report	Case reports a 61-year-old patient who developed WSN of penis while on warfarin for PE.
Weinberg AC et al	1983	Case report	Case reports a 33-year-old patient who developed WSN of penis while on warfarin for PE.
Koch-Weser J	1968	Review article	The article reviews the clinical presentation and the possible predisposing factors.
Essex DW et al	1998	Case report	Case reports a patient developed late onset WSN after 16 days of intuition of warfarin for DVT.
Pinzón A et al	2012	Case report	Case reports a patient who developed WSN in penile skin after the initiation of warfarin for venous and arterial thrombosis, in the presence of protein C and S deficiency.
O’Dempsey RM et al	2015	Case report	Case reports a 62-year-old patient who developed skin necrosis in multiple areas following resumption of warfarin therapy.
Parsi K et al	2003	Case report	Case reports a 36-year-old patient with acquired protein C deficiency who developed skin necrosis following reintroduction of warfarin.
Malik U et al	2017	Case report	The case reports a 68-year-old patient with factor V Leiden deficiency, who developed late-onset skin necrosis after 12 years of warfarin initiation, with renal involvement.
Kurt M et al	2007	Case report	The case reports a 53-year-old patient with acquired protein C and S deficiency who developed skin necrosis after 12 years of warfarin initiation.
Nsaful J et al	2020	Case report	Case reports a 47-year-old-patient who developed skin necrosis after reintroduction of higher dose of warfarin.
Franson TR et al	1984	Case report	Case reports a 25-year-old patient on warfarin, who developed skin necrosis with recent infection with EBV-caused mononucleosis.
Cameron AR et al	1974	Case report
Bayrakçı S and Korkmaz P	2023	Case report	Case reports a 53-year-old patient who developed skin necrosis 5.5 years after initiation of warfarin.
Goldberg SL et al	1991	Case report	Case reports a 38-year-old patient with inherited protein S deficiency who developed WSN after prolonged use of warfarin for 15 years.
Sklar LR and Messman A	2017	Case report	Case reports a 60-year-old patient who developed skin necrosis following recommencement of warfarin.
Stewart AJ et al	1999	Case series	The study reports three cases of WSN; in two of them, antiphospholipid antibodies were positive.
Ward CT and Chavalitanonda N	2006	Case report	Case reports a 43-year-old patient with protein S deficiency who developed WSN.
Schleicher SM and Fricker MP	1980	Case report	Case reports a 75-year-old patient presenting with skin necrosis following initiation of warfarin therapy.
Simman R et al	2015	Case report.	Case reports a 59-year-old patient who developed tissue necrosis extending to bone following warfarin therapy.
Marčić M et al	2016	Case report	Case reports a 50-year-old patient with protein C deficiency presenting with skin necrosis following warfarin therapy.
Park JE et al	2016	Case report	Case reports a 52-year-old patient with hyperparathyroidism and undergoing peritoneal dialysis, who developed skin necrosis mimicking calciphylaxis following the administration of warfarin.
Liaw TY and Chang CH	2014	Case report	Case reports a 15-year-old patient who developed skin necrosis with acquired protein C deficiency following warfarin administration.
Au AF et al	2012	Case report	Case reports a 53-year-old patient who developed skin necrosis of both breasts following warfarin initiation.
Patel NB and Jain G	2022	Case report	Case reports a 63-year-old patient who developed skin necrosis following warfarin therapy.
Mungalsingh CR	2012	Case report	Case reports a 82-year-old patient who developed extensive skin necrosis following prolonged warfarinisation.
Sallah S et al	1998	Case series	The study addresses the association between hereditary protein deficiency and WSN in family members.
Gelwix TJ and Beeson MS.	1998	Case report and review	The case reports a 72-year-old patient who developed skin necrosis of the left foot and breast after warfarin initiation.
Moll S	2004	Case report	Case reports a 29-year-old patient who developed skin necrosis of the right breast after warfarin initiation.
Makris M et al	1996	Case report	Case reports a 21-year-old patient with factor V Leiden mutation developed skin necrosis of the left breast after warfarin initiation.
Kakagia DD et al	2014	Case report	Case reports a 62-year-old patient presenting with skin necrosis following warfarin therapy.
Hermans C et al	2012	Case report	The case reports a 21-year-old patient with hereditary protein C deficiency who was put on dabigatran for the prevention of WSN.
Mitchell CA et al	1987	Case report	Case reports a 51-year-old patient who developed skin necrosis and acquired protein C deficiency following warfarin administration.
Mehta RL et al	1990	Case control study	The study assesses the association between protein C and systemic calciphylaxis.
Kant KS et al	1992	Case reports	Two cases with protein S deficiency and WSN suggesting the cause to be peritoneal dialysis loss of protein S.
Plana-Pla A et al .	2019	Case report	Case reports a 20-year-old patient with lupus and protein S deficiency who developed extensive skin necrosis in the absence of warfarin therapy.
Amster MS et al	1993	Case report	Case reports a 23-year-old patient with lupus and positive APS and protein S deficiency developed extensive skin necrosis in absence of warfarin therapy.
Fraga R et al	2018	Case report	Case reports a 40-year-old patient who developed skin necrosis after recommencement of warfarin therapy.
Gailani D et al	1990	Case report	Case reports a 30-year-old patient with hereditary protein S deficiency developed WSN after initiation of warfarin therapy.
Craig A et al	1990	Case report	Case reports a 21-year-old patient with hereditary protein S deficiency and skin necrosis following nicoumalone administration.
Kiehl R et al	1987	Case report	The case reports a 25-year-old patient with hereditary ATIII deficiency and development of skin necrosis following warfarin therapy.
Hirsh J et al	1989	Review article	The article reviews the incidence and the clinical features of ATIII deficiency.
Moreb J, Kitchens CS	1989	Case reports	Case report of a patient with lupus anticoagulant and protein S deficiency who developed acute cutaneous necrosis in the absence of prior warfarin exposure.
Smith EC et al	2023	Case report	Case reports a 58-year-old patient who developed skin necrosis at the site of PCC infusion for the reversal of warfarin toxicity.
Dhawan N	2020	Case report	Case reports a 56-year-old patient with HIT who developed WSN.
Fawaz B et al	2016	Case report	Case reports a 64-year-old patient who developed WSN in the setting of HIT.
Bhaijee F et al	2010	Retrospective study	The study reported the occurrence of WSN in patients with HIV and TB.
Tilton C et al	2019	Case report	The case reports a 44-year-old patient with May–Thurner syndrome who develops WSN.
Jukic I et al	2007	Case report	The case reports a 37-year-old patient with prothrombin mutation who presents with recurrent cerebral venous sinus thrombosis following discontinuation of anticoagulants.
Elrod JP et al	1990	Review article	The article reviews the history of WSN, its clinical presentation, pathogenesis, and possible treatments.
Miura Y et al	1996	Case series	The study reports four cases of WSN and a literature review about the disease.
Zahra T et al	2022	Case report	Case reports a 14-year-old patient who developed skin necrosis following re-initiation of warfarin.
Haimovici H, Bergan JJ.	1987	Literature review	Review of the difference between Coumadin-induced skin necrosis and venous gangrene of the extremities.

Figure 1.

Flowchart of literature search, screening, and selection process for the narrative review on warfarin-induced skin necrosis.

Data were synthesized thematically to identify patterns across risk factors, clinical features, diagnostic approaches, and treatment outcomes. Notable case reports, rare presentations, and key historical milestones were also highlighted to provide chronological and contextual depth. Due to the narrative nature of this review, no formal meta-analysis or quality assessment was conducted.

This methodology aims to ensure a broad yet focused overview of WSN, offering clinicians a practical and evidence-informed reference for improving patient care.

Bias mitigation and limitations

• To minimize selection and publication bias, a comprehensive search of three databases was conducted, and studies were screened in two stages. Articles were included based on predefined criteria focusing on relevance to WSN’s clinical and pathophysiological features. However, this review is narrative in nature, and no formal risk-of-bias or quality assessment tools were applied. Non-English publications translated by certified academic or professional means and unpublished literature were excluded, which may introduce language and publication bias. Despite these limitations, efforts were made to include diverse case presentations across time periods and geographic regions to enhance the generalizability of findings.

Although a broad literature search strategy was implemented, this review does not follow a formal systematic review (SR) protocol such as PRISMA, and findings should be interpreted accordingly.

Epidemiology

Incidence rates

WSN is a rare complication of anticoagulant therapy, with reported incidence ranging between 0.01% and 0.1% among patients receiving warfarin^[1,14]. While infrequent, its clinical significance is substantial due to the potential for severe tissue damage, surgical morbidity, and mortality.

Gender and age distribution

WSN most commonly affects middle-aged individuals, particularly postmenopausal obese women. The reported age range of affected individuals spans from 15 to 93 years, with a median age of approximately 54 years^[1,2]. Females account for 66%– 75% of reported cases, which may be attributed to hormonal and physiological differences influencing coagulation pathways^[1,8,14]. However, the risk in males appears to increase with advancing age and may approach that of females in older populations^[15].

Risk in specific patient populations

WSN is more likely to occur in patients with inherited thrombophilias, including protein C or S deficiency, antithrombin III deficiency, and factor V Leiden mutation^[14,16–18]. Increased risk is also noted in patients started on high-loading doses of warfarin without adequate heparin bridging, those with liver dysfunction, autoimmune diseases such as antiphospholipid syndrome (APS), and individuals restarting warfarin after interruption or non-compliance^{[1,2,17–21]}. Rare associations have been reported in patients with human immunodeficiency virus (HIV), those on dialysis, and those receiving warfarin reversal agents like Prothrombinex-VF or prothrombin complex concentrate (PCC), which can trigger transient hypercoagulable states^[22–25].

Clinical presentation

Onset and timing

Usually, the lesions appear within 2 weeks following the start of warfarin therapy, particularly between the 3rd and 10th day of therapy, but some studies reported that it could develop from months up to 10 years of warfarin use^[1,2,8,10]. In these cases, it is unclear whether the skin necrosis is due to warfarin or not^{[1,20–22,26–30]}. There is a reported case of a patient with infectious mononucleosis presenting with late onset of WSN (after 18 months of therapy), another case in which necrosis occurred 3 years after initiation of warfarin, another case presented after 5 years, and another one after 12 years^[19,31–35]. Many of the late-presenting cases were attributed to a prothrombotic state predisposition or drug–drug interactions, and some were due to patient non-compliance or discontinuation and recommencement of the drug^{[16,23,36–38]}.

Common sites affected

Usually, one body part is affected – most commonly the lower limbs, especially the thighs and buttocks^{[2,10,11,17,26,27]}. Other commonly affected areas include the breasts in women, the trunk (including chest and abdomen), face, extremities, feet, and the penile skin in men^{[1,2,14,17,39–41]}. In one-third of cases, there are multiple asymmetric lesions^[11,26,27].

Symptom progression

Usually, the patient presents initially with paresthesia or a pressure sensation and poorly demarcated erythema^[1,2,10,11]. These lesions are sudden and painful and may have a peau d’orange appearance (due to accumulation of edema in the dermis and subcutaneous tissue)^[1]. Petechial hemorrhages appear next, usually within the borders of the affected skin^[1,2]. Within 24 h of the appearance of initial lesions, hemorrhagic bullae and tissue necrosis typically develop^[1,2,14]. Necrosis usually extends to the subcutaneous tissue and is covered with eschar that eventually sloughs, leaving soft-tissue defects^[1,14]. Although uncommon, deeper involvement including muscle^[42], tendons, and bone has been reported^[43]. The spectrum of tissue damage ranges from self-limited, superficial loss that heals with granulation to extensive tissue sloughing requiring debridement, skin grafting, or even amputation^[14] (Table 2).

Table 2.

Summarizing the clinical presentation of WSN

Feature	Details
Commonly involved sites	Thighs, buttocks, breasts, and trunk
Presentation timing	2–10 days of starting warfarin therapy, rarely months or years after
Common associated risk factors	High loading dose of warfarin, lack of heparin-bridging therapy, protein C deficiency, protein S deficiency, anti-thrombin III deficiency

Diagnosis

The diagnosis of WSN is primarily clinical and relies on recognizing the temporal relationship between the initiation of warfarin therapy and the onset of symptoms, typically within the first 3–10 days^{[2,10,14,26–28]}. The presence of known risk factors such as protein C or protein S deficiency, high-dose warfarin loading, or lack of heparin bridging further supports the diagnosis^{[1,2,9,15,31,44,45]}. A detailed history of anticoagulant use, including dosing, duration, and any recent interruptions or re-initiations, is essential. In most cases, diagnosis is clinical, and skin biopsy is not routinely required^[1,46]. However, in atypical or late-onset presentations where the diagnosis is uncertain, biopsy may be helpful. Histopathological findings typically show sub-epidermal hemorrhage, epidermal necrosis, congestion, and thrombosis of superficial dermal capillaries, usually without significant inflammatory infiltrates^[9,11,14]. These histological features should be interpreted in the context of clinical findings, as they may overlap with other forms of skin necrosis.

Differential diagnosis

Due to the non-specific nature of early skin lesions and the potential for rapid progression, WSN can be mistaken for several other conditions. A broad differential diagnosis should be considered, particularly in patients with atypical features, delayed onset, or unusual lesion distribution. Among the conditions that may resemble WSN are pyoderma gangrenosum, cry fibrinogenemia, fulminant purpura, hematoma formation due to over-anticoagulation, purple toe syndrome, allergic dermatitis, and pressure ulcers. Other potential mimickers include necrotizing fasciitis, cellulitis, Fournier gangrene, and cutaneous loxoscelism caused by spider bites. Additionally, calciphylaxis, heparin-induced skin necrosis, snake venom-related dermal necrosis, and necrosis associated with APS should also be considered^[2,10,47]. Clinical overlap between WSN and calciphylaxis is particularly challenging in ESRD patients. In one case, a dialysis patient developed painful lower limb ulcers shortly after warfarin initiation; although calciphylaxis was initially suspected due to vascular calcification and hyperparathyroidism, biopsy revealed fibrinoid necrosis without vascular calcification, confirming WSN. This example highlights the critical role of biopsy and timing in distinguishing WSN from its mimics^[47].

Distinguishing WSN from these conditions requires careful attention to the clinical context, particularly the timing of symptom onset in relation to warfarin initiation (Table 3). As emphasized in a 1987 editorial by Haimovici and Bergan, “there is a fundamental difference between gangrene resulting from massive venous occlusion and the skin necrosis resulting from Coumadin, which involves capillary hemorrhage and thrombosis of localized skin venules,” underscoring the importance of differentiating WSN from venous gangrene secondary to phlegmasia cerulea dolens, which typically begins distally and progresses proximally^[40].

Table 3.

Differential diagnosis table: conditions mimicking WSN

Condition	Key features	Differentiation
Necrotizing fasciitis	Rapid spread, crepitus, systemic signs	No link with warfarin; deeper tissue involvement
Calciphylaxis	Painful nodules in dialysis patients	Associated with ESRD, high phosphate, not warfarin-specific
Pyoderma gangrenosum	Ulcerative, autoimmune background	No relation to anticoagulants
Purple toe syndrome	Cholesterol emboli, painful blue toes	Seen with warfarin but non-necrotic
HIT-related necrosis	Skin necrosis at heparin injection sites	Low platelet count + recent heparin exposure
Coumarin-induced vasculitis	Inflammatory component	Biopsy shows leukocytoclastic vasculitis
Spider bite (loxoscelism)	Necrotic ulcer at bite site	History of bite, localized lesion

Pathogenesis

The exact cause of WSN is still obscure, what determines which patient receiving warfarin will develop skin necrosis is also unknown. The most widely attributed theory is a transient hypercoagulable state that follows warfarin therapy^[1,2,10]. Other theories include hypersensitivity reaction to the drug, hemorrhage, factor VII deficiency, and direct toxic effects of warfarin^[9,26,27]. Other cases have been reported with factor V heterozygosity^[48]. Several predisposing factors are associated with the warfarin-induced hypercoagulable state, including hereditary thrombophilia’s e.g., protein C deficiency, protein S deficiency; anti-thrombin III deficiency; factor V Leiden, presence of lupus anticoagulant, warfarinisation with large loading doses with supratherapeutic international normalized ratio (INR) levels, lack of heparin-bridging therapy, and premature heparin discontinuation^{[1,2,9,15,31,44,45]}.

Protein C and protein S deficiency

Protein C and protein S are vitamin K-dependent glycoproteins that function as critical anticoagulants by regulating the coagulation cascade. Activated protein C, generated via thrombomodulin from vascular endothelium, inactivates factors Va and VIIIa^[1,4,6,32]. Protein S acts as a cofactor that enhances this action^[2,49].

Protein C deficiency, most commonly implicated in WSN, is typically inherited in an autosomal dominant pattern. It presents clinically as recurrent familial thrombosis and often necessitates long-term anticoagulation^[1,50]. Type I deficiency is characterized by reduced plasma levels of protein C, while Type II involves normal antigen levels but diminished functional activity^[9]. Acquired protein C deficiency can result from liver disease, vitamin K deficiency, sepsis, disseminated intravascular coagulation, or warfarin therapy itself^[9,32,51]. Notably, Mitchell et al described a rare case involving an acquired immunoglobulin inhibitor against protein C^[18].

Protein S deficiency can also be inherited or acquired and contributes similarly to recurrent thromboembolic events^{[1,24,52–54]}. Acquired protein S deficiency has been observed in patients with end-stage renal disease undergoing dialysis and in individuals with APS^[24,52–55]. Protein S enhances the anticoagulant effect of protein C by serving as its cofactor; thus, deficiency in either protein leads to impaired inactivation of factors Va and VIIIa, fostering a prothrombotic state^[2,49,56,57]. Figure 2 shows the effect of warfarin on protein C and S^[58].

Figure 2.

The effect of warfarin on protein C and protein S.

The initiation of warfarin therapy leads to a rapid decline in protein C and protein S levels due to their relatively short half-lives (protein C ~8 h), in contrast to other vitamin K-dependent clotting factors such as factors II, IX, and X (24–72 h)^[1,37]. This creates a transient hypercoagulable state, especially in individuals with underlying deficiencies, predisposing them to microvascular thrombosis and subsequent skin necrosis^{[1,9,32,39,44,49]}. This mechanism explains the early onset of WSN following warfarin initiation. However, late presentations may occur due to re-introduction of warfarin or patient non-compliance^[1].

Antithrombin III deficiency

Anti-thrombin III is a protein released by the liver, and its main function is to inhibit factor IIa (thrombin) and factor Xa, as well as factors IXa, XIa, and XIIa^[1]. Few cases have been reported about the association of antithrombin III deficiency with WSN^[59]. Antithrombin III deficiency is an inherited disorder with an autosomal dominant pattern and a variable range of severity from an asymptomatic state to thrombotic events in early teens^[51].

APS and lupus anticoagulant

Lupus anticoagulant is a group of antibodies usually associated with a hypercoagulable syndrome called APS, also associated with rheumatological diseases, especially systemic lupus erythematosus. It has been reported that the presence of lupus anticoagulant has been associated with WSN^[9,60].

Other risk factors

Rare complications were previously mentioned in the literature; this includes WSN associated with the use of an anticoagulation reversal agent, which was Prothrombinex-VF^[23,52]. In these cases, it was hypothesized that Prothrombinex-VF led to a state of transient hypercoagulability because it contains a concentrate of factors II, IX, and X with no protein C or protein S^[6].

Another case was reported in which WSN was associated with the administration of PCC for reversal of the warfarin effect, but its mechanism remains unclear^[25]. Some cases have linked WSN with heparin-induced thrombocytopenia (HIT), attributing it to the hypercoagulable state that occurs during HIT^[21,61]. A study done by Bhaijee et al reported that WSN is linked to hypercoagulability that occurs with HIV, which is a known risk factor for venous thromboembolism (VTE)^[22]. Another case reported a patient with WSN related to liver dysfunction and May–Thurner syndrome^[20] (Table 4).

Table 4.

Summary table: thrombophilic risk factors for WSN

Factor	Mechanism	Notes
Protein C deficiency	Loss of anticoagulant control → ↑ thrombosis	Most common, inherited or acquired
Protein S deficiency	Impairs protein C activity	Enhanced procoagulant state
Antithrombin III deficiency	Insufficient thrombin inhibition	Less common
Lupus anticoagulant/APS	Autoimmune → ↑ thrombosis	Consider in SLE patients
Factor V Leiden mutation	APC resistance	May coexist with protein C/S deficiency
High warfarin loading dose	Exaggerated protein C drop	Especially >10–15 mg
No heparin bridging	No cover during prothrombotic phase	Avoid in high-risk patients

Treatment

Early recognition and immediate discontinuation of warfarin are crucial in managing WSN, as continued use worsens hypercoagulability and necrosis^[1,6]. Intravenous vitamin K (5–10 mg) should be given slowly to restore clotting factors^[5,16]. In severe cases, PCC is preferred over fresh frozen plasma (FFP) due to higher efficacy and lower risk of fluid overload^[6,11,62].

For patients needing ongoing anticoagulation, unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) should be started promptly^[1,16]. Direct oral anticoagulants (DOACs) like rivaroxaban and apixaban are emerging alternatives due to favorable pharmacokinetics^[22]. In selected high-risk patients with severe protein C deficiency, DOACs may offer a safer alternative. A reported case demonstrated successful prevention of recurrent necrotic lesions after switching from warfarin to dabigatran, despite prior bridging failure. This suggests that direct thrombin inhibitors may be effective in managing hereditary thrombophilia when warfarin is poorly tolerated^[50]. In protein C or S deficiency, supplementation or activated protein C administration may improve outcomes^[8,28]. Management is further complicated when WSN coexists with thrombocytopenia or tropical infections. A case from conflict-affected Sudan involved a 34-year-old male with mechanical valves who developed WSN after self-dosing warfarin; concurrent dengue fever delayed anticoagulation and debridement. Tailored care with vitamin K, delayed LMWH, and staged wound management led to recovery, highlighting the need for context-specific protocols in low-resource settings^[63]. Wound management depends on severity. Mild cases require antiseptic dressings and antibiotics if needed^[2,64]. Hyperbaric oxygen therapy may aid healing^[38], while extensive necrosis necessitates surgical debridement or skin grafting; amputation is rare but lifesaving when needed^{[31,32,65,66]}. A management algorithm (Fig. 3), based on case reports and clinical recommendations, is proposed to guide anticoagulation reversal, wound care, and bridging strategies, despite the lack of formal American College of Chest Physicians (ACCP) or the American Society of Hematology (ASH) guidelines^[1,15,62]. If necrosis develops, prompt reversal with vitamin K, FFP, and heparin is indicated, bearing in mind that heparin itself can, rarely, cause necrosis or HIT^[1].

Figure 3.

Algorithm for the recognition and management of warfarin-induced skin necrosis. This clinical pathway illustrates a stepwise approach to managing WSN, including warfarin discontinuation, reversal of anticoagulation, bridging strategies, wound care based on severity, and long-term anticoagulation planning. The algorithm is based on consolidated evidence from over 60 case reports and review articles spanning 1943 to 2023.

While warfarin remains in use, DOACs are increasingly favored in non-valvular indications due to fewer complications. However, they are unsuitable for patients with mechanical valves or triple-positive APS^[67,68].

Emerging AI tools are increasingly being integrated into anticoagulation management and dermatologic diagnostics. For instance, machine learning algorithms have been applied to predict VTE risk in hospitalized patients and improve anticoagulation control in atrial fibrillation, which could be adapted to flag patients at risk of WSN^[69,70]. AI-powered clinical decision support systems have shown promise in improving adherence and medication safety in patients on warfarin therapy^[71]. Additionally, a recent AI-enhanced platform was developed to detect potential drug interactions with warfarin and suggest alternative regimens in real-time^[72]. In dermatology, convolutional neural networks are being trained to distinguish necrotic skin lesions from mimickers such as vasculitis or cellulitis, potentially aiding early differentiation of WSN^[73,74]. These advancements, though still in early stages, underscore the potential of AI to support clinicians in WSN diagnosis, risk stratification, and personalized therapy – especially in settings where specialist input is limited.

Prognosis

The prognosis of WSN depends on the timing of diagnosis, extent of necrosis, underlying comorbidities, and the promptness of intervention. Early recognition and discontinuation of warfarin before hemorrhagic bullae formation improves outcomes^[34,75]. Delayed treatment may lead to extensive tissue necrosis requiring surgical intervention in up to 40% of cases, with the overall mortality rate around 15% within 3 months, mainly due to severe necrosis, infections, sepsis, or multi-organ failure^[1,11]. Poor prognostic factors include advanced age, extensive tissue involvement, diabetes, and immunosuppression^[6,7]. Surgical intervention often leads to prolonged hospitalization and delayed recovery^[31,66].

Patients treated early may recover fully, especially if necrosis is superficial. However, deep tissue involvement can result in permanent disfigurement, disability, and psychological distress, particularly when cosmetically sensitive areas are affected^[41,65,76]. Severe cases may lead to chronic pain, limited mobility, and psychological trauma, necessitating multidisciplinary rehabilitation^[32,34]. Recurrence is a concern, notably in patients with hereditary thrombophilias or underlying pro-thrombotic conditions, even without warfarin re-exposure^[8,49].

Prevention

Preventing WSN hinges on early clinical vigilance, particularly during the initiation of anti-coagulation. Clinicians should respond promptly to patient complaints of pain, discomfort, or burning at cutaneous sites, as these may precede necrosis^[1]. Once necrosis occurs, treatment options become limited, emphasizing the need for early recognition^[9,77].

Screening high-risk individuals for inherited thrombophilias (protein C, protein S, and anti-thrombin III deficiencies) before starting warfarin is advisable, although its predictive value is debated and may delay therapy initiation^{[1,9,46,50,78]}. Preventive measures include using DOACs when possible^[22,62] and cautious warfarin reintroduction with low doses and heparin bridging^[16]. Protein C replacement is advised for congenital deficiencies^[18,30,40]. Warfarin should be introduced gradually, targeting a therapeutic INR over 10–12 days, avoiding high loading doses (>15 mg) and sharp INR fluctuations^[1,9,79]. Heparin bridging is critical, with concurrent heparin continued until a stable therapeutic INR is achieved, typically within 5 days^[14]. Regular INR monitoring and close observation for early skin changes are essential, especially during aggressive anti-coagulation phases^[14,75].

Limitations

This review has several limitations inherent to its narrative design. First, the literature search was restricted to articles published in English, which may have introduced language bias and excluded potentially relevant studies from non-English-speaking regions. Secondly, while multiple databases were searched and thematic synthesis was applied, no formal risk-of-bias assessment or quality appraisal tool (e.g., PRISMA and AMSTAR) was used due to the non-systematic nature of this review.

Thirdly, the included studies were largely composed of case reports and small case series, which may limit the generalization of findings due to publication bias and selective reporting. Additionally, there may be under-reporting of mild or self-resolving cases of WSN, leading to potential overestimation of severity and mortality in the literature.

Finally, variations in diagnostic criteria, management strategies, and follow-up duration across different studies make it difficult to perform uniform comparisons or establish causal relationships. Therefore, while this review offers a comprehensive synthesis of available evidence, its findings should be interpreted with caution.

Conclusion

WSN, although uncommon, requires a vigilant and proactive clinical mindset. Early recognition depends not solely on diagnostic tools but on the clinician’s ability to correlate risk factors, symptom timing, and anti-coagulation history. Biopsy findings are often non-specific, reinforcing the importance of clinical judgment in the early stages. Effective management begins with a high index of suspicion, careful risk stratification, and the prompt development of an individualized treatment plan. Clinicians should also incorporate emerging tools – such as AI-based prediction models and decision-support systems – to guide safer anti-coagulation strategies. By maintaining heightened awareness and adopting tailored preventive approaches, healthcare providers can significantly reduce the morbidity and long-term impact of WSN.

Ethical approval

Not applicable. This study is a narrative review of previously published literature and does not involve human participants or animal subjects.

Consent

Not applicable. This study is a narrative review and did not involve any individual patient data, case reports, or images requiring consent.

Sources of funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The study sponsors had no role in the collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.

Author contributions

R.M.O.: Conceptualization, Data curation, Formal analysis, Methodology, Project administration, Software, Supervision, Validation, Writing – original draft, and Writing – review & editing. A.S.: Conceptualization, Data curation, Formal analysis, Methodology, Project administration, Software, Supervision, Validation, Writing – original draft, and Writing – review & editing. R.M.: Data curation, Resources, Software, and Writing – original draft. E.M.: Data curation, Funding acquisition, and Visualization. T.T.: Data curation, Funding acquisition, and Visualization.

Conflicts of interest disclosure

The authors declare no conflicts of interest related to this work.

Research registration unique identifying number (UIN)

Not applicable. This study is a narrative review based on previously published literature and did not involve new research on human participants requiring registration.

Guarantor

Alsadig Suliman accepts full responsibility for the work, had access to the data, and controlled the decision to publish.

Provenance and Peer Review

Not commissioned; externally peer reviewed.

Data availability statement

No new data was generated or analyzed in this study. All data included are derived from published articles, which are cited in the references.

Presentation

None.