Skin necrosis induced by vitamin K antagonists

Abstracts

Os anticoagulantes orais que atuam através do antagonismo à vitamina K são utilizados na prática clínica há muito tempo, porém ainda há dificuldades no seu manejo e na condução das complicações. Entre as complicações, as mais conhecidas são os transtornos hemorrágicos, mas outras também devem ser reconhecidas, tais como a necrose induzida por varfarina. Esta é uma grave, porém rara complicação, cuja fisiopatologia é ainda obscura e cujas causas são indefinidas. Dentre as possíveis causas, as mais prováveis são a deficiência de proteína C e de proteína S, reações de hipersensibilidade e deficiência de fator VII. Há maior incidência desta complicação entre mulheres de meia-idade, acometendo preferencialmente mamas e glúteos. As medidas mais importantes para o tratamento são: suspensão imediata da droga, uso de heparina não fracionada ou de baixo peso molecular em doses terapêuticas, emprego da vitamina K e, eventualmente, infusão de plasma fresco congelado ou de proteína C ativada recombinante.

Anticoagulantes; varfarina; tromboembolismo venoso

REVIEW ARTICLE

Skin necrosis induced by vitamin K antagonists

Jose Manoel da Silva Silvestre^I; Fernando Thomazinho^II; Wander Eduardo Sardinha^I; Igor Schincariol Perozin^III; Domingos de Morais Filho^I

^IDoutor. Docente, Universidade Estadual de Londrina (UEL), Londrina, PR

^IIMédico, Serviço de Cirurgia Vascular, Hospital Universitário Regional do Norte do Paraná (HURNP), UEL, Londrina, PR

^IIIAcadêmico de Medicina, UEL, Londrina, PR.

Correspondence

Abstract

Oral anticoagulants acting via vitamin K antagonists have long been employed in the clinical practice. However, difficulties related to the management of treatment regimens and complications still persist. Among the complications, bleeding disorders are widely known, but others should also be taken into consideration, such as warfarin-induced skin necrosis. The pathophysiology of this rare but severe complication is still obscure, and its causes remain to be defined. Among possible causes, protein C and protein S deficiency, hypersensitivity reactions and VII factor deficiency are the most probable ones. There is an increased incidence of warfarin-induced skin necrosis among middle-aged women, usually affecting breasts and buttocks. The most important treatment measures are immediate discontinuation of the drug, use of unfractionated or low-molecular-weight heparin at therapeutic doses, use of vitamin K and, eventually, infusion of fresh-frozen plasma or recombinant activated protein C.

Keywords: Anticoagulants, warfarin, venous thromboembolism.

The oral anticoagulants were discovered in the 1930s through the observation of cattle that consumed spoiled sweet clover hay (Melilotus alba and M. officinalis) and showed hemorrhagic disease. Afterwards, this disease was attributed to the inhibition of prothrombin synthesis. Link isolated the causative agent, a compound he named dicumarol, and started a clinical investigation to create an anticoagulant, which was later used for rodenticidal purpose.¹ Link assigned patent rights of his compound to the Wisconsin Alumni Research Foundation, from which the name warfarin was derived. In the early 1950s, a failed attempted suicide of a U.S. navy recruit using the rodenticide led to a new clinical study in favor of warfarin in 1955; in the same year, the U.S. president at the time, Eisenhower, was treated with warfarin after a myocardial infarction.²

Warfarin is a coumarin derivative, as well as phenprocoumon and acenocoumarol. Its activity lies in the 4-hydroxycoumarin nucleus of a racemic mixture of two optical isomers, in which the S enantiomer has an anticoagulant action more potent than the R enantiomer.³ Among the coumarin derivatives, warfarin is the most widely used due to its favorable pharmacological properties, such as onset and duration of action with good bioavailability and rapid reversal.⁴

Warfarin acts on the vitamin K cycle by inhibiting reductase enzymes, particularly vitamin K epoxide reductase, which transforms vitamin K into its active form, vitamin KH2. Depletion of vitamin K-dependent coagulation factors — factors II, VII, IX, X — occurs as a consequence of warfarin action. Concomitantly, these oral anticoagulants also inhibit the production of the regulatory anticoagulant proteins C and S.⁵

Warfarin is a weak acid with high bioavailability and vigorous gastrointestinal absorption (ranging from 80 to 100%), and has albumin as the main binding protein. Peak warfarin plasma concentration occurs about 2 hours after administration, with a half-life of 36 to 42 hours. Warfarin accumulates in the liver, where it interferes directly with the synthesis of coagulation factors and is metabolized. It is excreted primarily via the kidneys, and age is the most important determinant of warfarin clearance, which falls at a rate of 1% per year, between the age of 20 and 70 years.⁶

The therapeutic effect of the vitamin K antagonists (VKA) varies from individual to individual, based on genetic and environmental factors that affect their pharmacokinetic and pharmacodynamic absorption.⁷ Genetic factors include mutations in the gene coding for the cytochrome P450 2C9 enzyme, which may reduce warfarin requirements in these individuals,^8,9 and mutation in the gene coding for factor IX, which may increase the risk of bleeding when VKA are used.^9-11 There is also a hereditary warfarin resistance, in which a 20-fold increase in warfarin dose might be necessary to achieve target anticoagulation.¹²

Several drugs can potentiate or inhibit the anticoagulant effect of warfarin,^1,10,13 which is also affected by diet type (lower or higher dietary intake of vitamin K).¹⁴ These facts require strict therapeutic control, with anticoagulant dose adjustments according to the prothrombin time, which should be performed using thromboplastins as the sensitivity index closest to the international sensitivity index and expressed as the international normalized ratio (INR).¹⁵

Warfarin has been widely used in the prevention of the development and propagation of thrombi, being employed in the treatment of deep venous thrombosis, pulmonary embolism,^7,9 cardiac arrhythmia, valvular heart disease, valvuloplasty using mechanical heart,⁷¹⁰ dilated cardiomyopathy, and in pharmacological or electrical cardioversion.⁵ Contraindications include: blood dyscrasias associated with hemorrhage or thrombocytopenia, cerebral aneurysms and dissections, known or suspected intracerebral hemorrhage, uncontrolled hypertension, ulcerations and active lesions in the gastrointestinal and urinary tract, recent neurological, ophthalmologic and urologic surgery, recent trauma, chronic alcoholism, and liver failure. Age alone is not a contraindication; however, special attention should be directed to the predertermined dose and therapeutic control, since in elderly patients, as previously commented concerning renal excretion, the predicted dose should be lower for an effective anticoagulation. The risk of accidental falls, hemorrhagic stroke and other complications is also potentially greater in this group of patients.¹²

Bleeding is the most frequent and important complication of treatment with VKA,^1,10,16,17 which might be related to INR values.¹⁸ Prospective studies analyzing these complications showed frequency of major bleeding ranging from 0.4 to 12%.¹⁷ However, recurrent thromboembolic events have been reported since the beginning of its history, including the purple toe syndrome, purpura fulminans, and priapism.¹⁴

Other adverse reactions include hypersensitivity reactions, cholestatic jaundice, hepatitis, vasculitis, nausea and vomiting, diarrhea, alopecia, etc..^1,7,10 The development of new thrombosis during treament has also been described as a complication, and the frequency of its occurrence in cases of venous thromboembolism is 3 to 15%.¹⁹

At a lower frequency, necrosis of the skin and subcutaneous tissue may occur in about 0.01 to 0.1% of the cases.^13,17,20-24 Warfarin-induced skin necrosis (WISN) was first described by Flood et al..¹⁵ At the time, however, it was erroneously diagnosed as thrombophlebitis migrans. Only in the late 1950s the causal relationship between tissue necrosis and oral anticoagulant administration was established.^15,18 According to Chan et al.,¹⁶ Verhagen, in 1954, established this relationship when he described 13 cases. It is worth noting that this complication may occur in the administration of any oral anticoagulant that antagonizes the action of vitamin K.

Of unknown etiology, it is still difficult to determine which patient might develop this side effect. Thrombosis, hypersensitivity, hemorrhage, deficiency in factor VII, protein C deficiency and toxicity of warfarin have been suggested as possible triggers for this complication.²⁵ It has also been observed in patients with systemic lupus erythematosus, as well as in association with protein C and/or S deficiency, lupus anticoagulant, and renal failure. In other situations, the occurrence of lesions has been observed in patients receiving treatment for deep venous thrombosis and pulmonary thromboembolism with daily warfarin doses greater than 10 mg, which are considered high initial doses, and their use might not be appropriate in the early treatment stage.^17,25

The concentration of protein C and S natural anticoagulants and factor VII, which have a short half-life, falls more rapidly than that of other factors involved in procoagulation (factors II, IX, and X), which have a half-life of 20 to 60 hours. As a result, the non-counterbalanced reduction of these proteins induces a period of potential prothrombotic effects, in which necrotic lesions may develop between the third and sixth day after oral anticoagulant administration in 90% of cases.^18,20 This leads to a recommendation for the concomitant use of heparin on the first days of treatment with VKA.⁵

The pathogenesis of WISN remains unclear. A failure is believed to occur in one or more natural anticoagulant factors in the microvasculature in addition to a pharmacologically induced fall in vitamin K-dependent coagulation factors.

Understanding the function of proteins C and S and antithrombin III has helped better elucidate the mechanisms involved in this complication. Hereditary protein C deficiency has been observed in one third of the patients who developed WISN.^14,16,21 These data are in agreement with the estimated frequency of 1 case of skin necrosis per 350 asymptomatic patients with protein C deficiency.¹⁹ However, this is not the only risk; other hypercoagulation disorders may be involved, such as protein S deficiency,^6,26 antithrombin III deficiency,²⁷ factor V Leiden,²⁸ and lupus anticoagulant.²⁹

Signs of WISN include paresthesia or feeling of pressure associated with sudden-onset, often painful, vaguely delineated erythematous lesions, which evolve with hemorrhagic spots. Dermal and subcutaneous edema produces lesions with an orange peel appearance. After 24 hours, petechiae and hemorrhagic blisters involve the area. The development of these hemorrhagic blisters characterizes an irreversible stage of skin necrosis. Ulcers might occasionally occur.

This condition affects mainly middle-aged, menopausal, obese women under treatment for deep venous thrombosis or pulmonary thromboembolism,³⁰ being less frequent in patients with cerebrovascular disease and atrial fibrillation.¹⁶ The reason for this prevalence among women remains unclear.

First symptoms occur between the first and 10th day of warfarin treatment, and lesions usually appear between the third and sixth day of treatment. There are some reports on late-onset WISN, 16 days after initiation of treatment.³¹ These cases are unlikely to have been caused by anticoagulant therapy; nevertheless, since anticoagulant levels fluctuate, the etiologic diagnosis of WISN should be considered.³²

Areas with greater abundance of adipose tissue are most frequently affected. In women, the most commonly affected area is the breast, followed by the buttocks and thighs; occasionally, the trunk, face and extremities are involved. In men, skin necrosis is rare in the trunk; however, it is more common in the penis, although this is also considered a rare occurrence.³³

Diagnosis is essentially clinical. Histopathological examination can be performed to better confirm the lesions; however, clinical history often prevails. Differential diagnosis of WISN should be made with necrotizing fasciitis, venous gangrene and other causes of skin necrosis, and this entity may also be confused with other skin diseases.¹⁶ Biopsy might show, initially, postcapillary microvascular injury with fibrin deposits in venules and small veins with hemorrhage sparing the arterioles and, at a later stage, diffuse necrosis in the dermis and subcutaneous tissue and microvascular thrombosis.²⁵ Direct immunofluorescence does not show specific alterations, and cases of IgM and/or C3 deposit have been described, possibly due to the concomitant presence of infectious mononucleosis.³⁴ Some authors have hypothesized that warfarin has a toxic effect on the precapillary and arteriolar junctions of the dermis. According to this hypothesis, warfarin produces endothelial injury that leads to proinflammatory cytokine release and capillary dilatation and rupture, resulting in petechiae, ecchymoses and necrotic lesions.^30,35,36 However, an associated immune mechanism has not been observed, as in heparin-induced lesions.³⁷

A single specific WISN treatment indicated by a specialist does not exist, neither do randomized controlled trials. Early phase treatment aims to prevent progression to skin necrosis by immediate withdrawal of oral anticoagulant and use of vitamin K, 10-20 mg intravenously. A dose of 10-20 mL/kg of fresh frozen plasma infusion may also be administered.²⁰ These measures aim to replace proteins C, S and coagulation factors, as well as to stimulate production (vitamin K). In protein C deficiency, replacement therapy with monoclonal antibody purified concentrate should be employed.²⁴ However, this therapy is not recommended over prolonged periods due to its high cost.

Interruption of warfarin treatment neither cures the patient nor changes the disease course. Therefore, anticoagulation should be maintained with heparin.³⁰ Although the use of heparin is also associated with skin necrosis, there are no reports in the literature concerning progression of this complication due to heparin use following warfarin-induced necrosis. The mechanism is different: heparin may induce immune-mediated thrombocytopenia, causing hemorrhage, or lead to an even more important clinical complication, which is the development of paradoxical thrombosis.³⁴

Despite using the measures described previously, most cases require debridement or even amputation.¹⁶ Prostacyclin has been used with promising clinical and histological results; however, validation of its use lacks randomized controlled clinical trials.^30,38 It is a potent vasodilator and inhibits antiplatelet aggregation, being used in vascular and thrombotic disorders.

As soon as clinical status has stabilized, warfarin therapy is resumed. However, reintroduction should be gradual and at low doses.^8,39 During this phase, heparin should be maintained for at least 1 week. Knowing the underlying cause is essential to treatment continuity; therefore, dosage of protein C, S, fibrinogen and fibrin degradation products should be assessed.This dosage assessment cannot be conducted during treatment with VKA. People suspected of having deficiency of vitamin K-dependent coagulation factors should be investigated only after oral anticoagulant therapy was discontinued for at least one week, as well as during heparin treatment, which does not change plasma protein C levels.

WISN is an uncommon situation, but with a severe course leading to the risk of amputation and death. Therefore, early detection and attention to the group at greater risk is essential to a rapid initiation of treatment. Of particular importance is the differential diagnosis with venous gangrene resulting from deep venous thrombosis, which has anticoagulation as treatment indication. Knowledge acquired from exams performed for studies on thrombophilia in cases of patients with a family history of venous thromboembolism is very useful in the care involving antithrombotic therapy and in the prevention of this complication.

References

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Publication Dates

• Publication in this collection
  26 Mar 2010
• Date of issue
  Dec 2009

History

• Accepted
  11 June 2009
• Received
  04 Mar 2008