Livedoid Vasculopathy

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Background

Livedoid vasculopathy (LV), or livedoid vasculitis, is a hyalinizing vascular disease characterized by thrombosis and ulceration of the lower extremities. Livedoid vasculopathy can evolve into a dermatologic finding termed atrophie blanche (AB). Livedoid vasculopathy is a distinct condition that is not usually the result of other diseases, as Jorizzo elegantly noted in 1998.[1]

A recent consensus document has determined AB is related to venous insufficiency. AB has 2 forms: the LV-AB complex and AB with chronic venous insufficiency. Those separate forms require different approaches to treatment.[2]

Biopsy specimens of livedoid vasculopathy aid in diagnosing this condition, but they are not pathognomonic. The skin manifests with segmental hyalinizing vascular involvement of thickened dermal blood vessels, endothelial proliferation, and focal thrombosis without nuclear dust. No true vasculitis is evident. While direct immunofluorescence study reveals immunoglobulin and complement components in the superficial, mid-dermal, and deep dermal vessels, this is merely the result of spongelike absorption of immune components in the thickened vessels. They do not appear to be pathogenic. Pathogenesis involves hyalinization and thrombosis rather than leukocytoclastic vasculitis.

In 1955, Feldaker et al[3] described what is now termed livedoid vasculopathy as livedo reticularis with summer ulcerations. In 1967, Bard and Winkelmann[4] used the terms segmental hyalinizing vasculitis and livedo vasculitis to describe livedoid vasculopathy.

In 1998, Papi et al[5] noted that platelet and lymphocyte activation was present in livedoid vasculopathy, whereas the levels of inflammatory mediators were in the reference range; in particular, they noted increased expression of platelet P-selectin.

Hairston et al[6] reviewed the records of 42 patients with proven livedoid vasculopathy. The following is a summary of the epidemiological and testing data:

Note the image below.


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Preferred sites of vascular involvement by selected vasculitides.

Pathophysiology

While the etiology of livedoid vasculopathy is not yet fully defined, it likely has a procoagulant pathogenesis.[6] Factor V Leiden mutation,[7] heterozygous protein C deficiency,[8] and other inherited hypercoagulable states have been linked to livedoid vasculopathy.[9] In particular, states such as hyperhomocysteinemia, which results in increased clotting, plays a role in livedoid vasculopathy.[10] Plasminogen activator inhibitor (PAI)–1 is an important inhibitor of the fibrinolytic system, and the PAI-1 promoter 4G/4G genotype, in which PAI-1 is increased, has been liked to livedoid vasculopathy.[9]

The histology of livedoid vasculopathy evolves according to the temporal stage of the lesion. Atrophie blanche is a scarring condition of white stellate scars that is an end stage of livedoid vasculopathy.

Most commonly, livedoid vasculopathy shows fibrin deposition within both the wall and the lumen of affected vessels. The absence of a substantial perivascular infiltrate or leukocytoclasia argues against a vasculitis, being more in keeping with a thrombo-occlusive process.

The underlying mechanism of the development of livedoid vasculopathy may be related to (1) the development of a fibrin cuff, (2) white-cell trapping, (3) microthrombi, (4) a defect of endothelial cell plasminogen activator, (5) platelet dysfunction, and (6) enhanced fibrin formation. The following is a summary of the excellent discussion of these mechanisms by Maessen-Visch et al[11] in 1999.

Browse and Burnand[12] posited the fibrin cuff theory. The fibrin cuff theory postulates that because of chronic venous compromise, fibrinogen leaks from the capillaries. This fibrinogen coagulates and hardens to form a fibrin cuff. This cuff surrounds the capillaries. The cuff establishes a barrier that prevents oxygen and nutrients from reaching the skin. However, Maessen-Visch et al[11] note that fibrin is an effective barrier to prevent the diffusion of oxygen to tissue. The cuffs then are an artifact rather than a seal. The fibrin cuffs are more an indication of disturbed microcirculation rather than an etiologic factor in chronic venous insufficiency; therefore, this theory is of uncertain accuracy.

In 1988, Coleridge Smith et al[13] suggested the white-cell trapping theory. In this schema, white cells adhere (trap) to the endothelium of the capillaries as a result of venous hypertension. This results in the induction of proteolytic enzymes and superoxide metabolites. These enzymes and metabolites cause tissue destruction. This molecular degrading effect on tissue appears to be a nonimmunologic phenomenon. Its etiology is due to the low flow in the wide capillaries. No up-regulation of binding molecules, such as intercellular adhesion molecule, vascular cellular adhesion molecule, and endothelial leucocyte adhesion molecule, occurs. A defect of endothelial cell plasminogen activator exists in some patients with livedoid vasculopathy. However, at least 20% of the 118 control subjects showed the same values as patients with livedoid vasculopathy.

Tissue-type plasminogen activator (tPA) levels appear to be lower in patients with livedoid vasculopathy. The average plasma level of releasable tPA was only 0.03 IU/mL in one study, versus an average tPA level of 0.70 IU/mL in 118 healthy controls.[14] Furthermore, Klein and Pittelkow[15] reported a high incidence of defective release of tPA and increased levels of PAI and a high incidence of antiphospholipid antibodies in patients with livedoid vasculopathy. levels of tPA in the reference range were found in patients with chronic venous insufficiency and atrophie blanche or lipodermatosclerosis.

Other evidence has implicated platelet dysfunction; one study noted that 7 patients with atrophie blanche and livedoid vasculopathy had increased platelet aggregation. These 7 patients were treated successfully with antiplatelet therapy.[16] The value of this study is limited because it was not controlled or designed to evaluate these factors and enzyme levels.

Enhanced fibrin formation, as evidenced by elevated levels of total fibrin-related antigen and D-dimer, has also been suggested as the cause for livedoid vasculopathy. This theory also needs to be tested via double-blinded studies. As of yet, well-crafted and adequate studies have not been performed.

Irani-Hakime et al noted livedoid vasculopathy associated with combined prothrombin G20210A and factor V (Leiden) heterozygosity and MTHFR C677T homozygosity, showing a range of thrombotic states can cause livedoid vasculopathy.[17]

Livedoid vasculopathy seems to be primarily an occlusive condition rather than an inflammatory condition.

Livedoid vasculopathy related to elevated levels of lipoprotein(a) has been noted.[18]

Also note the completed clinical trial, Correlation of Genetic Polymorphism and Livedo Vasculitis.

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Epidemiology

Frequency

United States

Livedoid vasculopathy is an uncommon disorder in the United States.

International

Livedoid vasculopathy is an uncommon condition worldwide. In China, a study of 21 patients was performed. The female to male ratio was 3:1. The peak age at beginning of disease was 14-20 years. This was a younger age of onset than in previous studies. More than 85% demonstrated exacerbation in the summer with ulcer formation; 58.33% demonstrated antiphospholipid antibodies; and 71.43% demonstrated multivalent insect antigens hypersensitivity.[19]

In Brazil, LV linked with peripheral neuropathy was noted in 2 cases.[20]

Mortality/Morbidity

Livedoid vasculopathy, although painful, is not associated with any loss of life or limb.

Sex

Women are affected by livedoid vasculopathy more often than men. Livedoid vasculopathy can occur during pregnancy when levels of protein C and S drop.[21]

Age

Livedoid vasculopathy lesions can occur at any age, but livedoid vasculopathy is most commonly a disease of adulthood. An interesting case of LV occurred in a child in an area on the leg where a cutaneous hemangioma had been present. The body coagulation suffered from pathology that included prothrombin pathologic mutations, proteins C and S activity reductions, and elevated lipoprotein (a).

History

In livedoid vasculopathy, the initial findings are typically painful purpuric macules or papules on the ankles and the adjacent dorsum of the feet. Patients may have a history of livedo reticularis on their lower legs. The history may help exclude other diagnostic considerations. Note the following:

Physical

The initial lesions of livedoid vasculopathy, which often appear in clusters or groups, eventually ulcerate over a period of months and years and form irregular patterns of superficial ulcers. When the ulcers finally heal, they leave behind atrophic porcelain-white scars, which are atrophie blanche. Note the following:

Causes

The etiology of livedoid vasculopathy is unknown.

Laboratory Studies

No specific laboratory examinations allow the physician to make a definitive diagnosis of livedoid vasculopathy, although levels of platelet P-selectin and endothelial thrombomodulin are elevated. Tests that assess the causes of diseases that result in lower leg ulcers can be used to diagnose other diseases but not livedoid vasculopathy.

Anavekar and Kelly[29] noted a heterozygous prothrombin gene mutation associated with livedoid vasculopathy.

Imaging Studies

Evaluation of a patient can include appropriate imaging studies to evaluate for venous and arterial peripheral vascular disease. For example, venous Doppler studies can be useful in evaluating the disease. Microcirculation can be studied by capillary microscopy, transcutaneous oxygen measurements, laser Doppler flowmetry, laser Doppler perfusion imaging, and microlymphography.

Procedures

A skin biopsy can be used to evaluate this condition.

Histologic Findings

The findings of livedoid vasculopathy are summarized in Histologic Diagnosis of InflammatorySkin Diseases:An Algorithmic Method Based on Pattern Analysis by Ackerman et al.[30]

Histopathologic findings in the early stage include the following:

Histopathologic findings at the full stage of disease include the following:

Histopathologic findings in the late stage in which lesions of livedoid vasculopathy appear include the following:

Direct immunofluorescence staining typically demonstrates immunoglobulin and complement components in the superficial, mid-dermal, and deep dermal vasculature. The granular immunofluorescence staining pattern, typical of immune complex disease, is not seen.

Electron microscopy shows dilatation of capillaries (with a diameter up to 100 μm), with a thin endothelium, together with obliterated capillaries. Vessels are present in a dense, fibrotic connective tissue. Fibrin deposition with occlusion of the lumina of superficial blood vessels can occur. Erythrocytes and platelets are noted as being trapped within the fibrin. In older lesions, endothelial cells are replaced by heavy fibrin depositions.

Pathologic features vary with the stage of evolution of livedoid vasculopathy. In the early purpuric stage, fibrinoid material may be observed in the upper dermis in the capillary walls and the lumina. Endothelial proliferation and thickened walls are also noted. Deeper dermal and subcutaneous vessels are not involved in this stage.

In the late scarring phase of livedoid vasculopathy, which appears as atrophie blanche, the epidermis is thinned and the fibrinoid material has replaced the dermal vessels. Little or no cellular infiltrate is present. The pattern of involvement may vary; in some patients, the upper dermis is more involved than the deeper dermis, and, in other cases, the deeper layers show more of the changes mentioned above.

Medical Care

While ruling out the various disease states that have been associated with livedoid vasculopathy, physicians can offer a number of therapies that have been very helpful in reducing pain and ulceration. Instituting treatment as soon as possible is best. Note the following:

Consultations

To fully evaluate for the comorbid conditions of livedoid vasculopathy, consult a hematologist (to evaluate for factors that lead to hypercoagulable states) and vascular surgeons (to evaluate and treat underlying defects of coagulation).

Medication Summary

Drugs stimulating endogenous fibrinolytic activity and drugs inhibiting thrombus formation (antiplatelet and anticoagulant) are possible treatments of livedoid vasculopathy.

Severe livedoid vasculopathy related to antibodies involving the antiphosphatidylserine-prothrombin complex has been successfully treated with warfarin.[43]

Treatment of livedoid vasculopathy using alprostadil (PGE-1) seems like a possible treatment option for livedoid vasculopathy.[44]

Low molecular weight heparin has been used to treat livedoid vasculopathy in a patient with a positive test for lupus anticoagulant and the presence of the MTHFR mutation.[45]

Pentoxifylline (Trental)

Clinical Context:  May alter rheology of RBCs, which, in turn, reduces blood viscosity.

Dipyridamole (Persantine, Aggrenox)

Clinical Context:  Platelet adhesion inhibitor that possibly inhibits RBC uptake of adenosine, which is an inhibitor of platelet reactivity. In addition, may inhibit phosphodiesterase activity, leading to increased cyclic-3',5'-adenosine monophosphate within platelets and formation of the potent platelet activator thromboxane A2. A vasodilator. Use with aspirin.

Aspirin (Bayer, Ascriptin, Empirin)

Clinical Context:  Inhibits prostaglandin synthesis preventing formation of platelet-aggregating thromboxane A2. Use in low dose to inhibit platelet aggregation and to improve complications of venous stases and thrombosis.

Nifedipine (Procardia)

Clinical Context:  Relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery. Causes vasodilation.

Enoxaparin (Lovenox)

Clinical Context:  Prevents DVT, which may lead to pulmonary embolism in patients undergoing surgery who are at risk for thromboembolic complications. Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa. Average duration of treatment is 7-14 d.

Class Summary

These agents are the DOCs. They may be useful in reducing pain and ulceration.

Further Outpatient Care

No specific care exists for livedoid vasculopathy besides the medications previously mentioned.

Complications

Livedoid vasculopathy can result in atrophie blanche or white stellate scars.

Prognosis

Livedoid vasculopathy, although painful, is not associated with any loss of life or limb.

Author

Noah S Scheinfeld, MD, JD, FAAD, Assistant Clinical Professor, Department of Dermatology, Weil Cornell Medical College; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Assistant Attending Dermatologist, New York Presbyterian Hospital; Assistant Attending Dermatologist, Lenox Hill Hospital, North Shore-LIJ Health System; Private Practice

Disclosure: Optigenex Salary Employment

Specialty Editors

Timothy McCalmont, MD, Director, UCSF Dermatopathology Service, Professor of Clinical Pathology and Dermatology, Departments of Pathology and Dermatology, University of California at San Francisco; Editor-in-Chief, Journal of Cutaneous Pathology

Disclosure: Apsara Consulting fee Independent contractor

Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Disclosure: Nothing to disclose.

Jeffrey Meffert, MD, Assistant Clinical Professor of Dermatology, University of Texas School of Medicine at San Antonio

Disclosure: Nothing to disclose.

Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital

Disclosure: Abvie Honoraria Speaking and teaching

Chief Editor

William D James, MD, Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, Richard H. Musgnug, MD, to the development and writing of this article.

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Preferred sites of vascular involvement by selected vasculitides.

Preferred sites of vascular involvement by selected vasculitides.