Livedoid vasculopathy

INTRODUCTION — Livedoid vasculopathy is a chronic, painful, thrombo-occlusive cutaneous vasculopathy that involves the distal lower extremities and feet. Characteristic clinical features include livedoid skin changes (linear or angular, erythematous nodules), atrophie blanche (smooth, ivory-white plaques), and intensely painful ulcerations. The diagnosis is confirmed through a skin biopsy that demonstrates characteristic vascular abnormalities, including intraluminal thrombosis, endothelial proliferation, and subintimal hyaline degeneration.

The pathogenesis of livedoid vasculopathy is unclear. The disorder can occur either independently or in association with acquired or inherited thrombophilia or various systemic diseases.

The clinical manifestations, diagnosis, and treatment of livedoid vasculopathy are reviewed here. Cutaneous vasculitis and other causes of leg ulcers are reviewed separately. (See "Overview of cutaneous small vessel vasculitis" and "Approach to the differential diagnosis of leg ulcers".)

NOMENCLATURE — The literature on livedoid vasculopathy is highly problematic with regard to nomenclature [1]. A variety of other terms have been used to refer to this condition, most often "atrophie blanche" and "livedoid (or livedo) vasculitis." However, "atrophie blanche" is most appropriately used as a descriptive term for the smooth, ivory-white plaques that characteristically occur in livedoid vasculopathy but may also occur in other disorders, particularly venous insufficiency. The use of "vasculitis" should be avoided because true vasculitis, as demonstrated by destructive inflammation within the blood vessel wall, is absent. (See 'Clinical features' below and 'Pathology' below.)

Less common terms that have been used to refer to livedoid vasculopathy in the literature include segmental hyalinizing vasculopathy, livedo reticularis with summer ulcerations, livedo reticularis with winter ulcerations, and painful purpuric ulcers with reticular patterning on the lower extremities (PURPLE).

EPIDEMIOLOGY AND PATHOGENESIS — Livedoid vasculopathy primarily occurs in young to middle-aged adults and is more common in females than males.

The pathogenesis is not well understood but is postulated to involve increased coagulation or impaired fibrinolysis that results in occlusion of dermal blood vessels with fibrin thrombi [2]. The thrombosing occlusive vasculopathy may be associated with occlusions of the small vessels of the nerves in the dermis, leading to an "ischemic form" of peripheral neuropathy and contributing to sensory disturbances [3]. (See 'Clinical features' below.)

CLINICAL FEATURES — Livedoid vasculopathy occurs on the lower leg (most common site), ankle, and/or dorsal foot [4]. The presentation is often bilateral, but unilateral involvement may also occur. The characteristic clinical findings are livedoid changes and atrophie blanche. Ulceration is an additional common finding; the ischemic/infarctive ulcerations are often pinpoint and intensely painful.

●Livedoid changes – Livedoid changes are deep, barely palpable, slightly erythematous macules, papules, or nodules that have a linear or angular shape. The appearance resembles patchy livedo reticularis (picture 1).

●Atrophie blanche – Atrophie blanche appears as smooth, ivory-white, atrophic plaques surrounded by hyperpigmentation and telangiectasias (picture 2A-C). The plaques often have small amounts of stippled pigment. Atrophie blanche can develop in sites of prior ulceration or in the absence of preceding ulcers.

●Ulcers – Superficial ulcers are common and typically range from 1 to 5 mm in diameter (picture 3A-B). Larger and deeper ulcers may also occur. Removal of eschar will reveal a punched-out, angular, or stellate ulcer.

Livedoid changes are often the initial clinical manifestation of livedoid vasculopathy. Alternatively, ankle edema or small, slightly raised papules with telangiectasias or purpura and peripheral petechiae may precede livedoid changes. Ulcers are often persistent; even with treatment, healing may take several months.

Most patients with livedoid vasculopathy experience substantial pain, burning, or itching in involved areas.

PATHOLOGY — The characteristic pathologic changes occur in the blood vessels of the upper, middle, and/or lower dermis. The blood vessels demonstrate thickening and focal thrombosis, with endothelial proliferation and hyaline degeneration of the subintimal layer [5]. The hyaline material stains positively by the periodic acid-Schiff technique but is also visualized well on hematoxylin eosin staining (picture 4).

The elastic laminae of involved vessels are usually preserved, and the vascular wall is rarely destroyed. Vessel lumina are occluded by proliferating cells embedded within loose, fibrinoid material. The surrounding inflammatory reaction is relatively mild and consists primarily of lymphocytes. Extravasation of red blood cells may be present.

ASSOCIATED DISORDERS — Livedoid vasculopathy can occur with or without identifiable predisposing risk factors for thrombosis. Examples of risk factors for thrombosis that have been linked to livedoid vasculopathy include antiphospholipid antibodies, paraproteinemias, and genetic disorders that predispose to thrombosis. (See "Overview of the causes of venous thrombosis", section on 'Inherited thrombophilia'.)

Livedoid vasculopathy can also occur in the setting of a defined illness, particularly a systemic rheumatic disease. The diseases most commonly diagnosed in the setting of livedoid vasculopathy are the primary antiphospholipid syndrome, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, mixed connective tissue disease, and undifferentiated connective tissue disease [4,6,7].

Re-emergence of ulcers in association with coronavirus disease 2019 (COVID-19) has been reported in a patient in whom livedoid vasculopathy was previously under control [8].

DIAGNOSIS — The diagnosis of livedoid vasculopathy is confirmed through the detection of consistent histologic findings in a patient with suggestive physical findings (eg, livedoid changes, atrophie blanche, ulcers) on the lower extremities. The cutaneous manifestations alone are insufficient to confirm the diagnosis, as similar findings may occur in other disorders. Thus, a skin biopsy is mandatory. (See 'Differential diagnosis' below.)

For patients with ulcers, a careful history and physical examination can be helpful for determining whether other diagnoses should be included in the differential diagnosis. The approach to the differential diagnosis of leg ulcers is reviewed separately. (See "Approach to the differential diagnosis of leg ulcers", section on 'Patient evaluation'.)

The ideal biopsy type is a fusiform incisional biopsy that includes subcutaneous fat. Alternatively, a 4 to 6 mm punch biopsy can be performed [2]. The optimal site for a biopsy is the edge of a new ulcer or a new purpuric papule. The histologic findings in the dermal vasculature that strongly support a diagnosis of livedoid vasculopathy are [2]:

●Intraluminal thrombosis

●Endothelial proliferation

●Subintimal hyaline degeneration

Direct immunofluorescence (DIF) is estimated to show positive immunoreactants in 43 to 100 percent of patients [9]. C3 and immunoglobulin M (IgM) deposited in the blood vessels and the dermal-epidermal junction are the most common finding [9].

After the diagnosis has been confirmed histopathologically, an underlying disorder must be excluded. (See 'Additional evaluation' below.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of livedoid vasculopathy includes a broad array of conditions that may cause skin discoloration, cutaneous ulcers, or nodules of the lower extremities. The most common disorders in the differential diagnosis are lower extremity chronic venous disease, peripheral vascular disease, and vasculitis:

●Chronic venous disease – Venous insufficiency involving the lower extremities often presents with cutaneous hyperpigmentation, edema, and varicosities on the lower extremities. Ulceration can occur and is most often found near the medial malleolus. Ulcers are typically shallow with irregular borders and yellow, fibrinous exudate (picture 5). Atrophie blanche may also occur. The diagnosis often can be made clinically; venous ultrasonography can be helpful when the diagnosis is uncertain. (See "Clinical manifestations of lower extremity chronic venous disease".)

●Peripheral vascular disease – Peripheral vascular disease of the lower extremities can result in ischemic ulcers, which are often located on the toes, heel, malleoli, or shin. The painful ulcers are well demarcated, with a "punched-out" appearance (picture 6). Peripheral pulses are diminished. The diagnosis can be substantiated through ankle-brachial index testing. (See "Clinical features and diagnosis of lower extremity peripheral artery disease".)

●Vasculitis – Vasculitis involving medium-sized cutaneous blood vessels (eg, cutaneous polyarteritis nodosa, antineutrophil cytoplasmic antibody [ANCA]-associated vasculitis, mixed cryoglobulinemia, thromboangiitis obliterans, lymphocytic thrombophilic arteritis) may present with subcutaneous nodules, ulcers, livedo reticularis, or livedo racemosa. A skin biopsy can differentiate livedoid vasculopathy from vasculitis. (See "Evaluation of adults with cutaneous lesions of vasculitis".)

Examples of other disorders in the differential diagnosis include pyoderma gangrenosum, factitial or traumatic skin injury, and the various additional causes of leg ulcers. An overview of the differential diagnosis of leg ulcers is provided separately. (See "Pyoderma gangrenosum: Pathogenesis, clinical features, and diagnosis" and "Approach to the differential diagnosis of leg ulcers".)

ADDITIONAL EVALUATION — After the diagnosis of livedoid vasculopathy has been confirmed histologically, patients should be evaluated for underlying disorders. The evaluation should begin with a complete history, review of systems, and physical examination to assess for findings suggestive of thrombophilia or a systemic rheumatic disease. Although we typically perform laboratory testing for thrombophilia in all patients, we limit laboratory investigation for systemic rheumatic diseases to patients who exhibit other findings suggestive of such diseases.

Examples of studies often included in our laboratory assessment include:

●Tests for acquired and inherited thrombophilia (see "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors", section on 'Hypercoagulable tests')

●Complete blood count

●Comprehensive metabolic panel

●Urinalysis

●Erythrocyte sedimentation rate and C-reactive protein

●Rheumatoid factor and antibodies to cyclic citrullinated peptides

●Serum complement levels (eg, CH50, C3, and C4)

●Antinuclear antibody titer

●Antineutrophil cytoplasmic antibodies (ANCA)

●Serum cryoglobulins

●Serum protein electrophoresis and immunofixation

The primary value in evaluating patients for a systemic rheumatic disease is the identification of patients at risk for other complications of the identified condition. Treatment of the underlying systemic rheumatic disease does not seem to have a consistent effect on livedoid vasculopathy, and the presence of a systemic rheumatic disease does not usually alter the approach to treatment. In contrast, the presence of thrombophilia influences our approach to treatment. (See 'Treatment' below.)

TREATMENT — Treatment of livedoid vasculopathy usually involves a combination of interventions. No single therapeutic approach is effective for all patients [10].

General measures — Pain management and wound care are important components of management. Smoking cessation and compression also may be beneficial:

●Pain management – Pain secondary to livedoid vasculopathy can be severe. Our first-line approach to pain management usually consists of acetaminophen or nonsteroidal anti-inflammatory drugs, such as indomethacin. Treatments typically used for neuropathic pain, such as tricyclic drugs, gabapentin, pregabalin, or carbamazepine, may be useful for patients with recalcitrant ulcerations [2].

●Wound care – Wound care should involve maintenance of a moist wound environment and control of superinfection. General principles of wound management are reviewed separately. (See "Basic principles of wound management".)

●Smoking cessation – Although the effects of smoking cessation on livedoid vasculopathy have not been studied, we encourage patients to stop smoking because of the negative effects of smoking on wound healing. In addition, there is a proposed relationship between livedoid vasculopathy and smoking. In a series of 45 patients with livedoid vasculopathy evaluated at a tertiary care center in the United States, 47 percent reported a history of smoking [4]. (See "Risk factors for impaired wound healing and wound complications", section on 'Smoking and nicotine replacement therapy'.)

●Compression – Clinical experience suggests that compression therapy is beneficial in patients with associated venous insufficiency provided ankle-brachial index results do not suggest concomitant arterial insufficiency [2]. Improvement may be related to a stimulatory effect of compression on fibrinolytic activity [11]. (See "Compression therapy for the treatment of chronic venous insufficiency".)

Pharmacologic therapy — Limited data suggest that therapies that minimize risk for thrombosis, including antiplatelet, anticoagulant, and fibrinolytic agents, can improve livedoid vasculopathy [2,12]. Benefit from immunomodulatory, vasodilatory, and other interventions has also been reported. Combination therapy is often necessary.

Our approach — No randomized trials have evaluated therapies for livedoid vasculopathy, and the best approach to treatment is unclear. Our approach is reviewed here. Other approaches may be reasonable.

The antiplatelet agent aspirin, a generally well-tolerated and widely available oral agent, is our preferred first-line therapy for patients without an identified thrombophilia. We typically prescribe aspirin alone for initial therapy, though combination therapy with dipyridamole is used by some clinicians. Pentoxifylline is our favored initial treatment for patients who cannot tolerate aspirin. For patients who can tolerate aspirin but fail to improve on aspirin alone, we typically add pentoxifylline.

When patients have insufficient responses to aspirin and pentoxifylline, we often proceed to anticoagulation. We typically use warfarin, low molecular weight (LMW) heparin, or a direct oral anticoagulant, such as rivaroxaban. Most patients respond to one of these agents. For our rare patients with refractory disease, we have had some success with tissue thrombolytic therapy (tissue plasminogen activator).

Our approach to patients with identified thrombophilia differs. Anticoagulants are often used as first-line therapy; however, selection of an initial agent should be based upon knowledge of the therapies known to reduce thrombosis in the specific thrombophilia.

There is no fixed endpoint for therapy in patients who respond to treatment. Discontinuation of treatment may be attempted after ulcer healing; however, continuous treatment may be necessary to maintain improvement.

Antiplatelet agents — Improvement from treatment with antiplatelet agents, such as aspirin, dipyridamole, and pentoxifylline, has been reported.

Aspirin with or without dipyridamole — Case reports and case series document benefit from aspirin alone or in combination with the antiplatelet agent dipyridamole [13-16]. Aspirin is typically given to adult patients at a dose of 325 to 365 mg per day; the typical dose for dipyridamole is 75 mg four times per day. Improvement in signs and symptoms of livedoid vasculopathy are expected within the first few months of treatment. Adverse effects of aspirin are discussed separately. (See "Nonselective NSAIDs: Overview of adverse effects".)

Pentoxifylline — Pentoxifylline can be given alone or in combination with aspirin. In particular, pentoxifylline is a favorable initial treatment for patients who cannot tolerate aspirin. Pentoxifylline improves hyperviscosity of the blood and has inhibitory effects on platelet and erythrocyte aggregation. The drug has appeared helpful for livedoid vasculopathy in case series [17,18].

Adults can be treated with 400 mg of pentoxifylline one to three times per day. Clinical improvement is expected within the first few months of treatment. Gastrointestinal distress is a potential side effect.

Anticoagulants — Improvement from treatment with anticoagulants, such as warfarin, heparin, and direct oral anticoagulants, has been reported.

Warfarin or heparin — Rapid clinical improvement during treatment with oral warfarin or subcutaneous LMW heparin is documented in case reports and case series [12,19,20]. Warfarin is dosed to achieve an international normalized ratio (INR) between 2 and 3 and may lead to marked improvement within the first two months of therapy [21-23]. The LMW enoxaparin can be given subcutaneously as 1 mg/kg every 12 hours for six months followed by once daily treatment. Marked clinical improvement has occurred within the first few months of LMW heparin treatment [24,25]. Monitoring requirements and adverse effects of warfarin and LMW heparin are reviewed in detail separately. Warfarin is contraindicated in pregnancy. (See "Warfarin and other VKAs: Dosing and adverse effects" and "Heparin and LMW heparin: Dosing and adverse effects".)

Direct oral anticoagulants — Direct oral anticoagulants are newer options for anticoagulation that do not require the frequent monitoring necessary for warfarin therapy and can be given orally, unlike LMW heparin therapy. In a 12-week uncontrolled study, treatment of 25 patients with painful livedoid vasculopathy with oral rivaroxaban (10 mg twice daily with the option to reduce to once-daily dosing upon improvement) was associated with reduced pain, erythema, and ulceration [26]. Benefit of rivaroxaban and other direct oral anticoagulants, including apixaban, edoxaban, and dabigatran, is documented in case reports or case series [12,27-31]. Risks of direct oral anticoagulants are discussed separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

Other therapies — Other therapies that may be useful based upon case reports or small case series include tissue plasminogen activator (10 mg intravenously given for 14 days) [32-34], doxycycline (100 mg twice daily), danazol (200 mg per day) [26,35], hyperbaric oxygen (1.5 to 2 hours for up to 15 treatment sessions) [36], intravenous immune globulin (monthly infusions of 0.5 g/kg given over two or three consecutive days) [37,38], nifedipine (10 to 20 mg three times per day) [39], topical becaplermin [40], psoralen plus ultraviolet A (PUVA; 0.5 to 1 mJ/cm² per treatment session) [41,42], sulfasalazine (1 g three times per day) [43,44], endovenous ablation for associated venous insufficiency [45], etanercept [46,47], adalimumab [46,48,49], rituximab [50,51], and tofacitinib [46,52].

PROGNOSIS — Livedoid vasculopathy often recurs upon discontinuation of treatment. Long-term treatment with an effective regimen is usually necessary.

SUMMARY AND RECOMMENDATIONS

●Overview – Livedoid vasculopathy is a chronic, recurrent, thrombo-occlusive vasculopathy of the distal lower extremities and feet that can lead to ulcer formation. Livedoid vasculopathy can occur independently or in the setting of a variety of thrombophilic states and underlying systemic disorders. (See 'Associated disorders' above.)

●Clinical features – Characteristic clinical features of livedoid vasculopathy include livedoid changes, atrophie blanche (ivory-white plaques with peripheral hyperpigmentation and telangiectasias), painful ulcers, and edema. (See 'Clinical features' above.)

●Diagnosis – A skin biopsy is necessary to confirm the diagnosis. The biopsy should include the full thickness of the dermis as well as subcutaneous fat. The optimal sites for biopsy are at the edge of a new ulceration or over a new purpuric papule. The histologic findings that strongly support a diagnosis of livedoid vasculopathy include intraluminal thrombosis, endothelial proliferation, and subintimal hyaline degeneration in dermal blood vessels. (See 'Diagnosis' above and 'Pathology' above.)

●Additional evaluation – Livedoid vasculopathy may occur in association with thrombophilia and systemic rheumatic diseases. Patients diagnosed with livedoid vasculopathy should be assessed for these conditions. (See 'Additional evaluation' above.)

●Treatment – Data on treatment options for livedoid vasculopathy are limited, and the best approach to treatment is unclear:

•General measures – Pain control and wound care are important components of management. Smoking cessation and compression may also be beneficial. (See 'General measures' above.)

•Pharmacologic therapy – Therapies reported as beneficial for livedoid vasculopathy have included antiplatelet, anticoagulant, fibrinolytic, immunomodulatory, and vasodilatory agents.

-Patients without thrombophilia – For patients without an identified thrombophilia, we suggest aspirin as initial treatment based upon case reports and case series that suggest benefit as well as the tolerability, wide availability, and low cost of this therapy (Grade 2C). Pentoxifylline is an alternative first-line treatment option that may be particularly useful for patients who cannot tolerate aspirin. Patients who do not respond to first-line treatments may benefit from other anticoagulants or other interventions. (See 'Pharmacologic therapy' above.)

-Patients with thrombophilia – Selection of treatment for patients diagnosed with thrombophilia is based upon knowledge of the therapies known to reduce thrombosis in the specific thrombophilia. (See 'Our approach' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges John Stone, MD, who contributed to an earlier version of this topic review.