Livedo / Livedoid Vasculopathy / Atrophie Blanche
- These terms describe a spectrum of diseases that result from decreased blood flow to the skin and varying degrees of tissue ischemia.
- Livedo reticularis and racemosa may be associated with a variety of underlying conditions including vasculitic, thrombotic, and embolic diseases, while livedoid vasculopathy is thought to reflect only thrombotic processes.
- The specific cutaneous morphology and histopathologic findings direct both the evaluation for a potential underlying etiology and management decisions.
This group of terms describes the findings of reticulated pink to violaceous skin discoloration primarily of the lower extremities accompanied at times by ulceration and scarring. These terms are commonly considered on a spectrum and reflect varying degrees of cutaneous vascular compromise.
Livedo reticularis refers to a common, non-fixed, reticulated pattern of complete rings that is thought to reflect transient decreased blood flow in the vascular plexus that feeds the skin. The term, physiologic livedo reticularis, refers to the skin changes that appear secondary to a vasospastic response to cold temperatures that fully disappears upon rewarming. It is common in women and children. It sometimes can be seen on the upper extremities as well. In contrast, secondary livedo reticularis has been associated with a variety of diseases (see below). If findings of livedo are extensive or do not improve with re-warming, it is important to consider secondary causes.
Synonyms: cutis marmorata.
Livedo racemosa is a term that refers to a fixed, reticulated pattern of irregular, patchy or broken rings that does not vary with temperature. Livedo racemosa is thought to reflect partial obstruction of the cutaneous vasculature leading to slowed blood flow and lower oxygen tension in specific areas of the skin. Livedo racemosa is not considered physiologic and has been associated with the diseases listed below.
Associated diseases (for secondary livedo reticularis and livedo racemosa)
- Hypercoaguable states (inherited and acquired)
- Vasculitides (especially those with medium vessel involvement)
- Connective tissue diseases (especially if underlying antiphospholipid antibody syndrome)
- Embolic processes
- Slow flow states (polycythemia vera, essential thrombocytosis)
- Abnormal proteins (cryoglobulins, cryofibrinogens, cold agglutinins, paraproteinemia)
- Medications (amantadine, minocycline, gemcitabine, heparin, quinidine/quinine, interferon beta, bismuth, warfarin)
- Neurological disorders (Sneddon syndrome, Parkinson’s disease, multiple sclerosis, reflex sympathetic dystrophy)
The term, livedoid vasculopathy (LV), is used when frank purpura, necrosis and punched-out ulcerations occur within the livedo pattern. It is thought to reflect complete occlusion of vessels within the cutaneous vasculature leading to cutaneous ischemia and infarction. The estimated incidence of LV is 1:100,000 and the disease usually affects young to middle-aged females. Skin findings depend on the age of the lesion that begins with painful purpuric papules and plaques that break down to form ulcerations and finally heal with porcelain white atrophic scars. These characteristic white scars are termed atrophie blanche. Though the terms livedoid vasculopathy and atrophie blanche have been used interchangeably in the literature, they are not the same entity. Atrophie blanche is a descriptive term that denotes the end-stage healed lesion of a variety of ulcerative processes including venous stasis ulcers. The ulcerations of LV typically occur episodically and can extend onto the dorsal foot and proximal lower leg, helping to differentiate them from other ulcerating processes.
Livedoid vasculopathy may be primary (idiopathic) or may occur secondary to an underlying disease. Unlike livedo reticularis and racemosa, which have been associated with a variety of pathologic processes including vasculitides and thrombotic and embolic diseases, livedoid vasculopathy is thought to result primarily from thrombotic disease. The thrombo-occlusive nature of livedoid vasculopathy may result from multiple mechanisms including a hypercoaguable state (inherited or acquired), impaired fibrinolysis, abnormal platelet function, and endothelial cell damage.
Synonyms: livedoid vasculitis (misnomer as true vasculitis is not seen), segmental hyalinizing vasculitis, livedo reticularis with summer/winter ulceration, and PURPLE (painful purpuric ulcers with reticular pattern of the lower extremities).
A full history and physical exam should be performed. Skin biopsy should be considered in all cases (with the exception of non-fixed, temperature responsive primary livedo reticularis). The histopathological findings in secondary livedo reticularis and livedo racemosa depend on the underlying associated disease and may include vasculitis, calcium deposition, thrombi, emboli, and cholesterol clefts. Often two biopsies are performed: one performed from the pale center of a fixed erythematous ring (in an attempt to capture the compromised blood vessel) and the other from a purpuric area.
In livedoid vasculopathy, the histopathological findings reflect the stage of the lesion sampled. Early lesions typically show hyaline thrombi within small vessels in the mid and upper dermis and endothelial cell proliferation. A perivascular lymphocytic infiltrate and fibrinoid material in the vessel wall may be seen but true vasculitis is rare (and is thought to result from the primary thrombotic process). Infarction of the dermis with frank ulceration may be seen. Finally, if scarred areas are sampled, epidermal atrophy and dermal sclerosis are seen.
Further work-up (to evaluate for a potential underlying etiology) should be determined based on the histopathological findings as well as the patient and family history and review of systems.
- Basic labs (CBC with diff, LFTs, BUN/Creatinine, UA with micro)
- Hypercoaguable work up
- PT/INR, PTT, platelet count
- APLS: Anticardiolipin IgA/G/M, beta-2-glycoproteins IgA/G/M, lupus anticoagulant
- Factor V Leiden
- Protein C/S deficiency: activated protein C resistance, protein C functional assay, free protein S antigen assay
- Prothrombin gene mutation (G20210A)
- Methylenetetrahydrofolate reductase C677T mutation
- Homocysteine level
- Plasminogen activator inhibitor-1
- Connective tissue disease work-up (ANA, ESR, CRP, RF, CH50, anti-DsDNA, anti-Ro/La, anti-RNP, anti-Smith)
- Vasculitis work-up (hepatitis B/C, ANCAs, Utox, ASO/DNase B, PPD or QuantiFERON®-TB Gold)
- Cryoglobulins, cryofibrinogens, cold agglutinins
- SPEP/UPEP, immunoglobulin levels, kappa/lambda light chains
- Echocardiogram if embolic disease suspected
- Lipoprotein (a) level (elevations in lipoprotein (a), which is also a risk factor for cardiovascular disease, have recently been reported in some patients with LV)
Livedo reticularis (non-fixed, pink to violaceous, mottled, complete rings)
- Erythema ab igne
- Cutis marmorata telangiectatica congenita
- Viral exanthems (parvovirus)
Livedo racemosa/livedoid vasculopathy (fixed, broken rings +/- ulcerations, purpura, necrosis)
- Chronic venous stasis
- Peripheral vascular disease
- Vasculitides (especially medium vessel vasculitides such as PAN and ANCA+ vasculitis)
- Pyoderma gangrenosum
- Lymphocytic thrombophilic arteritis
- Buerger’s disease
- Lichen sclerosis
- Localized scleroderma (morphea)
- Malignant atrophic papulosis
Erythema ab igne
Chronic venous stasis
Since this represents a spectrum of diseases, no single therapy works for all cases. Primary livedo reticularis is considered physiologic and no treatment is necessary. In secondary livedo reticularis or racemosa, management depends on severity and is typically aimed at treating the underlying disease if known. For livedoid vasculopathy, anticoagulants, fibrinolytic agents, and anti-platelet agents have all been used with success, though this condition is notoriously difficult to treat. Evaluation by hematology may be helpful. Leg elevation and compression is helpful in many cases (consider an ankle-brachial index prior to compressive therapy to rule out peripheral vascular disease). Patients should be encouraged not to smoke. Finally, pain management, particularly in livedoid vasculopathy, is imperative.
Therapeutic options for livedoid vasculopathy
- Agents that inhibit platelet function: Consider aspirin 81-365 mg per day +/- dipyridamole.
- Enhancement of cutaneous blood flow: Consider pentoxifylline 400 mg three times a day.
- Anticoagulants: Consider low molecular weight heparin (preventative dose), warfarin (INR 2-3). Recently, rivaroxaban (10 mg daily), which is a direct factor Xa inhibitor, was shown to improve pain and promote healing in an open label, multi-center study.
- Fibrinolytics: Danazol (4 mg/kg daily). Recent small case series showed benefit especially in patients with elevated lipoprotein (a) levels.
- Immunosuppressants/immunomodulators: Minocycline/doxycycline (100 mg bid), IVIg 2 gm/kg.
- If the patient responds to any of the above therapies, treat until the ulceration resolves. Treatment may be discontinued, but in most cases some maintenance therapy is required.
- Severe cases may respond to tissue plasminogen activator infusions (10 mg IV daily for 14 days), but this is impractical for prolonged management.
- Diligent wound care is important especially if extensive ulcerative disease is present. Hyperbaric oxygen has shown some benefit in these cases.
- Other therapies that have shown benefit in limited reports include nicotinic acid, PUVA, and sulfasalazine.
- Physicians must monitor for potential side effects of the various drugs used in treating this disease. Systemic androgen therapy (danazol) in females is complicated by virilization, and pregnancy must be avoided during therapy. Anti-platelet agents, anticoagulants, and thrombolytic therapy may be complicated by an enhanced bleeding tendency.
- Proper diagnosis of ankle ulceration is important. Ulcers may result from a variety of conditions, such as venous stasis, arterial insufficiency, cholesterol emboli, and other forms of small vessel vasculitis, which do not require the use of the agents listed above.
- 45-year-old male presents with intermittent, painful purpuric plaques on his bilateral lower extremities that have slowly worsened over the last 4 months. Two weeks ago the lesions began to ulcerate
- History of lupus currently taking hydroxychloroquine
- Review of systems negative except for skin involvement noted above
- Healthy appearing middle-aged male
- Bilateral lower extremities with fixed purpura in a livedo pattern with scattered ulcerations and white atrophic scarring extending from the midshins onto the dorsal feet
- Palpable pulses bilaterally
- Minimal edema and varicosities
- Rest of cutaneous exam is unremarkable
- Biopsy is performed that shows hyaline thrombi in small vessels in the mid and upper dermis. No vasculitis is seen
Diagnosis: Livedoid vasculopathy
- Given thrombi noted on biopsy, a full hypercoaguable work up is performed.
- Patient is found to have a positive lupus anticoagulant and positive anticardiolipin IgM
- A presumptive diagnosis of antiphospholipid antibody syndrome (APLS) is made
- Patient is referred to hematology who agrees with presumptive diagnosis of antiphospholipid antibody syndrome
- Given evidence of end-stage organ involvement (i.e., skin ulcerations), rivaroxaban is started at a dose of 10 mg per day
- Antiphospholipid antibodies are rechecked at 12 weeks to confirm the diagnosis
- Patient should continue close follow up with dermatology, rheumatology, and hematology. Treatment should be continued at least until all ulcerations are healed and further anticoagulation may be continued given the diagnosis of APLS
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Weishaupt C, Strölin A, Kahle B, et al. (2016). Anticoagulation with rivaroxaban for livedoid vasculopathy (RILIVA): a multicentre, single-arm, open-label, phase 2a, proof-of-concept trial. Lancet Haematol, Feb;3(2): e72-79. doi: 10.1016/S2352-3026(15)00251-3.