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), as shown in the image below. Livedoid vasculopathy is a distinct condition that is not usually the result of other diseases, as Jorizzo elegantly noted in 1998.
Atrophie blanche in livedoid vasculopathy. Courtesy of DermNet New Zealand (http://www.dermnetnz.org/assets/Uploads/vascular/atrophie3.jpg).
A 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.
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 described what is now termed livedoid vasculopathy as livedo reticularis with summer ulcerations. In 1967, Bard and Winkelmann used the terms segmental hyalinizing vasculitis and livedo vasculitis to describe livedoid vasculopathy.
In 1998, Papi et al 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 reviewed the records of 42 patients with proven livedoid vasculopathy. The following is a summary of the epidemiological and testing data:
While the etiology of livedoid vasculopathy is not yet fully defined, it likely has a procoagulant pathogenesis. Factor V Leiden mutation, heterozygous protein C deficiency, and other inherited hypercoagulable states have been linked to livedoid vasculopathy. In particular, states such as hyperhomocysteinemia, which results in increased clotting, plays a role in livedoid vasculopathy. 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.
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 in 1999.
Browse and Burnand 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 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 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. Furthermore, Klein and Pittelkow 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. 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.
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.
Livedoid vasculopathy was correlated with increased activity of plasminogen activator inhibitor (PAI-1) pathology and sticky platelets syndrome type III (also referred to as SPS type III).
In 2014, Criado noted 3 patients with high plasma levels of factor VIII:C activity and other associated thrombophilic factors in patients with chronic leg ulcers and livedoid vasculopathy.
Livedoid vasculopathy is an uncommon disorder in the United States.
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.
In Brazil, livedoid vasculopathy linked with peripheral neuropathy was noted in 2 cases.
Women are affected by livedoid vasculopathy more often than men. Livedoid vasculopathy can occur during pregnancy when levels of protein C and S drop.
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).
Livedoid vasculopathy, although painful, is not associated with any loss of life or limb.
Patients must understand that livedoid vasculopathy is a chronic condition whose effects can sometimes be improved by medications. When it resolves, it leaves white stellate scars that have been termed atrophie blanche.
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.
Medium-sized vasculitides, such as polyarteritis nodosa (PAN), occasionally present with ulceration, resulting in ivory-white, stellate scarring on the lower limbs. These conditions may potentially be misdiagnosed as livedoid vasculopathy.
Livedoid vasculopathy is not associated with edema or venous insufficiency, whereas stasis dermatitis with ulceration is usually not painful and is associated with obvious edema and signs of venous insufficiency.
Patients with livedoid vasculopathy may have a history of recurrent leg ulcerations. Such patients can have deficiencies in a variety of blood factors (eg, factor V Leiden, protein C). The factor V Leiden mutation is more frequent in patients with venous leg ulceration than in control subjects and the general population. Patients with the factor V Leiden mutation have an increased risk of developing deep venous thrombosis and recurrent leg ulceration. Patients may also have a history of increased plasma homocysteine levels, abnormalities in fibrinolysis, and increased platelet activation.
Livedoid vasculopathy is not particularly painful, whereas hypertensive ischemic ulcers are painful but are usually larger and lack telangiectatic purple borders.
History and careful follow-up care can rule out traumatic ulcers and distinguish them from livedoid vasculopathy.
Chronic periarteritis nodosa may be associated with painful ulcerations; however, the associated nodules should differentiate chronic periarteritis nodosa from livedoid vasculopathy.
In 2003, Toth et al noted mononeuropathy multiplex in association with livedoid vasculitis. It possible that there are neural links underlying livedoid vasculopathy.
In 2003, Marzano et al described a 37-year-old woman with a 13-year history of widespread livedo reticularis and recurrent, painful, ulcerative skin lesions. The recurrent ulcerations involved almost the entire body surface. In addition, malar erythema and edema, nonscarring alopecia, and fever were also associated with this patient's condition. Routine laboratory data, immunological investigations, and coagulation parameters were normal or negative.
In 2007, Cardoso et al noted livedoid vasculopathy and hypercoagulability in a patient with primary Sjögren syndrome.
The range of presentation of livedoid vasculopathy is wide, and Okada et al reported widespread livedoid vasculopathy with pain but no systemic symptoms, showing that sometimes the disease is confined to the skin.
Livedoid vasculopathy in a woman with multiple myeloma has been reported.
Livedoid vasculopathy has a complex relationship with lupus.
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. See the image below.
Atrophie blanche in livedoid vasculopathy. Courtesy of DermNet New Zealand (http://www.dermnetnz.org/assets/Uploads/vascular/atrophie3.jpg).
Patients with livedoid vasculopathy can manifest with livedo reticularis before ulceration, with ulcerations, or with no ulcerations.
Patients with livedoid vasculopathy can have Raynaud phenomenon and acrocyanosis.
Lipodermatosclerosis can be associated with livedoid vasculopathy.
Patients who have systemic diseases, such as lupus, rheumatoid arthritis, and Klinefelter syndrome, that can result in skin ulcers can manifest with atrophie blanche–like lesions. These patients do not have livedoid vasculopathy.
Livedoid vasculopathy and recurrent thrombosis in a patient with lupus has been recorded. This case, the first reported of livedoid vasculopathy in a patient with seronegative antiphospholipid syndrome and systemic lupus erythematosus, draws attention to livedoid vasculopathy, a thrombotic dermopathy that may be under-diagnosed in patients with antiphospholipid syndrome.
The etiology of livedoid vasculopathy is unknown.
Livedoid vasculopathy can result in atrophie blanche or white stellate scars.
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 noted a heterozygous prothrombin gene mutation associated with livedoid vasculopathy.
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.
A skin biopsy can be used to evaluate this condition.
The findings of livedoid vasculopathy are summarized in Histologic Diagnosis of InflammatorySkin Diseases:An Algorithmic Method Based on Pattern Analysis by Ackerman et al.
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, was not seen prior to 2014. In 2014, Criado et al noted that the most common finding was a granular pattern of immunoreactant deposition, mainly C3 and immunoglobulin M, in a study of 36 patients of which 20 had laboratory pathologic findings and evidence of procoagulant findings (eg, anticardiolipin antibodies [37%], heterozygous factor V Leiden gene mutation [16%], protein C and/or S deficiency [16%], hyperhomocysteinemia [5%], lupus anticoagulant [25%], antithrombin deficiency [2.5%], high levels of fibrinogen [12%] and antinuclear factor [>1:320, 7.5%]).
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.
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.
Pentoxifylline (Trental) (400 mg 3 times/d) may be effective. Pentoxifylline is believed to enhance the blood flow in the capillaries. The blood flow enhancement is attributed to making red blood cells more flexible and thereby reducing viscosity.
In 2003, Hairston et al described treatment of livedoid vasculopathy with low molecular weight heparin (LMWH).
As reported by Yang et al in 2003, intractable livedoid vasculopathy was successfully treated with hyperbaric oxygen therapy. Additionally, Juan et al reported a study of 12 subjects with active livedoid vasculopathy. Subjects received hyperbaric oxygen therapy 5 times/wk. Eight completed the study. Resumption of ambulation and reduction of analgesics were achieved after an average of 4.9 hyperbaric oxygen therapy sessions. Leg ulcers healed completely in these 8 subjects at a mean of 3.4 weeks (range, 2-5 wk). Six patients had relapses of ulceration and responded to additional hyperbaric oxygen therapy. No patients had adverse effects.
Also in 2003, Marzano et al noted a good clinical response was obtained using intravenous methylprednisolone combined with pentoxifylline for wide spread livedoid vasculopathy.
Dipyridamole (Persantine) (75 mg 4 times/d) with up to 325 mg of aspirin per day is reported to reduce pain after 3-6 weeks of therapy. Similar results have been reported using 50 mg of dipyridamole 3 times a day and 325 mg of aspirin once a day. Note that aspirin is not to be administered in conjunction with coumarin anticoagulants. Dipyridamole is not considered safe in children or breastfeeding mothers.
Nifedipine (Procardia) (20 mg 3 times/d) is reported to maintain perfusion in the superficial vessels; therefore, the deposition of fibrin in the vessel walls is impeded.
Deng et al noted that livedoid vasculopathy associated with plasminogen activator inhibitor-1 (PAI-1) promoter homozygosity (4G/4G) was effectively abated with tissue-type plasminogen activator (tPA). Antunes et al also reported on livedoid vasculopathy associated with PAI-1 promoter homozygosity (4G/4G) and prothrombin G20210A heterozygosity that responded to tPA treatment.
Some reports have noted that intravenous immunoglobulin can be useful in treating atrophie blanche and livedoid vasculopathy, but this remains an experimental treatment.
The combination of phenformin and ethylestrenol, which enhances endogenous blood fibrinolytic activity by increasing plasminogen activating enzymes, has been suggested as a treatment.
Browning and Callen reported that warfarin is a useful and effective treatment for livedoid vasculopathy associated with cryofibrinogenemia and hyperhomocysteinemia. Kavala et al reported successful warfarin therapy in livedoid vasculopathy associated with factor V Leiden mutation. Additionally, Davis and Wysokinski reported that livedoid vasculopathy associated with a prothrombotic state responded to warfarin.
Some reports have noted the use of heparin, LMWH, psoralen plus ultraviolet A (PUVA), and low molecular weight dextran.
If ulcers are superinfected, they should be treated with oral antibiotics.
Intravenous immunoglobulin (IVIG) has been reported as a last-resort treatment when other treatments have failed.
Meiss et al noted that hyperhomocysteinemia can be another cause of hypercoagulability and livedoid vasculopathy and that the combination of folic acid, vitamin B-12, and vitamin B-6 (cofactors of homocysteine metabolism) is an effective treatment for hyperhomocysteinemia, hypercoagulability, and livedoid vasculopathy.
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).
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.
Treatment of livedoid vasculopathy using alprostadil (PGE-1) seems like a possible treatment option for livedoid vasculopathy.
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.
A new drug, rivaroxaban, which has undergone phase II trials for livedoid vasculopathy, is undergoing development. Rivaroxaban exerts effects on the coagulation cascade. Rivaroxaban inhibits the factor Xa–dependent transformation of prothrombin to thrombin. Thus, rivaroxaban substantially reduces the risk of thrombosis.[51, 52]
Intravenous immunoglobulin (IVIG) holds promise of treating livedoid vasculopathy and was effective at 2 g/kg of IVIG every 4 weeks in a trial of 11 patients in ameliorating livedoid vasculopathy, with long-term follow up. Improvement occurred in 59% of patients after 3 cycles and 86% after 6 cycles. After 7 and 8 cycles in previous treatment failure, a 93% success rate was achieved. After two IVIG cycles, subscore analysis demonstrated resolution of pain in 80% of patients. Quality of life and disease severity and were very much improved after 6 cycles. The median duration of remissions appeared to be 26.7 months after the initial treatment and 7.5 months in subsequent disease episodes.
Treatment of sensory ganglionopathy with livedoid vasculopathy controlled by immunotherapy failed treatment with prednisolone and mycophenolate mofetil but succeeded when rituximab was added, in terms of nerve conduction stabilization and symptoms.
Clinical Context: Pentoxifylline may alter the rheology of red blood cells, which, in turn, reduces blood viscosity.
Clinical Context: Dipyridamole is a platelet adhesion inhibitor that possibly inhibits red blood cell uptake of adenosine, which is an inhibitor of platelet reactivity. In addition, it may inhibit phosphodiesterase activity, leading to increased cyclic-3',5'-adenosine monophosphate within platelets and formation of the potent platelet activator thromboxane A2. Dipyridamole is a vasodilator. Use with aspirin.
Clinical Context: Aspirin inhibits prostaglandin synthesis, preventing the formation of platelet-aggregating thromboxane A2. Use in a low dose to inhibit platelet aggregation and to improve complications of venous stases and thrombosis.
Clinical Context: Nifedipine relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery. Nifedipine causes vasodilation.
Clinical Context: Enoxaparin prevents deep vein thrombosis, which may lead to pulmonary embolism in patients undergoing surgery who are at risk for thromboembolic complications. Enoxaparin enhances the inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, it preferentially increases the inhibition of factor Xa. The average duration of treatment is 7-14 days.
These agents are the drugs of choice. They may be useful in reducing pain and ulceration.