Livedoid vasculopathy (LV) is an uncommon

thrombotic Thrombosis () is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thrombocytes) and fibrin to for ...

dermal

vasculopathy Vasculitis is a group of disorders that destroy blood vessels by inflammation. Both arteries and veins are affected. Lymphangitis (inflammation of lymphatic vessels) is sometimes considered a type of vasculitis. Vasculitis is primarily caused by ...

that is characterized by excruciating, recurrent

ulcers An ulcer is a discontinuity or break in a bodily membrane that impedes normal function of the affected organ. According to Robbins's pathology, "ulcer is the breach of the continuity of skin, epithelium or mucous membrane caused by sloughing ...

on the lower limbs.

Livedo racemosa Livedo racemosa is a skin condition with persistent red or violet discoloration, characterised by a broken, branched, discontinuous and irregular pattern. It can be restricted to the limbs or diffuse. It is usually the first sign of a systemic vas ...

, along with painful ulceration in the distal regions of the lower extremities, is the characteristic clinical appearance. It heals to form porcelain-white, atrophic scars, also known as Atrophie blanche. Livedoid vasculopathy has been linked to various conditions that can induce hypercoagulability, including

neoplasm A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

s, autoimmune connective-tissue diseases, and inherited and acquired

thrombophilia Thrombophilia (sometimes called hypercoagulability or a prothrombotic state) is an abnormality of blood coagulation that increases the risk of thrombosis (blood clots in blood vessels). Such abnormalities can be identified in 50% of people who ...

s. The history, clinical findings, and

histopathological Histopathology (compound of three Greek language, Greek words: 'tissue', 'suffering', and ''-logy, -logia'' 'study of') is the light microscope, microscopic examination of Tissue (biology), tissue in order to study the manifestations of dis ...

analysis are combined to make the diagnosis. Prompt and suitable intervention mitigates discomfort and averts the formation of wounds and additional complications. In addition to general supportive measures,

anticoagulant An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which ...

s and

antiplatelet An antiplatelet drug (antiaggregant), also known as a platelet agglutination inhibitor or platelet aggregation inhibitor, is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation. They are effectiv ...

medications can be considered the first-line treatments.

Signs and symptoms

Recurrent focal non-inflammatory

thrombosis Thrombosis () is the formation of a Thrombus, blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thrombocytes) and fib ...

of the superior superficial and medium dermal venulae, particularly on the lower extremities, bilaterally, is the initial clinical manifestation; upper extremity involvement has also been documented.

or, less commonly,

livedo reticularis Livedo reticularis is a common skin finding consisting of a mottled reticulated vascular pattern that appears as a lace-like purplish discoloration of the skin. The discoloration is caused by reduction in blood flow (ischemia) through the arter ...

are symptoms of such

, which causes blood and pressure to build up in the dermal superficial veins. The oxygen partial pressure in the skin decreases as a result of the blood flow obstruction, triggering a cutaneous response that presents as

pruritus An itch (also known as pruritus) is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both ...

with itchy

papule A papule is a small, well-defined bump in the skin lesion, skin. It may have a rounded, pointed or flat top, and may have a umbilication, dip. It can appear with a Peduncle (anatomy), stalk, be thread-like or look warty. It can be soft or firm a ...

s and

erythema Erythema (, ) is redness of the skin or mucous membranes, caused by hyperemia (increased blood flow) in superficial capillaries. It occurs with any skin injury, infection, or inflammation. Examples of erythema not associated with pathology inc ...

tous-violaceous, purpuric plaques. They quickly develop into bleeding vesicles, or bullae, which, when they burst, produce painful, small

about 5 mm in diameter. These

eventually combine to form painful, confluent, reticulate, and geometric ulcerations.

Complications

Due to the tissue exposure, the primary acute complications are pain and secondary infection. Atrophic scars, persistent

hyperpigmentation Hyperpigmentation, also known as the dark spots or circles on the skin, is the darkening of an area of Human skin, skin or nail (anatomy), nails caused by increased melanin. Causes Hyperpigmentation can be caused by sun damage, inflammation, or ...

mononeuritis multiplex Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropa ...

from vasa nervorum

, and cutaneous

hemosiderosis Hemosiderosis is a form of iron overload disorder resulting in the accumulation of hemosiderin. Types include: * Transfusion hemosiderosis * Idiopathic pulmonary hemosiderosis * Transfusional diabetes Organs affected: * Hemosiderin deposi ...

in the lower limbs from

erythrocytes Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...

oozing from the high-pressure regimen veins due to

hemosiderin Hemosiderin image of a kidney viewed under a microscope. The brown areas represent hemosiderin Hemosiderin or haemosiderin is an iron-storage complex that is composed of partially digested ferritin and lysosomes. The breakdown of heme gives ri ...

deposits in the skin are among the chronic complications associated with livedoid vasculopathy.

Causes

Few things are known about the origins of dermal vessel

in livedoid vasculopathy, what sets off its initial episodes and relapses, and why it primarily affects the lower limbs.

Risk factors

Livedoid vasculopathy has been linked to

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...

systemic lupus erythematosus Lupus, formally called systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Common ...

scleroderma Scleroderma is a group of autoimmune diseases that may result in changes to the skin, blood vessels, muscles, and internal organs. The disease can be either localized to the skin or involve other organs, as well. Symptoms may include areas ...

polyarteritis nodosa Polyarteritis nodosa (PAN) is a systemic necrotizing inflammation of blood vessels (vasculitis) affecting medium-sized muscular arteries, typically involving the arteries of the kidneys and other internal organs but generally sparing the lungs' ...

, mixed and undifferentiated

connective tissue disease Connective tissue diseases (also termed connective tissue disorders, or collagen vascular diseases), are medical conditions that affect connective tissue. Connective tissues protect, support, and provide structure for the body's other tissues a ...

s, and Sjogren's syndrome. Individuals with

who also have

antiphospholipid antibody syndrome Antiphospholipid syndrome, or antiphospholipid antibody syndrome (APS or APLS), is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS can lead to blood clots (thrombosis) in both arteries and veins, pregnancy-relate ...

are more vulnerable. Patients with hematological or solid organ cancers may also experience livedoid vasculopathy. Livedoid vasculopathy may deteriorate during pregnancy, particularly in the third trimester, though fetal compromise has not been documented. Still, a sizable fraction of cases are idiopathic.

Genetics

Livedoid vasculopathy is caused by a number of inherited and acquired coagulation abnormalities, such as polymorphisms in

factor V Coagulation factor V (Factor V), also less commonly known as proaccelerin or labile factor, is a protein involved in coagulation, encoded, in humans, by ''F5'' gene. In contrast to most other coagulation factors, it is not enzymatically active b ...

plasminogen activator inhibitor-1 Plasminogen activator inhibitor-1 (PAI-1) also known as endothelial plasminogen activator inhibitor (serpin E1) is a protein that in humans is encoded by the ''SERPINE1'' gene. Elevated PAI-1 is a risk factor for thrombosis and atherosclerosis. ...

(PAI-1),

prothrombin Prothrombin (coagulation factor II) is encoded in the human by the F2-gene. It is proteolytically cleaved during the clotting process by the prothrombinase enzyme complex to form thrombin. Thrombin (Factor IIa) (, fibrose, thrombase, throm ...

, and

methylenetetrahydrofolate reductase Methylenetetrahydrofolate reductase (MTHFR) is the rate-limiting enzyme in the methyl cycle, and it is encoded by the ''MTHFR'' gene. Methylenetetrahydrofolate reductase catalyzes the conversion of 5,10-Methylenetetrahydrofolate, 5,10-methylenet ...

(MTHFR).

Mechanism

At this point, the pathomechanism of livedoid vasculopathy is not fully understood. At first, livedoid vasculopathy was thought to be

vasculitis Vasculitis is a group of disorders that destroy blood vessels by inflammation. Both artery, arteries and veins are affected. Lymphangitis (inflammation of lymphatic vessels) is sometimes considered a type of vasculitis. Vasculitis is primarily c ...

. Presently, livedoid vasculopathy is understood to be a vascular illness in which procoagulatory factors predominate, resulting in

hypercoagulability Thrombophilia (sometimes called hypercoagulability or a prothrombotic state) is an abnormality of blood coagulation that increases the risk of thrombosis (blood clots in blood vessels). Such abnormalities can be identified in 50% of people who ...

. Defects in

endothelial The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the res ...

dysfunction, such as reduced

plasminogen Plasmin is an important enzyme () present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) is enco ...

activation,

platelet Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...

dysfunction, or increased or restricted

fibrin Fibrin (also called Factor Ia) is a fibrous protein, fibrous, non-globular protein involved in the Coagulation, clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerization, polymerize. ...

formation or

lysis Lysis ( ; from Greek 'loosening') is the breaking down of the membrane of a cell, often by viral, enzymic, or osmotic (that is, "lytic" ) mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a ...

, may be the cause of the thrombotic effect. As a diffusion barrier,

deposition and

thrombus A thrombus ( thrombi) is a solid or semisolid aggregate from constituents of the blood (platelets, fibrin, red blood cells, white blood cells) within the circulatory system during life. A blood clot is the final product of the blood coagulatio ...

formation cause a reduction in oxygen availability, which causes

necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. The term "necrosis" came about in the mid-19th century and is commonly attributed to German pathologist Rudolf Virchow, who i ...

. Furthermore, insufficient tissue perfusion results in inadequate wound healing, creating a vicious cycle. The so-called Virchow trias,

, stasis, and

damage, also serve as risk factors for livedoid vasculopathy microvascular

. The manifestation of livedoid vasculopathy on the lower extremities is thought to be caused by variations in temperature and perfusion pressure, as well as a lower concentration of thrombolytic factors.

Diagnosis

To diagnose livedoid vasculopathy and its causes, a thorough history, dermatological examination, and laboratory work-up are necessary. A

skin biopsy Skin biopsy is a biopsy technique in which a skin lesion is removed to be sent to a pathologist to render a microscopic diagnosis. It is usually done under local anesthetic in a physician's office, and results are often available in 4 to 10 day ...

should be performed to confirm the diagnosis of livedoid vasculopathy when it is clinically suspected. The most suitable type of biopsy is a fusiform incisional biopsy that contains subcutaneous fat.

Skin biopsies Skin biopsy is a biopsy technique in which a skin lesion is removed to be sent to a pathologist to render a microscopic diagnosis. It is usually done under local anesthetic in a physician's office, and results are often available in 4 to 10 day ...

histology Histology, also known as microscopic anatomy or microanatomy, is the branch of biology that studies the microscopic anatomy of biological tissue (biology), tissues. Histology is the microscopic counterpart to gross anatomy, which looks at large ...

reveals

proliferation,

deposition in the vessel walls (which is frequently difficult to identify), and a high frequency of intraluminal

hyaline A hyaline substance is one with a glassy appearance. The word is derived from , and . Histopathology Hyaline cartilage is named after its glassy appearance on fresh gross pathology. On light microscopy of H&E stained slides, the extracellula ...

thrombi in blood vessels, particularly in the upper and middle dermis, during the acute phase. Leukocytoclasia and a spare perivascular inflammatory infiltrate may be seen in the acute phase, but these results are not essential for the diagnosis. Following histopathological confirmation of the diagnosis, a more thorough evaluation of any potential underlying illnesses may be conducted. Naturally, the first steps in the assessment process should be a thorough history, a review of the systems, and a physical examination to look for any signs of underlying diseases. For every patient,

laboratory testing is advised. More testing is necessary to determine whether

is inherited or acquired, including looking into coagulating factors and their mutations. In the event that pertinent data suggestive of

s, such as

, and

mixed connective tissue disease Mixed connective tissue disease (MCTD) is a systemic autoimmune disease that shares characteristics with at least two other systemic autoimmune diseases, including Systemic scleroderma, systemic sclerosis (Ssc), systemic lupus erythematosus (SLE),� ...

, detailed laboratory research should be conducted. Furthermore, when

paraproteinemia Monoclonal gammopathy, also known as paraproteinemia, is the presence of excessive amounts of myeloma protein or monoclonal gamma globulin in the blood. It is usually due to an underlying immunoproliferative disorder or hematologic neoplasms, espe ...

or solid organ cancers are suspected, tests for protein

electrophoresis Electrophoresis is the motion of charged dispersed particles or dissolved charged molecules relative to a fluid under the influence of a spatially uniform electric field. As a rule, these are zwitterions with a positive or negative net ch ...

, Ig kappa and lambda chain levels, and

immunofixation Immunofixation permits the detection and typing of monoclonal antibodies or immunoglobulins in serum or urine. It is of great importance for the diagnosis and monitoring of certain blood related diseases such as myeloma. Principle The method ...

should be carried out. Again, testing for

HIV The human immunodeficiency viruses (HIV) are two species of '' Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the im ...

and

hepatitis Hepatitis is inflammation of the liver parenchyma, liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), Anorexia (symptom), poor appetite ...

should be done if there is a suspicion of an underlying infection. The initial step in the clinical work-up should be considering the differential diagnoses of additional common causes of atrophie blanche.

Vasculitis Vasculitis is a group of disorders that destroy blood vessels by inflammation. Both artery, arteries and veins are affected. Lymphangitis (inflammation of lymphatic vessels) is sometimes considered a type of vasculitis. Vasculitis is primarily c ...

, peripheral arterial vascular disease, and lower extremity

chronic venous insufficiency Chronic venous insufficiency (CVI) is a medical condition characterized by blood pooling in the veins, leading to increased pressure and strain on the vein walls. The most common cause of CVI is superficial venous reflux, which often results in ...

are the most frequent conditions to be taken into account during the differential diagnosis process.

Peripheral artery disease Peripheral artery disease (PAD) is a vascular disorder that causes abnormal narrowing of arteries other than those that supply the heart or brain. PAD can happen in any blood vessel, but it is more common in the legs than the arms. When narr ...

s are diagnosed with the help of clinical signs, abnormal arterial

Doppler ultrasound Doppler ultrasonography is medical ultrasonography that employs the Doppler effect to perform imaging of the movement of tissues and body fluids (usually blood), and their relative velocity to the probe. By calculating the frequency shift of a ...

findings, and the ankle-brachial index test. Cutaneous

is another common differential diagnosis that causes similar cutaneous lesions on the legs. A proper

can help differentiate

from livedoid vasculopathy.

Treatment

Although there are numerous distinct treatment modalities for livedoid vasculopathy, no published, standardized, evidence-based therapeutic strategies exist. The improvement of skin lesions, avoidance of relapses, and pain relief are the main goals of treatment for livedoid vasculopathy. Since not every patient responds to a single therapy approach equally, it is necessary to evaluate or combine a number of treatment options. Treating pain related to ulcers with

analgesia Pain management is an aspect of medicine and health care involving relief of pain (pain relief, analgesia, pain control) in various dimensions, from acute and simple to chronic and challenging. Most physicians and other health professionals ...

is crucial and frequently the patients' top priority.

UV light Ultraviolet radiation, also known as simply UV, is electromagnetic radiation of wavelengths of 10–400 nanometers, shorter than that of visible light, but longer than X-rays. UV radiation is present in sunlight and constitutes about 10% of t ...

, compression,

hyperbaric oxygen Hyperbaric medicine is medical treatment in which an increase in barometric pressure of typically air or oxygen is used. The immediate effects include reducing the size of gas emboli and raising the partial pressures of the gases present. Initial ...

, and routine wound debridement are examples of local therapies for livedoid vasculopathy.

Hyperbaric oxygen Hyperbaric medicine is medical treatment in which an increase in barometric pressure of typically air or oxygen is used. The immediate effects include reducing the size of gas emboli and raising the partial pressures of the gases present. Initial ...

and compression therapy have been demonstrated to enhance

fibrinolysis Fibrinolysis is a process that prevents blood clots from growing and becoming problematic. Primary fibrinolysis is a normal body process, while secondary fibrinolysis is the breakdown of clots due to a medicine, a medical disorder, or some other c ...

in addition to their respective roles in reducing

edema Edema (American English), also spelled oedema (British English), and also known as fluid retention, swelling, dropsy and hydropsy, is the build-up of fluid in the body's tissue (biology), tissue. Most commonly, the legs or arms are affected. S ...

and mitigating reperfusion injury. The most widely documented treatment for livedoid vasculopathy is oral

anticoagulation An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which h ...

, which directly addresses dermal vessel

. The most widely used of these is

rivaroxaban Rivaroxaban, sold under the brand name Xarelto among others, is an anticoagulant medication (blood thinner) used to treat and reduce the risk of blood clots. Specifically it is used to treat deep vein thrombosis and pulmonary emboli and prev ...

, which showed a significant reduction in pain after 12 weeks of therapy in an uncontrolled phase 2a trial. Common substitutes are antiplatelet agents like

aspirin Aspirin () is the genericized trademark for acetylsalicylic acid (ASA), a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and inflammation, and as an antithrombotic. Specific inflammatory conditions that aspirin is ...

and

pentoxifylline Pentoxifylline, also known as oxpentifylline, is a xanthine derivative used as a drug to treat muscle pain in people with peripheral artery disease. It is generic and sold under many brand names worldwide like Trental.Drugs.codrugs.com interna ...

. Patients who are not responding to traditional therapies may benefit from the use of low-dose systemic thrombolytics.

Epidemiology

According to estimates, the annual incidence of livedoid vasculopathy is 1:100,000, with women being affected at a ratio of 3:1. Patients may experience functional impairment for decades as the mean age of onset is in the 30s.

References

External links

DermNet
{{Cutaneous vasculitis Vascular-related cutaneous conditions