The protein C and S system is an important inhibitor of coagulation in small vessels in particular. Deficiencies in the system can give rise to severe microvascular occlusion syndromes that lead to purpura fulminans.1,2

Signs vary according to the degree of the deficiency. Homozygous mutations that seriously disrupt the system can cause severe symptoms of neonatal purpura fulminans, with retiform purpura and gangrene on the extremities.1,3 Partial deficiencies, on the other hand, in heterozygous mutations might pass unnoticed or manifest only in the presence of some external trigger, such as treatment with oral anticoagulants.1,2

Histopathologic findings are similar to those in other noninflammatory microvascular occlusive syndromes. Soft thrombosis of vessels of varying sizes is observed in the dermis and hypodermis. An inflammatory infiltrate is scant or nil, without signs of vasculitis.

Acenocoumarol and warfarin are widely used oral anticoagulants that work by inhibiting vitamin K, reducing plasma levels of vitamin K-dependent coagulation factors II, VII, IX, and X. These anticoagulants also affect the protein C and S inhibitor system.4 Because these proteins have short half-lives, a paradoxical procoagulant effect is observed in the early days of treatment.5,6 These anticoagulants have also recently been linked to nonuremic calciphylaxis.7

Cutaneous necrosis associated with anti-vitamin K therapy typically presents during the first week of treatment, coinciding with a relative decrease in protein C and protein S levels.4,5 Necrosis characteristically develops in areas where adipose tissue tends to accumulate, such as the breasts and thighs. Signs and symptoms overlap with those of other disorders that manifest with retiform purpura and erythematous and hemorrhagic lesions with characteristic necrotic centers; there may be branching features in the borders of lesions.4,7 Warfarin-associated nonuremic calciphylaxis also presents with retiform purpura, but that sign appears after months or years of treatment.7

Biopsies of classic cutaneous necroses due to vitamin K antagonists typically show signs of noninflammatory thrombotic vasculopathy4,5 with eosinophilic fibrin-like deposits occluding multiple vessels.4 Affected vessels vary in size; they may be superficial ones in the papillary dermis, or deeper in the reticular dermis, or still deeper at the dermal-hypodermal junction.4–6 It is common to observe extravasated blood cells surrounding the occluded vessels as well as associated epidermal necrosis.4 A very scant inflammatory infiltrate may be present, though there may be none at all; vasculitis is not present.4,5 The findings in warfarin-induced nonuremic calciphylaxis overlap with those of classic calciphylaxis.7

Disseminated intravascular coagulation (DIC) is an acquired syndrome triggered by various factors. When coagulation is activated, fibrin is deposited in vessels, obstructing them and compromising the blood supply to organs and systems. Coagulation proteins and platelets are consumed, leading to significant bleeding. A diagnosis of DIC requires the presence of an underlying disease. Certain analytical criteria must be met. The most common cause is bacterial sepsis.8,9

DIC involves multiple organs. The first sign often takes the form of skin lesions, typically a petechial rash and purpuric plaques that may progress to hemorrhagic blisters. Two common conditions that often develop in the context of DIC are purpura fulminans and symmetrical acral gangrene; the disease does not always progress to that degree, however. Purpura fulminans is characterized by confluent purpuric lesions that progress rapidly to well-circumcised necrosis. Mortality can reach 50%. Symmetrical acral gangrene consists of symmetrical ischemia in distal areas10,11 (Fig. 1A).

Figure 1.

A, Symmetrical acral gangrene, characterized by a well-circumscribed ischemic plaque on the left hand. Note the bluish discoloration of the nails. B, Fibrin thrombi in the superficial vascular plexus. Note the extravasation of red blood cells in the dermis. Hematoxylin-eosin, magnification × 400. C, Disseminated intravascular coagulation a few days old. Note the formation of a subepidermal blister, epidermal necrosis, and fibrin thrombi in small dermal vessels. Hematoxylin-eosin, magnification × 200.

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Histopathologic findings in DIC are not pathognomonic but may point to diagnosis in the context of certain clinical pictures. Thrombi containing fibrin and platelets are found, mainly in small dermal blood vessels. They vary in number from few to many. Occlusion of small arteries in the reticular dermis is seen less often. Red blood cell extravasation is also common, especially so in cases of purpura fulminans (Fig. 1B). An inflammatory infiltrate is usually scant or nonexistent. Biopsies of lesions only a few days old may display epidermal necrosis, subepidermal blistering, and necrosis of eccrine glands and hair follicles (Fig. 1C). Lesions that have progressed to gangrene show extensive necrosis in all skin structures.10 Bearing in mind that sepsis is the most common cause of DIC, mixed patterns of thrombotic and septic vasculopathy with fibrinoid necrosis or bacterial invasion of the vessel wall are often observed. An inflammatory infiltrate is more prominent in such cases.12

Antiphospholipid syndrome is an arterial or venous thrombotic autoimmune disease associated with the presence of antiphospholipids (lupus anticoagulant, anticardiolipin antibody, and anti-β2 glycoprotein). This syndrome is probably the most common acquired thrombophilic disorder. It may be idiopathic or associated with various other conditions, among them autoimmune diseases (especially lupus erythematosus), infections, hematologic or solid tumors, and other less frequent scenarios.13

Patients are most often young women. The early signs are usually skin necrosis, livedo reticularis, Raynaud phenomenon or subungual bleeding, particularly in primary forms associated with lupus. Diagnosis requires a relevant clinical sign along with a finding of one of the antibodies listed above.14 The relevant clinical criteria are confirmed vascular thrombosis in any location (skin, central nervous system, heart, lung, kidney, digestive tract) or a history of gestational problems (intrauterine fetal death, spontaneous abortion, premature delivery). Patients should be followed for 5 to 10 years after diagnosis because many develop systemic lupus erythematosus. Catastrophic illness develops in fewer than 1% of patients with antiphospholipid syndrome, but mortality exceeds 50% in such cases; death is usually due to generalized thrombotic microangiopathy involving multiple organs simultaneously or over a short period of time.15

Look for fibrin thrombi in the absence of inflammation of the vessel wall, in arteries or veins of any caliber (Fig. 2A–B). A few lymphocytes or plasma cells may occasionally be observed. Neovascularization and vascular proliferation (reactive angioendotheliomatosis) may occur when disease is of long duration.

Figure 2.

Catastrophic antiphospholipid syndrome. Note the skin necrosis on the nasal tip (inset, upper right corner). A, Venous thrombosis. Hematoxylin-eosin, × 100. B, Arterial thrombosis. Hematoxylin-eosin, magnification × 200.

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Sneddon syndrome is a rare, episodic or chronic neurocutaneous syndrome that progresses slowly and is characterized by generalized livedo racemosa and repeated strokes.16 More than 50% of patients have the primary form. The secondary form occurs in association with an autoimmune disease or a thrombophilic disorder (antiphospholipid syndrome). A familial form involving a mutation in the CECR1 (cat eye syndrome region, candidate 1) gene has been described; this form produces adenosine deaminase 2 deficiency.17

Around 80% of patients are women; the mean age at diagnosis is 40 years, although onset can also occur in childhood. The main skin sign is livedo racemosa, although the characteristic lesions were at first described as livedo reticularis.18 They usually appear first on the lower back and progress to the back of the arms and thighs, sparing the feet and face. The lesions are not painful, edema and ulceration are rare. The severity of skin signs does not correlate with neurologic symptoms. Rarely, acral cyanosis, Raynaud phenomenon, angiomatosis, circumscribed skin ulcers, atrophic annular lichen planus, or gangrene may be observed. Neurologic manifestations tend to begin with headache, nausea, and dizziness. Recurrent transient ischemic attacks and finally ischemic or hemorrhagic strokes ensue. Progressive cognitive decline and dementia occur in this phase.

Deep biopsy samples from the center, not the ring, of livedo racemosa lesions offer the best diagnostic yield in histologic evaluation.16 The earliest lesions, which are rarely biopsied, are endothelial and show inflammation in the walls of small- and medium caliber arteries. The most common observation is subendothelial thickening due to myocyte proliferation leading to total or subtotal occlusion of dermal and hypodermal blood vessels. Local hypoxia stimulates endothelial proliferation and adventitial angiogenesis in the final phase.19

Livedoid vasculopathy is a common chronic thrombotic skin disease characterized by ischemia. The main causes are coagulation disorders, autoimmune diseases, and certain infections. Venous insufficiency, a very important facilitator of thrombosis, can be added to the list.

This diagnosis is seen more often in middle-aged women, who develop papules and plaques on the lower extremities. The lesions are more or less purpuric, symmetrical, painful, and persistent. They give way to slowly progressing ulcers that, depending on size, may heal or lead to porcelain-white scars known as atrophie blanche. Thrombosis is caused by a hypercoagulability state due to circulating procoagulant antibodies (ie, cryoglobulins, antibodies in idiopathic antiphospholipid syndrome, or those appearing in autoimmune diseases such as lupus erythematosus, viral hepatitis, etc). Thrombocytosis might also be the culprit, or there may be hereditary abnormalities affecting coagulation factors (eg, Factor V Leiden mutation or fibrinolytic factor deficiency states). Chronic venous insufficiency and injuries must be added to the conditions that facilitate thrombosis. The condition is idiopathic in many cases, however. Skin signs are purpuric papules and plaques that tend to ulceration, leading to porcelain-white scars (Fig. 3A).

Figure 3.

Livedoid vasculopathy. A, Erythema, multiple ulcers, and discoloration of the skin due to red cell extravasation on the leg of a 62-year-old woman with lupus erythematosus and venous insufficiency. B, Glomerular-like vascular aggregates in the superficial dermis. Hematoxylin-eosin, magnification × 100. C, Detail of the previous microphotograph. Note the vascular wall thickening, elevated number of pericytes, and homogeneous deposits of eosinophilic fibrinoid material. Around the blood vessel, note extravasated red cells, occasional hemosiderin-laden macrophages, a lymphomacrophagic infiltrate, and collagen fibrosis; Hematoxylin-eosin, magnification × 200.

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The skin biopsy should include tissue adjacent to the ulcerated area to demonstrate the condition of the surrounding skin. There are no pathognomonic histologic signs. Livedoid vasculopathy affects vessels in the superficial to mid-dermis. Present are glomerular-like aggregates of dilated vessels, periodic acid–Schiff (PAS)-positive fibrinoid hyaline deposition in the walls, thrombosis, and bleeding that should not be confused with vasculitis. A variable perivascular lymphomacrophagic infiltrate can also be observed. Ulcers give way to scarring. Epidermal atrophy and intense collagen fibrosis due to chronic ischemia appear in the most advanced cases. This development is the cause of the characteristic clinical sign of porcelain-white atrophy (Fig. 3B and C). Direct immunofluorescence can reveal deposits of immunoglobulins, complement, and fibrinogen, suggesting the nature of the immune process. Other thrombosing vascular diseases must be ruled out in the differential diagnosis, for which reason clinicopathologic correlation is important.

Livedoid vasculopathy is histologically distinguishable from type I cryoglobulinemia and diabetic microangiopathy, neither of which show a glomerular-like vascular architecture. Distinguishing this diagnosis from stasis dermatitis or acroangiodermatitis is complicated, but these last 2 entities generally show marked ferrous deposition or intense vascular proliferation, respectively.

Degos disease, also called Kohlmeier–Degos disease or atrophic papulosis, is rare: fewer than 200 cases have been reported.20 Patients are mainly women between the ages of 20 and 50 years, although cases have also been reported in children.21 The etiopathogenesis is unknown, but associated coagulopathy and vasculitis of the endothelial lining, possibly related to complement factors, have been reported.20–22 Reports of familial cases suggest the possibility of genetic predisposition.

The following lesions are considered pathognomonic: atrophic papules measuring less than 1 cm, with porcelain-white centers and telangiectatic erythematous halos21 (Fig. 4A). A characteristic “crown of thorns” pattern is visible under a dermoscope.23 The trunk and extremities are affected but not the scalp or face. Two forms of Degos disease are currently considered. A benign form, affecting mainly the skin, has a good prognosis and accounts for 71% of the cases. The second form is systemic and involves malignant atrophic papulosis. It may be concurrent with the cutaneous form or develop later. The systemic form can lead to serious complications and even death in 75% of the cases due to cerebral, lung, kidney or other organ involvement; intestinal perforation may occur.20,21

Figure 4.

Degos disease. A, Atrophic papule with a porcelain-white center and a telangiectatic, erythematous halo. This lesion is considered a pathognomonic finding in this disease. B, Wedge-shaped infarct with a vertex extending downward. At the point of the vertex, a slight, chronic, perivascular lymphocytic infiltrate can be seen around the vessel. Hematoxylin-eosin, magnification × 20. C, Detail of the vessel shown above. Note the numerous intravascular thrombi. Hematoxylin-eosin, magnification × 400.

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Findings depend on when in the course of disease the examination takes place. Characteristic signs of established disease are vascular lesions and wedge-shaped infarcts in the dermis (Fig. 4B). Endothelial swelling and intraluminal fibrin thrombi can be observed (Fig. 4C). The nearby area of the dermis contains perivascular and periadnexal lymphocytic inflammatory aggregates and interstitial mucin deposition. The epidermis might show ischemic damage, lesions at the interface, and hyperkeratosis.24 Early lesions can be similar to cutaneous lupus erythematosus, with perivascular lymphocytic aggregates and interstitial mucin deposition.25

Stress reticulocyte adhesion is caused by changes in the rheologic properties of red cells, favoring viscosity and the propensity to thrombosis.26 Although various diseases can alter red cell rheology, this concept is applied mainly in sickle-cell anemia, in which an intraluminal occlusion is due to a 2-step mechanism. CD36+ stress reticulocytes that are released tend to adhere to the endothelium, increasing the expression of ICAM-1 (intercellular adhesion molecule 1). These processes activate coagulation, and the resulting hypoxia increases the release of new stress reticulocytes, with further expression of ICAM-1.

Painful single or multiple ulcers develop on the skin, especially on the internal surface of the ankle.27 Stroke, pulmonary hypertension, splenic infarction, and changes in kidney function secondary to thrombotic events in various organs can also occur.

Epidermal ulcers with granulation tissue are observed. Intraluminal fibrin thrombi may form, and vessel walls may show hyalinization, as in livedoid vasculopathy.28 Acanthosis and keratosis can usually be seen in the epidermis adjacent to the ulcer.

A multisystemic disorder releases cholesterol crystals from atherosclerotic plaques into the blood stream, which carries them distally into medium- and small-caliber arteries, where they partially or completely occlude the lumen. Arteries in skin can be affected. Although crystals may be released from a plaque spontaneously, the event is generally preceded by an angioinvasive procedure or the use of destabilizing anticoagulants or fibrinolytic agents.29

Signs are highly varied, but the most common ones are livedo reticularis, purpuric papules and nodules, petechiae, and cyanosis affecting distal areas of the extremities (Fig. 5A). Ulcers and gangrene may appear in the most severe cases.

Figure 5.

A, Livedo reticularis on the sole of the right foot of a patient with cholesterol crystal emboli. B, Cholesterol crystal emboli. Empty acicular spaces inside a blood vessel corresponding to cholesterol crystals that were dissolved during preparation of the biopsied tissue. A tissue response can be observed in the form of giant multinucleated cells surrounding the empty acicular spaces. Hematoxylin-eosin, magnification × 200. C, Late-phase emboli may show fibrosis surrounding the crystals and complete occlusion of the blood vessel. Hematoxylin-eosin, magnification × 200.

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A highly characteristic, specific finding is the presence of needle-shaped, biconvex clefts inside at least 1 small- or medium caliber vessel (100–200 μm) (Fig. 5B). These shapes are the negative image of cholesterol crystals dissolved while the biopsy specimen was being prepared. They are usually found in vasculature at the dermal-hypodermal junction.30 However, it may be necessary to prepare several sections in order to locate these crystals. Other common findings are neutrophils and eosinophils surrounding the crystals in early lesions and multinucleated cells and fibrosis in late phases of disease16 (Fig. 5C).

Oxalate deposition mainly occurs in primary hyperoxaluric states, a group of inherited autosomal recessive metabolic disorders in which serum oxalate is overproduced and subsequently deposited in tissues. Secondary oxalosis is the result of excessive intake or supply of oxalate or its precursors (ethylene glycol poisoning, the anesthetic methoxyflurane, ascorbic acid). Various intestinal diseases, ileal resection, and chronic hemodialysis may also lead to an oversupply of oxalate.