Chapter 122: The Vascular Purpuras

Purpura refers to visible hemorrhage into mucous membranes or skin, which corresponds to extravasation of red blood cells around small dermal vessels and chronic hemosiderin deposition.¹ Purpuric lesions, by definition, do not blanch completely upon compression, as opposed to erythema. Blanching is commonly tested by compression of skin lesions with a glass slide, referred to as diascopy (Fig. 122–1). Certain conditions give rise to lesions that mimic purpura with incomplete blanching upon diascopy, but are not purpura because no hemorrhage has occurred. Examples include disorders that impede on the red cell flow, such as tortuous veins.¹

Assessing lesion palpability is the first step in evaluating purpuric lesions (Fig. 122–2). The causes for palpability are varied and include fibrin deposition, localized edema, significant cellular infiltration, and subcutaneous extravasation of red blood cells.

Inspecting the lesion for inflammatory changes is the next step in evaluating purpuric lesions. The presence of pain, erythema, and palpation for warmth and localized swelling are signs of inflammation and suggest a vasculitis or immune complex disorder.

The shape of a purpuric lesion, either round or retiform (branching), is important in assessing the lesion. In the absence of accompanying inflammation, retiform purpuric lesions suggest small vessel occlusion. A retiform, inflammatory purpuric lesion supports the diagnosis of vasculitis as a result of immunoglobulin (Ig) complex formation.² Small, focal areas of hemorrhage are referred to as petechiae (≤4 mm). Larger lesions are referred to as intermediate or midsize purpura (>4 mm, <1 cm) or ecchymosis (≥1 cm).³

Purpuric lesions frequently appear purple; however, they can take on a variety of colors, according to the age of the lesion and the oxygen saturation of the hemoglobin in the extravasated blood. Ecchymosis usually starts as blue or purple, evolves to a greenish brown (a mixture of blue and yellow), and ultimately changes with variable speed to yellow as hemoglobin degrades to bilirubin.⁴ These examples of hemorrhage into the dermis must be distinguished from telangiectasia, which are vascular anomalies that blanch with pressure (see Fig. 122–1). Tables 122–1,122–2,122–3 classify the etiologies for purpura discussed in this chapter.

See Table 122–1.

DYSPROTEINEMIAS

Cryoglobulinemia

Cryoglobulinemia refers to the presence in plasma of cold-insoluble immunoglobulins,⁵ and is a secondary finding associated with several disease states. Cryoglobulins are commonly present in low concentrations, therefore approximately 90 percent of patients are asymptomatic or have minimal symptoms.⁶ Symptoms occur when the abnormal protein precipitates at the temperatures present in superficial venules in the skin and acral parts of the body. Cryoglobulinemia syndromes are divided into three main types based on the immunoglobulin composition of the precipitate. Type I cryoglobulinemia results from the accumulation of monoclonal IgG, IgM, or IgA. It is most commonly seen in association with lymphoproliferative disorders, such as myeloma, Waldenström macroglobulinemia, or lymphoma. Type II, or mixed cryoglobulinemia involves formation of complexes composed of polyclonal IgG with monoclonal immunoglobulins, typically IgM with anti-IgG specificity. Exposure to various exogenous antigens appears to cause polyclonal immunoglobulin production, with activity against bacteria, viruses, and fungi. Mixed cryoglobulinemia is commonly seen secondary to hepatitis C virus (HCV) infection,⁷ HIV, collagen vascular disorders, and hematologic neoplasias.^8,9 In mixed cryoglobulinemia secondary to HCV infection, the presence of active cutaneous vasculitis correlates with increased levels of the B-cell–attracting chemokine 1 (CXCL13).¹⁰ This process manifests with petechiae of the legs, palpable purpura, and necrotic skin ulcerations. First-line treatment includes use of interferon-α or other antiviral agents, often with adjunct glucocorticoids or plasmapheresis.¹¹ Direct treatment of the HCV infection with ribavirin, interferon, or other antiviral therapy, such as the protease inhibitors, ameliorates this associated lymphoproliferative disorder.¹² Deposition of immune complexes on vessel walls leads to tissue damage in the vasculature, nerves, joints, and skin leading to the hallmark findings of mixed cryoglobulinemia: weakness, arthralgia, and purpura. This purpura often is palpable and is accompanied by areas of hemorrhagic necrosis (Fig. 122–3) and occasionally follicular pustular purpura. Other cutaneous manifestations include lower-extremity ulcerations, urticaria, Raynaud phenomena, and subungual purpura (Fig. 122–4). Type III cryoglobulinemia associates polyclonal IgG and IgM complexes, also resulting in symptoms of mixed cryoglobulinemia.⁶ It is associated with a variety of infections, systemic lupus erythematous (SLE), and poststreptococcal glomerulonephritis.

Waldenström Hyperglobulinemic Purpura

A polyclonal increase of immunoglobulins, most commonly IgG₁, appears to be responsible for the varied cutaneous findings seen in this hypergammaglobulinemic purpura (HP). Waldenström first described a hyperproteinemic syndrome characterized by hypergammaglobulinemia, recurrent purpura, elevated erythrocyte sedimentation rate, and anemia.¹³ Most commonly seen in young women, this syndrome is associated with a large number of autoimmune disorders, including rheumatoid arthritis, Sjögren syndrome, SLE, hepatitis C, polymyositis, and sarcoidosis. Discrete to confluent collections of lower limb petechiae are its most common skin findings (Fig. 122–5), but lesions can occur in various body locations.¹⁴ Although lesions are usually self-limited and resolve in 7 to 10 days, recurrence of purpura is common and is associated with exposure to cold temperatures or increases in hydrostatic pressure, such as with the use of tight stockings or prolonged standing.¹⁵ Clinical manifestations consist of palpable purpura or diminutive macular erythematous lesions occurring on the lower legs. A reticulate pattern of purpura has been described.¹⁶ Development of edema and arthralgia has also been described.¹⁷

Common histologic findings include perivascular infiltrates, hemorrhage, and vascular necrosis. In addition to a polyclonal increase in either IgA, IgM, or IgG, serology may reveal cryoglobulinemia, rheumatoid factor, or antinuclear antibodies.¹⁸ Imbalances in IgG subclass expression, usually because of a decrease in IgG₂, appear to be associated with recurrent infections.¹⁷ Development of antilymphocyte antibodies results in lymphopenia. Anti-Ro/SSA antibodies occur in up to 78 percent of HP patients, suggesting that screening for anti-Ro/SSA should be considered in cases suspicious for Waldenström.¹⁹

Light-Chain Vasculopathy

Precipitates of immunoglobulin light chains that form crystalline deposits in the skin cause hemorrhagic palpable purpura. A nonamyloid monoclonal light chain of predominant κ type is involved in two-thirds of the cases.^20,21 Crystalline deposits are present in the skin and other tissues. Although the clinical presentation may mimic a systemic vasculitis, no histologic signs of inflammation are seen. Light-chain vasculopathy with cutaneous findings has also been described in association with multiple myeloma. Intravascular deposition of crystals containing IgG and λ light chains were found on immunohistochemical analysis and manifested with gangrene of the feet and intestinal perforation.²²

Cryofibrinogenemia

First described by Korst and Kratochvil in 1955, cryofibrinogenemia is a form of serum dysproteinemia characterized by formation of an abnormal cold-precipitable fibrinogen. Cutaneous manifestations include cyanosis, erythema, Raynaud phenomenon, and palpable purpura of the nose, ears, and distal extremities.²³ Tissue ischemia and gangrene may result. Pathogenesis of cryofibrinogenemia may involve an inhibition of normal fibrinolysis produced by a high plasma level of α₁-antitripsin and α₂-macroglobulin proteases.²⁴ Cryofibrinogenemia is commonly secondary to thromboembolic disorders, metastatic malignancies, infections, and collagen vascular disease.²⁵ Treatment modalities include avoidance of cold, plasmapheresis, and danazol, an anabolic glucocorticoid, or immunosuppression with glucocorticoids or cytotoxic agents.

THROMBOTIC PURPURA

Heparin Necrosis

Cutaneous reactions to heparin administration vary greatly from a type I urticarial rash to purpuric plaques with cutaneous ulceration or necrosis.²⁶ The syndrome occurs after both subcutaneous and intravenous administration of unfractionated heparin, but it has also been rarely described after low-molecular-weight heparin.²⁷ A delayed-type hypersensitivity reaction to the medication is involved. Skin lesions appear within 1 to 2 weeks after treatment initiation and include necrotic purpuric lesions.²⁸ Development of cutaneous lesions is closely related to heparin-induced thrombocytopenia (Chap. 118), which involves anti–platelet factor 4 antibody–mediated platelet aggregation with development of thrombosis and microvascular occlusion.²⁷

Warfarin Necrosis

The development of painful erythematous plaques and nodules is a potential complication of warfarin therapy (Fig. 122–6). These lesions can rapidly become hemorrhagic and necrotic, leading to large areas of infarct with black eschar formation and subsequent skin sloughing. Purpura, vesicular, maculopapular, or urticarial eruptions can be encountered.¹ Warfarin-induced necrosis has a prevalence between 0.01 and 0.1 percent and presents typically 3 to 10 days after initiation of anticoagulant treatment.^29,30 However, an atypical presentation can occur much later, for example, in a patient with protein S deficiency.^31,32 Although warfarin necrosis tends to develop in areas of greatest fat deposition, such as breasts, thighs, and buttocks, acral areas, including penis, fingers, and toes, can also be involved.³³ Warfarin necrosis results from the rapid decrease of vitamin K–dependent coagulation factors of relatively short half-life, such as proteins C and S, while longer-lasting coagulation factors, such as factor II and factor X, are not yet decreased, resulting in a net procoagulant state. Microvascular occlusion of small dermal and subcutaneous vessels by fibrin deposits is seen on histologic analysis, but true vasculitis is infrequent.²⁹ Treatment involves prompt cessation of the vitamin K antagonist, along with administration of heparin and vitamin K, and occasionally surgical debridement. Because patients with protein C or S deficiency are at increased susceptibility to warfarin necrosis, heparin should always be administered in these patients prior to initiation of Coumadin.³⁴

Proteins C and S Deficiencies

Clinical manifestations of proteins C and S deficiencies include venous thromboembolism, warfarin-induced skin necrosis, and neonatal purpura fulminans (Chap. 129). Congenital and acquired deficiencies in these proteins can lead to palpable necrotic purpura and ecchymosis.^35,36 Erythematous purpuric lesions associated with homozygous protein C deficiency can develop within hours of birth and can rapidly progress to hemorrhagic necrosis.³⁷ Acquired deficiencies of protein C are associated with autoantibodies to protein C, antibiotics administration, septic shock, HIV, and liver disease (Chap. 127).³⁸ Acquired protein S deficiency may occur after varicella infection, when it is associated with the generation of antiprotein S immunoglobulins.³⁹ Protein repletion with fresh-frozen plasma or protein C concentrate is effective as initial treatment for protein C deficiency to help clear both cutaneous lesions and venous occlusion, while lifelong anticoagulant treatment is used to prevent recurrence.^34,40

Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (Chap. 40) is a hematopoietic clonal disorder resulting in defective production of cell surface-binding proteins.⁴¹ Cutaneous manifestations are secondary to a hypercoagulable state and include palpable purpura, petechiae, ecchymosis, leg ulcers, plaques, necrosis, and hemorrhagic bullae.⁴² Parvovirus B19 may play an etiologic role in the development of cutaneous necrosis.⁴³ An association with pyoderma gangrenosum (Fig. 122–7)⁴⁴ and occurrence of purpura fulminans⁴⁵ have been described. Histology reveals formation of microvascular fibrin thrombi.⁴²

Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is a disease characterized by hypercoagulability associated with the presence of antibodies against phospholipids, such as anticardiolipin and lupus anticoagulant (Chap. 131).⁴⁶ Approximately 40 percent of patients with APS present with cutaneous lesions secondary to both large-vessel and microvascular thrombosis.⁴⁷ Skin manifestations include ecchymosis, livedo reticularis and racemosa, leg ulcerations, bullae, splinter hemorrhages, livedoid vasculopathy, superficial venous thrombosis, atrophie blanche, and extensive necrosis (Fig. 122–8).^47,48 Presence of livedo reticularis is frequently the presenting symptom of APS, most commonly when the syndrome is secondary to SLE, and its presence commonly precedes vascular events.⁴⁹ Development of acute bullous purpura has been described.⁵⁰ Treatment includes anticoagulant agents with immunosuppressant administration for associated thrombocytopenia. Prevention of thromboembolic events with aspirin is of uncertain value.⁵¹

Livedoid Vasculitis

Livedoid vasculitis (segmental hyalinizing vasculitis) is a chronic recurrent thrombo-occlusive disorder characterized by the initial development of erythematous purpuric lesions with telangiectasis and peripheral petechiae, and lower-extremity ulcerations. Subsequent healing leads to atrophie blanche, a term that refers to the appearance of ivory-white stellate scars commonly surrounded by hyperpigmented areas and telangiectasia. These lesions appear to be caused by small-vessel fibrin thrombi in the middle and lower dermis as a result of a procoagulant tendency.⁵² Although most commonly arising without associated cause, livedoid vasculitis is associated with polyarteritis nodosa, APS, and SLE.^53,54 Although not consistently beneficial, common therapies include discontinuation of oral contraceptives, anticoagulation and antiplatelet medications, glucocorticoids, and dapsone. Ketanserin, an S₂ serotoninergic receptor blocker, psoralen plus ultraviolet A therapy, and intravenous immunoglobulins also have been used successfully.⁵⁵

EMBOLIC PURPURA

Cholesterol Crystal Emboli

Also known as atheroemboli, cholesterol crystal emboli are responsible for a syndrome characterized by lower extremity pain and livedo reticularis with preservation of peripheral pulses. Other common cutaneous findings include gangrene, purpura, ulcerations, cyanosis, and nodules (Fig. 122–9).⁵⁶ Clinical symptoms include fever, myalgia, and altered mental status. Laboratory features include an elevated erythrocyte sedimentation rate, eosinophilia, and acute renal failure. Onset of symptoms varies from immediate after physical dislodgement of plaque, up to months later when caused by anticoagulant therapy.¹ A blue toe syndrome is, in fact, rare, and most atheroemboli are clinically silent.⁵⁷ Atherosclerotic lesions in the descending aorta are the most common source of cholesterol emboli. This explains the propensity for lower-extremity findings during intravascular procedures or initiation of thrombolytic or anticoagulant therapy.⁵⁶ Histologic evaluation can offer a definitive diagnosis with findings of intraluminal birefringent cholesterol crystals within blood vessel lumen, in the absence of vasculitis.⁵⁸ No effective treatment is available. Nevertheless, supportive care with proper hydration and dialysis may lessen the potential for end-organ damage.

Cutaneous Calciphylaxis

Calciphylaxis (calcific uremic arteriolopathy)⁵⁹ is a thrombo-occlusive disorder involving formation of cutaneous, subcutaneous, and vascular calcifications. It is most commonly seen in patients with end-stage renal disease, classically caused by the development of secondary hyperparathyroidism.⁶⁰ Approximately 4 percent of hemodialysis-dependent patients suffer from calciphylaxis. Survival is less than 50 percent at 5 years after diagnosis.⁶¹ Other etiologies include primary hyperparathyroidism, malignancy, alcoholic liver disease, and collagen tissue disorders.⁶² Cutaneous lesions present initially as reddish-purple plaques, evolving to tender, gangrenous ulcers or reticular hemorrhagic necrosis. Treatment involves a combination of medical and surgical interventions, such as parathyroidectomy, renal transplantation, wound debridement, and amputation.⁶¹

Emboli from Intracardiac Thrombi

Acral purpuric lesions secondary to emboli arise from left atrial myxomas or right atrial clots through paradoxical embolization.⁶³ These purpuric lesions include palpable purpura, livedo reticularis, erythematous macules and papules, cyanosis, petechiae, splinter hemorrhages, ulcerations, and cutaneous necrosis. Cyanosis, livedo reticularis, and lower-extremity ulcerations can also be seen.⁶⁴

ARTHROPOD BITES

Purpuric lesions are not uncommon after arthropod bites. Bites from bed bugs, Cimex lectularius, can give rise to localized purpuric macules or papules, while bites from kissing bugs, Reduviidae, often manifest as urticaria with hemorrhagic bulla.⁶⁵ Cutaneous findings after envenomation from a brown recluse spider, Loxosceles reclusa, include purpuric necrosis with surrounding erythema evolving to ulcer formation.

See Table 122–2.

PYODERMA GANGRENOSUM

Pyoderma gangrenosum is an idiopathic inflammatory skin condition characterized by early follicular erythematous papules and pustules or tender, fluctuant nodules with surrounding erythema that spread peripherally and ulcerate, surrounded by a violaceous rim (see Fig. 122–7).⁶⁶ In 50 percent of cases of pyoderma gangrenosum, there is an associated disorder, such as inflammatory bowel disorders (classically ulcerative colitis), arthritis, hematologic disorders, and solid tumors.⁶⁷ All four main clinical variants (ulcerative, pustular, bullous, and vegetative) share the histopathologic finding of a sterile abscess with central necrotizing neutrophilic infiltration, and a surrounding perivascular and intramural lymphocytic infiltration. First-line treatment involves wound care and immunosuppressants, such as glucocorticoids, cyclosporine, dapsone, azathioprine, and infliximab.⁶⁸

SWEET SYNDROME

Also referred to as acute, febrile neutrophilic dermatosis, Sweet syndrome is characterized by the acute manifestation of painful erythematous and violaceous papules, nodules, and plaques accompanied by fever and elevated neutrophil count (Fig. 122–10).⁶⁹ These papules, which most commonly appear on face, neck, and upper extremities, present a central yellowish discoloration and tend to coalesce, forming well-circumscribed, irregularly bordered plaques. Other organs can be involved, including the central nervous system, kidneys, lungs, and bones.⁷⁰ Classically more prominent in middle-aged women, this syndrome associates a complex cytokine dysregulation. Other manifestations include respiratory and urinary infections and autoimmune disorders (including rheumatoid arthritis), SLE, inflammatory bowel disease). Histologic analysis shows a distinct nonvasculitic neutrophilic infiltrate in the superficial dermis with dermal edema. Systemic glucocorticoid treatment is the standard treatment, while clofazimine, dapsone, colchicine, indomethacin, and cyclosporine have also been used successfully.⁷¹

BEHÇET DISEASE

Besides its classification as a neutrophilic dermatosis, Behçet disease is also an inflammatory disorder that affects multiple organ systems. Clinical features include chronic and relapsing cutaneous manifestations, such as palpable purpura, infiltrative erythema, and papulopustular lesions, as well as oral mucosal and genital ulcers, arthralgias, and gastrointestinal and central nervous system involvement.⁷² Genetic studies show an association between Behçet disease and human leukocyte antigen B51.⁷³ Histologic features include leukocytoclastic or lymphocytic vasculitis, hence its previous classification as a vasculitis. Antitumor necrosis factor-α directed therapies (infliximab, etanercept), interferon-α, immunosuppressive and immunomodulatory agents such as thalidomide, intravenous immunoglobulin, and even stem cell transplantation are used in Behçet disease.^74,75

SERUM SICKNESS

Serum sickness reflects the clinical manifestations of immune complex formation and deposition. Cutaneous lesions such as urticarial and morbilliform eruptions predominate, though palpable purpura and erythema multiforme can also be encountered. Serum sickness associated with infection or medical therapy can result in specific characteristic lesions. The use of antithymocyte globulin for marrow failure, for instance, results in 75 percent of patients developing serpiginous bands of erythema and purpura on the sides of their hands and feet (Fig. 122–11).⁷⁶ These characteristic lesions consistently appear 1 to 2 days prior to the onset of systemic symptoms of serum sickness, which include fever and malaise. Analysis of biopsies by direct immunofluorescence reveals deposition of IgM, IgE, IgA, and C3. This deposition appears to activate neutrophils leading to release of lysosomal enzymes and the development of dermal vasculitis.⁷⁷

HENOCH-SCHÖNLEIN PURPURA

Henoch-Schönlein purpura (HSP), is a predominantly pediatric vasculitic syndrome characterized by the acute onset of abdominal pain and lower-extremity eruption of diffuse urticarial plaques and palpable purpura. It was first described in 1801 by Dr. William Heberden.⁷⁸ HSP predominantly affects patients 2 to 20 years of age, 90 percent of patients being younger than 10 years old.⁷⁹ Several environmental triggers precede HSP onset, such as viral (upper respiratory infections, hepatitis B virus, HCV, parvovirus B19, and HIV) and bacterial (Streptococcus spp., Staphylococcus aureus, and Salmonella spp.) infections in children. Adult disease may be precipitated by medications (nonsteroidal antiinflammatory drugs [NSAIDs], angiotensin-converting enzyme inhibitors, and antibiotics), food allergies, vaccinations, and insect bites.⁸⁰ The pathogenesis of HSP leukocytoclastic vasculitis is complex. It appears to involve IgA₁ immune complex and complement deposition on vessel walls. Elevated values of thrombomodulin, tissue plasminogen activator, and plasminogen activator inhibitor-1 appear to correlate with endothelial injury and fibrinolytic activity in the acute phase of HSP.⁸¹

Cutaneous eruptions often begin acutely as urticarial papules and plaques evolving to petechiae, ecchymoses, and palpable and nonpalpable purpura over the lower extremities and buttocks (Fig. 122–12). Palpable purpura is a universal finding, being present in one series in 98.6 percent of patients.⁸² Clinically, lesions may take the form of retiform or patterned purpura, presence of a retiform edge of various inflammatory lesions, or skin necrosis.⁸³ Other common manifestations include localized subcutaneous edema, glomerulonephritis, arthritis, and (severe) abdominal pain.

In spite of its chronic relapsing pattern, the long-term evolution is benign in the majority of patients.⁸² The self-limited course of HSP may be contributed by an enhanced apoptosis of immune cells, which diminishes the severity of the acute inflammatory response.⁸⁴ Consequently, treatment is frequently supportive. Immunosuppressive drugs, including glucocorticoids, are typically reserved for cases with renal involvement.⁷⁸ Persistent purpura, severe abdominal symptoms, and diminished plasma coagulation factor XIII activity are predictive of renal involvement, requiring initiation of glucocorticoids.⁸⁵

INFECTIONS

Careful analysis of skin lesions of infectious etiology can provide important hints toward identifying the responsible pathogen. Purpura can arise through a variety of pathophysiologic mechanisms associated with infection: (1) vascular effects of toxins, (2) septic emboli, (3) direct invasion of vessels with subsequent vascular occlusion, and (4) immune complex formation.⁸⁶ Although the morphology of such purpuric lesions may be nonspecific, many pathogens lead to characteristic findings.

Bacterial

Gram-positive and Gram-negative infections may give rise to a large array of purpuric patterns depending on organism virulence and patient immune status. Skin lesions range from simple macules and papules to bullae, ulcers, and necrosis.

Purpura fulminans, a hemorrhagic infarction syndrome consisting of disseminated intravascular coagulation (DIC), acral purpura, and shock may manifest in the setting of bacterial sepsis with encapsulated organisms (Chap. 129).⁸⁷ Most commonly seen in immunocompromised hosts, purpura fulminans can also be produced by bacterial pathogens in immunocompetent patients.⁸⁸ This syndrome can be associated with asplenism or functional hyposplenism.⁸⁹ Although most patients are younger than the age of 10 years, adults can also be affected.⁹⁰ Retiform purpuric lesions result from fibrin-induced microvascular occlusion, and commonly have a rapid evolution toward necrosis and eschar formation. Adult patients with purpura fulminans as a result of meningococcemia have significantly depressed proteins C and S levels, which may explain the tendency toward fibrin deposition and development of cutaneous ischemic lesions, such as symmetrical peripheral gangrene.⁹¹ Facial purpura and livedo reticularis may be seen during fulminant pneumococcal infection in asplenic patients.⁹² Postinfectious purpura fulminans may also occur after infections with streptococci or varicella zoster,³⁹ and was associated with development of anti–protein S antibodies. Another characteristic lesion is the development of ecthyma gangrenosum in immunocompromised hosts (Fig. 122–13).

In children, more than 20 percent of cases admitted to the hospital with petechiae and fever were found to have invasive bacterial infections (Neisseria meningitidis, Haemophilus influenzae type B, and Streptococcus pneumoniae), and approximately 7 percent of cases were diagnosed with meningiococcemia.⁹³ Sepsis secondary to N. meningitidis can produce a characteristic pattern of purpuric lesions. Erythematous papules can quickly progress to numerous petechiae combined with violaceous reticular purpuric lesions.⁹⁴ A retiform aspect can be seen during progression of the infection to purpura fulminans. The finding of petechiae on a patient with symptoms and signs of bacterial meningitis is predictive of meningococcal meningitis.⁹⁵

Borrelia burgdorferi infection gives rise to erythema migrans, the characteristic lesion of Lyme disease. Skin lesion is classically a nonpruritic annular erythematous expanding plaque, occasionally including a central hemorrhagic bullae (Fig. 122–14). Other reported cutaneous findings associated with this infection include papular urticaria, Henoch-Schönlein–like purpura, and morphea.⁹⁶

Viral

Purpuric lesions can also be a manifestation of a viral infection. For example, the adenoviruses and enteroviruses have been associated with fever and petechiae in children.⁹⁷ Similarly, parvovirus B19 can produce a syndrome of petechiae or purpuric papules progressing to confluent purpuric papules or plaques in a sharply demarcated glove-and-sock distribution.⁹⁸ In addition to the cutaneous findings, the “gloves-and-socks syndrome” is characterized by fever and occasionally leukopenia, and can also be produced by the measles virus.⁹⁹ Purpura in the axilla and chest also has been described during parvovirus B19 infection (Fig. 122–15).¹⁰⁰ Histopathologic analysis of these purpuric lesions show an evolution from superficial perivascular lymphocytic infiltrate to a dermatitis accompanied by necrotic keratinocytes and hemorrhage.¹⁰¹ Hantavirus causes a syndrome of hemorrhagic fever and renal failure accompanied by headache, cutaneous and mucosal petechiae, and purpuric lesions.¹⁰²

Fungal

Fungal infections in the immunocompromised population are a growing medical issue, given the increasing number of patients receiving immunosuppressants for organ transplantation or malignancy. Disseminated or locally invasive infections can give rise to petechiae and hemorrhagic necrosis. Common fungal pathogens in disseminated disease includes Candida (Fig. 122–16), Aspergillus (Fig. 122–17), Histoplasma, and Fusarium.¹⁰³ Disseminated candidiasis can manifest as ecthyma gangrenosum in immunocompromised patients, suggesting consideration for a skin biopsy.¹⁰⁴ Cutaneous aspergillosis can also occur in immunocompetent individuals, and manifest as eruptive maculopapules, necrotizing plaques, or subcutaneous granulomas.¹⁰⁵

Parasitic

Immunocompromised patients are at risk of developing purpuric lesions secondary to parasitic infections, such as Pneumocystis jiroveci. Disseminated strongyloidiasis is characterized by larva currens, a serpiginous urticarial eruption caused by the migration of filiform larvae through the dermis.¹⁰⁶ Other cutaneous lesions include generalized petechiae and widespread reticular purpura of the arms, legs, and abdomen (Fig. 122–18), with a characteristic thumbprint periumbilical distribution.¹⁰⁷

Rickettsial

Infections caused by Rickettsia species can also lead to purpuric lesions as a result of their direct invasion of endothelial cells. This is followed by medial and intimal necrosis with subsequent thrombosis and hemorrhage.⁸⁶ Cutaneous lesions in Rocky Mountain spotted fever range from petechiae to acral purpuric lesions and hemorrhagic necrosis (Fig. 122–19). Maculopapular and vesicular rashes along with lower-extremity eschars produced by Rickettsia africae may also occur in travelers to sub-Saharan Africa.¹⁰⁸

ERYTHEMA MULTIFORME

Erythema multiforme (EM) is a cutaneous disorder characterized by the development of crops of well-demarcated, erythematous target lesions with central clearing,¹⁰⁹ most commonly representing a hypersensitivity reaction triggered by infection or drug exposure (Fig. 122–20). The severity of this disorder ranges from mild (EM minor), to severe (EM major or Stevens-Johnson syndrome). EM has been reported to be triggered by a number of viruses (most commonly herpes simplex, but also adenovirus, cytomegalovirus, and HIV),^110,111 and medications (sulfonamides, penicillins, bupropion, phenylbutazone, phenytoin, NSAIDs, adalimumab).¹¹² A cellular allergic reaction coupled with impaired histamine metabolism because of a decrease in histamine-N-methyltransferase activity may be causative.¹¹³ Treatment for mild cases is supportive, while the use of glucocorticoids is warranted in severe cases.

CUTANEOUS POLYARTERITIS NODOSA

Classic polyarteritis nodosa represents a systemic small- and medium-size vessel vasculitis most commonly involving the skin, heart, liver, and kidneys. A relatively benign cutaneous form exists that lacks significant systemic involvement¹¹⁴ and consistently involves the deep dermis and panniculus.¹¹⁵ Lesions develop as tender erythematous nodules¹¹⁶ with occasional retiform purpura and livedo reticularis localized to the upper and lower extremities, but the trunk, neck, and face can also be involved (Fig. 122–21). The duration of lesions varies from days to a few months.¹¹⁵ Histologic analysis of involved skin shows deep dermal artery necrosis with infiltration of neutrophils and eosinophils, and fibrin deposition. Treatment typically involves the use of NSAIDs and glucocorticoids, alone or in combination. Some cases of cutaneous polyarteritis nodosa are reported to have progressed on long-term followup,¹¹⁷ hence the need for close monitoring of patients diagnosed with an apparently benign, cutaneous form of disease.¹¹⁸

PARANEOPLASTIC VASCULITIS

Most common vasculitis associated with neoplasia are cutaneous leukocytoclastic vasculitis, paraneoplastic vasculitis, and HSP.^119,120 Paraneoplastic vasculitis is most commonly associated with hematologic neoplasia,¹²¹ and is commonly a result of paraproteinemia. However, an association with carcinomas of the lung, colon, breast, and cervix has been observed.^122,123,124 Solid tumors predominate in certain types of paraneoplastic vasculitis, such as the HSP.¹²⁵ Cutaneous manifestations include petechiae, urticaria, and palpable purpura, and are often intensely pruritic. In hematologic disorders, these lesions often precede the development of malignancy by an average of 10 months.¹²⁶ Histologic examination shows necrotizing leukocytoclastic vasculitis with neutrophilic infiltration.

DRUG-INDUCED VASCULITIS

A long list of drugs are reported to cause a vasculitis resulting in erythematous purpuric lesions. One-fifth of all cutaneous vasculitis are produced by drugs, including allopurinol, cefaclor, colony-stimulating factors, d-penicillamine, furosemide (Fig. 122–22), hydralazine, isotretinoin, methotrexate, phenytoin, minocycline, and propylthiouracil.¹²⁷

ANTINEUTROPHIL CYTOPLASMIC ANTIBODY–ASSOCIATED VASCULITIS

Wegener Granulomatosis

This small- to medium-vessel vasculitis most commonly affects upper and lower respiratory tracts and kidneys and is strongly associated with the development of circulating antineutrophil cytoplasmic antibodies (ANCAs).¹²⁸ Skin involvement has been reported in 35 to 50 percent of cases.¹²⁹ Cutaneous manifestations include a combination of palpable purpura, oral ulcers, and erythematous cutaneous and subcutaneous nodules (Fig. 122–23).¹³⁰ Necrotizing vasculitis, palisading granulomas, and granulomatous vasculitis are characteristic histologic findings.¹³¹

Churg-Strauss Syndrome

Churg-Strauss syndrome (CSS) is characterized by granulomatous inflammation in the lungs associated with asthma and eosinophilia.¹³² Cutaneous findings such as ulcers, papules, palpable purpura, cutaneous nodules, and infarcts of fingers and toes are encountered in 50 to 80 percent of cases.¹³⁰ CSS limited to the skin was described.¹³³ Eosinophilia accompanies elevated IgE levels and a positive perinuclear ANCA. Granulomatous inflammation and necrotizing vasculitis of small- to medium-size blood vessels are present histologically.¹³¹

See Table 122–3.

INCREASED TRANSMURAL PRESSURE GRADIENT AND TRAUMA

Acute increases in vascular transmural pressure gradients lead to extravasation of red blood cells resulting in nonpalpable, noninflammatory petechial and larger purpuric lesions. Examples include postictal purpura,¹³⁴ weightlifting,¹³⁵ postemesis facial purpura,¹³⁶ prolonged Valsalva, and childbirth. Acute decreases in extravascular negative pressure, referred to as suction purpura from gas mask, kissing, or cupping, can also increase this gradient, resulting in well-circumscribed lesions in the shape of the causative device.¹³⁷ The development of petechiae in mountain climbers, is presumably caused by significantly reduced atmospheric pressures at high elevations.¹³⁸ Lower-extremity venous incompetence, predominantly at the medial ankle, can result in macules or patches of yellowish-brown purpura.

Focal ecchymosis and other purpuric lesions can manifest as a result of trauma. Characteristic patterns of purpuric lesions are commonly used in forensic science. Traumatic asphyxia, for instance, is characterized by cervicofacial cyanosis and swelling, petechiae, and subconjunctival hemorrhage.¹³⁹ Factitious purpura, often related to deliberate suction purpura, should be considered in the differential for purpura.¹⁴⁰ Other physical causes of purpura consist of physical remedies, such as spooning (Quat Sha) or coin rubbing (Cao Gio). Exercise-induced purpura results in purpuric, erythematous, or urticarial lesions distributed on the lower legs.¹⁴¹

THROMBOCYTOPENIAS

Disseminated Intravascular Coagulation

DIC is defined as widespread, amplified and uncontrolled intravascular coagulation with a range of causes including sepsis, trauma, and malignancy.¹⁴² Petechiae and purpuric plaques result from thrombocytopenia, and are common manifestations of DIC (Chap. 129).

Immune Thrombocytopenia Purpura

Immune (or idiopathic) thrombocytopenia purpura is an acquired disease characterized by autoantibody-mediated platelet destruction commonly resulting in purpuric lesions of the skin and mucosa as well as other sites of abnormal bleeding (Chap 117).¹⁴³

Thrombotic Thrombocytopenia Purpura

Thrombotic thrombocytopenia purpura is characterized by nonimmune platelet consumption, microvascular hemolysis, and organ damage. It is associated with a deficiency in the von Willebrand factor cleaving protease, ADAMTS-13 (a disintegrin and metalloproteinase with thrombospondin domain 13; Chap. 132).¹⁴⁴ Petechiae and purpuric plaques may occur.

DRUG REACTIONS

A large number of medications are reported to result in vasculitic and nonvasculitic purpuric eruptions.¹⁴⁵ Nevertheless, any drug on the medication list of a patient with a purpuric lesion (within 2 weeks of starting a new drug or a few days if prior sensitization is suspected) may be involved.¹⁴⁶

COAGULATION DISORDERS

A large number of disorders manifest with thrombocytopenia or impaired thrombocyte function, that result in increased bruising. Also, impaired fibrin formation, resulting from coagulation factor deficiencies, the use of anticoagulants, vitamin K deficiency, or poor hepatic function may cause bruising and hematomas.

DECREASED VESSEL INTEGRITY WITHOUT TRAUMA

Senile Purpura

Synonymous with actinic purpura, senile purpura refers to the easy bruising seen in the aged and sun-damaged skin, commonly appearing on the dorsal aspect of the hands and forearms (Fig. 122–24). One proposed etiology is the degeneration of skin extracellular matrix components that leaves dermal capillaries unsupported and vulnerable to shearing injuries,¹⁴⁷ but zinc deficiency is also suspected.¹⁴⁸

Excess Glucocorticoid

The presence of excess endogenous (Cushing syndrome) or exogenous (iatrogenic) glucocorticoid use can result in dermal thinning and vessel fragility. Consequently, bright red, nonpalpable purpuric lesions tend to arise after slight or even undetected trauma and manifest in a linear or geometric pattern.¹⁴⁹

Scurvy—Vitamin C Deficiency

Vitamin C (ascorbic acid) deficiency occurs because of reduced dietary intake or absorption. A consequent disruption in normal collagen production results in blood vessel fragility leading to petechiae, perifollicular hemorrhage, and larger purpuric plaques, most commonly on the lower extremities (Fig. 122–25).¹⁵⁰ Thus, scurvy is usually a clinical diagnosis. Cutaneous features can also include follicular hyperkeratotic papules, poor wound healing, and bent or corkscrew-shaped body hairs.¹⁵¹ Vitamin C supplementation is rapidly effective.

Systemic Amyloidosis

Systemic amyloidosis is characterized by a clonal proliferation of plasma cells with consequent immunoglobulin light-chain deposition in vital organs. Microscopic 8 to 10 nm protofilaments aggregate to form fibrils.¹⁵² It can present as a primary disorder or secondarily to multiple myeloma (Chaps. 107 and 108). Characteristic features are periorbital “pinch purpura,” “raccoon eyes,” and macroglosia.¹⁵³

Waxy, purpuric cutaneous and mucocutaneous lesions manifest when light-chain aggregates deposit in dermal blood vessels. Although rare, palmodigital purpura has been reported as the sole cutaneous finding in a case of myeloma-associated systemic amyloidosis.¹⁵⁴ A distinct localized form, primary cutaneous amyloidosis, is caused by local dermal infiltration of plasma cells.¹⁵⁵

CONNECTIVE TISSUE DISORDERS

Ehlers-Danlos Syndrome

A rare autosomal dominant syndrome, Ehlers-Danlos syndrome is a consequence of a mutation in collagen synthesis, tenascin X, or lysyl hydroxylase, and others. This leads to loss of skin elasticity, delayed wound healing, easy bruising, joint hypermobility, and systemic organ and tissue fragility.¹⁵⁶ Cutaneous findings include thin skin and a tendency to develop nonpalpable purpuric lesions.¹⁵⁷

Pseudoxanthoma Elasticum

Pseudoxanthoma elasticum is genetic disorder characterized by mineralization and fragmentation of elastin in the skin, retina, and blood vessels.¹⁵⁸ This autosomally inherited disease is associated with a mutation in the ABCC6 gene, an ATP-binding cassette transporter, which may play an important role in connective tissue turnover.¹⁵⁹ Cutaneous lesions include small white or yellow papules classically appearing on the neck in a “gooseflesh” aspect,¹⁶⁰ but systemic hemorrhagic events are also encountered.

Melas Syndrome

Nonpalpable purpuric lesions can occur on the palms and soles in mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome.¹⁶¹ MELAS syndrome, one of a family of mitochondrial encephalomyopathies, has been associated with a mutation in a mitochondrial transfer RNA (tRNA) or the reduced form of nicotinamide adenine dinucleotide (NADH) dehydrogenase complex I.¹⁶² Skin manifestations can also include hypertrichosis, ichthyosis, and vitiligo.¹⁶³

RENDU-OSLER-WEBER DISEASE (HEREDITARY HEMORRHAGIC TELANGIECTASIA)

Rendu-Osler-Weber disease is an autosomal dominant hereditary disorder characterized by local angiodysplasia, mostly present in the skin, mucous membranes, and often in organs such as the lungs, liver, and brain.¹⁶⁴ It may lead to nose bleeding, acute and chronic digestive tract bleeding, and various problems resulting from the involvement of other organs. Vascular malformations may present as telangiectasias (small vascular malformations) in the skin (Fig. 122–26). Subcutaneous bleeding may occur as well, presenting as non-palpable purpuric lesions. Angiodysplasia in Rendu-Osler-Weber disease is caused by a defect in angiogenesis. Five genetic types of hereditary hemorrhagic telangiectasia (HHT) are recognized. More than 80 percent of all cases of HHT are caused by mutations in either ENG (endoglin, HHT1) or ALK1 (ACVRL1, HHT2).¹⁶⁵ Treatment of the disease is symptomatic, for example, by iron administration when iron-deficiency anemia occurs, or by laser treatment of small (bleeding) malformations in mucous membranes or embolization of larger arteriovenous malformations.