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CHAPTER 121 THE VASCULAR PURPURAS

CHAPTER 121 THE VASCULAR PURPURAS
Williams Hematology

CHAPTER 121 THE VASCULAR PURPURAS

PAUL I. SCHNEIDERMAN

Nonpalpable Purpura

Increased Transmural Pressure Gradient

Conditions Affecting the Integrity of the Blood Vessel Wall and its Supporting Tissues

Trauma to Blood Vessels
Palpable Purpura

Cutaneous Vasculitis

Dysproteinemias

Primary Cutaneous Diseases
Nonpurpuric Disorders Simulating Purpura

Disorders with Telangiectasias

Kaposi Sarcoma

Intravascular Large-Cell Lymphoma

Fabry’s Disease (Angiokeratoma Corporis Diffusum)

Extramedullary Hematopoiesis (“Blueberry Muffin” Baby)

Angioma Serpiginosum

Granuloma Annulare
Chapter References

Petechiae, purpura, and ecchymoses (collectively referred to as purpura) are all caused by the extravasation of red blood cells from the vasculature into the skin and/or subcutaneous tissue. Hemostatic disorders can cause petechiae, purpura, and ecchymoses but so can autoimmune, drug-induced, infiltrative, inflammatory, metabolic, neoplastic, primary cutaneous, and vascular disorders. Moreover, primary cutaneous and vascular lesions can simulate petechiae, purpura, and ecchymoses. the general category of purpuras can be conveniently divided into those in which the lesions are nonpalpable and those in which the lesions are palpable. Palpable lesions are more commonly due to vasculitic and/or inflammatory damage to blood vessels, but nonpalpable lesions may be due to hemostatic disorders, bland vascular damage, or vasculitic and/or inflammatory damage. the identification and classification of purpuric lesions can provide important diagnostic information.

Acronyms and abbreviations that appear in this chapter include: CREST, calcinosis, Raynaud phenomenon, esophageal motor dysfunction, sclerodactyly, and telangiectasia; DIC, disseminated intravascular coagulation; MELAS, mitochondrial encephalopathy,lactic acidosis, strokelike; PAI-1, plasminogen activator inhibitor 1; TGF-b, transforming growth factor beta.

Purpura, or skin hemorrhage, is defined as the extravasation of red cells from the vasculature into the skin and/or subcutaneous tissue. Blood leaking in minute amounts produces pinpoint red lesions less than 2 mm in size (petechiae), and blood leaking in larger amounts produces purpuric lesions (2 mm to 1 cm) or ecchymoses (>1 cm).1 Conventional usage often groups purpuric lesions and ecchymoses under the term purpura, and the general group of disorders that produces such lesions, including petechiae, is often referred to as the purpuras. All of these hemorrhagic lesions can be differentiated from erythema (reddened skin due to increased blood flow to superficial blood vessels) and telangiectasias (dilated superficial capillaries), in which the blood remains confined within the vasculature and which blanch on direct pressure. Blanching of lesions with pressure can be demonstrated using a glass slide or hand lens (diascopy) (see Plate XXV-1 and Plate XXV-2). Purpura may demonstrate partial blanching, but a nonblanchable component will remain. Superficial lesions of the purpuras are bright red or deep red; deeper lesions have more of a purple appearance. With time, purpuric lesions evolve into deep purple, brown, orange, or blue-green discolorations.
Extravasation of blood from the vasculature depends upon the integrity of blood vessels, which in turn depends upon: (1) the competence of the hemostatic mechanism to combat the basal level of ongoing vascular trauma, (2) the strength of the blood vessel and its surrounding tissues, and (3) the transmural pressure gradient tending to drive blood out of the vessel. Even if these systems are functioning normally, serious trauma may be sufficient to cause hemorrhagic extravasation.
A classification of disorders producing skin hemorrhage is given in Table 121-1.2,3 It is organized primarily according to etiology but is subdivided on the basis of the physical finding of palpability because palpability can be determined at the bedside; thus this finding can aid in developing a differential diagnosis. Palpability is most likely due to extravascular fibrin deposition. Presumably, the generalized increase in vascular permeability secondary to an inflammatory process results in marked extravasation of plasma proteins including fibrinogen and other coagulation factors, and cytokine activation of inflammatory cells triggers coagulation by causing the cells to express tissue factor. This palpable induration can be experimentally diminished in delayed hypersensitivity reactions by the administration of oral anticoagulants, supporting a major role for the coagulation mechanism.4 Palpability also may be secondary to extensive cellular infiltration as in certain inflammatory or malignant disorders.

TABLE 121-1 THE PURPURAS

Purpuric lesions secondary to hemostatic defects are described elsewhere (see Chap. 115).
NONPALPABLE PURPURA
INCREASED TRANSMURAL PRESSURE GRADIENT
Any activity or event that results in a dramatic increase in intrathoracic pressure can produce the clinical picture of minute petechiae of the face (“mask phenomenon”), neck, and upper chest, with a sharp demarcation at the nipple line, accompanying cervicofacial cyanosis and edema, and bilateral subconjunctival hemorrhage. Among the many causes are prolonged Valsalva maneuvers, coughing, vomiting,5 labor and delivery, weight lifting, vigorous exercise, generalized seizures,6 severe crush injury of the thorax or upper abdomen (thoracoabdominal compression), and child abuse.7,8,9 and 10 Eyelid and conjunctival petechiae are characteristic findings of neck compression (strangling).11 the clinical picture of acute increased transmural pressure gradient is caused by the reflux of blood from the heart retrograde through the valveless superior vena cava and great veins of the head and neck, causing the overlying capillaries to become engorged, with resultant egress of erythrocytes. These findings are similar to those observed in patients with the superior vena cava syndrome or in newborns with umbilical cord strangulation. Basilar skull fracture needs to be considered in the differential diagnosis of subconjunctival hemorrhage, but with this entity, periorbital ecchymosis and/or epistaxis are common.
Suction purpura encompasses a diverse collection of petechial and purpuric eruptions that result from the generation of negative pressure on the surface of the body. Well-demarcated, annular lesions are commonly produced by this mechanism, whether by vacuum extractors at the time of delivery, rubber suction cups on toys, cupping, ECG leads, kissing, or wearing a gas mask.12
Lesions on the lower extremities, especially in the elderly, may be due to acute venous stasis due to tight clothing or stockings. Occasionally such dependent purpura may be palpable, even in the absence of microscopic inflammation. Acute compression of the inferior vena cava, as, for example, by a large but unruptured aortic aneurysm, can produce edema and purpura of the lower extremities. In addition, common cutaneous disorders (drug rash, contact dermatitis,13 and sunburn) often progress to become petechial and purpuric after the first 24 h.
CHRONIC
Chronic venous stasis of the lower extremity, due either to venous valvular incompetence or chronic use of tight-fitting stockings or garments, can convert subclinical insults of diverse etiologies into frank purpura. Thus, it is common for the first signs of petechiae due to thrombocytopenia to appear at the ankles. Chronic venous stasis accompanied by recurrent episodes of extravasation of red cells leads to the development of purpuric and yellow-brown macules (“brown patches”), with the latter due to the persistent presence of hemosiderin, the hemoglobin breakdown product.
HIGH ALTITUDE
An increase in cutaneous petechiae has been noted in mountain climbers ascending higher than 3800 m above sea level.14 the mechanism for this purpura may be increased transmural pressure due to reduced extravascular pressure, rather than increased intravascular pressure.
CONDITIONS AFFECTING the INTEGRITY OF the BLOOD VESSEL WALL AND ITS SUPPORTING TISSUES
ACTINIC PURPURA (SENILE PURPURA)
Chronic solar damage and decreased collagen, elastin, and ground substance due to aging may result in characteristic red to purple irregular purpuric patches on the extensor surfaces of the forearms and hands (see Plate XXV-3 and Plate XXV-4).15 the skin in solar purpura is thin and lacks elasticity, making it particularly susceptible to tears induced by shearing forces.16 These purpuric changes occur after minor or inapparent trauma and may take months to resolve. Syndromes of premature aging such as the Hutchinson-Gilford syndrome (progeria), Werner’s syndrome (pangeria), acrogeria, and others may all give rise to acral purpuric changes identical to those of senile purpura.17
GLUCOCORTICOID EXCESS
The patches of purpura in Cushing syndrome may appear on both the flexor and extensor aspects of both the upper and lower extremities. As with actinic purpura, shearing stress is a common precipitating event, and the patches may last for weeks to months. the lesions have a characteristic bright red or purple appearance, and the skin is thin and fragile.2 Glucocorticoids administered parenterally, orally, or by inhalation all may produce similar dermal thinning and purpura.18
The use of potent fluorinated topical glucocorticoids, especially if applied under occlusive dressings, may result in cutaneous striae, atrophy, and purpura. If the atrophy is severe enough, ulceration with extrusion of fat to the surface of the skin (fat herniation) may ensue. Microscopic evaluation of the skin in glucocorticoid atrophy usually reveals loss of dermal connective tissue with thinning of the epidermis.
VITAMIN C (ASCORBIC ACID) DEFICIENCY (SCURVY)
Vitamin C is required for the formation of collagen and ground substance in the skin. Deficiency of vitamin C can develop after 2 to 3 months of inadequate intake19 and is characterized by the presence of horny keratinous plugs in the orifices of the hair follicles (follicular keratosis), petechiae, and perifollicular purpura with entrapped “corkscrew” hairs on the upper arms, legs, back, and buttocks (see Plate XXV-5). Initially, swelling, pain, and purpura are present. Large ecchymoses on the legs and mucous membrane purpura are seen in more severe cases, often produced by mild trauma. Hemorrhagic gingivitis, stomatitis, conjunctivitis, myalgias, arthralgias, and bone pain due to hemorrhage into muscles, joints, and bones may also occur.20 Chronic ascorbate deficiency may present with woody edema and hyperpigmentation of the lower extremities.21 Therefore, scurvy is characterized by the four H’s—hemorrhagic signs, hyperkeratosis of hair follicles, hypochondriasis (weakness and arthralgias), and hematologic abnormalities (impaired platelet aggregation).19 Alcoholics, the elderly, food faddists, and patients on dialysis have a higher risk for developing scurvy.
EHLERS-DANLOS SYNDROME AND PSEUDOXANTHOMA ELASTICUM
Easy bruising is one of the most prominent features of Ehlers-Danlos syndrome types IV and V (ecchymotic and X-linked), but it may also be seen in types I to III (gravis, mitis, and benign hypermobile) (see Plate XXV-6). Milder forms of Ehlers-Danlos syndrome have recently been described that also demonstrate mild to moderate bruising.22 An association between thumb hyperextensibility and purpura has been reported, and the hyperextensibility may be an indicator of Ehlers-Danlos syndrome.23 In evaluating patients for this heterogeneous group of connective tissue disorders, it is important to assess the elasticity of the skin, the extensibility of the joints, and the presence of other abnormalities such as high-arched palate and pectus excavatum. In pseudoxanthoma elasticum, recurrent mucous membrane hemorrhages may be a prominent physical finding. Patients with Marfan’s syndrome and Noonan’s syndrome may also demonstrate mild bleeding tendencies and increased capillary fragility.24
AMYLOID INFILTRATION OF BLOOD VESSELS
Mucocutaneous manifestations may be prominent in primary systemic amyloidosis associated with multiple myeloma or other paraproteinemias. Tissue biopsy reveals light-chain (AL) deposits of amyloid extensively infiltrating blood vessel walls and/or present diffusely throughout the dermis, resulting in increased vascular fragility. As a result, minimal trauma can produce hemorrhagic lesions (“pinch purpura”). Petechiae occur readily when there is an increase in transmural pressure (e.g., after a Valsalva maneuver or after proctoscopy), especially when the amyloidosis involves the eyelids and face (see Plate XXV-7 and Plate XXV-8). Other cutaneous lesions are seen on the face, neck, scalp, or anogenital region in approximately one-third of patients with primary amyloidosis, and so the presence of these lesions may help to suggest the diagnosis; these include brown- to tan-colored translucent papules, plaques, nodules, bullae, xanthoma-like nodules, and sclerodermoid plaques that may become hemorrhagic either spontaneously or following trauma. Macroglossia with central irregular enlargement and peripheral indentations secondary to pressure from the adjacent teeth (scalloped tongue); diffuse eyelid and bulbar conjunctival swelling; alopecia and nail changes; smooth, waxy infiltration of the palms and volar fingertips25; and a rim of purpura (“purpuric halo”) surrounding cherry angiomas have all been described in amyloidosis.26
COLLOID MILIUM
Colloid milium is characterized clinically by yellow papules and plaques, and histologically by the deposition of upper dermal amorphous material (similar to amyloid). Lesions of colloid milium may become purpuric after trauma.27
FEMALE EASY-BRUISING SYNDROME
The female predominance and the frequent association with phases of the menstrual cycle suggest that the female easy-bruising syndrome (purpura simplex) is due to hormonal effects on the blood vessel and/or its surrounding tissues.2 Concomitant use of nonsteroidal anti-inflammatory medications may inhibit platelet function and contribute to the severity of the symptoms. Patients complain of frequent purpuric and ecchymotic lesions on the thighs (“devil’s pinches”) with minimal trauma. Patients with this entity who do not have other platelet or coagulation disorders do not appear to be at increased risk of hemorrhage from more severe hemostatic challenges such as surgery.
ADMINISTRATION OF LORENZO’S OIL
Purpura from a defect in vessel wall function has been seen in a patient receiving Lorenzo’s oil (glycerol trioleate and glycerol trierucate).28
MELAS SYNDROME
Mitochondrial encephalomyopathy encompasses a group of disorders characterized by one or more enzymatic defects of aerobic metabolism leading to morphologic abnormalities of mitochondria in skeletal and cardiac muscle, the central nervous system, kidneys, liver, and endocrine organs. A 6-month-old boy with MELAS syndrome who demonstrated recurrent crops of purpuric macules on the palms and soles has been described.29
TRAUMA TO BLOOD VESSELS
PHYSICAL
Traumatic injury, if severe enough, causes skin hemorrhage even in normal individuals. It is thus important to know in detail the extent of an injury before deciding whether the skin hemorrhage is consistent with the magnitude of the trauma.7 Traumatic lesions usually have well-defined margins. Depending on the etiology, the pattern may be annular or circumferential (e.g., hardball injury), linear or loop-shaped (e.g., child beating), periorbital (swim goggle purpura),30 subungual (e.g., running shoe injury) (see Plate XXV-9), pinpoint (e.g., black dot heel, or talon noire), or genital (e.g., pinch marks from child abuse). the lesions associated with child abuse often include both cutaneous purpura, due to bruising from fingertip or hand pressure, and petechiae of the bulbar and palpebral conjunctivae, due to strangulation and/or smothering.31,32
Patients with factitial, or self-inflicted, purpura usually have medium- to large-sized ecchymotic lesions on the lower extremities, but the trunk or upper extremities may also be involved. These patients characteristically express indifference to the bruises.
Patients manifesting “coma bullae” present with irregular, clear or hemorrhagic bullae at sites of prolonged external pressure. Histologically, sweat gland necrosis is the diagnostic finding.
Purpura characteristically occurs after treatment of vascular anomalies with the 585-nm pulsed dye laser.33
ULTRAVIOLET RADIATION
Acute sunburn can have a petechial component if the damage is severe enough. Patients have been described who developed petechial lesions on the legs and trunk after suberythemal exposures to natural sunlight (solar purpura); these lesions were attributed to hypersensitivity to long-wave ultraviolet light [UVA (320 to 400 nm) or UVB (280 to 320 nm)]. Leukocytoclastic vasculitis was observed histologically in one patient.34,35 and 36
A syndrome has been reported in which transfused neonates with hyperbilirubinemia developed purpuric patches at sites of maximal exposure to blue light phototherapy.37 the eruptions resolved in 2 to 7 days after discontinuation of the ultraviolet light therapy. the etiology of this purpuric phototherapy-induced eruption in neonates may be elevated plasma porphyrins (coproporphyrin and protoporphyrin).
INFECTIOUS
Bacterial, fungal, viral, rickettsial, protozoal, and parasitic infections may produce purpura.38,39 the pathogenesis of infectious purpura is often complex and may include direct vascular invasion by the organism, disseminated intravascular coagulation, purpura fulminans, immune complex vasculitis, Shwartzman-like phenomena, septic emboli, direct effects of toxins released by the infecting organisms on the vasculature, and thrombocytopenia. Although characteristic patterns of purpura have been described for different infectious agents, overlap between the patterns is quite common.
Bacterial sepsis, including acute and subacute bacterial endocarditis due to gram-positive or gram-negative organisms, may cause a wide variety of dermatologic changes, including petechial or purpuric macules or papules; hemorrhagic bullae, erosions, or ulcers; or widespread ecchymoses and ischemic infarction of the skin (purpura fulminans, see below). the full syndrome of purpura fulminans can develop during bacterial infections, including streptococcal, staphylococcal, pneumococcal, and meningococcal bacteremias, and during scarlet fever, Haemophilus influenza, Rocky Mountain spotted fever, leptospirosis, and disease caused by Vibrio parahaemolyticus and dysgonic fermenter type 2. It is less common for it to follow viral (rubella, varicella, and roseola) or fungal (Candida spp.) infections. Asplenic patients with overwhelming pneumococcal sepsis may have facial petechiae and purpura, acral cyanosis, and/or livedo reticularis as their presenting symptoms.40 About 20 percent of children admitted to the hospital with fever and petechiae41 have documented invasive bacterial disease due to a variety of organisms, including N. meningitidis, H. influenzae, Streptococcus pneumoniae, Staphylococcus aureus, and Escherichia coli. Enteroviral and adenoviral pathogens can also be isolated on occasion. It has been reported that about 7 percent of children with fever and petechiae seen in emergency room departments have meningococcemia.42 Palpable purpuric lesions associated with bacterial endocarditis may be an indication of immune complex formation. Splinter hemorrhages of the nails, historically associated with subacute bacterial endocarditis, occur in healthy individuals and in association with a variety of illnesses and thus are of little specific diagnostic value.43
Gram-negative sepsis with Pseudomonas species, Klebsiella species, Aeromonas hydrophila, or E. coli in the setting of severe immunocompromise may produce characteristic lesions of ecthyma gangrenosum (see Plate XXV-10). These lesions, which are seen in about 5 percent of patients with Pseudomonas sepsis, begin as erythematous or purpuric macules, then progress to plaquelike edema and erythema with nodule formation surmounted by irregular purpura. Within 48 h, these lesions develop into hemorrhagic or necrotic vesicles or bullae, surrounded by concentric areas of normal skin and a thin band of erythema.44,45 Still later, the lesions evolve into edematous hemorrhagic plaques and then indurated painless ulcers. Lesions may be single or multiple and occur most often on the legs, abdomen, axillae, and anogenital areas. the palms and soles may occasionally be involved. the differential diagnosis of ecthyma gangrenosum includes fungal sepsis due to Candida species,46 drug eruptions, cryoglobulinemia (see below), pyoderma gangrenosum, necrotizing vasculitis, polyarteritis nodosa, hyperviscosity syndrome, Sweet’s syndrome, and leukemic infiltrates.
Meningococcemia initially produces erythematous papules, but these soon evolve into widespread petechiae with stellate purple to slate-gray purpuric lesions (see Plate XXV-11). These cutaneous lesions are the presenting sign in the vast majority of patients.47 the purpura of meningococcemia may be due to direct vascular invasion by the organism or to an endotoxin-induced Shwartzman reaction. Acrocyanosis and symmetrical peripheral gangrene may ensue and are thought to be due to ischemic damage secondary to fibrin deposition as a result of disseminated intravascular coagulation. Purpura fulminans then rapidly follows.47 the combination of purulent meningitis and petechiae strongly suggests that Neisseria meningitidis is the etiologic agent.48 the presence of a rash in meningococcal infections indicates that there is a high likelihood of a fatal outcome.49 Adult patients with meningococcemia and purpura fulminans have markedly depressed levels of proteins C and S and moderately decreased antithrombin III levels. Plasminogen activator inhibitor 1 (PAI-1), an acute phase protein inhibitor of tissue plasminogen activator, is increased in meningococcal purpura fulminans. Administration of antithrombin III concentrates,50 recombinant tissue plasminogen activator,51 or protein C52,53 have been reported to result in rapid clinical improvement in select patients (see Chap. 126).
In chronic, intermittent meningococcemia an immune complex dermatitis may develop, manifesting itself as a poorly defined erythema with or without hemorrhagic papulovesicles over the joints.
A clinical presentation nearly identical to that of acute meningococcemia is seen in children with Brazilian purpuric fever,54 a syndrome described in children aged 1 to 10. Purulent conjunctivitis caused by Haemophilus aegyptius heralds the syndrome, followed by purpura fulminans with fever, vomiting, abdominal pain, shock, and death. Bacterial endotoxin is probably the cause of this illness; treatment with antibiotics has been reported to improve the outcome.
In streptococcal pharyngitis, the erythrogenic toxin of S. pyogenes causes the classic rash of scarlet fever with associated linear purpuric lines in the skin folds (Pastia’s lines). Streptococcal pharyngitis without scarlet fever can produce perioral, neck, and truncal petechiae in 2 percent of patients.55
Rickettsial infections, including Rocky Mountain spotted fever and epidemic typhus, produce cutaneous changes; urticarial macules may be seen initially and then evolve into petechiae (see Plate XXV-12), ecchymoses, focal hemorrhagic bullae, and/or more extensive areas of hemorrhagic necrosis (see Plate XXV-13).
The characteristic lesion of Lyme borreliosis is a nonpurpuric annular expanding plaque (erythema migrans). the lesion may contain a central purpuric macule or papule, or a hemorrhagic bulla (see Plate XXV-14).
Patients with either disseminated fungal infections [e.g., caused by Cryptococcus, Candida (see Plate XXV-15), Zygomycetes, Aspergillus (see Plate XXV-16), Histoplasma, Alternaria, or Fusarium]56,57 or locally invasive fungal diseases (e.g., mucormycosis, aspergillosis) may have hemorrhagic necrosis, purpura, and/or petechiae early in the course of the illness58; they may also demonstrate ecthyma gangrenosum-like lesions (e.g., with Candida or A. niger infections).
Viral infections occasionally have primary purpuric eruptions as their presenting manifestation. Parvovirus B19 infection may result in a petechial or confluent purpuric rash on the buttocks, axilla, and/or chest59 (see Plate XXV-17). the papular-purpuric gloves and socks syndrome,47,60,61 and 62 a disorder of adolescents and young adults, is characterized by well-demarcated symmetrical pruritic or painful acral edema and erythema; confluent petechial/purpuric papules and plaques of the hands and feet (including the palms and soles); oral erythema and erosions; swelling of the lips and tongue; and angular or erosive cheilitis. Palatal petechiae are common. Other areas of involvement include the inner thighs, inguinal region, buttocks, elbows, and knees. Systemic manifestations include fever, fatigue, myalgias, anorexia, lymphadenopathy, and arthralgias. This syndrome has been associated with infections caused by parvovirus B19, measles virus,63 cytomegalovirus, Coxsackie B6 virus, and human herpes virus 6 (HHV-6).
Hemorrhagic fever with renal syndrome comprises a constellation of findings including fever, acute renal failure, headache, vomiting, and prostration associated with mucocutaneous petechiae, ecchymoses, facial flushing, periorbital edema, and both conjunctival and palatal petechiae.64 This disorder is caused by Hantaan virus and is transmitted to humans by wild rodents; it is endemic to the former Soviet Union, Asia, Scandinavia, and Europe.
Parasitic infections, especially in the immunocompromised host, may produce purpura. Migration of filariform larvae of Strongyloides stercoralis typically produces rapidly progressive periumbilical and abdominal “thumb-print,” linear, and reticulated purpura on a background of petechiae (see Plate XXV-18).65,66 and 67 Disseminated cutaneous Pneumocystis carinii infection in patients with AIDS may demonstrate purpuric papules and nodules that closely resemble lesions of Kaposi sarcoma (see below).68 Schistosomal cercarial dermatitis may begin as erythematous macules and urticarial lesions, which then develop central hemorrhage or vesiculation.
EMBOLIC
Atheroemboli with prominent cholesterol crystals, usually originating from atherosclerotic lesions in the aorta, can cause acral petechiae and purpura, acral livedo reticularis, nodules, unilateral peripheral ulcers, and bilateral cyanosis and gangrene69 (see Plate XXV-19 and Plate XXV-20). Distal pulses are present because these emboli are usually small and thus lodge in small blood vessels. Atheroemboli originating in the aortic arch or carotid arteries may affect the cerebral circulation and occasionally can be directly visualized in retinal arteries as refractile interruptions in the column of arterial blood. Transesophageal echocardiography is useful in identifying such lesions in the aorta.70 Atheroemboli occur most frequently in older men (>50 years old) after diagnostic or vascular repair procedures. There is also an association with oral anticoagulant use, presumably as a result of increased lesion friability due to diminished fibrin support. Cholesterol embolization to the pancreas makes elevations of serum amylase levels a common accompanying laboratory finding. Livedo reticularis in an elderly patient is the most common presentation of cholesterol embolization.
Fat embolism may occur 2 to 3 days after severe trauma or following liposuction. the initial findings include petechiae of the upper extremity, thorax, and/or conjunctivae. the full syndrome includes hyperthermia, respiratory distress, retinal fat emboli, neurologic symptoms, and pulmonary infiltrates (see Chap. 126).71,72
Emboli from left atrial myxomas may cause acral purpura (nonblanching serpiginous and annular violaceous lesions of the fingertips), splinter hemorrhages, acral necrosis, and palpable purpura, as well as nonpurpuric manifestations including acral red papules with claudication, peripheral cyanosis, acral livedo reticularis, leg ulcers, and Raynaud’s phenomenon.73
Calciphylaxis is defined as a syndrome of subcutaneous and vascular calcification in patients with secondary hyperparathyroidism due to end-stage renal failure. Hemorrhagic necrosis in a livedoid (vascular) pattern may be observed in these patients. the subcutaneous and vascular calcification following infusion of calcium gluconate or in chronic hypercalcemia may result in cutaneous necrosis and hemorrhage in a speckled or vascular pattern.
NEOPLASTIC
Infiltration of the skin in Langerhans cell histiocytosis (Chap. 78) can result in the development of a papular and crusted dermatitis of the scalp and intertriginous areas (see Plate XXV-21). Although these lesions usually simulate seborrheic dermatitis, they may have both petechial and purpuric features. Early cutaneous T-cell lymphoma may produce cutaneous lesions mimicking those seen in the pigmented purpuric eruptions. Similarly, skin infiltrations in patients with leukemias (see Plate XXV-27), lymphomas, and plasma cell disorders can be purpuric or can simulate purpura.74,75
ALLERGIC AND/OR INFLAMMATORY
In serum sickness, occurring either in association with drugs or infections, morbilliform or urticarial eruptions are the most common cutaneous manifestations. Petechiae, palpable purpura, and erythema multiforme lesions may occur. Linear or serpiginous bands of erythema may be seen at the margins of the palmar and/or plantar surfaces76 (see Plate XXV-22). If the patients are thrombocytopenic, purpura usually appears within these linear bands. This eruption often heralds the onset of the syndrome. Direct immunofluorescence of involved skin demonstrates immunoglobulin and complement deposits.
The pigmented purpuric eruptions,77,78 and 79 including Schamberg’s disease, Majocchi’s disease, and others, are a poorly understood group of disorders characterized by pinpoint petechiae and purpura on a background of red-brown or orange hyperpigmentation (see Plate XXV-23). Scaling, lichenification, and/or atrophy are occasionally seen. Itching may or may not be present. These eruptions characteristically involve the lower extremities, but they may be seen on the arms, trunk, and even the palms and soles.80 Unilateral, linear, and zosteriform variants of pigmented purpuric eruptions have been identified.81 the pigmented purpuric eruptions are not associated with any systemic manifestations. There is clinical overlap among these disorders, and a patient may have features of more than one pigmented purpuric eruption. Histologically, extravasation of red blood cells, hemosiderin deposits within macrophages, and a perivascular lymphohistiocytic (helper T cell)82 infiltrate with endothelial cell swelling are seen. the pathogenesis of these disorders is not established but may include increased capillary dilatation with increased fragility and subsequent rupture of the capillaries in the papillary dermis, aneurysmal dilatation of the microvasculature, and possibly abnormal cellular immune responses to an unknown antigen.83 Involved skin has been demonstrated to contain activated helper T cells along with keratinocytes positive for antigenic markers associated with receptors for effector immune cells.84 Decreased aggregation of platelets in response to collagen has been reported.85 Cutaneous T-cell lymphoma has been reported to produce lesions simulating those found in the pigmented purpuric eruptions, and so this disorder needs to be considered in the differential diagnosis.86 Other disorders included in the differential diagnosis are drug hypersensitivity,87 purpuric clothing dermatitis, sensitivity to food additives,88 and hyperglobulinemic purpura of Waldenström.
Purpuric eruptions can result from allergic or irritant contact dermatitis to benzoyl peroxide,89 clothing, cobalt, rubber, woolen garments, elastic dyes, Balsam of Peru,90 local anesthetic (EMLA) cream,91,92 or detergent whiteners, and these may simulate the pigmented purpuric eruptions.93
Pyoderma gangrenosum is a destructive, necrotizing ulceration of the skin presenting as a nodule, pustule, or hemorrhagic bulla (see Plate XXV-24). These furuncular nodules and pustules occur on the calves, thighs, buttocks, and face; they ulcerate rapidly, developing an undermined violaceous or blue border with surrounding erythema. the necrotic base is erythematous and edematous. Lesions heal with atrophic and cribriform scars. Systemic toxicity and high fever may accompany lesions of pyoderma gangrenosum. Clinical associations of these lesions include inflammatory bowel disease, rheumatoid arthritis, other polyarthritis syndromes, monoclonal gammopathies, hypogammaglobulinemia, blood dyscrasias, myeloma, lymphoma, and acute leukemia. Although any lesion of pyoderma gangrenosum may develop hemorrhagic necrosis, a specific superficial hemorrhagic bullous form with giant bullae is often associated with acute leukemia or other myeloproliferative disorder.
VISCERAL INFLAMMATORY DISEASE OR HEMORRHAGE
Intraabdominal inflammatory disease such as acute pancreatitis, ruptured ectopic pregnancy, or perforated duodenal ulcer may result in periumbilical purpura (Cullen’s sign) (see Plate XXV-25). Purpura or ecchymosis on the flanks may be an indicator of retroperitoneal hemorrhage (Grey-Turner sign) (see Plate XXV-26).
THROMBOTIC
Disseminated intravascular coagulation (DIC) may result from a variety of different insults (see Chap. 126). Since there is potential for both thrombotic and hemorrhagic manifestations in DIC, it is not surprising that the skin manifestations are diverse. the most common skin findings are acral cyanosis with variably associated petechial, purpuric, and ecchymotic lesions, but in severe cases hemorrhagic gangrene of fingers and toes can occur.49 the competence of the fibrinolytic system to digest deposited fibrin determines the extent of tissue compromise. the presence of peripheral gangrene may be an important consideration in the often difficult decision as to whether heparin is indicated in treating the syndrome39 (see Plate XXV-28). the administration of antithrombin III50 or protein C concentrate52 appears to be of therapeutic benefit in some patients with disseminated intravascular coagulation due to meningococcemia, and recombinant tissue plasminogen activator has been reported to restore perfusion in this syndrome.51
COUMARIN SKIN NECROSIS
This thrombotic disorder affects about 1 in 500 patients receiving coumarin, with clinical lesions appearing between days 2 and 14 of coumarin administration.94 Patients deficient in protein C are at a higher risk of developing coumarin necrosis because activated protein C functions as an anticoagulant, and it is one of the vitamin K–dependent factors that is most rapidly reduced by coumarin administration.95 Coumarin necrosis begins suddenly as painful erythematous patches (see Plate XXV-29) that rapidly become edematous and progress to irregularly shaped hemorrhagic and necrotic plaques, nodules, and bullae; eventually large tumid indurations and infarcts occur with eschar formation and sloughing.96 Coumarin necrosis is more common in women, with lesions occurring most often in fatty areas, such as the buttocks, thighs, and breasts. Acral areas, such as the fingers, toes, and penis, can occasionally be involved.97 Lesions may be symmetric and widely distributed and on occasion may require surgical intervention.98 Histologically, fibrin and platelet thrombi are observed in the dermal and subcutaneous vasculature. In one study, tumor necrosis factor was identified in the lesions, and endothelial cell adhesion molecules were upregulated.99 the syndrome of coumarin necrosis is usually easily differentiated from hemorrhage due to excessive anticoagulation, since the latter usually occurs in association with excessive anticoagulation, has no sex predilection, is unrelated to the onset of therapy, is corrected with vitamin K, is worsened by continuation of coumarin or heparin, and is not associated with necrosis histologically. In addition, the lesions of coumarin necrosis contain the black eschar in the center of the necrotic zone.
Skin necrosis due to subcutaneous or intravenous heparin administration also has been described.99 Necrosis of the skin may occur at the site of subcutaneous heparin injection or in a more widespread distribution. Skin lesions represent a hypersensitivity reaction to heparin and appear 6 to 14 days following initiation of therapy. This syndrome is to be differentiated from heparin-induced thrombocytopenia, which may also be associated with purpuric skin lesions, or even skin necrosis if disseminated intravascular coagulation is part of the syndrome.
PURPURA FULMINANS
Purpura fulminans is a syndrome characterized by a triad of fever, disseminated intravascular coagulation with acral purpura and ecchymoses, and hypotension (see Chap. 126).100 Clinical features include widespread arterial and venous thrombosis. Cutaneous discomfort develops initially, followed by erythema, edema, and petechiae. Thereafter, there is rapid development of painful purpuric papules and plaques with advancing erythematous borders. Finally, there is massive widespread ecchymoses, symmetric hemorrhagic necrosis, and bulla formation, often accentuated on the upper and lower extremities, abdomen, thighs, and buttocks.101,102 the lesions enlarge with time and progress to gangrene, often with autoamputation of the digits. In adults and children, bacterial sepsis may trigger the syndrome or it may occur without antecedent infection.39,103 In children, purpura fulminans most commonly follows Group A streptococcal, varicella, and/or upper respiratory infections, but a wide variety of organisms have been incriminated.104 In sepsis-associated purpura fulminans, the purpura and necrosis begin in the distal extremities, and hemorrhagic necrosis of internal organs is common. Hypotension may not, however, be present.105 Endotoxin is the most likely initiator of sepsis-associated purpura fulminans, leading to an increase in systemic cytokines, shock, and DIC. Prostration, fever, edema of the involved extremities, and hemorrhagic necrosis of the adrenal cortex may be seen, and death is not uncommon. the differential diagnosis includes thrombotic thrombocytopenic purpura, allergic or septic vasculitis, postinfectious thrombocytopenia, dermal hemorrhage, homozygous protein C or S deficiency, coumarin necrosis, ischemia due to lupus anticoagulant, Waldenström macroglobulinemia, and paroxysmal nocturnal hemoglobinuria. Histopathology reveals hemorrhagic necrosis of the dermis, with thromboses of the capillaries and small blood vessels. Fibrinoid necrosis of vessel walls and perivascular polymorphonuclear cell infiltrates have been described. the endothelial cell may be the target of both postinfectious and idiopathic purpura fulminans, and mechanisms similar to those described for DIC may be involved (see Chap. 126).106 Tumor necrosis factor alpha and IL-1 are the cytokines thought to be most responsible for mediating the vascular events of purpura fulminans,104,107 including increased leukocyte adherence and inflammation (see Chap. 67).
Homozygous protein C deficiency can produce essentially the same pattern in the neonate,101,108,109,110 and 111 with onset in the first 12 h of life of diffuse, symmetric purpuric and ecchymotic skin lesions (see Chap. 127). These rapidly turn red-purple and grow peripherally, evolving into irreversible hemorrhagic and necrotic lesions. Central nervous system thrombosis and blindness are common. Both the skin lesions and venous thrombosis respond rapidly to plasma therapy, and long-term anticoagulation with warfarin has been effective in preventing recurrence.112,113 Replacement therapy with protein C concentrate has been successful, as has liver transplantation.47 Cutaneous necrosis similar to coumarin necrosis has been observed in patients with acquired protein C deficiency due to liver disease, malabsorption, administration of antibiotics, or autoantibodies to protein C.114 Similarly, acquired protein C deficiency has been noted in some patients with sepsis-associated purpura fulminans. Several infants with homozygous protein S deficiency have also demonstrated neonatal recurrent purpura fulminans (see Chap. 127).115,116 Postinfectious purpura fulminans has also been reported in association with antiprotein S IgG and IgM antibodies.117 Resistance to activated protein C due to factor V Leiden has also been reported to cause neonatal purpura fulminans.47,118
In idiopathic purpura fulminans, 1 to 3 months after the initial infection, indurated and painful symmetric purple-gray lesions appear that are surrounded by a thin (10 mm) advancing erythematous border. These lesions then rapidly develop hemorrhagic necrosis and bullae,111 enlarge, and may progress to dry gangrene. Lesions most commonly occur on the lower half of the body, especially the thighs, legs, buttocks, and lower trunk. Head and neck involvement (nose and ears) occurs but is uncommon, and mucous membranes are spared. Distal extremities are not involved in idiopathic purpura fulminans, which helps to distinguish it from sepsis-associated purpura fulminans.
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (SEE Chap. 36)
Patients with this disorder may occasionally develop erythematous patches with dusky centers that may enlarge to form large, painful plaques of erythema with central necrosis.119 Hemorrhagic bullae, ulceration, petechiae, ecchymoses, palpable purpura, and eschar formation also have been described. Differential diagnosis of the cutaneous findings includes thrombocytopenia, Henoch-Schönlein purpura, purpura fulminans, coumarin necrosis, vasculitis, and ecthyma gangrenosum. the lesions may be painful. Intravascular thrombi in the absence of vasculitis is the histologic appearance.
“ANTIPHOSPHOLIPID” ANTIBODY SYNDROME
The “antiphospholipid” antibody syndrome is an acquired multisystem disorder characterized by the variable presence of a lupus-type anticoagulant and/or antibodies to protein-phospholipid complexes, usually in high titer, in association with a tendency to thrombosis, fetal wastage, and/or thrombocytopenia120,121 and 122 (see Chap. 128). Major clinical manifestations include recurrent thrombotic events (arterial or venous), recurrent fetal loss, thrombocytopenia, skin lesions, and neurologic complications. Visceral vascular occlusion may occur. Cutaneous findings may include widespread cutaneous necrosis with thrombi within the microvasculature (as seen in purpura fulminans), livedo reticularis, peripheral gangrene, painful skin nodules, leg ulcers, pyoderma gangrenosum-like lesions, thrombophlebitis, subungual splinter hemorrhages, porcelain-white scars, acral red to purple macules, and ecchymoses123 (see Plate XXV-30 and Plate XXV-31). the proposed mechanisms of thrombosis in antiphospholipid antibody syndrome include endothelial cell damage and activation, decreased prostacyclin release from endothelial cells, impaired fibrinolytic activity, inhibition of thrombomodulin-induced activation of protein C, inhibition of annexin V binding and platelet activation.122
KASABACH-MERRITT SYNDROME124
The Kasabach-Merritt syndrome is defined by the presence of an inflammatory bruised, reddish or purple mass in a neonate or young infant in association with profound thrombocytopenia and widespread ecchymoses. the large mass is a vascular lesion, previously believed to be a hemangioma but currently thought to be either a Kaposiform hemangioendothelioma or a tufted angioma. It is postulated that the vascular anomaly triggers platelet trapping and that platelet activation within the lesions sustains the growth of the cellular component of the vascular lesion.
DRUG-RELATED
Nonthrombocytopenic petechial and purpuric reactions can be observed after administration of a variety of drugs (see Plate XXV-32).87,125,126 the mechanism for some of these reactions is presumed to be allergic hypersensitivity.
UNKNOWN
The Gardner-Diamond syndrome (psychogenic purpura, autoerythrocyte sensitization, or painful bruising syndrome) usually affects young women and is characterized by grouped tender bruises, appearing spontaneously or after minimal trauma, that are often preceded by pain or tingling.127,128 and 129 the bruising may be so extensive that the patient loses the use of the limb. the onset of the disorder may coincide with surgical or accidental trauma. Many of the patients have significant psychological disturbances, and some of the patients are thought to have self-inflicted trauma. Intradermal injection of erythrocytes is said to elicit an ecchymotic response, indicating an “allergic” reaction to the patient’s own erythrocytes (or DNA), perhaps as a result of an immune response to altered membrane phospholipid distribution,130 but there is considerable controversy about the specificity and significance of this test.131 Histologically, edema and a mononuclear cell infiltrate with extravasated red blood cells are observed. Localized neurogenic release of fibrinolytic activity in the skin has been proposed as a mechanism to link the psychological and dermal components of the syndrome.132
Approximately 25 percent of children with familial Mediterranean fever were described as having nonspecific 1- to 2-cm petechial or slightly raised purpuric papules on the face, trunk, and extremities.133 These lesions resolved spontaneously in 1 to 3 weeks and were the most common cutaneous findings in these children.
PALPABLE PURPURA
CUTANEOUS VASCULITIS
HENOCH-SCHÖNLEIN PURPURA
This syndrome is manifested by leukocytoclastic vasculitis that predominantly affects children between the ages of 2 and 10, with a peak between the ages of 3 and 7.134,135,136 and 137 It is the most common vasculitis of childhood. Palpable purpuric cutaneous lesions, acute gastrointestinal symptoms (abdominal cramping), as well as renal (hematuria), arthritic (ankle and knee), cardiac, pulmonary, and central nervous system lesions are observed. Renal involvement in adults is more common, but the prognosis in children and adults is the same.138,139 In children, there is an increased incidence in boys,140 but there is no sex predilection in adults. A decreased incidence during the summer has been reported, and community outbreaks have been described. In spite of numerous reports linking various precipitating factors (infections, environmental chemicals, toxins, insect bites, complement component C2 deficiency, familial Mediterranean fever,141,142 and malignancies) to the development of Henoch-Schönlein purpura, there is no convincing evidence supporting such associations. Genetic factors may play a role in determining susceptibility or resistance to Henoch-Schönlein purpura. Thus, the presence of DRB*01, DRB*11, DQA*0301, as well as complement 4 locus II gene deletion makes an individual more prone to develop Henoch-Schönlein purpura,143 while DRB*07 may make one less likely to develop the disease.144
The clinical presentation in more than 50 percent of patients includes fever and the explosive onset over the legs and buttocks of urticarial papules, plaques, and targetoid plaques, with or without purpura, palpable purpura (see Plate XXV-33), or hemorrhagic vesicles or bullae; progression to larger stellate, reticulate, and necrotic lesions may occur. Lesions may be seen on the arms, hands, or face, but rarely on the trunk, and may recur over weeks to months. Occasionally, ecchymotic lesions resembling child abuse may be present, but, unlike the latter, the lesions of Henoch-Schönlein purpura are usually strikingly symmetric. Scrotal edema, purpura, and testicular pain may be the initial symptoms in Henoch-Schönlein purpura and must be differentiated from testicular torsion.145 Henoch-Schönlein vasculitis involves the precapillary, capillary, and postcapillary vessels of the skin, gastrointestinal tract, joints, and kidneys. Thus, arthralgias and abdominal pain usually accompany the rash. Occasionally, the characteristic cutaneous eruption is delayed and follows the appearance of abdominal pain.146 Melena and signs of peritonitis are common. There may be an association between decreased factor XIII activity in children with Henoch-Schönlein purpura and abdominal symptoms. Leukocytosis, elevated C-reactive protein, and thrombocytosis are significantly associated with gastrointestinal bleeding in children with Henoch-Schönlein purpura.147 Oligoarticular arthritis of the large joints is nearly always present, and proteinuria and hematuria occur in approximately 40 percent of patients. In older children and adults, renal disease progresses in 10 to 20 percent. In a review of 57 adults with Henoch-Schönlein purpura, the presence of a recent infection, fever, and truncal purpura correlated with renal involvement.148 Neither the presence of bullous or necrotic lesions, nor the histologic severity of the cutaneous vasculitis, were predictive of renal involvement.
Henoch-Schönlein purpura is thought to be an immune complex disease, with IgA, IgG, and C3 being deposited in the cutaneous and renal vasculature. the C5b-9 complex (membrane attack complex) is also found in cutaneous and renal vascular lesions in Henoch-Schönlein purpura,149 and a role for complement activation in the production of the vasculitic changes has been suggested. Approximately 50 percent of patients with Henoch-Schönlein purpura produce IgA rheumatoid factor,137,150 and IgA-containing immune complexes have been detected in the serum, especially during the early phases of the syndrome. Familial IgA nephropathy has also been described in association with Henoch-Schönlein purpura. IgA-fibronectin complexes and IgA-anti-cardiolipin antibodies have also been detected in serum. A stippled pattern of IgA in the dermal blood vessels is seen on direct immunofluorescence of the skin.151,152 the IgA-fibronectin aggregates detected in the sera of patients with Henoch-Schönlein purpura with IgA nephropathy may help to explain the binding of IgA to peripheral and glomerular vessels.153 the presence of IgA deposits in the vasculitic lesions has been correlated with a longer clinical course, a more favorable initial response to systemic glucocorticoid therapy, and a higher incidence of systemic involvement (renal and arthritic).154 the presence of decreased factor XIII, severe abdominal symptoms, and persistent purpura correlate with an increased risk of renal involvement,155 and the presence of high-titer IgA anti-endothelial-cell antibodies and elevated levels of soluble thrombomodulin in serum are associated with severe proteinuria and active renal disease.156 the IL-1 receptor antagonist allele may be a genetic marker shared by patients with Henoch-Schönlein purpura and those with IgA nephropathy with gross hematuria.157 Decreased IgA sialic acid content is found in Henoch-Schönlein purpura, a finding similar to that of patients with IgA nephropathy.158 Serum levels of malondialdehyde, a marker of lipid peroxidation, are significantly elevated in patients with Henoch-Schönlein purpura with renal involvement. Indicators of endothelial cell damage (von Willebrand factor, soluble thrombomodulin, and tissue plasminogen activator) as well as the cytokine tumor necrosis factor alpha are all increased in a significant number of patients with Henoch-Schönlein purpura.159,160 and 161
Inhibitors of prostacyclin have also been suggested as playing a role in the pathogenesis of Henoch-Schönlein purpura. Monoclonal antibodies to intercellular adhesion molecule-1 (ICAM-1) on endothelial cells and to CD18 or CD11b on leukocytes block the hemorrhagic vasculitis in experimentally induced Shwartzman reactions,162 suggesting that intravascular leukocyte aggregation can contribute to the hemorrhagic response in this disorder and perhaps related disorders such as Henoch-Schönlein purpura.
Ten percent of adults with other forms of leukocytoclastic vasculitis demonstrate livedoid superficial plaques with multifocal areas of hemorrhage or necrosis and reticulate margins connecting adjacent lesions.163 These lesions contain IgA and C3 within the blood vessel walls. Smooth-margined purpuric papules with uniform hemorrhage show IgA but more frequently demonstrate IgG or IgM vascular deposits.
ACUTE HEMORRHAGIC EDEMA OF INFANCY
This entity is composed of a triad of fever, irislike or medallion-like large purpuric cutaneous lesions, and edema affecting infants between the ages of 4 months and 2 years.164,165,166,167 and 168 It is heralded by the sudden onset of peripheral edema, purpuric targetoid plaques, and painful petechiae and ecchymoses, all of which resolve spontaneously within 1 to 3 weeks. Occasionally, reticulate purpura, tender necrotic lesions of the ears, and/or urticaria are observed. the cutaneous lesions and the accompanying edema are localized to the cheeks, eyelids, ears, extremities, and genitalia. As in Henoch-Schönlein purpura, lesions begin as urticarial plaques, then progress to an irislike pattern of purpura or ecchymoses. Joint or abdominal pain is very rarely seen. Histopathologic examination demonstrates leukocytoclastic vasculitis. Immunofluorescent studies of the skin reveal vascular deposits of IgG, IgM, IgA, C3, C1q, and fibrinogen. Acute hemorrhagic edema differs from Henoch-Schönlein purpura because it is found in patients under 2 years of age, it is limited to cutaneous manifestations, and the rash is more monomorphic. Acute hemorrhagic edema should be differentiated from meningococcemia, septic emboli, drug eruption, hemorrhagic erythema multiforme, Kawasaki disease, acute febrile neutrophilic dermatosis (Sweet’s syndrome), and child abuse.
COLLAGEN VASCULAR DISEASES (SEE Plate XXV-34)
These disorders may have an array of vasculitic purpuric lesions with a mixture of palpable and nonpalpable lesions, including petechiae, papules and nodules, ecchymoses, hemorrhagic bullae, hemorrhagic necrosis, purpuric ulcers, splinter hemorrhages, and periungual hemorrhage.169,170,171,172 and 173 Other disorders with systemic large and/or small vessel vasculitis, including hypocomplementemic vasculitis, polyarteritis nodosa (including microscopic polyarteritis nodosa)174 (see Plate XXV-35), Wegener’s granulomatosis (see Plate XXV-36), Churg-Strauss angiitis, mixed connective tissue disease,6 rheumatoid vasculitis, relapsing polychondritis, or rheumatoid arthritis with IgA immune complex vasculitis, may have a similar array of such lesions. Nonpurpuric cutaneous lesions also may be present including ulcers, subcutaneous nodules, livedo reticularis, blanchable erythema, erythematous plaques, and telangiectasia. Patients with urticarial vasculitis frequently have lesions that resolve with purpura.175
BEHÇET’S DISEASE
Behçet’s disease is a chronic inflammatory multisystem disorder characterized by recurrent oral and genital ulcerations, cutaneous lesions, arthralgias, and gastrointestinal, vascular, and central nervous system manifestations. A review of 42 patients from Japan reported leukocytoclastic vasculitis in 17 percent of the patients, some of whom had palpable purpura and hemorrhagic bullae.176
HYPERSENSITIVITY VASCULITIS
The constellation of findings characteristic of this disease includes palpable purpura, joint symptoms, and leukocytoclastic vasculitis. the prognosis is excellent.177 It may be seen as a drug reaction, in the setting of infection (e.g., staphylococcal or streptococcal, leprosy, acute or subacute bacterial endocarditis, hepatitis B or C, pulmonary or nodal tuberculosis, or HIV disease), or as a reaction to unknown antigens.178,179
Chronic infectious hepatitis may be associated with necrotizing vasculitis, hypocomplementemia, and cryoglobulinemia.180,181
Alpha-1 antitrypsin deficiency has been described in association with systemic vasculitis, including cutaneous involvement resembling that observed in microscopic polyarteritis, Wegener’s granulomatosis, and Henoch-Schönlein purpura.182
DRUG-INDUCED LEUKOCYTOCLASTIC VASCULITIS
This entity has been reported with acebutolol, amiodarone, amphetamine, anistreplase, aspirin, captopril, cefoxitin, chlorthalidone, cimetidine, ciprofloxacin, coumadin, didanosine, diltiazem, ethacrynic acid, furosemide (see Plate XXV-37), granulocyte colony-stimulating factor, hydantoin, hydralazine, hydrochlorthiazide, insulin, interferon, iodides, nifedipine, ofloxacin, penicillin, phenacetin, phenothiazines, procainamide, propranolol, propylthiouracil, quinidine, rifampin, streptokinase, sulfonamides, tamoxifen, tartrazine, zidovudine, and others.126,183,184 and 185
PARANEOPLASTIC VASCULITIS
This is a syndrome of petechiae, palpable purpura, urticaria, maculopapular lesions, leg ulcers, and/or erythema multiforme seen in association with hairy-cell leukemia and other lympho- and myeloproliferative disorders.186,187 and 188 Intense pruritus or dysesthesias accompany the dermatologic findings. the cutaneous lesions often precede or signal the recurrence of the malignancy. Carcinomas of the breast, lung, colon, cervix, prostate, nasopharynx, and kidney have all been reported in association with cutaneous vasculitis.188,189
LONG-DISTANCE WALKERS
Long-distance walkers may develop purpuric lesions of leukocytoclastic vasculitis on the lower legs.190
DYSPROTEINEMIAS
CRYOGLOBULINEMIA
Cryoglobulins are cold-precipitable proteins found in plasma or serum. Single-component cryoglobulins may be IgG, IgM, or IgA.191 These cryoproteins may be idiopathic in origin or occur in association with Waldenström macroglobulinemia, myeloma, or lymphoma. Mixed cryoglobulins have rheumatoid-factor-like activity and are usually composed of IgG molecules complexed with IgM molecules having anti-IgG reactivity (or less frequently IgG or IgA molecules with anti-IgG reactivity). Mixed cryoglobulins may be seen as an idiopathic phenomenon or in association with a wide variety of subacute and chronic disorders, most particularly hepatitis C. the immune complex may be composed of hepatitis C virus (HCV), anti-HCV, and IgA-type rheumatoid factor192 or HCV, IgM-like rheumatoid factor, and IgG.193 These high-molecular-weight complexes may initiate alterations in endothelial cells resulting in increased vascular permeability, neutrophil infiltration, and vessel wall damage. Mixed cryoglobulinemia is characterized by the classical clinical triad of purpura, weakness, and arthralgias. Cutaneous findings of cryoglobulinemia are common and include the intermittent appearance of acral hemorrhagic necrosis, macular and palpable purpura (see Plate XXV-38), livedo reticularis, subungual hemorrhage (see Plate XXV-39), hemorrhagic bullae, urticaria, leg ulcerations, Raynaud’s phenomenon, follicular pustular purpura, and erythema multiforme-like lesions.194,195 and 196 Cutaneous lesions often resemble those seen in the pigmented purpuric eruptions. Mucous membrane oral and nasal lesions are occasionally observed. Arthritis, nephropathies, neuropathies, and chronic hepatitis and/or cirrhosis are prominent associated findings.197 Treatment of hepatitis C–associated mixed cryoglobulinemia with interferon alpha may eradicate the cryoglobulins and their associated cutaneous and systemic manifestations.198 Monoclonal cryoglobulins may crystallize and result in livedo reticularis with purpuric necrosis, destructive arthropathy, and malignant hypertension (cryocrystalglobulinemia).199
HYPERGLOBULINEMIC PURPURA OF WALDENSTRÖM
The characteristic cutaneous findings of benign hyperglobulinemic purpura are crops of petechiae in the same stage of development on the lower legs and ankles of young women (age 18 to 40 years).200 These lesions can be macular and papular, discrete or confluent, with hemosiderin staining (see Plate XXV-40).201,202 and 203 Palpable purpura is rare, and ecchymoses do not occur. Lesions may be present on the thighs, abdomen, and arms. Lymphadenopathy is common. Lesions recur at intervals of days, weeks, or months, and precipitating factors may include increased hydrostatic pressure, hyperviscosity, and low temperatures.204 the polyclonal increase of globulins (mostly IgG) can be associated with Sjögren’s syndrome, systemic lupus erythematosus, polymyositis, rheumatoid arthritis, myeloma, thymoma, sarcoid, cystic fibrosis, or multiple sclerosis. the eruption closely resembles those seen in the pigmented purpuric eruptions and cryoglobulinemia. Histologically, leukocytoclastic vasculitis or perivascular lymphocytic infiltrates, red blood cells, and variable arteriolar necrosis are found. the hypergammaglobulinemia consists of elevated levels of IgG, as well as IgA and IgM. There is a decrease in IgG2.205 the sedimentation rate is usually elevated. Circulating IgG-anti-IgG (only IgG1 subclass) and/or IgA and IgM-anti-IgG immune complexes have been detected. Many patients have antibodies to Ro/SSA.206 Lymphocytotoxic antibodies against suppressor lymphocytes with resultant lymphopenia and antimyelin antibodies have also been noted. This disorder is not to be confused with Waldenström macroglobulinemia; the latter has multiple cutaneous findings including the IgM storage papule, infiltrative plaques and/or nodules, purpuric lesions secondary to cryoglobulins, and mucocutaneous oozing and bleeding as a result of the concomitant hyperviscosity syndrome. These patients have a monoclonal IgM paraprotein spike rather than the polyclonal broad-based gammopathy seen in hyperglobulinemic purpura of Waldenström.
CRYOFIBRINOGENEMIA
Cryofibrinogenemia indicates the presence in the blood of an abnormal cold-precipitable protein derived from fibrinogen or fibrin. the most common cutaneous manifestations are sensitivity to cold, purpura, livedo reticularis, cyanosis, ulcerations, erythema, hematoma, urticaria, gangrene, and Raynaud’s phenomenon. Lesions appear on the distal extremities, buttocks, nose, and ears.207 Acral blisters have also been described. Cryofibrinogenemia may occur as a primary (essential) or secondary form, usually in association with laboratory evidence of chronic disseminated intravascular coagulation. Secondary cryofibrinogenemia may occur in association with neoplastic, thromboembolic, and infectious disorders.
LIGHT-CHAIN VASCULOPATHY
A vasculopathy with deposition in the skin of l light-chain crystals has been described in two patients who demonstrated nonpalpable purpura, hemorrhagic vesicles, ischemic necrosis of the extremities, and rapidly progressive renal failure.208 Intravascular l light chains were observed on direct immunofluorescence of skin. Monoclonal l light chains were observed in serum, and extensive crystalline deposits were present in tissues. One case of IgG k intact paraprotein crystallization with cutaneous involvement has also been described.209 the clinical picture closely resembles severe necrotizing vasculitis, but no histologic evidence of vasculitis was present in these cases.
PRIMARY CUTANEOUS DISEASES
Allergic contact dermatitis (purple poison ivy), drug eruptions on the lower extremities, acne vulgaris, insect bites (especially black fly bites), dermatitis herpetiformis, pityriasis rosea, and other primary cutaneous disorders may present with purpuric papules and vesicles mimicking septic and vasculitic lesions.
NONPURPURIC DISORDERS SIMULATING PURPURA
DISORDERS WITH TELANGIECTASIAS
HEREDITARY HEMORRHAGIC TELANGIECTASIA (OSLER-WEBER-RENDU DISEASE)
This is an autosomal dominant inherited disorder with an estimated frequency of 1 in 50,000 characterized by widespread dermal, mucosal, and visceral telangiectasias.210 One form of the disorder, characterized by a high frequency of pulmonary arteriovenous malformations, has been identified as being due to abnormalities in the endothelial protein endoglin on chromosome 9, which appears to mediate the response of endothelial cells to members of the transforming growth factor beta (TGF-b) family.210 A number of the mutations involve the production of truncated forms of the receptor, opening up the possibility of a dominant negative mechanism to explain the autosomal dominant inheritance pattern.211 Another form of the disease has been linked to a region of chromosome 3 containing the TGF-b II receptor, and a third form has been linked to the activin-receptor-like kinase 1 gene on chromosome 12, which is a cell surface receptor for the TGF-b superfamily of ligands.212,213 Clinically, venous lakes and papular, punctate, matlike, and linear telangiectasias appear on all areas of the skin and mucous membranes, with a predominance of lesions on the dorsum and ventral aspects of the tongue, and on the face, lips, perioral region, nasal mucosa, fingertips, toes, and trunk.214 Recurrent epistaxis is a nearly universal finding in this disorder, with symptoms almost always becoming worse with age. It is estimated, however, that 10 percent of patients manifest no bleeding. the severity of the disorder relates to the age of onset of epistaxis, with the most severely affected patients developing recurrent nosebleeds during childhood. the cutaneous changes usually begin at puberty and progress through the third to fourth decades. Bleeding can occur in virtually every organ, with gastrointestinal, oral, and urogenital sites most common. In the gastrointestinal tract, the stomach and duodenum are more common sites of bleeding than the colon. Pulmonary arteriovenous fistulae may be seen in 20 percent of patients and may be associated with oxygen desaturation, hemoptysis, hemothorax, brain abscess, or cerebral ischemia due to paradoxical emboli. Hepatic and splenic arteriovenous fistulae, as well as intracranial, aortic, and splenic aneurysms have all been reported. Histologically, the vessels of hereditary hemorrhagic telangiectasia show a discontinuous endothelium and incomplete smooth muscle. the surrounding stroma lacks elastin. Thus, the bleeding tendencies are thought to be due to mechanical fragility of the abnormal vessels.
Therapy for hereditary hemorrhagic telangiectasias remains problematic, with laser treatment for cutaneous lesions; split-thickness skin grafting, embolization, or hormonal therapy (estrogen or estrogens plus progesterone) for epistaxis; pulmonary resection or embolization for pulmonary arteriovenous malformations; and hormonal therapy and laser coagulation for gastrointestinal lesions.210 the antifibrinolytic agent epsilon aminocaproic acid has been reported to be beneficial in controlling hemorrhage,215 but negative results have also been reported.216
OTHER TELANGIECTATIC SYNDROMES
Spiderlike telangiectatic mats seen in the CREST syndrome (calcinosis, Raynaud phenomenon, esophageal motor dysfunction, sclerodactyly, and telangiectasia) may be easily confused with the lesions of chronic actinic damage and those of hereditary hemorrhagic telangiectasia. Vascular nevi, angiokeratoma corporis diffusum, ataxia telangiectasia, and spider telangiectasias from chronic liver disease also must be differentiated. Spider telangiectasias have a central, prominent, easily blanchable feeding vessel with several smaller telangiectasias emanating from this central vessel. Spider telangiectasias seen in patients with chronic liver disease are distributed from the head to the nipple line and correlate with the risk of bleeding from esophageal varices.217 Spider and papular telangiectasias on the upper trunk and arms have been reported to be a cutaneous manifestation of AIDS.218
“PETECHIAL” CHERRY ANGIOMATA
Cherry angiomas are the common papular, brightly erythematous lesions seen on the trunk and extremities of middle-aged and older men and women. the lesions increase in size and number with age and may produce easy bruising, since they tend to bleed excessively with trauma. Pinpoint angiomas may be present in large numbers and may mimic a petechial eruption.
KAPOSI SARCOMA
AIDS-related Kaposi sarcoma is easily confused with purpuric and ecchymotic lesions, lichen aureus, as well as some of the other pigmented purpuric eruptions. Oral lesions of epidemic Kaposi sarcoma may mimic petechiae and purpura. Similarly, angiosarcoma may pre-sent as a purple-to-brown plaque resembling purpura.
INTRAVASCULAR LARGE-CELL LYMPHOMA
Intravascular large-cell lymphoma, previously referred to as malignant angioendotheliomatosis, may present with asymptomatic “purpuric” patches, ecchymotic-like plaques, or palpable purpura-like lesions.219 Associated neurologic signs and symptoms are common.
FABRY’S DISEASE (ANGIOKERATOMA CORPORIS DIFFUSUM)
This X-linked inherited disorder of glycolipid metabolism is due to a deficiency of the enzyme alpha-galactosidase A (ceramide trihexosidase).220 Accumulation of glycolipid throughout the body leads to cutaneous, renal, ophthalmologic, cardiac, and central nervous system manifestations. Angiokeratoma corporis diffusum lesions are pinpoint to 4-mm nonblanchable deep red, blue, or black macules or papules. the nonblanchable lesions are distributed over the trunk, extremities, and genitalia. In mild cases, lesions are localized to the thighs, scrotum, or periumbilical region. Grouping of lesions may occur. Superficial corneal dystrophy and varicosities of the bulbar conjunctivum are commonly seen. Glycolipid deposits are histochemically detected in the media and intima of small dermal blood vessels.
EXTRAMEDULLARY HEMATOPOIESIS (“BLUEBERRY MUFFIN” BABY)
These dark red, blue, or blue-gray 1- to 7-mm macules and/or papules are present at birth or within the first 48 h of life in infants with congenital rubella, cytomegalovirus, Coxsackie virus B2, parvovirus B19 infections,221 Rh incompatibility, hereditary spherocytosis, or twin transfusion syndrome.47 Rarely, healthy newborns may demonstrate extramedullary hematopoiesis. the lesions are most commonly found on the scalp, neck, and trunk but may be widely distributed. These lesions fade into tan- or copper-colored macules by 8 weeks of age. Adults with marrow infiltration (e.g., myelofibrosis) also may develop lesions of extramedullary hematopoiesis. Occasionally newborn infants with neoplastic or infiltrative diseases, such as neuroblastoma, rhabdomyosarcoma, leukemia, and Langerhans cell histiocytosis, can present with a blueberry-muffin-like appearance.
ANGIOMA SERPIGINOSUM
Angioma serpiginosum is a vascular nevoid lesion with pinpoint vascular ectasias on a background of erythema.2 the lesion is partially blanchable and is not petechial. Capillary microscopy demonstrates punctate dilated capillaries. This lesion is usually seen on the legs and buttocks of women but may occur anywhere and expand in childhood and regress with age. Differential diagnosis includes the pigmented purpuric eruptions (e.g., purpura annularis telangiectoides).
GRANULOMA ANNULARE
Granuloma annulare is a cutaneous disorder characterized by annular grouping of skin-colored to erythematous papules over the extensor surfaces (elbows, knuckles, ankles, and feet). the violaceous purpuric papules may be mistaken for septic emboli. Although usually idiopathic, it has been reported in association with a childhood myelodysplastic syndrome.222
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Books@Ovid
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

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