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Dermatopathology of Skin Necrosis Associated with Purpura Fulminans
Skin necrosis is a manifestation of pathologic injury intrinsic to the dermal vasculature or factors extrinsic to the integument. Extrinsic causes of skin necrosis include, extravasation of toxic chemotherapeutic agents, radiation injury, or pressure-induced damage as seen in barbiturate intoxication. Skin necrosis due to causes intrinsic to the dermis include vascular occlusion by fibrin, platelets, cholesterol emboli and foreign material, and vasculitis. Intrinsic causes such as occlusion of dermal vessels due to intravascular fibrin precipitation or thrombosis is an important and frequent cause of skin necrosis. Dermal vascular occlusion may be a manifestation of a variety of conditions, including sequelae to certain infectious diseases, anticoagulant therapy, disseminated intravascular coagulation (DIC), and homozygous protein C (PC) deficiency. Rarely is it associated with other clinical situations such as thrombotic thrombocytopenic purpura (TTP) or paroxysmal nocturnal hemoglobinuria (PNH). This article will review the various conditions associated with skin necrosis due to dermal vascular occlusion, with emphasis on the histopathology of these lesions.
DEFINITION OF PURPURA Purpura is a general term that describes hemorrhage or extravasation of formed blood elements (Fig. 1) from the dermal vessels into the substance of the skin.1'2
From the Department of Pathology, University of Colorado Health Sciences Center, and the Colorado Permanente Medical Group, Denver, Colorado, and the Department of Pathology, Baylor College of Medicine, Houston, Texas. Reprint requests: Dr. Adcock, Colorado Permanente Medical Group, Department of Pathology, 16601 East Centretech Parkway, Aurora, CO 80011.
Dermal hemorrhage may be described using more specific terms based on the appearance or etiology of the lesion. Petechiae refer to pinpoint hemorrhagic lesions that are well-demarcated, less than 3 mm in diameter, and appear red-brown. Petechiae commonly occur in areas of high venous pressure, such as the lower leg. These lesions do not blanch with external pressure. Ecchymoses are purpuric lesions larger than 3 mm in diameter. These hemorrhagic lesions generally have irregular margins and vary considerably in size and shape. Ecchymoses may be red, purple, blue, or yellowgreen, depending on the intensity of the skin hemorrhage and its duration. Palpable purpura refers to an elevated hemorrhagic dermal lesion. It usually implies the presence of both vasculitis and hemorrhage. A hematoma is a palpable lesion composed of extravasated blood that has developed between tissue planes and does not imply the presence of vasculitis. Purpura fulminans is a specific term that describes an acute syndrome of rapidly progressive, hemorrhagic necrosis of the skin due to dermal vascular thrombosis associated with vascular collapse and DIC. 3-5 In the following discussion, skin necrosis will refer to dermal lesions that are grossly and histopathologically similar to purpura fulminans but are not associated with the systemic manifestations of DIC or vascular collapse. Other terms that may be confused with a hemorrhagic dermal process include erythema and telangiectasia.1,2 Erythema of the skin is simply a reddened appearance and is due to a transitory hyperemia. Because formed blood elements have not extravasated into the dermis, this lesion blanches with external pressure. Telangiectasia is a condition in which redness of the skin results from a permanent enlargement in the caliber of small blood vessels and an increase in the number of vessels. Telangiectasias are pinpoint, relatively well-demarcated capillary aggregates of 1 to 3 mm diameter. Telangiectasias may be confused with petechiae; however, these
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TABLE 1. Pathophysiologic Categories of Purpura* Purpura not associated with any known disease entity Mechanical purpura Factitious purpura Purpura simplex Purpura associated with platelet abnormalities Thrombocytopenic purpura Thrombocytopathic purpura Purpura associated with rheumatic phenomena Leukocytoclastic vasculitis associated with disease of uncertain cause Leukocytoclastic vasculitis associated with specific agents
capillary masses blanch on external pressure, whereas petechiae do not.
CLASSIFICATION OF PURPURA Purpuric lesions have been classified using a number of schemes. In a comprehensive review of the anatomic basis of purpura, Kitchens6 proposed a logical classification system for these skin lesions based on common anatomic mechanisms (Table 1). One mechanism that produces purpuric skin lesions is dermal vascular thrombosis. Skin lesions induced by dermal vascular thrombosis may present clinically in a variety of ways, such as skin necrosis, ecchymoses, ulceration, cyanosis, and livedo reticularis. Skin necrosis due to dermal vascular thrombosis can occur in association with a number of clinical conditions (Table 1). Purpura fulminans is one category of skin necrosis due to dermal vascular thrombosis. Purpura fulminans is distinguished from other forms of skin necrosis by the presence of shock and signs of DIC. As originally defined7 purpura fulminans specifically refers to rapidly progressive skin necrosis occurring during a latent period following an acute infection. Since that time, the term "purpura fulminans" has been applied to a variety of disorders that do not fulfill this initial description. This term has been applied to dermal vascular skin necrosis that develops in conjunction with DIC in patients with acute infections or coagulation protein deficiencies.8-11 Also confusing the issue are reports of skin necrosis grossly and histologically similar to purpura fulminans, which occur in the absence of DIC and vascular collapse. 12-14 This category includes coumarin-induced skin necrosis (CISN) and rarely TTP, cryoglobulinemia, and PNH. These disorders must be distinguished from purpura fulminans. Due to the increasing knowledge of the underlying conditions
Purpura associated with decreased mechanical strength of The microcirculation Scurvy Hypercortisolism "Senile" purpura Hereditary diseases of connective tissue Amyloidosis Osier-Weber-Rendu disease Purpura associated with dermal vascular thrombosis Disseminated intravascular coagulation Coumarin-and heparin-induced skin necrosis Skin necrosis associated with anti-phospholipid antibodies Purpura fulminans Idiopathic purpura fulminans Acute infectious purpura fulminans Myeloblastemia Thrombotic thrombocytopenic purpura Paroxysmal nocturnal hemoglobinuria Cryoglobulinemia Purpura associated with vascular malignancy * Modified from Kitchens.6
associated with purpura fulminans and its distinction from skin necrosis, a new classification of purpura fulminans is proposed.
New Classification of Purpura Fulminans The term "purpura fulminans" should be reserved for dermal vascular skin necrosis that occurs in association with systemic manifestations of DIC or PC deficiency. As described by Francis later in this issue of Seminars, purpura fulminans may occur in three distinct situations: (1) in individuals with hereditary or acquired dysfunction of the protein C anticoagulant system, (2) in individuals with acute, current severe infection, and (3) in individuals without known abnormalities of the PC system or acute infection. The first category has been referred to simply as purpura fulminans. The second category may be referred to as acute infectious purpura fulminans. The third group of purpura fulminans occurring in individuals without known abnormalities has been
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FIG. 1. Simple purpuric skin lesion (senile purpura) demonstrating extravasation of formed blood elements into the substance of the dermis. (Hematoxylin & eosin; original magnification ×500.)
Purpura associated with direct endothelial cell damage Physical or chemical injury Anoxia Injury by microorganisms Antibody-mediated injury
coined idiopathic purpura fulminans by Francis. These terms will be used throughout this review.
CUTANEOUS VASCULATURE OF THE SKIN The following brief discussion of the cutaneous vasculature will be used as a basis to describe the histopathology of dermal vascular thrombosis.15 Briefly, the subcutis contains a plexus of small arteries that give rise to dermal arterioles. Within the papillary dermis, a terminal vascular plexus (subpapillary plexus) is formed by terminal or precapillary arterioles that anastomose into a system of capillaries and subsequently coalesce into the postcapillary venule system. The subpapillary plexus constitutes the microcirculation of the skin, which is the site where purpuric lesions form. The venous portion of the dermal vasculature plays the predominant role in mediating the cutaneous inflammatory response.
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DERMATOPATHOLOGY OF SKIN NECROSIS The histopathologic features of skin necrosis due to dermal vascular thrombosis are similar regardless of the etiology.5,16-19 This form of skin necrosis is characterized by occlusion of dermal venules and capillaries by microthrombi, resulting in hemorrhagic infarction (Fig. 2). The initial site of injury occurs at the junction of the terminal precapillary arterioles and capillaries. Occlusion may result from thrombosis within the subpapillary plexus of the dermis or may represent microvascular embolization of fibrin that has precipitated within the systemic circulation. In the majority of reports, arteries and arterioles are spared. The histopathology of dermal microthrombi24 has been described and classified as follows: pure fibrinous (hyaline), fibrin-platelet, platelet, or mixed types. Using a routine hematoxylin and eosin stain, microthrombi are characterized as amorphous, eosinophilic intravascular material that has a granular or globular appearance. In most instances, this amorphous material consists of fibrin
CUTANEOUS MANIFESTATIONS OF SKIN NECROSIS The cutaneous manifestations of skin necrosis due to vascular occlusion are similar, regardless of the underlying precipitating condition. 13,16-19 Clinically, this type of skin necrosis begins with a region of dermal discomfort that progresses within hours to a regional evanescent flush. This is quickly followed by the development of petechiae and, in some instances, edema. The petechiae rapidly coalesce to form purple ecchymoses surrounded by a zone of erythema. Up to this point, the cutaneous lesions may be completely reversible without progression to skin necrosis. This has been documented in cases of skin necrosis associated with both coumarin therapy and homozygous PC deficiency.20,21 The development of hemorrhagic bullae is the hallmark of hemorrhagic infarction, marking irreversible progression to frank skin necrosis. Gangrenous necrosis subsequently develops with the formation of a deeply pigmented eschar that eventually sloughs. In most instances, this process involves only the skin and subcutaneous tissue, sparing the underlying muscle. Skin necrosis is associated with considerable morbidity and is fatal in some cases. In those patients who survive, surgical intervention, including limb amputation, fasciotomy, wound debridement, or skin grafting, is usually necessary. Considerable reconstructive surgery may be required.22 In children, gangrene involving the lower extremities may result in ischemia of the epiphyseal growth plate resulting in arrest of growth.23 It is important to involve a general surgeon and, in some instances, an orthopedic surgeon early in patient care.
FIG. 2. Ischemic skin lesion demonstrating characteristic fibrinous microthrombi occluding the dermal vasculature without perivascular inflammation or vasculitis. This coumarin-induced lesion represents the reversible stage of skin ischemia. (Hematoxylin & eosin; original magnification x100.)
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FIG. 3. Mixed microthrombus involving the dermal vasculature with adjacent venous stasis, but without perivascular inflammation or vasculitis. (Hematoxylin & eosin; original magnification ×500.)
and proteinaceous material. Some microthrombi may consist largely of platelets. Platelet microthrombi also have an amorphous eosinophilic appearance. Mixed thrombi are composed of a fibrinous network containing erythrocytes, leukocytes, and platelets (Fig. 3). A variety of histochemical stains can be used to aid in the identification of vascular occlusive material.24,25 Phosphotungstic acid hematoxylin (PTAH) and periodic acidSchiff (PAS) stains are often used. Fibrin is strongly PAS-positive and colors deep blue with PTAH. Carstairs' stain is a picric acid-acid fuchsin-based stain that colors fibrin bright red and platelets gray-blue to navy. Immunofluorescent staining using antifibrin sera can also be used. Soon after the vascular occlusion, the endothelial cells undergo edematous changes, resulting in capillary dilation with congestion of the vessels by erythrocytes. Clinically, this stage is manifested as erythema and possibly edema at the site of skin injury. With progression, the endothelial cell nuclei become hyperchromatic and finally pyknotic. Persistence of the vascular ischemia results in separation of the junctions between individual endothelial cells. This allows for extravasation of formed blood elements into the dermis. Extravasation of formed blood elements continues with eventual rupture of the capillaries. At this point, small punctate, well-demarcated purpuric lesions develop and are seen clinically as petechiae. A minimal to mild inflammatory infiltrate may be found in the perivascular regions at this stage of purpura formation.16 In dermal vascular thrombosis, as occurs in purpura fulminans, no other abnormalities are seen initially in the epidermal or dermal regions. 16,26 In the majority of cases, excluding acute infectious purpura fulminans cases, there is no clinical or histopathologic evidence of vasculitis. Only rarely has a neutrophilic vasculitis been described in association with CISN.26 Continued ischemia and vascular damage leads to further
hemorrhage into the dermis and the development of ecchymoses. This is followed by the formation of subepidermal hemorrhagic bullae. Hemorrhagic bullae mark the point of irreversible damage. Stasis eventually induces thrombosis of venules distal to the dermovascular loop.17 The end result is coagulative necrosis (Fig. 4) of the dermal and subcutaneous tissues with extensive dermal hemorrhage manifested as gangrenous necrosis. In acute infectious purpura fulminans, the histopathologic characteristics are similar to those described previously. An important distinguishing feature of acute infectious purpura fulminans is the presence of an acute vasculitis in many cases. Histologically, acute infectious purpura fulminans closely resembles the local Shwartzman reaction. 27-30 The local Shwartzman reaction is a hemorrhagic and necrotizing inflammatory dermal lesion induced by intradermal injection of endotoxin from a gram-negative organism followed in 18 to 24 hours by intravenous injection of the same endotoxin. The initial or "preparatory" injection induces a dense perivascular infiltrate of polymorphonuclear leukocytes.27,28 The second or "provocative" injection results in thrombosis associated with a neutrophilic vasculitis. The microthrombi are of the mixed variety, as has been demonstrated by electron microscopy. Vessels become greatly dilated and formed blood elements extravasate into the dermis, resulting in clinically evident purpuric hemorrhage. Necrosis of the vessel wall occurs, leading to skin necrosis. In acute meningococcemia, which represents one type of acute infectious purpura fulminans, diffuse vascular involvement is common. 29,31 Vascular changes are not limited to the skin, but are widespread, involving multiple organ systems. Endothelial cell swelling and increased vascular permeability are prominent features of acute meningococcemia. This vascular injury is associ-
FIG. 4. Early coagulative necrosis of the dermis with marked ischemic changes, indicative of the irreversible stage of skin necrosis. (Hematoxylin & eosin; original magnification ×200.)
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ated with extravasation of formed blood elements leading to the development of purpura clinically. Coincident with this process is the development of vasculitis with a perivascular neutrophilic infiltrate that presents clinically as palpable purpura. Microthrombi are present in many of the affected dermal vessels and are invariably present in those patients with severe skin manifestations. Mixed microthrombi composed of fibrin, platelets, and leukocytes are seen during the initial period of neutrophilic infiltration. Gram-negative diplococci may be present within the microthrombi, the vessel walls, the perivascular regions, and the cytoplasm of neutrophils. Extensive hemorrhage diffusely involving the dermis is usually followed by coagulative necrosis. Purpura is also a characteristic finding in rickettsial diseases. 615,30 Purpura fulminans has been reported in patients with Rocky Mountain spotted fever. Histopathologically, this is due to a necrotizing vasculitis associated with thrombosis of the dermal vessels and hemorrhage into the skin. In summary, microthrombi are invariably present in dermal vascular skin necrosis. Purpura represents hemorrhage into the skin due to vascular ischemia and the resultant vascular injury caused by the microthrombi. In acute infectious purpura, a neutrophilic vasculitis is also frequently present.
PURPURA FULMINANS ASSOCIATED WITH CONGENITAL OR ACQUIRED DEFICIENCY OF THE PROTEIN C ANTICOAGULANT SYSTEM Hereditary or acquired deficiency of the PC anticoagulant pathway is associated with the potential for development of skin necrosis and in some instances, purpura fulminans. 6,16-19,26,32-34 Predisposing factors such as concomitant or recent infection are not necessary for skin necrosis to develop in individuals with PC deficiencies. Conditions associated with either decreased PC levels or impaired functional capacity of the PC system and skin necrosis include: (1) hereditary PC deficiency, (2) protein S (PS) deficiency,35,36 (3) coumarin therapy,17,18 (4) DIC, 37,38 (5) cholestasis associated with severe vitamin K deficiency,39 and (6) anti-phospholipid antibodies (the lupus anticoagulant). 40,41 Idiopathic purpura fulminans and acute infectious purpura fulminans are both, by definition, associated with DIC. Therefore these entities are most likely associated with an acquired PC deficiency.37 In these situations, however, it is not known whether the development of DIC is a sequela of microvascular thrombosis and subsequent purpura fulminans or if skin necrosis is, in part, a manifestation of reduced PC levels secondary to DIC. The conditions associated with congenital or
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acquired deficiencies of the PC anticoagulant system will be discussed separately.
Coumarin-lnduced Skin Necrosis CISN is a rare but serious complication occurring in approximately 1 per 1000 individuals receiving oral anticoagulant therapy. 16-19 Skin necrosis is associated with coumarin, phenprocoumon, and rarely phenindione derivatives.42 Dermal manifestations generally begin on the third to fifth day following initiation of therapy, with the majority of cases occurring within 2 to 10 days. The most common sites of involvement include areas rich in subcutaneous adipose tissue, such as the breasts, thighs, buttocks, abdomen, and rarely distal extremities.17 Most lesions occur on the lower half of the body, only rarely is the face involved. The lesions may be single or multiple and occasionally occur bilaterally with a symmetrical distribution. Approximately 75% of cases have been reported in women. 16-19 CISN may occur during the first course of coumarin therapy and is not dependent on the degree of anticoagulation.17 This adverse side effect of coumarin has been reported as frequently in those patients with subtherapeutic prothrombin times as in those with supratherapeutic prothrombin times. The fact that skin necrosis has occurred with one course of coumarin therapy does not imply recurrence of the skin necrosis with subsequent courses of coumarin therapy.17 The histopathologic appearance of CISN is that of dermal vascular thrombosis with resultant hemorrhagic infarction.15,16'18 Depending on the stage of the vascular injury, a mild perivascular infiltrate may be present. There is no clinical or histopathologic evidence of vasculitis. In most patients with CISN, the necrosis is diagnosed clinically and rarely are skin biopsies performed. In only a few cases has direct immunofluorescence been undertaken. Immunofluorescent studies of skin lesions have been reported in four patients.43-45 In only two of the cases were the immunofluorescent studies reported to be positive. A low-intensity C3 granular deposit was present at the dermoepidermal junction in one case.43 The second case revealed immunoglobulin M (IgM) deposition in vessel walls with diffuse deposition of IgG in the upper dermis.45 This second case was unusual in that the skin necrosis developed approximately 17 months after initiation of coumarin therapy. In addition, this individual had Klinefelter's syndrome, with CISN occurring during an episode of infectious mononucleosis with Epstein-Barr virus. Electron microscopic examination was carried out on the necrotic dermal lesions present in this patient. Vascular endothelial blebs inconsistent with deposition of immune complexes were found. Pathophysiologically, CISN is thought to be due to
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a more rapid decrease in PC levels when compared with the other vitamin K-dependent factors.17,18 This is because PC has a shorter half-life than most of the vitamin K-dependent factors. This transient deficiency of PC compared to the other vitamin K dependent factors results in an imbalance between the procoagulant and anticogulant factors and produces a transient hypercoagulable state. CISN has been associated with a number of predisposing factors, including hereditary or acquired PC deficiency, rarely PS deficiency, pregnancy, serious illness, such as sepsis, cholestasis, initiation of oral anticoagulant therapy with high doses of coumarin, and concomitant antibiotic administration.17,19 CISN has also been reported in isolated cases of antithrombin III deficiency46 and benign monoclonal gammopathy with associated DIC. 47
Homozygous Protein C Deficiency Skin necrosis is one of the primary manifestations of homozygous PC deficiency. 1 8 , 3 2 - 3 4 Although the clinical presentation is distinct from CISN, the cutaneous and histopathologic features are identical. Homozygous PC deficiency is a rare hereditary disorder that typically presents with DIC and purpura fulminans in the first few hours of life. Cutaneous lesions are characteristically the initial clinical manifestation and are most frequently described as ecchymoses when first noted.48 The extent and severity of skin involvement is variable. Almost any site can be involved. A symmetrical distribution of dermal necrosis is common. Skin biopsies reveal the same histopathologic features found with CISN, namely, bland fibrin thrombi within dermal vessels associated with perivascular hemorrhage.33 Direct immunofluorescent staining in a single case revealed a faint linear deposition of IgM and C3 at the dermoepidermal junction and faint vascular deposition of IgM. 33 In contrast to the cutaneous manifestations of CISN, the development of skin necrosis in homozygous PC deficiency is associated with DIC. Widespread venous thrombosis involving multiple organ systems may be present in a certain percentage of individuals with homozygous PC deficiency.49
Disseminated Intravascular Coagulation DIC is a dynamic process triggered by activation of the clotting system resulting in microvascular thrombosis, activation of the fibrinolytic system, and a consumptive coagulopathy. The clinical manifestations are a result of thrombosis, hemorrhage, or both. 24,50,51 Cutaneous manifestations are common in DIC. In up to 47% of patients, skin lesions represent the initial sign of this
disorder.50 The cutaneous manifestations of DIC include petechiae, purpura, palpable purpura, ecchymoses, hemorrhagic bullae, purpura fulminans, acral cyanosis, and gangrene.38 As in homozygous PC deficiency, microthrombi are not limited to the skin and are typically found in at least one other organ system.24 Skin biopsy is a valuable diagnostic tool to aid in the prompt recognition of DIC and hence implementation of therapy. In the initial stages of vascular occlusion due to DIC, skin biopsies from hemorrhagic lesions consistently reveal dermal microthrombi with extravasation of formed blood elements.24 No vasculitis is present in DIC-induced dermal vascular thrombosis. The hemorrhagic lesion may progress to frank skin necrosis. Symmetrical peripheral gangrene is an unusual, but distinct manifestation of DIC. 38,52 It is most commonly seen when DIC is related to an underlying infection, particularly group B Streptococcus, Staphylococcus, or meningococcus. Initially, the distal regions of the extremities (sometimes including the ear lobes, genitalia, and tip of the nose) become ischemic. This is characterized clinically by mottled cyanosis, pain, and edema. The lesions may progress rapidly to gangrenous necrosis. The skin biopsy reveals fibrin thrombi in the dermal vasculature with no evidence of vasculitis or arterial thrombosis.38,52 Symmetrical peripheral gangrene may be associated with other purpuric lesions or may exist independently.
Antiphospholipid Antibodies Antiphospholipid antibodies are a family of commonly encountered acquired antibodies associated with a significantly increased risk for recurrent venous or arterial thromboses.53,54 This family of antibodies includes both anticardiolipin antibodies and the lupus anticoagulant.55-57 These antibodies occur in association with a variety of clinical conditions, including autoimmune disorders, certain drug therapies, infectious disease, malignancies, and may arise in apparently normal individuals.53 Relatively little is known regarding the pathophysiology of thrombosis in patients with the antiphospholipid antibodies. A number of investigators have demonstrated dysfunctions in the PC anticoagulant system.58-61 A favored mechanism is antiphospholipid antibody-induced inhibition of thrombomodulin and impaired activation of PC. 61 Cutaneous manifestations associated with antiphospholipid antibodies include leg ulcers, livedo reticularis, distal cutaneous ischemia, and diffuse skin necrosis.40,41,62 In the two reported cases of skin necrosis associated with antiphospholipid antibodies, dermal vascular thrombosis without vasculitis has been described.42,63
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IDIOPATHIC PURPURA FULMINANS AND PURPURA FULMINANS ASSOCIATED WITH ACUTE INFECTION Idiopathic purpura fulminans is an uncommon entity characterized by progressive dermal vascular thrombosis and hemorrhagic skin necrosis associated with DIC in an individual who does not have an acute infection or a history of an acquired or hereditary hypercoagulable state. 5,7,64,65 Although adults may have this type of purpura fulminans, it is usually a disease of children, which is preceded by an unremarkable bacterial or viral infection. Idiopathic purpura fulminans is characterized by the sudden onset of chills and fever followed by dermal erythema and cyanosis, which progresses rapidly to hemorrhagic skin necrosis within 24 to 48 hours.3,7 Without interventional treatment, frank gangrenous necrosis develops. The lesions are most typically present on the thighs, legs, buttocks, and lower abdomen. In the male, the genitalia may be involved. The distal extremities are usually spared. Of particular interest is the absence of microthrombi involving other organ systems.5,7 The histopathologic features show diffuse dermal vasculature thrombosis similar to that seen in CISN, DIC, and hereditary homozygous PC or PS deficiency.3,5,65 Direct immunofluorescent studies performed in one case of idiopathic purpura were negative for IgG, IgM, IgA, C3, and fibrinogen.5 This disorder is also associated with the laboratory manifestations of DIC. Despite the absence of an acute infection, fever and leukocytosis with increased immature forms may be present. Acute infectious purpura fulminans is a rare disorder characterized by purpuric ecchymoses with progression to gangrenous necrosis, fever, profound hypotension, peripheral hypoperfusion, and DIC. 5,66 In contrast to idiopathic purpura fulminans, this type of purpura fulminans is associated with a severe acute bacterial or viral infection. It is usually a disease of young children but may be seen in adults on occasion. The organisms most commonly associated with this type of purpura fulminans include meningococci, gram-negative bacilli, staphylococci, streptococci, and rickettsia. 29-31,66,68 Acute infectious purpura fulminans presents with the signs and symptoms of sepsis. Concurrently, purpuric lesions develop most commonly over the distal aspect of the lower extremities and tend to be symmetrical. These lesions progress rapidly to hemorrhagic necrosis. Proximal extension of the lesions from the lower extremities or diffuse patchy involvement of the upper extremities and abdomen may occur. Rarely are lesions present on the chest or head. Thrombosis and hemorrhagic necrosis are also common in other organ systems, including the lungs, kidneys, and adrenal glands. The histopathology
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is essentially identical to the other forms of dermal vascular thrombosis except that a neutrophilic vasculitis is typically present. 29,30,66,67 In both idiopathic and acute infectious purpura fulminans, cultures of skin lesions are characteristically negative, although colonization with pseudomonal and streptococcal organisms may occur with time.
SKIN NECROSIS ASSOCIATED WITH HEPARIN THERAPY Heparin-induced skin necrosis was first described as a complication of heparin therapy in 1973.69 It is now a well-recognized, potential side effect associated with this medication. Since 1973, over 30 cases of heparininduced skin necrosis have been reported.70-72 The incidence of this complication is approximately 0.6% in patients receiving heparin therapy.71 This unusual side effect has been more frequently associated with subcutaneous heparin therapy but may occur with systemic therapy as well. Necrosis of the skin occurs most commonly at the site of subcutaneous heparin injection. When associated with intravenous therapy, there appears to be a predilection for areas rich in subcutaneous tissue.71 Skin necrosis represents a hypersensitivity reaction to heparin therapy.71,73 Skin lesions typically appear 6 to 14 days following initiation of heparin therapy. If patients have been previously exposed to heparin, skin necrosis may develop earlier. Thrombocytopenia is associated with the development of skin necrosis in some but not all patients.73 Heparin-associated skin necrosis may be a subset of the more frequently recognized syndrome of heparin-associated thrombocytopenia and thrombosis (HATT).73,74 There are a number of similarities between these two complications of heparin therapy. Both heparin-associated skin necrosis and HATT appear to represent hypersensitivity to heparin, may be associated with abnormal in vitro platelet aggregation in the presence of heparin, are associated with paradoxical thrombosis, and require cessation of heparin therapy for clinical improvement.71-74 In both situations, the thrombosis is thought to be due to heparin-associated antibodies that induce intravascular platelet aggregation.71'73 No specific risk factors have been identified that predispose an individual to heparin-associated thrombocytopenia and thrombosis, except previous exposure to heparin. In one patient studied, PC, PS, and antithrombin III levels were normal at the time of appearance of skin necrosis.70 Early recognition of thrombocytopenia in patients receiving heparin may alert the physician to the potential for thromboembolic complications.
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Skin biopsies from the affected areas show extensive necrosis with microthrombi present in the dermal vasculature.71,73 Vasculitis and perivascular inflammation are characteristically lacking in these biopsies.
MISCELLANEOUS CLINICAL CONDITIONS PNH is a rare form of hemolytic anemia associated with a generalized thrombotic tendency. Skin lesions are an uncommon manifestation of this disorder.75 The most common skin lesions reported are petechiae, ecchymoses, and leg ulcerations. Skin necrosis, similar to that seen in CISN, has been reported in two patients.76,77 In one case, the skin lesions developed shortly after the patient began antibiotic therapy (ampicillin and clindamycin) for acute abdominal symptoms. Skin biopsy in this case confirmed dermal vascular thrombosis and erythrocyte extravasation without vasculitis. This patient had no clinical evidence of renal or central nervous system disease, which is associated with a diagnosis of TTP. In addition, there was no evidence of DIC to otherwise explain the microvascular thrombosis. TTP is an uncommon disorder associated with widespread microvascular occlusions resulting in peripheral platelet consumption. The major manifestations include purpura, microangiopathic hemolytic anemia, fluctuating neurologic signs, renal impairment, and fever.78 TTP may be associated with the development of petechiae and ecchymoses. It is rarely associated with hemorrhagic skin necrosis and gangrene.79 Skin biopsies reveal microvascular thrombosis, composed largely of platelets, characterized histologically by amorphous, eosinophilic PAS-positive intravascular material.79,80 Characteristically, there is no associated vasculitis or perivascular inflammation. Electron microscopic examination reveals that the microthrombi are composed largely of platelets with small amounts of fibrin.80 Erythrocytes and leukocytes may also be trapped within the thrombi. Cryoglobulinemia may be associated with occlusion of the superficial dermal vasculature and has a histologic appearance similar to that previously described.15,81 Specifically, the dermal vessels may contain fibrinoid and hyalinized material.15 This intravascular material is PAS-positive and consists of precipitated cryoglobulin. A mild perivascular infiltrate may be present; however, there is no associated vasculitis. The clinical picture is typically that of livedo and ulceration usually involving the distal extremities. Gangrene is a rare clinical complication. Most patients have an underlying lymphoproliferative disorder associated with the production of a monoclonal protein.
SUMMARY Dermal vascular skin necrosis is associated with a complex group of clinical disorders. Many of these disorders are associated with an underlying abnormality of the PC anticoagulant system or DIC, or both. The clinical appearance and histopathologic features of dermal vascular skin necrosis are similar regardless of the etiology. Acute infectious purpura fulminans is distinct in that an acute vasculitis may be present in addition to microvascular thrombosis. Skin biopsy is a valuable diagnostic tool in the early recognition of these clinical disorders, since skin involvement is frequently an early manifestation of the disease process. Prompt recognition and institution of appropriate therapy at the reversible stages of dermal vascular thrombosis will, it is hoped, reduce the morbidity and mortality currently associated with skin necrosis and purpura fulminans.
REFERENCES 1. Williams WJ: Approach to the patient. In: Williams WJ, Ed: Hematology, 4th ed. McGraw-Hill, New York, 1990, pp 3-8. 2. Gottleib AJ: Nonallergic purpura. In: Williams WJ, Ed: Hematology, 4th ed. McGraw-Hill, New York, 1990, pp 1434-1440. 3. Hodge SJ: Purpura fulminans. Cutis 21:830-832, 1978. 4. Seagle MB, HG Bingham: Purpura fulminans. Ann Plast Surg 20:576-581, 1988. 5. Spicer TE, JM Rau. Purpura fulminans. Am J Med 61:566-571, 1976. 6. Kitchens CS: The anatomic basis of purpura. Prog Hemost Thromb 5:211-244, 1980. 7. Hjort PF, SI Rapaport: Purpura fulminans. Review of 50 cases from the literature. Scand J Haematol 1:169-192, 1964. 8. Bick RL, NR Arbegast, TP Comer: Fatal purpura fulminans following total cardiopulmonary bypass. J Cardiovasc Surg 14:569-571, 1973. 9. Targan SR, MR Chassin, LB Guze: Dilantin-induced disseminated intravascular coagulation with purpura fulminans. A case report. Ann Intern Med 83:227-230, 1975. 10. Preston FE, IR Edwards: Postpartum purpura fulminans: Successful management with streptokinase. Br Med J 3:329-330, 1973. 11. Waddel CC, M Franco: Purpura fulminans in an adult. South Med J 74:1533-1534, 1981. 12. Celoria GM, RH Steingart, B Banson, P Friedman, SW Rhee, JA Berman: Coumarin skin necrosis in a patient with heparin-induced thrombocytopenia. Angiology 39:915-920, 1988. 13. Kelly RA, JA Gelfand, SH Pincus: Cutaneous necrosis caused by systemically administered heparin. JAMA 246:1582-1583, 1981. 14. Gipstein RM, JW Coburn, DA Adams, DBN Lee, KP Parsa, A Sellers, WN Suki, SG Massry: Calciphylaxis in man. A syndrome of tissue necrosis and vascular calcification in 11 patients with chronic renal failure. Arch Intern Med 136:1273-1280, 1976. 15. Lever WF, G Schaumburg-Lever: Histopathology of the Skin. 7th ed. JB Lippincott, Philadelphia, 1990, pp 35-37, 191-192. 16. Koch-Wesser J: Coumarin necrosis. Ann Intern Med 68:13651366, 1968.
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17. Cole MS, PK Minifee, FJ Wolma: Coumarin necrosis—a review of the literature. Surgery 103:271-277, 1988. 18. Gladson CL, P Groncy, JH Griffin: Coumarin skin necrosis, neonatal purpura fulminans, and protein C deficiency. Arch Dermatol 123:1701-1706, 1987. 19. Becker CG: Oral anticoagulant therapy and skin necrosis: Speculations on pathogenesis. In: Wessler S, Becker CG, Nemerson, Eds: The New Dimensions of Warfarin Prophylaxis. Plenum Press, New York, 1987, pp 217-222. 20. Marlar RA, RR Montgomery, AW Broekmans, and the Working Party: Diagnosis and treatment of homozygous protein C deficiency. J Pediatr 114:528-534, 1989. 21. Boss JM, R Summerly: Prevention of warfarin-induced skin necrosis. (Letter.) Br J Dermatol 100:617, 1979. 22. Silbart S, W Oppenheim: Purpura fulminans. Medical, surgical and rehabilitative considerations. ClinOrthop 193:206-213, 1985. 23. Nogi J: Physeal arrest in purpura fulminans. J Bone Joint Surg 6:929-931, 1989. 24. Minna JD, SJ Robboy, RW Colman: Disseminated Intravascular Coagulation in Man. Charles C Thomas, Springfield, IL, 1974, pp 91-127. 25. Sheehan DC, BB Hrapchack: Theory and Practice of Histotechnology. 2nd ed Batelle Press, Columbus, 1980, pp 280-281. 26. Faraci PA, RA Deterling, AM Stein, HF Rheinlauder, RJ Cleveland: Warfarin induced necrosis of the skin. Surg Gyncol Obstet 146:695-700, 1978. 27. Movat HZ, CE Burrowes: The local Shwartzman reaction; endotoxin-mediated inflammatory and thrombo-hemorrhagic lesions. In: Berry LJ, Ed: Handbook of Endotoxins, vol 3, Elsevier Science Publishers, 1985, pp 260-302. 28. Movat HZ, CE Burrowes, MI Cybulsky, CA Dinarello: Acute inflammation and a Shwartzman-like reaction induced by interleukin-1 and tumor necrosis factor. Am J Pathol 129:463-476, 1987. 29. Hill WR, TD Kinney: The cutaneous lesions in acute meningococcemia. JAMA 134:513-516, 1947. 30. Griffin GL, EA Luce: Massive skin necrosis in Rocky Mountain spotted fever. South Med J 71:1337-1340, 1978. 31. Wong VK, W Hitchcock, WH Mason: Meningococcal infections in children: A review of 100 cases. Pediatr Infect Dis J 8:224-227, 1989. 32. Marciniak E, HD Wilson, RA Marlar: Neonatal purpura fulminans. A genetic disorder related to the absence of protein C in blood. Blood 65:15-20, 1985. 33. Auletta MJ, JT Headington: Purpura fulminans: A cutaneous manifestation of severe protein C deficiency. Arch Dermatol 124:1387-1391, 1988. 34. Rose VL, HC Kwaan, K Williamson, D Hoppensteadt, J Walenga, J Fareed: Protein C antigen deficiency and warfarin necrosis. Am J Clin Pathol 86:653-655, 1986. 35. Grimaudo V, F Gueissaz, J Hauert, A Sarroj, EKO Kruithof, F Bachmann: Necrosis of skin induced by coumarin in a patient deficient in protein S. Br Med J 298:233-234, 1989. 36. Dominey A, A Kettler, J Yiannias, JA Tschen: Purpura fulminans and transient protein C and protein S deficiency. Arch Dermatol 124:1442-1443, 1988. 37. Marlar RA, J Endes-Brooks, C Miller: Serial studies of protein C and its plasma inhibitor in patients with disseminated intravascular coagulation. Blood 66:59-63, 1985. 38. Baker WF Jr: Clinical aspects of disseminated intravascular coagulation: A clinician's point of view. Semin Thromb Hemost 15:1-57, 1989. 39. Michaels JJ, RM Bertina: Thrombo-hemorrhagic skin necrosis due to rapid development of severe vitamin K deficiency associated with cholestasis. (Abst.), Thromb Haemost 58:413, 1987.
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40. Lie JT: Recurrent thromboembolism, disseminated intravascular coagulation, and coumarin-induced skin necrosis associated with protein C deficiency. Pathol Res Pract 183:308-313, 1988. 41. Grob JJ, JJ Bonerandi: Cutaneous manifestations associated with the presence of the lupus anticoagulant. J Am Acad Dermatol 15:211-219, 1986. 42. Bork K: Cutaneous Side Effects of Drugs. WB Saunders, Philadelphia 1988, pp 222-225. 43. Hislop IG, PJ Zilko, M Peterson, N Ahmed: Dermal necrosis following coumarin: Is it immunologically induced? Aust NZ J Med 10:51-53, 1980. 44. Jones RR, J Cunningham: Warfarin skin necrosis: The role of factor VII. Br J Dermatol 100:561-565, 1979. 45. Franson TR, HD Rose, MR Spivey, J Maroney, JA Libnoch: Late-onset, warfarin-caused necrosis occurring in a patient with infectious mononucleosis. Arch Dermatol 120:927-931, 1984. 46. Kiehl R, P Hellstern, E Wenzel: Hereditary antithrombin III deficiency and atypical localization of coumarin necrosis. Thromb Res 45:191-193, 1987. 47. Friedenberg WR, M West, DJ Miech, SS Mazza: Atypical purpura fulminans with benign monoclonal gammopathy. Arch Dermatol 114:578-580, 1978. 48. Pegelow CH, R Curless, B Bradford: Severe protein C deficiency in the newborn. Am J Pediatr Hematol/Oncol 10:326-329, 1988. 49. Tarras S, C Gadia, L Meister, E Roldan, JB Gregorios: Homozygous protein C deficiency in the newborn: Clinicopathologic correlation. Arch Neurol 45:214-216, 1988. 50. Robboy SJ, MC Mihm, RW Colman, JD Minna: The skin in disseminated intravascular coagulation. Br J Dermatol 88:221— 229, 1973. 51. Colman RW, JN Minna, SJ Robboy: Disseminated intravascular coagulation: A dermatologic disease. Int J Dermatol 16:47-51, 1977. 52. Rahal JJ, HE MacMahon, L Weinstein: Thrombocytopenia and symmetrical peripheral gangrene associated with staphylococcal and streptococcal bacteremia. Ann Intern Med 69:35—43, 1968. 53. Triplett DA, JT Brandt, KA Musgrave, GA Orr: The relationship between lupus anticoagulants and antibodies to phospholipids. JAMA 259:550-554, 1988. 54. Asheron RA, EN Harris: Anticardiolipin antibodies—clinical associations. Postgrad Med J 62:1081-1087, 1986. 55. Sontheimer RD: The anticardiolipin syndrome. Arch Dermatol 123:590-594, 1987. 56. McNeil HP, CN Chesterman, SA Krillis: Binding specificity of lupus anticoagulants and anticardiolipin antibodies. Thromb Res 52:609-619, 1988. 57. Walker TS, DA Triplett, N Javed, K Musgrave: Evaluation of lupus anticoagulants: Antiphospholipid antibodies, endothelium associated immunoglobulin, endothelial prostacyclin secretion, and antigenic protein S. Thromb Res 51:267-281, 1988. 58. Cariou R, G Tobelem, C Soria, J Caen: Inhibition of protein C activation by endothelial cells in the presence of lupus anticoagulant. N Engl J Med 314:1193-1194, 1986. 59. Freyssinet JM, ML Wiessel, J Gauchy, B Boneu, JP Cazenave: An IgM anticoagulant that neutralizes the enhancing effect of phospholipid on purified endothelial thrombomodulin activity—a mechanism for thrombosis. Thromb Haemost 55:309-313, 1986. 60. Cariou R, G Tobelem, S Belluci, J Soria, C Soria, J Maclouf, J Caen: Effect of lupus anticoagulant on thrombogenic properties of endothelial cells—inhibition of thrombomodulin-dependent protein C activation. Thromb Haemost 60:54-58, 1988. 61. Freyssinet JM, JP Cazenave: Lupus-like anticoagulants, modulation of the protein C pathway and thrombosis. Thromb Haemost 58:679-681, 1987.
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62. Dodd HJ, I Sarkany, D O'Shaugnessy: Widespread cutaneous necrosis associated with the lupus anticoagulant. Clin Exp Dermatol 10:581-586, 1985. 63. Jindel BK, MFR Martin, A Gayner: Gangrene developing after minor surgery in a patient with undiagnosed systemic lupus erythematosus and lupus anticoagulant. Ann Rheum Dis 42:347349, 1983. 64. Gurses N, A Ozkan: Neonatal and childhood purpura fulminans: Review of seven cases. Cutis 41:361-363, 1988. 65. Brazilian Purpuric Fever Study Group: Brazilian purpuric fever: Epidemic purpura fulminans associated with antecedent purulent conjunctivitis. Lancet 2:757-761, 1987. 66. Hautekeete ML, ZN Berneman, R Bieger, WJ Stevens, C Bridts, N Buyssens, ME Peetermans: Purpura fulminans in pneumococcal sepsis. Arch Intern Med 146:497-499, 1986. 67. Adner MM, RE Kauf, JD Sherman: Purpura fulminans in a child with pneumococcal septicemia two years after splenectomy. Am J Dis Child 138:915-916, 1984. 68. Hill WR, TD Kinney: The cutaneous lesions in acute meningococcemia. JAMA 134:513-518, 1947. 69. O'Toole RD: Heparin: Adverse reaction. (Letter.) Ann Intern Med 79:759, 1973. 70. Stricker H, B Lämmle, M Furlan, I Sulzer: Heparin-dependent in vitro aggregation of normal platelets by plasma of a patient with heparin-induced skin necrosis. Am J Med 85:721-724, 1988. 71. Hartman AR, RM Hood, CE Anagnostopoulos: Phenomenon of heparin-induced thrombocytopenia associated with skin necrosis. J Vasc Surg 7:781-784, 1988.
72. White PW, JR Sadd, RE Nensel: Thrombotic complications of heparin therapy. Ann Surg 90:595-608, 1979. 73. Platell CF, ECG Tan: Hypersensitivity reactions to heparin: Delayed onset thrombocytopenia and necrotizing skin lesions. Aust NZJ Surg 56:621-623, 1986. 74. King DJ, JG Kelton: Heparin-associated thrombocytopenia. Ann Intern Med 100:535-540, 1984. 75. Ellenhorn MJ, LZ Feigenbaum, C Plumhof, SR Mettier: Paroxysmal nocturnal hemoglobinuria with chronic hemolytic anemia. Arch Intern Med 87:868-878, 1951. 76. Rietschel RL, CW Lewis, RA Simmons, RL Phyliky: Skin lesions in paroxysmal nocturnal hemoglobinuria. Arch Dermatol 114:560— 563, 1978. 77. Hansen NE, SA Killman: Paroxysmal nocturnal hemoglobinuria: A clinical study. Acta Med Scand 184:525-541, 1968. 78. Ridolfi RL, WR Bell: Thrombotic thrombocytopenic purpura: Report of 25 cases and review of the literature. Medicine (Baltimore) 60:413-429, 1981. 79. Luttgens WF: Skin necrosis in a patient with thrombotic thrombocytopenic purpura. Ann Intern Med 46:1200—1213, 1957. 80. Feldman JD, MR Mardiney, ER Unanue, H Cutting. The vascular pathology of thrombotic thrombocytopenic purpura. An immunohistochemical and ultrastructural study. Lab Invest 15:927-946, 1966. 81. Pinkus H, AH Mehregan: A Guide to Dermatopathology, Appleton-Century-Crofts, New York, 1981, p 180.
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Dermatopathology of Skin Necrosis Associated with Purpura Fulminans
Skin necrosis is a manifestation of pathologic injury intrinsic to the dermal vasculature or factors extrinsic to the integument. Extrinsic causes of skin necrosis include, extravasation of toxic chemotherapeutic agents, radiation injury, or pressure-induced damage as seen in barbiturate intoxication. Skin necrosis due to causes intrinsic to the dermis include vascular occlusion by fibrin, platelets, cholesterol emboli and foreign material, and vasculitis. Intrinsic causes such as occlusion of dermal vessels due to intravascular fibrin precipitation or thrombosis is an important and frequent cause of skin necrosis. Dermal vascular occlusion may be a manifestation of a variety of conditions, including sequelae to certain infectious diseases, anticoagulant therapy, disseminated intravascular coagulation (DIC), and homozygous protein C (PC) deficiency. Rarely is it associated with other clinical situations such as thrombotic thrombocytopenic purpura (TTP) or paroxysmal nocturnal hemoglobinuria (PNH). This article will review the various conditions associated with skin necrosis due to dermal vascular occlusion, with emphasis on the histopathology of these lesions.
DEFINITION OF PURPURA Purpura is a general term that describes hemorrhage or extravasation of formed blood elements (Fig. 1) from the dermal vessels into the substance of the skin.1'2
From the Department of Pathology, University of Colorado Health Sciences Center, and the Colorado Permanente Medical Group, Denver, Colorado, and the Department of Pathology, Baylor College of Medicine, Houston, Texas. Reprint requests: Dr. Adcock, Colorado Permanente Medical Group, Department of Pathology, 16601 East Centretech Parkway, Aurora, CO 80011.
Dermal hemorrhage may be described using more specific terms based on the appearance or etiology of the lesion. Petechiae refer to pinpoint hemorrhagic lesions that are well-demarcated, less than 3 mm in diameter, and appear red-brown. Petechiae commonly occur in areas of high venous pressure, such as the lower leg. These lesions do not blanch with external pressure. Ecchymoses are purpuric lesions larger than 3 mm in diameter. These hemorrhagic lesions generally have irregular margins and vary considerably in size and shape. Ecchymoses may be red, purple, blue, or yellowgreen, depending on the intensity of the skin hemorrhage and its duration. Palpable purpura refers to an elevated hemorrhagic dermal lesion. It usually implies the presence of both vasculitis and hemorrhage. A hematoma is a palpable lesion composed of extravasated blood that has developed between tissue planes and does not imply the presence of vasculitis. Purpura fulminans is a specific term that describes an acute syndrome of rapidly progressive, hemorrhagic necrosis of the skin due to dermal vascular thrombosis associated with vascular collapse and DIC. 3-5 In the following discussion, skin necrosis will refer to dermal lesions that are grossly and histopathologically similar to purpura fulminans but are not associated with the systemic manifestations of DIC or vascular collapse. Other terms that may be confused with a hemorrhagic dermal process include erythema and telangiectasia.1,2 Erythema of the skin is simply a reddened appearance and is due to a transitory hyperemia. Because formed blood elements have not extravasated into the dermis, this lesion blanches with external pressure. Telangiectasia is a condition in which redness of the skin results from a permanent enlargement in the caliber of small blood vessels and an increase in the number of vessels. Telangiectasias are pinpoint, relatively well-demarcated capillary aggregates of 1 to 3 mm diameter. Telangiectasias may be confused with petechiae; however, these
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TABLE 1. Pathophysiologic Categories of Purpura* Purpura not associated with any known disease entity Mechanical purpura Factitious purpura Purpura simplex Purpura associated with platelet abnormalities Thrombocytopenic purpura Thrombocytopathic purpura Purpura associated with rheumatic phenomena Leukocytoclastic vasculitis associated with disease of uncertain cause Leukocytoclastic vasculitis associated with specific agents
capillary masses blanch on external pressure, whereas petechiae do not.
CLASSIFICATION OF PURPURA Purpuric lesions have been classified using a number of schemes. In a comprehensive review of the anatomic basis of purpura, Kitchens6 proposed a logical classification system for these skin lesions based on common anatomic mechanisms (Table 1). One mechanism that produces purpuric skin lesions is dermal vascular thrombosis. Skin lesions induced by dermal vascular thrombosis may present clinically in a variety of ways, such as skin necrosis, ecchymoses, ulceration, cyanosis, and livedo reticularis. Skin necrosis due to dermal vascular thrombosis can occur in association with a number of clinical conditions (Table 1). Purpura fulminans is one category of skin necrosis due to dermal vascular thrombosis. Purpura fulminans is distinguished from other forms of skin necrosis by the presence of shock and signs of DIC. As originally defined7 purpura fulminans specifically refers to rapidly progressive skin necrosis occurring during a latent period following an acute infection. Since that time, the term "purpura fulminans" has been applied to a variety of disorders that do not fulfill this initial description. This term has been applied to dermal vascular skin necrosis that develops in conjunction with DIC in patients with acute infections or coagulation protein deficiencies.8-11 Also confusing the issue are reports of skin necrosis grossly and histologically similar to purpura fulminans, which occur in the absence of DIC and vascular collapse. 12-14 This category includes coumarin-induced skin necrosis (CISN) and rarely TTP, cryoglobulinemia, and PNH. These disorders must be distinguished from purpura fulminans. Due to the increasing knowledge of the underlying conditions
Purpura associated with decreased mechanical strength of The microcirculation Scurvy Hypercortisolism "Senile" purpura Hereditary diseases of connective tissue Amyloidosis Osier-Weber-Rendu disease Purpura associated with dermal vascular thrombosis Disseminated intravascular coagulation Coumarin-and heparin-induced skin necrosis Skin necrosis associated with anti-phospholipid antibodies Purpura fulminans Idiopathic purpura fulminans Acute infectious purpura fulminans Myeloblastemia Thrombotic thrombocytopenic purpura Paroxysmal nocturnal hemoglobinuria Cryoglobulinemia Purpura associated with vascular malignancy * Modified from Kitchens.6
associated with purpura fulminans and its distinction from skin necrosis, a new classification of purpura fulminans is proposed.
New Classification of Purpura Fulminans The term "purpura fulminans" should be reserved for dermal vascular skin necrosis that occurs in association with systemic manifestations of DIC or PC deficiency. As described by Francis later in this issue of Seminars, purpura fulminans may occur in three distinct situations: (1) in individuals with hereditary or acquired dysfunction of the protein C anticoagulant system, (2) in individuals with acute, current severe infection, and (3) in individuals without known abnormalities of the PC system or acute infection. The first category has been referred to simply as purpura fulminans. The second category may be referred to as acute infectious purpura fulminans. The third group of purpura fulminans occurring in individuals without known abnormalities has been
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FIG. 1. Simple purpuric skin lesion (senile purpura) demonstrating extravasation of formed blood elements into the substance of the dermis. (Hematoxylin & eosin; original magnification ×500.)
Purpura associated with direct endothelial cell damage Physical or chemical injury Anoxia Injury by microorganisms Antibody-mediated injury
coined idiopathic purpura fulminans by Francis. These terms will be used throughout this review.
CUTANEOUS VASCULATURE OF THE SKIN The following brief discussion of the cutaneous vasculature will be used as a basis to describe the histopathology of dermal vascular thrombosis.15 Briefly, the subcutis contains a plexus of small arteries that give rise to dermal arterioles. Within the papillary dermis, a terminal vascular plexus (subpapillary plexus) is formed by terminal or precapillary arterioles that anastomose into a system of capillaries and subsequently coalesce into the postcapillary venule system. The subpapillary plexus constitutes the microcirculation of the skin, which is the site where purpuric lesions form. The venous portion of the dermal vasculature plays the predominant role in mediating the cutaneous inflammatory response.
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DERMATOPATHOLOGY OF SKIN NECROSIS The histopathologic features of skin necrosis due to dermal vascular thrombosis are similar regardless of the etiology.5,16-19 This form of skin necrosis is characterized by occlusion of dermal venules and capillaries by microthrombi, resulting in hemorrhagic infarction (Fig. 2). The initial site of injury occurs at the junction of the terminal precapillary arterioles and capillaries. Occlusion may result from thrombosis within the subpapillary plexus of the dermis or may represent microvascular embolization of fibrin that has precipitated within the systemic circulation. In the majority of reports, arteries and arterioles are spared. The histopathology of dermal microthrombi24 has been described and classified as follows: pure fibrinous (hyaline), fibrin-platelet, platelet, or mixed types. Using a routine hematoxylin and eosin stain, microthrombi are characterized as amorphous, eosinophilic intravascular material that has a granular or globular appearance. In most instances, this amorphous material consists of fibrin
CUTANEOUS MANIFESTATIONS OF SKIN NECROSIS The cutaneous manifestations of skin necrosis due to vascular occlusion are similar, regardless of the underlying precipitating condition. 13,16-19 Clinically, this type of skin necrosis begins with a region of dermal discomfort that progresses within hours to a regional evanescent flush. This is quickly followed by the development of petechiae and, in some instances, edema. The petechiae rapidly coalesce to form purple ecchymoses surrounded by a zone of erythema. Up to this point, the cutaneous lesions may be completely reversible without progression to skin necrosis. This has been documented in cases of skin necrosis associated with both coumarin therapy and homozygous PC deficiency.20,21 The development of hemorrhagic bullae is the hallmark of hemorrhagic infarction, marking irreversible progression to frank skin necrosis. Gangrenous necrosis subsequently develops with the formation of a deeply pigmented eschar that eventually sloughs. In most instances, this process involves only the skin and subcutaneous tissue, sparing the underlying muscle. Skin necrosis is associated with considerable morbidity and is fatal in some cases. In those patients who survive, surgical intervention, including limb amputation, fasciotomy, wound debridement, or skin grafting, is usually necessary. Considerable reconstructive surgery may be required.22 In children, gangrene involving the lower extremities may result in ischemia of the epiphyseal growth plate resulting in arrest of growth.23 It is important to involve a general surgeon and, in some instances, an orthopedic surgeon early in patient care.
FIG. 2. Ischemic skin lesion demonstrating characteristic fibrinous microthrombi occluding the dermal vasculature without perivascular inflammation or vasculitis. This coumarin-induced lesion represents the reversible stage of skin ischemia. (Hematoxylin & eosin; original magnification x100.)
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FIG. 3. Mixed microthrombus involving the dermal vasculature with adjacent venous stasis, but without perivascular inflammation or vasculitis. (Hematoxylin & eosin; original magnification ×500.)
and proteinaceous material. Some microthrombi may consist largely of platelets. Platelet microthrombi also have an amorphous eosinophilic appearance. Mixed thrombi are composed of a fibrinous network containing erythrocytes, leukocytes, and platelets (Fig. 3). A variety of histochemical stains can be used to aid in the identification of vascular occlusive material.24,25 Phosphotungstic acid hematoxylin (PTAH) and periodic acidSchiff (PAS) stains are often used. Fibrin is strongly PAS-positive and colors deep blue with PTAH. Carstairs' stain is a picric acid-acid fuchsin-based stain that colors fibrin bright red and platelets gray-blue to navy. Immunofluorescent staining using antifibrin sera can also be used. Soon after the vascular occlusion, the endothelial cells undergo edematous changes, resulting in capillary dilation with congestion of the vessels by erythrocytes. Clinically, this stage is manifested as erythema and possibly edema at the site of skin injury. With progression, the endothelial cell nuclei become hyperchromatic and finally pyknotic. Persistence of the vascular ischemia results in separation of the junctions between individual endothelial cells. This allows for extravasation of formed blood elements into the dermis. Extravasation of formed blood elements continues with eventual rupture of the capillaries. At this point, small punctate, well-demarcated purpuric lesions develop and are seen clinically as petechiae. A minimal to mild inflammatory infiltrate may be found in the perivascular regions at this stage of purpura formation.16 In dermal vascular thrombosis, as occurs in purpura fulminans, no other abnormalities are seen initially in the epidermal or dermal regions. 16,26 In the majority of cases, excluding acute infectious purpura fulminans cases, there is no clinical or histopathologic evidence of vasculitis. Only rarely has a neutrophilic vasculitis been described in association with CISN.26 Continued ischemia and vascular damage leads to further
hemorrhage into the dermis and the development of ecchymoses. This is followed by the formation of subepidermal hemorrhagic bullae. Hemorrhagic bullae mark the point of irreversible damage. Stasis eventually induces thrombosis of venules distal to the dermovascular loop.17 The end result is coagulative necrosis (Fig. 4) of the dermal and subcutaneous tissues with extensive dermal hemorrhage manifested as gangrenous necrosis. In acute infectious purpura fulminans, the histopathologic characteristics are similar to those described previously. An important distinguishing feature of acute infectious purpura fulminans is the presence of an acute vasculitis in many cases. Histologically, acute infectious purpura fulminans closely resembles the local Shwartzman reaction. 27-30 The local Shwartzman reaction is a hemorrhagic and necrotizing inflammatory dermal lesion induced by intradermal injection of endotoxin from a gram-negative organism followed in 18 to 24 hours by intravenous injection of the same endotoxin. The initial or "preparatory" injection induces a dense perivascular infiltrate of polymorphonuclear leukocytes.27,28 The second or "provocative" injection results in thrombosis associated with a neutrophilic vasculitis. The microthrombi are of the mixed variety, as has been demonstrated by electron microscopy. Vessels become greatly dilated and formed blood elements extravasate into the dermis, resulting in clinically evident purpuric hemorrhage. Necrosis of the vessel wall occurs, leading to skin necrosis. In acute meningococcemia, which represents one type of acute infectious purpura fulminans, diffuse vascular involvement is common. 29,31 Vascular changes are not limited to the skin, but are widespread, involving multiple organ systems. Endothelial cell swelling and increased vascular permeability are prominent features of acute meningococcemia. This vascular injury is associ-
FIG. 4. Early coagulative necrosis of the dermis with marked ischemic changes, indicative of the irreversible stage of skin necrosis. (Hematoxylin & eosin; original magnification ×200.)
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ated with extravasation of formed blood elements leading to the development of purpura clinically. Coincident with this process is the development of vasculitis with a perivascular neutrophilic infiltrate that presents clinically as palpable purpura. Microthrombi are present in many of the affected dermal vessels and are invariably present in those patients with severe skin manifestations. Mixed microthrombi composed of fibrin, platelets, and leukocytes are seen during the initial period of neutrophilic infiltration. Gram-negative diplococci may be present within the microthrombi, the vessel walls, the perivascular regions, and the cytoplasm of neutrophils. Extensive hemorrhage diffusely involving the dermis is usually followed by coagulative necrosis. Purpura is also a characteristic finding in rickettsial diseases. 615,30 Purpura fulminans has been reported in patients with Rocky Mountain spotted fever. Histopathologically, this is due to a necrotizing vasculitis associated with thrombosis of the dermal vessels and hemorrhage into the skin. In summary, microthrombi are invariably present in dermal vascular skin necrosis. Purpura represents hemorrhage into the skin due to vascular ischemia and the resultant vascular injury caused by the microthrombi. In acute infectious purpura, a neutrophilic vasculitis is also frequently present.
PURPURA FULMINANS ASSOCIATED WITH CONGENITAL OR ACQUIRED DEFICIENCY OF THE PROTEIN C ANTICOAGULANT SYSTEM Hereditary or acquired deficiency of the PC anticoagulant pathway is associated with the potential for development of skin necrosis and in some instances, purpura fulminans. 6,16-19,26,32-34 Predisposing factors such as concomitant or recent infection are not necessary for skin necrosis to develop in individuals with PC deficiencies. Conditions associated with either decreased PC levels or impaired functional capacity of the PC system and skin necrosis include: (1) hereditary PC deficiency, (2) protein S (PS) deficiency,35,36 (3) coumarin therapy,17,18 (4) DIC, 37,38 (5) cholestasis associated with severe vitamin K deficiency,39 and (6) anti-phospholipid antibodies (the lupus anticoagulant). 40,41 Idiopathic purpura fulminans and acute infectious purpura fulminans are both, by definition, associated with DIC. Therefore these entities are most likely associated with an acquired PC deficiency.37 In these situations, however, it is not known whether the development of DIC is a sequela of microvascular thrombosis and subsequent purpura fulminans or if skin necrosis is, in part, a manifestation of reduced PC levels secondary to DIC. The conditions associated with congenital or
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acquired deficiencies of the PC anticoagulant system will be discussed separately.
Coumarin-lnduced Skin Necrosis CISN is a rare but serious complication occurring in approximately 1 per 1000 individuals receiving oral anticoagulant therapy. 16-19 Skin necrosis is associated with coumarin, phenprocoumon, and rarely phenindione derivatives.42 Dermal manifestations generally begin on the third to fifth day following initiation of therapy, with the majority of cases occurring within 2 to 10 days. The most common sites of involvement include areas rich in subcutaneous adipose tissue, such as the breasts, thighs, buttocks, abdomen, and rarely distal extremities.17 Most lesions occur on the lower half of the body, only rarely is the face involved. The lesions may be single or multiple and occasionally occur bilaterally with a symmetrical distribution. Approximately 75% of cases have been reported in women. 16-19 CISN may occur during the first course of coumarin therapy and is not dependent on the degree of anticoagulation.17 This adverse side effect of coumarin has been reported as frequently in those patients with subtherapeutic prothrombin times as in those with supratherapeutic prothrombin times. The fact that skin necrosis has occurred with one course of coumarin therapy does not imply recurrence of the skin necrosis with subsequent courses of coumarin therapy.17 The histopathologic appearance of CISN is that of dermal vascular thrombosis with resultant hemorrhagic infarction.15,16'18 Depending on the stage of the vascular injury, a mild perivascular infiltrate may be present. There is no clinical or histopathologic evidence of vasculitis. In most patients with CISN, the necrosis is diagnosed clinically and rarely are skin biopsies performed. In only a few cases has direct immunofluorescence been undertaken. Immunofluorescent studies of skin lesions have been reported in four patients.43-45 In only two of the cases were the immunofluorescent studies reported to be positive. A low-intensity C3 granular deposit was present at the dermoepidermal junction in one case.43 The second case revealed immunoglobulin M (IgM) deposition in vessel walls with diffuse deposition of IgG in the upper dermis.45 This second case was unusual in that the skin necrosis developed approximately 17 months after initiation of coumarin therapy. In addition, this individual had Klinefelter's syndrome, with CISN occurring during an episode of infectious mononucleosis with Epstein-Barr virus. Electron microscopic examination was carried out on the necrotic dermal lesions present in this patient. Vascular endothelial blebs inconsistent with deposition of immune complexes were found. Pathophysiologically, CISN is thought to be due to
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a more rapid decrease in PC levels when compared with the other vitamin K-dependent factors.17,18 This is because PC has a shorter half-life than most of the vitamin K-dependent factors. This transient deficiency of PC compared to the other vitamin K dependent factors results in an imbalance between the procoagulant and anticogulant factors and produces a transient hypercoagulable state. CISN has been associated with a number of predisposing factors, including hereditary or acquired PC deficiency, rarely PS deficiency, pregnancy, serious illness, such as sepsis, cholestasis, initiation of oral anticoagulant therapy with high doses of coumarin, and concomitant antibiotic administration.17,19 CISN has also been reported in isolated cases of antithrombin III deficiency46 and benign monoclonal gammopathy with associated DIC. 47
Homozygous Protein C Deficiency Skin necrosis is one of the primary manifestations of homozygous PC deficiency. 1 8 , 3 2 - 3 4 Although the clinical presentation is distinct from CISN, the cutaneous and histopathologic features are identical. Homozygous PC deficiency is a rare hereditary disorder that typically presents with DIC and purpura fulminans in the first few hours of life. Cutaneous lesions are characteristically the initial clinical manifestation and are most frequently described as ecchymoses when first noted.48 The extent and severity of skin involvement is variable. Almost any site can be involved. A symmetrical distribution of dermal necrosis is common. Skin biopsies reveal the same histopathologic features found with CISN, namely, bland fibrin thrombi within dermal vessels associated with perivascular hemorrhage.33 Direct immunofluorescent staining in a single case revealed a faint linear deposition of IgM and C3 at the dermoepidermal junction and faint vascular deposition of IgM. 33 In contrast to the cutaneous manifestations of CISN, the development of skin necrosis in homozygous PC deficiency is associated with DIC. Widespread venous thrombosis involving multiple organ systems may be present in a certain percentage of individuals with homozygous PC deficiency.49
Disseminated Intravascular Coagulation DIC is a dynamic process triggered by activation of the clotting system resulting in microvascular thrombosis, activation of the fibrinolytic system, and a consumptive coagulopathy. The clinical manifestations are a result of thrombosis, hemorrhage, or both. 24,50,51 Cutaneous manifestations are common in DIC. In up to 47% of patients, skin lesions represent the initial sign of this
disorder.50 The cutaneous manifestations of DIC include petechiae, purpura, palpable purpura, ecchymoses, hemorrhagic bullae, purpura fulminans, acral cyanosis, and gangrene.38 As in homozygous PC deficiency, microthrombi are not limited to the skin and are typically found in at least one other organ system.24 Skin biopsy is a valuable diagnostic tool to aid in the prompt recognition of DIC and hence implementation of therapy. In the initial stages of vascular occlusion due to DIC, skin biopsies from hemorrhagic lesions consistently reveal dermal microthrombi with extravasation of formed blood elements.24 No vasculitis is present in DIC-induced dermal vascular thrombosis. The hemorrhagic lesion may progress to frank skin necrosis. Symmetrical peripheral gangrene is an unusual, but distinct manifestation of DIC. 38,52 It is most commonly seen when DIC is related to an underlying infection, particularly group B Streptococcus, Staphylococcus, or meningococcus. Initially, the distal regions of the extremities (sometimes including the ear lobes, genitalia, and tip of the nose) become ischemic. This is characterized clinically by mottled cyanosis, pain, and edema. The lesions may progress rapidly to gangrenous necrosis. The skin biopsy reveals fibrin thrombi in the dermal vasculature with no evidence of vasculitis or arterial thrombosis.38,52 Symmetrical peripheral gangrene may be associated with other purpuric lesions or may exist independently.
Antiphospholipid Antibodies Antiphospholipid antibodies are a family of commonly encountered acquired antibodies associated with a significantly increased risk for recurrent venous or arterial thromboses.53,54 This family of antibodies includes both anticardiolipin antibodies and the lupus anticoagulant.55-57 These antibodies occur in association with a variety of clinical conditions, including autoimmune disorders, certain drug therapies, infectious disease, malignancies, and may arise in apparently normal individuals.53 Relatively little is known regarding the pathophysiology of thrombosis in patients with the antiphospholipid antibodies. A number of investigators have demonstrated dysfunctions in the PC anticoagulant system.58-61 A favored mechanism is antiphospholipid antibody-induced inhibition of thrombomodulin and impaired activation of PC. 61 Cutaneous manifestations associated with antiphospholipid antibodies include leg ulcers, livedo reticularis, distal cutaneous ischemia, and diffuse skin necrosis.40,41,62 In the two reported cases of skin necrosis associated with antiphospholipid antibodies, dermal vascular thrombosis without vasculitis has been described.42,63
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IDIOPATHIC PURPURA FULMINANS AND PURPURA FULMINANS ASSOCIATED WITH ACUTE INFECTION Idiopathic purpura fulminans is an uncommon entity characterized by progressive dermal vascular thrombosis and hemorrhagic skin necrosis associated with DIC in an individual who does not have an acute infection or a history of an acquired or hereditary hypercoagulable state. 5,7,64,65 Although adults may have this type of purpura fulminans, it is usually a disease of children, which is preceded by an unremarkable bacterial or viral infection. Idiopathic purpura fulminans is characterized by the sudden onset of chills and fever followed by dermal erythema and cyanosis, which progresses rapidly to hemorrhagic skin necrosis within 24 to 48 hours.3,7 Without interventional treatment, frank gangrenous necrosis develops. The lesions are most typically present on the thighs, legs, buttocks, and lower abdomen. In the male, the genitalia may be involved. The distal extremities are usually spared. Of particular interest is the absence of microthrombi involving other organ systems.5,7 The histopathologic features show diffuse dermal vasculature thrombosis similar to that seen in CISN, DIC, and hereditary homozygous PC or PS deficiency.3,5,65 Direct immunofluorescent studies performed in one case of idiopathic purpura were negative for IgG, IgM, IgA, C3, and fibrinogen.5 This disorder is also associated with the laboratory manifestations of DIC. Despite the absence of an acute infection, fever and leukocytosis with increased immature forms may be present. Acute infectious purpura fulminans is a rare disorder characterized by purpuric ecchymoses with progression to gangrenous necrosis, fever, profound hypotension, peripheral hypoperfusion, and DIC. 5,66 In contrast to idiopathic purpura fulminans, this type of purpura fulminans is associated with a severe acute bacterial or viral infection. It is usually a disease of young children but may be seen in adults on occasion. The organisms most commonly associated with this type of purpura fulminans include meningococci, gram-negative bacilli, staphylococci, streptococci, and rickettsia. 29-31,66,68 Acute infectious purpura fulminans presents with the signs and symptoms of sepsis. Concurrently, purpuric lesions develop most commonly over the distal aspect of the lower extremities and tend to be symmetrical. These lesions progress rapidly to hemorrhagic necrosis. Proximal extension of the lesions from the lower extremities or diffuse patchy involvement of the upper extremities and abdomen may occur. Rarely are lesions present on the chest or head. Thrombosis and hemorrhagic necrosis are also common in other organ systems, including the lungs, kidneys, and adrenal glands. The histopathology
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is essentially identical to the other forms of dermal vascular thrombosis except that a neutrophilic vasculitis is typically present. 29,30,66,67 In both idiopathic and acute infectious purpura fulminans, cultures of skin lesions are characteristically negative, although colonization with pseudomonal and streptococcal organisms may occur with time.
SKIN NECROSIS ASSOCIATED WITH HEPARIN THERAPY Heparin-induced skin necrosis was first described as a complication of heparin therapy in 1973.69 It is now a well-recognized, potential side effect associated with this medication. Since 1973, over 30 cases of heparininduced skin necrosis have been reported.70-72 The incidence of this complication is approximately 0.6% in patients receiving heparin therapy.71 This unusual side effect has been more frequently associated with subcutaneous heparin therapy but may occur with systemic therapy as well. Necrosis of the skin occurs most commonly at the site of subcutaneous heparin injection. When associated with intravenous therapy, there appears to be a predilection for areas rich in subcutaneous tissue.71 Skin necrosis represents a hypersensitivity reaction to heparin therapy.71,73 Skin lesions typically appear 6 to 14 days following initiation of heparin therapy. If patients have been previously exposed to heparin, skin necrosis may develop earlier. Thrombocytopenia is associated with the development of skin necrosis in some but not all patients.73 Heparin-associated skin necrosis may be a subset of the more frequently recognized syndrome of heparin-associated thrombocytopenia and thrombosis (HATT).73,74 There are a number of similarities between these two complications of heparin therapy. Both heparin-associated skin necrosis and HATT appear to represent hypersensitivity to heparin, may be associated with abnormal in vitro platelet aggregation in the presence of heparin, are associated with paradoxical thrombosis, and require cessation of heparin therapy for clinical improvement.71-74 In both situations, the thrombosis is thought to be due to heparin-associated antibodies that induce intravascular platelet aggregation.71'73 No specific risk factors have been identified that predispose an individual to heparin-associated thrombocytopenia and thrombosis, except previous exposure to heparin. In one patient studied, PC, PS, and antithrombin III levels were normal at the time of appearance of skin necrosis.70 Early recognition of thrombocytopenia in patients receiving heparin may alert the physician to the potential for thromboembolic complications.
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Skin biopsies from the affected areas show extensive necrosis with microthrombi present in the dermal vasculature.71,73 Vasculitis and perivascular inflammation are characteristically lacking in these biopsies.
MISCELLANEOUS CLINICAL CONDITIONS PNH is a rare form of hemolytic anemia associated with a generalized thrombotic tendency. Skin lesions are an uncommon manifestation of this disorder.75 The most common skin lesions reported are petechiae, ecchymoses, and leg ulcerations. Skin necrosis, similar to that seen in CISN, has been reported in two patients.76,77 In one case, the skin lesions developed shortly after the patient began antibiotic therapy (ampicillin and clindamycin) for acute abdominal symptoms. Skin biopsy in this case confirmed dermal vascular thrombosis and erythrocyte extravasation without vasculitis. This patient had no clinical evidence of renal or central nervous system disease, which is associated with a diagnosis of TTP. In addition, there was no evidence of DIC to otherwise explain the microvascular thrombosis. TTP is an uncommon disorder associated with widespread microvascular occlusions resulting in peripheral platelet consumption. The major manifestations include purpura, microangiopathic hemolytic anemia, fluctuating neurologic signs, renal impairment, and fever.78 TTP may be associated with the development of petechiae and ecchymoses. It is rarely associated with hemorrhagic skin necrosis and gangrene.79 Skin biopsies reveal microvascular thrombosis, composed largely of platelets, characterized histologically by amorphous, eosinophilic PAS-positive intravascular material.79,80 Characteristically, there is no associated vasculitis or perivascular inflammation. Electron microscopic examination reveals that the microthrombi are composed largely of platelets with small amounts of fibrin.80 Erythrocytes and leukocytes may also be trapped within the thrombi. Cryoglobulinemia may be associated with occlusion of the superficial dermal vasculature and has a histologic appearance similar to that previously described.15,81 Specifically, the dermal vessels may contain fibrinoid and hyalinized material.15 This intravascular material is PAS-positive and consists of precipitated cryoglobulin. A mild perivascular infiltrate may be present; however, there is no associated vasculitis. The clinical picture is typically that of livedo and ulceration usually involving the distal extremities. Gangrene is a rare clinical complication. Most patients have an underlying lymphoproliferative disorder associated with the production of a monoclonal protein.
SUMMARY Dermal vascular skin necrosis is associated with a complex group of clinical disorders. Many of these disorders are associated with an underlying abnormality of the PC anticoagulant system or DIC, or both. The clinical appearance and histopathologic features of dermal vascular skin necrosis are similar regardless of the etiology. Acute infectious purpura fulminans is distinct in that an acute vasculitis may be present in addition to microvascular thrombosis. Skin biopsy is a valuable diagnostic tool in the early recognition of these clinical disorders, since skin involvement is frequently an early manifestation of the disease process. Prompt recognition and institution of appropriate therapy at the reversible stages of dermal vascular thrombosis will, it is hoped, reduce the morbidity and mortality currently associated with skin necrosis and purpura fulminans.
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40. Lie JT: Recurrent thromboembolism, disseminated intravascular coagulation, and coumarin-induced skin necrosis associated with protein C deficiency. Pathol Res Pract 183:308-313, 1988. 41. Grob JJ, JJ Bonerandi: Cutaneous manifestations associated with the presence of the lupus anticoagulant. J Am Acad Dermatol 15:211-219, 1986. 42. Bork K: Cutaneous Side Effects of Drugs. WB Saunders, Philadelphia 1988, pp 222-225. 43. Hislop IG, PJ Zilko, M Peterson, N Ahmed: Dermal necrosis following coumarin: Is it immunologically induced? Aust NZ J Med 10:51-53, 1980. 44. Jones RR, J Cunningham: Warfarin skin necrosis: The role of factor VII. Br J Dermatol 100:561-565, 1979. 45. Franson TR, HD Rose, MR Spivey, J Maroney, JA Libnoch: Late-onset, warfarin-caused necrosis occurring in a patient with infectious mononucleosis. Arch Dermatol 120:927-931, 1984. 46. Kiehl R, P Hellstern, E Wenzel: Hereditary antithrombin III deficiency and atypical localization of coumarin necrosis. Thromb Res 45:191-193, 1987. 47. Friedenberg WR, M West, DJ Miech, SS Mazza: Atypical purpura fulminans with benign monoclonal gammopathy. Arch Dermatol 114:578-580, 1978. 48. Pegelow CH, R Curless, B Bradford: Severe protein C deficiency in the newborn. Am J Pediatr Hematol/Oncol 10:326-329, 1988. 49. Tarras S, C Gadia, L Meister, E Roldan, JB Gregorios: Homozygous protein C deficiency in the newborn: Clinicopathologic correlation. Arch Neurol 45:214-216, 1988. 50. Robboy SJ, MC Mihm, RW Colman, JD Minna: The skin in disseminated intravascular coagulation. Br J Dermatol 88:221— 229, 1973. 51. Colman RW, JN Minna, SJ Robboy: Disseminated intravascular coagulation: A dermatologic disease. Int J Dermatol 16:47-51, 1977. 52. Rahal JJ, HE MacMahon, L Weinstein: Thrombocytopenia and symmetrical peripheral gangrene associated with staphylococcal and streptococcal bacteremia. Ann Intern Med 69:35—43, 1968. 53. Triplett DA, JT Brandt, KA Musgrave, GA Orr: The relationship between lupus anticoagulants and antibodies to phospholipids. JAMA 259:550-554, 1988. 54. Asheron RA, EN Harris: Anticardiolipin antibodies—clinical associations. Postgrad Med J 62:1081-1087, 1986. 55. Sontheimer RD: The anticardiolipin syndrome. Arch Dermatol 123:590-594, 1987. 56. McNeil HP, CN Chesterman, SA Krillis: Binding specificity of lupus anticoagulants and anticardiolipin antibodies. Thromb Res 52:609-619, 1988. 57. Walker TS, DA Triplett, N Javed, K Musgrave: Evaluation of lupus anticoagulants: Antiphospholipid antibodies, endothelium associated immunoglobulin, endothelial prostacyclin secretion, and antigenic protein S. Thromb Res 51:267-281, 1988. 58. Cariou R, G Tobelem, C Soria, J Caen: Inhibition of protein C activation by endothelial cells in the presence of lupus anticoagulant. N Engl J Med 314:1193-1194, 1986. 59. Freyssinet JM, ML Wiessel, J Gauchy, B Boneu, JP Cazenave: An IgM anticoagulant that neutralizes the enhancing effect of phospholipid on purified endothelial thrombomodulin activity—a mechanism for thrombosis. Thromb Haemost 55:309-313, 1986. 60. Cariou R, G Tobelem, S Belluci, J Soria, C Soria, J Maclouf, J Caen: Effect of lupus anticoagulant on thrombogenic properties of endothelial cells—inhibition of thrombomodulin-dependent protein C activation. Thromb Haemost 60:54-58, 1988. 61. Freyssinet JM, JP Cazenave: Lupus-like anticoagulants, modulation of the protein C pathway and thrombosis. Thromb Haemost 58:679-681, 1987.
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62. Dodd HJ, I Sarkany, D O'Shaugnessy: Widespread cutaneous necrosis associated with the lupus anticoagulant. Clin Exp Dermatol 10:581-586, 1985. 63. Jindel BK, MFR Martin, A Gayner: Gangrene developing after minor surgery in a patient with undiagnosed systemic lupus erythematosus and lupus anticoagulant. Ann Rheum Dis 42:347349, 1983. 64. Gurses N, A Ozkan: Neonatal and childhood purpura fulminans: Review of seven cases. Cutis 41:361-363, 1988. 65. Brazilian Purpuric Fever Study Group: Brazilian purpuric fever: Epidemic purpura fulminans associated with antecedent purulent conjunctivitis. Lancet 2:757-761, 1987. 66. Hautekeete ML, ZN Berneman, R Bieger, WJ Stevens, C Bridts, N Buyssens, ME Peetermans: Purpura fulminans in pneumococcal sepsis. Arch Intern Med 146:497-499, 1986. 67. Adner MM, RE Kauf, JD Sherman: Purpura fulminans in a child with pneumococcal septicemia two years after splenectomy. Am J Dis Child 138:915-916, 1984. 68. Hill WR, TD Kinney: The cutaneous lesions in acute meningococcemia. JAMA 134:513-518, 1947. 69. O'Toole RD: Heparin: Adverse reaction. (Letter.) Ann Intern Med 79:759, 1973. 70. Stricker H, B Lämmle, M Furlan, I Sulzer: Heparin-dependent in vitro aggregation of normal platelets by plasma of a patient with heparin-induced skin necrosis. Am J Med 85:721-724, 1988. 71. Hartman AR, RM Hood, CE Anagnostopoulos: Phenomenon of heparin-induced thrombocytopenia associated with skin necrosis. J Vasc Surg 7:781-784, 1988.
72. White PW, JR Sadd, RE Nensel: Thrombotic complications of heparin therapy. Ann Surg 90:595-608, 1979. 73. Platell CF, ECG Tan: Hypersensitivity reactions to heparin: Delayed onset thrombocytopenia and necrotizing skin lesions. Aust NZJ Surg 56:621-623, 1986. 74. King DJ, JG Kelton: Heparin-associated thrombocytopenia. Ann Intern Med 100:535-540, 1984. 75. Ellenhorn MJ, LZ Feigenbaum, C Plumhof, SR Mettier: Paroxysmal nocturnal hemoglobinuria with chronic hemolytic anemia. Arch Intern Med 87:868-878, 1951. 76. Rietschel RL, CW Lewis, RA Simmons, RL Phyliky: Skin lesions in paroxysmal nocturnal hemoglobinuria. Arch Dermatol 114:560— 563, 1978. 77. Hansen NE, SA Killman: Paroxysmal nocturnal hemoglobinuria: A clinical study. Acta Med Scand 184:525-541, 1968. 78. Ridolfi RL, WR Bell: Thrombotic thrombocytopenic purpura: Report of 25 cases and review of the literature. Medicine (Baltimore) 60:413-429, 1981. 79. Luttgens WF: Skin necrosis in a patient with thrombotic thrombocytopenic purpura. Ann Intern Med 46:1200—1213, 1957. 80. Feldman JD, MR Mardiney, ER Unanue, H Cutting. The vascular pathology of thrombotic thrombocytopenic purpura. An immunohistochemical and ultrastructural study. Lab Invest 15:927-946, 1966. 81. Pinkus H, AH Mehregan: A Guide to Dermatopathology, Appleton-Century-Crofts, New York, 1981, p 180.
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