Vascular disorders associated with thrombohemorrhagic phenomena.

VASCULAR DISORDERS ASSOCIATED WITH THROMBOHEMORRHAGIC PHENOMENA

There are three integral components of hemostasis, and each has been recognized as an entity of varying importance depending upon the era in which it was discovered, degree of research into the particular component, and interest from a clinical standpoint. The three recognized components of hemostasis consist of (a) the blood protein system, including the coagulation proteins, the fibrinolytic enzyme system, the complement system, the kinin system and associated inhibitors, (b) the platelet compartment with its complex biochemistry and physiology, and (c) the vasculature. The early investigations in hemostasis were concerned primarily with the coagulation proteins and then with the fibrinolytic system. Only later was the platelet component of hemostasis subjected to intense investigation. This has led to a remarkable expansion of knowledge in the last several decades. The vasculature remains one of the more poorly understood components of hemostasis. All three of these components of hemostasis are completely interrelated, and the current issues of Seminars will deal in depth with the interrelationships between the endothelium and platelets with the intent of pointing out the role of the endothelium as a component of hemostasis — i.e., the vascular tree as one of the three important hemostatic compartments. This paper will summarize briefly those vascular disorders which may present as thrombohemorrhagic phenomena. An attempt will be made to characterize the clinical features of these vascular defects, with emphasis on the thrombotic or hemorrhagic manifestations. The pathophysiology will be highlighted where it is known. This synoptic approach to vascular disorders is designed to increase one's clinical awareness of these entities, thereby enhancing diagnostic accuracy and effective management. Acquired vascular defects are now diagnosed with increasing frequency. Nevertheless, even when a patient with a known vascular defect is subjected to stress such as trauma or surgery, hemorrhagic and/or thrombotic complications may ensue. The formidable diagnostic and management aspects of a patient with an unrecognized vascular disorder who sustains trauma or surgery and develops hemorrhagic or thrombotic problems is immediately apparent. Such unfortunate cases may end disastrously.

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Rodger L. Bick, M.D.

From the San Joaquin Hemostasis Thrombosis Laboratory, San Joaquin Community Hospital; San Joaquin Hematology Oncology Medical Group, Bakersfield, Center for the Health Sciences, Los Angeles, Calif

Seminars in Thrombosis and Hemostasis — Vol. V. No. 3 (Winter) 1979

Calif.; and UCLA

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The types of hereditary and acquired vascular disorders are highly varied; thus, it is not surprising that the clinical manifestations of vascular disorders may also vary greatly. It cannot be overstressed that in order to evaluate the vasculature, a thorough examination of the skin is important in a hemostasis work-up. One will usually find defects in the integument of patients with hereditary or acquired vascular disorders — although, as stated, the findings may be highly varied, depending upon the type of disorder being dealt with. Again, the importance of a careful examination of the integument cannot be overemphasized. Usually, however, the findings are not diagnostic but only suggestive. The few exceptions to this are hereditary hemorrhagic telangiectasia, where one will note the classic nonpulsatile pinpoint, nodular, or spider-like telangiectasia, giant cavernous hemangiomata, scleroderma, and Behcet's syndrome. The rest of the vascular disorders usually have nondiagnostic features. The most common clinical findings of a vascular disorder, although in many instances they must be searched for carefully, are petechiae and purpura, which are usually, but not always, dependent. Platelet function defects and thrombocytopenia, on the other hand, usually present as petechiae and purpura throughout the integumentary system and are usually not necessarily dependent. Additional common findings in the vascular disorders are a history of gingival bleeding with toothbrushing, a history of epistaxis, a history of easy and, more importantly, spontaneous bruisability and a history of other mucosal membrane bleeding, usually from the genitourinary or gastrointestinal tract. Although these are the most common and most easily recognized findings in patients who have hereditary or acquired vascular defects, there are other less subtle findings which may also be noted. One must always recall that what is noted in the integument may be potentially occurring in the parenchyma of vital organs as well in patients with generalized vascular disorders. Findings in the integument, which again may be assumed to be occurring in the parenchyma of vital organs as well, depend upon two factors: (a) the host reaction to the insult and/or disease, and (b) the severity of the vascular insult or damage. The host reaction to vascular insult or vascular disorder is obviously the product of numerous, including many as yet unknown, interrelationships, especially with respect to the coagulation proteins, fibrinolytic enzyme system, complement system, kinin generation, and cellular response, including the migration of leukocytes and response of the immediate normal perivascular cellular elements. The severity of the insult in combination with the host reaction will determine the amount of vascular permeability, with the usual attendant manifestations of increased vascular permeability and/or the development and degree of intravascular thrombosis. A mild insult to the vasculature usually results only in a mild increase in vascular permeability with effusion of serum; this in turn gives rise to the usual wheals of urticaria,


CLINICAL MANIFESTATIONS

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bullae, and some purpura. A moderate insult to the vasculature, in contrast, will usually give rise to effusion of serum as well as blood, with attendant activation of coagulation and resultant microthrombi with petechiae and purpura being found. A more severe insult will give rise to significantly increased vascular permeability, resulting in endothelial death, surrounding tissue damage and death, local large or small vessel thrombosis, and various degrees of end organ ischemia, damage, and death, and may result in diffuse disseminated intravascular coagulation and all of its attendant signs and symptoms. The particular manifestations of the moderate to severe vascular insults will depend somewhat upon the degree of leukocyte migration and release of clot-promoting as well as clotlysing enzymes. When many leukocytes migrate into the area, the usual manifestations of painful, erythematous vasculitis as depicted above will result. Alternatively, few leukocytes are usually found when the vascular insult slowly progresses to occlusive thrombosis with all of its usual associated findings, such as skin necrosis, ulceration, and various degrees of end organ damage in vital organs. Table 1 summarizes pathogenetic mechanisms. The laboratory diagnosis of a vascular disorder is often quite taxing and commonly requires an autoimmune investigation, connective tissue biopsy, and specific immunofluorescense staining technics as well as an investigation of the kinin system. The most common abnormal laboratory features of vascular disorders are the following screening tests: an abnormal Rumpel-Leede tourniquet test, abnormal template bleeding time, an abnormal aspirin tolerance test if a template bleeding time is borderline, and the demonstration of normal platelet function by adhesion and/or aggregation studies. The finding of an abnormal template bleeding time and abnormal aspirin tolerance test in the face of normal platelet function studies and in the absence of thrombocytopenia is strongly suggestive of a TABLE 1. Determinants of Clinical Manifestations A. Host Response to Vascular Disorder 1. Antigenic Response 2. Activation of Coagulation 3. Activation of Fibrino(geno)lysis 4. Activation of Kinins 5. Activation of Complement 6. Activation of Other Enzymes 7. Migration of Leukocytes B. Severity of Vascular Insult/Disorder 1. Mild (a) Serum effusion: bullae and erythema 2. Moderate: serum and blood effusion (a) Bullae, erythema, wheals (b) Petechiae and purpura 3. Severe (a) Effusion of blood and endothelial death (b) Petechiae and purpura (c) Gross hemorrhage (d) Small and/or large vessel thrombosis


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HEREDITARY VASCULAR DISORDERS

The following are the most common hereditary vascular (or collagenvascular) disorders which may present as thrombotic, hemorrhagic, or mixed disorders of hemostasis and thrombosis: A. Ehlers-Danlos Syndrome (ED Syndrome)

The ED syndrome is a rare connective tissue disorder which is inherited by autosomal dominance [32]. Interestingly, one of the earliest descriptions of this syndrome may have concerned the violin virtuoso Paganini, in that this disorder was thought to contribute to his remarkable dexterity and talent. The ED syndrome is characterized by extreme vascular fragility, skin fragility, hypermobile joints and molluscoid pseudotumors of the knees and elbows. Bleeding may be highly variable; however, easy and spontaneous bruisability is a hallmark of this syndrome. Patients commonly suffer gingival bleeding with tooth brushing and have undue bleeding after dental extraction. Also, petechiae, purpura, gastrointestinal bleeding, and hemoptysis are often present. The bleeding diathesis may be severe enough to suggest hemophilia. In addition, numerous patients were found to have platelet function defects as well as the characteristic vascular defects [54]. Other characteristics commonly noted in this syndrome are blue sclerae and angioid streaks. In addition, aortic insufficiency and the "floppy" mitral valve syndrome often occur. The common laboratory findings are a positive Rumpel-Leede tourniquet test, prolonged template bleeding times, and in many instances abnormal platelet aggregation and/or adhesion if the patient has an associated platelet function defect. The basic pathology of the ED syndrome is poorly understood but appears to represent a decrease in collagen and an increase in elastic tissue. In addition, the collagen from these patients is thought to contain an abnormal amino acid composition [51]. B. Marfan's Syndrome

This syndrome is well described and is the most popularized of the hereditary collagen vascular disorders. It is inherited as an autosomal


vascular disorder, and it is these tools which are relied upon most heavilv as screening technics to demonstrate the presence of a vascular, rather than a platelet function defect [5]. The more specific findings of the numerous hereditary and acquired vascular disorders are outside the scope of this article and can be found in several authoritative reviews [14,56]. Vascular disorders may be divided into two categories: hereditary and acquired. The acquired types are a much more common and a more frequent cause of hemorrhage when a patient is stressed by trauma or surgery.


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dominant trait and is characterized by skeletal defects (marked by long extremities and arachnodactyly), cardiovascular abnormalities (ascending aortic aneurysm and/or dissection) and ocular defects, primarily manifest as ectopia lentis [1,20]. In addition, hyperextensible joints are present. Of all the hereditary collagen vascular disorders, Marfan's syndrome is least characterized clinically by a hemorrhagic diathesis. However, many patients have easy and spontaneous bruisability, and some may demonstrate a poorly characterized platelet function defect as well.

Osteogenesis imperfecta is also one of the more common hereditary collagen vascular disorders and is inherited as an autosomal dominant trait. The disorder is characterized by a patchy lack of bone matrix. However, the matrix which does exist undergoes normal calcification. Osteogenesis imperfecta is clinically manifest as deformed and brittle bones which fracture easily. In addition, skin and subcutaneous hemorrhages are characteristic [1]. Death commonly occurs at childhood, due to intracranial hemorrhage caused by an abnormal calvarium coupled with a vascular hemorrhagic diathesis. Easy and spontaneous bruisability, hemopytis, epistaxis, and intracranial bleeding are common in osteogenesis imperfecta. An abnormal template bleeding time and a positive Rumpel-Leede tourniquet test are characteristic [59]. In addition, many cases have been described with abnormal platelet function as defined by adhesion and aggregation studies. The basic pathophysiology of osteogenesis imperfecta appears to be related to the inability of reticulin to mature into collagen. In addition, the collagen present demonstrates an abnormal amino acid composition. D. Pseudoxanthoma Elasticum (PE Syndrome) Pseudoxanthoma elasticum, unlike the other hereditary vascular diseases, often does not become manifest until the second or third decade in life [52]. This very rare disorder is inherited as an autosomal recessive trait. The PE syndrome is commonly characterized by significant hemorrhage since abnormal elastic fibers affect the entire arterial system. Hemorrhage can occur in any organ, most commonly the skin, eyes, kidneys, and gastrointestinal tract. In addition, these patients have a marked tendency to easy and spontaneous bruisability and commonly are noted to have petechiae and purpura. In addition, these individuals have a marked predisposition to thrombosis, especially cerebral vascular thrombosis, acute myocardial infarction, and peripheral vascular occlusion with resultant gangrene and loss of extremities. Other clinical characteristics include relaxed, inelastic, and redundant skin in facial, neck, axillary, orbital, and inguinal areas. Hyperkeratotic plaques develop in these areas and subcutaneous calcinosis is also common. Death is frequently caused by gastrointestinal hemorrhage. Excessive uterine bleeding and intra-articular bleeding with formation of characteristic hemarthroses are common. The


C. Osteogenesis Imperfecta (Brittle Bones and Blue Sclerae)

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basic vascular pathology of this disorder is poorly understood but thought to be due to metabolic (enzyme) defects in elastic fibers.

This rare hereditary collagen vascular defect bears a superficial resemblance to Marfan's syndrome, as these individuals usually have long limbs, kyphoscoliosis, and classic thoracic deformities. Their joints are restricted, however, rather than manifest as increases in mobility. Homocystinuria is inherited as an autosomal recessive trait. Elevated levels of methionine and homocystine demonstrated in the urine are usually diagnostic. This disorder is most likely due to a specific enzyme deficiency, and successful treatment has sometimes been rendered with a low methionine and high cystine diet. Arterial and venous thromboses are common, as is gastrointestinal hemorrhage. However, therapy aimed at controlling vascular thrombosis has been relatively unsuccessful. F. Giant Cavernous Hemangiomata and the Kasabach-Merritt Syndrome Giant cavernous hemangiomata are tumorous masses of dialated thinwalled vessels and sinuses lined by an abnormal endothelium. These masses are usually engorged with venous blood which may be in a semistatic state. These giant hemangiomata are commonly found in the skin and subcutaneous tissue. They are usually present at birth but occasionally appear later in life [23]. Also, these hemangiomatous lesions are frequently multiple, widespread, and may involve any organ or group of organ systems. Recurrent acute thromboses may occur especially if there is significant involvement of a particular extremity. All are familiar with the development of disseminated intravascular coagulation in many of these patients, the so-called Kasabach-Merritt syndrome [27,31]. The vast majority of patients with giant cavernous hemangiomata will usually manifest findings of chronic disseminated intravascular coagulation, which not uncommonly becomes acute, explosive DIC. Several mechanisms for the development of chronic or acute disseminated intravascular coagulation in patients with giant cavernous hemangiomata have been proposed, including blood stasis with initiation of the contact activation phase of coagulation as well as abnormal endothelium contacting the blood and perhaps resulting in not only contact phase activation but also the initiation of a platelet release reaction. These patients are extremely difficult to manage once they have developed either chronic or acute disseminated intravascular coagulation, but they often respond to heparin or mini-heparin therapy. After control of this syndrome, radiation therapy or surgery may be considered to remove these giant hemangiomatous masses. However, if surgery is performed before the disseminated intravascular coagulation process has been successfully controlled, the bleeding consequences are often disastrous.


E. Homocystinuria


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Hereditary hemorrhagic telangiectasia (HHT) is a relatively common disorder and, in fact, is the most common hereditary vascular disorder leading to a hemorrhagic diathesis [25,45,46]. The disorder is inherited as autosomal dominant but only 70% of individuals have a positive family history. The homozygous state is thought to be lethal [26]. In addition, there is evidence that the gene responsible for HHT is somehow linked to blood group 0 . The hallmark characteristic of this disease is epistaxis, which may be profuse and usually begins in early childhood. The classic telangiectatic lesions of HHT may not appear until later in life, commonly the second or third decade. The classic diagnostic triad of HHT is: (a) a hereditary basis, (b) telangiectasia, and (c) bleeding from telangiectatic lesions. Chronic blood loss, commonly from the GI tract, is often severe enough to be manifest as a significant iron deficiency anemia of unknown etiology. The telangiectatic lesions of HHT can be of three types: pinpoint, nodular and spider-like [47]. Unlike telangiectasia associated with chronic liver disease, those of HHT are nonpulsatile. Telangiectasia and bleeding usually increase with advancing age, although epistaxis often decreases with age. The bleeding of HHT may be occult, but common causes of gastrointestinal hemorrhage, genitourinary hemorrhage, hemoptysis, or heavy menstrual flow. Approximately 20% of patients develop A-V fistulae of the lungs [29]. In addition, there is an inordinately high incidence of Laennec's type cirrhosis occurring in these patients. Hepatomata of the liver and spleen may also be associated with HHT [16]. The basic pathophysiology of this disorder is poorly understood. Most studies have shown that elastic fibers are missing from the vascular walls. There are few characteristic laboratory findings in HHT. The tourniquet test and template bleeding time may be normal or abnormal, depending upon the integrity of the vascular wall in the particular area where the test is performed. The diagnosis is suggested by a history of recurrent epistaxis, occult gastrointestinal bleeding, and the noting of pinpoint, nodular, and/or spider-like telangiectasia, most commonly found in the skin, in sublingual areas, or in the buccal mucosa. HHT appears to be closely associated with other defects in hemostasis. Abnormal platelet function has been noted in many patients with HHT [6, 53]. In addition, a poorly defined defect in the fibrinolytic system may occur in these patients [38,57]. Of major importance, and previously unrecognized, is that many patients with HHT have an associated classic disseminated intravascular coagulation type syndrome. This is usually present in a chronic form but periodically may become acute. This is found in approximately 40 to 50% of patients with HHT, if searched for [7]. In some individuals, bleeding may be bad enough that spontaneous intra-articular bleeds with resultant hemarthroses may develop. Thus, HHT may be somewhat similar to the syndrome of giant cavernous hemangiomata and disseminated intravascular coagulation and hence a syndrome of a "mini-


G. Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Disease)

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Kasabach-Merritt syndrome" is present in many of these individuals although, as mentioned above, this is usually not recognized. When this occurs, treatment should be aimed at acute or chronic disseminated intravascular coagulation. Therapy of uncomplicated HHT depends upon the particular clinical situation and the age of the patient. Localized epistaxis can often be controlled with local supportive measures and vasocontrictive nasal sprays. However, electrocauterization may become necessary. Most instances of troublesome bleeding in HHT, such as gingival bleeding with toothbrushing, spontaneous bruising, and gastrointestinal/genitourinary bleeding, can often be controlled with Adrenosem [63]. This agent is usually used as 5-10 mg orally every three to four hours during waking hours and is without significant toxicity. High dose estrogens may be used to scarify telangiectatic lesions and control bleeding. However, this modality should be used as a last resort, especially in younger patients [34]. Specific therapy for significant bleeding associated with congenital vascular defects, other than HHT, is generally not satisfactory and depends primarily upon supportive measures and control of the underlying disease process. The hereditary collagen vascular disorders are depicted in Table 2.

TABLE 2. Hereditary Vascular (Collagen-Vascular) Diseases Presenting as or Complicated by Thrombohemorrhagic Defects A. Ehlers-Danlos Syndrome B. Marfan's Syndrome C. Osteogenesis Imperfecta D. Pseudoxanthoma Elasticum E. Homocystinuria F. Giant Cavernous Hemangiomata (and associated Kasabach-Merritt Syndrome) G. Hereditary Hemorrhagic Telangiectasia (and associated "mini-Kasabach-Merritt Syndrome")

ACQUIRED VASCULAR DISORDERS The acquired vascular disorders which may be complicated by, or give rise to, a thrombotic or hemorrhagic tendency are far more common than the hereditary disorders previously discussed. It is especially in these acquired disorders that careful attention must be paid to the patient who has a known diagnosis of one of the disorders depicted below so that one can be alerted to the potential of significant hemorrhage and/or thrombosis if trauma or surgery occurs. In addition, it is of paramount importance to consider the possibility of these disorders in the differential diagnosis of a patient who presents with vascular type bleeding (as outlined in the first part of this article) and in considering the differential diagnosis of the classic signs and symptoms of bleeding due to a defect in the vascular compartment.


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The numerous thrombotic and/or hemorrhagic tendencies in patients with malignant paraprotein disorders and amyloidosis, be they primary or secondary, are well recognized. In addition, these disorders especially can present with a wide spectrum of hemorrhagic and/or thrombotic tendencies, depending upon host response, size and site of the vasculature involved, and response of the particular end organ. There have been numerous proposed mechanisms for the vascular complications of these disorders and only the salient features of most of these mechanisms will be presented here. A detailed discussion is beyond the range of the intent of this article. Firstly, it has been proposed that increased circulating levels of IgG and IgM, which are complement fixing, thus leading to histamine release, chemotaxis of leukocytes, and platelet aggregation and lysis lead to increased vascular permeability, serum and/or blood effusion, and in some instances small vein thrombosis. Hyperviscosity in the malignant paraprotein disorders is a well known cause of stasis with resultant ischemia and acidosis. This will lead to increased vascular permeability, the consequences of which are retinal hemorrhage and exudates, epistaxis, and petechiae and purpura of the skin as well as hemorrhage into other organs. Frank necrotizing vasculitis may occur via unclear mechanisms in the malignant paraprotein disorders as well. Obviously, the clinical manifestation, whether it be thrombosis and/or hemorrhage, will depend upon the site and severity of the necrotizing vasculitis. When the malignant paraprotein disorders are associated with cryoglobulinemia (IgG and IgM paraprotein disorders), paraprotein is commonly found in the walls of the small vessels, which may lead to a frank vasculitis; again, the clinical manifestations obviously range from effusions, bullae, petechiae, purpura, or frank end organ damage (especially glomerulonephritis) to ischemia, cellular death and end organ damage. In all of the malignant paraprotein disorders there is a high incidence of thrombosis as well, especially manifest as diffuse recurrent deep vein thrombosis [36], thromboembolism, pulmonary emboli, and renal vein thrombosis. The mechanisms leading to this remain unclear but need not be related to the development of hyperviscosity except in cases of retinal vein thrombosis [60]. Also, disseminated intravascular coagulation is often seen in patients with malignant paraprotein disorders. Whether this is due to endothelial damage by the paraproteins or by other unexplained mechanisms remains unclear. In addition, the fibrino(geno)lysis which occurs in many individuals with malignant paraprotein disorders is initiated via as yet undefined mechanisms. This may represent fibrinolysis secondary to disseminated intravascular coagulation, secondary to endothelial damage or alternatively may be due to deranged endothelial plasminogen activator activity [8]. Amyloidosis further complicates the vascular changes of malignant paraprotein disorders, and thus leads to an increased incidence of hemorrhage and/or thrombosis via disruptions of the vasculature. Classically, primary amyloidosis is associated with an unknown etiology or the malignant para-


A. Malignant Paraprotein Disorders and Amyloidosis

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protein disorders. It characteristically involves the skin, tongue, heart, and GI tract, while secondary amyloidosis is seen with chronic inflammatory/ infectious diseases and characteristically involves the liver, spleen, kidney, and adrenals. However, many "crossovers" and mixtures of the two are also commonly seen and, in fact, one cannot often precisely define amyloidosis as being primary or secondary. There are numerous proposed mechanisms for vasculitis in patients with primary and secondary amyloidosis but, in fact, the precise mechanisms remain unclear. Hemorrhage due to a vascular defect is a classic hallmark of primary amyloidosis, especially petechiae, purpura, ecchymoses, easy and spontaneous bruisability, along with spontaneous hemorrhage into lymph nodes, recurrent hematuria, and spontaneous hemorrhage into other vital organs. Several proposed pathophysiologic events leading to a generalized vasculitis have included circulating antigen-antibody complexes, induced endothelial damage or deposits of amyloid on the endothelium as well as in the perivascular areas [61]. Endothelial and perivascular amyloid deposits seem to be more commonly noted in the secondary forms, especially in arterioles. This thus leads to a hemorrhagic as well as a thrombotic tendency. In secondary amyloidosis amyloid deposits are noted along the endothelium, and intimal deposits are noted to start in the intima and to progress to the media, with the amyloid being deposited in parallel with reticulum fibers rather than around the collagen fibers, as more commonly seen in primary amyloidosis. In addition, in primary amyloidosis the deposits are usually seen along the collagen with progression from the adventitia to the media of arterioles and veins. The same process appears to occur in veins, thus supposedly accounting for the thrombotic tendencies seen in these individuals. In some patients with systemic amyloidosis, a selective, acquired Factor X deficiency has been reported [19,21,22,30,35,39]. In two patients similarly afflicted, an acquired, combined deficiency of Factors IX and X was noted [39]. Furie et al. [19] investigated the mechanism of Factor X deficiency in such cases by use of 131 I-labeled Factor X. They discovered a triphasic plasma clearance pattern such that 85% of the labeled Factor X cleared in less than 30 seconds, about 10% in less than 90 minutes, and the remaining 5% was absent in 10½ hours. Subsequent surface scanning of the patients 24 hours after the labeled infusion showed high concentrations in hepatic and splenic regions. This observation, coupled with the rapid clearance of the label on initial transit in the circulation, led these investigators to conclude that the Factor X is deposited in some cases of systemic amyloidosis at prior tissue sites of amyloid. At first glance, it may seem that these cases should respond to therapeutic infusions with Factor II, VII, IX, and X concentrates. However, Krause [35] has reported only a transient correction by such preparations of Factor X-deficient cases of amyloidosis. The wide variability of hemorrhagic and thrombotic manifestations in patients with paraprotein disorders and amyloidosis will depend upon the particular end organ involved, the degree of vessel permeability, and/or occlusion.


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B. Autoimmune Disorders Associated with Thrombohemorrhagic Phenomena

Immunologic diseases associated with circulating immune complexes, especially those associated with circulating cryoglobulins, are of paramount importance as disorders associated with a diffuse vasculitis and thus thrombosis and/or hemorrhage. At least three potential (proposed) mechanisms by which circulating immune complexes, circulating cryoglobulins, or circulating antibodies may lead to vasculitis have been described: (1) The production of an antibody which is directed specifically against the endothelium [62]. This is probably the least common one. (2) The production of a nonspecific antibody, or immune complex which nonspecifically attacks and damages endothelium as well as other cellular systems [13]. (3) The generation of an antibody or immune complex which attaches to and damages perivascular tissues (including basement membrane), and secondarily causes endothelial damage and increased vascular permeability. The vascular response and clinical manifestations will depend upon severity, duration and degree of repetition of the endothelial or periendothelial insult and damage [37]. If the attack is mild, then increased vascular permeability, fibrin deposition, and a fibrinolytic response will occur. This will lead to minimal hemorrhage and thrombosis. If, however, the insult is persistent, then there will be excessive endothelial damage, depletion of fibrinolytic enzymes and endothelial fibrinolytic activators, increased fibrin and platelet deposition, more pronounced thrombosis and/or hemorrhage, and, as a second feature, more enhanced and perpetuated endothelial damage. In yet more severe attacks upon the endothelium or surrounding tissue by antibody, immune complex or cryoglobulins, endothelial death, sloughing, and more severe thrombosis, hemorrhage and end organ damage may occur. As mentioned above, an antibody directed specifically against the endothelium is a rare mechanism of autoimmune-induced vasculitis and is limited to the allergic purpuras (Henoch-Schonlein, etc.) and polyarteritis nodosum [62]. However, further immunologic investigations may, in the future, define other disorders in this class. The other two mechanisms of immune complex induced vasculitis are much more common and are seen in a wide variety of "autoimmune dis-


In summary, patients with malignant paraprotein disorders as well as amyloidosis may develop a diffuse vascular disease which may be manifest as hemorrhage, and/or thrombosis. A high variability of end organ damage may be seen. In dealing with this patient population it is important to recognize that they may suffer undue vascular bleeding, as well as bleeding from obvious other causes, when subjected to surgery or trauma. Alternatively, when seeing a patient with a vascular disorder presenting as hemorrhage and/or thrombosis, malignant paraprotein disorders as well as amyloidosis should be considered in the differential diagnosis. When a selective acquired Factor X deficiency in an adult is found, underlying systemic amyloidosis should be suspected.

RODGER L. BICK

orders." In many of these diseases, circulating immune complexes (IgG and IgM) attach to the endothelium, fix complement, and induce migration of leukocytes, which may disintegrate and destroy the vessel [11]. For example, all are familiar with the results of antistreptococcal antibody attaching to the glomerular endothelium or basement membrane, thus giving rise to renal vascular damage [18]. An extension of this is, of course, Goodpasture's syndrome, in which case antibody or immune complex is directed against both renal and pulmonary basement membrane with associated endothelial damage and thrombohemorrhagic manifestations. Many infectious agents are also known to be associated on more or less rare occasions with vasculitis and the attendant clinical manifestations aforementioned. These include numerous bacterial, viral, as well as mycoplasma infections. The mechanisms, where known, include the inducement of nonspecific antiendothelial antibody by the invading organism, the inducement of specific antiendothelial antibody by the invading microorganism, and the development of circulating immune complexes [49-51]. The above mechanisms are previously described Table 4 lists the most common infectious agents known to be associated with a vasculitis. In most circulating immune complex diseases the injury is nonspecific and not only the endothelium but also many other cellular systems are damaged. Diseases with circulating antibody, immune complex, or cryoglobulin-induced vasculitis are highly varied and include the collagen vascular disorders, drug reactions, serum sickness, and a large group of seemingly unrelated disorders. The author is far from an authority on autoimmune disorders, and this brief discussion serves only to point out those diseases with an autoimmune element which may be associated with endothelial damage, vasculitis, and clinical thrombosis and/or hemorrhage. Table 1 summarizes pathophysiologic mechanisms. Table 3 depicts the most common disorders which fit into this category of acquired diseases associated with endothelial damage, vasculitis and clinical thrombohemorrhagic phenomena. C. Malignant Hypertension, Eclampsia, Cushing's Disease, and Diabetes Associated with Thrombohemorrhagic Manifestations

In patients with malignant hypertension, advancing age, and diabetes mellitus, lipohyaline material is deposited in the subendothelium of arteries and arterioles. In addition, in malignant hypertension fibrinoid necrosis is an important feature. As constant unrelenting damage occurs, the vessels eventually develop increased vascular permeability with plasma seepage and fibrin deposition. This leads to thrombosis and thromboembolism, a common clinical manifestation of the above disorders [2]. The resultant downstream capillary stasis leads to the development of chronic purpura and local hyperpigmentation of the skin. The reader is referred to several authoritative reviews for the more complete pathophysiologic events in these disorders [15,33,57].


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I Collagen Vascular Diseases and Cryoglobulinemia (a) Systemic Lupus Erythematosis (b) Rheumatoid Arthritis (c) Dermatomyositis (d) Scleroderma (e) Polyarteritis Nodosa (f) Wegener's Syndrome II Drugs (penicillin) III Sjogrens Syndrome IV Glomerulonephritis (proliferative) V Malignant Hypertension VI Viruses (Epstein-Barr, CMV) VII Lymphoreticular Disorders VIII Chronic Infections (leprosy, lymphogranuloma venereum, chronic hepatitis, syphilis) IX Allergic Vasculitis (Henoch-Schonlein) X SBE

The findings in eclampsia are similar to the above, with the development of hypertension and localized intravascular coagulation (fibrin deposition) in the placental and renal microvasculature [40,55]. Some of these women develop classic findings of either chronic or acute disseminated intravascular coagulation with any and/or all of the attendant clinical manifestations of this secondary syndrome [65]. The vascular changes of Cushing's disease remain poorly defined, but they include loss of subcutaneous elastic tissues. This leads to poor endothelial support, increased vascular fragility and permeability, and the loss of elastic tissue in the vascular walls. In addition, advanced atherosclerotic changes occur in the larger vessels in these patients [17]. All clinicians are well aware of the easy and spontaneous bruising seen in most patients with Cushing's syndrome and the marked increase of thrombosis and thromboembolic disease in this patient population. Also, all should be aware that many patients with Cushing's syndrome will suffer profuse bleeding when subjected to surgery or trauma. D. Behcet's Syndrome

Behcet's syndrome is an ill defined disorder characterized by a typical triad of aphthous stomatitis, genital ulcerations and iritis [3,24]. In addition, many patients develop recurrent deep vein thromboses of ununexplained pathophysiologic origin; these usually involve large veins, the saphenous veins, calf veins, the superior vena cava, and the inferior vena cava [43]. Many of these patients develop a widespread, poorly defined arteritis [28]. Several well studied patients had fibrinoid necrosis of the arterial tree [58]. Numerous case reports have found impaired fibrinolysis, and some patients have responded to thrombolytic (fibrinolytic) therapy [10]. However, thus far the pathophysiologic mechanisms for the recurrent deep vein thrombophlebitis, arteritis, and hemorrhage, usually manifest as petechiae and purpura, have remained undefined in this disorder.


TABLE 3. Circulating Immune Complex /Circulating Cryoglobulinemic Diseases with Associated Vasculitis and Thrombohemorrhagic Phenomena

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RODGER L. BICK

Poorly understood defects in the vasculature may occur during cardiopulmonary bypass (CPB). A recently recognized syndrome of mild to moderate nonthrombocytopenic purpura, accompanied by splenomegaly and atypical lymphocytosis following CPB, has been reported [4]. In this series, purpura was benign, self-limiting, and frequently manifest only after discharge from the hospital. One patient in the series developed classic glomerulonephritis of the type often seen with allergic vasculitis. In addition, one case of fatal purpura fulminans has been reported following extracorporeal circulation for coronary artery bypass [9]. These two studies suggest that an inflammatory vasculitis may be associated with cardiopulmonary bypass; the mechanisms, however, remain totally unclear. F. Drug-Induced Vasculitis

Drug-induced vasculitis is a common occurrence in clinical medicine, and very often neglected as a cause of petechiae, purpura, skin necrosis and/or frank gangrene. There are numerous mechanisms by which drugs may induce vasculitis and most of these do not significantly differ from the mechanisms covered under circulating immune complex diseases. In many instances, however, the precise mechanisms are poorly understood. There are at least three mechanisms by which drugs can induce a vasculitis. These include the development of a specific antivessel antibody [62], the development of circulating immune complexes, in some instances associated with cryoglobulinemia [12], and, more rarely, drug-induced independent changes in vascular permeability. Those drugs which are commonly associated with vasculitis are depicted in Table 4. A particular and poorly recognized vasculitis due to warfarin anticoagulants has been reviewed and summarized by Nalbandian and co-workers [41]. This peculiar and not uncommon hemorrhagic skin vasculitis is manifest by hemorrhagic skin infarction, and in some instances has been associated with intravascular coagulation [44]. Virtually all warfarin derivatives have been incriminated: 90% of the cases have been women, and gangrene of the breast has occurred in at least 25% of cases reported in the literature. Nalbandian and co-workers have described the histologic features of this syndrome quite well, showing perivascular accumulations of inflammatory cells involving predominately the venules with extensive thrombosis of the TABLE 4. Common Drugs Causing Vasculitis Acetylsalicylic Acid Allopurinol Arsenicals Chloramphenicol Chlorthiazide Chlorpropamide Coumadin

Digoxin

Estrogens Furosemide Gold Salts Indomethacin Iodine Isoniazid Meprobamate

Methyldopa Piparazine Quinine Quinidine Reserpine Sulfonamides Tolbutamide


E. Vascular Defects Associated with Cardiopulmonary Bypass


181

draining veins with little or no involvement of arterioles [42]. Typically, the clinical picture develops 3 to 10 days after starting therapy and bears little relationship to the prothrombin time. The proposed mechanism is thought to be a direct toxic effect on the endothelium by warfarin and its derivatives. Many patients will respond to heparin therapy [42]. Table 5 summarizes the acquired vascular disorders. T A B L E 5. C o m m o n Acquired Vascular D i s o r d e r s Collagen Vascular Disorders 6. Immune Complex Diseases 7. Cushing's Syndrome 8. Allergic Purpuras 9. Myeloma and Macroglobulinemia

Diabetes Mellitus Amyloidosis Infectious agents Drug-Induced

SUMMARY This paper has attempted to summarize the more common disease entities which may be accompanied by or may lead to a disorder of hemostasis and/or thrombosis. It is to be emphasized that the vascular component of hemostasis is often overlooked by clinicians caring for individuals with disorders in hemostasis and thrombosis. It is hoped that this brief summary will alert clinicians that the vasculature is equal in importance to the coagulation protein system and to platelets in leading to a hemorrhagic or thrombotic diathesis. REFERENCES 1. 2. 3 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

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Neuroimaging of headaches associated with vascular disorders.

Evaluation of autoimmune phenomena in patients with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).

Relationship of thrombohemorrhagic complications to endothelial cell function in patients with chronic myeloproliferative disorders.

Fast epileptic discharges associated with ictal negative motor phenomena.

Psychiatric phenomena in Alzheimer's disease. IV: Disorders of behaviour.

Psychiatric phenomena in Alzheimer's disease. I: Disorders of thought content.

Clinical features of vascular disorders associated with chronic hepatitis virus infection.

Movement disorders associated with CLIPPERS.

PSYCHIATRIC DISORDERS ASSOCIATED WITH FXTAS.

Electrolyte disorders associated with cancer.

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Vascular Pathophysiology in Hearing Disorders.

Inflammasomes link vascular disease with neuroinflammation and brain disorders.

[Vascular complications associated with lumbar spinal surgery].

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Amaurosis fugax associated with congenital vascular defect.

Radiographic findings associated with vascular anomalies.

Acute cerebral vascular accident associated with hyperperfusion.

Adverse vascular effects associated with fluoxetine.

Major vascular lesions associated with orthopaedic injuries.

Infection risks associated with peripheral vascular catheters.

Genetic variants associated with sleep disorders.

Headache associated with metabolic and systemic disorders.

Psychiatric disorders associated with HIV disease.