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2240 Part XII: Hemostasis and Thrombosis Chapter 131: The Antiphospholipid Syndrome 2241

CUTANEOUS MANIFESTATIONS majority of patients with CAPS (see “Catastrophic Antiphospholipid
The cutaneous manifestations of APS may comprise the first signs of Syndrome” above) have dyspnea, and most of these individuals have
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APS in some patients. 198,199 Livedo reticularis is relatively common, ARDS.
occurring in 24 percent of a series of 1000 aPL patients, and occa-
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sionally presents in a necrosing form. Noninflammatory vascular ABDOMINAL MANIFESTATIONS
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thrombosis is the most frequent histopathologic feature. Necrotizing
vasculitis, livedoid vasculitis, thrombophlebitis, cutaneous ulceration The liver is the most frequently affected abdominal organ in APS, with
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and necrosis, erythematous macules, purpura, ecchymoses, painful skin occlusion of hepatic vessels, including those supplying the biliary tree.
nodules, and subungual splinter hemorrhages, anetoderma (macular aPL antibody levels frequently are elevated in patients with chronic liver
atrophy), discoid lupus erythematosus, and cutaneous T-cell lymphoma disease of various causes. In one prospective study of patients with liver
have all been reported. disease, approximately half of patients with alcoholic liver disease and
one-third of patients with chronic hepatitis C virus had elevated aPL
antibody levels. The frequency was even higher in patients with more
CORONARY ARTERY DISEASE severe cirrhosis. A review reported that approximately 20 percent of
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aPL antibodies are associated with increased susceptibility to coro- patients with chronic hepatitis B and hepatitis C had aPL antibodies,
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nary artery disease, particularly premature atherosclerosis. 203,204 APS most of which were cofactor independent. Some patients with hepati-
should be considered in patients who lack the usual risk factors for tis C present with true autoimmune aPL antibodies, the most common
coronary artery disease and in patients with evidence for thrombotic features reported being intraabdominal thrombosis and myocardial
or embolic coronary artery occlusion that lack angiographic evidence infarction. 222
of atherosclerotic disease. aPL antibodies appear to be a risk factor Reported gastrointestinal manifestations of APS also include
for adverse outcomes following all coronary revascularization proce- esophageal necrosis with perforation, intestinal ischemia and infarc-
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dures, and for restenosis after percutaneous transluminal coronary tion, pancreatitis, and colonic ulceration. Primary biliary cirrhosis,
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angioplasty. 205,206 An ultrasound study of carotid arteries provided evi- acute acalculous cholecystitis with gallbladder necrosis, 224,225 and giant
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dence supporting an association of aPL antibodies with premature ath- gastric ulceration are associated with APS. APS has been reported in
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erosclerosis; relatively young primary APS patients (mean age: 37 ± 11 patients with mesenteric inflammatory venoocclusive disease and in
years) had significantly increased intimal medial thickness compared to patients with mesenteric and portal venous obstruction. 228
control non-APS groups. 207
THROMBOCYTOPENIA
VALVULAR HEART DISEASE Approximately 20 to 40 percent of patients with APS have varying
Approximately 35 percent of patients with primary APS have cardiac degrees of thrombocytopenia. The decrease in platelet count is gener-
valvular abnormalities detected by echocardiography. In one study, ally mild or moderate and is rarely significant enough to cause bleed-
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approximately 20 percent of cardiac patients with valvular heart dis- ing complications or affect anticoagulant therapy. 229,230 The majority
ease had evidence for aPL antibodies compared with approximately of patients with APS and thrombocytopenia have antibodies against
10 percent of matched control subjects. Valvulopathy includes leaf- α β integrin and/or glycoprotein Ib-IX complex. Patients present-
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IIb 3
let thickening, vegetations, regurgitation, and stenosis. The mitral ing with immune thrombocytopenic purpura frequently have elevated
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valve is mainly affected, followed by the aortic valve. Histologically, aPL antibodies, and these patients are more prone to thrombosis.
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APS valvular lesions consist mainly of superficial or intravalvular fibrin aPL antibodies and antibodies against platelet membrane glycoprotein
deposits in association with variable degrees of vascular proliferation, were present simultaneously in approximately 70 percent of patients
fibroblast influx, fibrosis, and calcification. These can result in valve with immune-mediated thrombocytopenia. Thrombocytopenia itself
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thickening, fusion, and rigidity, and lead to functional abnormalities. is not protective against thrombosis in these patients. In a prospec-
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Deposits of immunoglobulins, including aCL antibodies, and of com- tive cohort study, 5-year thrombosis-free survival of aPL-positive and
plement components are commonly found in the affected valves. 213 aPL-negative immune thrombocytopenic purpura patients were 39 per-
cent and 98 percent, respectively. 234
PERIPHERAL VASCULAR DISEASE
Approximately one-third of patients with peripheral arterial disease BLEEDING
undergoing bypass grafting procedures had elevated aPL antibody lev- The presence of a concurrent hemostasis defect needs to be con-
els (mostly aCL antibodies). Intraarterial thromboembolic events are sidered when patients with APS exhibit a bleeding tendency (Table
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common at presentation of these patients and may complicate surgical 131–5). Acquired hypoprothrombinemia with severe bleeding has
management. However, these patients did not have an increased risk for been reported. 235,236 This diagnosis may be missed when coagulation
reocclusion, a finding that was attributable to the use of anticoagulant abnormalities are attributed only to the LA effect, so a specific assay
therapy.
PULMONARY MANIFESTATIONS TABLE 131–5. Causes of Bleeding in Antiphospholipid
Patients with APS may present with in situ thrombosis in pulmonary Syndrome
vessels. aPL antibodies are associated with pulmonary hypertension. • Hypoprothrombinemia
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In one prospective trial of 38 consecutive patients with precapillary • Thrombocytopenia
pulmonary hypertension, approximately 30 percent had aPL antibod- • Acquired platelet function abnormality
ies with various phospholipid specificities. An interinstitutional study • Acquired inhibitor to specific coagulation factor, e.g., factor VIII
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of 687 patients with chronic thromboembolic pulmonary hyperten-
sion reported that aPL antibodies were a significant risk factor. The • Acquired von Willebrand syndrome
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