Pelvic lipomatosis

Aortic thrombosis rarely occurs without severe atherosclerosis, aneurysm, or cardiosurgical or traumatic state. Arterial thrombosis is commonly related to an inherited and/or acquired hypercoagulable state. A 50-year-old woman presented with diffuse abdominal pain. One day after her admission, she experienced bloody stools. Computed tomography showed multiple extensive thromboses in the aorta and superior mesentery arteries. She underwent a partial jejunoileostomy and colectomy for extensive bowel infarction. Following surgery, her condition deteriorated and she died on the fourth hospital day. At autopsy, gross examination showed 2 large thrombi (7 and 8 cm in length) in the proximal and descending (thoracic) aorta, with mild atherosclerosis. A mesenteric artery thromboembolus with extensive bowel infarction was present. Postmortem laboratory studies revealed an elevated anticardiolipin immunoglobulin G antibody level. The thrombotic state in this patient was considered multifactorial secondary to acquired risk factors, including obesity, mild aortic atherosclerosis with coronary artery disease, and presence of a high titer anticardiolipin antibody.

(Arch Pathol Lab Med. 2005;129:247-250)

Aortic thromboembolism is relatively common among patients with severe aortic atherosclerosis and/or aneurysm, as well as following cardiovascular procedures and trauma.1 The distal abdominal aorta near the bifurcation is commonly involved. Extensive aortic thrombosis in the arch and thoracic portion without severe atherosclerosis is rarely reported. In one retrospective autopsy study,2 30 cases of nonatherosclerotic and nonaneurysmal aorto-arterial thrombosis during a 14-year period were identified to investigate etiology. The study concluded that nonatherosclerotic aortic thrombosis comprised a heterogeneous group of disorders, and patients who presented with abdominal ischemia or peripheral vascular disease should be investigated for hypercoagulable states and aortic disease. A recent case report3 attributed extensive arterial thrombosis of the aorta and its distal branches in a 37-year-old man to a high circulating level of lipoprotein (a). In addition, 2 cases of aortitis detected by computed tomography (CT) and magnetic resonance imaging in patients with antiphospholipid antibodies have been described. Aortitis was suggested as the possible initial pathologic process preceding aortic thrombosis, reported as a classic complication of antiphospholipid antibody syndrome.4

Based on the Vichow triad, thrombosis is caused by an imbalance among endothelium, blood flow, and coagulation. Inherited or acquired hypercoagulable states play a key role in thrombus formation in both the arterial and venous systems. Factors that cause hypercoagulability in arteries are slightly different from veins. Common factors that involve venous thromboembolism are factor V Leiden, prothrombin mutation G20210A, and deficiencies of protein C, protein S, and antithrombin. Elevated levels of C-reactive protein, homocysteine, and lipoprotein (a) are more likely to be involved with arterial thrombosis.5 Antiphospholipid antibodies are associated with both venous and arterial thromboembolic events. A recent study6 implicated the metabolic syndrome as a cause of atherothrombosis, and another study7 coupled increasing body mass index with elevated levels of coagulation factors and inhibitors of fibrinolysis. In this case report, death was due to sepsis and bowel infarction secondary to acquired risk factor for thrombosis, including obesity, mild atherosclerosis, and an elevated level of anticardiolipin antibody of immunoglobulin (Ig) G type. A laboratory investigation for hypercoagulability had not been undertaken before death, and only a limited number of tests for hypercoagulability could be performed post mortem. Anticardiolipin antibody and molecular studies were performed on serum and whole blood samples drawn during life and incorporated in the autopsy report. The finding of an elevated anticardiolipin IgG antibody level illustrates that such testing can be beneficial in an autopsy investigation.

REPORT OF A CASE

A 50-year-old woman presented to the emergency department with abdominal pain that extended from the xyphoid to the umbilicus and had lasted for 4 hours. She complained of stabbing pains, exacerbated with urination, and nausea, vomiting, urinary urgency, and loose bowel movements. There was no history of illicit drug use, alcohol abuse, or smoking. Physical examination revealed normal vital signs, but respiratory effort was decreased and shallow. Tenderness and guarding in the right lower and left lower quadrants were noted on physical examination. No costovertebral angle tenderness was elicited. Laboratory data included the following values: white blood cells, 18 000/µL with 87.3% granulocytes; hemoglobin, 15.9 g/dL; hematocrit, 47.8%; and platelets, 240000/µL. Coagulation screening test results were within reference ranges, with a prothrombin time of 10.4 seconds with an international normalized ratio of 1.1 and an activated partial prothrombin time of 25.8 seconds. An elevated blood sugar level was found, with a blood glucose level of 215 mg/dL (11.9 mmol/L). Serum electrolyte levels and liver function test results were within normal limits. Erythrocytes, protein, and bacteria were detected by microscopic examination of urinary sediment. An abdominal CT demonstrated a small focus of calcification in the left pelvic-urethral area and chronic pyelonephritis. Abdominal plain x-ray films showed no bowel obstruction or perforation. After receiving morphine and supportive treatment, the patient improved and was discharged. Two days later, she re-presented to the emergency department with increased epigastric and right upper quadrant abdominal pain. She was unable to lie down and had chills and diaphoresis. Abdominal examination revealed diffuse tenderness without rebound pain, guarding, and decreased bowel sounds. Laboratory studies again revealed leukocytosis, with a white blood cell count of 16000/µL. Subsequent abdominal x-ray films showed dilated loops of small bowel with air-fluid levels suggestive of an ileus. She was admitted to the hospital for further investigation. A CT after admission was negative for an intra-abdominal process. Technetium Tc 99m dimethylphenylmethyl-iminodiacetic acid (HIDA scan) was scheduled on hospital day 2. Maroon blood was passed per rectum during days 1 and 2, and on hospital day 3, her temperature rose to 37.86°C with a white blood cell count of 21000/µL and bandemia. Pulse was 141/min and blood pressure was 99/46 mm Hg. She was hypoxic with abdominal distention. An abdominal CT performed in the afternoon of day 3 revealed thrombi in her descending aorta and occlusion of her superior mesenteric artery (Figure 1). An immediate exploratory laparotomy was undertaken, and 254 cm of infarcted small bowel and right colon were resected. After surgery, her condition did not improve, and the patient developed mottled legs (ecchymosis). Therapy with intravenous unfractionated heparin was started. Based on her wishes, only comfort measures were instituted. She died on the fourth day of admission.

AUTOPSY FINDINGS

Postmortem examination showed a well-developed, moderately obese, white woman who weighted 119 kg and was 1.78 m tall, giving a body mass index of 38.4. A 37-cm recent surgical incision was present in the middle abdomen. Diffuse erythematous mottled areas were identified on the left leg and right thigh, and ecchymoses were present on the feet. Internal examination revealed a 500-g heart with left ventricular concentric hypertrophy and focal cardiac lipomatosis. There was focal occlusion (75%) of the proximal left anterior descending coronary artery and recent blood clots in the left atrium. No vegetations or thrombi were noted on the cardiac valves. No remote or recent myocardial infarctions were present on gross or microscopic examination. Mild aortic atherosclerosis was present, along with organized aortic thrombi: one (7.0 × 1.5 × 1.0 cm) in the first portion of the descending aorta, another (8.0 × 1.0 × 0.8 cm) at the level of the middle descending aorta (Figure 2, A), and another (0.8 × 0.6 × 0.3 cm) just before the abdominal bifurcation. A large, fresh thrombus (6.0 × 0.7 × 0.6 cm) was seen in the superior mesenteric artery. Examination of major veins revealed no antemortem clots. Lungs were diffusely congested and edematous bilaterally. The liver was 2500 g with diffuse congestion, and the gallbladder was unremarkable. Focal fatty infiltration was seen in the pancreas. A 1.5-cm cortical depression in her right kidney was associated with focal dense fibrosis. No renal or urethral calculi were found. The remaining small bowel appeared dark purple and gangrenous with yellow-green pseudo-membranous mucosa. The remaining large intestine was unremarkable. No pathologic changes were seen in the genital organs. The cause and mechanism of death was determined to be septic shock due to bowel infarction, secondary to thromboembolic disease. Because no tests for a hypercoagulable state were performed during hospitalization, a limited profile was completed as part of the postmortem examination. Whole blood specimens obtained during the patient's hospitalization and retained in the chemistry laboratory were sent for molecular studies to include factor V Leiden, prothrombin mutation G20210A, and mutation of methylene tetrahydrofolate reductase (MTHFR). No genetic mutations of prothrombin (G20210A) or factor V Leiden were found. A single copy of the mutation A1298C of the MTHFR gene was detected. Whole blood obtained at autopsy could have also been used for these studies. A serum sample, also drawn during the patient's hospitalization and retained in the chemistry department, was assayed for anticardiolipin antibodies by an enzyme-linked immunosorbent assay method (Bindazyme, The Binding Site, San Diego, Calif). An elevated titer of anticardiolipin IgG of 82 GPL units was found (reference range,

The significant postmortem microscopic findings included recent, extensive small bowel hemorrhagic infarctions (Figure 3) and aortic thrombi with foci of fibrosis, macrophage infiltration, and hemosiderin deposits (Figure 2, B and C). The mesenteric arterial emboli appeared fresh with focal organization (Figure 4). Additional findings were mild myocardial hypertrophy and focal lipomatosis (fatty dysplasia) that involved the right atrial septum and left ventricle; focal 75% arteriosclerotic occlusion of the left anterior descending coronary artery; pulmonary congestion and edema with focal consolidation and mild pleural effusion; sinusoidal congestion of the liver and fatty infiltration of the pancreas; chronic pyelonephritis; global cerebral hypoxia; and a pituitary chromphobic microadenoma (4 mm).

COMMENT

Factor V Leiden, which leads to an activated protein C resistance, is the most common inherited risk factor of venous thromboembolism.8 Prothrombin (G20210A) mutation is usually associated with venous thromboembolism but may play a role in arterial thrombosis, since the mutation in the 3'-nontranslated code region may cause an accumulation of messenger RNA and high circulating levels of prothrombin.9 MTHFR participates in regulating homocysteine metabolism, and a mutation of MTHFR may be a marker for possible elevated homocysteine levels when the serum folate level was lower than the reference range.10 High levels of homocysteine are thought to damage endothelium, producing arterial thromboses in arteries and veins. Currently, no causal role for hyperhomocystemia in venous or arterial thrombosis is yet established.11 Two common mutations involving the MTHFR gene have been identified: C667T and A1298C. A recent 772-case study demonstrated that the prevalence of the C677T and A1298C polymorphisms did not differ among individuals with coronary atherosclerosis disorders, with deep venous thromboses, or without vascular diseases.10 Finding an MTHFR mutation, therefore, is considered to be an indicator for measurement of homocysteine levels and possibly B vitamins or folic acid therapy.11 Therefore, a heterozygous mutation (A1298C) in the MHTFR gene without an accompanying fasting homocysteine level in our patient could not be evaluated as a contributor to her hypercoagulable state.

Antiphospholipid antibodies are the most common acquired blood protein defect associated with either venous or arterial thromboses. These antibodies include lupus anticoagulants, anticardiolipin antibodies, and newly recognized subgroups of antiphospholipid antibodies (eg, β^sub 2^-glycoprotein, β^sub 2^-glycoprotein-1, phosphatidylserine). Studies have shown that anticardiolipin antibodies play a major role in arterial and venous thrombosis.12 Three subtypes of anticardiolipin antibodies (IgA, IgM, and IgG) are independent risk factors for thromboses.13 Anticardiolipin antibodies interfere with hemostasis and coagulation by such mechanisms as blocking release of prostacyclin from endothelium, inactivating thrombomodulin, inhibiting the anticoagulant function of activated protein C and its co-factor protein S, and interacting with platelet membrane phospholipid, leading to activation of platelets.13 Clinically, anticardiolipin antibodies can occur in many situations, including inflammatory and infectious disorders, malignancies, immune thrombocytopenia purpura, leukemia, and medication use. The antibodies may be transient, which may or may not cause thrombotic events. However, persistence of the anticardiolipin antibodies (2 positive test results at an interval of 6 weeks or greater) is considered clinically significant. In addition, the finding of a positive anticardiolipin IgG antibody at medium or high titer on a single occasion may help identify patients at risk for thrombosis.14 The high level of anticardiolipin antibodies (>80 GPL units) in our patient should be considered an important risk factor for her aortic thromboses.

Testing for lupus anticoagulants is an additional way to detect antiphospholipid antibodies. It is less sensitive but more specific for detecting antiphospholipid antibodies than anticardiolipin antibodies. Screening tests for lupus anticoagulants are functional assays, as are the screening tests for protein C, protein S, and antithrombin, and cannot be performed on postmortem or unfrozen stored plasma. Thus, these important studies were not available for our patient.

Prothrombotic and antithrombotic balance in the body depends on an intact endothelium, normal blood flow, and balanced coagulation elements. In the described patient, the balance was disrupted by an acquired circulating anticardiolipin antibody level, obesity with occult metabolic syndrome, and other cardiovascular problems. She especially had cardiomegaly, lipomatosis in her atria and ventricles, and occlusion of her left anterior descending coronary artery, which caused an abnormal blood flow. Patients with coronary artery disease and damaged myocardium can experience decreased fibrinolytic activities and a hypercoagulable state due to increased factor VIII activity and fibrinogen levels (acute-phase reactants).15 In addition, aortic atherosclerosis, even mild, can damage an intact endothelium. In this case, moderate obesity was a potential cause of dyslipidemia, insulin resistance, and diabetes mellitus (metabolic syndrome). The patient, however, lacked primary care and had not undergone laboratory investigation for these disorders, although an elevated fasting glucose level was documented during hospitalization. Her increased body mass index and occult metabolic syndrome were acquired risk factors associated with hypercoagulability, as was her atherosclerosis, coronary artery disease, and elevated anticardiolipin antibody level, making her thrombotic tendency multifactorial. It is very likely that the anticardiolipin antibody was an initiator of the aortic-artery thromboses, which led to bowel infarction and sepsis. A high clinical index of suspicion for hypercoagulability could offer the opportunity to avoid such catastrophes. This index of suspicion can be carried over to an autopsy, and laboratory tests for a hypercoagulable state, using retained blood samples or postmortem whole blood for molecular studies, may be included as part of the postmortem examination.

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Ling Zhang, MD; Sandra Hollensead, MD; Joseph C. Parker, Jr, MD

Accepted for publication September 9, 2004.

From the Department of Pathology and Laboratory Medicine, The University Hospital of Louisville, Louisville, Ky.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Ling Zhang, MD, Department of Pathology and Laboratory Medicine, The University Hospital of Louisville, 530 S Jackson St, ULH Basement, Louisville, KY 40202 (e-mail: I0zhan05@gwise.louisville.edu).

Copyright College of American Pathologists Feb 2005
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