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We describe a patient with antiphospholipid antibody syndrome (APS) who died because of relentless inferior vena cava (IVC) tumor thrombosis due to an unsuspected leiomyosarcoma. Laboratory confirmation for APS was provided by functional identification of a lupus anticoagulant and anticardiolipin IgG and anti-β2-glycoprotein I IgM antibodies. Although sensitive for detecting vascular obstruction, radiocontrast venography and magnetic resonance imaging and angiography detected the IVC thrombosis but failed to distinguish its malignant nature. Concomitant refractory thrombocytopenia prevented further invasive diagnostic and therapeutic maneuvers for progressive, severe IVC thrombosis unresponsive to aggressive treatment of APS. Deep venous thrombosis refractory to anticoagulant and immunomodulatory therapies in a patient with APS may be due to a concomitant underlying malignancy, such as a leiomyosarcoma, causing vascular obstruction.
The diagnosis of the syndrome is based on these clinical manifestations plus the presence of antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies, or anti-β2-glycoprotein antibodies).
We describe a patient with APS who died because of relentless inferior vena cava (IVC) thromboembolism with a concomitant rare cause of malignant vascular obstruction.
REPORT OF A CASE
A 52-year-old woman was admitted to the Saint Louis University Hospital in June 2000 for epistaxis. One month before admission, she was diagnosed as having APS after developing deep venous thrombosis (DVT) of the right leg and was treated with warfarin to achieve international normalized ratio (INR) values of 2.5 or higher. At that time, her serum anticardiolipin IgG level was elevated, whereas the activated partial thromboplastin time, anticardiolipin IgM, and anticardiolipin IgA values were within the reference range (Table 1). A screen for abnormalities in antithrombin III, protein C, and protein S activity and factor V Leiden mutation was negative. Two weeks before admission, the patient developed abdominal pain, weight gain, and a decreased urinary output. Her abdominal pain was described as a generalized bloated sensation associated with anorexia, early satiety, and vomiting of almost everything she ate, including broth and gelatin, and relieved partially by frequent soft bowel movements (2-4 times per day). On the day of admission, she developed unprovoked epistaxis, described as noticing small quantities of blood on tissues, associated with elevated INR (>12.0) and creatinine (8.5 mg/dL) levels. She was admitted for management of nosebleed, reversal of anticoagulation, and evaluation of acute renal insufficiency. Other medical problems included hypertension, gout, type 2 diabetes mellitus, obesity, and colonic polyps. Family history was unremarkable. She denied using alcohol, tobacco, or other recreational drugs. Her medications were warfarin, allopurinol, tramadol, lisinopril, metformin, atenolol, and triamterene/hydrochlorthiazide combination.
Table 1Effect of Multiple Immunomodulatory Therapies
Therapies included systemic corticosteroids, cyclophosphamide, plasmapheresis, and intravenous immunoglobulin. APL = IgA antiphospholipid units; GPL = IgG antiphospholipid units; MPL = IgM antiphospholipid units; SAU = standard IgA units; SGU = standard IgG units; SMU = standard IgM units.
on the Patient's Antiphospholipid Autoantibody Panel
* Therapies included systemic corticosteroids, cyclophosphamide, plasmapheresis, and intravenous immunoglobulin. APL = IgA antiphospholipid units; GPL = IgG antiphospholipid units; MPL = IgM antiphospholipid units; SAU = standard IgA units; SGU = standard IgG units; SMU = standard IgM units.
† Ellipses indicate data not obtained at that time.
Physical findings revealed an alert and oriented obese woman (weight, 112 kg) in no apparent distress with abrasions on her trunk and abdomen from scratching due to xerosis, a grade 2/6 precordial systolic murmur, mild epigastric tenderness, and pitting edema of the lower extremities. Her epistaxis had resolved spontaneously by the time of admission. Initial laboratory tests revealed anemia (hemoglobin, 10.4 g/dL), leukocytosis (white blood cell count, 13,000), acute renal failure (azotemia [blood urea nitrogen, 114 mg/dL; creatinine, 8.3 mg/dL]), hyponatremia (sodium, 131 mmol/L), hyperkalemia (potassium, 5.6 mmol/L), and metabolic acidosis (bicarbonate, 17 mEq/L). Urinalysis showed trace proteinuria but no hematuria or pyuria. Although the patient's platelet count was normal (371×109/L), her activated partial thromboplastin time and INR were both markedly elevated at 132 seconds and more than 12.8, respectively; hence, warfarin was discontinued. The fibrinogen level was high at 960 mg/dL, but the fibrin monomer and the D-dimer levels were within the reference range. A hepatic panel showed low total protein (5.5 g/dL) and albumin (2.3 g/dL) levels, as well as elevated alkaline phosphatase (191 U/L) and aspartate aminotransferase (73 U/L) levels. Total bilirubin, alanine aminotransferase, amylase, and lipase levels were within the reference range. She had antibodies to the hepatitis C virus. Findings on initial chest radiography were normal.
To evaluate the cause of the patient's renal insufficiency, ultrasonography of the kidneys was performed; it showed mild elevation of the resistive indices consistent with renal parenchymal disease but failed to visualize the renal veins. Contrast venography was performed in the presence of acute renal failure to assess further the possibility of renal vein thrombosis as the cause of impaired renal perfusion and with the intention of using interventional techniques (ie, catheter-directed thrombolysis) if indicated. Venography revealed complete thrombosis of the infra- hepatic IVC with collateral veins draining the lower extremities. Magnetic resonance imaging and angiography (MRI/MRA) was performed subsequently for better delineation of the extent of IVC thrombosis. Abdominal MRI/MRA confirmed thrombosis of the IVC and right and left renal veins (Figure 1).
With the knowledge of the extent of IVC thrombosis and the concomitant development of dyspnea and worsening hypoxemia (alveolar-arterial gradient, 34 mm Hg), a ventilation-perfusion scan was ordered to determine whether subclinical pulmonary embolism had occurred. Although chest radiography at this time showed patchy right lower lobe infiltrates, the scan showed nonperfusion of the right lower lobe and other matched ventilationperfusion defects greater than the chest radiographic findings and was consistent with an intermediate probability for pulmonary embolism. Therapeutic anticoagulation with intravenous heparin and oral warfarin was reinstituted to prevent further propagation of the thrombus, based on recommended guidelines.
On the 12th day of heparin administration, the patient's platelet count decreased below 100×109/L. Heparin was discontinued, and lepirudin was substituted. A functional assay for the lupus anticoagulant was positive, and a repeated autoantibody panel showed elevated anticardiolipin IgG and anti-β2-glycoprotein I IgM antibody levels (Table 1). The antiplatelet antibodies, both heparin and non- heparin associated, were negative on repeated testing. Two days later, danaparoid was substituted for lepirudin to allow for improved monitoring of anticoagulant effect in the presence of lupus anticoagulant, and the dose was adjusted to achieve therapeutic factor Xa levels.
Repeated MRI/MRA at this time showed worsening of the IVC thrombosis, with extension to the right atrium, hepatic vein, and iliac veins. Catheter-directed thrombolysis was requested but could not be performed because of the perceived inability to cannulate the completely obstructed IVC and the profound thrombocytopenia. Surgical thrombectomy was considered but deferred because of the unacceptable operative risks due to the patient's refractory coagulopathy and obesity as well as the extent of cardiovascular involvement with thrombus. Cyclophosphamide, methylprednisolone, and plasmapheresis followed by intravenous immunoglobulin were administered for worsening thrombocytopenia and thrombosis and resulted in normalization of the antiphospholipid antibody values (Table 1). However, the patient's platelet counts remained depressed. A follow-up MRI/MRA done on the 31st hospital day showed no substantial change in the IVC thrombosis.
On the 36th hospital day, the patient developed sudden severe hypotension suggestive of obstructive shock, which was thought clinically to be secondary to massive throm- boembolism. Thrombolysis with systemic reteplase was immediately performed, but the patient remained in shock. The patient died after cardiopulmonary support (mechanical ventilation and vasopressors) was withdrawn the following day.
Autopsy confirmed the extensive IVC tumor necrosis and thrombosis involving the right femoral vein, right external iliac vein, right common iliac vein, renal veins, hepatic vein, and superior vena cava (Figure 2). Microscopic examination of the thrombus revealed a leiomyosarcoma arising from the vena cava wall and extending into the perivascular soft tissue. Additionally, a small hemorrhagic nodule in the left upper lobe showed a tumor metastasis.
To our knowledge, this is the first reported case of fatal IVC tumor thrombosis due to 2 concomitant conditions associated with hypercoagulability: leiomyosarcoma of the IVC and APS. Leiomyosarcoma of the IVC is a rare cause of tumor thrombosis of this major vein and its tributaries. An international registry was established by Mingoli et al
in 1992 to study the pathogenesis, natural history, and most rational treatment of IVC leiomyosarcoma. The tumor is commonly diagnosed in the mid-fifth decade of life and has an 80% female sex predilection.
luminal involvement occurred in 27%, whereas the IVC remained patent in 58% of the subjects as determined by IVC venography and computed tomography, which were used to detect vascular involvement with the tumor. Along the length of the IVC, the origin of the tumor is distributed as follows: 37% in the lower segment, 44% in the middle segment, and 20% in the upper segment.
Although our patient had no palpable abdominal mass or weight loss, she had a luminally occluding tumor extending from the right femoral vein cephalad into the right atrium that resulted in abdominal pain, lower limb swelling, and Budd-Chiari syndrome, all findings associated with increased mortality.
Nonsurgical management (eg, chemotherapy, hormonal manipulation, radiotherapy) and even nonresective surgical procedures (eg, thrombectomy of the IVC or right atrium) are universally associated with a fatal outcome.
Surgical therapeutic alternatives may involve only palliative resection or radical surgical resection ranging from simple caval wall resection with direct suture or patch to segmental caval wall resection with or without reconstruction and resection of adjacent organs.
Radical resection combined with adjuvant chemotherapy is associated with a high rate of recurrence (54% within a median of 25 months), but it is the only chance for cure, with a 5- and 10-year survival rate of approximately 50% and 30%, respectively.
The detection of a lupus anticoagulant, anticardiolipin IgG, and anti-β2-glycoprotein I IgM antibodies substantially affected the clinical course and outcome of the patient's malignancy. She developed severe refractory thrombocytopenia while receiving heparin, precluding any surgical diagnostic and therapeutic interventions (ie, thrombectomy and/or tumor resection) that could have improved outcome. Antiplatelet antibodies, both heparin and non-heparin associated, were not detected in our patient and may not be detectable in up to 1 of 4 patients with antiphospholipid antibodies and suspected heparin-induced thrombocytopenia.
Paradoxically, both APS-related thrombocytopenia and heparin-induced thrombocytopenia (as well as thrombotic thrombocytopenic purpura) are associated with increased risk of thrombosis. Therapies that have been used for APS-related thrombocytopenia, albeit with unproven success, include corticosteroids,
In our patient, immunomodulation with systemic corticosteroids, cyclophosphamide, plasmapheresis, and intravenous immunoglobulin, although effective in eliminating the lupus anticoagulant, anticardiolipin IgG, and anti-β2-glycoprotein I IgM antibodies (Table 1), did not result in any improvement of the platelet count. Accordingly, a plausible explanation for the refractory throm- bocytopenia is the continued platelet consumption precipitated by the tumor via the extrinsic coagulation pathway. Although heparin-platelet factor 4-induced antibodies can be found in up to 21% of patients with APS, whether APS increases the risk of heparin-induced thrombocytopenia is unknown.
Screening a patient with DVT for occult malignancy is indicated if the disease is recurrent, if it arises in a patient who is therapeutically anticoagulated, or if no other hypercoagulable conditions are found. Accordingly, our patient was not screened for malignancy because she had APS with high titers of multiple autoantibodies and venography and MRI/MRA results that were not suggestive of a malignant process. Multiple appropriate aggressive therapies for autoantibodies and thromboembolism were instituted. Moreover, diagnosis during earlier stages of the malignancy was not feasible because of unacceptable surgical risks; if the diagnosis had been made, it would have allowed surgical resection and/or adjuvant radiotherapy or chemotherapy for palliation and improvement of survival. The IVC thrombosis continued to propagate, and surgical intervention with thrombectomy to relieve the extensive vascular obstruction (which could conceivably have helped diagnose the tumor) was considered but not undertaken in view of the severe refractory thrombocytopenia. In retrospect, the failure of the IVC thrombosis to respond to therapeutic anticoagulation should have served as a clue, alerting the clinicians of the underlying leiomyosarcoma. However, it is unlikely that merely suspecting this diagnosis would have convinced the surgeon to consider the high-risk surgical option or would have altered the course of the patient's illness. Hence, in the setting of a previously known hypercoagulable state, persistent DVT unresponsive to maximal therapies potentially may be considered an indication for the evaluation of an occult malignancy, including an IVC leiomyosarcoma.
A rare cause of extensive thrombosis of the IVC and its tributaries is a leiomyosarcoma. Although MRI/MRA can be helpful in detecting the obstructive vascular process, it cannot distinguish its malignant nature. The combination of a leiomyosarcoma of the IVC and APS with associated thrombocytopenia refractory to intensive immunomodulatory therapy proved especially challenging because it precluded further invasive evaluation for malignancy. Deep venous thrombosis refractory to anticoagulant and immunomodulatory therapies in a patient with APS may be due to a concomitant underlying malignancy, such as a leiomyosarcoma, that causes vascular obstruction.
Pathogenesis and treatment of the antiphospholipid antibody syndrome.