Antiphospholipid syndrome

The clinical manifestations of antiphospholipid antibody syndrome (APLAS) are protean. Pulmonary manifestations are often thromboembolic in origin; ARDS and pulmonary hypertension have been reported as features of a widespread vasculopathy associated with systemic lupus or Sjogren's syndrome. This is the report of a woman with primary APLAS who died of a noninflammatory pulmonary vasculopathy. The case is unusual in its pulmonary manifestations, its initial response to corticosteroids and antithrombotic medications, its failure to stabilize with high-intensity warfarin sodium and aspirin treatment, and finally its fulminant progression despite multiple interventions.

Key words: antiphospholipid antibodies; case report; corticosteroids; pulmonary manifestations

Abbreviations: APLAS = antiphospholipid antibody syndrome; aCL = anticardiolipin; INR = international normalized ratio; SLE = systemic lupus erythematosus

The antiphospholipid antibody syndrome (APLAS) is associated with both venous and arterial thrombosis and can occur both as a primary disorder or in association with systemic diseases such as systemic lupus erythematosus (SLE) or Sjogren's syndrome. The antiphospholipid antibodies are a heterogeneous group with antigenic specificities directed against a variety of plasma proteins and proteins expressed on the surface of platelets or vascular endothelial cells. Many thrombogenic mechanisms have been proposed; the most consistent data involve inhibition of the protein C pathway.[1] Clinically, most thrombotic events are either venous with thromboemboli emanating from the deep leg veins or arterial with thromboemboli occurring in the carotid or peripheral arterial vessels.[2] Other than pulmonary emboli, pulmonary manifestations are rare. ARDS has been reported as a feature of the widespread noninflammatory vasculopathy in APLAS associated with SLE or Sjogren's syndrome.[3,4] This is a case of a woman with primary APLAS in whom a disease suggesting ARDS developed. The patient, however, died of refractory in situ pulmonary thrombosis despite multiple interventions.

Case Report

A 59-year-old woman had hypertension, type IV hyperlipidemia, and hereditary spherocytosis. A diagnosis was first made of APLAS in 1990 when painful livedo developed after an elective aorto-bifemoral bypass graft procedure. Follow-up angiography showed graft patency; anticardiolipin (aCL) IgG antibody level was measured at 304 (normal, [is less than]15). Initially, she was treated with aspirin; however, moderate intensity warfarin sodium was added the following year when ischemic symptoms accelerated in the left foot.

In December 1992, while receiving therapy with aspirin and warfarin (international normalized ratio [INR], 2.0 to 2.5), she presented with cough, fever, and dyspnea. Her course was characterized by rapidly progressive pulmonary infiltrates and profound hypoxemia consistent with ARDS. Despite bacteriologic and virologic studies, no cause was ascertained; she was treated empirically with broad-spectrum antibiotics, steroids, inotropic and ventilator support. Attempts to obtain tissue specimens for a more accurate diagnosis were not undertaken because of severe problems with oxygenation. Her recovery was protracted. The dosage of prednisone was eventually tapered over 2 months to 7.5 mg/d. Low-dose aspirin and moderate-intensity warfarin therapy were continued. However, 3 months later, she had recurrent fever, cough, dyspnea, and lung infiltrates. She refused open-lung biopsy, but lavage and transbronchial biopsy were performed. The material for review was limited; there was no evidence of vasculitis or infection. There was nonspecific inflammation of the pulmonary parenchyma with an occasional intra-arteriolar clot. Direct immunofluorescence of lung tissue was negative. Routine serologic studies of double-stranded DNA, extractable nuclear antigen, add total serum hemolytic complement were within normal limits. She was treated with intravenous methylprednisolone, 40 mg q6h, with rapid resolution of symptoms and infiltrates. The dosage of prednisone was tapered to 25 to 30 mg/d. Despite the moderate dose of steroids, she again developed cough and dyspnea. This time open-lung biopsy was done and disclosed two major features: chronic thromboembolic arteriopathy (consistent with underlying APLAS) and an acute and chronic interstitial pneumonitis and pleuritis (Figs 1-2). Another immunofluorescence stain and serologic tests for underlying connective tissue disease were negative. Warfarin dose was increased to maintain INR [is greater than]3.

Over the next several months, her exercise tolerance deteriorated, and cough recurred despite an increase of prednisone to 40 mg/d and administration of low-dose aspirin and high-intensity warfarin. The National Institutes of Health reviewed the histologic findings of the lung and the clinical course. With the suggestion of chronic interstitial pneumonitis and the possibility of a coexisting, but as yet undiagnosed, collagen vascular disease, a trial of cyclophosphamide was recommended. Despite three cyclophosphamide infusions at 0.5 g/[m.sup.2], her disease progressed. The side effects of prednisone became intolerable (disabling proximal myopathy and a painful compression fracture). Therapy with cyclophosphamide and warfarin was discontinued, and treatment with azathioprine and adjusted subcutaneous unfractionated heparin, 20,000 units bid, was begun. Aspirin treatment was continued and the mid-dose partial thromboplastin time was maintained at 90 to 110 s. Unfortunately, despite these interventions, she continued to deteriorate with progressive dyspnea and poor functional status. Finally, in December of 1993, 3 1/2 years after the initial diagnosis of APLAS and 1 year after the first episode suggestive of ARDS, she was again hospitalized with recurrent fever, pulmonary infiltrates, and mental status changes. Despite administration of high-dose steroids, aspirin, adjusted subcutaneous heparin, and azathioprine, the patient died on the 19th hospital day.

Significant postmortem pathologic findings were extensive pulmonary infarction with thrombi in alveolar capillary lumens. There was moderate interstitial fibrosis with organizing alveolar hemorrhage. There was no evidence of either valvular heart disease or intramural thrombus in the right atrial or ventricular appendages, nor was there evidence of another source for embolic disease.

Discussion

The clinical spectrum of thrombosis in the APLAS is broad, but what is so unusual about this case is the clinical presentation of ARDS with pulmonary vasculopathy. The first report of ARDS associated with APLAS was reported presented with multiple organ disease including ARDS, which occurred in the setting of serologic profiles consistent with Sjogren's syndrome. Lung biopsies were not done and both patients recovered. A third case of ARDS in a patient with SLE reported characteristic features of diffuse alveolar damage on autopsy.[4] This patient demonstrated consistently negative serologic findings and presented time and again with recurrent progressive pulmonary infiltrates without evidence of recurrent livedo or other organ involvement. The pathologic and autopsy specimens confirmed extensive thrombosis and a noninflammatory vasculopathy.

Pulmonary hypertension and thrombotic vasculopathy associated with APLAS have been reported in the literature.[5,6] One patient had underlying SLE with severe pulmonary hypertension and died despite aggressive treatment with multiple interventions. Another patient, with primary pulmonary hypertension and no serologic evidence of SLE, died of massive thrombotic occlusion of the right pulmonary artery which was associated with a primary arteriopathy and elevated titers of aCL antibodies.[6] However, this patient's course was complicated by heparin-induced thrombocytopenia, and the patient died early in the course of the illness. The patient reported here died of refractory thrombotic pulmonary, disease but after a 1-year illness and multiple interventions, including treatment with aspirin and high-intensity warfarin.

For years, there as been no consensus about the duration or extent of antithrombotic treatments in this disorder. In 1995, Khamashta et al[7] concluded in their review of 147 patients with APLAS and a history of thrombosis that long-term anticoagulation with warfarin to maintain an INR [is greater than]3 was desirable. Interestingly, even with high-intensity warfarin and antiplatelet therapy the patient reported here demonstrated multiple exacerbations of cough and dyspnea during steroid tapering and improvement in oxygenation and radiographic infiltrates after moderate doses of prednisone at ranges of 60 to 80 mg/d. However, the role of steroids in the management of this disorder remains undefined. Some groups[8,9] recommend prednisone and aspirin during pregnancy for recurrent miscarriages. It is thought that steroids generally suppress the immune response and can be associated with a reduction in the aCL antibody titer. In the 6 months before she died, this patient demonstrated a persistent reduction in the aCL IgG antibody titer to a level of 27; however, symptoms recurred even in this setting.

There has been one case of recurrent thromboemboli from a right ventricular thrombus treated with steroids and high-intensity warfarin.[10] Unfortunately in this patient, therapy with moderate-dose steroids was associated with unacceptable side effects, and alternative treatment options were explored. Some authors have altogether abandoned the use of immunosuppressives to treat patients with this disorder.[11] Cyclophosphamide and azathioprine therapy was initiated in this case in the hope of decreasing her steroid requirements as well as for the remote possibility of treating an undiagnosed primary collagen vascular disease.

Finally, as stated previously, there have been cases of thrombus of the right side of the heart and recurrent pulmonary thromboembolism secondary to APLAS published in the literature.[10,12] These cases were managed differently: one patient was treated with thrombolytic therapy and subsequently warfarin and the other, with high-intensity warfarin and steroids. However, our patient had multiple echocardiograms during her last year of life; none showed evidence of right atrial or ventricular thrombus formation. The absence of thrombi of the right side of the heart was ultimately confirmed at autopsy.

In summary, this is the report of a case of a woman with high titers of aCL IgG antibody who presented with refractory pulmonary thrombosis and who died despite multiple interventions. As far as is known, this appears to be the first case of a patient with primary APLAS who developed clinical features of ARDS responding initially to steroid therapy but with a lung biopsy specimen demonstrating a diffuse arteriopathy and postmortem findings of massive in situ pulmonary thrombosis with infarction despite high-intensity warfarin and aspirin therapy.

References

[1] Roubey RAS. Immunology of the antiphospholipid antibody syndrome. Arthritis Rheum 1996; 39:1444-54

[2] Rosove MH, Brewer PMC. Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients. Ann Intern Med 1992; 117:303-08

[3] Ingram SB, Goodnight SH, Bennett RM. An unusual syndrome of devastating noninflammatory vasculopathy associated with anticardiolipin antibodies: report of two cases. Arthritis Rheum 1987; 30:1167-72

[4] Kennedy M, Jackson J, Khan I, et al. Catastrophic antiphospholipid syndrome in the abscence of IgG anticardiolipin antibodies. Scand J Rheumatol 1995; 24:389-92

[5] Koike T, Tsutsumi A. Pulmonary hypertension and the antiphospholipid syndrome [editorial]. Intern Med 1995; 34:938

[6] Luchi ME, Asherson RA, Lahita RG. Primary idiopathic pulmonary hypertension complicated by pulmonary arterial thrombosis: association with antiphospholipid antibodies. Arthritis Rheum 1992; 35:700-05

[7] Khamashta MA, Cuadrado MJ, Mujic F, et al. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995; 332:993-97

[8] Eisenberg GM. Antiphospholipid syndrome: the reality and implications. Hosp Pract (Off Ed) i992: 27:77-87

[9] Bick RL, Baker WF. Anticardiolipin antibodies and thrombosis. Hematol Oncol Clin North Am 1992; 6:1287-99

[10] O'Hickey, Skinner C, Beattie J. Life-threatening right ventricular thrombosis in association with phospholipid antibodies. Br Heart Journal 1993; 70:279-81

[11] Lockshin MD. Answers to the antiphospholipid-antibody syndrome? N Engl J Med 1995; 332:1025-27

[12] Ryan J, Lasorda D, Spero J, et al. Thrombolysis of right atrial thrombus with pulmonary embolism in anticardiolipin antibody syndrome. Am Heart Journal 1995; 130:905-07

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