Primary Antiphospholipid Syndrome with Recurrent Coronary Thrombosis, Acute Pulmonary Thromboembolism and Intracerebral Hematoma
From the Department of Cardiology, Royal Hospital, Muscat, Oman.
The authors report no conflicts of interest regarding the content herein.
Manuscript submitted May 21, 2009, provisional acceptance given June 8, 2009, final version accepted June 24, 2009.
Address for correspondence: Dr. Panduranga Prashanth, Department of Cardiology, Royal Hospital, Post Box 1331, Muscat-111, Oman. E-mail: email@example.com
ABSTRACT: We present a young patient with myocardial infarction who had recurrent coronary thrombosis, in-stent thrombosis, and a major pulmonary arterial thromboembolism due to primary antiphospholipid syndrome. He also developed multiple intracerebral hematomas following anticoagulation therapy and thrombolysis. We describe this rare case of primary antiphospholipid syndrome presenting with varied arterial abnormalities along with hemorrhage and highlight the need for caution while treating them with anticoagulants and thrombolytics.
J INVASIVE CARDIOL 2009;21:E254–E258
Key words: APS, aPL, arterial thrombosis
Antiphospholipid syndrome (APS) is an autoimmune disease characterized by antiphospholipid antibodies (aPL) and at least one clinical manifestation, the most common being venous or arterial thrombosis and recurrent fetal loss. The syndrome occurs in isolation (primary antiphospholipid syndrome) or in association with connective tissue diseases (secondary antiphospholipid syndrome), particularly systemic lupus erythematosus.1 The thrombotic episodes are often multiple and repeated, but this syndrome is rarely initiated in the coronary arteries. Myocardial infarction (MI) in APS occurs in young patients and can be the first manifestation, although it is uncommon: in a cohort of 1,000 European APS patients, 2.8% initially presented with MI.2
We report a patient with MI who had recurrent coronary thrombosis and acute pulmonary thromboembolism who proved to have primary APS. He also developed multiple intracerebral haematoma following anticoagulation therapy and thrombolysis. We also review the associations between APS and the heart.
Case Presentation. A 38-year-old male non-diabetic, non-hypertensive, non-smoker with a positive family history of coronary artery disease (brother suffered a MI at 50 years of age) presented with chest pain of 2 hours’ duration and was diagnosed with inferior-wall ST-elevation myocardial infarction (STEMI) without right ventricular (RV) infarction. He was successfully thrombolysed with intravenous reteplase followed by unfractionated heparin (UFH) infusion for 48 hours. All blood investigations were normal except fasting dyslipidemia. He was treated with aspirin, clopidogrel, atenolol and simvastatin. His resting echocardiogram showed a hypokinetic inferior wall, normal valves, a normal right side, and no thrombus. His left ventricular ejection fraction (LVEF) was 45%.
After an uneventful initial follow-up period, we performed coronary angiography on the fourth day of admission, as the patient was complaining of exertional angina. His left coronary system was normal, his right coronary artery (RCA) was dominant and distally totally occluded, with thrombolysis in myocardial infarction (TIMI) 0 flow (Figure 1A), with retrograde filling of the posterior descending artery (PDA) and the posterolateral branch (PL) from the left system. He underwent balloon angioplasty to the distal RCA and was noted to have a thrombotic lesion. A bare-metal stent (BMS) 2.5 x 20 mm was implanted (Figure 1B) with restoration of TIMI 3 flow, but a few small clots were seen in the distal circulation. The patient was started on tirofiban (glycoprotein IIb/IIIa antagonist) and a UFH infusion for 24 hours followed by enoxaparin until discharge. The rest of his stay was uneventful, and he was discharged home after 5 days on dual-antiplatelet therapy.
After 1 week of hospital discharge, he was readmitted with chest pain with no significant new ischemic changes, but a rising troponin T level. His echocardiogram was the same as before. Coronary angiography showed a totally occluded distal RCA with in-stent thrombosis and TIMI 0 flow (Figure 2A). He was started on tirofiban and UFH infusion and the next day underwent balloon angioplasty to in-stent thrombosis and deployment of a stent in PL origin (BMS 2.25 x 12 mm), as there was a tight thrombotic lesion noted, followed by TIMI 3 flow (Figure 2B). He was administered tirofiban for another 24 hours and UFH was continued.
After 48 hours of his intervention while transferring out of CCU, he suddenly collapsed with a loss of consciousness, an absent pulse and heart sounds. The paddle rhythm showed ventricular fibrillation and was successfully defibrillated. Electrocardiography (ECG) done post resuscitation showed new right bundle branch block (RBBB) with no ST elevation or depression. He was suspected to have in-stent thrombosis, and an emergency coronary angiogram was performed, which showed patent stents with TIMI 3 flow and no significant clots. His blood pressure was 90/60 mmHg on inotropes, his heart rate was 110 beats/minute and room air saturation was 92%. His UFH was continued.
The following day, his ECG showed persistence of RBBB and an acute pulmonary embolism was suspected. He underwent an echocardiogram which showed LVEF of 40%, a dilated pulmonary artery and a right ventricle (RV) with RV free-wall akinesis, RV systolic dysfunction, and mild tricuspid regurgitation with RV systolic pressure of 60 mmHg, but no intracardiac thrombi. An urgent computed tomographic (CT) pulmonary angiogram was performed which showed a massive saddle pulmonary thrombus extending to both the right and left pulmonary arteries (Figure 3). An ultrasound Doppler of his leg veins was normal. His aPTT was 1.5 times the control. UFH was withheld for 4 hours. In view of the extensive nature of his pulmonary thrombus, an echocardiogram that showed RV strain and hypotension, he was thrombolysed with reteplase. After the first 10 units of intravenous bolus dose of reteplase was administered, he developed bleeding from the puncture sites; a second dose of reteplase was withheld, hemostasis was achieved, and this was followed by UFH infusion. The next day, he developed sudden-onset expressive dysphasia without any focal neurological deficit. His UFH was stopped and an urgent CT brain scan was performed, which showed multiple intracerebral hematomas (Figure 4). His aspirin and clopidogrel were withheld.
Because of the recurrent coronary thrombosis and thrombus formation in two different arterial systems at the same time, additional blood tests were performed after the discontinuation of heparin. The results of the routine biochemical tests, including hemoglobin and blood platelet count, were within normal limits. His prothrombin time and activated partial thromboplastin time were normal. His protein C, protein S, antithrombin III, Factor V Leiden and fibrinogen levels were normal. The patient’s antinuclear antibody, anti-DNA and lupus anticoagulant were negative. His antiphospholipid antibodies screening revealed anticardiolipin antibody IgG 54 U/ml (n = 0.1–15) and B 2 glycoprotein 1 IgG 584 U/ml (n = 0.1–20). After 3 days, clopidogrel was restarted to avoid in-stent thrombosis. After 2 weeks, a repeat CT brain scan showed resolving hematomas (Figure 4B) and the patient was discharged home on clopidogrel, a statin, and atenolol with a plan to start warfarin after 2 weeks in view of pulmonary thrombosis.
He was seen 2 weeks later and was doing well except for mild dysphasia. In view of the pulmonary thromboembolism and suspected antiphospholipid syndrome (APS), he was advised to take warfarin, but he refused. A repeat lupus anticoagulant after 3 months was positive; his anticardiolipin antibody IgG had come down to 1.08 U/ml, but he had an elevated B 2 glycoprotein 1 IgG at 86.4 U/ml. The patient was confirmed to have primary APS according to the Sapporo criteria.1 Long-term warfarin treatment was advised to prevent the recurrence of thrombotic events, but the patient refused. He was started on aspirin in addition to clopidogrel and other medications. At 1-year follow up, he was doing well, with no recurrence of thrombotic events.
Discussion. Antiphospholipid syndrome is the association of persisting antiphospholipid antibodies with a thrombotic event.1 The multicenter Euro-Phospholipid project,2 which analyzed data from 1,000 unselected patients who met the criteria for APS, found that 53% of the cohort had primary APS, and 41% had APS with SLE or lupus-like conditions. Primary APS was largely seen in young women, with a male-to-female ratio of 3.5:1, and the age of first thrombosis in APS was predominantly between 15 and 50 years. In this series, a total of 37% of patients presented with only venous thrombotic events, 27% with only arterial thrombosis,15% with both venous and arterial thrombosis,12% with only fetal loss, and 8% with only thrombosis of the microcirculation. “Catastrophic” APS (multi-organ involvement) was seen in 0.8% of patients.
The most common features of thrombotic disorders in APS are deep-vein thrombosis, pulmonary thrombo-embolism, and stroke. Cardiac manifestations in APS may include MI,2 MI with normal coronary arteries,3 early failure of percutaneous balloon angioplasty (PTCA),4 valve abnormalities,5,6 pulmonary hypertension,6 ventricular dysfunction, intracardiac thrombus,7,8 and coronary bypass rethrombosis.2 After MI, up to 15% of patients have aPL antibodies compared with approximately 4.4% in a control population.9 In addition, some investigators10 have found that aPL antibodies after MI are a risk factor for recurrent events, and anticardiolipin antibodies in healthy men have also been shown to confer a two-fold increased relative risk for MI.11
There are probably three relationships between aPL antibodies and coronary artery disease: first, aPL antibodies can cause thrombosis in normal vessels; secondly, they may be associated with accelerated atherosclerosis; and lastly, in some individuals, transient aPL antibodies may arise at the time of MI because of vascular injury and exposure of neoantigens.3 The possible mechanisms of thrombosis in APS include effects of aPL on platelet membranes, on endothelial cells and on clotting components such as prothrombin, protein C and protein S. The antiphospholipid antibodies persist for years, possibly for a lifetime.7 Recently circulating procoagulant microparticles are found to contribute to thrombotic propensity in patients with APS.8
Management of patients with MI in APS is similar to other patients, and thrombolysis has been found to be successful.12 The results of PTCA in patients with APS are variable, with initial reports being unfavorable,4 but many recent results being favorable.13–15 Ozer et al15 performed successful primary stenting and saw that the result was good through the 6-month follow-up period. They noted that although the most important factor is optimal stent placement to prevent in-stent thrombosis, the prothrombotic state may lead to thrombotic complications in patients with primary APS, as with our patient.
Our patient presented initially with STEMI and received reteplase, but he developed post-MI angina and underwent PTCA of a totally occluded RCA. Multiple thrombus was detected, thus we performed stent placement with good results, but he developed in-stent thrombosis and underwent a second successful PTCA. The stent was completely patent on repeat angiography performed later.
The other interesting event in our patient was the development of major pulmonary arterial thrombo-embolism in spite of triple antiplatelet therapy and anticoagulation, indicating the presence of highly potent antibodies. His platelet count was persistently normal, thus ruling out heparin-induced thrombocytopenia. Echocardiography and venous Doppler of the patient’s legs did not reveal any source of emboli. Pulmonary manifestations, including pulmonary embolism and infarction, pulmonary hypertension, adult respiratory distress syndrome, intra-alveolar hemorrhage, primary thrombosis of the lung vessels — both large and small — as well as pulmonary microthrombosis, may be associated with this syndrome.16 Pulmonary embolism constitutes the most common pulmonary manifestation of the APS and in a series was seen as the first manifestation of the disease in 9% of patients.2 Management of the acute thrombotic event is the same in patients with APS as in the general population. It has been noted that, in some patients, thrombotic obstruction occurs at the level of the large elastic pulmonary arteries and can give rise to chronic thrombo-embolic pulmonary hypertension and few of these patients have been successfully treated with thrombo-endarterectomy.16
Our patient developed intracerebral bleed following anticoagulation therapy and thrombolysis, but recovered early with no significant focal neurological deficit. In APS, a bleeding diathesis is not typically observed unless there is associated thrombocytopenia. In our patient, there was no thrombocytopenia, but he had received antiplatelets, anticoagulants and thrombolytics, which are well-known risk factors for bleeding. There are few reports of spontaneous intracerebral hemorrhage in the absence of known risk factors for bleeding in patients with lupus anticoagulant and antiphospholipid antibodies,17,18 thus raising the question of whether the presence of a lupus anticoagulant by itself may lead to an increased risk for certain types of hemorrhagic events.
Diagnostic criteria for APS includes a combination of clinical criteria (vascular thrombosis or pregnancy morbidity) and laboratory criteria (lupus anticoagulant and/or anticardiolipin IgG or IgM antibodies or anti-β-2 glycoprotein-1 IgG or IgM antibodies) at least 12 weeks apart.1 In our patient, antibodies were still high 3 months after the MI and fulfilling the sapparo criteria.1
The risk of recurrent thrombosis in patients with the antiphospholipid syndrome is high and the recommended treatment is high-dose oral anticoagulation. Long-term treatment includes life-long anticoagulation with target INR of 2–3 for venous19 and 3–4 for arterial thromboembolism,20 as it is thought that arterial thrombosis is caused by more potent antibodies with a higher recurrence rate. High-dose steroids, immunosuppressive therapy, plasmapheresis, or the administration of immunoglobulins have been considered as treatment options, particularly in catastrophic APS.16
Conclusion. We describe a middle-aged man with primary APS who had recurrent coronary and in-stent thrombosis associated with acute pulmonary embolism and an intracerebral hematoma. To our knowledge, this is the first case with this combination of vascular thrombosis and intracerebral hemorrhage in the same patient with APS. In young patients with MI or recurrent stent thrombosis, APS should be considered as a possible cause of coronary occlusion and should be investigated. Anticoagulation therapy and thrombolysis appear to be effective in treating thrombosis, but may cause hemorrhagic complications in such patients.
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