Acute myocardial infarction in young adults with Antiphospholipid syndrome: report of two cases and literature review

Acute myocardial infarction in young adults with Antiphospholipid syndrome: report of two cases and literature review

Leila Abid^1,&, Faten Frikha², Zouhir Bahloul², Samir Kammoun¹

¹Cardiology department, Hedi chaker hospital Sfax, Tunisia, ²Department of internal medicine, Hedi chaker hospital Sfax, Tunisia, ³Laboratory of Immunology, Habib Bourguiba hospital Sfax, Tunisia

^&Corresponding author

Dr Leila Abid, Cardiology Department, Hedi Chaker Hospital, Route Elain, Km 0.5, 3029, Sfax Tunisia

Antiphospholipid syndrome (APS) is an autoimmune disorder of acquired hypercoagulability characterized by the association of vascular thromboses (venous, arterial, small vessels) and or pregnancy morbidity (foetal loss, premature birth or recurrent embryonic losses) and persistent elevated serum levels of Antiphospholipid antibodies (anticardiolipin, lupus anticoagulant or anti- B2glycoprotein I) [1] It is also considered as a multisystemic disorder with a wide spectrum of presentations cutting across all subspecialties of medicine.

Acute myocardial infarction (AMI) is rarely associated with this syndrome with a frequency of approximately 4%. The treatment of these patients is a clinical challenge.

Herein, we report two cases of antiphospholipid syndrome in young adults revealed by acute myocardial infarction. Written informed consent was obtained from the patients for publication of this case report and accompanying images

Case 1

A 30 years old woman with a history of recurrent spontaneous abortion was admitted with severe midsternal chest pain, associated with sweating, nausea, and breathlessness. She had no risk factors for atherosclerosis (diabetes mellitus, hyperlipidaemia, hypertension, and smoking). She had never previously experienced chest pain at rest or on exertion. During physical examination, she was pale and sweaty with a tachycardia of 120 beats/min. Her blood pressure was 80/40 mm Hg. There was no peripheral oedema and all peripheral pulses were present. She had a systolic apical murmur and symptoms of left heart failure. A 12 lead electrocardiogram revealed ST-segment elevation in leads V1, V2, V3, V4, V5, and V6. We diagnosed acute anterior myocardial infarction complicated by cardiogenic shock. Two-dimensional echocardiography revealed a markedly reduced left ventricular ejection fraction (30%) and akinesis of the anterior, lateral inferior wall, and inferior interventricular septum consistent with infarction in the left anterior descending area. Emergent coronary angiography was performed, the left anterior descending artery presented thrombosis and stenosis at the level of the proximal section (figure 1). Left ventriculography revealed that the left ventricle was dilated and markedly hypo kinetic. Therefore, percutaneous transluminal coronary angioplasty (PCTA) with direct stenting was performed, with successful recanalisation (figure 2). Serum creatine kinase peaked at 3500 U/l, haematological tests were normal, other laboratory tests of liver and renal functions and lipid profiles were normal. Anticoagulation by intravenous heparin infusion was performed for the next 10 days, Clopidogrel, aspirin, pravastatine were also administrated. Congestive heart failure was controlled by diuretics, nitrate, and low doses of dobutamine.

We performed haematological tests for thrombotic disorders. Blood platelet count was 119 000 /ml and prothrombin time was normal. Levels of protein S, C, ATIII were normal. Lupus anticoagulant was negative. ACL were searched by for enzyme-linked immunosorbent assays (ELISA). ACL levels were expressed in IgM and IgG units with positive levels > 20 Units (U). Anti-2GPI antibodies (IgG and IgM) were also detected by ELISA. Anti-2GPI antibodies and ACL were detected at positive levels. The levels of Anticardiolipin antibodies (Ig M antibodies) and anti-B2-glycoprotein titres were 23.41 MPL and 26.74 U/ml respectively.

There was no evidence for infection or any other triggering event before the MIs in this patient. Antinuclear antibodies and Anti DNA antibody were negative. Antiphospholipid antibodies tests repeated 12 weeks later remained positive. These findings satisfy the update Sapporo Classification criteria [1] for the diagnosis of antiphospholipid syndrome. This latter was considered primary because the patient had no signs of other systemic auto-immune diseases, particularly systemic lupus erythematosus (SLE). We decided to treat the patient with oral anticoagulation for life. The follow-up (24 months) was uncomplicated. Effort tests performed 3 and 6 months after PCTA were negative.

Case 2

A 30-year-old Caucasian man was admitted in our intensive care unit because of bilateral acute ischemia of the two legs. He was regularly treated for Basedow disease. Smoking was the only risk factor of atherosclerosis disease. Physical examination showed a skinny patient. Peripheral pulses of the legs were absent. Arterial pressure was normal. The electrocardiogram showed a QS pattern in leads V1, V2, V3, and V4. Echocardiography revealed an apical large thrombus measuring 38 by 18 mm associated with a thinning left ventricular wall, suggesting painless myocardial infarction. It also demonstrated a markedly reduced left ventricular ejection fraction (19%) (Figure 3). The patient was immediately brought to the cardiovascular surgical department where bilateral Embolectomy to Fogarty probe was effectuated. Then amputation of the right leg was done because of so late consultation. Intravenous heparin was administrated with oral aspirin and clopidogrel.

Haematological tests showed normal levels of C, S and ATIII Protein. While FT4, FT3 were high, TSH was low. The patient was found to have a positive Lupus anticoagulant LA and a false positive VDRL. Anticardiolipin antibodies were also tested and subsequently came back positive for anticardiolipin antibody of the IgM isotype with a low level (19.25 MPL). The patient had no evidence for infection or any other triggering event before the MIs.

The patient was also found to have a false positive VDRL. Antinuclear antibodies, anti DNA, antiSm, anti SSA and anti SSB were negative. This was consistent with a primary antiphopholipid syndrome. Unfortunately, the patient died 15 days after his admission because of the failure of many of his organs (heart failure, acute renal failure, cytopenia).

The most common features of thrombotic disorders in antiphospholipid syndrome are deep vein thrombosis, pulmonary thromboembolism, and stroke. This syndrome is rarely initiated in the coronary arteries. On the other hand, acute myocardial infarction is unusual in young adults, but it has been reported in patients with antiphospholipid syndrome.

Antiphospholipid antibodies are the hallmark of the antiphospholipid syndrome which is characterized by thrombosis. It was first described in patients with systemic lupus erythmatosus and antiphospholipid antibodies [2]Antiphospholipid antibodies refer to auto antibodies that react to naturally occurring membrane bound phospholipids in human cells such as endothelial cells. These antibodies may be of IgG or IgM isotypes and consist of the lupus anticoagulant, anticardiolipin antibody, and false positive VDRL.

Antiphospholipid antibodies are associated with autoimmune diseases such as systemic lupus erythematosus, Patients often exhibit positive lupus anticoagulant activity but they infrequently suffer from the typical systemic lupus erythematosus (SLE) that satisfies diagnostic criteria. When they occur in isolation, this is known as primary antiphospholipid syndrome. The main antiphospholipid antibodies implicated in thrombosis and atherosclerosis are the anticardiolipin antibody, the lupus anticoagulant, and Ig G antibodies against plasma phospholipid –binding protein such as B2-glycoprotein I and prothrombin. Lupus anticoagulants were strong risk factors for both arterial and venous thrombosis and they are better predictors of thrombosis than anticardiolipin antibodies. Separate analysis of the different types of thrombosis showed anticardiolipin antibodies were associated with cerebral stroke and myocardial infarction but not with deep vein thrombosis.

Anticardiolipin antibody isotypes and titers are 2 important issues. Most studies investigated only IgG antibodies or did not distinguish between isotypes. With these limitations, IgM anticardiolipin antibodies were not associated with thrombosis, which limits their value in clinical practice. Anti-b2-glycoprotein I antibodies (anti-b2-GPI) represent one of the main subgroups of anticardiolipin antibodies (aCL) associated with antiphospholipid syndrome (APS). Positivity for anti-beta-2-glycoprotein I (anti-B2GPI) has been shown to be more closely associated with clinical manifestations of APS, including thrombosis.

Our two patients had both positive Ig M Anticardiolipin antibodies in a low level, but one had positive anti-B2-glycoprotein and the other had positive LA and so satisfied the criteria of primary APS. This can explain the occurrence of this coronary event. 

Systemic arterial and venous thromboses are prominent and typical features of APS. Vianna et al [3] reported episodes of deep vein thrombosis in 54% and arterial occlusions in 44% of cases. The major cardiac manifestations of APS include valve disease, myocardial infarction, intracardiac thrombus and myocardial microthrombosis [4] The frequency of myocardial infarction in patients with APS is reportedly 4%, and the presence of antiphospholipid antibodies has been associated with myocardial infarction in young patients. In a multicenter prospective Cohort of 1000 patients with APS, MI was the presenting manifestation in 2.8 % and appeared during the follow-up in 5,5% of the Cohort [5] There is an increased risk of myocardial infarction in patients with APS [6] caused by coronary thrombosis rather than by premature atherosclerosis. In table 1 we summarise reports of cases of antiphospholipid syndrome with myocardial infarction since the report of Harris [7,11-13,15-25]The actual mechanism of the thrombosis in APS is as yet unknown, but numerous mechanisms have been proposed. It has been attributed to inhibition of prekallikrein by the lupus anticoagulant or, as recently postulated, to interference with the activation of the protein C and protein S anti-coagulant pathways. Recent data show that the biding of certain autoantibodies to endothelial cells and platelets is dependent upon the presence of B2 glycoprotein I (B2GPI). Autoantibodies binding to B2GPI on the surface of endothelial cells induce expression of adhesion molecules and enhance monocyte adhesion to the endothelial cells [8]

Current data are supporting an association between these autoantibodies and atherosclerosis as well. Human studies suggest that anti-cardiolipin antibodies and anti-beta2-glycoprotein-I antibodies are elevated in patients having coronary artery disease compared with controls [9] Anti-cardiolipin antibodies are also associated with typical chest pain, significant coronary artery stenosis on angiography and are predictive of myocardial infarction. Laboratory studies and murine models support the pro-atherogenic role of these autoantibodies, as they are involved in uptake of oxidized LDL into macrophages, and immunization of mice with them results in enhanced atherosclerosis [9] There is some evidence that high anti-beta2-glycoprotein-I antibodies can present a risk factor for atherosclerosis, but more epidemiological data are required in order to confirm whether the pro-atherogenic properties of anti-phospholipid antibodies signifies an independent risk factor for atherosclerosis and its complications. Hamsten et al [10] studied 62 patients who were survivors of acute myocardial infarction under the age of 45, and found that 21% of these patients had anticardiolipin antibodies. In those surviving with positive antibodies, 61% experienced additional cardiovascular events in the subsequent 5 years compared with those without elevated anticardiolipin antibodies. Mattila et al [11] demonstrated an increase in anticardiolipin antibodies in 52% of patients within three months of an acute myocardial infarction.

Thus, the interaction of these atherosclerotic and prothrombotic risk factors substantially increased the risk of myocardial infarction in the young patients. Subjects at risk of developing early coronary artery disease often have clustering of multiple risk factors (case 3).The optimal management of AMI in APS is still under debate [4] Primary angioplasty may be considered the treatment of choice in case of myocardial infarction. However, patients with APS have higher rates of complications after coronary angioplasty or CABG, such as early failure or recurrent coronary stent thrombosis [4] Anticoagulant therapy started immediately after the PTCA may contribute to cause long term coronary patency and to prevent acute stent occlusion. Therefore, long-term oral anticoagulant appeared to be effective. When thrombi are diffuse as in the second case, PTCA could not be done in emergency; intravenously platelet glycoprotein IIbIIIa receptor inhibitor may be effective. Fibrinolysis may be effective as initial treatment for acute thrombotic disorder including acute myocardial infarction (Harpaz et al and Ho et al) [12,13]

When patients presented catastrophic antiphospholipid syndrome with diffuse thromboembolism (like our second case), treatment with methylprednisone under a broad spectrum of anti-infective therapy may be effective. We didn’t practice it in our case. More aggressive therapy modalities may be necessary to save the patient’s life, such as plasmapheresis, immunoglobulin and cyclophosphamide.

For chronic management, the Committee consensus recommends aggressive treatment of all risk factors for atherosclerosis (hypertension, hypercholesterolaemia, and smoking) and liberal use of folic acid, B vitamins and cholesterol-lowering drugs (preferably statins) in patients suffering from APS. Hydroxychloroquine for cardiac protection in APS patients may be considered. The Committee also recommends warfarin anticoagulation for those who have a history of thrombosis in the absence of atherosclerosis, but it recognizes that developing data may support the use of antiplatelet agents instead. In presence of intracardiac thrombi, the Committee recommends intensive warfarin anticoagulation [14]; but in a recent study, high-intensity warfarin therapy (INR 3 to 4) was not superior to moderate-intensity warfarin for thromboprophylaxis in patients with APS and previous thrombosis [15]

Acute myocardial infarction is unusual in young adults; antiphospholipid syndrome may be one of the aetiologies. Thus, immunological tests should be performed (lupus anticoagulant, anticardiolipin antibodies…), especially when there is a history of recurrent foetal loss or in the presence of symptoms of an associated connective tissue disorder. In such a case, PTCA followed by antithrombotic therapy is effective when angiographic data are favourable. Long term anticoagulant and antiplatelet therapies are recommended. Given the high rate of mortality of catastrophic antiphospholipid syndrome in some cases, this report emphasizes the need for rapid diagnosis and effective multimodal treatment in an intensive care unit setting for these patients.

The authors declare no competing interest

ICMJE authorship criteria met. All the authors contribute to the management of the patient and the writing up of the manuscript. The final version of the manuscript was reviewed and approved by all the authors.

Table 1: Literature data of some cases report of antiphospholipid syndrome with acute myocardial infarction

Figure 1: Left coronary arteriogram of a young patient with antiphospholipid syndrome and myocardial infarction on admission showing thrombotic stenosis of left descending coronary artery at the level of the proximal section

Figure 2: Arteriogram of a young patient with antiphospholipid syndrome and myocardial infarction after PTCA showing evidence of successful recanalization

Figure 3: Four-chamber view echocardiography of a young patient with antiphospholipid syndrome and myocardial infarction showing an apical large thrombus measuring 38x18 mm

1. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome. J Thromb Haemost. 2006; 4:295-306 . This article on PubMed

2. Sherer Y, Shoenfeld Y. Antiphospholipid antibodies: are they pro-atherogenic or an epiphenomenon of atherosclerosis?. Immunobiology. 2003; 207(1):13-6. This article on PubMed

3. Vianna JL, Khamashta MA, Ordi-Ros J, et al. Comparison of the primary and secondary antiphospholipid syndrome: a European Multicenter Study of 114 patients. Am J Med. 1994 Jan; 96(1):3-9. This article on PubMed

4. George D, Erkan D. Antiphospholipid Syndrome. Prog Cardiovasc Dis. 2009 Sep-Oct;52(2):115-25. This article on PubMed

5. Cervera R, Piette JC, Font J, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum. 2002; 46: 1019-1027. This article on PubMed

6. Petri M. The lupus anticoagulant is a risk factor for myocardial infarction (but not atherosclerosis): Hopkins Lupus Cohort. Thromb Res. 2004;114(5-6):593-5. This article on PubMed

7. Harris EN. Antiphospholipid antibodies. Br J Haematol. 1990 Jan;74(1):1-9. This article on PubMed

8. Lopez LR, Dier KJ, Lopez D, Merrill JT, Fink CA. Anti-beta 2-glycoprotein I and antiphosphatidylserine antibodies are predictors of arterial thrombosis in patients with antiphospholipid syndrome. Am J Clin Pathol. 2004 Jan;121(1):142-9. This article on PubMed

9. Soltész P, Szekanecz Z, Kiss E, Shoenfeld Y. Cardiac manifestations in antiphospholipid syndrome. Autoimmun Rev. 2007 Jun;6(6):379-86. This article on PubMed

10. Hamsten A, Norberg R, Bjorkholm M. Antibodies to cardiolipin in young survivors of myocardial infarction: an association with recurrent cardiovascular events. Lancet. 1986 Jan 18;1(8473):113-6. This article on PubMed

11. Mattila K, Vaarala O, Palosuo T, et al. Serologic response against cardiolipin and enterobacterial common antigen in young patients with acute myocardial infarction. Clin Immunol Immunopathol. 1989;51:414-8. This article on PubMed

12. Harpaz D, Glikson M, Sidi Y, Hod H. Successful thrombolytic therapy for acute myocardial infarction in a patient with the antiphospholipid antibody syndrome. Am Heart J. 1991 Nov;122(5):1492-5. This article on PubMed

13. Ho YL, Chen MF, Wu CC, Chen WJ, et al. Successful treatment of acute myocardial infarction by thrombolytic therapy in a patient with primary antiphospholipid antibody syndrome. Cardiology. Cardiology. 1996 Jul-Aug;87(4):354-7. This article on PubMed

14. Lockshin M, Tenedios F, Petri M, et al. Cardiac disease in the antiphospholipid syndrome: recommendations for treatment - Committee consensus report. Lupus. 2003; 12(7):518-23. This article on PubMed

15. Crowther MA, Ginsberg JS, Julian J, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003 Sep 18;349(12):1133-8. This article on PubMed

16. Kattwinkel N, Villanueva AG, Labib SB et al. Myocardial infarction caused by cardiac microvasculopathy in a patient with the primary antiphospholipid syndrome. Ann Intern Med. 1992 Jun 15;116(12 Pt 1):974-6.. This article on PubMed

17. Thorp JJ, Chescheir NC, Fann B. Postpartum myocardial infarction in a patient with antiphospholipid syndrome. Am J Perinatol. 1994 Jan;11(1):1-3. This article on PubMed

18. Miller DJ, Maisch SA, Perez MD, Kearney DL, Feltes TF. Fatal myocardial infarction in an 8-year-old girl with systemic lupus erythematosus, Raynauds phenomenon, and secondary antiphospholipid syndrome. J Rheumatol. 1995 Apr;22(4):768-73. This article on PubMed

19. Sakakibara N, Kawasuji M, Matsumoto Y, et al. Coronary artery bybass grafting in a patient with antiphospholipid syndrome. Ann Thorac Surg. 1996 Feb;61(2):739-40. This article on PubMed

20. Chambers JDJ, Haire WD, Deligonul U. Multiple early percutaneous transluminal coronary angioplasty failures related to lupus anticoagulant. Am Heart J. 1996 Jul;132(1 Pt 1):189-90. This article on PubMed

21. Kovacs KA, Burggraf GW, Dewar CL. Reversible cardiogenic shock in an angry woman—case report and review of the literature. Can J Cardiol. 1996 Jul;12(7):689-93. This article on PubMed

22. Derksen RH, Gmelig-Meijling FH, de Groot PG. Primary antiphospholipid syndrome evolving into systemic lupus erythematosus. Lupus. 1996 Feb;5(1):77-80. This article on PubMed

23. Susumu Takeuchi, Toshihiro Obayashi, Junji Toyama. Primary antiphospholipid syndrome with acute myocardial infarction recanalised by PTCA. Heart. 1998 Jan;79(1):96-8. This article on PubMed

24. Stoupakis G, Bejjanki R, Arora et al. Acute myocardial infarction in a 32-year-old white male found to have antiphospholipid antibody syndrome and MTHFR mutation homozygosity. Heart Lung. 2003 Jul-Aug;32(4):266-71. This article on PubMed

25. Ibrahim S, Abu R, Adnan K, et al. Myocardial Infarction Secondary to a Coronary Ostial Thrombus in Antiphospholipid Syndrome. Ann Thorac Surg. 2007 Mar;83(3):1170-1. This article on PubMed

26. Sajeev CG, Vivek Nambiar K, Fasaludeen M, Jayakumar TG, Krishnan MN, Venugopal K. Myocardial infarction in a young woman with antiphospholipid syndrome. Int J Cardiol. 2003 Sep;91(1):99-100. This article on PubMed