Abstract. Myocardial infarction has been reported as a rare manifestation of protein S deficiency. We describe the case of a 38-year-old woman with no traditional cardiovascular risk factors, presenting with myocardial infarction after a recent previous misdiagnosis of a non-ST elevation myocardial infarction as acute myocarditis. Coronary angiography revealed a thrombotic lesion in the proximal segment of the left anterior descending artery, successfully treated with coronary angioplasty. The laboratory test identified a protein S deficiency, and the appropriate treatment with oral anticoagulation was initiated.
Coronary artery disease (CAD) is the leading cause of death in the world,1 and myocardial infarction (MI) is a very common manifestation of this disease. While there is a very large database available for CAD, the literature focusing in the appearance of MI in young adults is lacking. The main cause of MI is atherosclerosis, process that can be accelerated by the presence of several traditional cardiovascular risk factors as insulin resistance, diabetes, familial lipid disorder, hypertension, and tobacco use.2 MI may have non-atherosclerotic etiologies such as congenital coronary artery anomalies, spontaneous coronary artery dissection, vasospasm, recreational and other drug use, and coagulation system disorders (antiphospholipid syndrome, as well as protein S, protein C, and antithrombin III deficiency).3-5
This is the case of a 38-year-old woman with no cardiovascular risk factors who presented to the emergency department with sudden onset of a severe chest pain. Physical examination showed a blood pressure of 120/70 mmHg and pulse rate of 74 beats per minute. Cardiac auscultation was normal and the lungs were clear. The electrocardiogram showed sinus rhythm with negative T waves in leads II, III, aVF and V3-V6 (Figure 1A). In the patient’s initial blood tests, troponin I concentration was 3.29 ng/mL (normal values <0.056 ng/mL). The transthoracic echocardiogram showed a mild hypokinesia in the lateral left ventricular wall with an estimated ejection fraction of 55%. Further laboratory investigations found full blood count with elevated white blood cell count, while common blood chemistry and lipid profile were all within normal values. A coronary angiogram showed no significant coronary artery stenosis (Figure 1B). The patient received medical treatment with dual antiplatelet therapy, an ACE inhibitor, beta blockers, and statin, and after 6 days, she was discharged home on the same medication, with recommendations to undergo a cardiovascular magnetic resonance imaging (MRI) scan. A month later she had the MRI scan, which showed sub-epicardial late gadolinium enhancement (LGE) pattern (residual fibrosis) in the anteroseptal and lateral wall of left ventricle, compatible with a the diagnosis of myocarditis. The patient was asymptomatic, and she was advised to continue the medical therapy with one antiplatelet agent (aspirin), ACE inhibitor, beta blocker, and the lipid-lowering agent she was taking (atorvastatin).
Three months later, our patient presented again to the emergency department of a nearby hospital with the same symptoms as in her first presentation. The electrocardiogram showed ST segment elevation in the anterior chest leads (Figure 2A), and in the lab tests, troponin I was increased to 382.89 ng/mL. She was led straight to the cath lab, where coronary angiography showed a 70% angiographic lesion in the proximal left anterior descending (LAD) coronary artery with a “hazy” appearance compatible with the presence of thrombus (Figure 2B). The circumflex and right coronary arteries were angiographically normal. Primary angioplasty was performed to the LAD, with the insertion and deployment of two drug-eluting stents, and a very good final angiographic result (Figure 2C). An echocardiogram showed akinesia of the anterior wall and the apex of the left ventricle, with an estimated ejection fraction of 30%. The lab results showed an elevated white blood cell count, 25,500/mL, normal hemoglobin, normal basic biochemistry values, and normal lipid profile. Due to the absence of significant coronary artery disease in her recent previous coronary angiogram and the lack of traditional risk factors, after discharge, the patient was readmitted to our department, where we proceeded to check her coagulation status. We had the following results: a decreased level of total protein S to 51% (normal range 55-140%), the level of free protein S was 60% (normal range 60-140%), the level of protein C was 89% (normal range 70-130%), the APC resistance was 205 seconds (sec) (normal range 110-300 sec), the level of antithrombin III was 93% (normal range 80-120%), the antiphospholipid level was normal, and the homocysteine level was normal. We immediately started anticoagulation therapy with low molecular weight heparin for 5 days overlapped with acenocoumarol. The patient was discharged 5 days post admission, on clopidogrel, aspirin, metoprolol, ramipril, atorvastatin, furosemide, eplerenone, pantoprazole, and acenocoumarol, with recommendations for strict control of international normalized ratio (INR) values in a range of 2-3. The plan is to stop dual antiplatelet therapy after 12 months, and continue with acenocoumarol for life.
Myocardial infarction in young adults is a relatively rare condition, with an incidence of approximately 4% in those aged ≤40 years of age.6 Males are typically more often affected, while females account for only 6% in this age group.7 The most common cause of MI in the young is atherosclerosis, but a number of other potential but uncommon causes have been described. Among these causes are some hypercoagulable states, as in our case. In the young patients presenting with MI who have no cardiovascular risk factors and in the absence of atheromatous coronary disease, it is important to expand the differential diagnosis towards a probable inherited thrombophilia syndrome. This syndrome includes protein S deficiency, protein C deficiency, hyperhomocysteinemia, antithrombin III deficiency, and factor V Leiden deficiency. Protein S, a vitamin K-dependent anticoagulant protein, was discovered in 1977 by Di Scipio,8 and its anticoagulant property has been discovered by Walker in 1980.9 Protein S deficiency is an autosomal dominant disorder with a prevalence of <0, 5% in the European population, and 2-12% in thrombophilic patients.10 Protein S deficiency may be caused by congenital or secondary etiologies. There are two circulating forms of protein S in plasma: 40% is in the free state (is capable of acting as a cofactor in the protein C system) and 60% exists as a covalent complex with the β-chain of the complement component C4b binding protein.11 There are three types of hereditary protein S deficiency:
- Type I characterized by low total and free protein S antigen level;
- Type II is characterized by reduced protein S activity but with normal antigen level of total and free protein S;
- Type III is characterized by a reduced antigen level activity of free protein S, but the antigen level of total protein S remains normal.12
Secondary deficiency may be caused by pregnancy, oral contraceptives, disseminated intravascular coagulation, liver failure, type I diabetes mellitus, nephritic syndrome, malignant tumors or autoimmune disease.13 Protein S deficiency is usually associated with venous thrombosis,14,15 and only some studies and case reports have discussed the implication of protein S deficiency in arterial thrombosis. Myocardial infarction has been reported as a rare manifestation of protein S deficiency. A recent systematic analysis study that included 24 articles describing 27 cases where arterial thrombosis occurred along with protein S deficiency, showed that only 4 cases (14.81% of cases) involved the coronary circulation. The cerebral and peripheral arteries are the most commonly involved circulations (each constitutes 29.63% of cases).16 Our patient had no cardiovascular risk factors, but the laboratory tests revealed a decrease in total protein S activity. However, the first time she was admitted to hospital, she had severe chest pain, negative T waves in the leads II, III, aVF, V3-V6, and elevated troponin I levels, common characteristics for both myocarditis and acute coronary syndrome.17-19 Coronary angiography showed no significant coronary artery stenosis, as in the majority of patients who actually have myocarditis,20 while the sub-epicardial pattern of LGE in the anteroseptal and lateral wall of the left ventricle in the cardiac MRI was supportive of the same idea. As cardiac MRI has an important role in the differentiating infarction from myocarditis,21 these findings led us to consider myocarditis as the most probable diagnosis, rather than the acute coronary syndrome. In the second hospitalization, when the real diagnosis was made, the patient had unfortunately already experienced an anterior wall STEMI, with the cost of significant damage to left ventricular function.
This case highlights that the diagnosis of acute coronary syndrome due to protein S deficiency in young patients is essential for the appropriate management and prevention of recurrent events. It requires a high suspicion level of the disorder and better plan for investigations in young patients, especially those without cardiovascular risk factors, in order to establish an early, correct diagnosis.
Disclosures: The authors report no conflicts of interest regarding the content herein.
The authors can be contacted via Dr. Delia Vlad at firstname.lastname@example.org
- World Health Organization. The top 10 causes of death. May 24, 2014. Available online at http://www.who.int/mediacentre/factsheets/fs310/en/. Accessed June 24, 2020.
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- Fennich N, Salwa A, Nadia B, et al. Acute coronary syndrome in a young woman with antithrombin III deficiency. J Cardiol Cases. 2013;7(4):e101-e103.
- Ogasawara N, Kijima Y, Ike S, et al. Hereditary protein s deficiency with a history of recurrent myocardial infarction. Circ J. 2003 Feb; 67(2): 166-168.
- Tiong IY, Alkotob ML, Ghaffari S. Protein C deficiency manifesting as an acute myocardial infarction and ischaemic stroke. Heart. 2003; 89(2): E7. doi:10.1136/heart.89.2.e7
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- Broekmans AW, Bertina RM, Reinalda-Poot J, et al. Hereditary protein S deficiency and venous thromboembolism. A study in three Dutch families. Thromb Haemost. 1985; 53: 273-277.
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- Porela P, Kytö V, Nikus K, Eskola M, Airaksinen KE. PR depression is useful in the differential diagnosis of myopericarditis and ST elevation myocardial infarction. Ann Noninvasive Electrocardiol. 2012; 17(2): 141-145. doi:10.1111/j.1542-474X.2012.00489.x
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