A 23-year-old man with acute myocardial infarction and pulmonary embolism for STAB2 gene mutation

doi:10.21203/rs.3.rs-2762259/v1

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Case Report

A 23-year-old man with acute myocardial infarction and pulmonary embolism for STAB2 gene mutation

https://doi.org/10.21203/rs.3.rs-2762259/v1

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Background

Thrombophilia is the tendency to thrombosis due to various acquired or genetic factors. Genetic thrombophilia refers to thromboembolism as a result of mutations in physiological anticoagulant or procoagulant genes, where persistent elevated factor VIII (FVIII) levels are also a common genetic factor in high thrombotic propensity. STAB2 variants can lead to increased plasma levels of the von Willebrand Factor (VWF) and/or its binding partner the coagulation cofactor factor FVIII. Nevertheless, venous thromboembolism has been the main clinical manifestation of STAB2 gene variants. In this paper, we report an interesting case in which a young armed police officer suffering from a STAB2 gene variant presented with acute myocardial infarction and pulmonary embolism.

Case presentation

A young armed police officer underwent emergency percutaneous coronary intervention(PCI) for ST-segment elevation myocardial infarction(STEMI) and his pulmonary image indicated pulmonary embolism. After thrombophilia testing, the diagnosis of arteriovenous thrombosis due to the STAB2 gene mutation and smoking was finally confirmed.

Conclusion

The STAB2 gene variant can manifest as venous and acute arterial thromboembolism. Young patients with unexplained arteriovenous thrombosis should undergo rigorous laboratory tests and related genetic screening of thrombophilia. While other arteriovenous thromboses should be excluded and antithrombotic therapy initiated promptly.

Myocardial infarction

Pulmonary embolism

Thrombophilia

STAB2 gene

Thrombophilia refers to a high propensity to thrombosis resulting from a wide range of acquired or genetic factors. Acquired thrombophilia refers to an increased thrombotic tendency due to altered inflammatory mechanisms caused by risk factors such as advanced age, trauma, prolonged braking, smoking, etc. Inherited thrombophilia is often caused by mutations in Thrombinogen (FII), Factor V Leiden (FVL), and protein C or S deficiency. What’s more, persistent elevated FVIII levels are also known as a common genetic factor for a high propensity to thrombosis. Stabilin-2 is an endocytic scavenger receptor that is involved in the clearance of FVIII complex. STAB2 variants can lead to increased plasma levels of the VWF and/or its binding partner the coagulation cofactor factor FVIII [1]. In a genome-wide screening study, variants in the human STAB2 gene were found to be associated with an increased incidence of unprovoked venous thromboembolism (VTE) [2]. However, STAB2 gene mutations have not been reported in acute arterial thromboembolic events. In this paper, we report a rare case in which a young military police officer with STAB2 gene mutation presented with STEMI and pulmonary embolism. He was discharged home on oral rivaroxaban and remained well at one year of follow-up.

A 23-year-old armed police officer was presented to the Emergency for acute myocardial infarction. Approximately 3 months prior to admission to the hospital, he was hospitalized for recurrent fever(38 to 39°C) and hemoptysis. He became chronically low fever (T < 38°C) with no more hemoptysis after IV cefoperazone sulbactam sodium and levofloxacin. He has smoked for 7 years༈1 to 2 packs per day༉, and his father passed away after a brain hemorrhage. Otherwise, he had no other cardiovascular disease risk factors. On physical examination, his body temperature was 38.5℃, with a pulse rate of 106 beats/min, while wet rales could be heard at the base of both lungs.

Initial laboratory studies suggested WBC count of 17.12×109/L, neutrophil ratio of 79.7%, and D-dimer concentration of 0.28mg/L. There was a rise in myocardial injury markers(Troponin I:8.8 microg/L, B-type natriuretic peptide:4650 ng/L, Creatine kinase isoenzyme:130 U/L). Moreover, the initial electrocardiogram(ECG) showed arch-back elevation of the ST segment in leads I, aVL, and V2-6, with Q waves visible in leads I and aVL(Fig. 1). Coronary angiography was performed immediately which presented complete occlusion of the proximal segment of the left anterior descending branch(LAD), and thrombi were seen in the proximal segment of the LAD and the opening of the left circumflex artery(LCX). We then conducted intracoronary thrombus aspiration, thrombolysis, and balloon dilatation. Given the patient's postoperative smooth vascular wall and restoration of blood flow, we did not implant a stent temporarily (Fig. 2).

Following operations, he still suffered from recurrent fever with a maximum temperature of 39°C after the IV piperacillin-tazobactam. We then conducted a pulmonary CT that revealed the right pulmonary artery embolism, left lower lobe pulmonary artery appendage thrombosis(Fig. 3), and pulmonary infection. What’s more, cardiac ultrasound showed a hypoechoic mass in the apical left ventricular anterior wall with consideration of thrombosis (13*6 mm) (Fig. 4). While ultrasound of both lower extremities and CTA of the head, neck, thoracic and abdominal arteries showed no significant abnormal sonograms.

To clarify the cause of the patient's arteriovenous thrombosis and fever, we screened for PC, PS, ACA, LCA, blood coagulation factor, homocysteine, and tumor markers, of which FVIII activity was 164.8% (reference value70-150%). What’s more, we sequenced 86 genes associated with thrombosis and found heterozygous mutations in the STAB2 gene(Fig. 5). In addition, blood NGS testing revealed a staphylococcal infection.

We gave him oral aspirin, clopidogrel, and rivaroxaban with IV heparin for antithrombotic. The deep vein placement was removed, and meropenem as well as vancomycin were administered intravenously. Both the temperature and the chest pain slowly recovered.

The review of coronary angiography 2 weeks later revealed that the wall of the proximal LAD branch was slightly irregular, and no significant stenosis was found in the gyral branch and right coronary artery(RCA). Optical coherence tomography (OCT) of the vessels detected localized thrombus shadow and plaque with lipid component in the proximal LAD, without plaque rupture or entrapment, which was consistent with plaque erosion(Fig. 6). He was discharged home on oral rivaroxaban and no thrombus was detected by follow-up pulmonary CTA and cardiac ultrasound 3 months later. The OCT of the coronary arteries one year later showed fibrous plaques in the proximal and middle parts of the LAD branch(Fig. 7).

We detected multiple thrombi in the coronary, left ventricular and pulmonary arteries in this young male. The coagulation cascade activated by vascular endothelial damage after myocardial infarction increases the risk of left ventricular thrombosis. Nevertheless, there were no significant abnormalities on the lower extremity ultrasound and no irregular atrioventricular pathways on the right and left cardiac sonograms in this patient, which could not explain the arteriovenous thrombosis in this patient. Thus, we screened for thrombophilia in the young with unexplained venous thromboembolism as well as arterial thrombosis.

The patient's clotting and immunological parameters were normal except for a slight increase in FVIII activity. However, we found STAB2 mutation in the thrombosis and hemostasis-related loci by second-generation sequencing, which is not a high-frequency variant of thrombophilia.

A previous study proposed that STAB2 gene mutations increase the risk of venous thromboembolism through the impact on clearance of vWF and reduced immune response to the VWF-F VIII complex [2]. Another recent paper implied that mutations in the STAB2 gene are associated with the development of SLE [3]. The pathologies in SLE are dominated by inflammatory responses and vascular abnormalities, with arterial and venous thrombosis as one of the common clinical manifestations of SLE.

This patient has a history of massive smoking that mediates vascular endothelial damage as a possible initiating factor for erosive plaque formation as well as coronary embolism. Therefore, it is suspected that the patient's arteriovenous thrombosis was triggered by the overlap of the genetic risk factor of STAB2 mutation and the acquired risk factors of heavy smoking and prolonged bed rest. In contrast, no positive results were observed for FVIII activity and lupus-related markers. This may be related to the fact that the administration of rivaroxaban leads to a decrease in a large number of coagulation factors and interferes with the assessment of lupus inhibitors [4]. In addition, the development of left ventricular thrombus in the patients may be relevant to the coagulation cascade activated by damaged vascular endothelium after myocardial infarction.

The patient possessed a history of recurrent fever, hence the possibility of infection-induced thrombosis could not be excluded. While the patient was still at low-grade fever even after antibiotic treatment before admission to the emergency, which was probably the result of a chronic pulmonary embolism. The patient subsequently sustained a high fever considered to be a catheter-related infection because of positive blood NGS and defervescence after the removal of the DVT.

Anticoagulation should be initiated in both coronary embolism and pulmonary embolism when not contraindicated. The presence of left ventricular appendage thrombosis after myocardial infarction is significantly associated with the occurrence of adverse cardiovascular events, and anticoagulation is an even more essential protocol to improve prognosis [5]. Current guidelines recommend warfarin as the first choice for left ventricular thrombosis after myocardial infarction, whereas studies have found that newer oral anticoagulants are faster to thrombolysis and safer than warfarin [6]. No matter what, lifelong anticoagulation has significant prognostic implications for this patient with hereditary thrombophilia in the context of low bleeding risk.

This case reminds us that the STAB2 gene variant can manifest as venous and acute arterial thromboembolism. In young patients with unexplained arteriovenous thrombosis, the possibility of thrombophilia should be considered and undergo rigorous laboratory tests and related genetic screening. Whether to place stents in patients with acute myocardial infarction requires a consideration of the patient's own vascular condition, which can be assessed by OCT examination. In addition, antithrombotic therapy needs to be started promptly.

FVIII factor VIII

VWF von Willebrand Factor

PCI percutaneous coronary intervention

STEMI ST-segment elevation myocardial infarction

FII Thrombinogen

FVL Factor V Leiden

VTE venous thromboembolism

ECG electrocardiogram

LAD left anterior descending branch

LCX left circumflex artery

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent was obtained from the patient for the publication of this case report.

Competing interests

The authors have no conflicts of interest to disclose

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Citations are included in the reference list

Funding

The authors have no funding to disclose.

Acknowledgements

Not applicable.

Authors’ contributions

YL and RF contributed mainly to the data curation, preparation and writing of the manuscript. JZ, TL, XL :had full access to all of the data in the study and takes responsibility for the integrity of the data. HJ and GL contributed substantially to the study design and revised the manuscript. All authors read and approved the final manuscript.

Michels A, Swystun LL, Dwyer CN, et al. Stabilin-2 deficiency increases thrombotic burden and alters the composition of venous thrombi in a mouse model. J Thromb Haemost. 2021,19(10):2440-2453. https://doi.org/10.1111/jth.15429.
Desch KC, Ozel AB, Halvorsen M, et al. Whole-exome sequencing identifies rare variants in STAB2 associated with venous thromboembolic disease. Blood. 2020,136(5):533-541. https://doi.org/10.1182/blood.2019004161.
Song Q, Lei Y, Shao L, et al. Genome-wide association study on Northern Chinese identifies KLF2, DOT1L and STAB2 associated with systemic lupus erythematosus. Rheumatology (Oxford). 2021,60(9):4407-4417. https://doi.org/10.1093/rheumatology/keab016.
Bonar R, Favaloro EJ, Mohammed S, et al. The effect of the direct factor Xa inhibitors apixaban and rivaroxaban on haemostasis tests: a comprehensive assessment using in vitro and ex vivo samples. Pathology. 2016,48(1):60-71. https://doi.org/10.1016/j.pathol.2015.11.025.
Lattuca B, Bouziri N, Kerneis M, et al. Antithrombotic Therapy for Patients With Left Ventricular Mural Thrombus. J Am Coll Cardiol. 2020,75(14):1676-1685. https://doi.org/10.1016/j.jacc.2020.01.057.
Jones DA, Wright P, Alizadeh MA, et al. The use of novel oral anticoagulants compared to vitamin K antagonists (warfarin) in patients with left ventricular thrombus after acute myocardial infarction. Eur Heart J Cardiovasc Pharmacother. 2021,7(5):398-404. https://doi.org/10.1093/ehjcvp/pvaa096.

No competing interests reported.

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A 23-year-old man with acute myocardial infarction and pulmonary embolism for STAB2 gene mutation

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Background

Case presentation

Conclusion

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Background

Case

Discussion

Conclusion

Abbreviations

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