Multiple thromboembolic events associated with bilateral superior vena cava and anomalous drainage into the left atrium

A 49-year-old female patient presented with acute-on-chronic chest pain. She was diagnosed with multiple systemic thromboemboli, including myocardial infarctions, bilateral chronic pulmonary emboli, ischaemic stroke, deep venous thrombosis and superficial thrombophlebitis. She had a background of sickle cell trait. Cardiac magnetic resonance showed bilateral superior vena cava (SVC). The right-sided SVC (RSVC) was joined by the right upper pulmonary vein and drained anomalously into the left atrium. This caused a small volume right to left shunt. The persistent left SVC drained into the right atrium (RA) via a dilated coronary sinus. The overall clinical impression was recurrent paradoxical emboli due to anomalous venous anatomy with a thrombophilia secondary to sickle cell trait. In the normal embryo, the right common cardinal vein develops to become the RSVC, which drains into the RA by term.

venous thromboembolism, clinical diagnostic tests, radiology (diagnostics), haematology (incl blood transfusion), radiology

The differential diagnoses for a thrombophilia in a middle-aged woman include factor V Leiden mutation, protein S, protein C and antithrombin III deficiency, membranous glomerulonephritis, systemic lupus erythematosus and antiphospholipid syndrome.1 The patient presented with recurrent paradoxical emboli due to anomalous venous anatomy. She also had a thrombophilia and venous thrombosis secondary to sickle cell trait. Common causes of paradoxical emboli include atrial septal defect (ASD) and patent foramen ovale (PFO).2 A congenital anomaly of the venae cava is rare cause.3 Anomalous systemic venous drainage in the form of a persistent left-sided superior vena cava (LSVC) is usually of no clinical significance. In this patient, the systemic venous blood drains anomalously into the left atrium via the right-sided SVC (RSVC), and from there, into the systemic circulation.4 The risk of paradoxical emboli is further increased in the context of a prothrombotic tendency, which is attributed to sickle cell trait.5–10 Case presentation A 49-year-old woman had five hospital admissions in 11 months. From April 2019 to February 2020, she presented with two myocardial infarctions, one ischaemic cerebrovascular accident (CVA), chronic bilateral pulmonary emboli, a deep venous thrombosis (DVT) and a superficial thrombophlebitis. Table 1 shows the timeline of hospital admissions and diagnoses on discharge. Table 1. | Hospital admission date | Presenting complaint | Diagnoses on discharge | | April 2019 | Chest pain | MI with non-obstructive coronary arteries (MINOCA) Chronic bilateral pulmonary emboli | | July 2019 | Chest pain | MI with non-obstructive coronary arteries (MINOCA) | | September 2019 | Headache Visual loss on the right side | Subacute left occipital infarct | | December 2019 | Left leg swelling and pain | Left small saphenous vein thrombophlebitis | | February 2020 | Right arm pain | Right arm proximal DVT of the axillary vein | DVT, deep venous thrombosis. April 2019 myocardial infarction: first episode The patient presented to the emergency department with a 2-day history of chest pain. It was heavy and pleuritic in nature, radiating to her left arm. She felt dizzy and dyspnoeic at rest. On physical examination, her chest was clear. Her heart sounds demonstrated a pan-systolic murmur radiating to the axilla. Her jugular venous pressure was not elevated, and there was no evidence of pedal oedema or deep vein thrombosis. Her vital signs were as follows: blood pressure 140/90 mm Hg, pulse 78/min, respiratory rate 18/min and O2 saturation 95% on room air. Her medical history included systemic arterial hypertension, mitral valve prolapse with moderate mitral regurgitation (MR) and moderate tricuspid regurgitation (TR) diagnosed in 2012. This was diagnosed incidentally on an echocardiogram, after she presented with chest pain. At the time, she had an angiogram, which showed unobstructed coronary arteries. Thereafter, she was symptom-free until 2018, when she was re-referred to the cardiologist for atypical chest pain. She also had nine previous miscarriages, uterine fibroids, menorrhagia, chronic iron deficiency anaemia and sickle cell trait. She was under regular follow-up by the gynaecology team for menorrhagia and infertility. She was referred for a hysterectomy because of symptoms of severe menorrhagia and dysmenorrhoea, and she was no longer trying to conceive. Her medication history included amlodipine 5 mg once daily, bendroflumethiazide 2.5 mg once daily, ferrous sulfate 200 mg once daily, tramadol 50 mg as required and tranexamic acid 1 g three time a day. Her family history is as follows: her mother had a myocardial infarction at middle age and known sickle cell disease. There was no family history of thrombophilia or other cardiac conditions. She worked as an administrator for special education schools. She was an ex-smoker 30 years prior, and rarely consumed alcohol. She lived with her husband and had no children. July 2019 myocardial infarction: second episode The patient presented for the second time, with a 3-day history of chest pain. Her physical examination was unremarkable. There was no clinical evidence of heart failure or deep venous thromboembolism. Her vital signs were as follows: blood pressure 133/81 mm Hg, pulse 106/min, respiratory rate 19/min and O2 saturation 93% on room air. September 2019 ischaemic cerebrovascular accident The patient presented with a 4-day history of headache and visual loss on the right side for 1 week. On cranial nerve examination, there was a right-sided homonymous hemianopia. There were no cranial nerve palsies or cerebellar signs. Her speech was normal. Neurological examination of her limbs revealed normal tone, power sensation, proprioception and vibration sense. December 2019 superficial thrombophlebitis She presented with a 1-week history of left calf pain. February 2020 proximal deep vein thrombosis The patient presented with a 2-day history of oedema and redness of the right upper arm with pain. Investigations Myocardial infarction: first and second episodes Table 2 shows the timeline of radiological examinations performed over these two hospital admissions. Table 2. | Date | Test | Diagnosis | | April 2019 | Invasive coronary angiogram | Normal coronary arteries | | CT pulmonary angiogram | Chronic bilateral PE | | | Echocardiogram | Good left ventricular function | | | June 2019 | cMRI (outpatient) | Inferior myocardial infarction | | July 2019 | Bubble echocardiogram | No PFO or shunt | | Invasive coronary angiogram | Normal coronary arteries | | | September 2019 | cMRI (outpatient) | Inferior myocardial infarction | PE, pulmonary embolism; PFO, patent foramen ovale. In April 2019, her blood tests on admission showed a microcytic anaemia. The haemoglobin (Hb) was 80 g/L (normal range 110–153 g/L) and the mean corpuscular volume was 55.6 fL (normal range 81–100). Her Hb had been between 60 and 107 g/L for the last 5 years, attributed to menorrhagia. A troponin was sent for suspected acute coronary syndrome, and it was positive at 0.36 μg/L (normal <0.04). A D-dimer was sent for suspected pulmonary embolism (PE) due to the pleuritic nature of the pain. The D-dimer was positive at 1084 ng/mL (normal range 0–230). She had a chest X-ray, which was unremarkable. Her ECG showed normal sinus rhythm with T-wave inversion in inferior and lateral leads. She was diagnosed with non-ST-elevation myocardial infarction (NSTEMI). There was no evidence of atrial fibrillation (AF) while she was on the cardiac monitor in the cardiology ward. When she presented to the emergency department for the second time, the high sensitivity troponin I was positive at 632 ng/L (normal range 0–120). Her ECG again showed normal sinus rhythm with T-wave inversion in the inferior and lateral leads. She was diagnosed with NSTEMI. Given the ECG changes and troponin rise, the patient had two invasive coronary angiograms in order to diagnose and treat obstructive coronary artery disease causing an NSTEMI. On both occasions, the angiogram showed unobstructed coronary arteries. She had an echocardiogram to look for evidence of heart failure. The echocardiogram revealed normal left ventricular systolic function with an ejection fraction of 65%. It also showed a dilated right ventricle with normal systolic function and an estimated pulmonary artery pressure elevated at 61 mm Hg. Both atria were dilated. The coronary sinus was dilated, which is pathognomonic of a left-sided SVC (figure 1, videos 1–3).11 The echocardiogram revealed bilateral SVCs (figure 1, videos 4–6) Despite the normal coronary angiograms, there was still a strong suspicion of myocardial infarction. She therefore had an outpatient cardiac MRI after both presentations with chest pain to look for evidence of this. On both occasions, the cMR showed a subendocardial myocardial infarction of the basal inferolateral left ventricle (figure 2) and bilateral SVCs (figure 3, videos 7–9). The LSVC drained into the RA via the dilated coronary sinus. The RSVC was joined by the right upper pulmonary vein and drained anomalously into the LA. This caused systemic venous blood from the right upper limb and head to mix with pulmonary venous blood, bypassing the lungs and going into the systemic arterial circulation (figures 3–5). There was no evidence of atrial or ventricular septal defect. Flow mapping was performed to look for evidence of a shunt. A shunt is expressed as the ratio of total pulmonary blood flow to total systemic blood flow and is termed the Qp:Qs ratio.12 It is used for quantifying the net shunt. A Qp:Qs ratio of 1:1 is considered normal, and if less than 1:1, is consistent with a right to left shunt. In this patient, the flow mapping showed a small volume right to left shunt, with a Qp:Qs ratio of 0.9. At this point, the possibility of coronary emboli causing myocardial infarction was suspected. A bubble echocardiogram was obtained to exclude other anatomical causes of shunt. There was no evidence of a PFO or other shunt. Due to the elevated D-dimer, a CT pulmonary angiogram (CTPA) was performed to look for evidence of a PE. This showed chronic bilateral PEs in the lower lobar branches and segmental arteries bilaterally. This appearance was consistent with chronic PEs; however, it was not possible to age the PEs based on the CTPA appearance.13 She had intermittent chest pain since 2018, but it is unclear whether this pain was a manifestation of chronic pulmonary thromboembolic disease or myocardial ischaemia. It may have been a combination of both. September 2019 cerebrovascular accident The patient had CT of her head, which demonstrated a subacute left occipital infarct. She then had a CT intracranial angiogram, which showed left vertebral artery thrombosis, with no evidence of vertebral artery dissection. An MRI of her head later confirmed a subacute infarct in the left posterior cerebral artery territory. The clinical impression was suspected acute venous thromboembolism with paradoxical embolisation to the brain. Superficial thrombophlebitis and proximal DVT In December 2019, the patient had a left lower limb ultrasound scan, which confirmed superficial thrombophlebitis of the small saphenous vein. In February 2020, she had a positive D-dimer (906 ng/mL, normal range 0–230). She had a right upper limb ultrasound scan, which confirmed proximal DVT of the axillary artery. She was on warfarin, with an international normalised ratio (INR) of 2.6 at the time. She also had a repeat CTPA, which excluded further PE. Treatment Myocardial infarctions: April–July 2019 The patient was treated with dual antiplatelet therapy with aspirin 75 mg and clopidogrel 75 mg for NSTEMI. She was also prescribed atorvastatin 80 mg and ramipril 2.5 mg once daily. This was in addition to her already taking amlodipine, bendroflumethiazide and ferrous sulfate. Cerebrovascular accident: September 2019 The patient was treated with aspirin 300 mg for stroke. She did not receive thrombolysis, as her symptoms had been present for 4 days. After 2 weeks, she was started on warfarin, with a target INR of 2–3, after the haematologist reviewed her case. After having several thromboembolic events, it was felt on balance, she would benefit from anticoagulation to prevent further episodes. Clopidogrel 75 mg was stopped, and she continued aspirin 75 mg because of her recent history of NSTEMI. She was also treated with bisoprolol 2.5 mg once daily. Superficial thrombophlebitis and proximal DVT: December 2019–February 2020 The patient continued to take warfarin and aspirin until follow-up with the haematologist. Outcome and follow-up Myocardial infarction: April–July 2019 The patient had a 4-day admission for NSTEMI in April, and a 7-day admission for NSTEMI in June–July. She was off work for 4 weeks after each admission with NSTEMI. The cardiologist followed her up every 4 months. She continued to complain of intermittent chest pain. She was referred to the Adult Congenital Cardiac team for multidisciplinary team discussion and consideration of surgical management. A transoesophageal echocardiogram was performed by the Adult Congenital Cardiac team at follow-up. No evidence of ASD, PFO or other cause of shunt was identified. Cerebrovascular accident: September 2019 The patient had a 2-day admission to the Stroke Unit in September. She had minimal disability from her stroke on discharge and was able to return home with community physiotherapy. She returned to work after a few months. Her only deficit was the right-sided hemianopia. She was followed up by the Stroke team 3 months after discharge. She had no further evidence of visual field defect on cranial nerve examination, and the neurological examination of her limbs was unremarkable. She had an outpatient 72-hour Holter ECG, which showed sinus rhythm throughout the reading, with no evidence of AF as a possible cause for stroke. Haematology follow-up Given this presentation of recurrent arterial emboli and rare venous anatomy, a thrombophilia was strongly suspected by the haematologist. Table 3 shows the results of the thrombophilia screen. Table 3. | Test | Result | Normal range | Interpretation | | Antithrombin IIIa | 99 IU/dL | 80–130 | Negative | | Factor V Leiden | Not detected | N/A | Negative | | Cardiolipin antibody IgG | 6 GPL-U/mL | 0–10 | Negative | | Cardiolipin antibody IgM | 3 MPL-U/mL | 0–10 | Negative | | B2-Glycoprotein-1 antibody IgG | <1 U/mL | 0–10 | Negative | | Free protein S | 53 IU/dL | 60–130 | Borderline low | | Protein C | 72 IU/dL | 70–140 | Negative | | dRVV ratio (lupus anticoagulant) | 0.89 ratio | 0–1.2 | Negative | | APTT lupus ratio | 0.89 ratio | 0–1.2 | Negative | | Thrombin time | 22.5 s | 11.6–16 | Negative | APTT, Activated Partial Thromboplastin Time; dRVV, Dilute Russell's Viper Venom Time. The clinical impression was venous thrombosis secondary to sickle cell trait by the haematologist. The borderline low free protein S was not felt to be clinically significant. She had weekly INR monitoring. She was given low molecular weight heparin whenever the INR was subtherapeutic. By March 2020, the aspirin was stopped, and the target INR for warfarin was readjusted to 2.5–3.5, given the upper limb DVT and lower limb thrombophlebitis. Gynaecology follow-up The patient was followed up every 6 months by the Gynaecology team. She had an MRI of her pelvis, which confirmed a large multifibroid uterus. The largest fibroid measured 34 weeks, with evidence of adenomyosis. She had a biopsy of the endometrium, which excluded malignancy. She was on aspirin and warfarin, which worsened her menorrhagia and anaemia. She required red blood cell transfusions on multiple occasions. She was treated with norethistone 5 mg three times per day and goserelin injections 4 weekly (a gonadotropin-releasing hormone—GNRH agonist). Her recurrent miscarriages and menorrhagia were attributed to the large uterine fibroids and adenomyosis.14 Her scheduled hysterectomy was postponed due to her hospital admissions for NSTEMI, PE and stroke.

Bilateral SVC The patient has an LSVC draining into the RA, and an RSVC draining into the LA. LSVC is prevalent in 0.3%–0.5% of the population.3 15–19 RSVC drainage into the LA is extremely rare. A study from 1975 reports only 19 of 5127 congenital cardiac patients having RSVC drainage into the LA.4 The authors were able to identify a further six case reports describing an RSVC drainage into the LA.20–25 In the normal embryo, the right common cardinal vein develops to become the RSVC, which drains into the RA by term.26 Failure to obliterate the connection between one of the two right pulmonary veins and the right common cardinal vein results in a partial persistent pulmonary anomalous circulation.26 In this case, the pulmonary vein is abnormally connected to the SVC, and drains anomalously into the LA, causing a small right to left shunt. A persistent LSVC results from the failure of regression of the left anterior cardinal vein.26 Clinical significance of LSVC LSVC is commonly asymptomatic and is usually detected incidentally as a dilated coronary sinus on echocardiogram.4 In this patient, the LSVC is draining via the dilated coronary sinus into the RA, therefore not causing a shunt. This explains why her bubble echocardiogram was negative when the agitated saline was injected into her left arm. The agitated saline arrived into the LSVC and eventually drained into the RA. The most common consequence of an LSVC is that it can complicate a left-sided pacemaker implantation.3 LSVC may be associated with arrhythmias. It may possess ectopic electrical activity as well as abnormal electrical communications within the atria.3 This can lead to AF and sudden death.2 The dilated coronary sinus can cause stretching of the atrioventricular node and bundle of His, also causing arrhythmias.3 The patient had inpatient cardiac monitoring on her three hospital admissions, as well as a 72-hour Holter monitor. No arrhythmias were found. However, it is possible that paroxysmal AF was not captured during these recordings. Clinical significance of RSVC drainage into the LA There have been occasional previous reports of SVC drainage into the LA causing paradoxical thromboembolisms,4 air and septic emboli.27–30 As well as CVA, the patient also had a myocardial infarction confirmed on CMRI, with normal coronary arteries (MINOCA). MINOCA can be caused by a thromboembolic myocardial infarction, and the thrombus might dissipate before the angiogram is performed.31 Alternatively, there could be a side branch occlusion not identified at angiography. The minor degree of right to left shunt is the explanation for systemic arterial saturations of 92%–95%. Although our clinical conclusion was that all three systemic arterial embolic events were related to paradoxical emboli, alternative possibilities include a transient episode of AF leading to thromboembolism from the left atrial appendage. In this patient, one must not insert a peripheral cannula or inject into the right arm, as it will reach the right SVC, which drains into the left atrium. This could cause further paradoxical emboli, including stroke. Thrombophilia Sickle cell trait is associated with an increased risk of venous thrombi.5–10 This could explain her DVT and chronic bilateral PE. Further research is required to explain the mechanisms underlying this increased thrombotic risk with sickle cell trait.32 We found no other explanation for a thrombophilia.

In summary, the patient has an RSVC draining into the LA, causing a small right to left shunt, and in addition, an LSVC draining into the RA. She has had three systemic arterial thrombotic events, including two NSTEMI and one CVA. We have attributed these to paradoxical emboli due to her right to left shunt. She has a mild prothrombotic tendency due to sickle trait and this combined with her anatomical anomaly is likely to explain her presentations. In conclusion, this rare combination of congenital anomalies might have remained asymptomatic in this patient, if she did not have a prothrombotic tendency. Patient’s perspective. The above conditions have affected my life in many ways. I struggle with lethargy, recurrent palpitations and chest pains. I was told by the doctors to seek medical advice if I get chest pains in the future. However, the pains tend to be short lasting, and usually resolve before an ambulance arrives. I find this confusing. I am unable to exercise the way I wish I could, and I struggle with many daily activities. I also become very tired at work. I would be keen to pursue surgical correction of the bilateral SVC, if it would help me feel better, and if I could be more physically active. However I am worried about the complications of the surgical procedure, given my age and previous medical problems. Learning points. Young people with strokes should be investigated for causes of paradoxical emboli if no other cause is found. A congenital defect of venous return in isolation may be asymptomatic. If there is a mild prothrombotic tendency, there is risk of thromboembolic disease. Dilated coronary sinus on echocardiogram usually signifies persistent left-sided superior vena cava (SVC) draining into the right atrium and should be investigated. If there is an anomalous SVC draining into the left atrium, the upper limb on the same side of the SVC should not be used for injections or peripheral cannulation. Footnotes Contributors: MEK drafted the case report and the discussion and revised the manuscript; MEK helped edit the figures and consented the patient. NK has supervised the case report write up. NK diagnosed the patient’s anatomy on cardiac MRI, and revised, edited and drafted the case report, and created the figures and annotations. MH-C has helped draft and has revised the manuscript. Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests: None declared. Patient consent for publication: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

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