Axillary artery thrombus in a patient with critical bicuspid aortic stenosis

Key Message

Thrombosis at unusual locations should provoke a systematic evaluation of risk factors to exclude an underlying condition.

Introduction

Virchow's triad describes three factors that influence the development of both venous and arterial thrombi: stasis, hypercoagulability, and endothelial damage. ¹ Arterial thrombotic events are typically associated with atrial fibrillation, atherosclerosis, or overt hypercoagulable states, and the clinical spectrum includes myocardial infarction, ischaemic stroke, and acute limb and abdominal ischaemia.^1,2 Axillary artery thromboses are exceedingly rare, with reported cases after complex shoulder surgery and in throwing athletes.^3,4

Bicuspid aortic valve results from abnormal fusion of valvular cusps during embryonic development. ⁵ Early aortic stenosis is a common complication, leading to reduced exercise tolerance, exertional chest pains, or syncope. It is characterised by fibro-calcific remodelling of the valve leaflets, and when severe, may increase systemic coagulability.^6,7 To our knowledge, this is the first reported case of axillary artery thrombus presenting in a patient with bicuspid aortic valve stenosis. Theorised mechanisms include vascular stasis provoked by a low-flow state and valvular thrombus formation with systemic embolisation.

Case presentation

A 44-year-old lady presented to her general practitioner with a sudden onset of right arm pain and associated heavy sensation, with intermittent distal numbness and paraesthesiae. There was no history of injury and no history of breathlessness, chest pain, or syncope.

Her history was significant for inherited glomerulonephritis (COL4A4 mutation), for which she was under local nephrology care, but had not required immunosuppression or renal replacement therapy. She also had hypertension and two pulmonary embolisms; one provoked by oral contraception at the age of 24, and one unprovoked at the age of 33. She was an ex-smoker, drank no alcohol, and her family history included ischaemic heart disease in her brother and lower limb peripheral arterial disease in her mother. At the time of presentation, she was taking a therapeutic dose of rivaroxaban (20 mg OD).

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Figure 1.

Arterial duplex ultrasound images demonstrating right axillary artery thrombus (L) and low velocity monophasic flow in the right brachial artery (R).

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Figure 2.

Transthoracic echocardiogram demonstrating severely thickened and calcified aortic valve (L) and mean aortic velocity 4.38 milliseconds (R).

Vital signs were within normal range, and examination demonstrated a normal appearance to the right upper limb. There were absent right radial and brachial pulses, but a palpable right subclavian pulse. There was no neurological deficit, and examination of the left upper limb was unremarkable. The chest was clear, and cardiovascular examination demonstrated an ejection systolic murmur, which radiated to the carotid arteries. Both calves were soft and non-tender, with no signs of deep vein thrombosis (DVT), and there was no peripheral oedema. Body mass index (BMI) was 33.

Laboratory investigations showed an unremarkable full blood count, with haemoglobin 151 g/L, white cell count 7.1 × 10⁹/L, and platelets 234 × 10⁹/L. Renal function was at the patient's baseline, with urea 4.8 mmol/L, creatinine 67 µmol/L, and eGFR >90 mL/min. International normalised ratio (INR) was 1.1, fibrinogen 3.7 g/L, and prothrombin time 11.1 s. D-dimer was not performed. Glucose was 3.9 mmol/L, and the lipid profile was within normal range.

Duplex ultrasound of the right upper limb arteries demonstrated a 1 cm occlusive thrombus in the distal axillary artery (Figure 1). Additionally, there was a turbulent Doppler signal in the brachio-cephalic artery, and the brachial, radial, and ulnar arteries had low velocity, monophasic flow. Venous ultrasound of the lower limb was not performed as this was not deemed clinically indicated.

An urgent echocardiogram was arranged, which showed a bicuspid aortic valve with critical aortic stenosis (Figure 2) (peak gradient 143 mmHg, mean gradient 79 mmHg, valve area 0.4 cm²). There was moderate left ventricular concentric hypertrophy with preserved systolic and impaired diastolic function. Computed tomography (CT) upper limb angiography showed normal anatomy with no evidence of atherosclerosis. The patient underwent a thrombophilia screen (including antithrombin III levels, lupus anticoagulant, anticardiolipin IgG and IgM, anti-beta-2 glycoprotein-1 antibody, PNH flow cytometry, and JAK2 and CALR screen), which was negative. Urinary protein-creatinine ratio was stable at 308 mg/mL (NL <0.3 mg/mL), and serum albumin levels were 38 g/L. Nephrology referral was not undertaken, as results were unchanged from previous and outpatient follow-up was already arranged.

The patient underwent surgical aortic valve replacement with no complications. During the procedure, the native valve was noted to be severely dysmorphic, with a unicuspid appearance. She commenced on warfarin treatment, and at three-month follow-up, her right arm symptoms had completely resolved.

Discussion

According to May et al., ² non-atherosclerotic thromboses at unusual locations or in younger patients should provoke systematic evaluation of risk factors to determine aetiology. An electrocardiogram should be performed to exclude atrial fibrillation, and a transthoracic echocardiography for structural heart disease. Any clinical evidence of deep vein thrombosis should provoke transoesophageal echocardiography or bubble study to investigate for patent foramen ovale (PFO) leading to paradoxical embolism. Use of oestrogen-containing medication, heparin, cocaine, amphetamines, and anabolic steroids should be excluded. Basic thrombophilia work-up includes a full blood count at baseline to evaluate any cytopenias or cytoses as evidence of malignancy or rheumatological disease. Thrombophilia testing should be performed, including factor V Leiden, protein C, protein S, and antithrombin levels, antiphospholipid syndrome testing, JAK2 mutation testing, and flow cytometry for paroxysmal nocturnal haemoglobinuria. Contrast angiography is recommended to exclude anatomic or vascular malformation, such as thoracic outlet syndrome or fibromuscular dysplasia.

In our patient, the critical aortic stenosis likely significantly contributed to the formation of axillary artery thrombus. The static left ventricular outflow tract obstruction induced by aortic stenosis increases afterload, which causes left ventricular hypertrophy over time and eventually reduces stroke volume. ⁶ The impact of decreased systemic perfusion can become magnified downstream, theoretically exposing arteries to low-flow states and turbulence, risk factors for thrombogenesis. ⁷ This is reflected in our patient's Doppler demonstrating both turbulent proximal flow and monophasic, low-velocity distal flow.

Thrombus formation on a native valve is rare, but there have been reported cases in severe aortic stenosis with subsequent systemic embolisation, including upper limb thrombosis. ⁷ Raised transvalvular gradients lead to increased haemodynamic shear stress and turbulence. This disruption in laminar flow results in the production of thrombin-antithrombin complexes, platelet activation, and the triggering of tissue-factor-mediated coagulation, which increases the likelihood of spontaneous valve thrombi, even in patients with sinus rhythm. ⁸ Valvular thrombus was not detected in our patient, but notably, transoesophageal echocardiography was not performed.

Arterial thromboses in nephrotic syndrome are more rare than venous thromboses but occur more frequently than in the general population. The pathophysiology is multifactorial and influenced by hyperviscosity, increased platelet activity, urinary losses of antithrombin and protein S, and increased hepatic synthesis of haemostatic proteins such as fibrinogen. ⁹ Our patient had inherited glomerulonephritis and had historically presented with nephrotic syndrome. In this presentation, her urinary protein-creatinine ratio was persistently raised, but she was euvolaemic and anti-thrombin III, albumin, and fibrinogen levels were normal. The implication of heavy proteinuria without nephrotic-range physiological consequences on thrombosis risk is unclear, but may illustrate a spectrum of hypercoagulability. Notably, there are two reported cases of arterial thrombosis in nephrotic syndrome, where both patients had normal anti-thrombin III, protein C, and protein S levels. ¹⁰

Conclusion

This is a rare case of axillary artery thrombosis leading to the diagnosis of critical aortic stenosis. Despite a normal clotting profile and thrombophilia screen, there was a clear prothrombotic tendency, evidenced by prior pulmonary emboli and underlying proteinuric disease process. This case highlights the physiological changes in critical aortic stenosis and should prompt systematic evaluation of venous or arterial thrombosis at unusual sites or in young patients to exclude an underlying condition.