Chronic management of pulmonary embolism in thromboangiitis obliterans

Abstract

Thromboangiitis obliterans (TAO), also known as Buerger’s disease, is a rare small vessel vasculitis that is associated with an increased risk of arterial occlusion. Although venous thromboembolism has been described, the risk of its recurrence and the best long-term anticoagulation management is not known. Considering this, we would like to share our experience with two patients admitted to our hospital with recurrent pulmonary embolism and previous diagnosis of TAO, aiming to discuss the indication for indefinite anticoagulation in this population.

Background

Thromboangiitis obliterans (TAO) or Buerger’s disease is a rare vasculitis of young smokers characterised by inflammation and thrombosis of the small-sized and medium-sized arteries of the extremities.^1–3 Larger vessel occlusion has been reported, but risk factors for its occurrence are not well characterised and it is mentioned as a very unusual event.² Although pulmonary embolism (PE) has been described in a few case reports,^4–6 it is not known whether it is a consequence of deep vein thrombus embolisation or local thrombus formation in the pulmonary artery. Also, there is no evidence regarding the risk of venous thromboembolism (VTE) recurrence and the best chronic management of these patients is not established.

Cases presentation

For each case, the timeline of events is presented in figure 1.

Figure 1.

Timeline of events in both patients. PE, pulmonary embolism; TAO, thromboangiitis obliterans; LMWH, low-molecular-weight heparin; FUP, follow-up.

Case 1

The first case refers to an ex-smoker man with hypertension and dyslipidaemia, diagnosed with TAO in the beginning of his fifth decade of life after toe ischaemia and amputation. In the same year, he also had an episode of PE, treated with indefinite warfarin for 20 years. Due to the absence of thromboembolic recurrence, anticoagulation was switched to clopidogrel 75 mg one time a day. He was not taking any antithrombotic drug other than clopidogrel.

Within 1 month, he was admitted at our emergency department for a few hours history of sudden thoracic pain, exertional dyspnoea and palpitations. At admission, he presented with severe hypotension (blood pressure 50/30 mm Hg) unresponsive to fluids, bradycardia (heart rate 35–55 beats/min), polypnoea and central cyanosis, requiring oxygen supplementation. Arterial blood gas under a FiO₂ 35% revealed metabolic acidosis (pH 7.38, HCO₃ 16 mEq/L), hypoxaemia and hypocapnia (pCO₂ 27 mm Hg, pO₂ 167 mm Hg); lactacidaemia was not available. A 12-lead ECG revealed sinusal bradycardia and S1Q3T3 pattern.

Case 2

The second case refers to a male smoker, diagnosed with TAO in his thirties, complicated with bilateral lower limb ischaemia and amputation. One year before TAO diagnosis, he had an acute PE event treated with warfarin for 6 months. Autoimmune diseases and antiphospholipid syndrome (APS) screening were negative. Genetic testing detected heterozygoty for methylenetetrahydrofolate (MTHFR A1298C), with increased values of homocysteine and low serum folate. Five years after anticoagulation suspension, he came to our emergency department for a 3-day history of pleuritic, progressive thoracic pain and non-productive cough. At admission, he was haemodynamically stable (blood pressure 99/66 mm Hg), normocardic (heart rate 98 beats/min) and mildly hypoxaemic (pO₂ 59 mm Hg) on room air.

Investigation and treatment

Case 1

On suspicion of acute PE, a bedside transthoracic echocardiogram was performed and was compatible with severe pressure overload and dysfunction of the right ventricle. Blood tests also revealed increased high-sensitivity troponin T of 152 ng/L. The diagnosis of high-risk acute PE was confirmed after thoracic tomography with pulmonary angiography (figure 2, panel A). Given the haemodynamic instability, the patient was treated with systemic alteplase 10 mg bolus followed by 90 mg infusion. Clinical improvement was achieved in the first hours after hospital admission with fast inotrope and oxygen weaning. Predischarge transthoracic echocardiogram showed normal right ventricle function and only mild tricuspid regurgitation. Lower limb doppler to exclude deep vein thrombosis was not performed.

Figure 2.

Central bilateral pulmonary embolism (red arrows) in patient 1 (panel A) and patient 2 (panel B).

Screening for autoimmune diseases and APS was negative. Acquired and genetic thrombophilia testing was also negative. Therefore, the patient was discharged on indefinite warfarin therapy, adjusted to periodic international normalised ratio.

Case 2

On suspicion of acute PE, D-dímer measurement showed an increased value of 2.68 μg/mL and negative initial high-sensitive troponin T level. The diagnosis was confirmed after thoracic tomography with pulmonary angiography (figure 2, panel B), that showed central and bilateral perfusion defects and right heart overload, allowing the diagnosis of intermediate-high risk PE. Right popliteal vein thrombosis was also diagnosed with lower limb doppler. The patient started anticoagulation with enoxaparin 1 mg/kg two times a day and 1 week transthoracic echocardiogram reevaluation showed good right ventricle function. He was discharged under warfarin, which he took for 6 months. Indefinite treatment with rivaroxaban 20 mg one time a day was decided.

A new screening for genetic or acquired thrombophilia was positive for the previously known heterozygoty of MTHFR A1298C. Screening for APS and paroxysmal nocturnal haemoglobinuria were negative.

Outcome and follow-up

Case 1

At 9 years follow-up, he had recurrent lower limb arterial ischaemia (without the need for amputation). The patient kept close follow-up in our thromboembolism department and there was no evidence of symptomatic PE recurrence and no pulmonary hypertension in transthoracic echocardiogram.

Case 2

At 5 years follow-up, he was admitted with a complete thrombosis of abdominal aorta and bilateral kidney infarct requiring life-long haemodialysis. Rivaroxaban was switched to subcutaneous enoxaparin 1 mg/kg one time a day (due to patient preference over warfarin). There was no VTE recurrence and ventilation/perfusion lung scan was negative for new embolic events. Follow-up transthoracic echocardiogram had no signs of pulmonary hypertension and was compatible with a good right ventricle function.

Discussion

According to the most recent American and European guidelines for VTE, the recurrence of PE is itself an indication for indefinite anticoagulation,^{7 8} but the level of recommendation is lower after a first event with an intermediate risk of recurrence.⁷ Patients with no risk factors or with an active autoimmune disease fall into this intermediate risk category.⁷

The association between TAO and thrombophilia has been described,1 2 9 10 the most common being APS and prothrombin 20 210 G/A mutation,^{1 2} but factor V Leiden and MTHFR gene mutations have also been reported.^9–11 The role of these prothrombotic states in TAO prognosis remains controversial,¹⁰ but some authors suggest a correlation with vessel inflammation and peripheral disease severity.^{2 11} No link has been made to atypical presentation in TAO, such as large vessel involvement.

The presence of such mutations, particularly hyperhomocysteinaemia in MTHFR polymorphisms, does not seem to increase VTE recurrence risk in the general population and they do not determine prolonged anticoagulant treatment after a first VTE event.^{9 12 13} Specifically in TAO, some MTHFR mutations increase the susceptibility to the disease, but there is no evidence that they increase the risk of major thrombotic events.³ The association between TAO and the specific MTHFR A1298C mutation has been previously described.¹⁴

Chronic anticoagulation in TAO has been proposed to alleviate peripheral symptoms, but its benefit is still controversial.² Some authors suggest that the effect of anticoagulants goes beyond their action in the coagulation cascade, with low-molecular-weight heparin and warfarin being able to reduce inflammatory markers in patients with TAO.³ The same effect is suggested for rivaroxaban.³

For both cases reported in this article, anticoagulation did not prevent arterial events, but warfarin and rivaroxaban seemed effective for long-term VTE secondary prevention. In the first case, the patient did not have any risk of recurrence other than TAO; in the second case, MTHFR mutation by itself should not be sufficient to predict the risk of recurrence. Therefore, the authors believe that a first VTE event may warrant long-term oral anticoagulation, taking in consideration the proinflammatory state in TAO, as already happens with other autoimmune diseases, such as APS or inflammatory bowel disease.^{6 7}

Regardless, the authors acknowledge that this is a very rare presentation in these patients and that we need more evidence to determine the most suitable approach.

Learning points.

• Thromboangiitis obliterans (TAO) is a small vessel vasculitis most frequently associated with peripheral arteries inflammation and thrombosis and in rare cases with larger vessel occlusion.

• The risk of venous thromboembolic (VTE) events as well as its best long-term management in patients with TAO is not known.

• Given the proinflammatory state in TAO, indefinite oral anticoagulation may be warranted after a first VTE event, as already happens with other autoimmune diseases.

Ethics statements

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