Efeovbokhan, Nephertiti MD; Zaidi, Junaid MD; Efeovbokhan, Elvis Osayi MD; Khouzam, Rami N. MD, FACC, FACP, FASNC, FASE, FSCAI
A 39-year-old woman with history of recurrent pulmonary emboli (PE) presented to the ED with increasing shortness of breath. At baseline, she was short of breath on moderate exertion; however, in the week before presentation, she noticed shortness of breath at rest. She also complained of increasing swelling of both lower extremities for the past 4 weeks.
Her first episode of PE occurred about 1 year ago, and she has had five episodes since then. An extensive workup for hypercoagulable disorders, including factor V Leiden, protein S and C, anti-cardiolipidin antibodies, and age-appropriate screening for malignancies, was negative. She was prescribed oral anticoagulation with warfarin and received an inferior vena cava (IVC) filter.
A review of systems was otherwise negative. On physical examination, she appeared malnourished. She was in obvious respiratory distress as evidenced by use of accessory muscles of respiration. Her vital signs were: temperature, 36.3° C (97.3° F); BP, 98/65 mm Hg; heart rate, 112 beats/minute; respirations, 20; and SpO2, 84% on room air. Neck examination showed elevated jugular venous pulse to 10 cm above the sternal angle, indicating volume overload. A lung examination revealed bibasilar crackles. The patient's cardiovascular examination revealed a regular rhythm with tachycardia, normal first heart sounds, and a loud pulmonary component of the second heart sound in the second left intercostal space. Her extremities showed 2+ pitting pedal edema bilaterally.
A 12-lead ECG showed sinus tachycardia at a rate of 101 beats/minute and right bundle-branch block. Her N-terminal pro-brain natriuretic peptide level was 1,882 pg/mL (normal range is less than 125 pg/mL).
A transthoracic echocardiogram showed normal global left ventricular systolic function with an estimated left ventricular ejection fraction of 65%, abnormal septal wall motion from right ventricular volume overload, and a moderately dilated right ventricle with reduced global systolic function. Right ventricular systolic pressure was estimated to be 90 to 95 mm Hg (normal range, 15 to 25 mm Hg). Moderately severe tricuspid and pulmonic regurgitation were noted.
WHAT IS YOUR DIAGNOSIS?
* acute PE
* chronic PE
* chronic thromboembolic pulmonary hypertension (CTEPH)
* acute right-sided heart failure secondary to pulmonary arterial hypertension
After a chest CT with IV contrast revealed bilateral large central PEs within the main pulmonary arteries, the patient was diagnosed with CTEPH.
In a study of 866 survivors of acute PE, the incidence of CTEPH was 0.57% in the overall cohort and 1.5% in patients with unprovoked embolism (those with no identifiable cause for PE).1 Acquired and hereditary risk factors may play a role in the development of CTEPH, but their mechanisms have not been fully elucidated. Genetic disorders such as antiphospholipid antibody syndrome and increased factor VIII levels are more common in patients with CTEPH than controls.2 The antiphospholipid antibody was found in up to 20% of patients diagnosed with CTEPH.3 Acquired conditions such as myeloproliferative syndromes, chronic inflammatory states, and chronic indwelling central venous catheters have also been associated with CTEPH.3 The exact pathogenesis of the vasculopathy in CTEPH is still unclear.2 CTEPH is thought to result from obstruction of the pulmonary vascular bed from incomplete thromboemboli resolution, which leads to mechanical intraluminal obstructions with some degree of arteriopathy in nonoccluded areas.4 Over time the development of distal, small-vessel vasculopathy contributes to the right ventricular afterload and progression of pulmonary hypertension.2
Clinical presentations include exertional dyspnea and exertional presyncope, or frank syncope and exertional chest pain. On examination, the patient may have signs suggestive of pulmonary hypertension, including prominent right ventricular impulse, short split second heart sound with accentuation of the pulmonic component, right ventricular S4 gallop, and a systolic murmur in the left fourth parasternal border due to tricuspid regurgitation.2
As the disease progresses and right ventricular failure develops, signs of frank right-sided heart failure develop, including jugular venous distension, a right-sided S3, widened split of the second heart sound, hepatomegaly, ascites, and peripheral edema.2
Transthoracic echocardiography reveals elevated pulmonary pressures, although this noninvasive modality only provides estimates of true pulmonary hemodynamics. Ventilation-perfusion (V/Q) scintigraphy is essential in the diagnosis of CTEPH.5 One or more segmental mismatched defects are noted on V/Q scintigraphy. CT angiogram also is helpful in the diagnosis. Combined right heart catheterization and conventional pulmonary angiography remain the gold standard for diagnosing CTEPH. Angiographic abnormalities that may be noted in chronic thromboembolic disease include pouch defects; pulmonary artery webs or bands; intimal irregularities; abrupt, usually angular narrowing of the major pulmonary arteries; and complete obstruction of main, lobar, or segmental vessels at their points of origin.2,6
Once a diagnosis of CTEPH has been made, begin anticoagulation with heparin (IV or subcutaneous) and warfarin.7 Once the patient achieves an INR of 2 to 3, heparin may be discontinued. Anticoagulation with warfarin is required indefinitely.7 The newer oral anticoagulants such as rivaroxaban, dabigatran, and apixaban have not been studied in patients with CTEPH. Drug interactions exist between these agents and others used in the treatment of CTEPH (such as phosphodiesterase-5 inhibitors), so a switch to these agents is not recommended until more evidence is available.8
All patients should be evaluated for pulmonary thromboendarterectomy.2,7 These four factors should be considered:
* the surgical accessibility of the thrombi
* presence of hemodynamic and/or ventilatory impairment
* effect of the patient's comorbidities on the risks of the surgery
* the patient's willingness and motivation to undergo surgery.2
Pulmonary thromboendarterectomy is only suitable for thromboemboli in the proximal main, lobar, and segmental arteries.
Medical therapy is indicated for patients who are not surgical candidates because of choice, underlying comorbidities, or the anatomic distribution or extent of their disease. Pulmonary vasodilators and remodeling agents are used to lower the pulmonary vascular resistance and pulmonary artery pressure, improving signs and symptoms such as exercise capacity and oxygenation.2 Agents such as prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and soluble guanylate cyclase stimulants are used.2
N-terminal pro-brain natriuretic peptide has been proposed as a tool to be used for long-term follow-up in patients with CTEPH because the level increases as disease burden increases and right ventricular function decreases.9
Because the patient remained hypoxic during her hospital course despite increasing use of supplemental oxygen and noninvasive mechanical ventilation, a surgical consultation was obtained. The patient underwent pulmonary thromboendarterectomy; multiple large clots were removed from both pulmonary arteries (Figure 1).
Anticoagulation with heparin and warfarin was restarted. A repeat echocardiogram showed right ventricular systolic pressure of 30 mm Hg. The patient was discharged in a stable condition, and follow-up at 2 weeks and then 2 months confirmed that she was adhering to her medication regimen and had had no recurrence of symptoms.
CTEPH may develop after an acute episode of PE. In addition to lifelong anticoagulation, patients should be evaluated for surgical thromboendarterectomy, the only potential curative therapy.
1. Klok F, van Kralingen KW, van Dijk AP, et al. Prospective cardiopulmonary screening program to detect chronic thromboembolic pulmonary hypertension in patients after acute pulmonary embolism. Haematologica. 2010;95(6):970–975.
2. Fedullo P, Kerr KM, Kim NH, Auger WR. Chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med. 2011;183(12):1605–1613.
3. Wolf M, Boyer-Neumann C, Parent F, et al. Thrombotic risk factors in pulmonary hypertension. Eur Respir J. 2000;15(2):395–399.
4. Pepke-Zaba J, Jansa P, Kim NH, et al. Chronic thromboembolic pulmonary hypertension: role of medical therapy. Eur Respir J. 2013;41(4):985–990.
5. Tunariu N, Gibbs SJ, Win Z, et al. Ventilation-perfusion scintigraphy is more sensitive than multidetector CTPA in detecting chronic thromboembolic pulmonary disease as a treatable cause of pulmonary hypertension. J Nucl Med. 2007;48(5):680–684.
6. Auger WR, Fedullo PF, Moser KM, et al. Chronic major-vessel chronic thromboembolic pulmonary artery obstruction: appearance at angiography. Radiology. 1992;182(2):393–398.
7. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e419S-494S.
8. Delcroix M. Chronic post-embolic pulmonary hypertension: a new target for medical therapies. Eur Respir Rev. 2013;22(129):258–264.
9. Suntharalingam J, Goldsmith K, Tosher M, et al. Role of NT-proBNP and 6MWD in chronic thromboembolic pulmonary hypertension. Respir Med. 2007;101(11):2254–2262.
© 2014 American Academy of Physician Assistants.