Subsegmental pulmonary embolism

An example patient with sickle cell disease provides a lesson in diagnosing subsegmental pulmonary embolism.


Case presentation

A 28-year-old man presented to the ED with chest, abdominal, and back pain. His history was significant for sickle cell disease with recurrent crises, and the majority of his pain was consistent with previous pain crises. On further questioning, he noted pleuritic chest pain localized to his right chest and dyspnea on exertion for two days. He reported no recent travel, leg swelling, or personal history of malignancy but he had had a subsegmental pulmonary embolism three years prior that was treated with four months of dabigatran. Surgical history included multiple surgical repairs of a fractured right femur. He had no family history of coagulopathy. Outpatient medications included cholecalciferol 2000 IU/d; folic acid 1 mg/d; oxycodone extended release 40 mg every 12 hours; and oxycodone 30 mg every 4 hours.

The patient was in no acute distress and was afebrile, with a blood pressure of 139/62 mm Hg, a heart rate of 90 beats/min, a respiratory rate of 20 breaths/min, and an oxygen saturation of 91% on room air. The physical exam was remarkable for clear lungs without wheezing or rhonchi, lower extremities without edema, and reproducible bony tenderness over the thorax in various areas including the right and left lateral chest walls. The remainder of the examination was normal. An electrocardiogram (EKG) demonstrated sinus bradycardia, left ventricular hypertrophy, and no ST-T wave abnormalities. Admission labs revealed a hemoglobin level of 9.3 g/dL, a white blood cell count of 8.14 cells/mm3, a platelet count of 502,000 cells/mm3, a creatinine level of 0.6 mg/dL, a troponin level below 0.03 ng/mL, and a reticulocyte count of 11.60%. The rest of his labs were normal.

A chest X-ray with two views showed no active disease. Given the patient's history of pulmonary embolism, pleuritic chest pain, and hypoxia, CT angiography of the chest was obtained, which revealed a right-lower-lobe subsegmental pulmonary embolism.

Background

Subsegmental pulmonary emboli (SSPE) are peripheral emboli limited to the subsegmental pulmonary arteries and involving one or more subsegmental branches but not including any larger vessels (11. Kearon C, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149:315-52. [PMID: 26867832], 22. Stein PD, Goodman LR, Hull RD, Dalen JE, Matta F. Diagnosis and management of isolated subsegmental pulmonary embolism: review and assessment of the options. Clin Appl Thromb Hemost. 2012;18:20-6. [PMID: 21949040]). SSPE differ radiographically from centrally located emboli and are distinguished from submassive pulmonary emboli by the absence of elevated cardiac biomarkers or signs of right ventricular strain on EKG, CT scan, or echocardiogram (11. Kearon C, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149:315-52. [PMID: 26867832], 33. Konstantinides SV, et al; Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35:3033-69, 3069a-3069k. [PMID: 25173341]). No randomized clinical trials regarding management of SSPE exist to date and therefore it is unclear exactly how to proceed when SSPE is diagnosed.

SSPE can be found incidentally or during work-up for presumed pulmonary embolism. Furthermore, it may be isolated, that is, without concomitant deep venous thrombosis (DVT). The use of CT angiography for pulmonary embolism and the introduction of multiple detectors have improved diagnostic accuracy but have also increased rates of SSPE diagnosis (22. Stein PD, Goodman LR, Hull RD, Dalen JE, Matta F. Diagnosis and management of isolated subsegmental pulmonary embolism: review and assessment of the options. Clin Appl Thromb Hemost. 2012;18:20-6. [PMID: 21949040], 44. Stein PD, et al; PIOPED II Investigators. Multidetector computed tomography for acute pulmonary embolism. N Engl J Med. 2006;354:2317-27. [PMID: 16738268]-66. Carrier M, et al. Subsegmental pulmonary embolism diagnosed by computed tomography: incidence and clinical implications. A systematic review and meta-analysis of the management outcome studies. J Thromb Haemost. 2010;8:1716-22. [PMID: 20546118], 77. Wiener RS, Schwartz LM, Woloshin S. Time trends in pulmonary embolism in the United States: evidence of overdiagnosis. Arch Intern Med. 2011;171:831-7. [PMID: 21555660]). The incidence of isolated SSPE is estimated to have increased from approximately 4% to approximately 10% with the introduction of multiple-detectors CT pulmonary angiography but estimates vary widely (11. Kearon C, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149:315-52. [PMID: 26867832], 44. Stein PD, et al; PIOPED II Investigators. Multidetector computed tomography for acute pulmonary embolism. N Engl J Med. 2006;354:2317-27. [PMID: 16738268], 66. Carrier M, et al. Subsegmental pulmonary embolism diagnosed by computed tomography: incidence and clinical implications. A systematic review and meta-analysis of the management outcome studies. J Thromb Haemost. 2010;8:1716-22. [PMID: 20546118]). It is unclear if SSPE represents a more benign clinical entity or if rates of recurrence and risk factors truly mirror other types of venous thromboembolism (22. Stein PD, Goodman LR, Hull RD, Dalen JE, Matta F. Diagnosis and management of isolated subsegmental pulmonary embolism: review and assessment of the options. Clin Appl Thromb Hemost. 2012;18:20-6. [PMID: 21949040], 88. Bariteau A, Stewart LK, Emmett TW, Kline JA. Systematic review and meta-analysis of outcomes of patients with subsegmental pulmonary embolism with and without anticoagulation treatment. Acad Emerg Med. 2018;25:828-35. [PMID: 29498138]-1010. Carrier M, Righini M, Le Gal G. Symptomatic subsegmental pulmonary embolism: what is the next step? J Thromb Haemost. 2012;10:1486-90. [PMID: 22672341]). One large retrospective study suggested similar risk of recurrence of venous thrombembolism (VTE) during three months of anticoagulation among patients with SSPE and patients with larger or central pulmonary emboli (1111. den Exter PL, et al. Risk profile and clinical outcome of symptomatic subsegmental acute pulmonary embolism. Blood. 2013;122:1144-9; quiz 1329. [PMID: 23736701]). However, some data suggest that SSPE patients are actually more likely to have adverse outcomes from anticoagulation than from the clot itself (55. Donato AA, Khoche S, Santora J, Wagner B. Clinical outcomes in patients with isolated subsegmental pulmonary emboli diagnosed by multidetector CT pulmonary angiography. Thromb Res. 2010;126:e266-70. [PMID: 20709366]).

CHEST 2016 guidelines recommend ruling out proximal DVT when SSPE is detected. If lower-extremity ultrasound reveals no proximal DVT and the patient is considered to be at low risk for recurrence, then simply monitoring with lower-extremity ultrasound is recommended (11. Kearon C, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149:315-52. [PMID: 26867832]). Patients may be considered to have low risk for recurrence if they are not hospitalized, have normal mobility, do not have cancer, and have no history of recent surgery.

Despite these guidelines, there is controversy about whether anticoagulation or clinical monitoring is preferred for patients with cancer (1212. van der Hulle T, et al. Risk of recurrent venous thromboembolism and major hemorrhage in cancer-associated incidental pulmonary embolism among treated and untreated patients: a pooled analysis of 926 patients. J Thromb Haemost. 2016;14:105-13. [PMID: 26469193]-1515. den Exter PL, et al. Physicians' management approach to an incidental pulmonary embolism: an international survey [Letter]. J Thromb Haemost. 2013;11:208-13. [PMID: 23088591]). Survey data suggest that one-third of thrombosis subspecialists would not prescribe anticoagulation in a patient with cancer and isolated SSPE (1616. Carrier M, et al. The management of a sub-segmental pulmonary embolism: a cross-sectional survey of Canadian thrombosis physicians [Letter]. J Thromb Haemost. 2011;9:1412-5. [PMID: 21501379]). That said, it is recommended that patients with cancer who are diagnosed with SSPE receive anticoagulation regardless of whether SSPE was discovered incidentally or in isolation (1212. van der Hulle T, et al. Risk of recurrent venous thromboembolism and major hemorrhage in cancer-associated incidental pulmonary embolism among treated and untreated patients: a pooled analysis of 926 patients. J Thromb Haemost. 2016;14:105-13. [PMID: 26469193], 1414. Liebman HA, O’Connell C. Incidental venous thromboembolic events in cancer patients: what we know in 2016. Thromb Res. 2016;140 Suppl 1:S18-20. [PMID: 27067973]). In patients with SSPE and cancer, low-molecular-weight heparin (LMWH) and warfarin are associated with similar risk of recurrence but bleeding rates are lower with LWMH (1212. van der Hulle T, et al. Risk of recurrent venous thromboembolism and major hemorrhage in cancer-associated incidental pulmonary embolism among treated and untreated patients: a pooled analysis of 926 patients. J Thromb Haemost. 2016;14:105-13. [PMID: 26469193]). More recent prospective studies suggest that treatment with edoxaban or rivaroxaban reduces risk of recurrent VTE but increases risk of clinically relevant non-major bleeding compared to LMWH (1717. Young AM, et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018;36:2017-23. [PMID: 29746227], 1818. Büller HR, et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406-15. [PMID: 23991658]).

Sickle cell disease creates a pro-thrombotic state with risk of in-situ thrombosis. This may be a separate entity from VTE. Nonetheless, rates of VTE in patients with sickle cell disease mirror those of patients with inherited thrombophilia (1919. Shet AS, Wun T. How I diagnose and treat venous thromboembolism in sickle cell disease. Blood. 2018;132:1761-9. [PMID: 29764840].-2121. Naik RP, Streiff MB, Haywood C Jr, Nelson JA, Lanzkron S. Venous thromboembolism in adults with sickle cell disease: a serious and under-recognized complication. Am J Med. 2013;126:443-9. [PMID: 23582935]) which would suggest also a higher risk of VTE recurrence. It has been extrapolated that a provoked VTE in a patient with sickle cell disease carries a much higher risk of recurrence compared to the general population and therefore indefinite anticoagulation should be recommended (1919. Shet AS, Wun T. How I diagnose and treat venous thromboembolism in sickle cell disease. Blood. 2018;132:1761-9. [PMID: 29764840].).

Conclusion

This case highlights several challenges in the management of SSPE. No prospective data exist to guide the management of SSPE. Patients with underlying pro-thrombotic disorders—especially those with malignancy or sickle cell disease—could very well be at risk for clot propagation. According to current guidelines, when SSPE is detected, clinicians should rule out concomitant lower-extremity DVT. If it is ruled out and the patient is at low risk for recurrence, it is reasonable for anticoagulation to be held and the patient to be monitored with lower-extremity ultrasound (11. Kearon C, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149:315-52. [PMID: 26867832]). No clear recommendations exist on how to treat patients with high risk of bleeding. For patients at risk for recurrence or with diminished cardiopulmonary reserve, anticoagulation is recommended. Patients with cancer or sickle cell disease likely represent a population at greater risk for recurrence and therefore should receive anticoagulation. The duration of anticoagulation for SSPE in these populations is unclear.

Back to the case

After our patient was diagnosed with SSPE, a lower-extremity ultrasound was done and no DVT was seen. In light of his previous pulmonary embolism and presumed increased risk of recurrence due to sickle cell disease, we decided to treat him with anticoagulation indefinitely. His symptoms were probably due to symptomatic SSPE. His pain improved and he was discharged on rivaroxaban.