Vascular Disease Patient Information Page: Post-pulmonary embolism syndrome,CTEPD,and CTEPH

What is post-pulmonary embolism syndrome?

Pulmonary embolism (PE) is the medical term for blood clots that are located in the arteries of the lungs. PE affects between 300,000 and 400,000 people in the United States annually. With anticoagulation therapy (i.e., blood thinners), blood clots typically resolve without permanent damage; however, approximately half of patients who have a new PE will experience some degree of exercise limitation. Post-PE syndrome includes a spectrum of patients with persistent shortness of breath, exercise limitation, and/or impaired quality of life after at least 3 months of treatment with anticoagulation therapy.

What is chronic thromboembolic pulmonary disease (CTEPD) and chronic thromboembolic pulmonary hypertension (CTEPH)?

Post-PE syndrome may range from persistent shortness of breath to chronic thromboembolic pulmonary disease (CTEPD) with or without pulmonary hypertension.^1,2 CTEPD is defined by persistent thrombosis (blood clots) within the pulmonary vasculature (arteries of the lung), causing chronic thrombotic obstructions without the presence of elevated blood pressure in the pulmonary arteries. Chronic thromboembolic pulmonary hypertension (CTEPH) represents the most severe form of post-PE syndrome, characterized by chronic residual thrombotic obstructions with elevated blood pressure in the pulmonary arteries.

How common are post-PE syndrome, CTEPD, and CTEPH?

Up to 50% of patients will have persistent problems following a PE. The true incidence of post-PE syndrome, including CTEPD and CTEPH, is unknown. Approximately 30–50% of patients will have evidence of residual blood clots months after the acute PE, but not all patients with residual blood clots will develop CTEPH. A recent meta-analysis of 16 studies reported that approximately 3% of PE survivors develop CTEPH.^1–3

What are the risk factors for developing CTEPD and CTEPH?

The exact cause of CTEPD and CTEPH is unknown. In general, obesity, smoking, pregnancy, or use of oral contraceptives containing estrogen increase the risk of developing blood clots (including PE). Most patients (75%) have a history of a PE, and most are ‘unprovoked’ PE.^1–3 A blood clot is considered ‘unprovoked’ when there is no clear trigger for the event (e.g., surgery, prolonged immobilization > 72 hours during or after a hospitalization, or long periods of inactivity such as car rides or flights > 6 hours).^1–3

Other factors that may increase the risk of CTEPD or CTEPH include a history of cancer, chronic inflammatory diseases, low thyroid hormone levels, non-O blood type groups, prior spleen removal, long-term intravenous catheter use, history of prior blood clot events, certain medical conditions, and blood-clotting disorders (hypercoagulable state or thrombophilia).^1–4 Antiphospholipid syndrome (APS) is a blood clotting disorder that is particularly associated with an increased risk for CTEPH. In one study, 20% of patients with CTEPH also had APS antibodies.^1–3 Interestingly, up to 25% of patients with CTEPH do not carry a prior history of PE.

Unfortunately, the natural course of post-PE syndrome remains poorly understood and challenging to characterize because there can be months to years between the initial PE event (which may go undetected) and the CTEPD and CTEPH diagnosis.^1–3

What are the signs and symptoms of CTEPD and CTEPH?

CTEPD and CTEPH are difficult to diagnose because the symptoms are nonspecific and can resemble other heart and lung disorders like asthma, chronic obstructive pulmonary disease (COPD), obesity (overweight), and congestive heart failure. Common signs and symptoms include progressive shortness of breath and/or fatigue, especially during exercise or when climbing stairs. When CTEPH develops, more severe symptoms may occur, including fluid retention with swelling of the feet, ankles, legs, and/or abdomen; dizziness or fainting spells; intermittent chest pain, tightness, or pressure; palpitations (heart pounding in the chest); dry cough; and in rare cases, coughing up blood.^1–3 The oxygen levels in the blood may become very low, making the lips, fingers, or skin turn blue. ⁵

What are the potential complications of CTEPH?

High pressures in the arteries of the lungs due to CTEPH can affect the heart. CTEPH can make it harder for the right side of the heart to pump blood into the lungs, resulting in right heart enlargement and failure. Failure of the right side of the heart can also lead to the signs and symptoms described above (fatigue and fluid retention with swelling of the feet, legs, ankles, and abdomen). ⁵

How are CTEPD and CTEPH diagnosed?

Diagnosis of post-PE syndrome remains challenging because of the nonspecific signs and symptoms, particularly in the early stages. Therefore, following up after an acute PE is crucial in the early detection of CTEPD and CTEPH.

Importantly, patients who experience any of the signs and symptoms described above should be evaluated by their healthcare provider for pulmonary hypertension, even if they do not have a history of blood clots.

To help with diagnosis, the following tests might be performed:

• • Echocardiogram (echo): An echo is an ultrasound of the heart and is usually the initial test ordered. It provides detailed information on the size and function of the right side of the heart, which is abnormal in pulmonary hypertension.

• • Chest X-ray: The lung and heart may appear to be normal in CTEPH, or the X-ray may reveal an enlarged heart or enlarged central pulmonary arteries.

• • Computed tomographic pulmonary angiography (CT PA): CT PA is a type of CT scan with administration of an intravenous contrast agent (dye) that can reveal subtle findings suggestive of chronic blood clots in the blood vessels in the lungs.

• • Ventilation/perfusion (V/Q) lung scan: This nuclear medicine scan is the best imaging test for patients with signs and symptoms suspicious for CTEPD and CTEPH. During the V/Q scan, a special material (radioisotope) is injected into a vein and measures the airflow (ventilation) and blood flow (perfusion) inside of the lungs. A normal V/Q lung scan can safely rule out both CTEPD and CTEPH. ¹

• • Right heart catheterization (RHC): This is the confirmatory test for the diagnosis of CTEPH. RHC involves the insertion of a small rubber tube (catheter) into a vein in the neck, arm, or groin. It is then advanced to the right-sided heart chambers and pulmonary arteries to measure the blood pressure. These measurements help to determine the severity of the pulmonary hypertension. The RHC is complemented with pulmonary arteriography. In this test, a contrast agent is injected into the pulmonary arteries to help identify the location and extent of blood clots.^1,2,5–7 These tests are helpful to distinguish between CTEPD and CTEPH. Patients with CTEPD do not have elevated pressures during a resting RHC, but CTEPH patients do.^1,2,5–7

Table 1 summarizes the similarities and differences between CTEPD and CTEPH.

Table 1.

Similarities and differences between CTEPD and CTEPH.

Diagnostic criteria	CTEPD	CTEPH
Symptoms	With activity	At rest and with activity
TTE	Normal or abnormal	Abnormal
Lung V/Q scan	Abnormal	Abnormal
CTPA	Abnormal	Abnormal
RHC	Normal at rest; abnormal with exercise	Abnormal at rest
Anticoagulation (blood thinners)	Evaluate risk–benefit	Lifelong

CTEPD, chronic thromboembolic pulmonary disease; CTEPH, chronic thromboembolic pulmonary hypertension; CTPA, computed tomographic pulmonary angiography; RHC, right heart catheterization; TTE, transthoracic echocardiography; V/Q, ventilation/perfusion.

What are the treatments for post-PE syndrome, CTEPD, and CTEPH?

To prevent blood clot recurrence, a lifetime regimen of blood thinners is recommended for patients with CTEPD and CTEPH. Anticoagulants are not necessarily recommended for all patients with post-PE syndrome. The duration of anticoagulation after a PE will depend on the underlying reason for the PE and other patient-related factors, such as bleeding risk and other chronic diseases. Warfarin was used for many years, but a newer type of blood thinner called direct oral anticoagulants (DOACs, e.g., apixaban and rivaroxaban) have been prescribed more frequently over the last decade.^8,9 If blood oxygen levels are low, some patients may need supplemental oxygen. Exercise is encouraged and can improve breathing and endurance. To help achieve the goal of restoring the patient to better health, pulmonary rehabilitation programs offer a supervised medical exercise program.

What additional treatment may be needed for CTEPH?

All patients with CTEPH should be evaluated by a multidisciplinary and multispecialty team at an expert center, as outlined in Table 2. Additional treatment may be necessary, including surgery, endovascular therapy (minimally invasive procedures), and other medications. A combination of procedures and/or medical therapy has been increasingly utilized in these patients, as outlined below, and illustrated in Figure 1. ¹⁰

• • Surgery: Certain patients may be candidates for a surgical intervention called pulmonary endarterectomy (PEA), in which chronic blood clots are removed from the pulmonary vessels. PEA may offer a cure for CTEPH and is the most effective way to improve pulmonary hypertension. Therefore, it is considered the first-line treatment for CTEPH, although it is a major surgical procedure similar to other types of open-heart surgery.^1,2

• • Endovascular therapy: Some patients may not be good candidates for surgery. For example, the lung blood clots may not be located in large enough arteries to allow surgical instruments to reach them, or some patients may not be strong enough to survive such a complex surgery due to other medical problems. In these cases, medical therapy (discussed below) and/or an endovascular procedure called balloon pulmonary angioplasty (BPA) should be considered.^1,2,9,10 During this minimally invasive procedure, a catheter with a balloon in its tip is introduced into the pulmonary arteries and inflated, displacing the blood clots and restoring blood flow. Multiple (three to six) BPA sessions may be required depending on the extent of the clots.^1,2,9,10 Complications may occur in ~10–15% of BPA sessions, including bleeding inside of the lungs (pulmonary hemorrhage), coughing up blood (hemoptysis), pulmonary vascular injury, and/or pulmonary artery perforation/dissection. The mortality rate related to BPA is around 3–4%.^1,2,9,10

• • Medications: Pulmonary vasodilators are medications that dilate or ‘open up’ the pulmonary arteries, reducing the elevated pressures within the lungs.^9,10 Currently, riociguat is the only medicine approved by the US Food and Drug Administration for treatment of CTEPH.^9,10

Table 2.

Key members of a multispecialty/multidisciplinary physician team for patients with CTEPD and CTEPH.

• Pulmonologist or cardiologist with expertise in pulmonary hypertension • Cardiologist with expertise and training in performing BPA • Cardiothoracic surgeon with expertise in performing PEA • Cardiothoracic radiologist and nuclear medicine specialist with expertise in imaging studies • Vascular medicine specialist or hematologist with expertise in the management of blood thinners and hypercoagulable states • Cardiovascular anesthesiologist with expertise in cardiac surgeries like PEA

BPA, balloon pulmonary angioplasty; CTEPD, chronic thromboembolic pulmonary disease; CTEPH, chronic thromboembolic pulmonary hypertension; PEA, pulmonary endarterectomy.

Figure 1.

CTEPH multimodality therapeutic algorithm. Once the diagnosis of CTEPH is confirmed, patients are evaluated for PTE surgery. In cases deemed unsuitable for surgery or those with an unacceptable risk for complications during or after the surgery, targeted medical therapy and/or BPA may be considered. Often patients undergo combined medical therapy and BPA for optimal results.

Additional information

The following list includes helpful website resources of professional scientific organizations that provide valuable information for patients with pulmonary hypertension and CTEPH.

• • Pulmonary Hypertension Association (PHA)

• • International CTEPH Association

• • PHA Europe (European Pulmonary Hypertension Association)

• • American Thoracic Society (ATS)

• • American Heart Association (AHA)

• • American College of Chest Physicians (ACCP) Chest Foundation

• • National Organization for Rare Diseases (NORD)

• • American Lung Association (ALA)

Conclusion

In patients who survived an acute PE episode, the post-PE syndrome may occur, representing a well-known complication. CTEPD and CTEPH may not cause signs or symptoms in the early stages but represent important long-term consequences of PE. They may also develop in patients without a prior history of blood clots. Diagnostic testing can differentiate CTEPD from CTEPH. A specialized, multidisciplinary team can personalize evaluation and treatment, with the goals of improving quality of life and survival.