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Diagnosis & Treatment

WHO Group 4: Chronic Thromboembolic Pulmonary Hypertension

Overview | Definition | Epidemiology | Pathophysiology | Diagnosis | Treatment


Overview

Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is a form of pulmonary hypertension that results from the obstruction of the pulmonary vascular bed with chronic, organized thromboemboli. Though generally considered a rare disease, it is likely under-recognized, and if left untreated, can be life threatening. 

Common symptoms of CTEPH are similar to those of other types of pulmonary hypertension (PH), as well as those of other more common diseases, like asthma and chronic obstructive pulmonary disease. Most frequently reported symptoms include:

  • Progressive exercise intolerance
  • Fatigue
  • Exertional dyspnea

Patients may also report1

  • Chest discomfort
  • Light-headedness
  • Syncope
  • Hemoptysis
  • Peripheral leg edema

It is largely because these symptoms are nonspecific that the diagnosis of CTEPH can be overlooked. As is true in other types of pulmonary hypertension, CTEPH patients face many of the same barriers and miscues in establishing the correct diagnosis.2, 3 The subtleties of presentation and physical exam findings often lead the clinician astray and for those with CTEPH, diagnostic difficulties are confounded by the observation that up to 30% of patients have no overt history of an acute pulmonary embolism.4

In addition, due to the common misconception that patients lacking prior known history of DVT and/or PE are not at risk for CTEPH, patients are sometimes thought to have pulmonary arterial hypertension (PAH).5 Consequently, a high index of suspicion is essential in identifying patients with CTEPH. For those individuals presenting with inexplicable dyspnea and fatigue, pulmonary vascular disease should be considered; and for all patients with pulmonary hypertension, CTEPH needs to be ruled out.

Although it may present in much the same way, CTEPH is not PAH. CTEPH is unique among the five types of pulmonary hypertension (PH) in that it is potentially curable via pulmonary thromboendartectomy (PTE) surgery. This surgery is also sometimes referred to as a pulmonary endarterectomy (PEA). As such, PTE surgery is considered the treatment of choice for CTEPH, and every patient diagnosed with CTEPH should undergo evaluation by an expert CTEPH team and their candidacy for PTE surgery should be assessed.

Definition

Clinically, CTEPH is defined as:

  • Mean pulmonary artery pressure (mPAP) ≥ 25mmHg
  • Pulmonary occlusion wedge pressure (PAOP) <15mmHg
  • Presence of multiple chronic or organized occlusive thrombi or emboli in the elastic pulmonary arteries - main, lobar, segmental or sub-segmental - after at least three months of effective anti-coagulation.7 

Epidemiology

While the natural history and prevalence of CTEPH continues to be the focus of ongoing investigation, data from multiple observational studies has been helpful to better characterize the disease epidemiology.

  • CTEPH has an estimated incidence of 500-2,500 cases per year in the United States (1.6 to 7.9 cases per million population).8
  • 0.57% to 4.8% of patients may go on to develop CTEPH within 2 years of their first acute PE.9, 10

Pathophysiology 

CTEPH can result from a single pulmonary embolic event or recurrent pulmonary emboli.11

According to the widely held “embolic hypothesis,”12 these PE result in endothelialized residua that obstruct or significantly narrow pulmonary arteries. The basis for this transition is not completely understood, though failed thrombolysis, a localized inflammatory response (“inflammatory thrombosis”), “deficient angiogenesis” and/or localized endothelial dysfunction, may be operative in various ways.13 And although the inciting event may be the presence of organized thrombus within the pulmonary vascular bed, pulmonary hypertension and right ventricular overload eventually results from the development of a coexisting small-vessel arteriopathy in the unobstructed pulmonary vessels. This small vessel arteriopathy is characterized by medial hypertrophy, intimal proliferation and thickening, microthrombi formation, and plexiform lesions.14 The pathogenesis of this arteriopathy, which is similar to that seen in idiopathic PAH, remains unclear.15

Diagnosis

All patients in whom pulmonary hypertension is confirmed or suspected should undergo ventilation/perfusion (V/Q) scanning to exclude CTEPH. In addition, patients who have already been diagnosed with other forms of pulmonary hypertension but have not had a V/Q scan should have one to exclude CTEPH.17

A properly performed V/Q scan has excellent (90-100%) sensitivity and serves as an effective screening tool. Absence of perfusion defects (i.e. a normal perfusion scan) rules out operable CTEPH. However, the V/Q scan lacks specificity in that a number of competing diagnoses may manifest unmatched perfusion defects by V/Q scan. Consequently, additional diagnostic studies are required in the setting of an abnormal perfusion scan with three goals:

  1. To establish the diagnosis of chronic thromboembolic disease (CTED);
  2. To rule out competing diagnoses; and
  3. In the presence of CTED, to establish the proximal extent of disease within the pulmonary vascular bed. 

When interpretive expertise is available, CT angiography of the chest, conventional pulmonary angiography, and/or chest magnetic resonance (MR) imaging can provide the necessary information to confirm the diagnosis of CTEPH and to establish operability.18 Whether or not an individual patient is a candidate to undergo PTE surgery should be established at a clinical center with expertise in the diagnosis and surgical management of CTEPH patients. An assessment of pulmonary hemodynamics and right heart function, typically with right heart catheterization, is an essential component of this evaluation as it helps to establish operative risk.

Treatment

Without appropriate treatment, CTEPH patients typically experience profound functional disability with a relatively poor long-term survival.20, 21
However, a substantial number of CTEPH patients, pulmonary thromboendartectomy (PTE) surgery can potentially cure or reduce the debilitating pulmonary hypertension and right heart failure that characterizes this disease by restoring normal circulation to the pulmonary vessels.22

PTE Procedure

PTE is a 6-8-hour open chest procedure through which chronic clots and scar tissue are removed from the pulmonary arteries.

  • The patient is attached to a cardiopulmonary bypass machine, and their body temperature cooled to about 64-68 degrees Fahrenheit, reducing the body's need for oxygen and providing organ protection.
  • The cardiopulmonary bypass machine is turned off for intervals of up to 20 minutes per lung, creating a bloodless surgical field.
  • The pulmonary arteries are viewed and dissected, and organized clots removed from the lining of the pulmonary arteries. 

Not every patient is a candidate for PTE surgery, but every patient diagnosed with CTEPH should be evaluated by an expert CTEPH team, including CTEPH physicians and PTE surgeons, to assess their suitability for PTE surgery. 

Although formal criteria have yet to be standardized, disease in the small pulmonary arteries in patients with CTEPH may adversely impact affect surgical outcomes from pulmonary thromboendartectomy.23

Patients may be deemed inoperable due to:

  • Distal or inaccessible disease.24
  • Comorbidities
  • Imbalance between degree of elevation of pulmonary vascular resistance (PVR) and amount of accessible thromboembolic material.

Medical Therapy

Soluble guanlyate cyclase stimulators (Adempas® [riociguat]) are approved for the treatment of CTEPH. However, medical therapy should not be used in lieu of a careful evaluation for PTE at an expert center, and is only indicated for patients deemed not to be good candidates for PTE or for patients with residual pulmonary hypertension after PTE.25 

 

Authors

Ivan M. Robbins, MD
Vanderbilt University
April 30, 2015 

Bill Auger, MD
University of California, San Diego
April 29, 2015 

 

References

1 Fedullo PF, Kerr KM, Kim NH, et al. Chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2011;183(12):1605-1613. doi: 10.1164/rccm.201011-1854CI.

2 Piazza G and Goldhaber SZ. Chronic Thromboembolic Pulmonary Hypertension. N Engl J Med. 2011;364(4):351-360. doi: 10.1056/NEJMra0910203.

3 Tapson V and Humbert M. Incidence and prevalence of chronic thromboembolic pulmonary hypertension: from acute to chronic pulmonary embolism. Proc Am Thorac Soc. 2006;3(7):564-7. PMID: 16963534.

4 Pepke-Zaba J, Delcroix M, Lang I, et al. Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry. Circulation. 2011;124(18):1973-1981. doi: 10.1161/CIRCULATIONAHA.110.015008.

5 Piazza G and Goldhaber SZ. Chronic Thromboembolic Pulmonary Hypertension. N Engl J Med. 2011;364(4):351-360. doi: 10.1056/NEJMra0910203.

6 Piazza G and Goldhaber SZ. Chronic Thromboembolic Pulmonary Hypertension. N Engl J Med. 2011;364(4):351-360. doi: 10.1056/NEJMra0910203.

7 Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med. 2004;350(22):2257-2264. PMID: 15163775.

8 Tapson V and Humbert M. Incidence and prevalence of chronic thromboembolic pulmonary hypertension: from acute to chronic pulmonary embolism. Proc Am Thorac Soc. 2006;3(7):564-7. PMID: 16963534.

9 Fedullo P, Kerr KM, Kim NH, et al. Chronic thromboembolic hypertension. Am J Respir Crit Care Med. 2011;183(12):1605-1613. PMID: 21330453.

10 Guérin L, Couturaud F, Parent F, et al. Prevalence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism. Prevalence of CTEPH after pulmonary embolism. Thromb Haemost. 2014;112(3):598-605. doi: 10.1160/TH13-07-0538.

11 Fedullo PF, Kerr KM, Kim NH, et al. Chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2011;183(12):1605-1613. doi: 10.1164/rccm.201011-1854CI.

12 Humbert M. Pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: pathophysiology. Eur Respir Rev. 2010;19(115):59-63. doi: 10.1183/09059180.00007309.

13 Lang IM, Pesavento R, Bonderman D, et al. Risk factors and basic mechanisms of chronic thromboembolic pulmonary hypertension: a current understanding. Eur Resp J. 2013;41(2):462-468. doi: 10.1183/09031936.00049312.

14 Piazza G and Goldhaber SZ. Chronic Thromboembolic Pulmonary Hypertension. N Engl J Med. 2011;364(4):351-360. doi: 10.1056/NEJMra0910203.

15 Fedullo PF, Kerr KM, Kim NH, et al. Chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2011;183(12):1605-1613. doi: 10.1164/rccm.201011-1854CI.

16 Kim NH, Delcroix M, Jenkins DP, et al. Chronic thromboembolic pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 suppl):D92-D99. PMID:24355646.

17 Kim NH, Delcroix M, Jenkins DP, et al. Chronic thromboembolic pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 suppl):D92-D99. PMID:24355646.

18 Coulden R. State-of-the-art imaging techniques in chronic thromboembolic pulmonary hypertension. Proc Am Thorac Soc. 2006;3(7):577-583. PMID:16963537.

19 Auger WR, Kerr KM, Kim NH, et al. Evaluation of patients with chronic thromboembolic pulmonary hypertension for pulmonary endarterectomy. Pulm Circ. 2012;2(2)::155-162. PMID:22837856.

20 Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med. 2004;350(22):2257-2264. PMID:15163775.

21 Pepke-Zaba J, Delcroix M, Lang I, et al. Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry. Circulation. 2011;124(18):1973-1981. doi:10.1161/CIRCULATIONAHA.110.015008.

22 Jamieson SW, Kapelanski DP, Sakakibara N. Pulmonary endarterectomy: Experience and lessons learned in 1,500 cases. Ann Thorac Surg. 2003;76(5):1459-1464. PMID:14602267.

23 Galiè N and Kim NH. Pulmonary microvascular disease in chronic thromboembolic pulmonary hypertension. Proc Am Thorac Soc. 2006;3(7):571-576. PMID:16963536.

24 Pepke-Zaba J, Delcroix M, Lang I, et al. Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry. Circulation. 2011;124(18):1973-1981. doi:10.1161/CIRCULATIONAHA.110.015008.

25 Ghofrani HA, D'Armini AM, Grimminger F, et. al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369(4):319-29. doi: 10.1056/NEJMoa1209657.



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