Background
Pulmonary hypertension is divided into five distinct World Health Organization (WHO) groups, which are categorized according to similar pathophysiologic changes, clinical presentation, and available therapies. WHO group 4 is classified as pulmonary hypertension due to pulmonary artery obstructions, of which there are two subdivisions: (1) chronic thromboembolic pulmonary hypertension (CTEPH) and (2) other pulmonary artery obstructions. [1] CTEPH is defined by mean pulmonary arterial pressure (mPAP) greater than 20 mm Hg in the presence of organized, nonacute, thromboembolic material and altered vascular remodeling in the pulmonary vasculature. [2] It is a rare but life-threatening complication of acute pulmonary embolism (PE) and differs from other forms of pulmonary hypertension in terms of pathophysiology and treatment.
The 6th World Symposium on Pulmonary Hypertension Task Force on pulmonary hypertension diagnosis and classification has defined precapillary pulmonary hypertension by a mPAP greater than 20 mm Hg, a pulmonary artery wedge pressure (PAWP) less than 15 mm Hg, and a pulmonary vascular resistance (PVR) greater than 3 Wood units. These hemodynamic thresholds may be applied to CTEPH. Residual pulmonary vasculopathy without evidence of pulmonary hypertension is termed chronic thromboembolic disease (CTED). Despite clear criteria, CTEPH and CTED can be difficult to diagnose and appropriate evaluation is often delayed. There is, however, an increasing interest in CTEPH as the only surgically curable form of pulmonary hypertension. [3]
Pathophysiology
Pathological specimens in CTEPH look very different than in acute PE. The acute PE thrombus consists of a mesh of fibrin with red blood cells. Clots in CTEPH are yellow; contain collagen, fibroblasts, elastin, recanalization vessels, and inflammatory cells; and are firmly adhered to the vascular wall. [4] CTEPH presents with bands and webs, stenosis, and occlusion developing in the area of the former PE, primarily in large and median arteries. These changes cause a redistribution of blood flow to unobstructed vessels, thereby increasing the pressures and shear stress experienced by the vessels. [5] These vessels then show tendencies toward vasoconstriction, hypertrophy, and microvascular thrombi, and ultimately lead to vascular remodeling that lends itself to much higher pressures than originally expected, with eventual disease progression. [6] Alongside this, a pulmonary arteriopathy similar to the one developed in WHO group 1 pulmonary arterial hypertension (PAH) occurs in small, low-resistance vessels. [7] In patients with CTEPH, a reduction in the production of nitric oxide contributes to platelet dysfunction, vascular remodeling, and reduction of antiproliferative stimuli. [8] As the disease progresses, connections between the bronchial artery branches and precapillary pulmonary arterioles or veins can be formed, triggering further remodeling. [9]
The combination of small-vessel arteriopathy with in situ thrombosis, dysfunction of the pulmonary vascular endothelium, secretory abnormalities in the vascular active substances and cytokines, vascular remodeling, and macrovascular formation of bands and webs with obstruction and vasoconstriction results in pulmonary hypertension and right ventricular pressure overload and failure. [6] There is also an increase in PVR, which results in elevated pulmonary artery systolic pressure (PASP) that is usually greater than those observed in acute PE. [10]
Risk Factors
Multiple clinical conditions may predispose to CTEPH (see below). [11] It is well known, for example, that patients with cancer have an increased risk of developing thromboembolic events resulting from activation of fibrinolytic and coagulation systems, acute-phase reactions, inflammation, and cytokine production. [12] CTEPH is also most common in patients with non-O blood groups; 77% of patients with CTEPH have this blood group, compared with 58% in patients with PAH. [13] Patients with CTEPH have a higher prevalence of abnormal fibrinogen molecule (Aα-Thr312A1a mutation), and levels of thrombin-activatable fibrinolysis inhibitor, an enzyme that inhibits fibrinolysis, are higher in CTEPH patients. [14] Certain platelet-activating conditions (eg, thyroid hormone therapy) and splenectomy are associated with increased CTEPH risk, which suggests a role for platelets in this disease. [15] Levels of C-reactive protein are elevated in patients with CTEPH, and they decrease after pulmonary thromboendarterectomy (PTE), which suggests there may be an inflammatory component to CTEPH development. [16] Other inflammatory markers (eg, interleukin 10, monocyte chemotactic protein-1, macrophage inflammatory protein-1α, and matrix metalloproteinase 9) are also elevated in CTEPH. Chronic Staphylococcus aureus infection has also been identified in CTEPH patients, and some postulate that thrombus infection is a trigger for the development of this entity. [17] Impaired angiogenesis, biological factors, and genetic factors have also been associated with CTEPH.
Risk factors for the development of CTEPH
Acute PE-related risk factors are as follows:
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Recurrent pulmonary embolic events
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Large perfusion defect
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Higher pulmonary artery pressure at the time of initial PE diagnosis
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Idiopathic (unprovoked) PE
Hemostatic risk factors are as follows:
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Elevated factor VIII, von Willebrand factor, or type 1 plasminogen activator inhibitor
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Abnormal fibrinogen structure
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Antiphospholipid antibodies and lupus anticoagulant
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Non–type-O blood groups
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Elevated lipoprotein(a)
Associated medical conditions are as follows:
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Splenectomy
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Ventriculoatrial shunt
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Infected intravenous catheters/devices
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Chronic inflammatory disorders
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Hypothyroidism
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Malignancy
Epidemiology
According to registry data, there are no sex differences in the prevalence of CTEPH. The average age onset is usually in the 60s. Nonresolution of PE is the most common cause of CTEPH. [7] In a European registry, 75% of patients with CTEPH reported previous PE. [15]
The incidence of CTEPH after acute PE is not clear. A review estimates that the full incidence of CTEPH in the United States is 4,886 cases per year, [18] based on an incidence of CTEPH after PE of 0.57% reported by Klok et al. [19] Possibly the most quoted study related to PE incidence was published in the New England Journal of Medicine in 2004. [20] In this study, 223 patients with acute PE and without a previous venous thromboembolic event were followed for 10 years. Seven (3.8%) of 223 patients developed symptomatic CTEPH 2 years after the initial thromboembolic event. Other studies corroborated the fact that the majority of CTEPH cases developed 2 years after the initial event of acute PE. [21] Historically, between 0.1% and 0.5% of patients with PE were thought to develop CTEPH. [3] In 2006, another study showed that CTEPH developed in 1% of patients with acute PE, but this study excluded patients with known venous thromboembolic risk development. Since then, other studies have revealed a prevalence of 0.4-4.8%. [22] These rate differences are likely due to the different populations studied, different methods of screening, and follow-up duration. In summary, irrespective of the rate of CTEPH from PE used in estimates, it is clear that a large proportion of CTEPH cases are underdiagnosed each year. Factors contributing to this underdiagnosis and treatment include poor specificity of initial signs and symptoms and unknown PE history at presentation. [7]
The epidemiological analysis suggests that the full incidence of CTEPH in the United States and Europe ranges from 3-5 cases per 100,000 population per year. The average diagnosis rate was 14.2% for the United States and Europe in 2013, which equates to a diagnosed incidence of 4-7 cases per million. Although the incidence of PE in Japan is substantially lower than the incidence observed in United States and Europe, the rate of CTEPH is much higher. This disparity might be related to genetics, population demographics, or lifestyle, among other factors. An alternative explanation is that only severe cases of PE might be diagnosed, while mild cases might not be recognized or reported. [23]
Not only diagnosis, but also proper referral to an expert center, seem to be delayed in CTEPH. In one study, the mean delay from symptom onset to diagnosis of CTEPH was 18 ±26 months. This also transpires in the severity of disease, since most of the patients present with WHO functional class III and IV. [24] Late diagnosis can negatively impact treatment options and overall quality of life.
Epidemiological projections in seven countries indicate that the incidence of CTEPH, especially late-stage disease, will increase over time from 32,636 cases (16%) diagnosed in 2015 to 37,009 cases (28%) in 2025. [25]
Prognosis
In a 3-year span, outcomes comparing PTE versus medical therapy for the diagnosis of CTEPH revealed a survival rate of 89% versus 70%, respectively. Factors that influence these outcomes include old age (>70 years), residual postoperative pulmonary hypertension, intraoperative complications or additional cardiac surgeries, patient comorbidities (eg, coronary artery disease, chronic obstructive pulmonary disease, heart failure, history of cancer or dialysis), and factors related to the extent of the disease, including elevated right atrial pressure (RAP), WHO functional class IV, and PVR greater than 15 Wood units. [26, 27] Of patients undergoing PTE, 17-30% had residual pulmonary hypertension and postoperative PVR is an independent risk factor for in-hospital and 1-year mortality. [28]
Patient Education
Patients should be educated about the symptoms of CTEPH. If the patient is a surgical candidate, detailed information about the procedure itself, risks, benefits, and prognosis should also be discussed at an expert center. If the patient is not a surgical candidate, education about the importance of strict medication and diet adherence to avoid progression of symptoms should be emphasized. Symptoms that require prompt medical evaluation and treatment should also be communicated to patients. Patients also should be encouraged to comply with weight and fluid monitoring.
The following further patient resources from medical societies are also available:
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American Thoracic Society: Chronic Thromboembolic Pulmonary Hypertension
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CHEST Foundation: Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
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Ventilation perfusion scan showing bilateral large wedge-shaped mismatched perfusion defects and areas of gray indicating decreased perfusion. Right-sided heart catheterization for this patient showed combined precapillary and postcapillary pulmonary hypertension and the following: right atrial pressure 10 mm Hg, right ventricular pressure 82/8 mm Hg, pulmonary artery wedge pressure 22 mm Hg, and pulmonary artery pressure 83/27 mm Hg with a mean of 49 mm Hg. He was referred to an expert center for pulmonary endarterectomy evaluation, where he underwent pulmonary angiography. Findings from the right side showed an occluded upper lobe anterior segment, a proximal web in the upper lobe, and disease in all lower segments. Findings from the left side showed an occluded superior segment of the lower lobe with disease in basal segments, proximal web in lingula, and intact upper lobe vessels. He underwent pulmonary endarterectomy with intraoperative University of California San Diego classification of thrombus as right 1 and left 2. Postoperatively, he has had dramatic improvement in his symptoms and is off all pulmonary arterial hypertension therapy.
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Extensive pulmonary emboli are seen in both lungs, with a dominant, eccentric thrombus related to the left main pulmonary artery. More distal emboli were noted in the subsegmental pulmonary arteries (not shown). This is a 42-year-old woman with a history of multiple pulmonary emboli and protein S deficiency who initially presented with severe dyspnea (New York Heart Association functional class IV) and was initiated on multiple pulmonary arterial hypertension medications, including intravenous prostacyclin. She underwent pulmonary endarterectomy, and the images of the clots that were removed intraoperatively are shown in another image.
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The heart is enlarged, with right atrial and ventricular enlargement in addition to reflux of contrast into the intrahepatic inferior vena cava. The main pulmonary artery itself measures approximately 3 cm. There was mosaic attenuation of both lungs, most pronounced related to the right-middle and upper lobes (not shown).
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Mosaic pattern seen on expiratory images of a chest CT scan in a patient with chronic thromboembolic pulmonary hypertension. The same patient’s ventilation/perfusion scan is also shown. The areas of hypovascularity in blood vessels with clots cause areas of relative hypoperfusion, which appear darker than normal lung and give rise to the differential opacities seen on this image.
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Intraoperative clot during pulmonary endarterectomy. This is a 42-year-old woman with a history of multiple pulmonary emboli and protein S deficiency who initially presented with severe dyspnea (New York Heart Association functional class IV) and was initiated on multiple pulmonary arterial hypertension medications, including intravenous prostacyclin. Preoperative right-sided heart catheterization showed right atrial pressure of 16 mm Hg, pulmonary artery pressure of 124/29 mm Hg with a mean of 67 mm Hg, cardiac output of 4.53, and pulmonary vascular resistance of 12 Wood units. Immediate postoperative right-sided heart catheterization showed right atrial pressure of 9 mm Hg, pulmonary artery pressure of 40/15 mm Hg with a mean of 25 mm Hg, cardiac output of 5.15, and pulmonary vascular resistance of 2.9 Wood units. She came off all her pulmonary arterial hypertension therapy immediately postoperatively and continues to do well.
