Chronic thromboembolic pulmonary hypertension

Introduction

Venous thromboembolism (VTE), despite increasingly used primary prevention is still a serious epidemiological, clinical, and social problem and its serious complications like pulmonary thromboembolic hypertension and posthrombotic syndrome are associated with a significant reduction in quality of life and often lead to disability [1].

Epidemiological data on the prevalence of VTE are divergent. It is well known, VTE is ranked among three most common cardiovascular diseases along with coronary heart disease and stroke [2].

The precise incidence of deep vein thrombosis in both legs (DVT) and pulmonary embolism (PE) in the population is difficult to determine, due to the fact that the clinical symptoms of both diseases are nonspecific. In patients with confirmed DVT, symptoms like pain and swelling of the limbs do not occur in more than half of the cases, and half of the patients with typical DVT symptoms can be excluded from performing objective tests.

Clinical presentation of acute pulmonary embolism is also nonspecific, and because of diagnostic errors it is not diagnosed in the acute phase [3, 4]. Relying on autopsy findings in hospitalized patients, it is known that even 60–70% of fatal PE is not diagnosed intravitaly [5–7]. Therefore, approximately two thirds of VTE cases remain undiagnosed [8]; 20-50% of patients with a history of deep vein thrombosis develop post thrombotic syndrome [9].

Chronic thromboembolic pulmonary hypertension (CTEPH), defined as mean pulmonary artery pressure ≥ 25 mm Hg lasting for more than 6 months after acute episode of PE [10], is a relatively rare complication of acute pulmonary embolism. However, it should be noted that its exact occurrence is still unknown.

Epidemiology

Incidence of CTEPH is estimated at 0.5–3.8% in patients with clinically confirmed acute PE [11, 12] while in patients with right heart overload in the course of pulmonary embolism this parameter rises to 7% [13].

Chronic thromboembolic pulmonary hypertension commonly develops in patients with a history of unrecognized and/or not properly treated acute PE episode. Accordingly to published data 36–70% of patients are positive in respect of previous pulmonary embolism episode [4, 14-17].

Therefore, the actual incidence of CTEPH seems to be significantly higher. Houk and colleagues [18] analyzed in 1963 data of 240 patients with chronic occlusion of pulmonary vessels with thromboembolic material, stating that the disease was correctly diagnosed intravitaly only in 6 patients.

Pathogenesis

Chronic thromboembolic pulmonary hypertension pathogenesis remains complex and unclear, and is probably multifactor. Thrombi resting in pulmonary circulation after acute PE episode develop resolution in one of three mechanisms: fragmentation, dissolution by the endogenous fibrinolytic system and by recanalization.

Incorrect organization of the thromboembolic material is considered as the principal mechanism of CTEPH development after acute or recurrent PE episodes, usually clinically silent. Thrombus in the pulmonary arteries become incompletely recanalised, and the remaining residue progressively fibrotise narrowing caliber of the vessels, which causes an increase in pulmonary vascular resistance and progressive right-heart failure. Overloaded right ventricle becomes hypertrophic, and then progressively expanded which leads to its failure, development of low cardiac output syndrome and death.

Some authors’ posts express the views that the disease results of local clotting in the pulmonary artery and its branches [19]. This thesis corresponds with the fact that almost half of the patients denied history of acute PE prior to disease development [4, 14, 15]. In addition, as early as 1973 Moser and Braunwald found intimae proliferation, medial hypertrophy associated with blood clotting in the vessels of the pulmonary microcirculation in histopathological bioptates obtained with surgical pulmonary endarterectomy. Similar findings were observed in patients with idiopathic pulmonary arterial hypertension [20]. It’s still unclear why the complete dissolvement of the thrombus does not occur in some patients. Based on available data CTEPH risk factors were identified. Those include, among others: recurrent PE episodes, idiopathic PE, large perfusion defects in imaging testing, high pulmonary hypertension in course of acute PE, anticardiolipin antibodies or lupus anticoagulant in serum, splenectomy, neoplasm, thyroid hormone replacement therapy [21]. CTEPH risk factors are shown in table 1 [21].

Table 1. Chronic thromboembolic pulmonary hypertension risk factors [21]

Tabela 1. Czynniki ryzyka rozwoju przewlekłego zakrzepowo-zatorowego nadciśnienia płucnego [21]

Chronic thromboembolic pulmonary hypertension risk factors

Czynniki ryzyka rozwoju przewlekłego zakrzepowo-zatorowego nadciśnienia płucnego

Factors related to pulmonary embolous/Czynniki związane z zatorem tętnicy płucnej

  • Idiopathic character of pulmonary embolous/idiopatyczny charakter zatoru tętnicy płucnej

  • Recurrent character of pulmonary embolous/nawrotowy przebieg zatoru tętnicy płucnej

  • Extensive perfusion defects related to pulmonary embolous /rozległe zaburzenia perfuzji związane z zatorem tętnicy płucnej

  • Advanced and younger age of pulmonary embolous onset/starszy i młodszy wiek wystąpienia zatoru tętnicy płucnej

  • High pulmonary hypertension (> 50 mm Hg) during the acute pulmonary embolous episode/wysokie nadciśnienie płucne (> 50 mm Hg) podczas ostrego epizodu zatoru tętnicy płucnej

  • Persistent pulmonary hypertension 6 months after an acute pulmonary embolous episode/utrzymujące się nadciśnienie płucne po 6 miesiącach od wystąpienia ostrego epizodu zatoru tętnicy płucnej

Coexistent chronic diseases/Przewlekłe schorzenia towarzyszące

  • Surgical vascular anastomoses or intracardiac electrodes/obecność chirurgicznych połączeń naczyniowych lub elektrod wewnątrzsercowych

  • Splenectomy/stan po splenektomii

  • Chronic inflammatory condition/obecność przewlekłych stanów zapalnych

  • Thyroid hormone supplement therapy/suplementacja hormonów tarczycy

  • Neoplasms/nowotwory

Hypercoagulation factors/Czynniki zwiększające krzepliwość krwi

  • Lupus anticoagulant or anticardiolipin antibodie/antykoagulant tocznia lub przeciwciała antykardiolipinowe

  • Elevated factor VIII/podwyższone stężenie czynnika VIII

  • Dysfibrynogenemia/dysfibrynogenemia

Genetic factors/Czynniki genetyczne

  • Blood group other than 0/grupa krwi inna niż 0

  • HLA genes polymorphism/polimorfizm genów HLA

  • Incorrect endogenic fibrinolysis/nieprawidłowa endogenna fibrynoliza

The clinical presentation

Nonspecific clinical presentation of the disease in the initial period, insidious and progressive course and lack of awareness CTEPH in both medical and patients’ community results in significant delay from onset of symptoms to diagnosis. Clinical symptoms usually appear when more than 40% of vessels in pulmonary circulation become obliterated.

CTEPH clinical presentation is unspecific. As in other forms of pulmonary hypertension is the main symptom of progressive reduction in exercise tolerance due to shortness of breath or fatigability. Patients often seek help from doctors of different specialties, are diagnosed in the direction of lung diseases (asthma, interstitial disease), heart disease (coronary artery disease, valvular disease) or mental disorders. Initially, shortness of breath and fatigue results only from a large effort. Progressively, significant reduction in physical activity tolerability occurs and finally dyspnoea at rest occurs.

Later, in the natural history of the disease, fully-clinically presented right-heart failure develops with presincope, faintness resulting from the reduced right ventricle output, or exercise angina associated with effort coronary pain syndrome, hepatomegaly, ascites, legs swelling, pleural and pericardial effusion. Rarely right ventricle hypertrophy can provoke cardiac arrhythmias, including atrial fibrillation.

The physical examination prior to the right heart failure decompensation CTEPH has no pathognomonic importance. Hiperaccentation of pulmonary component of II heart tone can be detected with auscultation as in other forms of pulmonary hypertension patients may present over-filled jugular veins with venous pulse and the tricuspid regurgitation murmur deepening with the in-breath.

Characteristic and differentiating thromboembolic etiology symptom is a vascular murmur interscapular region probably due to the turbulent blood flow through the obliterated pulmonary vessels. However, it is not a common symptom, can be found in approximately 30% of patients [1].

The presence of chronic venous insufficiency symptoms, especially post thrombotic syndrome in patients with pulmonary hypertension may also suggest the thromboembolic etiology of the disease.

Diagnosis

Transthoracic echocardiography still remains a valuable initial diagnostic tool in suspected pulmonary hypertension. Due to its non-invasive nature of which is used either in screening of pulmonary hypertension and also to monitor patients undergoing invasive procedures or in assessing the treatment efficacy. Transthoracic echocardiography with Doppler flow imaging is a useful test that allows to suspect pulmonary hypertension if it finds a tricuspid valve (TVPG) > 30 mm Hg. Except some rare cases, when the thrombus in the proximal pulmonary artery branches [22] can be visualized, the echocardiography usually cannot confirm the etiology of thromboembolic pulmonary hypertension. While transthoracic echocardiography allows an initial differential diagnosis, allows pre-estimate the pulmonary artery pressure and assess right ventricular function.

One of the initial signs of right-heart overload is hypertrophy, resulting in tricuspid ring dilatation and its functional failure. Usually seen as dilated pulmonary trunk enlargement is usually seen, and in an advanced stage – also hypertrophy of the right atrium. Hypertrophic right-heart cavities can compress left-heart cavities significantly worsening the prognosis. Also inferior vena cava extended, which loses its respiratory mobility and natural collapse during inspiration, which is a consequence of increased pressure in the right atrium. The pericardiac effusion in expression of right-heart failure and is associated with the poor prognosis.

The perfusion-ventilation pulmonary scintigraphy is used in diagnostics of CTEPH. The lack of abnormalities can practically exclude the diagnosis of CTEPH. Detection of at least segmental perfusion defects differentiates arterial and thromboembolic pulmonary hypertension [23].

However, disposing perfusion-ventilation pulmonary scintigraphy cannot determine precisely anatomical location and upon on this – qualify a patient for surgery.

An integral component of CTEPH diagnostic process is angiography using multi slice spiral computed tomography of the chest. This study allows the visualization of the pulmonary arteries to the level of subsegmental arteries, wide assessment of the pulmonary artery and to investigate the characteristics of right ventricular enlargement as its dimensions. In addition, CT scans to exclude other conditions of the clinical picture, which may suggest CTEPH such as interstitial lung disease, mediastinal disease, adenopathy, anomalies, and pulmonary tumors. An additional advantage is the possibility of computed tomography assessment of the exact location and extent of changes in the proximal pulmonary arteries prior to any qualification of patients for surgery. Sensitivity is the largest computed tomography in the assessment of lesions located in the main and lobar arteries and decreases gradually segmental vessels [24].

Equally efficient diagnostic tool, especially in imaging of proximal pulmonary vessels is magnetic resonance angiography [12]. This test has limited sensitivity (78%) in the diagnostic of acute CTEPH [25, 26].

Pulmonary arteriography combined with right heart catheterization remains a diagnostic gold standard in the diagnosis of chronic thromboembolic pulmonary hypertension. It allows excluding other pathologies provoking pulmonary hypertension confirms thromboembolic etiology, enables the assessment of the severity and location of the lesions in the pulmonary circulation. It is an essential test in qualification for surgical treatment [1].

Angiographic image of chronic thromboembolic pulmonary hypertension with characteristic meanders of irregular outline formed on the recanalization and organized thrombi differs significantly from findings in acute pulmonary embolism with its well marked and bounded intravascular contrast defect. However, this study, because of its invasive nature and the need to accurately assess the location and nature of the changes before a decision about surgical treatment, should be performed at qualified facility co-working with an experienced team performing cardiac pulmonary endarterectomy procedures. Pulmonary angiography examination precedes right heart catheterization, which most accurately evaluates the pulmonary artery pressure and the severity of the disease. The test measures the heart rate, right atrial pressure (RAP), pulmonary artery pressure (PAP), systolic, diastolic and mean pulmonary capillary wedge pressure (PCWP), the mean artery pressure (MAP), mixed venous saturation (MVSAT), and oxygen saturation of arterial blood. Other measures are calculated: pulmonary vascular resistance (PVR), total pulmonary resistance (TPR), systemic vascular resistance (SVR), cardiac output (CO) calculated by thermodilution, cardiac index (CI) [27]. Pulmonary hypertension is diagnosed if the mean pulmonary artery pressure is ≥ 25 mm Hg. Figure 1 shows the diagnostic algorithm for CTEPH.

Chronic thromboembolic pulmonary hypertension

Figure 1. Diagnostic algorithm of chronic thromboembolic pulmonary hypertension [21]

Rycina 1. Algorytm diagnostyczny przewlekłego zakrzepowo-zatorowego nadciśnienia płucnego [21]

Other tests used in the initial evaluation of the patient with CTEPH do not indicate the etiology of the disease, but may be useful in diagnostic. The deep venous ultrasonography of the lower limbs in 45% of patients with CTEPH reveals post-thrombotic changes [1].

The chest X-ray can determine hypo-perfusion and hyper-perfusion areas, dilated pulmonary artery trunk and increased right heart dimensions. In functional pulmonary evaluation lowering of diffusion lung capacity for carbon monoxide (DLCO) can be found in most patients and in approximately 20% of them are reported as moderate restrictions changes.

In gasometry, in advanced stages of the disease, remains chronic hypoxemia. In the ECG, in the initial phase deviations are not considered. With the progressive damage of the right ventricle the symptoms of hypertrophy and overload starts visible, with the presence of high R-wave in lead up from the right ventricle, there may be a block of the right branch block, negative T waves in leads over the front and bottom wall. Enlargement of the right atrium draws the presence of pulmonary P. ECG changes are not specific for thromboembolic pulmonary hypertension etiology.

A useful test for monitoring patients is a 6-minute walk test, because it reflects the severity of the disease and correlate well with clinical and hemodynamic evaluation of patients [28]. Bridging the gap in the study of marching is an expression of disease progression and therapy failure.

In blood biochemistry increased levels of troponin T and B-type natriuretic peptide can be observed, suggesting progressive myocardial damage of the right ventricle and are unfavorable prognostic factors [29].

Screening

Chronic thromboembolic pulmonary hypertension is significantly underestimated, too rarely suspected and diagnosed complication of VTE. If untreated, the disease leads to the development of right heart failure and death. However, if it is diagnosed in time and treated in some cases it is a potentially curable disease. Pulmonary hypertension is a challenge for clinicians. It should be actively investigated, identified, diagnosed and effectively treated.

For this purpose, it is important to distinguish CTEPH development risk groups by routine echocardiography testing in all patients after acute PE episode, especially prior to the decision to discontinue anticoagulation. In some places the control echocardiography is performed 12 weeks after acute PE episode [30]. Other researchers have found it useful to repeat echocardiography at 6 months after an acute PE episode [31]. It should also be considered performing a control echocardiography in patients with a history of DVT in the proximal segment, as it is known that clinically silent PE appears in 40-50% of patients in this group [32-35].

Treatment

Pulmonary endarterectomy is the treatment of choice for patients with CTEPH with changes localized in proximal pulmonary artery, which allows a significant release of symptoms and improvement in hemodynamic parameters and in particular reduce mortality in these patients [1, 36, 37].

This procedure consists of removal of organized thromboembolic material with the intima of pulmonary arteries to which the material is interwoven [15, 38, 39]. The procedure is performed in deep hypothermia with external circulation. Cardio surgeons from California University, San Diego, developed the technique of this complex procedure [40]. Pioneering operations were already performed at this centre in the 1960. Since 1970 they performed more than 2300 treatments of pulmonary endarterectomy of which more than 1300 patients were operated on after 1997 [41]. Over the years, improved technology has resulted in a significant reduction of perioperative mortality rate, which currently is of about 4.5% in this leading center [42]. In other world centers 30-day mortality does not exceed 10% [43–45]. The best candidates for surgical treatment are CTEPH patients with thromboembolic changes located in the main pulmonary artery stem and its branches, lobar artery or proximal segmental arteries. More distally located changes are not surgically accessible.

In Poland, the first successful pulmonary endarterectomy surgery was carried out by prof. Religa and prof. Zembala in the Department of Cardiosurgery, Silesian Medical University, Zabrze, Poland [46].

Results of dr Wieteska doctoral thesis evaluating the effectiveness of pulmonary endarterectomy performed by the team of prof. Biederman of the Department of Cardiac Surgery, Institute of Cardiology in Anin, Poland, in the treatment of right heart overload and failure in patients with thromboembolic pulmonary hypertension, demonstrated that patients treated surgically had more than 3 fold lower risk of death compared with those treated conservatively (midsurvival time in surgically treated group was 4.2 years in the group treated conservatively 1.6 years).

Periprocedural mortality rate in the center was 9.1%. Patients left in conservative treatment manifested more pronounced symptoms of congestive heart failure and had higher right atrial pressure than patients treated surgically [47].

Continuing anticoagulation is recommended to all patients with CTEPH, in the absence of contraindications, although randomized studies confirming the validity of such a procedure in this group of patients were not performed. The logical explanation for the use of anticoagulation is prevention of recurrence of VTE and prevention of rising thromboembolic process of pulmonary circulation in situ. The evidence of this strategy is also confirmed by randomized trials proving the reduction of recurrent VTE episodes in patients with a history of long-term treatment of idiopathic VTE.

Conservative treatment is used in cases where pulmonary endarterectomy cannot be performed, as the coexistence of diseases significantly increasing perioperative death risk or, in the case of thrombotic lesions located distally. About 10–50% of the patients and disqualified of the procedure [39]. In these patients, attempts are made to use therapies targeted for pulmonary arterioles. The rationale for the use of drugs affecting the pulmonary arterioles is similar pulmonary vascular remodeling in patients with CTEPH as found in pulmonary arterial hypertension, which demonstrated the efficacy of this treatment.

Reduced synthesis of nitric oxide and prostacyclin plays an important role in pathogenesis of pulmonary arterial hypertension causing endothelial damage and and increased synthesis of endothelin-1. These three elements are the bracket points for the appropriate treatment of both hypertension and thrombi-embolic pulmonary hypertension drugs inhibiting pulmonary vascular remodeling.

Prostacyclin is a tissue hormone produced by the endothelium possessing a strong relaxing effect on smooth muscles. In the treatment of its analogues are used: intravenous epoprostenol (not available in Poland), subcutaneous treprostinil, inhalable form – iloprost and oral formulation – beraprost (not available in Poland).

Other drugs effectively acting on the vascular dilation are nitric oxide and phosphodiesterase type 5 inhibitors: sildenafil used in oral form. Vasoconstriction factor strongly influencing on the pulmonary vessels is synthesized by endothelial endothelin. It also stimulates the proliferation of myocytes, possess prothrombotic and proinflammatory properties. Inhibitors of endothelin receptors, which include the non-selective, oral endothelin receptor antagonist: bosentan are also used in the treatment of pulmonary hypertension.

Accessory treatment

In addition to treatment focused on pulmonary arterioles, patients usually require symptomatic treatment. Diuretic therapy is used to reduce the initial load and oxygen therapy is recommended in case of hypoxemia. Symptomatic treatment reduces clinical signs, but does not affect the prognosis of patients with CTEPH [15, 48].

Summary

Chronic pulmonary hypertension in the course of venous thromboembolic disease is a rare, but potentially dangerous condition with nonspecific clinical presentation in early stage. While changes are located in the proximal parts of the pulmonary arteries an effective surgical procedure as pulmonary endarterectomy can be performed in the specialized centers. CTEPH should be kept in mind in the differential diagnosis of patients with dyspnoea, even in patients without a previous history of acute PE, and especially to promote active search for patients at risk by recommending mandatory screening echocardiography in all patients after an acute episode of PE with right heart overload and in patients with proximal leg DVT.

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