**3. Risk factors for CTEPH**

To better identify patients with pulmonary embolism who are more likely to develop CTEPH, many studies have assessed the potential risk factors for CTEPH including demographic factors, the specific details of pulmonary embolism, the presence of co-morbidities and underlying thrombophilia (table 1) [23, 30]. An increased risk of CTEPH is associated with splenectomy, cancer, chronic inflammatory diseases (Crohn's disease and ulcerative colitis), hypothyroidism, an atrioventricular shunt and infected cardiac pacemaker [30, 31]. Compli‐ cations associated with pulmonary embolism such as acute perfusion defects, idiopathic, recurrent thromboemboli, massive pulmonary emboli, and delayed diagnosis may also predispose patients to CTEPH. Patients older than 70 years whose systolic pulmonary artery pressure is above 50 mmHg have a higher risk of persistent pulmonary hypertension one year after an acute pulmonary embolism [30, 32].

Independent clinical risk factors for CTEPH

• Splenectomy

**2. Epidemiology of CTEPH**

144 Pulmonary Hypertension

Pulmonary embolism (PE) is a common condition with an annual incidence estimated at 50 per 100,000 persons [12]. This is an acute disease and usually reversible after anticoagulation and / or after thrombolysis. Patients are frequently deemed to be "cured" after treatment. However, studies based on V/Q lung or computed tomography pulmonary angiogram (CTPA) reported the presence of residual perfusion disorders after acute pulmonary embolism [13]. Other echocardiographic studies have also shown that 30% of patients with PAH have residual or impaired right ventricular wall motion abnormalities and functional impairment after acute pulmonary embolism [14]. These data suggest that a significant proportion of patients with acute symptomatic PE develop persistent pulmonary vascular sequelae with serious long-term consequences [14.15]. Initial estimates of the frequency of CTEPH are of the order of 0.1% to 0.5% of patients surviving an episode of acute pulmonary embolism [16, 17]. More recent data suggest that 1% to 4% of patients may develop CTEPH after a first episode of pulmonary embolism [18, 19]. This frequency is even higher after recurrent thromboembolic events [20].

In a series of 866 patients with acute pulmonary embolism, all patients who had not previously been diagnosed with pulmonary hypertension (PH) and had survived until inclusion in the study were asked to undergo echocardiography. Patients suspected of having PH by echo‐ cardiogram underwent complete assessment to test chronic thromboembolic pulmonary hypertension. This procedure includes V/Q scintigraphy and right heart catheterization. The

In a prospective study, after a first episode of symptomatic pulmonary embolism for pa‐ tients with unexplained persistent dyspnea, echocardiographic abnormality, a V/Q scan, pulmonary angiography, and right heart catheterization, the cumulative incidence of symptomatic CTEPH was 1.0% at six months, 3.1% at one year and 3.8% at two years [23]. In another study of 320 patients who presented with a symptomatic pulmonary em‐ bolism, V/Q scintigraphy results showed persistent perfusion defects 6 and 12 months af‐ ter pulmonary embolism. The cumulative incidence of CTEPH was 0.9% to 1.3% [24]. The true incidence of CTEPH may have been underestimated due to exclusion of pa‐ tients with a history of venous thromboembolism, thrombophilia or other potential caus‐ es of pulmonary hypertension. In addition, a significant proportion of patients with CTEPH have not shown any previous episode of symptomatic pulmonary embolism [25, 26]. The discrepancy between theoretical estimates and the number of patients diagnosed with CTEPH emphasizes that CTEPH is likely to be underdiagnosed. The time between an acute pulmonary embolism episode and the development of CTEPH is also a matter of debate. Most cases of CTEPH are diagnosed during the first two years after the acute symptomatic pulmonary embolism [23]. However, some patients may experience symp‐ toms of CTEPH many years later [27, 28]. This variability was attributed to progressive

results showed the incidence of CTEPH to be about 0.5% [21, 22].

vasculopathy which affected the distal small pulmonary arteries [29].


Risk factors associated with CTEPH after symptomatic PE


Plasmatic risk factors associated with CTEPH


APA, antiphospholipid antibodies; LAC, lupus anticoagulans.

Thrombolytics are frequently used to treat acute pulmonary emboli. The rapid and complete recanalization of the pulmonary arteries may decrease the subsequent development of CTEPH [33]. 23 of 40 patients who had angiographically proven pulmonary embolism and who had initially been randomized to an IV infusion of heparin (n = 11) or a thrombolytic agent (urokinase or streptokinase, n = 12) were restudied after a mean follow-up of 7.4 years to


Thrombophilia studies have shown that lupus anticoagulant may be found in 10% of CTEPH patients, and 20% carry antiphospholipid antibodies, lupus anticoagulant, or both. A recent study has demonstrated that the plasma level of factor VIII, a protein associated with both primary and recurrent VTE, is elevated in 39% of patients with CTEPH [12]. No abnormalities of fibrinolysis have been identified. Blood groups type A, B, and AB were found to be significantly more common in patients with CTEPH compared to patients with PAH (88% vs. 56%). Plasma lipoprotein levels (a) (Lp(a)), a subgroup of the low density lipoprotein with high atherogenic potency, were significantly higher in patients with CTEPH than in patients with PAH and control subjects, indicating an overlap of venous and arterial thrombotic risk factors. Antiphospholipid antibodies (APLA) have been documented in a significant proportion of patients followed for CTEPH [30, 37, 38]. There is also evidence that underlying genetic

Chronic Thromboembolic Pulmonary Hypertension

http://dx.doi.org/10.5772/54749

147

The pathophysiological basis of CTEPH is not yet well known. Despite progress in determining the pathophysiology and treatment of PH, CTEPH pathogenesis is complex and poorly understood [39]. The mechanisms by which acute pulmonary embolism evolves into chronic thromboembolic residues incorporated into the pulmonary vessel wall have been difficult to define [39,40]. The incomplete resolution of pulmonary emboli rather than in situ thrombosis of pulmonary arteries appears to be the main contributing factor [41]. Pulmonary hypertension in patients without preexisting cardiopulmonary disease occurs when at least 30% of the pulmonary vascular bed is obstructed [42]. Development of pulmonary hypertension is not simply related to a simple mechanical obstruction by chronic thromboembolic material, but rather the appearance of a secondary vasculopathy developed in regions injured by shear stresses caused by persistent thromboembolic lesions [43]. Vascular injury and shear stress eventually lead to the proliferation of endothelial cells and smooth muscle cells of the pulmo‐ nary arterial bed [42, 43, and 44]. These results were reported from pathological observations in patients examined for CTEPH who displayed an organization of the clot into fibrous tissue, but also vascular remodeling with disappearance of the intima and infiltration of the media arterial wall [45, 46, 47, 48, and 49]. This hypothesis was initially suggested by Moser and Braunwald in 1971 [4]. Indeed, they observed that the pulmonary arteries of small caliber located in the unobstructed territories had remodeling lesions similar to those described in

Generally, the clinical history is not helpful in the diagnosis of CTEPH.. Indeed, up to half of patients with CTEPH have no documented history of pulmonary embolism [50]. In one series, 63% of patients had no specific history of acute venous thromboembolism [51]. Therefore, the clinical index of suspicion has been clarified below. The Hispanic clinic has an important place

predisposition may be involved in the pathogenesis of CTEPH.

**4. Natural history and pathogenesis of CTEPH**

idiopathic pulmonary arterial hypertension.

**5. Clinical presentation**

**Table 2.** Recommendations of the ESC/ERS guidelines for CTEPH [93].

measure the right-sided pressures at rest and after supine bicycle ergometry exercise. At rest, the pulmonary artery (PA) mean pressure and the pulmonary vascular resistance (PVR) were significantly higher in the heparin group compared with the thrombolytic group (22 vs. 17 mmHg, p<0.05, and 351 vs. 171 dynes s (-1) cm (-5), p<0.02, respectively). During exercise both parameters rose to a significantly higher level in the heparin group (from rest to exercise, PA: 22-32 mmHg, p<0.01; PVR: 351-437 dynes s (-1) cm 5, p<0.01, respectively), but not in the thrombolytic group (rest to exercise, PA: 17-19 mm Hg, p = NS; PVR: 171-179 dynes s (-1) cm (-5), p = NS). Thus, thrombolytic therapy preserves the normal hemodynamic response to exercise in the long-term and may prevent the development of pulmonary hypertension [34].

CTEPH may be related to a disorder of hemostasis such as elevated levels of factor VIII. The expression of plasminogen activator inhibitor (PAI-1) of type 1 was found to be higher in patients monitored for CTEPH [30, 35, 36]. Abnormalities in the structure of fibrinogen and function were also observed in other series. Traditional risk factors for venous thromboemb‐ olism (VTE) include antithrombin deficiency, protein C deficiency, protein S deficiency, factor V Leiden, plasminogen deficiency, and anticardiolipin antibodies [26]. However, in 147 consecutive patients with CTEPH, the prevalence of hereditary thrombotic risk factors was not increased when compared to 99 consecutive patients with IPAH or to 100 control patients.

Thrombophilia studies have shown that lupus anticoagulant may be found in 10% of CTEPH patients, and 20% carry antiphospholipid antibodies, lupus anticoagulant, or both. A recent study has demonstrated that the plasma level of factor VIII, a protein associated with both primary and recurrent VTE, is elevated in 39% of patients with CTEPH [12]. No abnormalities of fibrinolysis have been identified. Blood groups type A, B, and AB were found to be significantly more common in patients with CTEPH compared to patients with PAH (88% vs. 56%). Plasma lipoprotein levels (a) (Lp(a)), a subgroup of the low density lipoprotein with high atherogenic potency, were significantly higher in patients with CTEPH than in patients with PAH and control subjects, indicating an overlap of venous and arterial thrombotic risk factors. Antiphospholipid antibodies (APLA) have been documented in a significant proportion of patients followed for CTEPH [30, 37, 38]. There is also evidence that underlying genetic predisposition may be involved in the pathogenesis of CTEPH.
