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disease usually have a different appearance from PE and training is required to detect such differences.17 The pathway from acute PE to CTEPH encompasses the progression from acute thrombus, composed primarily of fibrin and erythrocytes, to organised obstructive fibrotic material, and finally to pre-capillary PH. Although CTEPH has been known as a clinical entity for decades, no single biological aetiologic cause has been identified. Most probably, the disease is the final result of a complex interplay of the factors shown in Figure 1. It seems that intrinsic properties of the thrombus lead to incomplete resolution and subsequent scarification. Incomplete lysis may occur due to large amounts of the embolic material, resistance of fibrin to plasmin-mediated lysis or anomalous endothelial response to acute thrombosis.18

In addition,

misguided cellular mechanisms attenuate endothelial cell-mediated resolution of the thrombi and enhance mesenchymal cell-mediated remodelling, deficient angiogenesis and scarification. Finally, the association of CTEPH with chronic inflammatory conditions reinforces the scenario that inflammation may cause a prothrombotic state and impair resolution of pulmonary thrombemboli.19–21 Based on the observations by Kenneth Moser and Nina Braunwald in the early 1970s,22

it has been

appreciated that in addition to major vessel vascular thrombosis and remodelling, there is a component of small pulmonary vessel disease (pulmonary arteriopathy). This microvascular disease resembles idiopathic pulmonary arterial hypertension and is possibly modified by infection, immunological factors, chronic inflammatory disorders and malignancy.23

In situ thrombosis may

also accompany secondary small-vessel arteriopathy.24

In fact, it has been

proposed that an acute PE may act as just an initiating event, but progression of PH results from progressive pulmonary vascular remodeling due to small-vessel disease.


Follow-up after a PE episode Pulmonary artery pressure normally declines to a plateau at approximately 38 days after the acute PE and then stabilises with no further resolution,

Predisposing factors Traditional risk factors for venous thromboembolism, such as hereditary thrombophilic conditions (antithrombin III deficiency, protein C deficiency, protein S deficiency, factor V Leiden mutations, plasminogen deficiency), have been shown to be no different from those seen in patients with idiopathic PAH or in control subjects. The exception is the presence of


Vascular remodelling


Impaired fibrinolysis

Figure 1. The pathway from acute pulmonary embolism to CTEPH Acute PE

with a similar plateau for right ventricular function, which suggests that an echocardiogram six weeks after acute PE might predict subsequent CTEPH. However, screening programmes for CTEPH lack cost- effectiveness and their utilisation remains an issue of debate. Due to these uncertainties, the 2014 Guidelines of the European Society of Cardiology on the diagnosis and management of acute pulmonary embolism do not recommend routine screening for CTEPH in every asymptomatic survivor of PE.25

Because early diagnosis of

CTEPH is essential, many would limit screening to certain patient populations with certain high-risk characteristics. A recent post hoc analysis of three prospective cohorts included 772 patients with acute pulmonary embolism and concluded that six variables independently were associated with CTEPH diagnosis: unprovoked PE, known hypothyroidism, symptom onset more than two weeks before diagnosis of pulmonary embolism, right ventricular dysfunction on CT or echocardiography, and the absence of diabetes mellitus and other therapy than thrombolysis or embolectomy.13

antiphospholipid antibodies and elevated levels of factor VIII, which have both been identified in patients with CTEPH. In particular, lupus anticoagulant occurs in ≈10% of CTEPH patients, and 20% of patients carry antiphospholipid antibodies, lupus anticoagulant, or both. Additionally, plasma levels of factor VIII, a protein associated with venous thromboembolism, were elevated in 39% of patients with CTEPH. The risk of development of CTEPH is increased by factors associated with PE, certain chronic medical and inflammatory conditions, thrombophilia and a genetic predisposition. Table 2 shows predisposing or associated

Table 2: Predisposing risk factors for development of CTEPH

Factors specific to PE Recurrent or unprovoked PE Large perfusion defect Young or old age Pulmonary artery systolic pressure >50mmHg at time of index PE

Persistent elevated right ventricular systolic pressure six months after PE

Chronic medical diseases Malignancy Hypothyroidism Splenectomy

Myeloproliferative disorders

Chronic inflammatory conditions Inflammatory bowel disease Chronic osteomyelitis Ventriculoatrial shunt (for hydrocephalus) Infected pacemaker

Thrombotic factors Lupus anticoagulant Antiphospholipid antibodies Increased levels of factor VIII

Genetic factors Non-O blood groups

Human leukocyte antigen polymorphisms

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