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PE/CTEPH: Link


been known as a clinical entity for decades, no single biological aetiologic cause has been identified. Most probably the disease is the final pathway of a complex interplay of the factors shown in Figure 1.


It seems that intrinsic properties of the thrombus led to incomplete resolution and subsequent scarification. Incomplete lysis may occur due to large amount of the embolic material, resistance of fibrin to plasmin-mediated lysis or anomalous endothelial response to acute thrombosis.16


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.17–19


Based on the observations by Kenneth Moser and Nina Braunwald in the early 1970s,20


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.21


In situ thrombosis may


also accompany secondary small-vessel arteriopathy.22


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 Following an episode of PE, some patients present with symptomatic persistent PH, while others develop symptoms after an asymptomatic interval that can last from several months to years.7


This ‘honeymoon


period’ during which PH is present but the patient exhibits few symptoms represents the time lag that compensatory right ventricular hypertrophy has occurred in an effort to maintain cardiac output in the setting of elevated pulmonary vascular resistance. Pulmonary artery pressure normally declines to a plateau at approximately 38


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 under thyroid replacement 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 Figure 1. The pathway from acute pulmonary embolism to CTEPH


days after the acute PE and then stabilises with no further resolution, with a similar plateau for right ventricular function, which suggests that an echocardiogram six weeks after acute PE might predict subsequent CTEPH. Following patients for as much as two years after the acute event is reasonable, given that cases of CTEPH after acute PE have not been discovered after more than two years of follow-up. In order to reduce cost, many would limit screening to certain patient populations, such as those with thrombus in central vessels, those with significant haemodynamic changes (or evidence of right ventricular dysfunction) and those with documented thrombophilia.23


According to the latest 2014 Guidelines of the European Society


of Cardiology on the diagnosis and management of acute pulmonary embolism, routine screening for CTEPH in every asymptomatic survivor of PE is not recommended.24


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 that seen in patients with idiopathic pulmonary arterial hypertension or in control subjects. The exception is the presence of 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 conditions that appear to be independent risk factors for CTEPH.


Conclusions


CTEPH is likely to be complication of residual thrombotic material in the pulmonary arteries that transforms into intravascular scars. Pulmonary artery residua are relatively common after


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