Risk factors and basic mechanisms of chronic thromboembolic pulmonary hypertension: a current understanding

Abstract

All available evidence today indicates that chronic thromboembolic pulmonary hypertension (CTEPH) is primarily caused by venous thromboembolism, as opposed to primary pulmonary vascular in situ thrombosis. Both the initial magnitude of clot and pulmonary embolism (PE) recurrence may contribute to the development of CTEPH. Only few specific thrombophilic factors, such as phospholipid antibodies, lupus anticoagulant and elevated factor VIII, are statistically associated with CTEPH.A mechanistic view of CTEPH as a disease caused by obliteration of central pulmonary arteries by pulmonary emboli is too simplistic. Based on available data one may speculate that PE may be followed by a pulmonary vascular remodelling process modified by infection, immune phenomena, inflammation, circulating and vascular-resident progenitor cells, thyroid hormone replacement or malignancy. Both plasmatic factors (hypercoagulation, ''sticky'' red blood cells, high platelet counts and uncleavable fibrinogens) and a misguided vascular remodelling process contribute to major vessel and small vessel obliteration. Endothelial dysfunction and endothelialmesenchymal transition may be important, but their precise roles remain obscure. There exists no animal model for CTEPH; therefore, experimentation in the future must include human tissues and clinical data in parallel.

Serial imaging after pulmonary embolism and correlation with functional limitation at 12 months: Results of the ELOPE Study

“…The lack of correlation in the current study between imaging findings and long‐term exercise limitation may reflect the uncertainty surrounding the exact definition of “post‐PE syndrome.” While chronic thromboembolic pulmonary hypertension is widely recognized as the end‐stage manifestation of post‐PE syndrome, a comprehensive definition of this syndrome has yet to be proposed 23. Studies addressing this issue convey common themes of self‐reported dyspnea and/or measured decreased poor physical performance 24.…”

Red cell distribution width

“…23 Based on the similarities with these chronic medical conditions and on available data, one may speculate that chronic inflammatory processes are involved in the pathogenesis of CTEPH. 24 This hypothesis is augmented by some studies showing that inflammation may cause a prothrombotic state by reducing the resolution of pulmonary thromboemboli, and CTEPH has some common features with focal and systemic inflammation. [25][26][27] Figure 2.…”

Development and Characterization of an Inducible Rat Model of Chronic Thromboembolic Pulmonary Hypertension

“…The latter hypothesis is supported by a history of PE in ≤75% of all CTEPH patients and by the beneficial effects of timely performed pulmonary endarterectomy. 2,6 Finally, several risk factors for CTEPH including specific procoagulation factors such as phospholipid antibodies, protein S and protein C, factor V mutations, malignancy, inflammatory bowel disease, and previous deep vein thrombosis are also risk factors for recurrent PE. 6,7 It is not yet understood how PE progresses to CTEPH, and the mechanisms behind thrombi escape to thrombolysis and subsequent fibrotic transformation are still unknown.…”

“…2,6 Finally, several risk factors for CTEPH including specific procoagulation factors such as phospholipid antibodies, protein S and protein C, factor V mutations, malignancy, inflammatory bowel disease, and previous deep vein thrombosis are also risk factors for recurrent PE. 6,7 It is not yet understood how PE progresses to CTEPH, and the mechanisms behind thrombi escape to thrombolysis and subsequent fibrotic transformation are still unknown. Consequently, there is a need for simple and reproducible CTEPH animal models that not only permit the analysis of molecular signals involved in the pathology of this disease but also enable the evaluation of new therapeutic strategies to improve the fate of individuals diagnosed with CTEPH.…”