Role for Staphylococci in Misguided Thrombus Resolution of Chronic Thromboembolic Pulmonary Hypertension

Abstract

Objective-Acute pulmonary emboli usually resolve within 6 months. However, in 0.1% to 3.8% of cases thrombus transforms into fibrous masses. If vascular obstruction is severe, the resulting condition is chronic thromboembolic pulmonary hypertension (CTEPH). Patients who carry ventriculo-atrial (VA-) shunts for the treatment of hydrocephalus and report a history of shunt infection are at an increased risk for CTEPH. Because CTEPH lacks traditional plasmatic risk factors for venous thromboembolism, we hypothesized that delayed thrombus resolution rather than abnormal coagulation is important, and that bacterial infection would be important for this misguidance. Methods and Results-Human CTEPH thromboemboli were harvested during pulmonary endarterectomy. The effects of Staphylococcal infection on thrombus organization were examined in a murine model of stagnant-flow venous thrombosis. Staphylococcal DNA, but not RNA, was detected in 6 of 7 thrombi from VA shunt carriers. In the mouse model, staphylococcal infection delayed thrombus resolution in parallel with upregulation of transforming growth factor (TGF) beta and connective tissue growth factor. Conclusions-In the present work, we propose a mechanism of disease demonstrating that infection with Staphylococci enhances fibrotic vascular remodeling after thrombosis, resulting in misguided thrombus resolution. Thrombus infection appears to be a trigger in the evolution of CTEPH.

Risk factors for chronic thromboembolic pulmonary hypertension

“…However, recent research has provided evidence suggesting that the mechanistic view of chronic thromboembolic pulmonary hypertension as a disease caused by obliteration of central pulmonary arteries due to a classic thrombotic process may have been too simplistic [24,34]. The current authors speculate that pulmonary embolism may be followed by a pulmonary vascular remodelling process that is modified by infection [7], immune phenomena [3] and, possibly, by thyroid hormone replacement therapy and malignancy.…”

“…Because of their small number, patients from Bratislava were added to the Vienna cohort. According to recent data demonstrating staphylococcal DNA in the majority of PEA specimens from VA shunt carriers [7], these subjects were grouped with those with infected pacemakers. Blood group analyses could not be included in the main analysis owing to the unavailability of blood group determinations in Prague in patients who were not scheduled for a surgical procedure.…”

“…Data from consecutive patients with nonthromboembolic pre-capillary pulmonary arterial hypertension (nonthromboembolic PH) were contributed from participating centres to serve as controls. Viennese patient data included patient data previously referred to in other studies [4,5,[7][8][9]. The respective ethics committees of the participating institutions approved the study.…”

Managing chronic thromboembolic pulmonary hypertension: pharmacological treatment options

“…Thus, acute PE is likely to be the initiating event, but progression of PH results from misguided pulmonary vascular remodelling (i.e. major and small vessel disease) [1,19]. This theory is also supported by the histopathology of resistance vessels in the pulmonary vascular bed, which show arteriopathic changes not only in areas directly affected by the PE, but also in portions that were not involved ( fig.…”

“…In addition to in situ thrombosis, other factors that might influence the incomplete resolution of PE and organisation of thrombi in patients with CTEPH include infection [19], inflammation and autoimmunity [26]. It should be noted that recent research suggests that infection with Staphylococci in patients with CTEPH enhances fibrotic vascular remodelling after thrombosis, resulting in misguided thrombus resolution, thus thrombus infection appears to be a trigger in the evolution of CTEPH [19].…”