The current study investigated the plasma levels of D-dimer and their diagnostic performance in predicting PE in TPE patients. Our results indicated that most (75%) of the TPE patients had D-dimer levers higher than 0.5 mg/L. Furthermore, in TPE with PE patients D-dimer levels are significantly higher than that of patients without PE. With the cut off value of 1.18 mg/L, D-dimer showed a high sensitivity of 89.7% and specificity of 77.8% in predicting PE.
Pulmonary embolism (PE) due to endogenous or exogenous thrombosis in pulmonary arterial trunk or its branches is a potentially life-threatening disease . An accurate and prompt diagnosis is essential to reduce the mortality. D-dimer is formed when cross-linked fibrin is broken down, in patients who are suspected of having PE, the plasma D-dimer levels correlate with the probability of having PE . In order to increase the specificity of D-dimer testing and avoid unnecessary, costly even potentially harmful CTPA test, the 2019 ESC Guidelines endorse using clinical pretest probability (C-PTP) together with D-dimer level to rule out PE instead of a fixed cut-off level . However, recently studies suggested that strategies using clinical probability and D-dimer have limited diagnostic performance when PE with complications. As Goodacre and colleagues reported, in pregnancy, the YEARS/D-dimer strategy had a sensitivity of 58.3% and a specificity of 44% while the Geneva/D-dimer strategy had a sensitivity of 75% and a specificity of 20.8% for PE . According to our study, the most common symptoms of TPE are cough (74.6%), fever (51.7%), chest pain (50.8%) and dyspnea (49.6%). Chest pain, hemoptysis, dyspnea is the PE triad without specificity . When PE co-occurred with TPE, the symptoms are confusing. It is difficult to distinguish PE from the TPE patients by using symptoms. Furthermore, fever, chest pain and dyspnea often accelerate the heart rate which may increase the wells score . When together with the elevated D-dimer level, the clinical decision may incline to let patients do the further radiological test. Increased wells score influenced by complications may partly explain the limited diagnostic accuracy of the C-PTP/D-dimer strategy for PE in patients with complications.
Although D-dimer levels elevated in most of the TPE patients, it is also an objective biomarker to rule-out non-PE patients. According to receiver operating curve analysis of this study, area under the curve of D-dimer was 0.893 which indicated a significant statistical correlation between D-dimer and PE among TPE patients. In this cohort, when using the threshold level of 0.5 mg/L, D-dimer showed a high sensitivity of 100%, but a very low specificity of nearly 0%. At a D-dimer level of 1.18 mg/L, the sensitivity was 89.7% while the specificity reached to 77.8% which indicates high value of D-dimer in predicting PE in TPE patients.
According to this study, the morbidity of PE in TPE patients is no less than 19.3%, which is higher than that in normal population . To elucidated the underlying mechanism, we compared inflammatory biomarkers between different patients. The inflammation processes of TPE are orchestrated by cytokines and chemokines. Cytokines and chemokines also participate in all stage of embolism from the early endothelial dysfunction to the late formation of embolus . Maria and colleagues reviewed recent studies and revealed that cytokines including IFNγ, IL-6, CCL2, IL-17A, IL-9, IL-1β and TGF-β exert prothrombotic effects while other cytokines such as IL-10, TNF-α and IL-8 appear to promote thrombus resolution in late phase of venous thromboembolism . In addition, another study revealed that IL-8 enhances thrombus resolution through neovascularization and neutrophil recruitment . The limitation of these studies is that most of the subjects are experimental models. Study on human is scarce. In currently study, IL-8 level and WBC count of PE patients were significantly lower than that of non-PE patients which indicated dysfunction of antithrombotic cytokine in PE patients. While IL-2 receptor was significantly higher in PE patients than that in non-PE patients. This result was consistence with the study of Mirjana which revealed a positive correlation between IL-2R and anti-annexin A5 antibodies, a risk factor of embolism, in primary antiphospholipid syndrome (PAPS) patients with pulmonary embolism . Nonetheless, IL-6, TNF-α, ESR and CRP showed no significant differences between PE and non-PE patients in this study. Interestingly, none of the patients in this study who underwent deep vein ultrasound of the lower extremity had deep venous thromboembolism (DVT) (data not shown). Whether TPE only promotes local venous thrombosis is worth further study. Our study sheds light on the role of cytokines in PE among TPE patients. Prospective large-scale studies are needed to determine whether there are cytokines induced procoagulant and anticoagulant dysfunction in patients with TPE.
There are several limitations of our study that must be addressed. First, the small number of patients must be emphasized bearing the risk of a sample size error. Second, our used D-dimer cut-out level of 0.5 mg/L was not age-adjusted, for the case collection time span was from 2014 to 2020, most of the early cases received CTPA test when D-dimer was more than 0.5 mg/L. Third, retrospective design of the study limited the richness of the research. Information associated with clinical pretest probability was not record or we could study the C-PTP/D-dimer strategies’ diagnostic performance in predicting PE among TPE patients. A prospective, ideally designed study, with physicians randomly blinded to routinely collected D-dimers would be required to solve the above problems.