Discussion
To the best of our knowledge, this is the first study to clarify the association between coagulation and IVIG resistance in patients with KD based on a relatively large clinical dataset. In this prospective study, we support the hypothesis that there are marked differences in coagulation profiles, including longer PT and APTT, higher D-dimer levels, and lower ATIII activity, that may predict initial IVIG resistance. In addition, using multivariate logistic regression analysis, we found that longer PT, APTT, higher D-dimer and lower ATIII activity before initial IVIG were significant independent risk factors for initial IVIG resistance. Furthermore, significantly lower ATIII activity was found in patients with repeated IVIG resistance. Our results suggest that patients with impaired coagulation who are resistant to IVIG (initial and/or repeated) may need more aggressive treatment to reduce the likelihood of developing CALs.
Previous evidence has shown that coagulative profiles play an important role in sepsis and are associated with severe outcomes8. However, whether coagulative biomarkers can predict the development of IVIG resistance in KD remains unclear as few studies have been published to date. Recently, Chen et al. compared the changes in coagulation between acute KD patients and healthy controls9. The authors showed higher D-dimer levels and prolonged APTT and PT in KD, suggesting hypercoagulation as a common complication of KD. However, the results were limited by the small sample size (n=20) and retrospective nature of the study. Unlike previous studies, we found the predictive validity of coagulation biomarkers in IVIG resistance based on a relatively larger sample size. Severe infection and inflammation might be the possible pathomechanisms for impaired coagulation in IVIG-resistant patients10. First, infection is one of the most recognized causes in patients with KD11. In our preliminary study, we found that serum procalcitonin was significantly elevated in both the initial and repeated IVIG-resistant groups compared to that in non-responders12. Procalcitonin has been widely proven to be a significant biomarker for severe bacterial infection and sepsis13. In addition, cytokine storms, which have been demonstrated in systemic infections, play a central role in the different effects on the coagulation and fibrinolysis pathways14. Therefore, longer PT and APTT, higher D-dimer levels, and lower ATIII activity in IVIG-resistant patients with KD in our study may suggest a more noticeable impact of coagulation and reflect more severe inflammation in this population.
The present study indicated that initial IVIG-resistant patients have longer PT and APTT. The results of our study were consistent with those of Benediktsson et al., who found prolonged APTT and PT in sepsis patients15. PT and APTT are traditionally modeled as extrinsic and intrinsic pathways that join to form a common pathway16. In the study by Aird et al., inflammation-induced activation of the coagulation system was found to be initiated by the extrinsic pathway and amplified by the intrinsic pathway via crosstalk and a feedback loop17. Several studies have revealed that blocking tissue factor activity completely decreases inflammation-induced coagulation activation in models of experimental endotoxemia or bacteremia14, 18. Therefore, elevated PT and APTT may be associated with initial IVIG resistance in KD. However, APTT should be cautiously used in clinical settings as a single biomarker for predicting initial IVIG resistance because of the relatively low sensitivity (32.0%).
AT, also called AT III, is the main inhibitor of thrombin and factor Xa, which plays a role in thrombin generation19. In our study, significantly lower ATIII activity in the initial and repeated IVIG-resistant patients was observed. This finding is consistent with previous reports20 and corresponds with the fact that inflammation leads to the activation of coagulation, and coagulation markedly affects inflammatory activity21. In the study by Xie et al., ATIII reduction was found to be closely related to the prognosis of patients with sepsis22. One possible explanation is that decreased ATIII activity increases fibrin formation and insufficient fibrinolysis, which could cause microvascular thrombus23. Therefore, based on the results of the present study, ATIII activity may be a risk factor for predicting IVIG resistance in patients with KD.
D-dimer is the smallest FDP (molecular weight: 180 kDa) in the process of fibrinolysis, it is relatively stable and considered the final product of fibrinolysis24.25. Previous studies have found that D-dimer is associated with severe sepsis or septic shock8. In our study, patients with initial IVIG resistance had higher D-dimer levels. This result was in line with a study by Panigada et al., who found that sepsis patients were characterized by higher levels of D-dimer8. Similar results were also reported by Wang et al., who demonstrated that elevated D-dimer was a risk factor for severe outcomes in patients with bacterial infections26. The above findings may be explained by the imbalance between the coagulation system and inflammatory pathways in infected patients as fibrinolytic activators and inhibitors modulate the inflammatory response by their effects on inflammatory cell recruitment and migration27, 28. In a study by Shorr et al., higher proinflammatory cytokine levels were found in those with higher D-dimer levels, indicating a potential relationship between the coagulation system and inflammation29. Therefore, in the acute stage of KD, increased D-dimer levels may be used as a predictor for initial IVIG treatment failure.
The strengths of this study were its prospective design and relatively large sample size. However, the present study has several limitations. First, this study was performed at a single institution. Our hospital is the largest pediatric medical center in Southwest China, which may lead to a selection bias due to a higher number of severely ill patients being admitted to this facility. Second, the present study was a prospective cohort study with strict inclusion and exclusion criteria. The findings of this study are, therefore, applicable only to Chinese patients with KD receiving standardized IVIG treatment (2 g/kg) within 10 days of fever onset.
Despite these limitations, this prospective study is the first to report pronounced changes in PT, APTT, D-dimer levels, and ATIII activity in the acute stage of KD, which may serve as complementary laboratory biomarkers for predicting IVIG resistance. In addition, the predictive validity of ATIII activity as a single biomarker for IVIG resistance may be superior to other coagulation biomarkers with a relatively high sensitivity.