This study indicated that the relationship between the change trend of plasma D-dimer levels before and after CDT treatment and thrombolytic outcomes for ALI. By analyzing the plasma D-dimer change trends, we can predict the reperfusion of ischemic lower limbs after thrombolytic therapy and know the results of CDT in a timely manner. This has rarely been reported in previous studies.
ALI is caused by a sudden interruption of the main blood perfusion of the lower limb for various reasons, and it usually requires immediate revascularization. CDT has become one of the most commonly used methods for the treatment of ALI 11,12. After thrombolytic therapy, the vascular stenosis, occlusion and other lesions can be treated simultaneously with interventional therapy, which improves the short-term and long-term patency rate of such occlusive lesions and reduces the need for open surgery in most of these patients4.
D-dimer is the degradation product of cross-linked fibrin, and its plasma level reflects the formation and degradation of fibrin. D-dimer is considered a useful biomarker because of its potential to identify individuals in a high coagulation state. D-dimer is often associated with thrombi, and its elevation should be of continuing concern13–15. D-dimer has been widely used in the diagnosis of VTE 8,16,17. If the plasma D-dimer test is negative, the diagnosis of acute VTE can be ruled out; if the plasma D-dimer test is positive, the diagnosis of VTE can be confirmed by the symptoms and an ultrasound examination8. There have also been many relevant studies in some cardiovascular diseases, such as atrial fibrillation18–20, coronary heart disease13,21,22, stroke23,24 and aortic dissection 25–27, and D-dimer can even be used as a predictor of the diagnosis and prognosis of such diseases28–31.
D-dimer levels are lower in the circulation in healthy individuals and higher in the presence of thrombi8. During the CDT process, the fibrin in the thrombus degrades, and D-dimer is produced. These dissolved substances are continuously released into the blood, causing the plasma D-dimer content to change constantly9,32,33. The D-dimer level increases continuously during thrombolysis and is positively correlated with the degree of thrombolysis5. D-dimer has a half-life of approximately 8 hours until it is cleared by the kidney and reticuloendothelial system34. In the later stage of thrombolysis, with the gradual opening of the occluded vessels, the thrombus load in the vessels decreases, and the D-dimer content in the blood decreases continuously until it returns to the prethrombolysis level. Monitoring the changes in plasma D-dimer content pre- and posttreatment is also often used to evaluate the therapeutic effect7,32,33,35. Davies, J. et al. analyzed systemic inflammatory response syndrome following catheter-directed thrombolysis of acute iliofemoral deep venous thrombosis and found that plasma D-dimer increased from 1465 ng/ml to 182,835 ng/ml after 48 hours of thrombolysis and then decreased to the prethrombolysis level 36 hours later. As a result of this presentation, thrombus occlusion of the iliofemoral vein had restored patency after CDT treatment9. Cakar, M. A. et al. analyzed D-dimer levels pre- and post-thrombolysis in 186 patients with acute coronary syndrome treated with intravenous tissue-type plasminogen activator (100 mg) or streptokinase (1,500000 U) and found that D-dimer levels were markedly high after thrombolytic therapy versus before (155 mg/dl, 362 mg/dl, P < 0.005)6.
For the convenience of analysis, we grouped our patients according to the results of thrombolysis. The change trends of D-dimer in the three groups during thrombolysis are shown in Fig. 2. During thrombolytic therapy, the lower limb arteries of patients whose plasma D-dimer level rose rapidly, reached its peak, and then rapidly dropped to the preoperative level obtained complete recanalization. The lower limb arteries of patients whose plasma D-dimer level rose slowly, then reached its peak slowly or had two peaks, and then dropped slowly to the preoperative level might achieve partial recanalization or remain occluded.
Accordingly, we believe that after CDT treatment of ALI, if the plasma D-dimer levels show a significant increase within a short period of time and then a rapid decline without a rebound, this suggests that the thrombolytic therapy was effective. If the plasma D-dimer continues to rise slowly and decline slowly, this suggests that the thrombolytic catheter may not be insufficient contact with the thrombus or the thrombolytic drug dose is insufficient, which requires appropriate adjustments. If the D-dimer exhibits multiple peaks, this may be due to the presence of a new thrombus, unobstructed vascular outflow tract or occlusion of the artery by the old thrombus, which should be solved by combining CDT with other treatment methods. According to the DSA results on the third day, we confirmed the reasons for the ineffective treatment of CDT for the patients in this study, and then corresponding measures were taken, such as adjusting the location of the thrombolytic catheter, increasing the time and amount of the thrombolytic agent, or combining the CDT with percutaneous transluminal angiography (PTA)/stent implantation. These additional measures improved the blood supply of the ischemic limbs, avoiding gangrene. As a result, the limb salvage rate of patients with ALI was improved.
Several limitations of this analysis should be acknowledged. In this study, patients with CDT thrombolysis for 1–2 days were excluded because these patients did not have 3 days of complete D-dimer data, which reduced the sample size of our study. In addition, the grouping in this study was based on the recovery of the lower limb blood supply of patients on the third day of CDT. In fact, patients with a poor CDT response were still receiving treatment after 3 days, such as continued CDT treatment or a combination of other treatments, so the final clinical results for all of the patients were not provided in this study. In addition, CDT therapy for non-ALI is also widely used in clinical practice36,37, but the lesions in these patients are not mainly thrombotic and often require PTA and/or stent implantation, so they were excluded from this study. Therefore, a multicenter, prospective, randomized controlled study may be the best way to further understand the trends and clinical significance of plasma D-dimer changes during CDT in patients with ALI.