Cardiovascular manifestations and complications are the major contributors to morbidity and mortality associated with KD, both during the acute illness phase and in the long-term progression . Rupture of CAA in KD is rare. If the blood flow in CAA is unobstructed, the cardiac function will not be significantly impacted. In the subacute stage and recovery stage of KD, the elevated platelet count and platelet activity will increase the risk of thrombosis . Meanwhile, KD children with CAA usually do not respond to IVIG treatment very well, and therefore will need repeated treatment with IVIG and glucocorticoids. Both drugs will increase platelet abnormally, increasing the risk of thrombosis [10–12]. The symptoms of ischemia are obvious in a short term and the time of occurrence can be clearly indicated in adults. Therefore, thrombolytic therapy can be managed within 12 hours of the onset. Thrombosis in children with Kawasaki disease occurs in dilated coronary aneurysms, and the formation process is slow and the possibility of complete occlusion in the short term is low. Therefore the symptoms are not as obvious as in adults . In addition, it is difficult for young kids to accurately describe the specific time of ischemia symptoms. As a result, thrombolytic therapy has been rarely carried out and clinical experience of treatment is limited . Currently, only 2 cases of 29-day-old  and 3-month-old infant  with coronary artery thrombosis have been reported being treated with alteplase in the United States. An adult KD was treated with combination of alteplase and actilyse for KD associated coronary aneurysm thrombosis . At present, anticoagulation and antiplatelet are mainly used for thrombus treatment in world wide. However, the treatment data at our center suggests that these two methods have better results for preventing thrombosis than for treating existing thrombosis.
The treatment summary of our center is as follows: We did comparison of treatments in 2010 and 2015, a combination treatment of warfarin + aspirin + dipyridamole treatment was used to treat 2 misdiagnosed children with LAD thrombosis. At the end, 1 patient died and the other patient is disabled [supplementary file]. Similarly, the LAD was almost completely occluded in the first case. After the thrombolytic treatment with Alteplase, heparin was given for a week, followed by combination of warfarin + aspirin + clopidogre treatment, the thrombus disappeared completely 2 months later. In 2018, a case of distal RCA thrombosis was treated with heparin for 1 week, followed by combination of warfarin + aspirin + dipyridamole. There was no change in thrombosis observed 10 months later. CMR confirmed the formation of myocardial transmural necrosis in the inferior left ventricular wall [Figure 5]. It took 26 months for the thrombus to partially mechanize, but myocardial necrosis was irreversible. In the second similar case, blood flow was interrupted by a distal thrombosis of the RCA. After 2 months of treatment with Alteplase, then heparin for 1 week, followed by warfarin + aspirin + clopidogre treatment, blood flow in the distal trunk of the RCA was significantly recanalized. 2. For patients who have low density thrombosis, heparin IV for 7 days followed with warfarin plus antiplatelet therapy has a good prognosis (case 1 at the first times of thrombosis) . 2.Thrombolytic therapy + heparin/warfarin + antiplatelet therapy should be performed with alteplase for large low-high density thrombus projecting to the lumen or affecting blood flow (case 1 second times/case 2 at the first times/case 3 at the second times/case 4 of thrombosis). Although the course of treatment is longer, the prognosis is good as long as the treatment persists. The side effects of alteplase in children are mainly bleeding in pursuance of pinhole and bleeding in the gingival area of caries, which usually occur within 1 hour of medication. Local cotton ball compression and halving the infusion speed of alteplase can stop the bleeding. Because heparin can lead to thrombocytopenia, blood routine should be monitored during heparin administration . Most children didn’t present with myocardial ischemia symptoms, which might be related to an adaption due to the slow formation, and also the restriction on vigorous activities by the child's parents. KD Patient # 2 had myocarditis and was IVIG resistance. Thus, he was given IVIG 2g/kg for 2 times and oral glucocorticoids for one month, his platelet increased to 770×109/L at 19 days of illness. Thrombosis was found at 30 days after the disease, the platelets were recovered to 336×109/L while it was normal at 25 days of illness. 6 days later, alteplase treatment was performed and 10 days later, thrombosis diminished. This could be related to that platelet activity increased in the subacute stage and thrombosis is likely to be formed  [20–21]. Aspirin and dipyridamole, besides their anti-platelet activity, also reduce tissue factor procoagulant activity, and aspirin inhibits the STING pathway upstream of STING . Patient # 3 was a 1.5-year-old boy at onset, and warfarin, asprin, and dipyridamole were used to treat bilateral coronary aneurysms. The medication was not continuous. Hyperechoic thrombosis in the LAD was found 5.5 years after the onset of the disease (more than 1 year after the last ECHO examination). There was no change in thrombus after half a month of treatment with treated with haprin, warfarin, asprin, and dipyridamole. Myocardial ischemia after strenuous activity occurred 6.5 years after the onset of the disease. Mixed density thrombosis was still found in LAD. After treatment with alteplase and then continued with haprin, warfarin, asprin, and clopidogrel, the low-density part thrombus disappeared 2 weeks later, and his daily activity recovered. Interventional coronary thrombolysis has been established for adult patients. However, coronary artery openings in children are much narrower, and specialists prefer not to perform similar coronary thrombolysis procedures in infant patients [23–25]. In the United States, it has been reported that in the treatment of adult KD coronary thrombosis, thrombolysis should be performed in the coronary artery first, and if the thrombolysis is not successful, intravenous thrombolysis should be continued (the time is far longer than 12 hours, and the drug has been given for several times), which also achieves good results . In Japan, it has been reported that intracoronary urokinase and post-thrombolytic regimen is successful in treating an infant patient with Kawasaki disease and acute myocardial infarction. Thus, it is possible to dissolve thrombus formed in the vascular lumen with treatment even if it occurred over 12 hours. But it takes a longer time to treat thrombosis formation lasting more than 12 hours .
To sum up, since adult coronary atherosclerosis can be accompanied by cerebral atherosclerosis and gastrointestinal ulcers, the biggest risk of thrombolysis is internal bleeding, and even thrombolytic therapy of pulmonary embolism is likely to cause bleeding . However, after multivariate analysis, thrombolytic therapy using alteplase for myocardial infarction/cerebral infarction has not been associated with gastrointestinal tract or cerebral hemorrhage . Children basically do not have cerebral atherosclerosis, and gastrointestinal ulcers are rare in them. So bleeding usually occurs in superficial area where it will be easily observed (eg. epistaxis, the site of skin puncture, caries oozing blood and so on). Therefore risk is relatively low when using thrombolytic therapy. In addition, coronary heart disease in adults occurred after coronary atherosclerosis stenosis lumen. The symptoms due to thrombus blocking blood flow are obvious, and the onset time can be captured clearly. In children with KD, thrombosis occurred within expanded aneurysm, and the thrombus grew relatively slow, rarely obstructs blood flow suddenly. It is also hard for young children to describe symptoms. Therefore it is difficult to manage the treatment within 12 hours of onset. In addition, the effect of anticoagulant and antiplatelet drugs alone is limited. Intravenous alteplase is an excellent remedy even after more than 12 hours the onset of symptoms. Therefore, in the case of KD complicated with coronary aneurysm thrombosis, our clinical experience in treating KD complicated with thrombus in coronary aneurysms is as follows: 1. When Giant CAA mural thrombus does not affect blood flow, only anticoagulant and antiplatelet therapy is required. 2. For central thrombus in one of the following situations, as long as DIC and platelets are within the safe range, it is not necessary to strictly limit the occurrence time of thrombus <12 hours.