Thrombo-inflammation and Rethinking the Role of Aspirin in Kawasaki Disease

TL;DR

This paper reviews the role of aspirin in Kawasaki Disease, focusing on its use in managing thrombosis and inflammation in children with coronary artery aneurysms.

Contribution

The paper re-examines aspirin dosing ambiguity and explores complementary therapies for thrombosis in Kawasaki Disease.

Findings

Standard therapy with aspirin and IVIG may be sufficient for small aneurysms but insufficient for large ones.

Low-dose aspirin shows potential superiority, though consensus remains elusive due to ethnic and individual variability.

Thrombolytic therapy is recommended in cases of thrombosis formation.

Abstract

Kawasaki Disease (KD) is a medium vessel vasculitis of young children that affects coronary arteries (CAs). The aim of therapy is to control inflammation and prevent coronary artery damage and alleviate thrombosis. This review aims to summarize the thrombosis-related complications and complementary therapy approaches to combat them. It also focuses on the ambiguity regarding the optimal aspirin dose in standard KD therapy.

KD patients with large or giant coronary artery aneurysms (CAAs) in particular face the risk of developing thrombosis. The standard therapy regimen during the acute phase consists of intravenous immunoglobulin (IVIG) plus aspirin. Although the dosing for IVIG is constant, the aspirin dose continues to be debated. The standard treatment with aspirin and IVIG might be adequate for individuals with small aneurysms whereas, patients suffering from large aneurysms and in a hypercoagulable state might need additional and extended therapy consisting of several antiplatelet reagents and anticoagulants. In case of thrombosis formation, thrombolytic therapy is also recommended.

Cardiac and thrombotic problems are severe outcomes of KD. Patients need to be screened on a regular basis with echocardiography. The ideal aspirin dose during acute KD treatment is still controversial and while several recent studies pinpoint the superiority of low doses, there is no universal consensus. The variation in treatment response might be due to the different ethnic composition of study groups and inter-individual differences. Overall, close monitoring of patient response and finding the optimal treatment strategy is crucial.

Full text

Introduction

KD is an acute inflammatory disease mainly affecting medium-sized arteries, in particular coronary arteries and the leading cause of acquired heart disease among children [1]. Although it was first described in 1974, the etiology of KD still remains elusive. The increased prevalence of the disease in Asian countries [2], the association of HLA-DRB1, -B5, -Bw51 and -Bw44 with KD susceptibility [3] and single nucleotide polymorphisms in FcγR2a, CASP3, HLA class II, BLK, ITPKC and CD40 genes [1] indicate the likelihood of a genetic predisposition. In addition, the incidence rate shows significant increment in specific areas and specific months which may point to the involvement of an infectious agent in disease etiology [4]. Indeed, the rise in absolute neutrophil and monocyte count and γδT cell activation pattern in patients’ peripheral blood clearly show the activation of innate and adaptive immune systems [5]. The young age of affected children suggests that individuals subsequently become immune to the infectious agent. Overall, the widely accepted postulation is that an unknown microorganism, likely a novel virus, affects infants with genetic susceptibility, thus triggering KD vasculitis [6]. This hypothesis is further supported by the fact that siblings have a higher risk of developing the disease and most sibling cases occur within a short period of each other [7].

The diagnosis of Kawasaki disease (KD) has been based on clinical signs, cardiac evaluation, and laboratory findings, as outlined in the American Heart Association (AHA) scientific statements published over the years [1, 8, 9]. Symptoms of complete KD are defined as the presence of persistent fever along with four or five of the following clinical features: bilateral nonexudative conjunctival injection, changes of the peripheral extremities, mucosal changes in the oropharynx, cervical lymphadenopathy and polymorphous maculopapular rash [1]. In addition to these common signs, the reactivation of the Bacillus Calmette-Guérin (BCG) vaccination scar is considered as an important clinical sign for KD [10]. However, because KD presents with variable clinical features, diagnosis can be challenging. Furthermore, its overlap with the manifestations of other febrile illnesses in children can further delay early recognition.

The goal of therapy is to reduce inflammation and prevent thrombosis, thus the common treatment modality for KD is the administration of IVIG and aspirin. However, 10%-20% of patients show resistance to IVIG treatment and remain febrile putting them at higher risk of developing coronary artery lesions (CALs) [11]. For IVIG-refractory patients, a second round of IVIG, intravenous methylprednisolone (IVMP), oral prednisone, infliximab or anakinra are recommended yet there is no consensus on their success rate or superiority of one over another [1].

Long Term and Short Term Cardiac Complications

KD is the most common cause of acquired heart disease globally [12]. The course of the disease can be divided into three stages: systemic inflammation, coronary inflammation and coronary damage. Systemic inflammation is dampened over time whereas persistent coronary arteritis results in aneurysm formation. In some patients aneurysms show regression, whereas other individuals may face with coronary artery occlusion [13]. Larger aneurysms have a higher tendency to persist. These aneurysms are inclined to suffer from thrombotic complications and stenosis which in turn may cause myocardial ischemia. These patients’ major coronary artery segments and myocardial functions need to be examined by echocardiography on a regular basis to evaluate luminal dimensions, thrombosis or ventricular dysfunction. Other risk factors for KD-related myocardial ischemia are discussed in detail elsewhere [1].

Cardiovascular complications are the main cause of mortality in KD patients and their presence is a supportive criterion for KD diagnosis. The most common complications are coronary artery abnormalities such as coronary arteritis, arterial fistula, dilatation, coronary ectasia, stenosis, aneurysm and myocardial infarction (MI) [14]. Myocarditis is widely observed in the early phase of the disease; however, it subsides as patients receive anti-inflammatory treatment [1]. The pericardium and endocardium, including valves, may also be inflamed. During acute phase, hyperdynamic precordium, arrhythmia, tachycardia and diastolic dysfunction are detected [1, 15]. Moreover, thrombosis, endothelial cell necrosis and obliteration of vascular lumen is observed in the coronary arteries of patients dying 2–3 weeks after the onset of the disease [16]. Aortic root dilation is also detected in the early stages of the disease and shows association with aortic regurgitation [1]. Dilations resolve within 4 to 8 weeks in most patients, whereas large aneurysms may stay deformed. The regressed aneurysms do not always show full recovery. Thickened intima and impaired vasodilation capacity are observed in these vessels [17]. In extreme cases, concurrent loss of intima, media and elastica is detected. Although rare, during the acute phase quickly enlarging aneurysms may rupture subsequently leading to myocardial ischemia, pericardial tamponade or even death [1].

Long-term management begins with the end of the acute course and aims to alleviate thrombosis, MI and cardiovascular problems. Long-term complications may arise due to injured CAs, arteriosclerosis or atherosclerosis. Damaged endothelium due to acute vasculitis puts patients at risk of developing atherosclerosis [18]. Sudden death due to MI may happen many years later in KD patients complicated with CAA and stenoses. In fact, overlooked KD cases are held responsible for most of the MI cases in young adults. Non-occlusive thrombi in CAA with distal embolization and progression of calcified stenoses may also lead to non-ST-segment elevation myocardial infarction (NSTEMI)/unstable angina in the long term [1]. Notably, patients with regressed aneurysms may still suffer from distorted myocardial flow reserve and endothelial dysfunction in the distant future and thus still face the risk of myocardial ischemia [1]. The likelihood of developing these conditions increases if patients are not treated. Given this situation, it is clear that pediatricians should work closely with cardiologists for successful disease management.

Changes in Platelet Numbers and Functions in Kawasaki Disease

Platelet count changes throughout the course of KD. Thrombocytosis is usually observed in the 2^nd^ to 3^rd^ week of the disease and platelet count drops by 4–6 weeks after onset [19]. Elevated platelet counts are also seen in the Lactobacillus casei cell wall extract (LCWE)-induced murine model of KD vasculitis [20]. In support of this notion, thrombopoietic factors increase both in patients and in the mouse model model of KD [19, 20]. Aside from increased platelet production, their clearance from circulation might be hampered due to the saturation of the reticuloendothelial system by immune complexes thus resulting in elevated platelet counts [21]. Moreover, platelet characteristics differ between KD patients and febrile controls. In particular, lower platelet distribution width and mean platelet volume in the febrile period of KD patients might be used as an extra supportive finding for differential diagnosis [22]. Higher peak platelet count was detected in patients with CALs [21] and IVIG resistance [23] implying its association with poor prognosis. Moreover, a higher platelet count following IVIG treatment shows positive correlation with the duration of coronary artery dilation [24]. Platelet number is related with the severity of heart vessel inflammation and abdominal aorta aneurysm in the mice model as well [20].

Thrombocytopenia might also be detected in the acute phase of the illness [25] hence, even if thrombocytosis serves as a supportive lab finding for KD diagnosis, low platelet count does not exclude the presence of the disease. Although the exact mechanism of thrombocytopenia is not known in KD patients, it is believed that disseminated intravascular coagulation [26], development of idiopathic thrombocytopenic purpura [27] or macrophage activation syndrome [28] might be the underlying cause. Intriguingly, KD patients with concomitant thrombocytopenia are also at higher risk of developing CALs and MI [26].

Alterations in platelet biology is also observed at the functional level. Platelet activation markers are upregulated in patients and mouse model of KD [29]. These changes are related to worse outcome; increased levels of β-thromboglobulin shows strong association with CAA formation [30] and platelet vascular endothelial growth factor (VEGF) levels of naive patients shows correlation with the severity of CAA [31].

Thrombotic Complications of Kawasaki Disease

Thrombosis is considered to be a serious complication of KD and mostly occurs in the early phase, with a median time of 16 days after onset [32]. The left anterior descending artery is the branch where most of the thrombotic complication occurs thus needs to be examined vigilantly with echocardiography in long-term management [32]. In severe cases thrombotic complications and rupture may also be observed at other medium-sized arteries [33]. In particular, giant CAAs have a higher tendency to suffer from thrombosis. Indeed, a Z score > 10 and an absolute coronary artery diameter ≥ 8 is associated with higher thrombosis risk [1]. Therefore, these patients are recommended to use anticoagulants for an extended duration. Notably, males with giant CAAs are more prone to develop thrombosis and this might be attributed to lower shear stress and higher platelet activation profile [32]. In addition, genetic factors were found to be a risk factor for thrombosis as ITPKC rs7251246 T > C polymorphism is associated with thrombotic complications in KD children [34]. Thrombosis might lead to stenosis, MI, ischemia or recanalization [35]. Although recanalization might sustain blood flow, recanalized vessels are also susceptible to occlusion due to intimal thickening.

Platelets play a primary role in coagulation and as mentioned above, their count and activation profile differ in KD patients. Activated platelets are prone to form aggregates which in turn regulate coagulation. In line with this, platelet activation markers are further elevated in KD patients with thrombosis [36]. Circulating aggregates are observed in LCWE-induced KD mouse model [20] and KD patients and preserve their hyperaggregation state throughout acute and convalescent periods [21]. Thrombotic complications such as peripheral gangrene might be present in individuals [37] and thrombocytosis is associated with an increased risk of peripheral gangrene in KD patients [38]. A study by Dogan et al. suggested that the use of prostacyclin analogue might be beneficial for the treatment of KD complicated by peripheral gangrene [39].

On the other hand, thrombosis and inflammation are two interlinked processes. The inflammatory response in KD patients results in changes in vascular endothelial cells, platelets and the coagulation system which in turn triggers a hypercoagulable state. Indeed, D-dimer levels are not only upregulated [40] but also shows association with C-reactive protein (CRP) in KD [41]. Inflammatory cytokines trigger vascular endothelial cell damage and injured endothelium is a hallmark of KD. Intriguingly, damage markers remain elevated for 10–15 days following IVIG treatment [42]. Dysregulated endothelium results in the loss of hemostatic protection. Consequently, a pro-coagulant environment is formed where platelet-activating factors are released from endothelial cells. Indeed, von Willebrand factor (vWF) [43] and soluble thrombomodulin [44] levels are upregulated in KD. Infiltration of inflammatory cells to the vascular wall may also result in the loss of endothelial lining, which in turn leads to exposing collagen and decreases prostacyclin production in the injured endothelium. This damage can also cause a drop in platelet cyclic adenosine monophosphate levels, which may result in platelet aggregation. Dysfunctional endothelium is also responsible for impaired fibrinolytic response following KD [45].

The thrombotic state is supported by the distorted blood flow resulting from CAAs, stenosis and lower shear stress. Consequently, heart attack, stroke and even death may occur thus thrombotic occlusion of coronary arteries is a major risk factor for patients. In fact, thrombin-antithrombin III complex, a marker for intravascular coagulation, is upregulated in KD [44]. Upregulation in fibrinogen and D-dimer levels in KD compared to the healthy group is notable [46]. Moreover, patients with CAL and IVIG resistance have further elevation in D-dimer levels, implying the presence of a predisposition for thrombus formation [47, 48]. FVIII activity and fibrinogen levels are elevated, whereas the antithrombin III amount decreases, particularly during the acute phase [30].

Individuals developing a hypercoagulable state during the acute phase are predisposed to face IVIG resistance and several coagulation parameters might be used to assess the likelihood of IVIG non-responsiveness [49]. Paradoxically, prothrombin time (PT) and activated partial thromboplastin time (aPTT) are prolonged in KD and might be due to extensive consumption of coagulation factors or liver injury. Indeed, increased levels of serum liver enzymes, hypoalbuminemia, hyperbilirubinemia is more profound in IVIG resistant children [49]. In addition, IVIG administration shortens PT and aPTT remarkably [42].

Prevention of Coronary Artery Thrombosis (thromboprophylaxis), Low-dose Versus High-dose Aspirin and Outcomes

Giant CAAs are major risk factors for thrombosis in KD patients. Therefore, judicious measures to diminish thrombosis risk are valuable. The routine treatment during the acute febrile period of KD is IVIG plus aspirin. However, it was not until 1984 that IVIG was considered as a potential treatment modality for KD [50]. Prior to this, aspirin alone was considered the standard treatment for KD as it exerts its effects through the inhibition of the cyclooxygenase (COX) enzyme, thus resulting in lower prostaglandin and thromboxane (TX) levels. In KD patients, TXA2 [51] and TXB2 [52] levels were found to be upregulated which served as one of the justifications for the use of aspirin. Indeed, the sole use of high-dose aspirin (HDA) (80–180 mg/kg/day) was shown to reduce CAA incidence [53].

The controversy over high-dose versus moderate- or low-dose aspirin (LDA) in the treatment of acute Kawasaki disease (KD) centers on balancing anti-inflammatory effects with safety and efficacy. Traditionally, HDA (80–100 mg/kg/day) has been used for its anti-inflammatory properties during the acute febrile phase, alongside intravenous immunoglobulin (IVIG) [54]. However, recent studies suggest that lower doses (30–50 mg/kg/day or even 3–5 mg/kg/day) may be equally effective in reducing inflammation and preventing coronary artery aneurysms [54–63], while minimizing side effects such as gastrointestinal irritation, liver enzyme elevations, and Reye syndrome risk [60, 64], (Table 1). Several retrospective and prospective studies, particularly from Japan and the U.S., have shown no significant difference in coronary artery outcomes between high and moderate-dose aspirin (MDA) groups [59, 60, 63, 65], (Table 1). As a result, practice patterns vary globally. It is also important to note that, while HDA is favored in some observational studies and clinical trials for clinical course such as fever duration, hospital stay, and IVIG resistance, there is no obvious benefit of HDA use for CAL formation. On the other hand, meta-analyses, which primarily focus on CAL as the endpoint, indicate that HDA does not offer an advantage over LDA in preventing CAL. Overall, there is still no universal consensus, highlighting the need for a large-scale, randomized controlled trial to definitively guide aspirin dosing in acute KD.Table 1. Summary of studies comparing the the outcomes of higher and lower doses of aspirin treatment regimens in Kawasaki Disease. The types of studies are indicated with letters. a denotes observational studies, b denotes reviews with meta-analysis and c denotes clinical trialsStudyTreatment RegimenNumber of patientsComparison(Acute Phase)OutcomeHayashi et al. [75] a30–50 mg/kg/day aspirin vsNo aspirin (3–5 mg/kg/day aspirin in case of CAL formation)IVIG: N/A735MDA + IVIG vsOnly IVIG or LDA + IVIGHigher dose aspirin use is not superior regarding the risk of CAL formation, IVIg response. No aspirin group is associated with shorter duration of feverChiang et al. [74] b ≥ 30 mg/kg/day aspirin vs3–5 mg/kg/day aspirin or no aspirinIVIG: 2 g/kg12182HDA/MDA + IVIG vsLDA + IVIG or Only IVIGPrescribing lower dose or no aspirin during the acute phase of KD is associated with a reduced incidence of CALJia et al. [78] b ≥ 30 mg/kg/day aspirin vs3–5 mg/kg/day aspirin or no aspirinIVIG: 2 g/kg as a single infusion or 400 mg/kg/day (4 days)12176HDA/MDA + IVIG vsLDA + IVIG or Only IVIGElevated doses of aspirin do not provide a significant reduction in CAL incidence. Receiving HDA is associated with shorter duration of fever while there is no significant difference regarding duration of hospital stay and IVIg resistance between two groupsPlatt et al. [89] a ≥ 10 mg/kg/day aspirin vs < 10 mg/kg/day aspirin260HDA/MDA + IVIG vsLDA + IVIGLower dose of aspirin is not associated with an increased rate of CAL formation, recrudescent fever, and longer hospital stay thus is a suitable option for initial treatmentWang et al. [90] a40–50 mg/kg/day aspirin vs30–39 mg/kg/day aspirin vs20–29 mg/kg/day aspirinIVIG: No use / 1 g/kg / 2 g/kg23693 aspirin dosage regimens are comparedAspirin dose escalation does not improve IVIG response and CAL formationDallaire et al. [55] a80 mg/kg/day aspirin vs3–5 mg/kg/day aspirinIVIG: N/A1213HDA + IVIG vsLDA + IVIGLDA is not associated with the increased risk of coronary artery abnormalities, IVIG resistance, and longer fever duration compared to HDAKim et al. [2] b ≥ 30 mg/kg/day aspirin vs3–5 mg/kg/day aspirinIVIG: 2 g/kg8456HDA/MDA + IVIG vsLDA + IVIGWhile the HDA/MDA group has a higher incidence of CAA, the LDA group has a higher IVIG resistance rate and longer duration of feverAmarilyo et al. [54] a80–100 mg/kg/day aspirin vs3–5 mg/kg/day aspirinIVIG: 2 g/kg358HDA + IVIG vsLDA + IVIGHDA group has no superiority over LDA group with regard to CAA and fever duration, however LDA group is associated with a shorter hospital staySaulsbury [62] a80–100 mg/kg/day aspirin vs3–5 mg/kg/day aspirinIVIG: 2 g/kg as a single infusion or 400 mg/kg/dose (4 days)70HDA + IVIG vsLDA + IVIGHDA showed no significant benefit in shortening the duration of fever and CAA formation compared to LDATerai et al. [63] c80–120 mg/kg/day aspirin vs30–50 mg/kg/day aspirinTotal IVIG: 100 mg/kg – 2 g/kg1629HDA vsHDA + IVIG vsMDA vsMDA + IVIGAspirin dose does not affect the prevalence of coronary artery abnormalities, whereas HDA leads to shorter duration of fever compared to LDADurongpisitkul et al. [57] a > 80 mg/kg/day aspirin vs ≤ 80 mg/kg/day aspirinIVIG: > 1 g/kg4151HDA + IVIG vsLDA + IVIGHigher doses of aspirin show no significant difference in CAA incidence compared to lower doses of aspirin in both short-term and long-term follow-upAkagi et al. [65] c100 mg/kg/day aspirin vs30 mg/kg/day aspirinIVIG: None60HDA vsMDAHDA is not recommended as an initial treatment option due to its tendency to cause liver toxicity, and inability to reduce the incidence of CAL, however HDA is associated with shorter fever durationSuzuki et al. [91] a > 50 mg/kg/day aspirin vs30–50 mg/kg/day aspirin vs5–30 mg/kg/day aspirin vs3–5 mg/kg/day aspirinIVIG: N/A821094 aspirin dosage regimens are comparedLower dose of aspirin use shows association with higher proportion of CAA and longer hospital stay. 30–50 mg/kg/day aspirin administration increases IVIG resistance rateIto et al. [92] a50 mg/kg/day aspirin vs30 mg/kg/day aspirinIVIG: 2 g/kg5872 aspirin dosage regimens are comparedHigher doses of aspirin provide lower rate of IVIG resistance, although do not show significant difference in the incidence of coronary artery aneurysmsZheng et al. [77] b ≥ 30 mg/kg/day aspirin vs3–5 mg/kg/day aspirinIVIG: 2 g/kg11103HDA/MDA + IVIG vsLDA + IVIGLower dose of aspirin is not inferior to higher doses of aspirin regarding the incidence of CAL, and the duration of fever or hospital stay, and the incidence of IVIG resistanceDhanrajani et al. [56] a80–100 mg/kg/day aspirin vs3–5 mg/kg/day aspirinIVIG: 2 g/kg249HDA + IVIG vsLDA + IVIGLDA is linked with the increased rates of IVIG resistance compared to HDA. No significant difference is shown on the duration of hospital stay and the incidence of CAAYokoyama et al. [93] c100–150 mg/kg/day aspirin vs30 mg/kg/day aspirin vs23HDA vs. MDAHDA administration is associated with a shorter duration of feverKuo et al. [79] a80–100 mg/kg/day aspirin vsNo aspirinIVIG: 2 g/kg134HDA + IVIG vsOnly IVIGHDA administration during the acute phase of KD can not reduce the incidence of CAL and IVIG resistance rate significantlySafar et al. [61] a ≥ 30 mg/kg/day aspirin vs3–5 mg/kg/day aspirin vsNo aspirinIVIG: 2 g/kg or N/A66126HDA + IVIG vsLDA + IVIG or Only IVIGThere are no significant differences observed between 3 groups regarding CAA incidence, IVIG resistance rate, duration of fever and hospital stayHuang et al. [59] a80–100 mg/kg/day aspirin vs30–50 mg/kg/day aspirin vs3–5 mg/kg/day aspirin vsNo aspirinIVIG: 2 g/kg1944Different doses of aspirin were comparedHigher dose of aspirin is not superior to lower doses of aspirin regarding CAL incidence, IVIG resistance rate, and duration of hospital staySanati et al. [94] a80–100 mg/kg/day aspirin vsNo aspirinIVIG: 2 g/kg62HDA + IVIG vsOnly IVIGHDA administration does not confer any benefit regarding coronary artery abnormalitiesKwon et al. [60] a80–100 mg/kg/day aspirin vs30–50 mg/kg/day aspirin vsNo aspirinIVIG: 2 g/kg323HDA + IVIG vsMDA + IVIG vsOnly IVIGEven though there is no significant difference in the incidence of coronary artery dilatations, duration of fever and hospitalization among groups, high-dose aspirin use is associated with Reye Syndrome while no aspirin use was associated with IVIG resistanceHuang et al. [58] a30–50 mg/kg/day aspirin vs3–5 mg/kg/day aspirin vsNo aspirinIVIG: 2 g/kg910MDA + IVIG vsLDA + IVIG vsOnly IVIGThere is no association between aspirin dosage and the development of CALMigally et al. [95] a80–100 mg/kg/day aspirinFor > 7 days vsFor 1–7 days vsNo aspirinIVIG: 2 g/kg or no IVIG1263 aspirin treatment plans were comparedThe duration of HDA administration does not affect the CAA persistenceKuo et al. [67] a ≥ 30 mg/kg/day aspirin vsNo aspirinIVIG: 2 g/kg851MDA/HDA + IVIG vsOnly IVIGNo significant differences were found between no aspirin group and aspirin group in CAL formation, IVIG resistance, and duration of hospitalizationLee et al. [96] a80–100 mg/kg/day aspirin vsNo aspirinIVIG: 2 g/kg180HDA + IVIG vsOnly IVIGHDA has no impact on IVIG resistance and CAL formation, although it causes shorter duration of feverLiu et al. [76] a ≥ 30 mg/kg/day aspirin vs < 10mk/kg/dayIVIG: 2 g/kg12258HDA/ MDA + IVIG vsLDA + IVIGLDA + IVIG is as effective as HDA/MDA + IVIG in preventing CAA. Higher doses of aspirin is associated with shorter duration of fever

There are also papers questioning the necessity of aspirin in KD treatment. Hsieh et al. and Kuo et al. demonstrated that the absence of aspirin in the treatment regimen during the acute phase did not affect IVIG resistance, incidence of CAAs and duration of fever [66, 67].

The common dosing for IVIG is 2g/kg and as mentioned above, thrombosis and inflammation processes are closely related; IVIG acts as an indirect anticoagulant by dampening inflammation and coagulation activation markers decrease following IVIG administration [42]. However, current treatment regimens vary in terms of the optimal dose for aspirin in KD treatment. At higher doses, it has anti-inflammatory effects, whereas at lower doses anti-platelet function is pronounced. In North America, the use of HDA (80–100 mg/kg per day) may be preferred during the acute phase [68] on the other hand, a moderate dose (30–50 mg/kg per day) is favored in Japan [69]. During the acute febrile phase, the AHA continues to recommend either moderate-dose (30–50 mg/kg/day) or high dose (80–100 mg/kg/day) aspirin, divided into multiple doses, alongside IVIG treatment [8]. Some clinicians choose to use higher doses of aspirin for 2 weeks regardless of patients’ fever status [70]. Once the patient is afebrile, the recommendation is to transition to LDA, typically 3-5mg/kg/day once a day, which is then continued for 6 to 8 weeks or longer depending on coronary artery involvement. If any abnormality is detected in the coronary arteries, then LDA is used until normal echocardiographic values are obtained. It is important to note that concomitant use of ibuprofen or other nonsteroidal anti-inflammatory drugs interfering with the cyclooxygenase pathway with aspirin should be avoided as it antagonizes the antiplatelet action of aspirin [71].

Previous studies had suggested the benefits of using high doses of aspirin in KD treatment (Table 1). However high doses may have potential side effects such as hepatic toxicity, anemia, sensorineural hearing loss, Reye’s syndrome and bleeding events may arise, especially during the subacute phase when albumin levels return to normal levels [67]. However, the superiority of HDA over MDA or vice versa is not clear; thus, recent studies and AHA also support the use of MDA in the acute phase [8]. There are additional possible concerns of HDA, as higher doses of aspirin inhibit cyclooxygenase in the vascular wall as well which may diminish prostacyclin levels, thus promoting platelet aggregation [72]. Decreased hemoglobin levels with HDA use is also observed and might result from elevated hepcidin levels leading to distorted iron metabolism [67]. Moreover, high doses of salicylate treatment, either alone or combined with IVIG augments TNF-α production, a critical cytokine in CAL formation, has been reported in the mouse model of KD [73]. The impeding effect of HDA with regard to anti-inflammatory action of IVIG was also recapitulated in human studies. Patients receiving HDA have a delayed decrease in C-reactive protein (CRP) levels following IVIG treatment [67].

These findings strongly suggest that administration of MDA, maybe more beneficial and thus better reflect the current practice. On the other hand, recent studies from Asian countries also suggest to start with LDA from the start [58, 59, 74–77] or even omit aspirin altogether [58, 59, 67, 74, 75, 78, 79], (Table 1). We await further studies to confirm that coronary complications are not increased with LDA. It should also be noted that the LDA studies are from Asia and have not been confirmed in Caucasian populations.

Treatment of Coronary Artery Thrombosis with Antiplatelet Agents, Antithrombotic and Fibrinolytic Therapy in Kawasaki Disease

Early diagnosis and treatment of thrombi is crucial to reduce the risk of cardiac complications. Platelet-mediated thrombotic complications are widely seen during the course of KD and aspirin is the prime treatment of choice. The fact that thrombosis is still observed in individuals taking aspirin also underlines the presence of other platelet activation pathways. Therefore, it is clear that the addition of alternative antiplatelet reagents to standard therapy might be required. The presence of severe CALs requires the concomitant use of other antiplatelet reagents with aspirin [64]. In that sense, the adenosine diphosphate (ADP)-receptor antagonist clopidogrel and GP IIb/IIIa inhibitor abciximab show promising effects in KD treatment (Table 2). Patients who do not respond to standard therapy might also receive these medications as a secondary treatment. Indeed, the use of abciximab resulted in regression and even resolution in CAAs of non-responders [80]. In addition, the phosphodiesterase inhibitor dipyridamole was shown to increase peripheral blood flow in coronary arteries, which in turn may alleviate stasis and eventually thrombosis [81]. Individuals with aspirin intolerance or G6PD deficiency are in need of alternative therapies. In these cases, other antiplatelet reagents need to be administered rather than aspirin. In addition, liver injury is a rare complication of KD. A study by Gao et al. indicated that children receiving aspirin are predisposed to have exacerbated liver injury compared to patients administered clopidogrel, suggesting it as a safer treatment option in this subgroup [82].Table 2. Summary of studies comparing the outcomes of anti-platelet treatment regimens in Kawasaki DiseaseStudyTreatment RegimenNumber of patientsComparisonOutcomeLiu et al. [97]N/A77Clopidogrel + Aspirin vsLow-Molecular-Weight Heparin + AspirinLower dose aspirin combined with clopidogrel is a safe and effective option in antithrombotic therapy for children with KD complicated by coronary artery aneurysmsWilliams et al. [98]IVIG: 2 g/kg as a single doseAspirin: 80–100 mg/kg/dayAbciximab: 0,25 mg/kg IV loading bolus dose followed by an infusion of 0,125 μg/kg/minute for 12 h15Abciximab + IVIG + Aspirin vsIVIG + AspirinThe addition of abciximab to standard therapy led to a more significant reduction in coronary artery aneurysm diameter compared to standard therapy aloneMcCandless et al. [99]IVIG: 2 g/kgAspirin: 80- 100 mg/kg/dayAbciximab: 0,25 mg/kg IV loading bolus dose followed by an infusion of 0,125 μg/kg/minute for 12 h18Abciximab + IVIG + Aspirin vsIVIG + AspirinLarge CAAs are successfully regressed with abciximab combined with standard therapy compared to standard therapy alone at 3–5 years of follow-up

It is believed that platelets are mainly responsible for the initiation of arterial thrombi. However, humoral clotting factors are also involved in thrombus formation in KD thus anticoagulants such as warfarin or low molecular weight heparin (LMWH) are recommended to be combined with the standard treatment regimen by the AHA. Indeed, combined use of anticoagulants with aspirin decreases MI incidence in patients with giant aneurysms [83]. Although warfarin is the prime choice if dosing and maintenance are problematic, LMWH can be used as an alternative. It provides a similar antithrombotic profile with more minor but fewer major bleeding problems. Of note, a transient decrease in antithrombin levels is widely observed in KD patients, which may hamper the success of LMWH treatment [30]. Under these circumstances, fresh-frozen plasma or antithrombin might be given to patients. Recent studies also suggest that rivaroxaban is a safe alternative and prevents thrombotic risk in KD patients with large CAAs [84].

The balance between coagulation and the fibrinolytic system is crucial for homeostasis. The hypercoagulable state in KD is reinforced by coagulation activation as well as fibrinolytic system malfunction. In fact, elevated levels of plasminogen activator inhibitor-1 (PAI-1) [85] and lower tissue plasminogen activator (tPA)/PAI-1 ratio in patients with CAL [86] and increment in euglobulin lysis time [30] highlight the distortion in fibrinolysis. A study by Horigome et al. suggested that KD patients with thrombotic complications benefit from intracoronary tPA administration [87]. The superiority of treating intracoronary thrombolysis with plasminogen activators is a matter of discussion: i) It resolves thrombus faster than intravenous coronary thrombolysis [88], ii) patients who did not benefit from heparin or warfarin respond well to this approach [87] iii) the prevalent abundance of fibrin meshwork in KD-associated thrombus may render fibrinolytic therapy desirable [3].

Overall, successful medical management of KD patients hinges on judicious use of anti-inflammatory, antithrombotic and fibrinolytic therapies. It is clear that this regimen requires attention for the extra risk of bleeding complications and the therapeutic armamentarium for KD with large/giant aneurysms involves the combination of several antiplatelet agents and anticoagulants. Furthermore, in serious cases, invasive revascularization procedures such as catheterization, CA bypass operations, might be preferred.

Conclusion

KD is the main cause of acquired heart disease. Inflammation-driven thrombotic complications are extensively described for many diseases, including KD. Disruption of hemostasis leads to major drawbacks such as ischemia, stenosis, MI or even death highlighting the importance of therapies targeting the coagulation system. The use of aspirin is a part of standard therapy, whereas there is still no universal consensus on the recommended dosing regimen during acute KD. 2017 AHA guidelines suggest the use of HDA and MDA for treatment, while some studies show that LDA is not inferior to higher doses of aspirin. Importantly, for individuals with big/giant aneurysms is inadequate and treatment should be supplemented with other antiplatelet agents and anticoagulants. Thrombolytic therapy is another important part of the treatment and plasminogen activators are found at the center of this treatment modality. Overall, it is clear that prophylaxis is critical for KD patients accompanied with a hypercoagulable state.

Key References

• Jone PN, Tremoulet A, Choueiter N, Dominguez SR, Harahsheh AS, Mitani Y et al. Update on Diagnosis and Management of Kawasaki Disease: A Scientific Statement From the American Heart Association. Circulation. 2024;150:e481-e500.
• ○ This paper provides the current guidelines for the diagnosis and management of the Kawasaki disease.
• Noval RM, Kocaturk B, Franklin BS, Arditi M. Platelets in Kawasaki disease: mediators of vascular inflammation. Nat Rev Rheumatol. 2024.
• ○ This article presents an in-depth summary of platelet alterations, platelet-mediated changes, and platelet-targeted therapies in Kawasaki disease.
• Peng Y, Yi Q. Incidence and timing of coronary thrombosis in Kawasaki disease patients with giant coronary artery aneurysm. Thromb Res. 2023;221:30-4.
• ○ This study defines the timing and risk factors associated with thrombotic complications in Kawasaki disease.
• Kuo HC, Lo MH, Hsieh KS, Guo MM, Huang YH. High-Dose Aspirin is Associated with Anemia and Does Not Confer Benefit to Disease Outcomes in Kawasaki Disease. PLoS One. 2015;10:e0144603.
• ○ This paper highlights the side effects of HDA use in the treatment of Kawasaki disease, particularly anemia and impaired inflammation suppression.
• Zheng X, Yue P, Liu L, Tang C, Ma F, Zhang Y et al. Efficacy between low and high dose aspirin for the initial treatment of Kawasaki disease: Current evidence based on a meta-analysis. PLoS One. 2019;14:e0217274.
• ○ A comprehensive meta-analysis comprising 11103 patients demonstrating the lack of superiority of higher doses of aspirin with respect to CAL incidence, duration of fever, length of hospital stay and IVIG resistance.