Abstract
Coronary artery thrombosis is the major risk associated with Kawasaki disease (KD). Long-term management of KD patients with persistent aneurysms requires a thrombotic risk assessment and clinical decisions regarding the administration of anticoagulation therapy. Computational fluid dynamics has demonstrated that abnormal KD coronary artery hemodynamics can be associated with thrombosis. However, the underlying mechanisms of clot formation are not yet fully understood. Here we present a new model incorporating data from patient-specific simulated velocity fields to track platelet activation and accumulation. We use a system of Reaction-Advection-Diffusion equations solved with a stabilized finite element method to describe the evolution of non-activated platelets and activated platelet concentrations [AP], local concentrations of adenosine diphosphate (ADP) and poly-phosphate (PolyP). The activation of platelets is modeled as a function of shear-rate exposure and local concentration of agonists. We compared the distribution of activated platelets in a healthy coronary case and six cases with coronary artery aneurysms caused by KD, including three with confirmed thrombosis. Results show spatial correlation between regions of higher concentration of activated platelets and the reported location of the clot, suggesting predictive capabilities of this model towards identifying regions at high risk for thrombosis. Also, the concentration levels of ADP and PolyP in cases with confirmed thrombosis are higher than the reported critical values associated with platelet aggregation (ADP) and activation of the intrinsic coagulation pathway (PolyP). These findings suggest the potential initiation of a coagulation pathway even in the absence of an extrinsic factor. Finally, computational simulations show that in regions of flow stagnation, biochemical activation, as a result of local agonist concentration, is dominant. Identifying the leading factors to a pro-coagulant environment in each case—mechanical or biochemical—could help define improved strategies for thrombosis prevention tailored for each patient.
Highlights
Coronary artery thrombosis is the major risk associated with Kawasaki disease (KD) [1]
Coronary arteries with aneurysms classified as low risk for thrombosis, presented with [AP] generally lower than the cases classified as high risk of thrombosis and confirmed clot formation
Future studies aiming to simulate thrombus growth and concentrated on the microscale region near the wall would need to consider a more precise diffusivity value for PolyP, which is specific for PolyP chains released upon platelet activation. This computational modeling study illustrates possible mechanisms for thrombus initiation under low shear conditions, such as those induced by aneurysms
Summary
Coronary artery thrombosis is the major risk associated with Kawasaki disease (KD) [1]. Long-term management of KD patients with persistent aneurysms requires thrombotic risk assessment and clinical decisions regarding the administration of anticoagulation therapy [1]. Oral Xa direct inhibitors or direct thrombin inhibitors may be used as an alternative anticoagulation therapy in KD [1]. These are currently not approved for pediatric use, clinical trials are on-going [2]. Patientspecific computational modeling has provided new insight regarding thrombotic risk for KD patients [3,4,5,6], demonstrating that hemodynamic variables obtained from computational fluid dynamics (CFD) simulations have the potential to identify regions prone to thrombosis [3]. The underlying mechanisms of clot formation, which could help determine favorable strategies for thrombosis prevention, are not fully understood
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