Thrombosis is a serious condition where one or more blood clots form inside the blood vessels, which prevents blood from flowing normally through the circulatory system and threatens the health of patients seriously [1], [2]. Although significant advance has been made in treatment, the prognosis of these patients is still poor [3], and thrombosis tends to recur [4], [5]. Alterations in hemostatic balance, including changes in prothrombotic and fibrinolytic coagulation factor activity [6], [7], platelet hyperactivity [8], [9], [10], and endothelial dysfunction [10], [11], remarkably increase the risk of undesirable thrombus formation. Among them, platelets play a vital part in the process of hemostasis via initiating the blood coagulation mechanism, due to its highly efficient activation, adhesion, aggregation, and procoagulation after tissue injury.

Blood is a biological fluid that transports oxygen and nutrients to living cells and carries away carbon dioxide and other waste products. It has four main components, namely blood plasma, red blood cells (RBCs), white blood cells (WBCs), and platelets. According to the relative concentration in whole blood, the ratio of the number of RBCs, platelets, and WBCs is approximately 600 : 40 : 1 [12]. A normal RBC is a biconcave disk-shaped cell of 8.0 μm in diameter and 2.0 μm in thickness (Fig. 1a). Under physiological conditions, the RBC is remarkably deformable, which allow itself to squeeze through microcapillaries without any damage [13], [14]. Compared with the RBC, a platelet is much smaller and stiffer. In the inactivated resting form, the platelet is generally a biconvex discoid structure of 2-3 μm in diameter (Fig. 1a) [10]. When the shear-induced lift force acts on the blood cells, the lateral migration of RBCs takes place in blood flow, leading to the formation of cell-free layer (CFL) adjacent to the vessel wall where the platelets tend to concentrate (Fig. 1b) [15], [16]. Through this underlying mechanism, platelets sufficiently approach the wall trauma, build a platelet plug, and release the thrombin that promotes the conversion of fibrinogen (FN) to the insoluble fibrin network [17]. The network structure captures more cellular components into stable coagulation, providing adequate hemostasis at the bleeding site [18], [19]. Hence, the margination and adhesion of platelets play important roles in hemostasis and thrombus formation at the site of injured endothelium.

Several significant experimental studies have been undertaken to elucidate the margination and adhesion dynamics of platelets. As early as the 1980s, Reneman et al. utilized intravital microscopy to conduct experiments in vivo for platelet distribution in rabbit mesenteric arterioles [20], [21]. They found excess aggregation of platelets near the vascular wall. Corattiyl and Eckstein performed in vitro studies to investigate the influences of blood hematocrit and wall shear rate on the blood cell distribution in microtubes with diameters ranged from 50.0 μm to 200.0 μm [22]. They showed that the proportion of platelets observed near the tube wall increased as the blood hematocrit increased in the range of 10-40%. They also found that an elevated shear rate in a medium range (80-800 s-1) would enhance the platelet margination, whereas this effect tended to be diminished beyond such range. Rosa et al. performed a microfluidic study to investigate the margination of rigid microparticles under different shear flow conditions [23]. They showed that the blood hematocrit also plays a key role in the microparticle margination dynamics. Additionally, Savage et al. investigated the underlying mechanism initiating the platelet adhesion in a parallel plate flow chamber [24]. They pointed out that it is hard to form firm adhesion between platelet and immobilized fibrinogen under high shear rate.

Along with the aforementioned experimental studies, recent advances in computational modeling and simulations enable the investigation of a broad range of dynamic properties of blood cells in both health and disease [25], [26], [27]. Currently, there is a great variety of modeling approaches since there is no universal solution for all blood flow related problems. Traditionally, continuum-based (or mesh-based) models [28], [29], [30], [31], [32], [33], which treat the cell membrane and intracellular fluids as homogeneous materials, enable simulations of blood flow on macroscopic length and time scales; however, they do not provide the detailed dynamics of local subcellular structures. Blood cell models based on particle-based numerical methods [34], [35], [36], [37], [38],which account for the membrane structure, can resolve cellular and sub-cellular scales. Although these particle-based blood cell models have lower accuracy than the mesh-based ones, they are increasingly popular as a promising tool for modeling the microscopic blood flow in health and disease [25], [39]. For example, Yazdani et al. employed the dissipative particle dynamics (DPD) method to study the transport and dynamics of platelets flowing through microchannels with constriction [37]. They found that the high constriction level enhanced post-stenosis platelet aggregation, and interpreted the effects of the complex geometry on distribution of blood cells systematically. In a subsequent study, Chang et al. utilized the DPD model to examine blood cell concentration distribution and platelet margination in microtubes containing adherent WBCs [40]. They concluded that platelet margination was enhanced by increasing the flow rate or hematocrit, and found that the platelet shape and the motion of WBCs played a role in platelet distribution. Despite these interesting outcomes, many important aspects of the margination and adhesion of platelets in blood flow remain unclear, a more fundamental study on the shear-induced margination of circulating platelets should still be done. Such studies may deepen understanding of the predominant processes governing the early stages of thrombosis.

In this study, we perform a detailed computational simulation to investigate the shear-induced margination and adhesion of platelets in microvascular blood flow, with a focus on the influences of wall shear rate, fibrinogen concentration level, and adhered platelets on the margination and adhesion processes of circulating ones. The rest of the article is organized as follows: firstly, we describe the simulation methods; subsequently, we present and discuss the simulation results; finally, we summarize the main findings and draw the conclusions.