Epidemiology, etiology, and pathophysiology of infection-associated venous thromboembolism in children

Introduction Venous thromboembolic events (VTE) are increasingly being recognized in children. The clinical spectrum of VTE constitutes deep venous thrombosis (DVT) and pulmonary embolism (PE). Unlike in adults, VTE in children is usually secondary to complications of a primary illness like sepsis, cancer or treatment of primary illness including placement of central venous lines (CVLs) and surgical intervention for correction of underlying diseases [1]. The reported incidence of VTEs in children ranges from 5.4 [2] to 9.7 [3] per 10,000 hospital admissions. Although the presence of CVLs accounted for 95% of thromboembolic events in hospitalized children [4], it is becoming clear that underlying infection in itself predisposes for the development of thrombosis [1,2,4–13]. A key reason is the intricate relationship between the coagulation system and the immune system [14]. The coagulation system is one of the primitive components of the host defense against bacterial infection [15]. Local thrombosis can serve as a part of the first line of host defense against bacterial invasion in vertebrates and non-vertebrates. An interesting example of the interaction between the host coagulation system and pathogens is the horseshoe crab, which uses endotoxin to trigger a clotting response that presumably walls off the bacteria, providing an initial defense against invasion [16]. The clotting system of the horseshoe crab consists of three serine proteases and one clottable protein that are functionally similar to mammalian fibrinogen and share some sequence homology with primate fibrinopeptide B [16]. This coagulation response to bacterial infections also appears to be preserved in mammals, in which infections trigger tissue factor (TF) expression on the surface of monocytes, which in turn initiates the coagulation cascade (Figure 7.1). To combat the host immune response, bacteria have developed virulence strategies to interact with host hemostatic factors such as plasminogen and fibrinogen in order to achieve widespread dissemination. Many investigators around the world are extensively studying the potential link between bacterial infections and thrombosis, and knowledge in this area is growing.