Chapter 6: The Effects of Engineered Nanomaterials on the Plasma Coagulation System
The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any agency determination or policy.
The plasma coagulation system (PCS) consists of plasma proteins and other factors that, together with platelets and vascular endothelial cells, maintain hemocoagulation balance. Under physiological conditions, these systems prevent blood clotting and, in cases of vascular injury, facilitate hemostasis to prevent blood loss. The dysregulation of hemocoagulation may lead to life-threatening thrombotic and/or bleeding pathologies. Since 1) various engineered nanomaterials are being designed for biomedical applications that will come into contact with the blood and 2) other nanomaterials may reach the circulation as a result of occupational, environmental, or other types of exposure, it is necessary to evaluate the effects of engineered nanomaterials on the PCS. In the introduction of this chapter, the components and mechanisms of the kallikrein–kinin system (KKS), the PCS, fibrinolysis, and the pathophysiology of the possible adverse effects of nanomaterials on these systems are briefly described. Next, the methods that are used for the in vitro evaluation of the effects of nanomaterials on the KKS, PCS, and fibrinolysis are reviewed. Screenings for the effects of nanomaterials are primarily based on their preincubation with citrated platelet-poor plasma (PPP). The PPP is subsequently subjected to clotting tests, including measurements of the activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), and recalcification time. In certain studies, plasmas that are deficient in specific plasma coagulation factors are used for comparison purposes. The activities of certain specific coagulation factors can be assayed photometrically using chromogenic or fluorogenic substrates, while antigens can be detected using ELISAs. Thromboelastography is another technique that is used for the complex analysis of the effects of nanomaterials on blood clotting and fibrinolysis. Gravimetric in vitro thrombolytic assays have also been used to this end. Lastly, a summary of the published results regarding the in vitro effects of various nanomaterials on the KKS, the PCS, and fibrinolysis is presented.
