Action of Nanoparticles on Platelet Activation and Plasmatic Coagulation

Abstract

Nanomaterials can get into the blood circulation after injection or by release from implants but also by permeation of the epithelium after oral, respiratory or dermal exposure. Once in the blood, they can affect hemostasis, which is usually not intended. This review addresses effects of biological particles and engineered nanomaterials on hemostasis. The role of platelets and coagulation in normal clotting and the interaction with the immune system are described. Methods to identify effects of nanomaterials on clotting and results from in vitro and in vivo studies are summarized and the role of particle size and surface properties discussed. The literature overview showed that mainly pro-coagulative effects of nanomaterials have been described. In vitro studies suggested stronger effects of smaller than of larger NPs on coagulation and a greater importance of material than of surface charge. For instance, carbon nanotubes, polystyrene particles, and dendrimers inferred with clotting independent from their surface charge. Coating of particles with polyethylene glycol was able to prevent interaction with clotting by some particles, while it had no effect on others and the more recently developed bio-inspired surfaces might help to design coatings for more biocompatible particles. The mainly pro-coagulative action of nanoparticles could present a particular risk for individuals affected by common diseases such as diabetes, cancer, and cardiovascular diseases. Under standardized conditions, in vitro assays using human blood appear to be a suitable tool to study mechanisms of interference with hemostasis and to optimize hemocompatibility of nanomaterials.

Fig. (1)

Overview of platelet surface receptors with their respective ligands (A) and the most important signaling pathways involved in platelet signaling (B). Abbreviations: AC, adenylate cyclase; cAMP, cyclic adenosylmonophosphate; CLEC-2, C-type lectin-like receptor 2; DAG, diacylglyceride; GAS6: growth arrest specific gene 6; IP, prostacyclin receptor; IP3, inositoltrisphosphate; MLCK, myosin light chain phosphatase kinase; MAPK, mitogen-activated protein kinase; PAR, protease-activated receptor; PLA2, phospholipase A2; SFK, sarcoma family kinase; TPa, thromboxane A2 receptor alpha; TXA2, thromboxane A2; vWF, von Willebrand factor.

Fig. (2)

Factors of plasmatic coagulation cascade that lead to generation of the fibrin network (left) and regulators for fibrinolysis of the fibrin clot (right). Role of the specific factors to clotting (initiation, propagation and fibrin formation) is indicated. Boxes in darker shade surrounded by black lines indicate activated factors (suffix ‘a’), while squares in lighter shades of the same color and surrounded by white lines indicate the respective non-activated factors. Left: TF in combination with factor VIIa start the coagulation cascade and lead to activation of factors IX and X. Xa induces the final step prior to fibrin formation. Right: Plasminogen is activated to plasmin by tPA and uPA and by factors XIa, XIIa, and kallikrein. The activation to plasmin is inhibited indirectly by PAI-1 and directly by α2-antiplasmin and α2-macroglobulin. The degradation of fibrin to its degradation products (D-dimers) can be inhibited by TAFI. Abbreviations: TF, tissue factor; AT, antithrombin III, HMWK, high molecular weight kininogen; tPA, tissue-type plasminogen activator; PAI-1, plasminogen activator inhibitor 1; TAFI: thrombin activatable fibrinolysis inhibitor; uPA: urokinase-type plasminogen activator. Black arrows indicate activation and red arrows stand for inhibition.

Fig. (3)

Interplay of coagulation and inflammation. Inflammation-induced endothelial cell activation with secretion of cytokines and activation of the complement system in combination with activation of the coagulation cascade act synergistically (black arrow). Increased levels of TF start both processes. Inhibition is achieved by anticoagulation (blackberry box) and anti-inflammatory (violet box) factors. Abbreviation: AT, antithrombin III; CD62E, endothelial leukocyte adhesion molecule 1; CRP, C-reactive protein; Fibr.gen, fibrinogen; Fnlysis, fibrinolysis; ICAM, intercellular adhesion molecule-1; IL, interleukin; IL-1Ra, interleukin-1 receptor antagonist; MASP-2: mannan-binding lectin serine protease 2; PARs, protease-activated receptors; PC/APC, protein C/activated protein C; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TGF-ß, transforming growth factor beta.

Fig. (4)

Potential effects of NPs on hemostasis. Abbreviation: ⇑: increase; ⇓: decrease