Control of Blood Coagulation by Hemocompatible Material Surfaces-A Review

Abstract

Hemocompatibility of biomaterials in contact with the blood of patients is a prerequisite for the short- and long-term applications of medical devices such as cardiovascular stents, artificial heart valves, ventricular assist devices, catheters, blood linings and extracorporeal devices such as artificial kidneys (hemodialysis), extracorporeal membrane oxygenation (ECMO) and cardiopulmonary bypass. Although lower blood compatibility of materials and devices can be handled with systemic anticoagulation, its side effects, such as an increased bleeding risk, make materials that have a better hemocompatibility highly desirable, particularly in long-term applications. This review provides a short overview on the basic mechanisms of blood coagulation including plasmatic coagulation and blood platelets, as well as the activation of the complement system. Furthermore, a survey on concepts for tailoring the blood response of biomaterials to improve the hemocompatibility of medical devices is given which covers different approaches that either inhibit interaction of material surfaces with blood components completely or control the response of the coagulation system, blood platelets and leukocytes.

Keywords: biomedical devices; blood platelets; blood-material interaction; coagulation; complement system; hemocompatibility; surface modification.

Figure 1

(A) Activation of coagulation by the intrinsic system through autoactivation of factor XII (FXIIa) with amplification by kallikrein (KK) and the extrinsic system after injuries through tissue factor (TF) leading both to activation of factor X (FXa). This is a component of a prothrombinase complex formed on the cell membrane of activated platelets exposing phosphatidylserine. KK also splits high-molecular-weight kininogen leading to release of vasoactive bradykinin (BK). Thrombin (FIIa) causes activation of fibrinogen leading to fibrin polymerization which is cross-linked by factor XIIIa. Thrombin is also the strongest agonist of platelets leading to their activation and aggregation. (B) Activation of complement system by covalent reaction of complement factor C3b with nucleophilic groups on material surfaces (e.g., OH), bound antibodies, and immune complexes through factor C1q with generation of C3 and C5 convertase and release of anaphylotoxins C3a and C5a with activation of leukocytes, as well as the release of TF connecting complement with coagulation. As the final step of complement activation the membrane attack complex (MAC) is formed. Adhesion and activation of platelets can happen through adsorbed plasma proteins followed by shape change, release of platelet agonists like thromboxane A2, and ADP. Platelets provide a procoagulant surface for the formation of the prothrombin complex connecting them to the coagulation cascade. Moreover, thrombosis is dependent on flow conditions with formation of red thrombi and inclusion of red blood cells into the fibrin network at low shear stress, while high shear stress leads to the formation of white thrombi and can also induce rupture of red blood cells that release ADP-activating blood platelets.

Figure 2

Survey on different design of blood compatible surfaces by steric repulsion through immobilization of mobile hydrophilic macromolecules (A), zwitterionic molecules that lead to tight binding of water molecules causing strong repulsive hydration forces (B), preferential binding of a passivating protein layer from plasma, like immobilization of C18 fatty acids for preferential adsorption of albumin (C), end-on immobilization of heparin for binding anti-thrombin III for inactivation of thrombin (FIIa), factor Xa and other coagulation factors (D), immobilization of antibodies or aptamers for preferential adhesion of endothelial progenitor cells from circulation for formation of an endothelial lining (E) and NO releasing/generating surfaces for control of leukocyte and platelet activation (F).