The thromboinflammatory response of blood after exposure to a biomaterial surface. Although seemingly complex, this is a simplified representation of the multiple cellular and molecular interactions that occur when blood meets a biomaterial surface. Immediately upon contacting a biomaterial surface, plasma proteins (eg, fibrinogen, VWF, immunoglobulin [Ig], and complement proteins [C3, C3(H₂O), C3b], FXII, and HK) are adsorbed. Complement is activated via all 3 pathways (AP, CP, and LP) as a result of deposition of C3 (C3, C3(H₂O), C3b), complement-fixing Ig (recognized by C1q), and binding of MASPs. The activation of the plasma contact system, its key components being HK, PK, and FXII/FXIIa, results in generation of thrombin (IIa) via the intrinsic pathway, as well as PKa, both of which amplify the thromboinflammatory response via several pathways. Platelets rapidly adhere to adsorbed fibrinogen, augmented under high shear rate, by VWF. These are activated by the intrinsic pathway-generated thrombin and C3a and C5a, that also exert proinflammatory and prothrombotic effects on all immune cells via their respective cell-surface receptors (Figure 3). Cytokines and chemokines are released from the platelets and recruit inflammatory leukocytes, which themselves then release more cytokines and chemokines. C5a and C5b-9 (MAC) activate TF on the monocytes/macrophages which were recruited by chemokines that are released by activated platelets and neutrophils, the latter of which may undergo NETosis, thereby further promoting local and systemic inflammation, thrombin generation, and clot formation. Thrombin, generated via the intrinsic and extrinsic (TF-dependent) pathways, also triggers inflammatory responses via PAR signaling on all immune cells. On the right side, adjacent host vascular endothelium with underlying smooth muscle cells, is shown to highlight how its integrity may be jeopardized during the innate thromboinflammatory response.