Potential Role of Contact Pathway Factors in Catheter-Related Thrombosis: Emerging Evidence and Therapeutic Strategies

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  Figure 2. Mechanisms of catheter-associated coagulation activation as well as current and promising therapeutic strategies. Catheters can promote in vitro coagulation activation by inducing a conformational change and the activation of contact pathway factor (F) XII and XI to their activated forms, FXIIa and FXIa, respectively. Catheters have also been shown to augment the activation of FXI by FXIIa and thrombin [34]. The above mechanism accelerates thrombin activation, leads to fibrin clot formation and contributes significantly to catheter-related thrombosis (CRT) pathology. Current anticoagulants against CRT (shown in blue font) rely mainly on heparins, which exert an anticoagulant effect by serving as a cofactor of antithrombin, thereby accelerating its inhibition of thrombin and FXa. Direct oral anticoagulants against FXa and thrombin are also being used for CRT. However, the above medications also impede normal hemostasis potential, thus increase the risk of bleeding. Inhibitors of contact pathway factors XII and XI have been shown to impede catheter-induced thrombin generation and clotting in various in vitro, animal and human trials of catheter placement or extracorporeal…

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  Figure 1. Illustration of common types of intravenous catheters and catheter-associated blood clotting, intraluminal catheter occlusion and thromboembolism. (A) Common types of intravenous catheter: (1) peripherally inserted central catheter (PICC), which is inserted through a vein in the upper arm and ends in larger veins near the heart; (2) midline catheter, which is inserted through a vein in the upper arm, with tip located at or near the level of the axilla and distal to the shoulder; (3) central venous catheter (CVC), which is placed through the internal jugular vein or subclavian vein and ends in larger veins near the heart; (4) sometimes the CVC is connected to an implanted port that is placed under the skin in the chest, arm, or abdomen. The arrows indicate insertion sites. (B) Catheter placement can lead to activation of the coagulation system and fibrin formation, leading to fibrin sheath deposition on the catheter, intraluminal catheter occlusion, mural thrombosis, or thromboembolism. Schematic diagram created using Nano-banana, with modifications.

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  Figure 3. Schematic domain structures of the contact pathway factors and catheter-induced conformational change in FXII. (A) Domain structure of FXII, prekallikrein (PK), high molecular weight kininogen (HK) and FXI. (B) The proposed mechanism of catheter-induced conformational change in FXII, which makes it more prone to activation by PKa. Recent studies indicate that FXII zymogen is in a closed conformation, in which the activation loop (containing the PKa cleavage site Arg353) is buried by the interactions between the kringle and the FnII domains, and possibly also the protease domain [35]. Upon contact with a catheter, positively charged patches in the EGF1 and FnI domains interact with the catheter surface and result in exposure of the FXII Arg353 cleavage site to enzymes such as PKa. Red arrows indicate the major cleavage sites of the enzymes. The plus signs in (B) indicate positively-charged domains.