Fig. 8

Correlation between TF expression and D-dimer levels in patients after UC-MSC administration. a TF expression was analyzed in 30 different UC-MSC batches. b-d. D-dimer levels in patient serum before cell therapy (b) and at 24 h (c) and 48 h (d) after the first UC-MSC infusion showed no correlation with the frequency of TF-expressing cells. e–g Fibrinogen levels in patient serum were comparable between the indicated analyzed time points. h Next, PT tests of patient serum were examined in the presence of UC-MSCs, showing a normal range of PT. Furthermore, the PT values were independent of TF expression on UC-MSCs. I The plot depicts the extrinsic (yellow box), intrinsic (blue box), and common (green box) coagulation cascades. TF, the initiator of the extrinsic pathway, is activated during blood vessel damage or in the presence of external factors such as bacterial endotoxin, inflammatory cytokines, and thrombin. During the initiation phase of coagulation, procoagulant factors such as TF, collagen, von Willebrand factor (vWF), laminin, vitronectin, and high molecular weight kininogen (HMWK) in subendothelial tissues are exposed to platelets and circulating coagulant factors FVII, FVIII, FIX, FX, etc. An extrinsic coagulation cascade is intermediately initiated. TF is decrypted, leading to proteolytic activation of its ligands FVII and FX into FVIIa and FXa. FXa cleaves prothrombin in thrombin. Thrombin proteolyzes fibrinogen into fibrin to form clots. Thrombin further activates platelets, FVa, and FVIIIa via a positive feedback loop to propagate the coagulation cascade. When clots are dissolved in the body, fibrin is broken into small protein fragments known as D-dimers. Genetic downregulation or pharmacological inhibition of TF could reduce TF-induced extrinsic coagulation. On the other hand, the data suggest that other coagulant factors are also involved in this process upon UC-MSC administration. Therefore, prophylactic treatment with anticoagulant drugs such as heparin is of benefit, as the drug also targets the common coagulant pathway. Furthermore, local administration might reduce the risk of thrombogenic events compared to systemic infusion