Background: Atherosclerosis is a systemic disease. Among patients with atherosclerosis, those suffering from peripheral arterial disease (PAD) represent a group of individuals with particularly high death risk, especially during the course of critical limb ischemia (CLI). In the pathogenesis of PAD/CLI complications, blood coagulation disorders play a significant role. The study aim was to examine the activation of the coagulation system depending on tissue factor (TF) in patients with CLI as compared with those with intermittent claudication (IC). Methods: Before initiating proper treatment (invasive or maintenance), blood samples were collected from 65 patients with CLI and 15 with IC to measure the following selected hemostasis parameters: concentrations and activation of tissue factor (TF Ag and TF Act) and tissue factor pathway inhibitor (TFPI Ag and TFPI Act), concentrations of thrombin–antithrombin complex (TAT Ag) and fibrinogen, platelet count (PLT), and concentrations of tissue-plasminogen activator (t-PA Ag), plasminogen activator inhibitor 1 (PAI-1), and D-dimer. The control group included 30 healthy volunteers (10 female/20 male). Results: The values of all analyzed parameters (except for lower TFPI Act) were significantly higher in the blood of PAD patients (with respect to PLT only in the CLI subgroup) in comparison with healthy subjects. The blood of patients with CLI as compared to the IC subgroup revealed much higher concentrations of TF Ag (p < 0.001), with slightly decreased TF Act, significantly lower concentrations of TFPI Ag (p < 0.001), slightly increased TFPI Act, and significantly higher levels of TAT Ag (p < 0.001), fibrinogen (p = 0.026), and D-dimer (p < 0.05). Conclusions: In patients with CLI, we can observe coagulation activation and a shifting balance toward prothrombotic processes. Furthermore, increased concentrations of D-dimer suggest a secondary activation of fibrinolysis and confirm the phenomenon as a prothrombotic condition with heightened fibrinolysis.

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