Implications of Hemostasis Disorders in Patients with Critical Limb Ischemia—An In-Depth Comparison of Selected Factors

Abstract

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.

Antithrombotic Therapy in Patients with Peripheral Artery Disease: A Focused Review on Oral Anticoagulation

“…increases vascular involvement, and leads to adverse clinical outcomes with more limited prognosis (Figure 1). The main initiator of clot formation is the tissue factor (TF), which is released by endothelial cells after a vascular damage (for example, in the case of a ruptured or ulcerated atherosclerotic plaque) [26]. Indeed, elevated levels of TF have been shown in patients with PAD [27].…”

“…They do not only adhere and aggregate at the site of the vascular lesion but also contribute to assemble of the prothrombinase complex, thus promoting thrombin generation and fibrin clot formation [25]. Importantly, fibrin clot itself exhibits significant thrombin-binding potential since the concentration of The main initiator of clot formation is the tissue factor (TF), which is released by endothelial cells after a vascular damage (for example, in the case of a ruptured or ulcerated atherosclerotic plaque) [26]. Indeed, elevated levels of TF have been shown in patients with PAD [27].…”

“…In addition, the prothrombotic character of platelets is influenced by the presence of numerous plasma hemostasis factors in their membrane microvesicles (platelet microparticles), which contributes to the activation of the coagulation system [26]. Glycoprotein (GP) Ib-IX-V interacts with vWF on exposed subendothelial components, and tethered platelets bind to collagen through GPVI and integrin αIIβ1.…”

“…This enzyme, with important proteolytic properties, dissolves the fibrin clot into fibrin degradation products (such as D-dimer). The activation of fibrinolysis is inhibited by plasminogen activator inhibitor type 1 (PAI-1) released from endothelium and platelets [26,29]. If the balance of fibrinolytic activators to their inhibitors is disturbed, this may result from the depletion of PAI-1 [45] and in patients with PAD, previous studies have demonstrated and increased fibrinolysis and fibrinolysis inhibition [46][47][48].…”

Circulating Biomarkers in Lower Extremity Artery Disease

“…In case-control studies, PAI-1 concentrations were higher both at rest and after exercise in LEAD patients compared with healthy controls. [ 17 , 77 – 79 ]…”