The results of this study suggest that there may be some association between coagulation/fibrinolysis function and serum lipid levels in patients with advanced KOA, although the correlation may be small.
Numerous studies have shown that osteoarthritis can occur articular cartilage destruction, chondrocyte apoptosis, subchondral sclerosis, cystic changes, osteophyte formation at the joint edge, local blood circulation abnormalities, etc., and its pathogenesis is still unclear [5, 21]. So far, studies have suggested that both immune and inflammatory reactions exist in the pathological process of OA . The NF-κB signaling pathway is ubiquitous in eukaryotic cells and has various regulatory functions such as regulating immune and inflammatory responses. In the physiological state, the balanced NF-κB response maintain the stability of internal environment. However, in the pathological state, the NF-κB response promotes the expression of pain-causing mediators and inflammatory mediators, which results in catabolic processes, cell death or apoptosis. Many studies have shown that NF-κB signaling pathway plays a major role in the pathogenesis and development of osteoarthritis [22, 23]. NF-κB, a member of the transcription factors family of proteins, exists in cells mainly as heterodimer formed by P50 and P65 binding in vivo. In normal state, NF-κB (P50 / P65) binds to inhibitory protein IkB, which puts it in a state of inactivation. Proinflammatory cytokines, excessive mechanical stress, and/or matrix-degrading enzymes can trigger a series of reactions which cause proteasome degradation of IkB, and then result in the release of active NF-κB (RelA/ NF-ΚB1 dimer) . NF-κB is highly activated at the site of synovial inflammation in patients with KOA . The roles of NF-κB in OA chondrocytes and cartilage have been well-documented . Increasing evidence has shown that many types of miRNAs suppress chondrocyte catabolism by inhibiting molecular components of the NF-κB signaling pathway. For example, Yanjie Ding found that miR-93 inhibited the NF-κB pathway by targeting toll-like receptor-4 (TLR4), which was the upstream regulators of NF-κB . Cytokines are a kind of bioactive protein molecules synthesized and secreted by immune cells and some non-immune cells after stimulation . The role of cytokines in the pathophysiology of OA is well-documented. They participate in inflammation and immune response through the exchange and regulation of information between cells. In normal human body, the inflammatory factors and anti-inflammatory factors maintain a dynamic balance. IL-1, IL-6, IL-8, IL-17 and TNF-α are the main inflammatory cytokines. IL-1Ra, IL-4, IL-10 and IL-13 are the main anti-inflammatory cytokines [1, 29, 30]. The NF-κB signaling pathway promotes the transcription of genes encoding cytokines like TNF-α and IL-1β and then induces the production of IL-6, IL-8, and cyclooxygenase-2 (COX-2). After that, the NF-κB signaling pathway stimulates the production of matrix metalloproteinases (MMPs) in synovial cells, monocytes, or chondrocytes, and ultimately mediates critical events in inflammatory response . In addition to regulating the expression of TNF-α and IL-1β, NF-κB is activated by these cytokines as well. Inflammatory factors and activated NF-κB actually form a positive cycle of regulation .
The relationship between serum lipid levels and OA has not been determined yet. More and more evidence suggests that OA is a "metabolic disorder" in which the associated lipid metabolism contributes to the progression of the disease [6, 32]. In the in vitro experiment of Dominique et al. , the levels of TC, LDL-C and ApoA1 were strongly correlated in the articular cavity of OA patients, and were correlated with the local inflammatory process in the OA articular cavity through IL-6 and MMP-3. Dominique considered that the downstream pathways of NF-κB and MAPK were induced by ApoA1 stimulation . ApoA1 induced the expression of IL-6, MMP-1 and MMP-3 in primary chondrocytes and fibroblast-like synovial cells through TLR4 receptor, and was directly or indirectly involved in local inflammatory responses. Onat et al. also found that ApoA1 could be converted into pro-inflammatory particles by aggregation to Lp(a) .
Activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen (FIB) and D dimer (D-D) are common indexes for detecting coagulation and fibrinolysis function in clinic. APTT and PT are the most sensitive and commonly used screening tests in the internal and external coagulation system, which mainly reflect whether the internal and external coagulation is normal. Fibrinogen, also known as coagulation factor I, is the highest content of coagulation factor in plasma and the main protein in the coagulation process. D dimer is a cross-linked fibrin degradation product, and its level changes can be used as one of the markers of hypercoagulability and fibrinolysis in vivo. Therefore, the above four indicators were selected to evaluate the coagulation and fibrinolysis function of patients in this study . A number of studies have focused on the relationship between coagulation/fibrinolytic system and inflammation recently [12, 36, 37]. Thrombin mediates hemostasis and inflammatory response and directs the immune response to tissue damage . Activation of PARs on platelets plays an important role in hemostasis and thrombosis. Several studies found that PARs involved in the development of both inflammatory responses and thrombin [13, 38]. Stimulation of isolated monocytes by thrombin or a receptor-selective PAR1-AP (TFLLRNPNDK) resulted in release of IL-6 . The study of Y. Xiang showed that thrombin increased the expression of inflammatory cytokines such as IL-1𝛽, TNF-α, transforming growth factor-𝛽 1 (TGF-𝛽1), IL-6 and COX-2 in osteoblasts or osteoblast cells . On the other hand, the proteolytic activity of plasmin contributes to inflammation and remodeling in disease . A.K. 's study showed that in OA patients, elevated D dimer levels demonstrated increased intra-articular coagulation and increased fibrin dissolution . Plasmin is the main enzyme mediator of fibrinolysis, forming TLR-4 and activating fibrin degradation products (FDPs). Whether activated by TLR-4 for FDPs formation, or by MMPs and/or PAR-1, the proteolytic activity of plasmin contributes to inflammation and remodeling [37, 41]. Proteases such as FXa, FVIIa, thrombin, plasminase, urokinase-type plasminogen activator (u-PA) and tissue-type plasminogen activator (t-PA) not only participate in extravascular coagulation or fibrinolysis, but also mediate inflammation response and tissue remodeling . Some studies showed that patients with hypercholesterolemia or triglyceridemia had higher levels of fibrinogen and factor VII and shorter PT and APTT values than patients with lower cholesterol levels [17, 19]. Jung-Ah Kim et al. discovered that procoagulant factors II, VII, IX, X, and XI and anticoagulant factors protein C and protein S were significant correlated with triglyceride . The increase of procoagulant factors may be greater than that of anticoagulant factors, and the total hemostatic balance may tend to change to hypercoagulability in hyperlipidemia.
This was the first study to explore the association between coagulation/fibrinolysis function and serum lipid levels in patients with KOA. Based on previous findings, there may be a link among coagulation/fibrinolysis function, blood lipid levels and inflammatory response. Lp (a) is a complex formed by Apo (a) (apolipoprotein (a)) and LDL, which main apolipoproteins are ApoB100 and Apo (a). Nathalie Busso et al. found co-deposition of plasma Apo (a) with fibrin in arthritic joints, suggesting that Apo (a) locally regulated fibrinolytic activity and may contribute to the persistence of fibrin and bone matrix degradation in inflammatory arthritis . Tsimikas Sotirios et al. confirmed that Lp (a) was highly homologous with fibrinolytic enzyme, which could competitively bind its receptor and lead to the reduction of thrombolysis by interfering with the physiological activity of fibrinolytic enzyme . Similar results were obtained in this study, that is, fibrinogen was positively correlated with Lp(a). TLR4, an upstream regulator of NF-κB, mediated the expression of IL-6, MMP-1 and MMP-3 in primary chondrocytes and fibroblast-like synovial cells induced by ApoA1 . Interestingly, plasmin was able to form TLR-4 and activate FDPs . Onat’s study showed that ApoA1 could be transformed into pro-inflammatory particles by polymerization to Lp (a) . ApoA1 is the main apolipoproteins of chylomicrons (CM) and HDL-C, while CM is a TG-rich lipoprotein, which may partly explain the relationship between TG, HDL-C and coagulation function in this study. It is still necessary for us to further improve the relevant basic research of coagulation factors, lipoprotein, as well as pro-inflammatory and anti-inflammatory factors, so as to obtain more accurate results. Joint replacement surgery is still the preferred treatment for advanced KOA so far [45, 46]. With the increasing understanding of osteoarthritis, there are currently some non-surgical treatments. One of them is intra-articular therapy with platelet-rich plasma, which requires us to pay attention to the coagulation/fibrinolysis function of patients . It is a new idea brought by this study to control serum lipid levels through lifestyle or medication to avoid abnormal coagulation/fibrinolysis state. There is considerable evidence that statins have antithrombotic properties, as they may lead to significant downregulation of the clotting cascade, most likely due to decreased tissue factor expression leading to reduced thrombin production .
Despite the advantages above, some limitations have to be considered. Since our subjects were from the local population, we could not rule out the effect of ethnic differences on our results. And the cross-sectional study design was inevitably open to confounding factors which may exaggerate or reduce the association between exposure and the primary outcome. In addition, only patients with advanced KOA were included in our study, which needed to be further supplemented. Moreover, we did not have blood coagulation factor measurements except factor I at that time, so we could not examine if coagulation factor was associated with serum lipid levels in KOA patients. Due to the lack of relevant data, we did not include the symptom severity and radiographic data in this study, which would be remedied and improved in the future research of our group.