Our study first found that after PSM, the risk for preoperative DVT formation in TKA patients with preoperative anemia increased by 1.97 times [95% (CI 1.05–3.69)], P = 0.035. Different from other studies, we investigated the association between preoperative anemia and DVT before surgery in terms of both inflammation and RBCs.
Association between preoperative anemia and DVT in patients with KOA
Spahn DR. found that preoperative anemia was highly prevalent, ranging from 24 ± 9 to 44 ± 9% in patients undergoing THA, TKA and hip fracture surgery\*MERGEFORMAT [4]. In the present study, preoperative anemia occurred in 342 patients (33.7%), consistent with the incidence indicated by Spahn DR. *MERGEFORMAT [4]. Previous studies have found that 18–40% of patients undergoing TKA had received blood transfusion [10]. Low preoperative Hb level was considered a risk factor for moderate and severe postoperative anemia in patients with primary TKA [12]. Additionally, it has been found that preoperative anemia increased the risk for prosthetic-related infection in patients undergoing TJA [13]. In patient who underwent colorectal surgery, anemia is associated with the increased incidence of DVT and PE [14]. Xiong X and Bo Cheng found that the decrease in erythrocyte count was a high risk factor for preoperative DVT in KOA patients before TKA [15]. However, their study only revealed that the decrease in erythrocyte count contributed to preoperative DVT in TKA patients, and did not verify whether anemia is a high risk factor for preoperative DVT before TKA. Before and after PSM, we found the risk for DVT in TKA patients with preoperative anemia increased by 1.88 times ([95% CI 1.16–3.03], P = 0.01) and 1.97 times ([95% CI 1.05–3.69], P = 0.035), respectively.
Possible mechanism of preoperative anemia and DVT in patients undergoing TKA
To date, anemia is defined by Hb levels in most studies. As per the WHO standards, the decrease in RBC counts (female < 3.5 × 1012/L, male < 4 × 1012/L) is also one of the indicators for diagnosing anemia\*MERGEFORMAT [9]. Both the inflammatory mechanism and the RBC mechanism could be plausible explanations of thrombosis formation in patients with preoperative anemia.
Mechanism of inflammation
Over the last several decades, OA and the metabolic syndrome are increasingly recognized as the low-grade inflammatory condition with elevations in systemic inflammatory mediators such as Interleukin-1 (IL-1), Interleukin-6 (IL-6), and Tumor necrosis factor (TNF), and Interleukin-17 (IL-17)\*MERGEFORMAT [16]. In RA patients, IL-17 coordinates local inflammation, induces proinflammatory cytokines to prolong the inflammation process\*MERGEFORMAT [18]. In both OA and RA, IL-17 lead to cartilage inflammation [17]\*MERGEFORMAT [18]. During inflammation, IL-6 stimulates the liver to produce hepcidin that binds to ferroportin, decreasing intestinal iron absorption, the release of the iron stored in hepatocytes and macrophages, production of functional iron and RBC [20]. Cytokines, including TNF-α, IL-1, and IL-6, are produced after the onset of inflammation. These cytokines restrict RBC and shorten the lifespan of RBCs [21]. Elevation of C-reactive protein, IL-6, IL-8, and TNF during a response to systemic inflammation is associated with increased VTE risk [22]. Activation of endothelial cells, platelets, and leukocytes, onset of inflammation and formation of microparticles are the earliest events following thrombosis, which can trigger the coagulation system through the induction of tissue factor [22].
Mechanism of RBC
Firstly, our data show that the number of platelets (PLTs) in anemia group patients are higher than that in non-anemia group patients. As the PLT count increases, more PLTs aggregate near the vessel wall. RBC deformability is mainly due to RBCs’ biconcave shape. The more rigid RBCs are, the more difficult it is for them to pass through capillaries, and the easier to marginate PLTs [23]. Together with the increase in PLT count, thrombosis can be easily formed. Symeonidis A and Athanassiou G found that DM, hypertension, VTE of the lower extremity, and CHD, could make RBCs very hard, likely leading to thrombosis [24]. And most of the patients in our study were aged patients with hypertension, CHD or DM. Secondly, during inflammation, RBCs were damaged [21]. In the view of membrane asymmetry of RBCs, phosphatidylserine were exposed in the context of cell injury induced by inflammation or oxidative stress [25]. Due to the large amount of RBCs in blood, even a small amount of them in contact with phosphatidylserine could lead to thrombosis [26]. Finally, RBCs may interact with the activated endothelial cells and/or expose and bind to subendothelial matrix, which leads to the formation of thrombosis [26].
Optimization of preoperative anemia in patients undergoing TKA
It’s been proven that patient blood management implemented for patients undergoing TJA or TKA would decrease blood transfusion, length of stay, morbidity, and readmission [27]. Effective methods to preoperative correction of anemia include the use of erythropoietin (EPO) and oral or intravenous (IV) iron supplementation [28]. However, EPO may increase the risk of thromboembolism [29]. To ensure its safety and efficacy, EPO must be administered together with iron to enhance its therapeutic effect. In the meantime, measures to prevent thrombosis formation must be taken [30]. Oral iron is a low-cost way to treat anemia, but to be more effective, patients must take oral iron 3–6 month before surgery [28]. Compared with oral iron, intravenous iron therapy is faster in improving Hb levels and has better tolerance [31]. However, as intravenous iron administration is invasive and costs higher, Smith A and Moon, T do not recommend preoperative IV iron therapy for all patients scheduled for major orthopedic surgery [32].
The normal lifespan of human RBCs is approximately 120 days, and even if the lifespan is decreased by inflammation, a clinically significant reduction in erythrocyte count does not usually develop until weeks to months after the onset of the underlying inflammatory disorder [21]. The disease course of TKA patients is relative long, with a mean onset time ranging from months to decades, and most TKA patients are with advanced KOA, the surgeries for these patients are not life-threatening. Therefore, when preoperative anemia is found in TKA patients, they can choose the appropriate method to optimize the state of preoperative anemia.
