Relationship between the severity of preoperative anemia and postoperative deep vein thrombosis in patients with bone trauma: a cohort study

doi:10.21203/rs.3.rs-3144592/v1

Objective

To analyze the relationship between preoperative anemia and postoperative deep vein thrombosis (DVT) in patients with lower limb bone trauma who have a high rate of preoperative anemia.

Method

In this retrospective cohort study, 957 patients at our center were included. Patients were categorized based on their last preoperative hematocrit (HCT) results. The univariate analysis included general preoperative conditions, complications, surgical and fracture-related factors, preoperative laboratory indicators, anticoagulation, and anemia in patients with DVT (284 cases) and those without DVT (673 cases) after surgery.

Results

Among the 284 cases with postoperative thrombosis, 61(21.5%) had no anemia before surgery, while 223(78.5%) had anemia before surgery. Among those with anemia, 65(22.9%) had mild anemia, and 158 had moderate to severe anemia. Age over 65 years old, total length of stay (LOS) exceeding 14 days, preoperative anticoagulation, delay of more than 24 h in starting anticoagulation after surgery, 30%≤HCT < 33% and blood transfusion, and HCT < 27% and blood transfusion were identified as independent risk factors for postoperative DVT formation. The ROC curves showed that a preoperative HCT of 35.15% (AUC = 0.670, sensitivity = 64.6%, specificity = 61.2%) in males and 33.45% (AUC = 0.637, sensitivity = 63.7%, specificity = 60.2%) in females were the cut-off values for predicting postoperative DVT occurrence.

Conclusions

The risk of postoperative DVT increases with the severity of preoperative anemia in patients with bone trauma, and perioperative blood transfusion further increases the risk of DVT.

Trial registration:

ChiCTR2100049356.

lower limb bone trauma

Deep vein thrombosis

Preoperative anemia

Red blood transfusion

hematocrit

Deep vein thrombosis (DVT) is a common perioperative complication in patients with bone trauma, particularly in those with lower extremity fracture. Despite the routine use of anticoagulants, the incidence of DVT remains very high. Among them, the incidence of DVT can range from 13.5–29% in patients with fractures of the femur, pelvis, and acetabulum, which are often associated with high-energy trauma [1–3]. DVT of the lower extremities can lead to fatal pulmonary embolisms. Early preoperative identification of high-risk groups, early intervention, and prevention are crucial for reducing the incidence of DVT. However, certain risk factors for perioperative DVT in patients with bone trauma, such as advanced age, preoperative complications, and trauma-related factors, remain unmodifiable.

The formation of venous thrombosis is related to vascular endothelial function and erythrocyte stasis. The mechanism by which high hematocrit (HCT) levels promote venous thrombosis through increased blood viscosity has been recognized. However, a limited number of studies have found that anemia is a possible risk factor for perioperative DVT in patients with bone trauma currently[4–6]. Furthermore, preoperative anemia is a potential risk factor that can be modified. However, this hypothesis, although not yet proven, suggests that blood viscosity decreases with decreasing HCT levels in patients with anemia. However, in patients with anemia, the incidence of DVT increases. In the past, red blood cells were assumed to be passive participants in the coagulation process. However, increasing evidence has shown that red blood cells play an active role in blood coagulation[7–9], beyond changes in blood flow mechanics. The preoperative anemia rate in patients with bone trauma range from 24–47.9%[5, 10, 11], and the HCT gradually decreases with the severity of anemia. This study investigated relationship between different degrees of preoperative anemia and postoperative DVT formation in patients with lower limb bone trauma.

2.1 Data collection

This retrospective cohort study collected the medical records of patients who underwent surgery at our center for traumatic fractures of the femur, pelvis, or acetabulum between May 2018 and December 2022. The study's inclusion criteria were as follows: (1) a confirmed diagnosis of a non-pathological fracture of the femur, pelvis, or acetabulum; (2) aged over 18 years; and (3) complete medical records. The exclusion criteria were as follows: (1) long-term use of anticoagulant drugs; (2) coagulation dysfunction or hematological diseases; (3) pregnancy; (4) severe mental illness; and (5) presence of DVT before fracture. Overall, 1606 patients were recruited for this study. However, 399 patients who did not undergo ultrasonography after surgery, 230 who had thrombosis before surgery, and 20 who were excluded for other reasons were subsequently excluded. Overall, 957 patients were included in this study.

2.2 Research method

An electronic medical record system was used to collect patient data. DVT was diagnosed based on preoperative and postoperative color Doppler ultrasonography of the bilateral deep veins of the lower extremities, which included the identification of vascular filling defects, blood flow interruption, and vascular diameter widening[12]. Based on the results of the postoperative lower-extremity venous ultrasound, the patients were categorized into two groups: the DVT group (including patients with newly formed DVT or postoperative progression of DVT) and the perioperative group without DVT. Pulmonary embolism (PE) diagnosis was confirmed through pulmonary computed tomography (CT) angiography. Anemia was defined and classified according to the diagnostic criteria established by World Health Organization (WHO) and previous studies[13, 14]. Patients were classified into five groups based on the HCT value from the last preoperative blood routine examination: (1) no anemia (HCT ≥ 39% in males and ≥ 36% in females), (2) mild anemia (HCT ≥ 33% and < 39% in males or HCT ≥ 33% and < 36% in females), and moderate to severe anemia when HCT < 33%, which were further classified into three groups: (3) HCT ≥ 30% and < 33%, (4) HCT ≥ 27% and < 30%, and (5) HCT < 27%. We further classified the anemia groups into non-transfusion and transfusion groups. Blood transfusion was defined as the perioperative infusion of at least one unit of erythrocytes, which helped to avoid the influence of blood transfusion on the results. We compared the preoperative basic condition and degree of anemia between the DVT and non-DVT groups and analyzed the relationship between different degrees of preoperative anemia and postoperative DVT occurrence. The Ethics Committee of the First Affiliated Hospital of Chongqing Medical University approved this study (approval number 2022-K73, dated March 3, 2022) and was registered with the WHO International Clinical Trial Registration (ChiCTR2100049356, registered on August 1, 2021).

2.3 Statistical methods

All analyses were performed using the statistical package SPSS 26.0 and Empower Stats. Continuous variables that followed a normal distribution were presented as mean ± standard deviation, while those that did not conform to a normal distribution were presented as median and quartile. Categorical variables were expressed as counts and percentages. The Mann–Whitney rank and chi-square tests were used to analyze continuous and categorical variables, respectively. First, we compared the sociodemographic characteristics of the study population with those of the excluded population (patients without postoperative ultrasound and no postoperative progress before surgery) to analyze the presence of selection bias. After comparing the population characteristics, surgical and fracture conditions, preoperative complications, anticoagulation conditions, and preoperative laboratory test results between the DVT group and the non-DVT group, variables that exhibited significant differences in the univariate analysis (p < 0.1) were included in the binary logistic multivariate analysis to investigate the independent risk factors influencing DVT occurrence. The odds ratios (OR) and 95% confidence intervals (CI) for each variable are shown. In the multivariate analysis, a significance level of p < 0.05 was considered statistically significant.

A receiver operating characteristic (ROC) curve was used to assess the predictive power of preoperative HCT on postoperative DVT occurrence. Additionally, to understand the influence of HCT on postoperative DVT in patients with bone trauma, a smooth curve fitting technique was used to examine the relationship between different HCT levels and the postoperative incidence of DVT.

3.1 Patient characteristics

This study excluded 649 out of the 1606 participants who had hip fractures between May 2018 and December 2022 for the following reasons: 20 patients did not meet the inclusion and exclusion criteria, 399 patients did not undergo postoperative lower extremity venous ultrasound, and 230 patients had DVT before surgery without postoperative progression. Finally, 957 patients met the inclusion criteria and were enrolled in the study.

Table 1 shows a comparison of population characteristics between the excluded population (629 cases) and the study population. No statistically significant differences were observed between the two groups regarding general characteristics, underlying diseases, complications, or anticoagulation therapy (p > 0.05), indicating an absence of distribution bias between the two groups.

The average age of the 957 patients in this study was 67.8 ± 19.1 years. Among them, 402 were men and 555 women. Overall, 284 patients developed postoperative thrombosis, resulting in an approximate incidence of DVT of 29.68%. Additionally, eight patients (0.84%) developed pulmonary embolism. Before surgery, there were 324 patients (33.9%) without anemia and 633 patients (60.1%) with preoperative anemia, including 61 patients (18.83%) with no anemia who developed DVT after surgery, and 223 patients (35.23%) with anemia and developed DVT after surgery. In the anemia group, the cases of thrombosis of mild anemia, 30%≤HCT<33%, 27≤HCT<30%, and HCT<27% were 65(29.15%), 50(22.42%), 50(22.42%) and 58(26.01%), respectively. Among the 399 patients excluded in the final study who did not undergo ultrasonography after surgery, 179 (44.9%) were not anemic before surgery, while 220 (55.1%) were anemic before surgery.

3.2 Univariate analysis

Univariate analysis results (Table 2) indicate that several factors showed statistically significant differences between the DVT group and the non-DVT group (p < 0.1). These factors include age, preoperative pulmonary infection, hypoalbuminemia, anemia degree, ASA grade, time from injury to surgery greater than 1 week, a total length of stay greater than 14 days, operation time greater than 2 h, open fracture, multiple fractures, comminuted fractures, multiple injuries, post-traumatic shock, preoperative use of iron sucrose, preoperative anticoagulation, postoperative anticoagulation start time greater than 24 h, percentage of lymphocytes, distribution width of red blood cells, preoperative C-reactive protein, preoperative fibrin degradation products, and preoperative D-dimer.

3.3 Multivariate analysis between preoperative anemia severity and postoperative DVT

The results of multivariate analysis (Table 3) revealed several independent risk factors for postoperative DVT. These factors included age older than 65 years (OR:2.761, 95%CI[1.673–4.557], p < 0.001), a total length of hospital stay longer than 14 days (OR:1.683, 95%CI[1.175–2.410], p = 0.005), preoperative anticoagulation (OR:1.608, 95%CI[1.099–2.352], p = 0.015), postoperative anticoagulation for more than 24 h (OR:1.865, 95%CI[1.221–2.848], p = 0.004), preoperative HCT ranging 33–30% and perioperative blood transfusion (OR:3.052, 95%CI[1.603-5.881], p = 0.001), and preoperative HCT <27% and blood transfusion (OR:2.979, 95%CI[1.574–5.639], p = 0.001).

In patients without transfusion (Figure 2), the OR increased as the HCT level decreased: mild anemia (OR 1.369, 95%CI [0.839-2.236], p = 0.209), 30%≤HCT<33% (OR 1.742, 95%CI [0.913–3.324], p = 0.092), 27≤HCT< 30% (OR 2.056, 95% CI [0.948–4.461], p = 0.068), and HCT< 27% (OR 3.373, 95% CI [0.951–11.964], p = 0.06). However, this trend was not observed in transfusion patients: no anemia (intraoperative and postoperative blood transfusion) (OR 2.090, 95% CI [0.811–5.386], p = 0.127), mild anemia (OR 1.520, 95% CI [0.760–3.038], p = 0.236), 30%≤ HCT < 33% (OR:3.052, 95% CI [1.603–5.881], p = 0.001), 27 ≤HCT< 30% (OR 1.847, 95% CI [0.990–3.447], p = 0.054), and HCT< 27% (OR:2.979, 95%CI [1.574–5.639], p = 0.001).

3.4 ROC curves and curve fitting

The ROC curves (Figures 3 and 4) show the sensitivity and specificity of preoperative HCT in predicting postoperative DVT occurrence and postoperative moderate-to-severe anemia in patients with bone trauma. Under the maximum Youden index, the optimal preoperative HCT cut-off values for predicting postoperative DVT were determined to be 35.15% for males and 33.45% for females. These values were associated with an area under the ROC curve (AUC) of 0.670 (95%CI [0.611–0.7 28], p<0.001, sensitivity =64.6%, specificity =61.2%) and 0.637 (95%CI [0.586–0.687], p<0.001, sensitivity =63.7%, specificity =60.2%), respectively. Additionally, for predicting moderate and severe anemia 1 day after surgery, the preoperative anemia thresholds were determined to be 36.35% (AUC=0.875, 95%CI [0.836-0.914], p<0.001) in males and 35.85% (AUC=0.853, 95%CI [0.812-0.895], p<0.001) in female. The corresponding sensitivity and specificity were 72.4% and 93.1% in males and 77.0% and 82.3% in females, respectively. Furthermore, Figure 5 displays a curve fit demonstrating the association between preoperative and postoperative DVT occurrence. The smooth curve fitting plots indicate an overall increase in the occurrence of postoperative DVT with decreasing HCT.

4.1 Relationship between preoperative anemia of different degrees and DVT in patients with bone trauma

In this study, the prevalence of preoperative anemia was as high as 66.14% among patients with lower limb femur, pelvis, and hip fractures. This high prevalence may be attributed to using HCT as the diagnostic basis for anemia. Our study revealed a significant association between preoperative anemia (HCT < 39% in males and < 36% in females) and postoperative DVT in patients with lower limb bone trauma, which aligns with the results of previous studies [4], To avoid the interference of blood transfusion on the research results, we performed separate analyses for patients with and without blood transfusion respectively. Our results showed that in patients without perioperative blood transfusion, mild anemia only slightly increased the incidence of postoperative DVT (OR:1.369, 95%CI [0.839–2.236], p = 0.209), which was consistent with previous findings [6, 10]. However, the postoperative DVT risk in patients with moderate to severe anemia in the three groups was 1.742, 2.056, and 3.373 times higher than that in patients without anemia, respectively. These results support our hypothesis that the risk of postoperative DVT increases with the severity of anemia.

4.2 Causes of preoperative anemia in patients with bone trauma

Preoperative anemia in patients with bone trauma is primarily caused by acute blood loss. High-energy injuries are frequently associated with lower limb bone trauma, often leading to more severe anemia and prolonged hospital stay [15], Inflammation and red blood cell injury resulting from trauma are additional factors contributing to anemia. In addition to open wound bleeding, fractures are often accompanied by latent blood loss, and the prolonged time from trauma to surgery prolongs the bleeding time. In patients with lower limb bone trauma, anticoagulants are routinely administered to prevent thrombosis caused by immobilization. However, preoperative anticoagulation leads to prolonged bleeding, aggravating anemia [16]. In addition, a higher proportion of elderly patients experienced lower extremity bone trauma, with a median patient age of 72 years. Elderly patients often experience weakness, malnutrition, and chronic inflammation, leading to chronic anemia [17, 18].Notably, anemia commonly coexists with cardiac and renal insufficiency in elderly patients. Preoperative anemia represents a common perioperative complication in patients with lower limb bone trauma. Nevertheless, the specific mechanism through which anemia increases the incidence of postoperative DVT remains unclear. Therefore, we hypothesize that the factors mentioned in the following section may contribute to this association.

4.3 Possible mechanism of preoperative anemia increasing the occurrence of DVT.

In this study, it was observed that 39.8% of patients without preoperative anemia had a total hospital stay > 14 days; 48.61% of patients with mild anemia and 56.20%, 62.02%, and 74.1% of patients with moderate and severe anemia, respectively, had a total hospital stay > 14 days. The severity of anemia before surgery was associated with a prolonged hospital stay for patients. In addition, the perioperative infection rate [14, 19], the occurrence of multiple postoperative complications, and preoperative waiting time contribute to the aggravation of anemia [20, 21]. Infection, preoperative waiting time, and total hospital stay also increase the incidence of postoperative DVT [22]. Preoperative anemia can also affect postoperative functional recovery, subsequently affecting the patient's postoperative rehabilitation and ambulation. Notably, Sim et al. found that severe anemia continued to affect the physiological function of patients with hip fracture, while mild anemia had a minimal effect [23], suggesting that severe anemia may increase the long-term risk of DVT after surgery.

The perioperative blood transfusion rate of orthopedic surgery ranged from approximately 6.9–56.8% [24–26]. Specifically, the perioperative blood transfusion rate for femur fracture operations and hip replacements can be as high as 70–80% [25, 27]. In this study, the perioperative blood transfusion rate for patients with femoral, hip, or pelvic fractures was 36.0%. Blood transfusion has been identified as a risk factor for DVT, as supported by multiple studies [28, 29]. Those studies have shown a synergistic effect of preoperative anemia and blood transfusion in increasing postoperative complications [14]. However, our study results revealed that with the transfusion population, when HCT levels were ≥ 30%, the risk in each group was higher compared to the corresponding group without blood transfusion. Conversely, when HCT was < 30%, the risk of each group was higher than that of the corresponding group without blood transfusion. The risk ratio was higher in the non-transfusion group, suggesting that the effects of blood transfusion and preoperative anemia on postoperative DVT were not purely synergistic and that there may be by further interactions between them. Previous studies have focused on perioperative blood transfusion while neglecting the role and degree of anemia in this process. Compared to preoperative blood transfusion, intraoperative and postoperative blood transfusions increases the risk of DVT[30], and the treatment of preoperative anemia can significantly reduce the rates of intraoperative and postoperative blood transfusion[31]. Therefore, we believe that compared to blood transfusion, more attention should be paid to preoperative anemia, particularly moderate-to-severe anemia.

The formation of venous thrombosis is primarily associated with Virchow's triad, which consists of vascular endothelial injury, blood flow stasis, and a hypercoagulable state. Erythrocytes can influence thrombus formation by impacting hemodynamics and endothelial factors [32]. However, this effect is attenuated in anemia. Notably, our clinical evidence reveals a contracting observation indicating that the incidence of DVT increases with the severity of anemia. This finding leads us to further investigate whether a potential mechanism through which red blood cells, mainly in low HCT levels, promote venous thrombosis exists. Erythrocytes may influence the development of venous thrombosis through various mechanisms or other pathways, including hemodynamic changes. Previous studies have demonstrated that anemia contributes to thrombosis through various mechanisms. These include: (1) an increase in platelet aggregation and stimulation of platelet production [33, 34];(2) the promotion of inflammatory mediators [35] and plasminogen activator inhibitors [36]. In addition, higher serum hepcidin levels may increase the risk of venous thrombosis development [37], regulated by erythropoiesis, serum iron availability and inflammatory cytokines [38]. Recent studies have provided new insight into the regulation of red blood cell retention in venous thrombosis by changing the activity of coagulation factor XIII, thereby influencing the formation of venous thrombosis [39, 40]. This mechanism presents a promising target for new interventions to prevent venous thrombosis. Furthermore, vascular endothelial injury caused by trauma and the release of various inflammatory mediators can lead to red blood cell injury and hemolysis. The release of hemoglobin and heme can also contribute to a procoagulant state [8, 32, 41]. Generally, the relationship between erythrocytes and venous thrombosis is complicated, and further exploration is warranted. Furthermore, the specific mechanisms by which anemia affects thrombosis remain elusive.

4.4 Preoperative management and optimization of anemia in patients with bone trauma

Preoperative anemia increased the risk of poor prognosis, perioperative blood transfusion, and more severe postoperative anemia in the past. In this retrospective cohort study, the rates of anemia were as high as 92.1% (872/947) within1 day after surgery and 94.4% (793/840) within 3 days after surgery. Postoperative anemia was also associated with increased postoperative complications, prolonged hospital stays, and higher readmission rates. Preoperative hemoglobin levels were found to be effective predictors of the risk of postoperative moderate-to-severe anemia and perioperative blood transfusion; however, there was no consensus on the ideal cut-off value for preoperative hemoglobin. Our study results showed that in men and women, the preoperative HCT cut-off value for predicting moderate and severe anemia 1 day after surgery were 36.35% (AUC = 0.875, sensitivity = 72.4%, specificity = 93.1%) and 35.85% (AUC = 0.853, sensitivity = 77.0%, specificity = 82.3%), respectively. Additionally, the preoperative HCT cut-off values for predicting the occurrence of postoperative DVT occurrence were 35.15% (AUC = 0.670, sensitivity = 64.6%, specificity = 61.2%) in males and 33.45% (AUC = 0.637, sensitivity = 63.7%, specificity = 60.2%) in females. Li et al. found that the HCT level at admission could help to predict preoperative DVT occurrence. Although their study demonstrated that the severity of HCT reduction did not have a linearly relationship with preoperative DVT when the HCT was < 33.50%, while their results showed that when the HCT was > 33.50%, as each unit increased, the risk of DVT reduced by 6% in HCT [42]. Yeh et al. suggested that a preoperative hemoglobin level of 12.4 g/dL for patients aged over 70 years and 12.1 g/dL for patients aged under 70 years could predict the risk of blood transfusion after total knee arthroplasty (TKA) [43]. Kim et al. showed that the preoperative hemoglobin concentration of 11.8 g/dL and 12.8 g/dL were the cut-off values for blood transfusion after unilateral and bilateral TKA, respectively [44]. Cao et al. considered the cut-off value of 138.5 g/L for males and 131.5g/L for females to predict moderate and severe postoperative anemia. Furthermore, their study results indicated that postoperative anemia was not a risk factor for postoperative DVT [45]. Additionally, a study reported that intravenous iron injection after surgery did not effectively improve postoperative hemoglobin levels or reduce the blood transfusion rate [46]. Therefore, compared with passive measures after surgery, more attention to preoperative should be given to preoperative patient blood management and proactive interventions (such as preoperative iron or erythropoietin therapy, and hemostasis), especially for patients with bone trauma who have moderate and severe anemia before surgery.

Perioperative blood transfusion can increase the incidence of multiple postoperative complications and entail additional risks and cost. Therefore, blood transfusion should be used discreetly. The American Association of Blood Banks recommends against blood transfusion for hip fracture surgery when hemoglobin levels are not below 8g/L, and for intensive care patients with stable hemodynamics, the hemoglobin threshold for transfusion should not exceed 7g/L [47]. It is estimated that every 1000 ml of blood lost results in a net loss of 360 mg of hemoglobin-bound iron, which the body releases to produce hemoglobin. Consequently, patients with preoperative anemic bone trauma may experience persistent iron deficiency[48]. Therefore, apart from blood transfusion, routine iron supplementation and intravenous injection of erythropoietin can be used to correct preoperative anemia in patients. In addition, tranexamic acid can be used to reduce perioperative hemorrhage. Preoperative blood management is crucial in patients with moderate-to-severe anemia, as it is expected to significantly reduce the risk of postoperative DVT and the rate of intraoperative and postoperative blood transfusion by correcting moderate-to-severe anemia to mild anemia in patients with fractures.

Many elderly patients with bone trauma often suffer from anemia because of asthenia, malnutrition, chronic inflammation, and other underlying diseases. They are considered high-risk individuals for DVT. With advancement in orthopedic surgery technology, the hospitalization turnover of patients with bone trauma has accelerated, leading to a gradual reduction in postoperative lower extremity veins thrombosis examination. In our study, 399 patients (24.8%) cases did not undergo postoperative ultrasound. However, most bone trauma patients (especially elderly patients) have multiple simultaneous risk factors, including long-term anemia, weakness, and malnutrition, before surgery. For such high-risk patients, postoperative screening for venous thrombosis is beneficial and necessary [49]。

Limitation

This study had several limitations. First, our study was conducted at a single center with a small sample size, limiting the generalizability of the findings. Future studies should consider increasing the sample size to enhance the accuracy and reliability of the results. In addition, as our retrospective study, it was susceptible to confounding factors and biases that could not be completely avoided. Furthermore, we only assessed the occurrence of DVT during hospitalization and did not conduct follow-up after discharge, potentially leading to an underestimation of postoperative DVT incidence. However, unlike previous studies that focused solely on verifying preoperative anemia as a risk factor for DVT, our study explored the relationship between the degree of preoperative anemia and postoperative DVT in patients with lower limb bone trauma. Furthermore, we demonstrated an association between perioperative blood transfusion and DVT.

Preoperative anemia has been identified as a risk factor for postoperative DVT in patients with bone trauma, and this association is more obvious in patients with moderate-to-severe anemia. Therefore, it is important to prioritize perioperative DVT examinations in patients with preoperative anemia and implement more proactive measures in clinical practice to correct or reduce the degree of preoperative anemia, aiming to reduce the occurrence of perioperative DVT. Further investigation is needed to elucidate the underlying mechanism by which anemia contributes to venous thrombosis.

DVT

Deep vein thrombosis

PE

Pulmonary embolism

HCT

Hematocrit

BMI

Body mass index

ASA

American Society of Anesthesiologists

COPD

Chronic obstructive pulmonary disease

LOS

Length of stay

WBC

White blood cell

PLT

Platelet count

NEUT%

Neutrophil percentage

LYM%

Lymphocyte percentage

RDW

Red blood cell distribution width

BUN

Blood urea nitrogen

Crea

Creatinine

CRP

C-reactive protein

PT

Prothrombin time

APTT

Activated partial thromboplastin time

FDP

Fibrin degradation products

D-D

D-dimer

OR

Odds ratio

AUC

Area under the curve

TKA

Total knee arthroplasty.

Ethics approval and consent to participate

This study has been approved by the First Affiliated Hospital of Chongqing Medical University; ratification number is 2022-K73.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This study was supported by the National Key Clinical Specialty Construction Project of the Ministry of Health, Ministry of Finance (2011)170, and the Chongqing Medical Key Discipline project No Yu Wei Science and Education (2007)2.

Authors’ contributions

Bo Cheng and Yitong Yang contributed to the study's conception and design. Yitong Yang was contributed to data acquisition and analysis. Linqin Wu and Hui Zhang contributed to the data acquisition. Yitong Yang drafted the manuscript. The authors have read and approved the final manuscript.

Acknowledgements

None.

Wang P, Kandemir U, Zhang B, Wang B, Li J, Zhuang Y, Wang H, Zhang H, Liu P, Zhang K: Incidence and Risk Factors of Deep Vein Thrombosis in Patients With Pelvic and Acetabular Fractures. Clin Appl Thromb Hemost 2019, 25:1076029619845066.
Zhao W, Zhao J, Liu T, Liu Z, Liu L, Zhang Y: Incidence and risk factors of preoperative deep venous thrombosis following pelvic and acetabular fractures: a retrospective case-control study. J Orthop Surg Res 2022, 17(1):77.
Ren Z, Yuan Y, Qi W, Li Y, Wang P: The incidence and risk factors of deep venous thrombosis in lower extremities following surgically treated femoral shaft fracture: a retrospective case-control study. J Orthop Surg Res 2021, 16(1):446.
Feng L, Xu L, Yuan W, Xu Z, Feng Z, Zhang H: Preoperative anemia and total hospitalization time are the independent factors of preoperative deep venous thromboembolism in Chinese elderly undergoing hip surgery. BMC Anesthesiol 2020, 20(1):72.
Zhang H, Wu L, Cheng B: Preoperative anemia and deep vein thrombosis in patients with perioperative bone trauma: a cohort study. BMC Musculoskelet Disord 2022, 23(1):905.
Folsom AR, Wang W, Parikh R, Lutsey PL, Beckman JD, Cushman M, Atherosclerosis Risk in Communities Study I: Hematocrit and incidence of venous thromboembolism. Res Pract Thromb Haemost 2020, 4(3):422-428.
Walton BL, Byrnes JR, Wolberg AS: Fibrinogen, red blood cells, and factor XIII in venous thrombosis. J Thromb Haemost 2015, 13 Suppl 1(Suppl 1):S208-215.
Weisel JW, Litvinov RI: Red blood cells: the forgotten player in hemostasis and thrombosis. J Thromb Haemost 2019, 17(2):271-282.
Aleman MM, Walton BL, Byrnes JR, Wolberg AS: Fibrinogen and red blood cells in venous thrombosis. Thromb Res 2014, 133 Suppl 1(0 1):S38-40.
Doan MK, Pollock JR, Moore ML, Hassebrock JD, Makovicka JL, Tokish JM, Patel KA: Increasing severity of anemia is associated with poorer 30-day outcomes for total shoulder arthroplasty. JSES Int 2021, 5(3):360-364.
Aali Rezaie A, Blevins K, Kuo FC, Manrique J, Restrepo C, Parvizi J: Total Hip Arthroplasty After Prior Acetabular Fracture: Infection Is a Real Concern. J Arthroplasty 2020, 35(9):2619-2623.
Rabinov K, Paulin S: Roentgen diagnosis of venous thrombosis in the leg. Arch Surg 1972, 104(2):134-144.
Gu A, Malahias MA, Selemon NA, Wei C, Gerhard EF, Cohen JS, Fassihi SC, Stake S, Bernstein SL, Chen AZ et al: Increased severity of anaemia is associated with 30-day complications following total joint replacement. Bone Joint J 2020, 102-B(4):485-494.
Gabriel RA, Clark AI, Nguyen AP, Waterman RS, Schmidt UH: The Association of Preoperative Hematocrit and Transfusion with Mortality in Patients Undergoing Elective Non-cardiac Surgery. World J Surg 2018, 42(7):1939-1948.
Lv B, Wang H, Zhang Z, Li W, Han G, Liu X, Zhang C: Dynamic Changes and Relevant Factors of Perioperative Deep Vein Thrombosis in Patients with Thoracolumbar Fractures Caused by High-Energy Injuries. Clin Appl Thromb Hemost 2023, 29:10760296231153123.
Lopez S, da Casa C, Pablos-Hernandez C, Pescador D, Diaz-Alvarez A, Asensio N, Blanco JF: The impact of antithrombotic therapy on surgical delay and 2-year mortality in older patients with hip fracture: a prospective observational study. Eur Geriatr Med 2020, 11(4):555-561.
O'Neill DE, Graham MM: Anemia, Cardiovascular Disease, and Frailty in the Older Adult. Can J Cardiol 2022, 38(6):715-717.
Lanier JB, Park JJ, Callahan RC: Anemia in Older Adults. Am Fam Physician 2018, 98(7):437-442.
Rodriguez-Merchan EC, Delgado-Martinez AD: Risk Factors for Periprosthetic Joint Infection after Primary Total Knee Arthroplasty. J Clin Med 2022, 11(20).
Gu A, Chen AZ, Selemon NA, Tornberg H, Wei C, Fassihi SC, Campbell JC, Sculco PK: Preoperative Anemia Independently Predicts Significantly Increased Odds of Short-Term Complications Following Aseptic Revision Hip and Knee Arthroplasty. J Arthroplasty 2021, 36(5):1719-1728.
Abdullah HR, Sim YE, Hao Y, Lin GY, Liew GHC, Lamoureux EL, Tan MH: Association between preoperative anaemia with length of hospital stay among patients undergoing primary total knee arthroplasty in Singapore: a single-centre retrospective study. BMJ Open 2017, 7(6):e016403.
Colling ME, Tourdot BE, Kanthi Y: Inflammation, Infection and Venous Thromboembolism. Circ Res 2021, 128(12):2017-2036.
Sim YE, Sim SD, Seng C, Howe TS, Koh SB, Abdullah HR: Preoperative Anemia, Functional Outcomes, and Quality of Life After Hip Fracture Surgery. J Am Geriatr Soc 2018, 66(8):1524-1531.
Malcherczyk D, Hack J, Klasan A, Abdelmoula A, Heyse TJ, Greene B, El-Zayat BF: Differences in total blood loss and transfusion rate between different indications for shoulder arthroplasty. Int Orthop 2019, 43(3):653-658.
Verlicchi F, Desalvo F, Zanotti G, Morotti L, Tomasini I: Red cell transfusion in orthopaedic surgery: a benchmark study performed combining data from different data sources. Blood Transfus 2011, 9(4):383-387.
Terada R, Stewart K, Hansen S, Shettar SS, Butt A, Vallurupalli S, Martin M, Tanaka K: Temporal changes and predictors of perioperative blood transfusion in elective spine surgery: a retrospective analysis of a large surgical database. Br J Anaesth 2023, 130(4):421-429.
Yue R, Yang M, Deng X, Zhang P: Allogeneic Red Blood Cell Transfusion Rate and Risk Factors After Hemiarthroplasty in Elderly Patients With Femoral Neck Fracture. Front Physiol 2021, 12:701467.
McGurk KJ, Collier BR, Bradburn EH, Love KM, Lollar DI, Baker CC, Hamill ME: Association between Blood Transfusion, Transfusion Setting, and the Risk of Venous Thromboembolism in Patients with Isolated Orthopedic Trauma. Am Surg 2016, 82(9):e247-248.
Jiang T, Song K, Yao Y, Pan P, Jiang Q: Perioperative allogenic blood transfusion increases the incidence of postoperative deep vein thrombosis in total knee and hip arthroplasty. J Orthop Surg Res 2019, 14(1):235.
Goel R, Patel EU, Cushing MM, Frank SM, Ness PM, Takemoto CM, Vasovic LV, Sheth S, Nellis ME, Shaz B et al: Association of Perioperative Red Blood Cell Transfusions With Venous Thromboembolism in a North American Registry. JAMA Surg 2018, 153(9):826-833.
Keating EM, Meding JB, Faris PM, Ritter MA: Predictors of transfusion risk in elective knee surgery. Clin Orthop Relat Res 1998(357):50-59.
Byrnes JR, Wolberg AS: Red blood cells in thrombosis. Blood 2017, 130(16):1795-1799.
Calişkan U, Oner AF, Kabakuş N, Koç H: Diminished platelet aggregation in patients with iron deficiency anemia. Clin Appl Thromb Hemost 1999, 5(3):161-163.
Xiong X, Li T, Cheng B: Anemia and formation of deep vein thrombosis before operation in patients with knee osteoarthritis: a cross-sectional study. J Orthop Surg Res 2023, 18(1):33.
Ganz T: Anemia of Inflammation. N Engl J Med 2019, 381(12):1148-1157.
Patel N, Sundaram N, Yang M, Madigan C, Kalra VK, Malik P: Placenta growth factor (PlGF), a novel inducer of plasminogen activator inhibitor-1 (PAI-1) in sickle cell disease (SCD). J Biol Chem 2010, 285(22):16713-16722.
Ellingsen TS, Lappegård J, Ueland T, Aukrust P, Brækkan SK, Hansen JB: Plasma hepcidin is associated with future risk of venous thromboembolism. Blood Adv 2018, 2(11):1191-1197.
Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, Beaumont C, Kahn A, Vaulont S: The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 2002, 110(7):1037-1044.
Aleman MM, Byrnes JR, Wang JG, Tran R, Lam WA, Di Paola J, Mackman N, Degen JL, Flick MJ, Wolberg AS: Factor XIII activity mediates red blood cell retention in venous thrombi. J Clin Invest 2014, 124(8):3590-3600.
Byrnes JR, Duval C, Wang Y, Hansen CE, Ahn B, Mooberry MJ, Clark MA, Johnsen JM, Lord ST, Lam WA et al: Factor XIIIa-dependent retention of red blood cells in clots is mediated by fibrin α-chain crosslinking. Blood 2015, 126(16):1940-1948.
Delvasto-Nuñez L, Jongerius I, Zeerleder S: It takes two to thrombosis: Hemolysis and complement. Blood Rev 2021, 50:100834.
Li DY, Lu DX, Yan T, Zhang KY, Zhang BF, Zhang YM: The Association between the Hematocrit at Admission and Preoperative Deep Venous Thrombosis in Hip Fractures in Older People: A Retrospective Analysis. J Clin Med 2023, 12(1).
Yeh JZ, Chen JY, Bin Abd Razak HR, Loh BH, Hao Y, Yew AK, Chia SL, Lo NN, Yeo SJ: Preoperative haemoglobin cut-off values for the prediction of post-operative transfusion in total knee arthroplasty. Knee Surg Sports Traumatol Arthrosc 2016, 24(10):3293-3298.
Kim TW, Park HJ, Chang MJ, Kang SY, Kang KS, Chang CB, Kang SB: Effect of severity and cause of preoperative anemia on the transfusion rate after total knee arthroplasty. Sci Rep 2022, 12(1):4083.
Cao G, Yang X, Xu H, Yue C, Huang Z, Zhang S, Quan S, Yao J, Yang M, Pei F: Association between preoperative hemoglobin and postoperative moderate and severe anemia among patients undergoing primary total knee arthroplasty: a single-center retrospective study. J Orthop Surg Res 2021, 16(1):572.
Jeong JH, Chang MJ, Kang SB, Park HJ, Lee KH, Chang CB: Postoperative Intravenous Iron Supplementation Does Not Improve Hemoglobin Level and Transfusion Rate Following Staged Bilateral Total Knee Arthroplasty. J Arthroplasty 2020, 35(9):2444-2450.
Carson JL, Guyatt G, Heddle NM, Grossman BJ, Cohn CS, Fung MK, Gernsheimer T, Holcomb JB, Kaplan LJ, Katz LM et al: Clinical Practice Guidelines From the AABB: Red Blood Cell Transfusion Thresholds and Storage. JAMA 2016, 316(19):2025-2035.
Andrews NC: Disorders of iron metabolism. N Engl J Med 1999, 341(26):1986-1995.
Lim HJ, Jeon JY, Jeong YM, Lee BG, Sim JA, Lee SW: Triaging deep vein thrombosis using ultrasonography after lower-extremity orthopedic surgery: analysis of a single-center experience. Ultrasonography 2021, 40(3):442-448.

Table 1. Baseline characteristics of participants with and without research.

Covariates

Participant

n=957

Nonparticipant

n=629

c²

p value

Age(year)

BMI(kg/m²)

Sex

69.6±17.1

22.04(20.00,24.44)

67.8±19.1

22.22(19.96,24.22)

0.801

0.189

0.811

Male

Female

402(42.0%)

555(58.0%)

250(39.7%)

379(60.3%)

0.371

Smoking history

No

Yes

752(78.6%)

205(21.4%)

499(79.3%)

130(20.7%)

0.129

0.719

Drinking history

No

Yes

808(84.4%)

149(15.6%)

522(83.0%)

107(17.0%)

0.583

0.445

Hypertension

No

Yes

632(66.0%)

325(34.0%)

408(64.8%)

221(35.2%)

0.232

0.630

Diabetes

No

Yes

766(80.0%)

191(20.0%)

516(82.0%)

113(18.0%)

0.915

0.339

Coronary heart disease

No

Yes

Ischemic stroke

No

Yes

Hyperlipidemia

No

Yes

Hepatic diseases

No

Yes

Renal diseases

No

Yes

Cancer

No

Yes

COPD

No

Yes

Pneumonia

No

Yes

Respiratory failure

No

Yes

Lung cancer

No

Yes

Osteoporosis

No

Yes

846(88.4%)

111(11.6%)

831(86.8%)

126(13.2%)

926(96.8%)

31(3.2%)

847(88.5%)

110(11.5%)

898(93.8%)

59(6.2%)

903(94.4%)

54(5.6%)

895(93.5%)

62(6.5%)

833(87.0%)

124(13.0%)

909(95.0%)

48(5.0%)

950(99.3%)

7(0.7%)

608(63.5%)

349(36.5%)

554(88.1%)

75(11.9%)

552(88.1%)

75(11.9%)

593(94.3%)

36(5.7%)

554(88.1%)

75(11.9%)

582(92.5%)

47(7.5%)

602(95.7%)

27(4.3%)

591(94.0%)

38(6.0%)

563(89.5%)

66(10.5%)

600(95.4%)

29(4.6%)

622(98.9%)

7(1.1%)

401(66.8%)

228(36.2%)

0.039

0.529

5.788

1.596

1.040

1.428

0.123

2.186

0.135

0.631

0.008

0.844

0.467

0.012

0.450

0.308

0.232

0.726

0.139

0.713

0.427

0.929

Anticoagulation

No

881(92.1%)

561(89.2%)

3.785

0.052

Yes

76(7.9%)

68(10.8%)

Abbreviations: COPD, Chronic obstructive pulmonary disease.

Table 2. The demographic and clinical characteristics of the patients(N=957)

Variable	Overall	Non-DVT	DVT	P value
Age(year) M (,-.,-.)	72(53,84)	71(52，83)	77(63，86)	0.005
BMI (kg/m²)	22.04(20.00,24.44)	22.22(20.00,24.39)	21.64(19.60,24.23)	0.530
Sex
Male	402(42.1%)	289(42.9%)	113(39.8%)	0.367
Female	555(58.0%)	384(57.1%)	171(60.2%)
Smoking history	205(21.4%)	147(21.8%)	58(20.4%)	0.625
Drinking history	149(15.6%)	99(14.7%)	50(17.6%)	0.259
Comorbidity
hypertension	325(34.0%)	223(33.1%)	102(35.9%)	0.407
diabetes	191(20.0%)	128(19.0%)	63(22.2%)	0.263
Coronary heart disease	111(11.6%)	72(10.7%)	39(13.7%)	0.181
Renal diseases	59(6.2%)	40(5.9%)	19(6.7%)	0.661
Hepatic diseases	92(9.8%)	61(9.2%)	31(11.1%)	0.379
Ischemic stroke	126(13.2%)	85(12.6%)	41(14.4%)	0.450
Hyperlipidemia	31(3.2%)	22(3.3%)	9(3.2%)	0.936
COPD	62(6.5%)	42(6.2%)	20(7.0%)	0.645
Pneumonia	124(13.0%)	72(10.7%)	52(18.3%)	0.001
Respiratory failure	48(5.0%)	28(4.2%)	20(7.0%)	0.062
Cancer	54(5.6%)	43(6.4%)	11(3.9%)	0.123
Hypoalbuminemia	186(19.4%)	104(15.5%)	82(28.9%)	<0.00
HCT cohort				<0.00
No anemia	324(33.9%)	263(39.1%)	61(21.5%)
Mild anemia	251(26.2%)	186(27.6%)	65(22.9%)
30%-33%	137(14.3%)	87(12.9%)	50(17.6%)
27%-30%	129(13.5%)	79(11.7%)	50(17.6%)
<27%	116(12.1%)	58(8.6%)	58(20.4%)
Surgery and trauma
ASA classification>2	712(74.4%)	483(71.8%)	229(80.6%)	0.004
Time from trauma to surgery>1 week	455(47.5%)	295(43.8%)	160(56.3%)	<0.00
LOS>14 days	494(51.6%)	307(45.6%)	187(65.8%)	<0.00
Operation times>2 hours	338(35.3%)	223(33.1%)	115(40.5%)	0.030
Central venous catheter	25(2.6%)	15(2.2%)	10(3.5%)	0.252
Bone cement	180(18.8%)	128(19.0%)	52(18.3%)	0.798
Open fractures	73(7.6%)	43(6.4%)	30(10.6%)	0.026
Multiple fracture	254(26.5%)	162(24.1%)	92(32.4%)	0.008
Comminuted fracture	309(32.3%)	190(28.2%)	119(41.9%)	<0.001
Multiple injuries	245(25.6%)	158(23.5%)	87(30.6%)	0.020
Shock	38(4.0%)	20(3.0%)	18(6.3%)	0.015
Transfusion	344(36.0%)	200(29.8%)	144(50.7%)	<0.001
Use Iron supplementation	156(16.3%)	96(14.3%)	60(21.1%)	0.009
Use Erythropoietin	137(14.3%)	88(13.1%)	49(17.3%)	0.092
Preoperative anticoagulation	663(69.3%)	447(66.4%)	216(76.1%)	0.003
Anticoagulation after surgery>24h	157(17.8%)	88(14.3%)	69(25.6%)	<0.001
Laboratory inspection
WBC (10^9/L)	7.94(6.30,9.68)	7.83(6.25,9.60)	7.93(6.31,9.67)	0.709
PLT (10^9/L)	175(137,225)	174(137,218)	181(141,238)	0.059
NEUT% (%)	74.5(69.2,80.4)	74.3(68.6,80.1)	74.5(70.2,80.3)	0.265
LYM% (%)	14.6(10.6,19.4)	15.4(11.1,19.6)	14.2(10.1,18.6)	0.036
RDW (%)	13.3(12.7,14.3)	13.2(12.7,14.1)	13.4(12.8,14.5)	<0.001
BUN (mmol/L)	6.1(4.9,7.8)	6.0(4.9,7.6)	6.4(5.1,8.2)	0.064
SCR (mmol/L)	66.0(55.0,79.0)	66.0(55.0,79.0)	65.0(54.5,81.0)	0.290
CRP (mg/L)	26.7(12.7,67.9)	25.0(12.2,61.8)	29.5(15.1,72.3)	0.038
PT (s)	13.5(12.9,14.1)	13.4(12.9,14.0)	13.5(12.9,14.2)	0.062
APTT (s)	36.5(33.6,39.6)	36.6(33.9,39.6)	36.1(33.2,39.7)	0.319
FDP (mg/L)	12.9(6.5,27.8)	12.0(6.0,25.1)	14.3(7.6,27.8)	0.008
D-D (mg/L)	4.87(2.23,11.06)	4.44(2.01,9.64)	5.60(2.96,11.65)	0.001

Abbreviations: DVT, deep vein thrombosis; BMI, body mass index; COPD,chronic obstructive pulmonary disease; HCT, hematocrit; ASA, American Society of Anesthesiologists; LOS, length of stay; WBC, white blood cell; PLT, platelet count; NEUT%, neutrophil percentage; LYM%, lymphocyte percentage; RDW, red blood cell distribution width; BUN, blood urea nitrogen; SCR, serum creatinine; CRP, C-reactive protein; PT, Prothrombin time; APTT, activated partial thromboplastin time; FDP, fibrin degradation products; D-D, D-dimer;

Table 3. Multivariate results by logistic regression (N=957)

variables

b value

Exp(B)

95%CI

p value

Age≥65years

Time from trauma to surgery>1 week

1.010

0.035

2.746

1.035

1.661-4.540

0.721-1.487

<0.0001

0.852

LOS>14 days

Pneumonia

Respiratory failure

Open fracture

Multiple fracture

Comminuted fracture

Multiple injuries

Shock

ASA classification>2

Operation time>2h

Preoperative anticoagulation

Anticoagulation after surgery >24h

HCT cohort

0.517

0.109

0.429

0.057

0.182

0.311

0.222

-0.249

-0.071

0.004

0.438

0.654

1.676

1.115

1.536

1.059

1.199

1.365

1.248

0.779

0.931

1.004

1.550

1.923

1.171-2.400

0.691-1.800

0.767-3.077

0.554-2.024

0.701-2.052

0.955-1.952

0.720-2.163

0.316-1.925

0.596-1.454

0.688-1.465

1.061-2.265

1.260-2.933

0.005

0.656

0.226

0.863

0.507

0.088

0.429

0.589

0.754

0.984

0.024

0.002

No anemia

Mild anemia

30%-33%

27%-30%

<27%

HCT cohort：transfusion interaction term

No anemia

No anemia + transfusion

Mild anemia +transfusion

30%-33% + transfusion

27%-30% + transfusion

<27% + transfusion

Hypoalbuminemia

PLT (10^9/L)

LYM% (%)

RDW (%)

BUN (mmol/L)

CRP (mg/L)

PT (s)

D-D (mg/L)

0.314

0.555

0.721

1.216

0.737

0.419

1.116

0.613

1.092

0.189

0.002

-0.004

-0.025

0.004

0.000

-0.060

0.005

Reference

1.369

1.742

2.056

3.373

Reference

2.090

1.520

3.052

1.847

2.979

1.208

1.002

0.996

0.975

1.004

1.000

0.941

1.005

0.839-2.236

0.913-3.324

0.948-4.461

0.951-11.964

0.811-5.386

0.760-3.038

1.603-5.811

0.990-3.447

1.574-5.639

0.792-1.841

1.000-1.003

0.970-1.022

0.914-1.040

0.969-1.040

0.996-1.004

0.835-1.061

0.995-1.016

0.209

0.092

0.068

0.060

0.127

0.236

0.001

0.054

0.001

0.380

0.089

0.380

0.446

0.828

0.879

0.323

0.312

Abbreviations: CI, confidence interval; LOS, length of stay; ASA, American Society of Anesthesiologists; HCT, hematocrit; PLT, platelet count; LYM%, lymphocyte percentage; RDW, red blood cell distribution width; BUN, blood urea nitrogen; CRP, C-reactive protein; PT, prothrombin time; D-D, D-dimer.

No competing interests reported.

Relationship between the severity of preoperative anemia and postoperative deep vein thrombosis in patients with bone trauma: a cohort study

Status:

Version 1

Abstract

Objective

Method

Results

Conclusions

Trial registration:

Figures

1. Introduction

2. Materials and methods

2.1 Data collection

2.2 Research method

2.3 Statistical methods

3. Results

4. Discussion

4.1 Relationship between preoperative anemia of different degrees and DVT in patients with bone trauma

4.2 Causes of preoperative anemia in patients with bone trauma

4.3 Possible mechanism of preoperative anemia increasing the occurrence of DVT.

4.4 Preoperative management and optimization of anemia in patients with bone trauma

5. Conclusion

Abbreviations

Declarations

References

Tables

Additional Declarations

Status:

Version 1