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Abstract

Background

Neurosurgical patients are at an increased risk of deep venous thrombosis (DVT), which, if not properly managed, can lead to pulmonary embolism. This study aimed to investigate the accuracy of age-adjusted D-dimer thresholds combined with the modified Wells score as a predictor for lower extremity DVT diagnosis.

Methods

We conducted a study among patients aged >50 years with suspected lower extremity DVT in the neurosurgery intensive care unit between December 2019 and December 2020. Receiver operating characteristic curve analysis was performed to examine the diagnostic capacity of age-adjusted D-dimer combined with the modified Wells score.

Results

A total of 233 participants, with an average age of 71.81 ± 12.59 years, were enrolled in the study. The mean D-dimer levels were 0.73 ± 0.39 mg/L. Among the participants, 57 (57.9%, 33 males) were diagnosed with DVT. The age-adjusted D-dimer combined with the modified Wells score had the highest area under the curve for diagnosing lower extremity DVT compared to D-dimer and age-adjusted D-dimer alone, with an AUC of 0.858. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the age-adjusted D-dimer combined with the modified Wells score for DVT diagnosis were 78.95%, 80.68%, 57%, 92.2%, and 80.26%, respectively. When analyzing subgroups, the accuracy was 79.55% for participants with cerebral hemorrhage, 81.69% for those with craniocerebral injury, 74.99% for participants with intracranial infection, and 88.89% for those with craniocerebral tumor.

Conclusion

The combination of the age-adjusted D-dimer thresholds with the modified Wells score might effectively predict lower extremity DVT.

Keywords

Wells score D-dimer deep vein thrombosis of the lower limbs predictive study

Introduction

Venous thromboembolism (VTE) clinically consists of pulmonary embolism (PE) and deep vein thrombosis (DVT).^1–3 There is a high incidence of DVT among neurosurgical patients, and the improper prevention and treatment of DVT can lead to PE, with approximately 90% of PEs being caused by DVT.⁴ PE is a condition with high morbidity and mortality.^1–3 Therefore, it is essential to achieve early detection, diagnosis, and treatment of DVT. D-dimer is a fibrin degradation product, and its blood concentration is often used as a predictor of VTE occurrence,^5,6 but the assay has a high sensitivity (Sen) and a low specificity (Spe), limiting its clinical value.⁷

Age is an independent factor contributing to high D-dimer levels,⁸ and D-dimer values are generally higher in older patients, resulting in high Sen, high negative predictive value (NPV), and low Spe for predicting the occurrence of DVT in older adults, further limiting the clinical application of D-dimer levels for DVT detection. Therefore, the diagnostic value of D-dimer for DVT needs to be improved. It has been shown that adjusting the value of serum D-dimer for age, ie, by (age × 0.01) mg/l for patients aged >50 years, could improve the Spe of serum D-dimer for predicting lower extremity DVT.⁹

The Wells scoring system is currently the most widely used scoring model to assess the occurrence of VTE,^10,11 but it was found that the effectiveness of the Wells score for diagnosing VTE was low due to its high sensitivity and low specificity.¹² Given that the age-adjusted D-dimer levels improved the specificity of predicting VTE occurrence, it was hypothesized that the combination of the age-adjusted D-dimer levels and Wells score might result in improved diagnostic value for predicting VTE occurrence at an early stage, reducing the occurrence of DVT-related complications, and accelerate patient recovery.

There are few studies on the combination of the Wells score and age-adjusted D-dimer thresholds to predict lower limb DVT. Therefore, this study aimed to explore whether combining these two factors could improve efficacy for predicting DVT occurrence. The results could provide basic data for promoting the clinical application of the combined factors for managing patients at risk of DVT.

Methods

Study Design and Population

This prospective study was conducted in the neurosurgery intensive care unit of ours between December 2019 and December 2020. Patients with suspected lower extremity DVT and aged >50 years were enrolled. This study was approved by the Ethics Committee of XXX Medical University (***). Written informed consent was obtained.

Inclusion Criteria: Participants were eligible (1) if they were admitted to the intensive care unit after surgical treatment, (2) had a Glasgow coma scale score ≤10, (3) were at low to medium risk of suspected DVT with the first onset, and a Wells score <3, and (4) received subcutaneous enoxaparin sodium injection 4000AxaIU/d after surgery.

Exclusion Criteria: Participants were excluded (1) if they had suspected second DVT episode, (2) severely abnormal liver and kidney function, abnormal coagulation and bleeding, (3) DVT clinical signs and symptoms lasting more than 1 month, (4) suspected PE or a final diagnosis of thrombophlebitis, or (5) during prophylactic anticoagulation treatment, patients with active bleeding and large subcutaneous ecchymosis were immediately stopped using low molecular weight heparin.

The ultrasound diagnostic criteria of suspected DVT of the lower extremity were (1) enlargement of the lumen below the site of thrombus obstruction, thickening of the wall, and the presence of parenchymal dense light clusters in the lumen, (2) homogeneous hypoechogenicity in acute cases and inhomogeneous, irregular moderate or strong echogenicity in subacute or chronic cases, and (3) color Doppler showing no flow signal in complete occlusion and filling defects and peripheral slit-like flow signal in incomplete occlusion, in which the proximal end of the thrombus may float slightly with the up and down pulsation of the blood flow in some acute cases. The diagnostic criteria for DVT in this study were formulated in reference to the Guidelines for the Diagnosis and Treatment of Deep Vein Thrombosis (Third Edition) of the Vascular Surgery Group of the Chinese Medical Association's Surgery Branch.¹³

Data Collection and Definition

Demographic information, including sex, age, and cause of admission, was recorded. The participants were assessed for the clinical probability of a DVT diagnosis based on the Wells score. For each participant, a color Doppler ultrasound examination of the lower limbs was performed after admission according to a standardized protocol. Fasting-state blood samples (5 ml) were drawn early in the morning on 3 consecutive days, and the D-dimer levels were measured.

The gold standard was lower limb vascular ultrasound.⁶ Sen, Spe, positive predictive value (PPV), NPV, and accuracy (Acc) were calculated as Sen = a/(a + d), Spe = c/(c + b), Ppv = a/(a + b), Npv = c/(c + d), Acc = (a + d)/(a + b + c + d), where (a) represents the number of true positive cases, (b) represents the number of false positive cases, (c) represents the number of true negative cases and (d) represents the number of false negative cases. When calculating the Sen and PPV, a positive age-adjusted D-dimer and modified Wells score were considered positive, while a negative age-adjusted D-dimer and modified Wells score were considered negative when calculating the Spe and NPV.

Statistical Analysis

Statistical analyses were performed using SPSS 22.0 (IBM Corp., Armonk, NY, USA). Continuous data with a normal distribution (according to the Kolmogorov–Smirnov test) were expressed as means ± standard deviations and analyzed using Student's t-test. The continuous data with a skewed distribution were expressed as medians and quartiles (M [P25, P75]) and analyzed using the Mann–Whitney U-test. The categorical data were presented as n (%) and analyzed with the chi-square test.

Logistic regression was used to calculate the joint predictive probability (age-adjusted D-dimer) of D-dimer and age for predicting DVT, and the area under the curve of the receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic performance. Based on the above model, we further introduced the modified Wells score in the logistic regression model to continue assess the diagnostic value of the age-adjusted D-dimer combined with modified Wells scoring system. In addition, subgroup analyses of ROC curves were also explored by cause of admission. Two-sided P-values <0.05 were considered statistically significant.

Results

A total of 233 participants, comprising 120 (51.5%) males and 113 (48.5%) females, with an average age of 71.81 ± 12.59 years, were enrolled in the study (Table 1). Among them, 88 (37.8%) participants had cerebral hemorrhage, 71 (30.5%) had cranial injury, 56 (24.0%) had intracranial infection, and 18 (7.7%) had craniocerebral tumor. The mean D-dimer levels were 0.73 ± 0.39 mg/L. Deep venous thrombosis (DVT) occurred in 57 participants (33 males and 24 females) out of the 233 participants with suspected lower limb DVT, resulting in an incidence rate of 24.4%. Within this group, there were 19 (33.3%) participants with cerebral hemorrhage, 16 (28.1%) with craniocerebral injury, 17 (29.8%) with intracranial infection, and 5 (8.8%) with craniocerebral tumor (Table 1). DVT occurred in the right lower extremity in 30.00% of cases, in the left lower extremity in 36.67% of cases, and in both lower extremities in 33.33% of cases.

Table 1.

Characteristics of the Participants.

Variables	All(N = 233)	Non-DVT (n = 176)	DVT (n = 57)	P-value
Age (years)	71.81 (12.59)	69.82 (12.86)	77.93 (9.44)	<0.001
Sex, n (%)
Male	120 (51.5)	87 (49.4)	33 (57.9)	0.267
Female	113 (48.5)	89 (50.6)	24 (42.1)
Cause of admission, n (%)
Cerebral hemorrhage	88 (37.8)	69 (39.2)	19 (33.3)	0.638
Cranial injury	71 (30.5)	55 (31.2)	16 (28.1)
Intracranial infection	56 (24.0)	39 (22.2)	17 (29.8)
Cranial tumor	18 (7.7)	13 (7.4)	5 (8.8)
Wells score, n (%)
≤0 score	139 (59.7)	124 (70.5)	15 (26.3)	<0.001
1–2 score	94 (40.3)	52 (29.5)	42 (73.7)
D-dimer assay day1 (mg/l)	0.73 (0.39)	0.65 (0.37)	0.96 (0.34)	<0.001
D-dimer assay day2 (mg/l)	0.80 (0.31)	0.77 (0.33)	0.88 (0.24)	0.018
D-dimer assay day3 (mg/l)	0.76 (0.32)	0.73 (0.32)	0.85 (0.29)	0.012
White blood cell	10.62 (5.86)	10.44 (5.71)	11.17 (6.33)	0.417
Neutrophils	9.30 (6.10)	8.92 (5.90)	10.45 (6.59)	0.1
Lymphocytes	1.37 (0.60)	1.35 (0.60)	1.43 (0.61)	0.386
Monocytes	0.67 (0.40)	0.64 (0.37)	0.76 (0.47)	0.055
Platelets	234.03 (59.82)	235.57 (62.40)	229.28 (51.26)	0.491
ALT	55.40 (57.51)	58.94 (61.55)	44.46 (41.24)	0.098
AST	63.81 (83.76)	64.15 (85.48)	62.75 (78.90)	0.913
Alkaline phosphatase	103.67 (52.27)	105.35 (54.15)	98.46 (46.02)	0.388
Albumin	43.33 (3.59)	43.25 (3.76)	43.60 (3.01)	0.514
Globulin	26.29 (3.67)	26.12 (3.71)	26.82 (3.53)	0.213
Prothrombin time	10.93 (1.48)	11.04 (1.39)	10.59 (1.68)	0.043
Fibrinogen	3.37 (2.33)	3.40 (2.07)	3.30 (3.02)	0.79

Abbreviations: DVT: deep vein thrombosis; ALT: alanine transaminase; AST: Aspartate aminotransferase.

The age-adjusted D-dimer combined Wells score has the highest accuracy (80.26%), significantly greater than age-adjusted D-dimer (74.67%) and D-dimer (71.25%) (all P < 0.05, Table 2, Figure 1). The sensitivity and area under the curve of the age-adjusted D-dimer for the diagnosis of lower extremity DVT were significantly higher than those of the D-dimer (all P < 0.05, Table 2, Figure 1). The sensitivity, specificity, PPV, NPV, and area under the curve of the age-adjusted D-dimer combined Wells score for the diagnosis of lower extremity DVT were significantly higher than those of the age-adjusted D-dimer (all P < 0.05, Table 2, Figure 1).

Figure 1.

Diagnostic efficacy of joint prediction indicators in the whole participants.

Table 2.

Diagnostic Efficacy of Joint Prediction Indicators.

Method	AUC	95% CI	Sen (%)	Spe (%)	PPV (%)	NPV (%)	Accuracy
D-dimer	0.746	0.685–0.801	68.42	72.16	44.3	87.6	71.25
Age-adjusted D-dimer	0.794a	0.737–0.844	77.19^a	73.86	48.9	90.9	74.67^a
Age-adjusted D-dimer combined with the Wells score	0.858ab	0.806–0.900	78.95^a	80.68^a,^b	57^a,^b	92.2^a	80.26^a,^b

Indicates P < 0.05 compared with the D-dimer; ^bIndicates P < 0.05 compared with the Age-adjusted D-dimer; Sen: sensitivity; Spe: specificity; PPV: positive predictive value; NPV: negative predictive value; Acc: accuracy; AUC: area under the curve.

The accuracy of age-adjusted D-dimer combined Wells score for lower limb DVT in the different admission subgroups was significantly higher than D-dimer (P < 0.05, Table 3). In order to validate the diagnostic efficacy of the age-adjusted D-dimer critical value with its combined modified Wells score in patients with early lower extremity DVT, a subgroup analysis was performed according to the type of disease. In the brain hemorrhage group, sensitivity (78.95%), PPV (61.7%), area under the curve (82.7%), and accuracy (79.55%) were significantly higher than those of the D-dimer (all P < 0.05, Table 3, Figure 2). In the craniocerebral injury group, hemorrhage group, sensitivity (81.25%), specificity (81.82%), PPV (56.5%), NPV (93.8%), area under the curve (86.6%), and accuracy (81.69%) were significantly higher than those of the D-dimer (all P < 0.05, Table 3, Figure 3). In the intracranial infection group, hemorrhage group, sensitivity (88.2%), specificity (69.23%), PPV (55.6%), NPV (93.1%), area under the curve (80.7%), and accuracy (74.99%) were significantly higher than those of the D-dimer (all P < 0.05, Table 3, Figure 4). Finally, in the craniocerebral tumor group, hemorrhage group, sensitivity (100%), specificity (84.62%), NPV (100%), area under the curve (84.6%), and accuracy (88.89%) were significantly higher than those of the D-dimer (all P < 0.05, Table 3, Figure 5).

Figure 2.

Diagnostic efficacy of joint prediction indicators in cerebral hemorrhage participants.

Figure 3.

Diagnostic efficacy of joint prediction indicators in the craniocerebral injury participants.

Figure 4.

Diagnostic efficacy of joint prediction indicators in the intracranial infection participants.

Figure 5.

Diagnostic efficacy of joint prediction indicators in the craniocerebral tumor participants.

Table 3.

Diagnostic Efficacy of Joint Prediction Indicators in Different Cause of Admission.

Method	AUC	95% CI	Sen (%)	Spe (%)	PPV (%)	NPV (%)	Accuracy
Cerebral hemorrhage
D-dimer	0.719	0.613–0.810	68.42	75.36	43.3	89.7	73.86
Age-adjusted D-dimer combined with the Wells score	0.827*	0.731–0.899	78.95*	79.71	61.7*	93.2	79.55*
Craniocerebral injury
D-dimer	0.736	0.618–0.834	68.75	70.91	40.7	88.6	70.42
Age-adjusted D-dimer combined with the Wells score	0.866*	0.764–0.935	81.25*	81.82*	56.5*	93.8*	81.69*
Intracranial infection
D-dimer	0.776	0.645–0.877	82.36	61.54	48.3	88.9	67.86
Age-adjusted D-dimer combined with the Wells score	0.807*	0.679–0.900	88.2*	69.23*	55.6*	93.1*	74.99*
Craniocerebral tumor
D-dimer	0.75	0.531–0.940	60	92.31	75	85.7	83.34
Age-adjusted D-dimer combined with the Wells score	0.846*	0.677–0.992	100*	84.62*	71.4	100*	88.89*

*Indicates P < 0.05 compared with the D-dimer; Sen: sensitivity; Spe: specificity; PPV: positive predictive value; NPV: negative predictive value; Acc: accuracy; AUC: area under the curve.

Discussion

The results of this study indicate that the combination of the age-adjusted D-dimer thresholds with the modified Wells score might provide a favorable accuracy for detecting DVT in patients suspected of lower limb DVT, which may provide a reference for the management and prediction of patients at risk for DVT.

The Wells score is a well-known tool for evaluating the risk of DVT.^10,11 It is based on clinical signs/symptoms of DVT, no alternative diagnosis, heart rate >100 bpm, immobilization >3 days or surgery in the past 4 weeks, history of VTE, hemoptysis, and cancer and active treatment in the past 6 months or palliative care.^10,11 Still, its Acc is low due to a low Spe despite a high Sen.^10–12 While the Wells score evaluates qualitative factors associated with a higher risk of VTE, the presence of D-dimer indicates the presence of fibrinolysis and fibrinogenesis in the body, and a significant increase in fibrinolysis may indicate the presence of hyperfibrinolysis.^5,6 Still, the use of D-dimer alone for detecting VTE also has high Sen and low Spe.⁷ Monitoring D-dimer levels can reflect the degree of patient blood hypercoagulation and might have a reference value for the early determination of patients with suspected DVT in the lower extremities.¹⁴ Nevertheless, because of the low Acc, further imaging examinations are typically required for suspected DVT, and additional examinations not only cost patients time and energy but also increase the unnecessary economic burden on the patients and the healthcare system.

Age is a major confounder in the analysis of the D-dimer levels for the screening of VTE. Indeed, Harper et al¹⁵ found that plasma D-dimer levels increased with age. Hongxia et al¹⁶ also showed that plasma D-dimer values were higher in China's healthy older adults than in younger adults. Hence, plasma D-dimer levels are correlated with age. Stratified analyses showed that D-dimer values are relatively stable until 65 years of age, after which they increase.^17,18 Therefore, using non-adjusted D-dimer thresholds would result in large numbers of false positives.

Therefore, in recent years, the use of age-adjusted D-dimer threshold values has gradually attracted attention in the screening of VTE.^19–22 The use of age-adjusted D-dimer thresholds to predict DVT formation can improve the diagnostic value of D-dimer.^23–25 In this study, the D-dimer and age-adjusted D-dimer of 233 patients were evaluated. The AUC, Sen, ACC of age-adjusted D-dimer for diagnosing lower extremity DVT was significantly higher than that of the D-dimer, with no significant differences in Spe, PPV, and NPV. Douma et al²⁶ found that using age-adjusted D-dimer in patients aged ≥60 years improved the diagnostic value for DVT.

Therefore, combining the Wells score with the age-adjusted D-dimer thresholds was hypothesized to yield a higher diagnostic value than either factor alone. Indeed, the present study showed that the combination yielded significantly higher Sen, Spe, PPV, NPV, and AUC than age-adjusted thresholds. It is also supported by two studies that showed that combining the two could improve the predictive efficacy of these factors for DVT and other VTE formations at an early stage, reduce DVT-related complications, and accelerate patient recovery.^27,28 Schouten et al²⁹ were able to effectively exclude DVT by adjusting the age-adjusted D-dimer threshold in 647 patients rated as low risk, especially in those older than 60 years. Similar results were also shown by Li et al.³⁰

In order to validate the diagnostic efficacy of the age-adjusted D-dimer threshold with its combined modified Wells score in patients with early lower extremity DVT, a subgroup analysis was performed according to the cause of admission. The age-adjusted D-dimer threshold combined with the modified Wells score retained high diagnostic value among the subgroups but without significant differences, similar to Douma et al.²⁶ Such results might be related to the small sample size.

This study still has some limitations. First, the participants included in this study were all patients aged >50 years, and no assessments have been performed for patients aged ≤50. Secondly, due to the limitation of sample size in a single center, the stability of the results in subgroup analysis may be reduced. Due to limitations in the included population, the extrapolation of our findings to other populations needs to be further explored in other studies. Lastly, there were some shortcomings concerning patient enrollment continuity and laboratory test quality control. Therefore, further studies including large sample size are needed to confirm the findings.

In conclusion, the age-adjusted D-dimer thresholds combined with the Wells score might have good diagnostic value in patients with suspected lower extremity DVT and might predict the occurrence of early lower extremity DVT more accurately than the traditional thresholds.

Footnotes

Authors’ Contributions

Wei Hao and Rongcai Jiang conceived and designed the study and analyzed the data; Ye Tian, Wei Quan, and Jian Sun developed the methodology. Wei Hao, Xuanhui Liu, Yu Qian, and Shuo An carried out the experiments. Wei Hao, Jiancheng Feng, and Rongcai Jiang analyzed the data and interpreted the results. Wei Hao wrote the manuscript. Shuo An, Yingsheng Wei, and Xinjie Zhang provided technical support. Rongcai Jiang reviewed and revised the manuscript and supervised the study. All authors have read and approved the manuscript. All authors read and approved the final manuscript.

Data Availability Statement

All data generated or analyzed during this study are included in this published article.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics approval and informed consent

The study was conducted in accordance with the Declaration of Helsinki. The study was reviewed and approved by the Ethics Committee of Tianjin Medical University (IRB2022-YX-006-01). The requirement for individual consent was waived by the committee because of the retrospective nature of the study.

Funding

This work was supported by grants from the National Natural Science, Foundation of China (grant 82071390) and the Key R&D Program Science and Technology Support Key Projects of Tianjin (grant 19YFZCSY00650).

ORCID iD

Rongcai Jiang

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Age-adjusted D-Dimer Thresholds Combined with the Modified Wells Score as a Predictor of Lower Extremity Deep Venous Thrombosis

Abstract

Background

Methods

Results

Conclusion

Keywords

Introduction

Methods

Study Design and Population

Data Collection and Definition

Statistical Analysis

Results

Discussion

Footnotes

Authors’ Contributions

Data Availability Statement

Declaration of Conflicting Interests

Ethics approval and informed consent

Funding

ORCID iD

References