Sex Differences in Clinical Presentation of Lower Extremity Deep Vein Thrombosis

Abstract

Background:

Differences between men and women in the clinical features and extent of lower limb deep vein thrombosis (DVT) may influence DVT diagnostic algorithms involving pretest clinical probability (PTP) assessment, D-dimer, and compression ultrasonography (CUS).

Aims:

To assess differences in DVT clinical presentation between men and women and their effect on PTP and D-dimer.

Methods:

We conducted a retrospective study in outpatients referred for suspected DVT of the lower limbs to our vascular emergency department from January 2005 to December 2019. Patients underwent PTP assessment with the Wells score, D-dimer testing, and CUS.

Results:

More women were referred for suspected DVT than men (M/F: 1,785/2,821; F: 61.4%; p < 0.0001). Women were older than men (median age: 71 vs. 67 years; p = 0.0001), DVT was diagnosed in 436 patients (9.4%) but in more men than women (M: 210 [11.8%] vs. F: 226 [8%]; p = 0.0002), with more proximal DVT in men than women (M: 131 7.3% vs. F: 124 [4.4%]; p = 0.00021). PTP was more likely in men (355 [19.9%]) than women (455 [16.2%]) (p = 0.0011); more men had swelling in the entire limb, increased calf circumference by >3 cm compared with the contralateral limb, and pitting edema, than women. D-dimer levels (available in 65% of patients) were more frequently positive in women with DVT than in men (94.6% vs. 85.7%; p = 0.016). However, a positive D-dimer and/or likely PTP was similarly frequent in men (92%) and women (96%) with DVT.

Conclusions:

More women than men are referred for suspected DVT, and men have a higher prevalence of proximal DVT. However, current algorithms for DVT diagnosis perform similarly in men and in women.

Introduction

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a frequent disorder occurring in 1–2 per 1,000 persons-years, and it is the third most common cardiovascular disorder after acute coronary syndromes and stroke.¹ Studies have shown that both women and men have a substantial lifetime risk of VTE but suggest that men have an intrinsically higher risk of VTE than women, although these differences have not been fully explained.²

Differences in the presenting location of VTE between women and men have also been reported. PE as presenting location was found to be relatively more common in women than in men.³ Among patients with first symptomatic isolated acute DVT, women presented with distal DVT more often than men, whereas men had a higher proportion of proximal DVT events, especially with increasing age and in unprovoked index events.⁴

Differences in PE clinical presentation between men and women have also been observed with men having more frequent symptoms of onset episodes of hemoptysis and chest pain, whereas women more often have dyspnea or syncope.^5
–7 In addition, women have been shown to present with isolated PE, with men having DVT more frequently associated with PE.^8,9 An individual patient data meta-analysis of 10,002 patients in 13 studies has suggested that more women (62%) than men were investigated for DVT of the lower limbs.¹⁰ If DVT prevalence is similar in men and women, but more women are investigated for suspected DVT, this may imply that the prevalence of DVT among investigated patients is lower in women than in men. Indirectly, this would suggest that DVT clinical features differ between men and women.¹¹

Sex-related differences in VTE presentation could influence current diagnostic algorithms for VTE, which include the assessment of pretest clinical probability (PTP) as the first step, D-dimer (DD), and imaging tests such as compression ultrasonography (CUS) for DVT and pulmonary angiography computed tomography for PE. Several scores have been proposed for PTP assessment of DVT among which the Wells score is the most widely validated.¹⁰ Previous studies have shown that in outpatients with suspected DVT, the overall prevalence of thrombosis and the prevalence of thrombosis in those with low or moderate PTP, as assessed by the Wells score, were higher in men than in women.¹¹

In addition, clinical signs and symptoms of DVT may differ between men and women. Two studies previously addressed this issue with conflicting results. Andreou et al. have shown that in patients diagnosed with DVT, swelling of the entire leg occurred more often (41.5% vs. 15.7%; p < 0.001), and thrombosis was more extensive (involvement of both popliteal and common femoral veins in 47.9% vs. 21.6%), in women than in men.¹¹ In contrast, in a cohort of 4,976 outpatients with clinically suspected DVT in whom the diagnosis of DVT was based on CUS in 96% of patients, Bauersachs et al. showed that the prevalence of DVT was higher in men and their thrombotic events were more severe, with women being more frequently referred for a diagnostic workup for DVT and diagnosed with calf DVT than men.¹² Nevertheless, the Wells PTP correctly identified low- and high-risk groups in both men and women.

No data on DD were provided by either of the two studies addressing sex differences in DVT presentation.^11,12 DD has been shown to be influenced by sex, as men have significantly lower DD than women, and female sex is a significant predictor of a positive DD. Women have also been found to have significantly higher DD levels among those with a positive DD.¹³

The aim of our study was to assess whether men and women differ in the clinical presentation of lower limb DVT and DD and whether any such differences can influence the performance of clinical prediction rules and diagnostic algorithms for DVT diagnosis.

Materials and Methods

We conducted a retrospective study in consecutive outpatients referred to our vascular emergency department for suspected symptomatic DVT of the lower limbs during business hours from January 2005 to December 2019. Patients were excluded if younger than 18 years, if they were receiving vitamin K antagonists or direct oral anticoagulants or low-molecular-weight heparin or fondaparinux for >24 hours, pregnant or in puerperium, with clinical suspicion of either PE or acute superficial vein thrombosis.

Procedures

Patients underwent: (1) personal and family history elicited by the physician in charge who also performed a physical examination and assessed the PTP for DVT; (2) DD testing; and (3) complete compression ultrasonography (C-CUS) of both lower limbs.

The study was approved by the local ethics committee. Informed consent was waived for the retrospective design of the study.

D-dimer testing

Blood samples were drawn by a clean venipuncture from an antecubital vein with a 19-gauge butterfly needle and collected into 4 mL PET (polyethylene teraftalate) tubes containing 0.4 mL 0.106M trisodium citrate (Kima, Italy). Whole blood was centrifuged at 2,000 g for 20 minutes at 20°C. Technicians performing DD testing were unaware of patients’ symptoms.

The STA Liatest^® D-Di (Diagnostica Stago, Asniéres, France) is an automated rapid microlatex DD assay. Monoclonal antibody-coated latex particles agglutinate in the presence of DD fibrin degradation products. The STA Liatest^® DD was performed on the STA Compact^® coagulation analyzer as previously described.¹⁴ The results were expressed in microgram per milliliter (expressed in fibrinogen equivalent unit [FEU]). As previously described, the cutoff value for DVT exclusion was 0.5 μg/mL as indicated by the manufacturer.¹⁵ DD was classified as positive if it was above the cutoff as indicated by the manufacturers.

Pretest clinical probability

PTP was assessed according to Wells and associates.¹⁶ Based on such clinical prediction rule, the PTP for DVT could be estimated to be unlikely (score = ≤1) or likely (score = ≥2).

Complete compression ultrasonography investigation

Patients underwent a real-time, B-mode, color Doppler CUS examination of both legs by a vascular medicine physician as previously described.¹⁷ CUS was performed with an EnVisor C HD instrument (Philips Medical System S.p.A, Monza, Italy), with a high-resolution broadband width linear array transducer 12-5 MHz, according to the method of Schellong et al.¹⁸ The proximal deep veins were first examined down to the trifurcation, then the calf veins were evaluated. The following veins were scanned in the transverse plane over their entire length: posterior tibial veins, fibular veins, internal and external gastrocnemius veins, and soleal veins. DVT diagnosis was confirmed if there was lack of compression of the vein, combined with the absence of venous flow with distal compression. Ipsilateral recurrent DVT was diagnosed by the presence of either a new noncompressible venous segment or an increase in vein diameter of >4 mm, when compared with the most recent previous ultrasonography results.¹⁹

Statistical analysis

Categorical variables were expressed as frequency and percentage with 95% confidence intervals (95% CIs); continuous variables are expressed as mean, median, and interquartile range. Relationships between continuous variables were assessed using t-test for continuous variables, using Mann–Witney U test for nonparametric variables and chi-square or Fisher’s exact test for categorical variables.

The significance level was set at ≤0.05. Analysis was carried out using the Statistical Product and Service Solutions (SPSS) software package (version 19.0; SPSS Inc. Chicago, Illinois, USA).

Results

Table 1 shows the characteristics of the 4,606 included patients. More women than men were evaluated for suspected DVT (2,821 women [61.4%]; p = 0.0001), women were older than men (mean, median: 66.6, 70.8 years in women vs. 64.5, 67.4 years in men; p = 0.0001). The duration of symptoms was available in only 25% of patients, and it was similar in the two groups. DVT was excluded in more women than men (92% vs. 88%), with a higher DVT prevalence in men than in women (210 [11.8%] vs. 226 [8%]; p < 0.000022). Proximal DVT was more frequently diagnosed in men than in women (131 [7.3%] vs. 124 [4.4%]; p = 0.0011) with similar frequency of calf DVT in the two groups (79 [4.4%] vs. 102 [3.6%]; p = 0.16). PTP was more likely in men than women (355 [19.9%] vs. 455 [16.2%]; p ≤ 0.00001). DD was available in 2,995 patients (65%), and it was positive in 677/1,171 (57.7%) of men and in 1,022/1,823 (56.6%) of women. Left lower limb was more frequently symptomatic in both men and women. Table 2 shows the items of the Wells score in all patients and in men and women. Active cancer and immobilization due to paralysis/plaster cast were more frequent in men than women, as well as swelling of the entire limb and increase in calf circumference by >3 cm compared with the contralateral limb, and pitting edema.

Table 1.

Characteristics of Included Patients with Suspected DVT

	Total patients	Men	Women	P ^a
n	4,606	1,785 (38.7%)	2,821 (61.4%)
Age (mean; median; IQR)	65.8; 69.3	64.5; 67.4; 23.63	66.6; 70.8; 25.31	0.0001
Duration of symptoms (days) (mean; median) (only in 1,152 patients; 25%)	9.29; 4	10; 5	9; 4	ns
Suspected but excluded DVT	4,170 (90.5%)	1,575 (88.2%)	2,595 (92%)	0.000022
Total DVT	436 (9.5%)	210 (11.8%)	226 (8%)
Proximal DVT	255 (5.5%)	131 (7.3%)	124 (4.4%)	0.000021
Distal DVT	181 (3.9%)	79 (4.4%)	102 (3.6%)	0.16
Wells PTP
Unlikely	3,796 (82.4%	1,430 (80.1%)	2,366 (83.8%)
Likely	810 (17.6%)	355 (19.9%)	455 (16.2%)	0.0011
D-dimer positive (determined in 2,995 [65%])	1,699 (56.7%)	677/1,171 (57.7%)	1,022/1,823 (56.6%)	ns
Site of DVTright/left/bilateral^b	1,959/2,251/251 (42.6%;48.9%;8.2%)	799/853/126 (44.8%;47.8%;7.1%)	1,160/1,398/251 (41.1%;49.6%;8.9%)	—

Comparisons between men and women.

16 missing (0.3%).

DVT, deep vein thrombosis; PTP, pretest clinical probability; IQR, interquartile range.

Table 2.

Elements of the Wells Score in all Patients and in Men and Women

	Total patients	Men	Women	p
n	4,606	1,785	2,821
Active cancer	238 (5.2%)	112 (6.3%)	126 (4.5%)	0.008
Paralysis/plaster cast	209 (4.5%)	96 (5.4%)	113 (4%)	0.035
Bedridden for >3 days	250 (5.4%)	109 (6.1%)	141 (5.0%)	0.109
Tenderness along deep vein	1,591 (34.5%)	595 (33.3%)	996 (35.3%	0.107
Swelling of entire limb	399 (8.7%)	190 (10.6%)	209 (7.4%)	0.0001
Calf circumference increased by >3 cm compared with the contralateral limb	386 (8.4%)	203 (11.4%)	183 (6.5%)	0.0001
Pitting edema	1,148 (24.9%)	485 (27.2%)	663 (23.5%)	0.006
Previous documented DVT	567 (12.3%)	227 (12.7%)	340 (12.1%)	0.485
Dilated superficial veins	75 (1.6%)	35 (2%)	40 (1.4%)	0.188
Alternative diagnosis as likely	2,253 (48.9%)	864 (48.4%)	1,389 (49.3%)	0.565

Deep vein thrombosis, (DVT).

Characteristics of patients with suspected but excluded DVT

Table 3 shows the characteristics of patients in whom DVT was excluded (n = 4,170). There were more women than men (2,595 [62.4%] vs. 1,575 [37.6%]; p < 0.0001), and women were older than men (mean, median age: 66.2, 70.3 vs. 64.4, 67.6; p = 0.0001). Duration of symptoms was similar among men and women. PTP was similarly unlikely in men and women (2,366 [91.2%] vs. 1,430 [90.7%]). Active cancer, paralysis/plaster cast, swelling of the entire limb, and increase in calf circumference by >3 cm compared with the contralateral limb, and pitting edema were more frequent in men than in women. Mean DD values were 0.99 μg/mL (median, 0.53; range, 0.01–24) in men and 0.97 μg/mL (median, 0.53; range, 0.01–34) in women, whereas DD was negative in 474/1,032 men (45.0%) and in 794/1,693 women (46.8%). Negative DD with unlikely PTP was observed in 408/821 (49.6%) men and 691/1,391 (49.6%) women.

Table 3.

Characteristics of Patients with Suspected but Excluded DVT

	Total patients	Men	Women	P ^a
n	4,170 (90.5%)	1,575 (37.6%)	2,595 (62.4%)
Age (mean, median, IQR)	65.5; 69.1	64.4; 67.6; 23.42	66.2; 70.3; 25.59	0.0001
Duration of symptoms (days) (mean; median; only in 1,029 patients)	9; 5; 90	9.4; 5; 90	8.6; 4; 89	0.297
Wells PTP unlikely	3,796 (91%)	1,430 (90.7%)	2,366 (91.2%)	ns
Active cancer	199 (4.8%)	93 (5.9%)	106 (4.1%)	0.008
Paralysis/plaster cast	166 (4%)	74 (4.7%)	92 (3.5%)	0.065
Bedridden for >3 days	196 (4.7%)	89 (5.6%)	108 (5.6%)	0.35
Tenderness along deep vein	1,359 (32.6%)	482 (30.6%)	877 (33.8%)	0.035
Swelling of entire limb	300 (7.2%)	143 (9.1%)	157 (6.1%)	0.0001
Calf circumference increased by >3 cm compared with the contralateral limb	304 (7.3%)	158 (10%)	146 (5.6%)	0.0001
Pitting edema	1,016 (24.4%)	420 (26.7%)	596 (23%)	0.007
Previous documented DVT (3 missing)	471 (11.3%)	180 (11.4%)	292 (11.2%)	0.572
Dilated superficial veins	70 (1.7%)	32 (2%)	38 (1.5%)	0.173
Alternative diagnosis as likely (1 missing)	2,221 (53.3%)	843 (53.5%)	1,378 (53.1%)	0.823
Right/left/bilateral limb (15 missing)	1,759/2,050/34342.2%/49.2%/8.2%	697/757/11544.3%/48.1%/7.3%	1,062/1,293/22840.9%/49.8%/8.8%	0.085
D-dimer μg/mL (mean, median, range) (available in 2,725 patients [65.3%])	0.98; 0.53; 0.01–34	0.99; 0.53; 0.01–24	0.97; 0.53; 0.01–34	0.63
Negative (total) according to PTP	1295 (47.5%)	487/1032 (47%)	808/1,693 (48%)
Unlikely	1,099/2,212 (49.6%)	408/821 (49.6%)	691/1,391 (49.6%)
Likely	195/513 (38%)	77/211 (36.4%)	118 /302 (39%)

comparison between men and women.

Deep vein thrombosis, (DVT); pre-test clinical probability (PTP); interquartile range, (IQR).

Characteristics of all patients with DVT diagnosis

Table 4 shows the characteristics of patients in whom DVT was diagnosed (n = 436; M/F: 210/226). Women were older than men (mean, median: 71, 76 vs. 65.5, 66; p = 0.0001), with similar duration of symptoms. Men were more frequently diagnosed with proximal DVT than women, although the difference was not significant. Calf DVTs were diagnosed more in women with unlikely PTP, than in men (60/100 vs. 45/95; p = 0.07), but the difference did reach statistical significance. There were more calf DVT diagnosed among patients with unlikely PTP than likely PTP in both sexes. The items of PTP had similar frequency in men and women, except for alternative diagnosis as likely, which was higher in men than women (21/210 vs. 11/226; p = 0.045). DD was more frequently positive in women than men (123/130 [94.6%] vs. 120/140 [85.7%]; p = 0.016), although the frequency of positive DD and/or likely PTP was similar in men and women.

Table 4.

Characteristics of all Patients with DVT Diagnosis

	Total patients	Men	Women	P ^a
n	436	210 (48%)	226 (52%)
Age (mean, median, IQR)	68.4; 72; 85.28	65.5; 66; 23.72	71; 76; 19.29	0.0001
Duration of symptoms (days; mean; median) (only in 124)	10.73; 4	10; 5	11; 3	0.74
Proximal DVT	255 (58.5%)	131 (62.2%)	124 (55%)	0.120
Distal DVT	181 (42%)	79 (37.8%)	102 (45%)	0.11
Prevalence of DVT according to PTP
Likely (L)	241 (55.3%)	115 (54.5%)	126 (55.9%)
Prox-calf	165 (68%); 76 (32%)	81 (70%); 34 (30%)	84 (67%); 42 (33%)	0.0007
Unlikely (U)	195 (44.7%)	95 (45.5%)	100 (44.1%)	UvsL
Prox-calf	90 (46.1%); 105 (53.9%)	50 (52.6%); 45 (47.4%)	40 (40%); 60 (60%)	0.07
Active cancer	39 (8.9%)	19 (9%)	20 (8.8%)	0.537
Paralysis/plaster cast	43 (9.9%)	22 (10.5%)	21 (9.3%)	0.399
Bedridden for >3 days	54 (12.4%)	21 (10 %)	33 (14.6 %)	0.15
Tenderness along vein	232 (53.2%)	113 (53.8%)	119 (52.7%)	0.84
Swelling of entire limb	99 (22.7%)	47 (22.4%)	52 (23%)	0.91
Calf circumference increased by >3 cm compared with the contralateral limb	82 (18.8%)	45 (21.4%)	37 (16.4%)	0.18
Pitting edema	132 (30.3%)	65 (31%)	67 (29.8%)	0.83
Dilated superficial veins	5 (1.1%	3 (1.4%)	2 (0.9%)	0.87
Previous documented DVT	96 (22%)	47 (22.4%)	49 (21.7%	0.91
Alternative diagnosis as likely	32 (7.4%)	21 (10%)	11 (4.9%)	0.045
Site of DVT right/left/bilateral (1 missing)	200/201/3446%; 46%; 8%	102/96/1148.6%; 45.7%; 5.2%	98/105/2343%; 47%; 10%
D-dimer μgr/mL (mean, median) (available only in 270-62%)	5.4; 2.37	5.07; 2.76	5.7; 2.27	0.603
Positive (total)	243 (90%)	120/140 (85.7%)	123/130 (94.6%)	0.016
Positive according to PTP	135/146 (92.4%)	66/75 (88%)	69/71 (97%)
Likely positive DD and/or likely PTP	254/270 (94%)	129/140 (92%)	125/130 (96%)	0.16

comparison between men and women.

Deep vein thrombosis, (DVT); interquartile range, (IQR); pre-test clinical probability, (PTP).

Discussion

Limited data are available on the differences in the presentation of DVT between men and women. Such differences may influence the performance of DVT diagnostic algorithms, which include PTP and DD and ultrasonography.

Most studies on diagnostic strategies for DVT have evaluated more women than men, with approximately 60% of women. These findings are consistent across studies performed from the ’90’s to the most recent years, in different countries with different algorithms.^{11,12,20

–36} A higher prevalence of DVT in men than women has also been reported.^{11,12,22,23,26,27,34}

Only two previous studies specifically addressed the differences in clinical presentation of DVT between men and women. The study by Andreou et al.¹¹ retrospectively analyzed clinical characteristics, clinical pretest probability for DVT, and prevalence and extent of DVT of 1,838 outpatients enrolled in three prospective studies conducted in Canada and published in 2001, 2003, and 2005. These studies evaluated diagnostic algorithms for a suspected first episode of DVT, comprising PTP expressed as low, intermediate, and high and DD and CUS of the proximal veins, including the calf trifurcation. In all three studies women (61.6% overall) were evaluated more than men, with a longer duration of symptoms in women than men. DVT prevalence was higher in men than in women in all three studies (overall 14.4% vs. 9.4%), in particular in men with low and moderate PTP. In patients with DVT, swelling of the entire leg occurred more often (41.5% vs. 15.7%; p < 0.001), and thrombosis was more extensive (involvement of both popliteal and common femoral veins in 47.9% vs. 21.6%) in women than in men. In the latter study, only data on proximal DVT were available in all three studies. The other study by Bauersachs et al. evaluated 4,777 patients who were prospectively recruited and had a diagnostic workup for DVT by 326 vascular medicine physicians in the German ambulatory care sector in 2005.¹² More women were enrolled (n = 2,998–63%) than men, but the prevalence of confirmed DVT was higher in men (37.0%) than women (24.3%) (p < 0.001). Proximal DVT was more common in men than in women (59.6% vs. 44.5%), p < 0.001), with calf DVTs seen more in women. The swelling of the entire leg, pitting edema, and dilated superficial veins were more frequently reported by men (p < 0.001). The percentage of patients with a high-probability Wells clinical pretest score was higher in men than in women (67.0% vs. 57.0%, p < 0.001). However, overall, the score equally discriminated risk groups for DVT in both sexes. No data on DD were provided by either of the latter two studies.^11,12

Our data confirm previous observations that women are more frequently referred for suspected DVT, but they have a lower prevalence of diagnosed DVT than men, with frequencies in line with those reported by literature. In our study, the overall DVT prevalence was similar, although slightly lower, than that reported by Andreou et al.,¹¹ but it was much lower than that reported by Bauersachs et al.¹² who reported a higher overall prevalence of both proximal (15%) and calf DVT (14%). Men reported active cancer and paralysis/plaster cast more frequently than women. In our study, swelling of the entire limb, increase in calf circumference by <3 cm compared with the contralateral limb, and pitting edema were more frequently observed in men than in women, outcomes similar to the observations by Bauersachs et al. but differently from the study by Andreou et al.¹¹ In our study, men with unlikely PTP more frequently had proximal DVT and less frequently calf DVT than women. Likely PTP was more frequent in men than women, with a higher prevalence of proximal DVT also observed in men, whereas DD was more frequently positive in women. However, positive DD and/or likely PTP were similarly frequent in men and women in whom DVT was diagnosed.

The limitations of our study are the retrospective design in a single center, although with a large sample, the lack of complete data on the duration of symptoms (only in 25% of patients), the anatomic extension of diagnosed DVT, and the lack of data on 3-month follow-up in those patients in whom DVT was excluded by the initial evaluation. Strengths are the availability of data on DD, although only in 65%, and also about calf DVT.

In conclusion, more women than men are referred for suspected DVT, and men have a higher prevalence of proximal DVT than women. However, the performance of current algorithms for DVT diagnosis is similar in men and women.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

References

Brink

, Elf

, Svensson

, et al. Sex-specific risk factors for deep venous thrombosis and pulmonary embolism in a population-based historical cohort study of middle-aged and older individuals. J Am Heart Assoc, 2023; 12(5):e027502; doi: 10.1161/JAHA.122.027502

Scheres

LJJ

, van Hylckama Vlieg

, Cannegieter

. Sex-specific aspects of venous thromboembolism: What is new and what is next? Res Pract Thromb Haemost, 2022; 6(4):e12722; doi: 10.1002/rth2.12722

Scheres

LJJ

, Brekelmans

MPA

, Beenen

LFM

, et al. Sex-specific differences in the presenting location of a first venous thromboembolism. J Thromb Haemost, 2017; 15(7):1344–1350.

Trinchero

, Scheres

LJJ

, Prochaska

, et al. Sex-specific differences in the distal versus proximal presenting location of acute deep vein thrombosis. Thromb Res, 2018; 172:74–79; doi: 10.1016/j.thromres.2018.10.025

Ciarambino

, Crispino

, Para

, et al. Gender medicine: A new possible frontiers of venous thromboembolism. Stresses, 2023; 3(1):167–181; doi: 10.3390/stresses3010013

McHugh

, Visani

, DeRosa

, et al. Gender comparisons in pulmonary embolism (results from the International Cooperative Pulmonary Embolism Registry [ICOPER]). Am J Cardiol, 2002; 89(5):616–619.

Barrios

, Morillo

, Guerassimova

, et al. Sex differences in the characteristics and short-term prognosis of patients presenting with acute symptomatic pulmonary embolism. PLoS One, 2017; 12(11):e0187648.

Robert-Ebadi

, Le Gal

, Carrier

, et al. Differences in clinical presentation of pulmonary embolism in women and men. J Thromb Haemost, 2010; 8(4):693–698.

Palareti

, Antonucci

, Dentali

, et al. Patients with isolated pulmonary embolism in comparison to those with deep venous thrombosis. Differences in characteristics and clinical evolution. Eur J Intern Med, 2019; 69:64–70; doi: 10.1016/j.ejim.2019.08.023

10.

Geersing

, Zuithoff

, Kearon

, et al. Exclusion of deep vein thrombosis using the Wells rule in clinically important subgroups: Individual patient data meta-analysis. BMJ, 2014; 348:g1340; doi: 10.1136/bmj.g1340

11.

Andreou

, Koru-Sengul

, Linkins

, et al. Differences in clinical presentation of deep vein thrombosis in men and women. J Thromb Haemost, 2008; 6(10):1713–1719.

12.

Bauersachs

, Riess

, Hach-Wunderle

, et al. Impact of gender on the clinical presentation and diagnosis of deep-vein thrombosis. Thromb Haemost, 2010; 103(4):710–717; doi: 10.1160/TH09-10-0705

13.

Reagh

, Zheng

, Stolz

, et al. Sex-related differences in D-dimer levels for venous thromboembolism screening. Acad Emerg Med, 2021; 28(8):873–881; doi: 10.1111/acem.14220

14.

Escoffre-Barbe

, Oger

, Leroyer

, et al. Evaluationof a new rapid D-dimer assay for clinically suspected deep venous thrombosis (Liatest D-dimer). Am J Clin Pathol, 1998; 109(6):748–753.

15.

Sidelmann

, Gram

, Larsen

, et al. Analytical and clinical validation of a new point-of-care testing system for determination of D-Dimer in human blood. Thromb Res, 2010; 126(6):524–530.

16.

Wells

, Owen

, Doucette

, et al. Does this patient have deep vein thrombosis? JAMA, 2006; 295(2):199–207.

17.

Cosmi

, Legnani

, Cini

, et al. Thrombotic burden, D-dimer levels and complete compression ultrasound for diagnosis of acute symptomatic deep vein thrombosis of the lower limbs. Thromb Res, 2022; 213:163–169; doi: 10.1016/j.thromres.2022.03.019

18.

Schellong

, Schwarz

, Halbritter

, et al. Complete compression ultrasonography of the leg veins as a single test for the diagnosis of deep veinthrombosis. Thromb Haemost, 2003; 89(2):228–234.

19.

Prandoni

, Cogo

, Bernardi

, et al. A simple ultrasound approach for detection of recurrent proximal-vein thrombosis. Circulation, 1993; 88(4 Pt 1):1730–1735.

20.

Huisman

, Buller

, ten Cate

, et al. Serial impedance plethysmography for suspected deep venous thrombosis in outpatients. The Amsterdam General Practitioner Study. N Engl J Med, 1986; 314(13):823–828.

21.

Heijboer

, Buller

, Lensing

AWA

, et al. A comparison of real-time compression ultrasonography with impedance plethysmography for the diagnosis of deep-vein thrombosis in symptomatic outpatients. N Engl J Med, 1993; 329(19):1365–1369.

22.

Wells

, Anderson

, Bormanis

, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet, 1997; 350(9094):1795–1798.

23.

Cogo

, Lensing

AWA

, Koopman

MMW

, et al. Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: Prospective cohort study. BMJ, 1998; 316(7124):17–20.

24.

Bernardi

, Prandoni

, Lensing

AWA

, et al. D-dimer testing as an adjunct to ultrasonography in patients with clinically suspected deep vein thrombosis: Prospective cohort study. BMJ, 1998; 317(7165):1037–1040.

25.

Tick

, Ton

, van Voorthuizen

, et al. Practical diagnostic management of patients with clinically suspected deep vein thrombosis by clinical probability test, compression ultrasonography, and D-dimer test. Am J Med, 2002; 113(8):630–635.

26.

Kraaijenhagen

, Piovella

, Bernardi

, et al. Simplification of the diagnostic management of suspected deep vein thrombosis. Arch Intern Med, 2002; 162(8):907–911.

27.

Anderson

, Kovacs

, et al. Combined use of clinical assessment and ddimer to improve the management of patients presenting to the emergency department with suspected deep vein thrombosis (the EDITED Study). J Thromb Haemost, 2003; 1(4):645–651.

28.

Wells

, Anderson

, Rodger

, et al. Evaluation of Ddimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med, 2003; 349(13):1227–1235.

29.

Stevens

, Elliott

, Chan

, et al. Withholding anticoagulation after a negative result on duplex ultrasonography for suspected symptomatic deep venous thrombosis. Ann Intern Med, 2004; 140(12):985–991.

30.

Bernardi

, Camporese

, Büller

, et al. Serial 2-point ultrasonography plus D-dimer vs. whole-leg color-coded Doppler ultrasonography for diagnosing suspected symptomatic deep vein thrombosis: A randomized controlled trial. JAMA, 2008; 300(14):1653–1659.

31.

Linkins

, Bates

, Lang

, et al. Selective D-dimer testing for diagnosis of a first suspected episode of deep venous thrombosis: A randomized trial. Ann Intern Med, 2013; 158(2):93–100; doi: 10.7326/0003-4819-158-2-201301150-00003

32.

Ageno

, Camporese

, Riva

, et al. Analysis of an algorithm incorporating limited and whole-leg assessment of the deep venous system in symptomatic outpatients with suspected deep-vein thrombosis (PALLADIO): A prospective, multicentre, cohort study. Lancet Haematol, 2015; 2(11):e474–e480.

33.

Parpia

, Takach Lapner

, Schutgens

, et al. Clinical pre-test probability adjusted versus age-adjusted D-dimer interpretation strategy for DVT diagnosis: A diagnostic individual patient data meta-analysis. J Thromb Haemost, 2020; 18(3):669–675; doi: 10.1111/jth.14718

34.

Oudega

, Hoes

, Moons

. The Wells rule does not adequately rule out deep venous thrombosis in primary care patients. Ann Intern Med, 2005; 143(2):100–107.

35.

Beebe

, Scissons

, Salles-Cunha

, et al. Gender bias in use of venous ultrasonography for diagnosis of deep venous thrombosis. J Vasc Surg, 1995; 22(5):538–542.

36.

Kahn

, Joseph

, Abenhaim

, et al. Clinical prediction of deep vein thrombosis in patients with leg symptoms. Thromb Haemost, 1999; 81(3):353–357.