a b s t r a c t

Objective: Clinical features may be different in patients with PE without co-existing DVT compared to those with PE with co-existing DVT. This prospective study aims to investigate the different clinical features between patients with isolated pulmonary embolism (PE) and those with PE associated with deep venous thrombosis. Method: This is a prospective study conducted in 107 consecutive patients diagnosed with acute PE in the emer- gency department or other departments of Kirikkale University Hospital. The diagnosis of PE was confirmed by Computed tomography pulmonary angiography , which was ordered on the basis of symptoms and find- ings. Bilateral lower extremity Compression ultrasound with standard 7.5 MHz linear array probe was applied to all patients. According to compression ultrasound results, the patients were divided into two classes as with and without deep venous thrombosis. Embolism in the main or lobar pulmonary arteries were classified as central, and those found only in segmental or subsegmental arteries were classified as peripheral. Laboratory parameters and Oxygen saturation were assessed on admission.

Results: 67 of 107 (62.6%) patients with PE were isolated pulmonary embolism, and 40 (37.4%) were PE + DVT. Patients with PE with co-existing DVT have wider pulmonary artery, higher d-dimer and pro BNP level, and lower saturation than those with isolated pulmonary embolism. central pulmonary embolism is more common in patients with deep vein thrombus than those without it. (87.5% (35/40) vs 32.8% (22/67),p = 0.001). 38.6% of central pulmonary embolism occur without deep vein thrombosis of the lower extremities.

Patients with PE with co-existing DVT have 42.5% mosaic perfusion pattern,70% chronic infarct appearance such as linear band, pleural nodule, %15.0 thickened, small arteries and, %12.5 shrunken complete artery occlusion, suggesting the chronic background.

Conclusion: PE patients with co-existing DVT are clinically more serious than those who do not have a DVT. An acute picture may be present in the chronic background in a significant proportion of patients with PE with co-existing DVT. In the presence of deep vein thrombosis, pulmonary embolism is usually central, but more than one-third of central pulmonary emboli occur without lower extremity deep vein thrombosis.

(C) 2021 Published by Elsevier Inc.

1. Introduction

Pulmonary embolism and deep vein thrombosis are two clinical manifestations of Venous thromboembolic disease [1].Pulmonary em- bolism can be considered as a complication of acute DVT. Pulmonary embolism, especially if it is centrally located, can cause serious life- threatening problems and even death [2].According to recent studies, most pulmonary emboli are thought to be caused by deep vein

Abbreviations: pro BNP, Pro-Brain Natriuretic Peptide; RDW, Red blood cell distribu- tion width; Htc, hematocrit; CTPA, computed tomography pulmonary angiography; DVT, deep vein thrombosis.

* Corresponding author at: Ziya Gokalp Cad. Fabrikalar Mah. Umut Sitesi D blok. Daire: 1, 07100 Kirikkale, Turkey.

E-mail address: [email protected] (M. Ekici).

thrombosis of the lower extremities [3,4]. Compression ultrasound as a pre-test for DVT in patients with suspected PE can be particularly ef- fective and safe [5]. In the literature, the prevalence of DVT accompany- ing PE varies considerably due to the different population and methods studied. [6-8]. The prevalence of DVT in PE, which has been proven in studies, ranges from 10 to 93% [4,9-15]. Among patients with negative findings with compression ultrasound, some of the DVTs responsible for PE may originate from pelvic or other veins [16]. In a study, a total body MRI scan was performed in 99 patients with PE, and more than half of these patients could not detect peripheral thrombus. [17]. They suggested that some of the PE cases who appeared without DVT may arise de nova in the lungs [17]. The clinical significance of accompanying deep vein thrombosis in patients with acute pulmonary embolism is not well known [6]. Clinical features may be different in patients with PE without co-existing DVT compared to those with PE with co-existing

https://doi.org/10.1016/j.ajem.2021.03.031 0735-6757/(C) 2021 Published by Elsevier Inc.

DVT. This prospective study aims to investigate the different clinical fea- tures between patients with isolated pulmonary embolism [PE] and those with PE associated with deep venous thrombosis.

1. Methods

This is a prospective study conducted in 107 consecutive patients(69 women and 38 men; mean age 61.5 +- 15.4 years) diagnosed with acute PE between March and November 2020 in the emergency or other de- partments of Kirikkale University Hospital. The diagnosis of PE was con- firmed by computed tomography pulmonary angiography (CTPA), which was ordered on the basis of symptoms and findings.

There is no systematic use of pretest probability scoring (e.g., Well or

Revised Geneva scores in our center. Many pulmonary CTA examina- tions in our center are ordered by phsician based on clinical suspicion. On the basis of signs and symptoms such as dyspnea, chest pain, hemoptysis,syncope, hypoxia (PaO2 < 80 mmHg),Oxygen desaturation (> 5% decline from baseline) or hypocapnia (PaCO2 < 40 mmHg), S1Q3T3 (Prominent S wave in lead I, Q wave in lead III, and inverted T wave in lead III) on electrocardiogram, Right bundle branch block on electrocardiogram,hypotension (systolic blood pressure < 90 mmHg), increased troponins, Right ventricular dilation on echocardiogram or CT, tachypnea (respiratory rate > 20), and tachycardia (heart rate > 100), PE was suspected and CT angiography was performed [18].

The diagnosis of PE was verified by computed tomography pulmonary angiography (CTPA).

Bilateral lower extremity compression ultrasound with standard

7.5 MHz linear array probe was applied to all patients. The protocol for diagnosing DVT contained compression of the common femoral, superficial femoral, popliteal, and great safeus vein in every 3 cm.Bilat- eral proximal lower extremity veins CUS were performed within 48 h after the diagnosis of PE. The only diagnostic criterion for DVT was vein incompressibility. C-reactive protein,creatinine, D-dimer,ProBNP, RDW,HTC and oxygen saturation were assessed on admission.

The sequential exclusion criteria were applied: preceding anticoagulation therapy,previous PE,bypass,terminal cancer,co-existing trauma and CT findings related to alternative diagnosis, such as, pneu- monia,massive pleural effusion,tumor,significant atelectasis,wide- spread bronchiectasis, extensive emphysema, serious heart failure, chronic parenchymal disease and enlarged mediastinal or hilar lymph nodes, scarring or calcifications or other diagnoses. If it was not second- ary to pleural effusion, was only accepted significant atelectasis. In addi- tion, patients who were PCR positive during the covid 19 pandemic and patients who were radiologically and clinically compatible with covid 19 despite their PCR negative were excluded from the study.

All patients provided written informed consent. The study was approved by local ethics committees(Decision number:06/01- Date: 19.3.2020).

• 1. anticoagulant treatment“>Anticoagulant treatment

Although the study was in strict adherence to a standard protocol, patients were treated similarly. The study monitored the adequacy of the treatment. Typically, patients initially received Therapeutic doses of subcutaneous Low Molecular Weight Heparin. Heparin treatment was discontinued after three months of treatment. 20 mg riveroxoban was started and treatment was continued for three month.

Thrombolytic therapy of acute PE was administered to patients with cardiogenic shock defined as a persistent systolic arterial pressure below 90 mmHg in case of clinical signs of organ hypoperfusion (oliguria,cold and clammy skin,clouded sensorium or lactic acidosis). [6].

Multidetector computed tomography (MDCT).

After injecting 50-75 mL of contrast medium containing high iodine, CT angiograms were obtained with 64-row scanners (MSCT, Philips Medical System, Brillance 64, Best, Netherlands). Imaging was per- formed using the 160-250 HU threshold and bolus tracking technique

in the main pulmonary artery. Images were created at the mediastinal and parenchymal windows at a slice thickness of 1 mm.

• 1. Image analysis

The final consensus of the two chest physicians, who were blinded to the patients’ clinical records, was accepted as the reference standard for the diagnosis of PE. Emboli found in the main or lobar pulmonary arter- ies were classified as central, and those found only in segmental or subsegmental arteries were classified as peripheral. The most proximal location of the PE defined its category (central or peripheral) [19,20].

The diagnostic criteria for acute pulmonary embolism include the following:

• • 1. Complete artery occlusion in which the entire lumen is unenh- anced and the artery can be wider than adjacent open vessels.
    2. A partial fill defect surrounded by Contrast material that pro- duces a “polo mint” mark in images obtained perpendicular to the long axis of a vessel and a “railroad track” mark in longitu- dinal images of the vessel.
    3. Eccentric acute thrombus makes acute angles with the arterial wall.

Peripheral wedge-shaped areas of hyperattenuation that may repre- sent infarcts, along with linear bands, have been demonstrated to be statistically significant ancillary findings associated with acute pulmo- nary embolism.

The diagnostic criteria for Chronic pulmonary embolism include:

1. complete occlusion of a vessel that is smaller than adjacent patent vessels;
2. a peripheral, crescent-shaped intraluminal defect that forms obtuse angles with the vessel wall;
3. contrast material flowing through thickened, often smaller arter- ies due to recanalization (abrupt vessel narrowing can lead to a pulmonary artery stenosis).
4. web or bands within a contrast material-filled artery; and a intimal irregularities.
5. secondary signs, including chronic infarct appearance such as linear band, pleural nodule,poststenotic dilatation,segmental vessel size disparity,tortuous vessels,enlargement of the main pulmonary artery, mosaic perfusion pattern,enlargement of bronchial arteries,enlargement of nonbronchial arteries and pericardial fluid[21-26].

The presence of two or more of the direct radiologic signs was ac- cepted as chronic pulmonary embolism for this study(21). However, cases with almost all CT features of acute pulmonary embolism were accepted as acute pulmonary embolism with chronic features when they also had the features of chronic pulmonary embolism.

• 1. Statistical analyses

Results were defined as frequency and percentage for categorical variables and as mean +- SD for continuous variables.Comparative ana- lyzes for categorical data were performed using Fisher’s exact-test or chi-square test.Differences between groups according to distribution characteristics for continuous variables were compared using t-test or Mann-Whitney U test. P < 0.05 values were evaluated statistically sig- nificant. All statistical analyzes were made with SPSS Statistics software (version 17.0).

1. Results

Mean age of patients with PE with co-existing DVT was higher than those with isolated pulmonary embolism(60.6 +- 17.2 vs

51.2 +- 15.3 years, p = 0.004,respectively), but their Gender distribution (m/f:32.5% vs. 37.3, p = 0.6,respectively) was similar. 67 of 107 (62.6%) patients with PE were isolated pulmonary embolism, and 40 (37.4%) were PE + DVT. Clinical features of PE with co-existing DVT and PE without co-existing DVT is shown in Table 1.

Patients with PE with co-existing DVT compared to those with iso- lated pulmonary embolism have wider pulmonary artery, higher d-dimer and pro BNP level, and lower saturation.

Central pulmonary embolism is more common in patients with deep vein thrombus than those without it. (87.5% (35/40) vs 32.8% (22/67), p = 0.001).

The clinical features of central and peripheral PE are shown in Table 2, when the patients were divided into two according to their lo- cation. The age and gender distribution of patients with central and pe- ripheral embolism was similar. Deep vein thrombus is more common in patients with central pulmonary embolism than in patients with pe- ripheral embolism (61.4% vs. 10%, p = 0.0001) (Figs. 1 and 2). 38.6% of central pulmonary embolism occur without deep vein thrombosis of the lower extremities. As expected,syncope/presyncope in patients with central pulmonary embolism was more common.

5.3% of central pulmonary embolism and 82.0% of peripheral pulmo- nary embolism have CT features of chronic pulmonary embolism.

Table 1

Clinical features of PE with co-existing DVT and PE without co-existing DVT.

Table 2

Clinical features of Central PE and Peripheral PE.

DVT

PE with	PE without	P		Central PE	Peripheral	P
co-existing	co-existing	value			PE	value

DVT

n:57 n:50

	n:40	n:67		Median age, years	56.6	52.6	0.2
Median age, years	60.6	51.2	0.004		+- 17.1	+- 16.0
	+- 17.2	+- 15.3		Male sex %	29.8	42.0	0.1
Male sex %	32.5	37.3	0.6	Cerebral %	17.5	4.0	0.02
Cerebral %	17.5	7.5	0.1	Oncologic %	1.8	0	0.3
Oncologic %	2.5	0	0.1	Heart disease %	12.5	0	0.01
Heart disease %	10.3	4.5	0.2	Chronic kidney disease%	3.5	0	0.1
Chronic kidney disease%	5.0	0	0.06	Dyspnea%	82.5	76.0	0.4
Dyspnea%	77.5	80.6	0.7	Chest pain%	35.1	38.0	0.7
Chest pain%	32.5	38.8	0.5	Syncope/presyncope%	15.8	4.0	0.04
Syncope/presyncope%	20.0	4.5	0.01	Cough%	21.1	40.0	0.03
Cough%	20.0	35.8	0.08	Hemoptysis%	10.5	4.0	0.2
Hemoptysis%	2.5	10.4	0.1	CRP	75.5	29.3	0.001
CRP	75.7	36.0	0.004		+- 68.2	+- 53.9
	+- 70.8	+- 56.6		Creatinine, mg/dL	0.84 +- 0.3	0.79 +- 0.3	0.4
Creatinine, mg/dL	0.91	0.76	0.02	D-dimer, ng/dL	4073.3	665.7	0.0001
	+- 0.36	+- 0.29			+- 4993.9	+- 1176.5
D-dimer, ng/dL	3546.9	1844.6	0.03	negative D-dimer assay%	1.8	62.0	0.0001
	+- 4040.1	+- 4016.1		ProBNP, ng/dL	3578.5	234.0	0.02
ProBNP, ng/dL	4714.3	331.1	0.002		+- 7376.6	+- 469.7
	+- 8388.8	+- 595.7		RDW	16.9 +- 4.1	14.1 +- 1.6	0.0001
RDW	15.9 +- 3.6	15.3 +- 3.4	0.4	HTC	38.7 +- 6.9	42.2 +- 4.8	0.004
HTC	38.5 +- 6.7	41.5 +- 5.7	0.01	Oxygen saturation	90.3 +- 6.9	95.9 +- 1.7	0.0001
Oxygen saturation	89.6 +- 7.1	94.8 +- 4.0	0.0001	Enlarged complete artery occlusion%	96.5	20.0	0.0001
Enlarged complete artery occlusion	87.5	44.8	0.0001	Polo mint %	84.2	8.0	0.0001
Polo mint %	75.0	32.8	0.0001	Railroad track	78.9	4.0	0.0001
Railroad track	67.5	29.9	0.0001	Partial filling defect with acute angle %	96.5	14.0	0.0001
Partial filling defect with acute angle %	87.5	40.3	0.0001	Triangular subpleural consolidation %	49.1	14.0	0.0001
Triangular subpleural consolidation %	40.0	28.4	0.2	Peripheral intraluminal defect obtuse angles	1.8	0	0.3
Peripheral intraluminal defect obtuse angles with the vessel wall	0	1.5	0.4	with the vessel wall Shrunken complete artery occlusion%	3.5	82.0	0.0001
Shrunken complete artery occlusion%	12.5	56.7	0.0001	Thickened, small arteries%	7.0	80.0	0.0001
Thickened, small arteries %	15.0	56.7	0.0001	Poststenotic dilatation %	3.5	36.0	0.0001
Poststenotic dilatation %	7.5	25.4	0.02	Band/web,intimal irregularities %	3.5	28.0	0.0001
Band/web, intimal irregularities %	2.5	22.4	0.005	Tortuous vessel %	0	0
Tortuous vessel %	0	0		Bronchial collaterals %	1.8	2.0	0.9
Bronchial collaterals %	2.5	1.5	0.7	Nonbronchial collaterals %	1.8	0	0.3
Nonbronchial collaterals %	2.5	0	0.1	Unilateral Pleural effusions %	17.5	4.0	0.02
Unilateral pleural effusions %	15.0	9.0	0.3	Bilateral pleural effusions %	15.8	6.0	0.1
Bilateral pleural effusions %	15.0	9.0	0.3	Chronic infarct appearance such as linear	68.4	92.0	0.003
Chronic infarct appearance such as linear band, pleural nodule %	70.0	85.1	0.06	band, pleural nodule % Peripheral parenchymal densities %	7.0	28.0	0.004
Peripheral parenchymal densities %	7.5	22.4	0.04	Variation in the size of segmental vessels %	3.5	4.0	0.8
Variation in the size of segmental vessels %	7.5	1.5	0.1	Pulmonary artery diameter	27.9 +- 3.9	24.9 +- 3.8	0.0001
Pulmonary artery diameter	28.6 +- 4.2	25.2 +- 3.6	0.0001	Bronchial dilatation %	0	2.0	0.2
Bronchial dilatation %	2.5	0	0.1	Mosaic perfusion pattern %	40.4	50.0	0.3
Mosaic perfusion pattern %	42.5	46.3	0.7	Central pulmonary arteries %	75.4	0	0.0001
Central pulmonary arteries %	80.0	16.4	0.0001	Lobar %	24.6	0	0.0001
Lobar %	7.5	16.4	0.1	Segmental %	0	66.0	0.0001
Segmental %	12.5	41.8	0.001	Subsegmental %	0	34.0	0.0001
Subsegmental %	0	25.4	0.001	Unilateral pleural thickening %	0	0
Unilateral pleural thickening %	0	0		Bilateral pleural thickening %	1.8	0	0.3
Bilateral pleural thickening %	0	1.5	0.4	Pericard %	0	0
Pericard %	0	0		Atelectasis %	3.5	6.0	0.5
Atelectasis %	2.5	6	0.4	Infiltration %	10.5	12.0	0.8
Infiltration %	10.0	11.9	0.7	Chronic pulmonary embolism %	5.3	82.0	0.0001
Chronic pulmonary embolism %	15.0	56.7	0.0001	DVT %	61.4	10.0	0.0001

Fig. 1. 50-year-old female patient. Peripheral pulmonary embolism. A. The filling defect in the right lower lobe lateral segment artery (arrow). B. Mosaic perfusion pattern(arrows) in the same patient. Doppler ultrasound: Non-thrombosed varicose dilatations in right vena safena magna were observed.

Patients with PE with co-existing DVT have 42.5% mosaic perfusion pat- tern,70% chronic infarct appearance such as linear band, pleural nodule,

%15.0 thickened, small arteries and, %12.5 shrunken complete artery occlusion, suggesting the chronic background. 15.5% of PE patients with DVT and 56.7% of PE patients without DVT have CT features of chronic pulmonary embolism.

1. Discussion

In present study, 37.4% of patients with PE have proximal DVT. Patients with PE with co-existing DVT have wider pulmonary artery, higher d-dimer and pro BNP level, and lower saturation than those with isolated pulmonary embolism. In addition, in the presence of deep vein thrombosis, 87.5% of pulmonary embolism is in central local- ization. According to this, patients with PE with co-existing DVT is more serious than those without it. In the literature, the reported prevalence of concomitant DVT in patients with PE is highly variable. In previous re- ports, the prevalence of DVT in patients with symptomatic pulmonary embolism ranged from 10% to 93% between studies, depending on the different method used and the different population studied. [4,9-15]. Further, a similar study indicated that in the presence of DVT, PE almost always occurs as a central embolism but the patients with peripheral PE had no coexisting DVT [27]. In two studies by Velmahos and Van Gent,

71-58% of patients with DVT had central PE compared with 33-36% of patients without DVT [18,28]. Similar to our results, a study have shown that in PE patients with coexisting DVT, the embolism is usually in a central location and clinically in the more Severe form of PE. [29].

Patients with PE with co-existing DVT have 42.5% mosaic perfusion pattern,70% chronic infarct appearance such as linear band, pleural nod- ule, %15.0 thickened, small arteries and, %12.5 shrunken complete ar- tery occlusion, which suggests that an acute picture may occur on a chronic background. We could not find information about the presence of chronic CT features in patients with PE with co-existing DVT in the lit- erature. However, in a study to evaluate the prevalence of CTEPH in patients with PE, patients with definitive CTEPH at follow-up had a higher systolic pulmonary artery pressure and at least two signs of CTEPH on the initial CT at the time of PE diagnosis [30].In addition, autopsy-proven, previously untreated, organized thrombus-confirmed PE was shown in 92% of sudden death cases with acute PE 31].According to the authors, information about the natural course of acute PE before a fatal attack is scanty, but in autopsy cases, organized thrombus in the pulmonary artery is pathological evidence of previous PE [31].In the presence of deep vein thrombus, it is important to investigate whether there is a chronic background in acute central pulmonary embolism. In the presence of a chronic basis, the cases should be evaluated with V/Q scintigraphy and echocardiogram at the end of 3 months of treatment in terms of chronic pulmonary embolism.

Fig. 2. 64-year-old female patient. Acute lobar pulmonary embolism with chronic findings such as old infarction sequelae, mosaic perfusion, main PA: 32 mm (arrows). Doppler Ultrasound: Thrombus starting from the iliac bifurcation and extending into the posterior tibial vein.

Important limitation of the current study are relatively small sample size. The relatively small number of patients can make it difficult to ob- tain reliable estimates. Another drawback of the study is that patients were not evaluated by V/Q scintigraphy and echocardiogram. Prospec- tive, multi-center, larger cohort studies are needed to confirm our findings.

In conclusion, patients with PE with co-existing DVT is more serious than those without it.

In the presence of deep vein thrombosis, pulmonary embolism is usually central, but more than one-third of central pulmonary emboli occur without lower extremity deep vein thrombosis. It should be kept in mind that life-threatening pulmonary embolism may occur even if no thrombus is detected in the lower extremity. Failure to detect a thrombus in the lower extremity cannot guarantee that a life- threatening embolism will not develop. An acute picture may be present in the chronic background in a significant proportion of patients with PE with co-existing DVT.

Ethical approval

The study was approved by local ethics committees(Decision num- ber:06/01- Date: 19.3.2020).

Funding

The authors state that this work has not received any funding.

Guarantor

The scientific guarantor of this publication is Dr. Mehmet Ekici.

Statistics and biometry

Dr. Mehmet Ekici has significant statistical expertise.

Informed consent

Written informed consent was obtained from all patients in this study.

Study subjects or cohorts overlap

Some study subjects or cohorts have been previously reported in papers asking different clinical questions:

Sane MA, Laukkanen JA, Graner MA, Piirila PL, Harjola VP, Mustonen PE.Pulmonary embolism location is associated with the co-existence of the deep venous thrombosis. Blood Coagul Fibrinolysis. 2019;30 (5):188-192. doi: 10.1097/MBC.0000000000000813.

Methodology

• prospective
• observational
• performed at one institution

Declaration of Competing interest

The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article.

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