Predictive factors of venous recanalization in upper-extremity vein thrombosis.

BACKGROUND: Upper extremity venous thrombosis (UEVT) represents about 10% of venous thrombo-embolic disease. This is mainly explained by the increasing use of central venous line, for oncologic or nutritional care. The factors associated with venous recanalization are not known.
OBJECTIVE: The aim of this study was to investigate prognosis factor associated with venous recanalization after UEVT.
METHODS: This study included patients with UEVT diagnosed with duplex ultra-sonography (DUS) from January 2015 to December 2017 with DUS evaluations during follow-up. A multivariate Cox proportional-hazards-model analysis was performed to identify predictive factors of UEVT complete recanalization.
RESULTS: This study included 494 UEVT, 304 proximal UEVT and 190 distal UEVT. The median age was 58 years, 39.5% were women. Clinical context was: hematological malignancy (40.7%), solid cancer (14.2%), infectious or inflammatory context (49.9%) and presence of venous catheters or pacemaker leads in 86.4%. The rate of recanalization without sequelae of UEVT was 38%. For all UEVT, in multivariate analysis, factors associated with complete vein recanalization were: thrombosis associated with central venous catheter (CVC) (HR:2.40, [1.45;3.95], p<0.001), UEVT limited to a venous segment (HR:1.94, [1.26;3.00], p = 0.003), occlusive thrombosis (HR:0.48 [0.34;0.67], p<0.0001), the presence of a PICC Line (HR:2.29, [1.48;3.52], p<0.001), a thrombosis of deep and distal topography (HR:1.70, [1.10;2.63], p = 0.02) or superficial thrombosis of the forearm (HR:2.79, [1.52;5.12], p<0.001). For deep and proximal UEVT, non-occlusive UEVT (HR:2.23, [1.49;3.33], p<0.0001), thrombosis associated with CVC (HR:1.58, [1.01;2.47], p = 0.04) and infectious or inflammatory context (HR:1.63, [1.10;2.41], p = 0.01) were factors associated with complete vein recanalization.
CONCLUSION: In this study, factors associated with UEVT recanalization were UEVT limited to a venous segment, thrombosis associated with CVC, a thrombosis of deep and distal thrombosis topography and superficial thrombosis of the forearm. Occlusive thrombosis was associated with the absence of UEVT recanalization.

Introduction

Upper extremity venous thrombosis (UEVT) is an increasingly venous thromboembolic disease (VTED). Today, UEVT represent 10% of all venous thrombosis, whereas it represented 1 to 4% in the 2000s [1, 2]. This is mainly explained by the increasing use of peripherally inserted central catheter -line (PICC-LINE) and of central venous catheter (CVC).

The major UEVT-related diseases and conditions are: venous catheter [3], a solid neoplasia [4], a hematological malignancy [5], a thoracic outlet syndrome (TOS) [6], an estrogenic hormonal impregnation, hereditary or acquired biological thrombophilia (APLS) [7], acute kidney failure or kidney failure requiring dialysis [8] or other situations such as flares of inflammatory diseases [9].

The epidemiology, pathophysiology, treatment and management of UEVT [10], although much less studied than the lower extremities, have long been considered like lower extremity vein thrombosis (LE-VT). However, it is a particular form of VTED: diagnostic elements, clinical features, risk factors and recurrent VTED risks seem different between these two types of thrombosis [11]. UEVT characteristics are poorly known, only a few studies have studied UEVT and they only concerned deep thromboses [12-17]. The factors associated with venous recanalization of UEVT and thrombotic recurrences are also poorly known. Moreover, in patients with chronic diseases such as cancer, it is important to preserve venous capital of the upper limbs to allow treatments administration.

The objective of this study was to describe the predictive factors of venous recanalization in a large cohort of patients with UEVT [5].

Methods

This retrospective and monocentric study included patients with UEVT, diagnosed between January 1, 2015 and December 31, 2017, defined on duplex ultrasonography (DUS) by a hypo or isoechoic endoluminal picture, without Doppler flow, and/or with incompressibility of the vein. UEVT linked to the CVC was defined by a blood clot facing the catheter with blood clot in contact with the vein wall with a length > 5 mm [5].

The included patients had to have had at least one DUS control of the UEVT during follow-up.

The location of UEVT is described according to the most proximal thrombosed venous segment. The innominate, internal jugular, subclavian and axillary veins belong to the deep and proximal venous network. The humeral, ulnar and radial veins belong to the deep and distal network. Cephalic and basilic veins belong to the superficial network.

The data were collected using a standardized collection grid. Minor or major bleeding was defined according to International Society of thrombosis and Hemostasis (ISTH) criteria [18, 19].

Pulmonary embolism (PE) at diagnosis was diagnosed by CT angiography or by pulmonary ventilation scintigraphy between UEVT diagnosis until 14 days before UEVT diagnosis.

At each DUS follow-up, thromboses were categorized as extending, stable or regressing and the absence or the type of venous sequelae (wall thickening> 4mm, persistence of occlusive thrombosis) were recorded.

UEVT sequelae were defined as a persistent occlusive thrombosis, presence of vein synechia with vein wall thickening> 4mm or vein shrinkage.

Patients for whom the computerized medical record was incomplete and isolated superior vena cava thrombosis were excluded.

The study was approved by the ethics committee of Nantes University Hospital (GNEDS) and complies with the requirements of the National Commission for Computing and Liberties, in accordance with current French legislation. Each patient included in this study received written information and no patient objected to this study.

Quantitative values were expressed in terms of counts and percentages. The mean or median comparisons were made using t-test or Mann Whitney test. Frequency comparisons by a Chi square test or a Fisher exact test according to the statistical headcount. Prognostic factors associated with complete UEVT recanalization were evaluated with Cox models. Hazard Ratios (HR) with their 95%CI has been estimated as association measures. Variables with p < 0.05 in univariate model and all the variables already known to be confounding factors were candidate variables for the first multivariate model (manual step by step selection model). Survival curves were estimated with their 95% confidence interval (95%CI) using Kaplan-Maier estimators and Log rank tests were performed to compare complete UEVT recanalization free survival between groups. SAS version 9.4 software was used to perform analyzes.

The data underlying the results presented in the study are available on S1 File.

Results

This study included 494 patients; 304 (61.5%) proximal UEVT and 190 (38.5%) distal UEVT (Fig 1).

Fig 1

Flow chart of patient selection included with UE-VT.

(UEVT: Upper Extremity Venous Thrombosis).

Patient’s and UEVT characteristics and evolution are presented in Table 1. The most frequent solid neoplasia was colonic or bowel cancer (n = 17, 24.3% of solid cancer) and the most frequent hematological malignancy was acute leukemia (n = 101, 50.2% of hematological malignancy); 53 UEVT occurred in a context of renal failure (10.8%) and 3 in patients with inherited thrombophilia (0.6%).

Table 1

Characteristics of UEVT depending on their proximal or distal topography.

Variables	Total Cohort (UEVT) n = 494	Proximal Thrombosis (Proximal-VT) n = 304	Distal Thrombosis (Distal-VT) n = 190	p
Characteristics
Mean Age (years) ±SD	54 ± 18.6	54 ± 19.6	55 ± 17	0.31
Female n (%)	195 (39.5%)	123 (40.5%)	72 (37.9%)	0.58
Infectious or inflammatory context n (%)	212 (42.9%)	129 (42.4%)	83 (43.7%)	0.78
Hematological malignancy n (%)	201 (40.7%)	110 (36.2%)	91 (47.9%)	<0.01
Solid cancer n (%)	70 (14.2%)	56 (18.4%)	14 (7.4%)	<0.001
Thoracic Outlet Syndrome n (%)	12 (2.4%)	10 (3.3%)	2 (1.0%)	0.14
APLS n (%)	6 (1.2%)	3 (1.0%)	3 (1.6%)	0.68
Pregnancy or PostPartum n (%)	5 (1.0%)	2 (0.7%)	3 (1.6%)	0.38
Location of venous thrombosis
Median number of thrombosed segments [Q1;Q3]	1[1;2]	2[1;3]	1[1;2]	<0.0001
Right laterality n (%)	327 (66.2%)	208 (68.4%)	119 (62.6%)	0.19
Bilateral n (%)	9 (1.8%)	7 (2.3%)	2 (1.1%)	0.49
Deep VT n (%)	349 (70.6%)	304 (100%)	45 (23.7%)	<0.0001
Characteristics of the UEVT
Asymptomatic n (%)	60 (12.2%)	50 (16.4%)	10 (5.3%)	0.0002
Endovenous device n (%)	427 (86.4%)	263 (86.5%)	164 (86.3%)	0.95
Occlusive thrombosis n (%)	292 (63.9%)	158 (52.0%)	134 (70.5%)	<0.0001
PE at diagnosis between D-14 and D-0. n (%)	11 (2.2%)	10 (3.3%)	1 (0.5%)	0.06
Treatment of UEVT
Compression n (%)	25 (5.0%)	21 (6.9%)	4 (2.1%)	0.02
Symptomatic local care n (%)	44 (8.9%)	5 (1.6%)	39 (20.5%)	<0.0001
VKA n (%)	72 (15.4%)	59 (19.4%)	13 (7.5%)	0.0003
NOAC n (%)	34 (7.6%)	26 (8.6%)	8 (4.6%)	0.09
Therapeutic LMWH n (%)	336 (71.8%)	213 (72.2%)	123 (71.1%)	0.80
UFH n (%)	49 (10.5%)	38 (12.5%)	11 (6.4%)	<0.0001
Prophylactic LMWH n (%)	45 (9.6%)	8 (2.6%)	37 (21.4%)	<0.0001
Follow Up
Median follow-up time (days) [Q1-Q3]	46 [29–90]	59 [31–104]	42 [22–57]	<0.0001
Recanalization without venous sequelae n (%)	188 (38.0%)	109 (35.9%)	79 (41.6%)	0.001
Major Bleeding n (%)	25 (5.0%)	14 (4.6%)	11 (5.6%)	0.45
Minor Bleeding n (%)	19 (3.2%)	14 (4.6%)	5 (2.7%)	0.53
PE within 3 months n (%)	10 (2.0%)	8 (2.6%)	2 (1.1%)	0.37
Death within 3 months n (%)	39 (7.9%)	23 (7.6%)	16 (8.4%)	0.10

(APLS: Antiphospholipid syndrome. NOAC: non-vitamin k antagonist oral anti-coagulants. LMWH: Low Molecular-Weight Heparin. PE: Pulmonary Embolism. SD: Standard Derivation. UE: Upper Extremity. UFH: UnFractionned Heparin. VKA: Vitamin K Antagonists. VT: Vein Thrombosis).

Regarding the presence of an endovenous device, the most frequent devices were PICC-LINE (n = 177, 41.5% of the devices); peripheral venous catheter (PVC) (n = 66, 15.5%); CVC (n = 64, 15.0%); implantable ports (n = 57, 13.4%); dialysis catheters (n = 31, 7.3%); Pace-Maker (PM) and implantable cardioverter defibrillator (n = 13, 3.1%) and MIDLINE (n = 11, 2.6%). Regarding the topography of UEVT, 90 thromboses (18.2%) affected both deep and superficial veins, 112 thromboses (22.6%) the superficial veins of the arm and 73 (14.8%) thrombosis exclusively forearm veins. The most proximal thrombosed segments were the innominate veins (n = 106, 21.5%), the internal jugular veins (n = 84, 17.0%), the brachial basilic veins (n = 70, 14, 2%), subclavian veins (n = 67, 13.6%), axillary veins (n = 47, 9.5%), humeral veins (n = 45, 9.1%), brachial cephalic veins (n = 42, 8.5%), antebrachial cephalic veins (n = 26, 5.3%) and the antebrachial basilic veins (n = 7, 1.4%).

Regarding treatments, two patients had angioplasties without stenting, three angioplasties with stenting and a pharmaco-mechanical thrombectomy.

Major and minor Bleedings occurred during follow-up in 44 cases respectively in 25 (5.0%) and in 19 (3.2%) patients; the median times after UEVT were 16 and 30 days respectively.

Two deaths were considered to be related to UEVT (0.4%): none related to PE and 2 related to major bleedings under anticoagulant therapy. A 73-year-old man with gallbladder cancer treated with therapeutic LMWH who have gastrointestinal bleeding and a 49-year-old woman postoperatively after cardiac surgery with ECMO under therapeutic LMWH who have a fatal intracerebral hemorrhage. Neither of these two patients had an over dosage of LMWH.

After UEVT, 469 (94.9%) patients had anticoagulant treatment, 336 (71.8%) had therapeutic LMWH (tinzaparin 175 IU/kg/d, enoxaparin 100 IU/kg twice daily), 45 (9.6%) had prophylactic LMWH (enoxaparin 4,000 IU/d), 34 (6.9%) had NOAC (33 rivaroxaban 20mg/d, 1 apixaban 5mg twice daily) and 72 (14.6%) had VKA. Twenty-five cases remained untreated due to thrombocytopenia <20G/l or bleeding complications. The catheter was removed in 327 (66.2%) cases. The median duration of anticoagulant treatment was 45 days for both patients with hematological malignancies and patients with solid neoplasia. There was no significant difference in the duration of anticoagulant treatment compared to patients without hematological malignancies (p = 0.27) and without solid neoplasia (p = 0.34). The median treatment duration was 77.5 days for deep and proximal UEVT while it was 45.0 days for other UEVT (p<0.0001). For patients with UEVT and a central catheter (PICC line, implantable port, CVC or dialysis catheter), the median treatment duration was 45.0 days for both patients with catheter removal and patients with catheter continuation (p = 0.30).

The median time to UEVT recanalization was 100 days; venous occlusion was persistent in 96 (19.4%) at the end of follow-up and 210 (42.5%) had venous recanalization with sequelae. Median recanalization was 43 days [21–85 days] for the 188 (38%) UEVT without sequelae.

Survival with complete UEVT recanalization was significantly different between proximal and distal UEVT (log rank p = 0.001) (Fig 2).

Fig 2

Survival curve of venous patency without sequelae according to UEVT topography.

The percentages of repermeabilization are expressed according to the number of patients still followed at the time of repermeabilization (VT: Venous Thrombosis).

The multivariate Cox model analysis of factors associated with UEVT recanalization without sequelae is presented in Table 2. Anticoagulant treatment durations were not included in the multivariate analysis since treatment was most often continued if the veins were not recanalized. Fig 3 presents survival curves of venous recanalization without sequelae according to duration of anticoagulant treatment. Patients who received anticoagulant treatment for less than 90 days had significantly more venous recanalization without sequelae than patients treated for more than 90 days (p<0.0001).

Table 2

Cox analysis of factors associated with patency of UEVT without sequelae.

Variable	Univariate analysis				Multivariate analysis (recanalization factors without sequelae) n = 457
	Without Sequelae n = 188	With Sequelae n = 306	HR [95IC]	p	HR [95IC]	p
Characteristics
Mean age (years) ±SD	54 ± 18.6	55 ± 18.7	1 [0.99; 1.01]	0.82	-	-
Female n (%)	81 (43.1%)	114 (37.2%)	1.3 [0.99; 1.77]	0.06	†
Infectious or inflammatory context n (%)	91 (48.4%)	121 (39.5%)	1.56 [1.17; 2.08]	<0.01
Solid Cancer n (%)	18 (9.6%)	52 (17.0%)	0.64 [0.39; 1.04]	0.07	-	-
Hematological malignancy n (%)	94 (50.0%)	107 (35.0%)	1.29 [0.97; 1.71]	0.08	-	-
AVF n (%)	1 (0.5%)	11 (3.6%)	0.13 [0.02; 0.90]	0.04	-	-
VT location
Distal UEVT n (%)	79 (42.0%)	111 (36.3%)	1.62 [1.21; 2.18]	0.001	-	-
Superficial VT of forearm n (%)	28 (14.9%)	45 (14.7%)	1.34 [0.89; 2.01]	0.16	2.79 [1.52; 5.12]	<0.001
Superficial VT of arm n (%)	78(41.5%)	122(39.9%)	0.96 [0.72;1.28]	0.77	0.89 [0.57; 1.38]	0.60
Deep and distal VT n (%)	51 (27.1%)	51 (16.7%)	1.31 [0.95; 1.81]	0.10	1.70 [1.10; 2.63]	0.02
Deep and proximal VT n (%)	109(58.0%)	195(63.7%)	0.62 [0.46; 0.83]	0.001	0.80 [0.50; 1.31]	0.38
VT characteristics
Occlusive VT n (%)	87 (50.9%)	205 (71.7%)	0.41 [0.27; 0.62]	<0.0001	0.48 [0.34; 0.67]	<0.0001
Short thrombosis (one segment) n (%)	108 (57.4%)	159 (52.0%)	1.8 [1.34; 2.40]	<0.0001	1.94 [1.26; 3.00]	0.003
Endovenous devices n (%)	165 (87.8%)	255 (83.3%)	1.61 [1.01; 2.57]	0.05	-	-
PICC LINE n (%)	87 (46.3%)	90 (29.4%)	1.55 [1.17; 2.07]	0.03	2.29 [1.48; 3.52]	<0.001
CVC n (%)	29 (15.4%)	35 (11.4%)	1.5 [1.01; 2.23]	0.05	2.40 [1.45; 3.95]	<0.001
Treatment
Venous compression n (%)	8 (4.3%)	17 (5.6%)	0.46 [0.23; 0.95]	0.04	-	-
Anticoagulant treatment	183 (97.3%)	286 (93.5%)	0.68 [0.28; 1.67]	0.40	-	-
Prophylactic LMWH	19 (10.1%)	26 (8.5%)	1.31 [0.81; 2.10]	0.27	-	-
VKA n (%)	22 (12.1%)	50 (17.5%)	0.59 [0.38; 0.92]	0.02	-	-
Treatment median (days) [Q1;Q3]	45 [45; 90]	60 [45; 90]	0.98 [0.98; 0.99]	<0.0001	-	-

(AVF: Arterio-Venous Fistula, CI: confidence interval, CVC: Central Venous Catheter, HR: Hazard Ratio, LMWH: low molecular weight heparin, PICCLINE: Peripherally Inserted Central Catheter–Line, SD: Standard Derivation, UE: Upper Extremity, VKA: Vitamin K Antagonist, VT: Venous Thrombosis).

†The female gender is a predictive factor for venous patency without sequelae if the context was infectious or inflammatory (HR: 2.02 [1.31; 3.12], p = 0.04).

Fig 3

Survival curves of venous recanalization without sequelae according to duration of anticoagulant treatment.

The multivariate Cox model analysis of factors associated with deep and proximal UEVT recanalization without sequelae is presented in Table 3. In this group of proximal vein thromboses, non-occlusive UEVT, thrombosis associated with CVC and infectious or inflammatory context were associated with UEVT recanalization without sequelae.

Table 3

Cox analysis of factors associated with vein patency of deep and proximal UEVT.

Variable	Univariate analysis				Multivariate analysis (recanalization factors without sequelae) n = 289
	Without Sequelae n = 109	With Sequelae n = 195	HR [95IC]	p	HR [95IC]	p
Characteristics
Mean age (years) ±SD	51.7±20.0	54.8±19.4	1.0 [0.99; 1.01]	0.55	-	-
Female n (%)	49 (45.0%)	74 (38.0%)	0.73 [0.50; 1.07]	0.11	-	-
Infectious or inflammatory context n (%)	55 (50.5%)	74 (38.0%)	1.90 [1.30; 2.77]	<0.001	1.63 [1.10; 2.41]	0.01
Solid Cancer n (%)	14 (12.8%)	42 (21.5%)	0.69 [0.39; 1.21]	0.20	-	-
Hematological malignancy n (%)	48 (44.0%)	62 (31.8%)	1.11 [0.76; 1.62]	0.60	-	-
AVF n (%)	1 (0.9%)	4 (2.1%)	0.34 [0.05; 2.45]	0.29	-	-
VT characteristics
Non-occlusive VT n (%)	42 (40.4%)	116 (62.7%)	0.40 [0.27; 0.59]	<0.0001	2.23 [1.49; 3.33]	<0.0001
Short thrombosis (one segment) n (%)	54 (49.5%)	76 (39.0%)	1.94 [1.33; 2.89]	<0.001	-	-
Endovenous devices n (%)	98 (89.9%)	162 (83.1%)	1.86 [0.99; 3.47]	0.05	-	-
PICC LINE n (%)	42 (38.5%)	51 (26.1%)	1.33 [0.9; 1.96]	0.15	-	-
CVC n (%)	29 (26.6%)	35 (18.0%)	1.94 [1.26; 2.97]	0.002	1.58[1.01; 2.47]	0.04

AVF: Arterio-Venous Fistula, CI: confidence interval, CVC: Central Venous Catheter, HR: Hazard Ratio, LMWH: low molecular weight heparin, PICCLINE: Peripherally Inserted Central Catheter–Line, SD: Standard Derivation, VT: Venous Thrombosis.

Only 92 UEVT patients were evaluated for post-thrombotic syndrome of upper limbs. Thirteen of these patients (14.1%) had upper extremity post-thrombotic syndrome (UE-PTS) with modified Villalta score ≥4. In 12 (92.3%) cases of UE-PTS, there was a history of deep vein thrombosis.

Discussion

To our knowledge, this is the first study investigating venous recanalization of UEVT in a large cohort of 494 UEVT. This study showed that clinical context, the type and topography of the thrombosis and the presence of central catheter were associated with recanalization after UEVT. The rate of recanalization without sequelae of UEVT was low (38%) with a median time to recanalization of 43 days.

Forearm superficial-VT (cephalic and basilic veins); deep and distal UEVT, VT affecting only one venous segment and non-occlusive UEVT were factors associated with total recanalization in this study. These better rates of recanalization without sequelae could be explained by the lower thrombus volume in these situations, allowing faster and more efficient thrombus lysis. In contrast, Proximal-VT occurring in larger veins with a larger thrombus would have lower rates of recanalization without sequelae.

Female gender associated with the occurrence of thrombosis in an acute context of infection or inflammation was also a factor associated with better recanalization without sequelae. In contrast, the occurrence of UEVT in a context of solid neoplasia was associated with a lower rate of recanalization. A provoked, transient, modifiable context would logically appear as a factor associated with better recanalization: the disappearance of the transient factor would allow a reduction in pro-thrombotic factors allowing better recanalization. The transient nature is also important for catheter-related thrombosis: PICCLINE and CVC were associated with recanalization rates without sequelae higher than in situations where endovenous device was present for a prolonged period. The larger the volume occupied by the catheter in vein lumen, the greater the risk of thrombosis [20], but, in UEVT with endovenous devices, first volume of thrombus is lower and secondly the withdrawal of the catheter would allow the restoration of a greater blood flow and therefore the return to rheological parameters conducive to recanalization. In the case of pace-makers, their removals are rare even in the event of thrombosis, which does not allow the removal of the pro-thrombotic factors necessary for optimal recanalization.

The occurrence of bleeding under anticoagulant therapy, PE or death did not modify venous recanalization in this study. The occurrence of these events is mainly related to the patient’s comorbidities [5] but do not directly impact on recanalization.

Topographically, there are similarities between recanalization of LE-VT and UEVT with better recanalization rates in LE-VT affecting only distal and deep segments are described [21]. The female sex also appears to be a factor of better recanalization [22], as well as the absence of comorbidity [23]. The use of NOAC has been shown to be a better treatment than VKA for venous recanalization after deep LE-VT [24]. However, this study does not allow us to compare this result. D-dimer analysis was not performed in our study, yet this biological endpoint associated with the persistence of ultrasound venous sequelae appeared to be a reliable marker for predicting the occurrence of VTED recurrence after deep LE-VT [25].

The limits of this work come from its retrospective design, resulting in a lack of exhaustiveness in the DUS follow-up. Moreover, in this study several factors influenced the duration of anticoagulant treatment, which depended on the practice of each physician, on the presence of active cancer and had little relationship to catheter removal. The topography of venous thrombosis, catheter removal, the presence of active cancer and the presence of venous recanalization on ultrasound controls [26] were the main factors taken into account. Thus, it was difficult to evaluate the role of anticoagulation duration on venous recanalization in this study because this duration was influenced by venous recanalization. The use of VKA, venous compression or long-term anticoagulation treatment were factors associated with the absence of recanalization without sequelae but there is a bias because in this study anticoagulation was most often maintained in the event of persistent sequelae.

Patients with UEVT frequently have thromboses on catheters necessary for their oncologic management. However, in these patients, bleeding risks are high, it is necessary to carry out prospective studies on optimal duration of anticoagulation. Conversely, when the thrombosis occurs with a transient risk factor, shorter anticoagulant treatment could be considered once the factor has resolved, a fortiori, if the thrombosis involves only a venous segment, and it is non-occlusive; again prospective studies are needed.

Conclusion

In a study on a large cohort of UEVT, the rate of recanalization without sequelae of UEVT was low (38%) with a median time to recanalization of 43 days. The factors significantly associated with recanalization without sequelae were non-occlusive vein thrombosis, UEVT affecting only one segment venous, UEVT associated with PICCLINE or CVC, a superficial thrombosis of the forearm and a deep distal UEVT and female sex in infectious or inflammatory transient context. For deep and proximal UEVT, non-occlusive UEVT, thrombosis associated with CVC and infectious or inflammatory context were factors associated with complete vein recanalization.

Prospective studies in UEVT are needed to assess VTED recurrence, bleeding, venous recanalization and post-thrombotic syndromes.

(XLSX)

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17 Mar 2021

PONE-D-21-05068

Predictive factors of venous recanalization in upper-extremity vein thrombosis.

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**********

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Reviewer #1: I have a number of questions regarding this manuscript:

1. In the abstract, in line 47, occlusive thrombus is associated with complete recanalization (HR 0.48). Then in the conclusion, it states that the “absence of occlusive thrombus” as one of the factors associated with UEVT recanalization. I understand since the HR is 0.48 that the negative of occlusive thrombus is the factor associated with complete recanalization, but I must say it is initially confusing to have it say “occlusive thrombus” in the Results and then the “absence of occlusive thrombosis” in the Conclusion. Can the authors please be consistent in their wording?

2. In the Abstract in line 44, what is the meaning of the term “presence of endovascular material in 86.4%”? Is this scar tissue within the vein from a previous DVT? Is so, then the authors should state this rather than the non-descript terminology they use.

3. On page 4, line 68, when is kidney failure non-serious? I would remove the word serious in front of kidney failure, or change to….kidney failure requiring dialysis.

4. On page 5, line 87, what does the term …” adherent thrombus whose major axis was >5 mm” mean?

5. Can the authors be more complete in the description of the two patients who died “related to major bleedings under anticoagulant therapy” on page 8, lines 158-159? What anticoagulant were they on, where was the bleeding, etc.? This is an important piece of information that they should share with the readers.

6. I was surprised on page 9, line 171-172 that the median treatment time was the same for patients with UEVT and a central catheter who had both catheter continuation and catheter removal. I would expect that with catheter continuation, anticoagulation would have remained intact and not stopped, while with catheter removal, anticoagulation could more readily stop. Can the authors please explain this?

7. I would have expected that an important finding from this study is that the rate of recanalization without squeal of UEVT was low (38%) with a median time to recanalization of 43 days, as reported in the first sentence of the Conclusion. Why is this not included in the abstract? Why is this fact buried in the middle of the Results (page 9, line 175)?

8. Finally, I am concerned about mixing superficial thrombosis in with DVT in this study? Not only are they different entities with different treatment modalities, they are called by different names in the paper…..” superficial thrombosis of the forearm” in the Abstract and “superficial forearm UEVT” in the Conclusion. This is confusing on multiple levels. Would the authors consider moving superficial thrombosis out of the paper, or separating this away from DVT?

**********

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Reviewer #1: No

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8 Apr 2021

Dear Editor,

Please find enclosed a revised manuscript entitled “Predictive factors of venous recanalization in upper-extremity vein thrombosis” for submission to your journal.

All the remarks were taken into account. The answers are detailed in the response to the reviewer file.

Sincerely

Dr Olivier Espitia

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Manuscript has been changed, now it respects PLOS ONE style.

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Manuscript has been changed; ethics statement should only appear in the Methods section.

5. We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed:

- https://journals.lww.com/md-journal/Fulltext/2020/02070/A_STROBE_cohort_study_of_755_deep_and_superficial.27.aspx

The text that needs to be addressed involves the Introduction.

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

Introduction has been changed.

Additional Editor Comments:

The manuscript is potentially interesting but some revisions are needed.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

________________________________________

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

________________________________________

3. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

________________________________________

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Reviewer #1: No

Manuscript has been changed and native English speaker reviewed the manuscript.

________________________________________

5. Review Comments to the Author

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Reviewer #1: I have a number of questions regarding this manuscript:

1. In the abstract, in line 47, occlusive thrombus is associated with complete recanalization (HR 0.48). Then in the conclusion, it states that the “absence of occlusive thrombus” as one of the factors associated with UEVT recanalization. I understand since the HR is 0.48 that the negative of occlusive thrombus is the factor associated with complete recanalization, but I must say it is initially confusing to have it say “occlusive thrombus” in the Results and then the “absence of occlusive thrombosis” in the Conclusion. Can the authors please be consistent in their wording?

Abstract has been changed: Occlusive thrombosis was associated with the absence of UEVT recanalization.

2. In the Abstract in line 44, what is the meaning of the term “presence of endovascular material in 86.4%”? Is this scar tissue within the vein from a previous DVT? Is so, then the authors should state this rather than the non-descript terminology they use.

Endovascular material referred to venous catheter or pacemaker leads. Changes have been made in the manuscript.

3. On page 4, line 68, when is kidney failure non-serious? I would remove the word serious in front of kidney failure, or change to….kidney failure requiring dialysis.

Serious has been deleted and replaced by acute kidney failure or kidney failure requiring dialysis.

4. On page 5, line 87, what does the term …” adherent thrombus whose major axis was >5 mm” mean?

We have clarified the definition of venous blood clot and modified the sentence: UEVT linked to the CVC was defined by a blood clot facing the catheter with blood clot in contact with the vein wall with a length > 5 mm

5. Can the authors be more complete in the description of the two patients who died “related to major bleedings under anticoagulant therapy” on page 8, lines 158-159? What anticoagulant were they on, where was the bleeding, etc.? This is an important piece of information that they should share with the readers.

Indeed, it’s interesting data. These two patients are now described in the manuscript. They had therapeutic LMWH, none had over dosage.

“Two deaths were considered to be related to UEVT (0.4%): none related to PE and 2 related to major bleedings under anticoagulant therapy. A 73-year-old man with gallbladder cancer treated with therapeutic LMWH who have gastrointestinal bleeding and a 49-year-old woman postoperatively after cardiac surgery with ECMO under therapeutic LMWH who have a fatal intracerebral hemorrhage. None had LMWH over dosage.”

6. I was surprised on page 9, line 171-172 that the median treatment time was the same for patients with UEVT and a central catheter who had both catheter continuation and catheter removal. I would expect that with catheter continuation, anticoagulation would have remained intact and not stopped, while with catheter removal, anticoagulation could more readily stop. Can the authors please explain this?

I agree with you about the duration of anticoagulation which was the same depending on whether the catheter was removed or not.

However, there are several factors that explain this lack of difference. On the one hand, the duration of anticoagulation treatment was not standardized and depended on the practice of each physician taking care of these patients. On the other hand, many of these patients had active neoplasia at the time of thrombosis, and the anticoagulant treatments were therefore prolonged because of active treatment of the cancer, whether the catheter was removed or not.

Changes have been made in the manuscript in limits section page 13 line 247.

7. I would have expected that an important finding from this study is that the rate of recanalization without squeal of UEVT was low (38%) with a median time to recanalization of 43 days, as reported in the first sentence of the Conclusion. Why is this not included in the abstract? Why is this fact buried in the middle of the Results (page 9, line 175)?

I thank the reviewer for this remark, I fully agree. We have put forward this data which is now quoted in the abstract and in the first part of the conclusion.

8. Finally, I am concerned about mixing superficial thrombosis in with DVT in this study? Not only are they different entities with different treatment modalities, they are called by different names in the paper…..” superficial thrombosis of the forearm” in the Abstract and “superficial forearm UEVT” in the Conclusion. This is confusing on multiple levels. Would the authors consider moving superficial thrombosis out of the paper, or separating this away from DVT?

We understand the comment made by the reviewer, but this study analyzed all the venous thromboses of the upper limbs, which have never been reported before. It analyzed numerous venous territories: deep and proximal, deep and distal, superficial of the arm and forearm.

However, we agree with the reviewer's opinion on proximal venous thrombosis because of a daily clinical problem. Thus, we performed in 304 patients’ new analyses on the factors associated with venous recanalization studying only deep and proximal venous thrombosis with cox model.

We performed a univariate analysis presented in Table 3 and then a multivariate analysis with a stepwise selection. We started with 6 variables: presence of a central venous catheter, infectious context, number of thrombosed venous segments, context of neoplasia, non-occlusive thrombosis, and sex. The final analysis is presented in Table 3. The presence of a central venous catheter, infectious context, and non-occlusive thrombosis were factors associated with venous recanalization.

I our opinion, data on distal thromboses are also interesting; as there is very little data on superficial vein thrombosis of the upper limbs, we wish to present these data in the manuscript, to better understand the factors associated with their recanalization. Thus, in time, their treatments could be better codified.

It is important to differentiate distal veins of the arm, particularly the basilic veins and the humeral veins, which are frequently used for PICC Line placement, and superficial veins of the forearm which are very often punctured for blood sampling.

We have clarified these notions in the manuscript. When analyzing the factors associated with recanalization, it was only superficial forearm venous thrombosis and not superficial arm venous thrombosis.

Changes have been made in the manuscript and superficial thrombosis of the forearm is now the only formulation used in the manuscript.

Submitted filename: response to reviewers.docx

Click here for additional data file.

15 Apr 2021

PONE-D-21-05068R1

Predictive factors of venous recanalization in upper-extremity vein thrombosis.

PLOS ONE

Dear Dr. Espitia,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The manuscript now sounds good. There are some minor revisions before final acceptance.

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Prof. Raffaele Serra, M.D., Ph.D

Academic Editor

PLOS ONE

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Additional Editor Comments (if provided):

The manuscript is substantially improved. There are only minor revisions now.

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Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

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Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I have two additional comments for the authors.

1. On page 9, line 167 in the revised final version, please change "None had LMWH over dosage" to "Neither of these two patients had an over dosage of LMWH".

2. On page 13, line 248 in the revised final version, please change the abbreviation "PM" to what it actually means.

**********

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Reviewer #1: No

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15 Apr 2021

Dear Editor,

Please find enclosed a revised manuscript entitled “Predictive factors of venous recanalization in upper-extremity vein thrombosis” for submission to your journal.

All the remarks were taken into account. The answers are detailed in the response to the reviewer file.

Sincerely

Dr Olivier Espitia

Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I have two additional comments for the authors.

1. On page 9, line 167 in the revised final version, please change "None had LMWH over dosage" to "Neither of these two patients had an over dosage of LMWH".

The changes have been made in the manuscript.

2. On page 13, line 248 in the revised final version, please change the abbreviation "PM" to what it actually means.

PM means pace-maker, the abbreviation has been changed in the manuscript.

Submitted filename: R2 response to reviewers.docx

Click here for additional data file.

23 Apr 2021

Predictive factors of venous recanalization in upper-extremity vein thrombosis.

PONE-D-21-05068R2

Dear Dr. Espitia,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Raffaele Serra, M.D., Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Amended manuscript is acceptable.

Reviewers' comments:

27 Apr 2021

PONE-D-21-05068R2

Predictive factors of venous recanalization in upper-extremity vein thrombosis.

Dear Dr. Espitia:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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on behalf of

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PLOS ONE