Systematic assessment of venous thromboembolism in COVID-19 patients receiving thromboprophylaxis: incidence and role of D-dimer as predictive factors

Abstract

Coagulopathy in COVID-19 is a burning issue and strategies to prevent thromboembolic events are debated and highly heterogeneous. The objective was to determine incidence and risk factors of venous thromboembolism (VTE) in COVID-19 inpatients receiving thromboprophylaxis. In this retrospective French cohort study, patients hospitalized in medical wards non-ICU with confirmed COVID-19 and adequate thromboprophylaxis were included. A systematic low limb venous duplex ultrasonography was performed at hospital discharge or earlier if deep venous thrombosis (DVT) was clinically suspected. Chest angio-CT scan was performed when pulmonary embolism (PE) was suspected. Of 71 patients, 16 developed VTE (22.5%) and 7 PE (10%) despite adequate thromboprophylaxis. D-dimers at baseline were significantly higher in patients with DVT (p < 0.001). Demographics, comorbidities, disease manifestations, severity score, and other biological parameters, including inflammatory markers, were similar in patients with and without VTE. The negative predictive value of a baseline D-dimer level < 1.0 µg/ml was 90% for VTE and 98% for PE. The positive predictive value for VTE was 44% and 67% for D-dimer level ≥ 1.0 µg/ml and ≥ 3 µg/ml, respectively. The association between D-dimer level and VTE risk increased by taking into account the latest available D-dimer level prior to venous duplex ultrasonography for the patients with monitoring of D-dimer. Despite thromboprophylaxis, the risk of VTE is high in COVID-19 non-ICU inpatients. Increased D-dimer concentrations of more than 1.0 μg/ml predict the risk of venous thromboembolism. D-dimer level-guided aggressive thromboprophylaxis regimens using higher doses of heparin should be evaluated in prospective studies.

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Vol.:(0123456789)
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Journal of Thrombosis and Thrombolysis (2020) 50:211–216
https://doi.org/10.1007/s11239-020-02146-z
Systematic assessment ofvenous thromboembolism inCOVID‑19
patients receiving thromboprophylaxis: incidence androle ofD‑dimer
aspredictive factors
MathieuArtifoni1· GwenvaelDanic1· GiovanniGautier1· PascalGicquel2· DavidBoutoille3,4· FrançoisRa3,4·
AntoineNéel1,5· RaphaëlLecomte3,4
Published online: 25 May 2020
© Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract
Coagulopathy in COVID-19 is a burning issue and strategies to prevent thromboembolic events are debated and highly het-
erogeneous. The objective was to determine incidence and risk factors of venous thromboembolism (VTE) in COVID-19
inpatients receiving thromboprophylaxis. In this retrospective French cohort study, patients hospitalized in medical wards
non-ICU with confirmed COVID-19 and adequate thromboprophylaxis were included. A systematic low limb venous duplex
ultrasonography was performed at hospital discharge or earlier if deep venous thrombosis (DVT) was clinically suspected.
Chest angio-CT scan was performed when pulmonary embolism (PE) was suspected. Of 71 patients, 16 developed VTE
(22.5%) and 7 PE (10%) despite adequate thromboprophylaxis. D-dimers at baseline were significantly higher in patients
with DVT (p < 0.001). Demographics, comorbidities, disease manifestations, severity score, and other biological parameters,
including inflammatory markers, were similar in patients with and without VTE. The negative predictive value of a baseline
D-dimer level < 1.0µg/ml was 90% for VTE and 98% for PE. The positive predictive value for VTE was 44% and 67% for
D-dimer level ≥ 1.0µg/ml and ≥ 3µg/ml, respectively. The association between D-dimer level and VTE risk increased by
taking into account the latest available D-dimer level prior to venous duplex ultrasonography for the patients with monitor-
ing of D-dimer. Despite thromboprophylaxis, the risk of VTE is high in COVID-19 non-ICU inpatients. Increased D-dimer
concentrations of more than 1.0μg/ml predict the risk of venous thromboembolism. D-dimer level-guided aggressive throm-
boprophylaxis regimens using higher doses of heparin should be evaluated in prospective studies.
Keywords Venous thromboembolism· Pulmonary embolism· D-dimer· COVID-19
Highlights
• The incidence of venous thromboembolism (VTE) in
non-ICU COVID-19 patients with thromboprophylaxis
is unknown.
• Consecutive COVID-19 inpatients had systematic venous
duplex ultrasonography at discharge.
• Of the 71 patients included, 16 developed VTE (22.5%)
and 7 pulmonary embolisms (PE) (10%). The negative
predictive value of baseline D-dimer level <1.0 µg/ml
was 90% for VTE, 98% for PE.
• D-dimer level-guided aggressive thromboprophylaxis
regimens using higher doses of heparin should be evalu-
ated in prospective studies.
* Raphaël Lecomte
raphael.lecomte@chu-nantes.fr
1 Service de Médecine Interne, CHU de Nantes,
44093Nantes, France
2 Service de Médecine Polyvalente, CH de Châteaubriant,
44110Châteaubriant, France
3 Service de Maladies Infectieuses et Tropicales, CHU de
Nantes, 44093Nantes, France
4 CIC UIC 1413 INSERM, CHU de Nantes, 44093Nantes,
France
5 Faculté de Médecine, Université de Nantes, 44093Nantes,
France

212 M.Artifoni et al.
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Introduction
Since the first cases reported in Wuhan in December 2019,
coronavirus disease 2019 (COVID-19) has contributed to
significant mortality worldwide [1]. Coagulopathy is fre-
quently reported [1, 2] and elevated D-dimer is a significant
poor prognosis factor [3, 4]. Moreover, some authors have
suggested a particularly high frequency of thromboembolic
events, including fatal pulmonary embolism [5]. Use of hep-
arin was associated with reduced mortality in COVID-19
patients, suggesting that thromboembolism prophylaxis is
critical in the management of COVID-19 [6–8]. The Inter-
national Society of Thrombosis and Haemostasis has recom-
mended systematic pharmacological thromboprophylaxis in
all patients who require hospital admission for COVID-19
[9]. However, the incidence of venous thromboembolism in
patients hospitalized for COVID-19 is unclear, particularly
under thromboprophylaxis. Whether some clinico-biological
parameters could predict venous thromboembolism risk and
guide thromboprophylaxis management is also unknown.
The objectives of the study were to determine the frequency
and to identify predictive factors of venous thromboembo-
lism in COVID-19 inpatients receiving pharmacological
thromboprophylaxis.
Methods
Study population
In this retrospective cohort study, all consecutive patients
with confirmed COVID-19 hospitalized for more than 48h
in two French centers (Nantes University Hospital and Châ-
teaubriant Hospital) were screened between March 25, 2020
and April 10, 2020. Inclusion criteria were age > 18years
and adequate thromboprophylaxis and available low limb
venous duplex ultrasonography. Exclusion criteria were
previous anticoagulation and contraindication to thrombo-
prophylaxis. A confirmed case of COVID-19 was defined
as a positive result on real-time reverse-transcriptase–poly-
merase-chain-reaction assay of nasopharyngeal swab speci-
mens for SARS-CoV-2 or typical pattern on chest CT-scan
[10]. Thromboprophylaxis was considered adequate if it was
implemented within 24h of hospital admission, included
daily administration of weight-appropriate enoxaparin
following institutional recommendations (40mg/day for
BMI < 30kg/m2, 60mg/day for BMI 30 to 40kg/m2 and
40mg twice daily for BMI > 40 kg/m2) and covered the
whole hospital stay.
Data collection
Relevant data were extracted from electronic health records
using a standardized form. The study was performed in
accordance with French legislation (articles L.1121–1 par-
agraph 1 and R1121-2, Public health code) and Helsinki
Declaration.
Outcome measures
All patients were systematically examined for deep-vein
thrombosis by low limb venous duplex ultrasonography at
hospital discharge or earlier if thrombosis was clinically
suspected. Chest angio-CT scan was performed in case of
suspicion of pulmonary embolism.
Statistical analysis
Data were expressed as number (percentage) or median
(IQR), except otherwise indicated. Frequency comparisons
were performed using Fischer Exact t test. Quantitative vari-
ables were compared using Mann–Whitney test. To estimate
the correlation between two variables, a Spearman’s test was
used. Data were analyzed using GraphPad Prism version 5.
All tests were two-sided, with p-values < 0.05 considered as
statistically significant.
Results
Study population
Between March 25th and April 10th 2020, 133 COVID-19
inpatients were managed in the centers. Sixty-two patients
were excluded: 1 died, 17 were transferred to intensive care
unit, 5 were discharged early (< 48h), 9 received oral anti-
coagulant, 21 were discharged without duplex ultrasonogra-
phy, and 9 were not yet discharged. Seventy-one patients had
a duplex ultrasonography before discharge (median [IQR]
after admission: 13.0 [11.0–17.5] days) and were included
in the study. The median age was 64years (25th–75th per-
centile, 46–75years). The majority of patients were males
(61%). The most frequent comorbidities were hypertension
in 41% of cases and diabetes in 20%. The median body mass
index was 27.3kg/m2 (25th–75th percentile, 25.0–31.2kg/
m2). Details of characteristics are reported in Table1.
Venous thromboembolism events
Venous thromboembolism incidence was 22.5%. Deep
venous thrombosis (DVT) was detected in 15 of 71

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Table 1 Demographics, clinical, laboratory, radiographic characteristics at admission and treatment of the patients
Data are median (IQR), n (%), or n/N (%). p values were calculated by Mann–Whitney U test, χ. test, or Fisher’s exact test, as appropriate
VTE venous thromboembolism, BMI body mass index, VDU venous duplex ultrasonography, ICU Intensive care unit
Normal range Total
(n = 71)
VTE
(n = 16)
No-VTE
(n = 55)
p value
Demographics
Age, year 64 (46.0–75) 61.0 (40.8–79.0) 64.0 (47.5–75.0) 0.92
Male sex 43 (60.6%) 11 (68.7%) 32 (58.2%) 0.56
BMI—kg/m227.3 (25.0–31.2) 27 (25.5–29.1) 27.4 (24.2–32.3) 0.59
Underlying conditions
Hypertension 29 (41) 3 (19) 26 (47) 0.35
Diabetes 14 (20) 0 (0) 14 (25) 0.029
Cancer 4 (6) 0 (0) 4 (7) 0.56
Current smoker 6 (9) 0 (0) 6 (12) 0.32
History of VTE 5 (7) 2 (13) 3 (5) 0.31
Surgery < 3months 7 (10) 2 (13) 5 (9) 0.65
Time from illness onset to hospital admission, days 9.0 (5.0–11.0) 8.5 (7.0- 10.0) 9.5 (4.0- 12.0) 0.59
Physical examination
Body temperature—°C 38.6 (37.9–39.1) 38.7 (38.5–39.4) 38.4 (37.8–39.1) 0.21
Fever 55 (79) 14 (93) 41 (75) 0.33
Respiratory rate > 24/min 46 (65) 8 (50) 35 (64) 0.40
Clinical suspicion of venous thrombosis 3 (4) 2 (12) 1 (2) 0.12
NEWS score 6 (4- 7) 8 (5–8) 4 (4- 7) 0.096
SOFA score 1 (1–2) 2 (1- 4) 1 (1- 2) 0.22
Laboratory findings
White-cell count, × 10−9/L (N 4.0–10.0 6.36 (4.85–9.21) 5.96 (3.97–9.89) 6.56 (5.19–9.21) 0.34
Lymphocyte count, × 10−9/L 1.5–4.0 0.94 (0.72–1.28) 0.92 (0.75–1.25) 0.99 (0.72–1.29) 0.65
Platelet count, × 10−9/L 150–400 212 (162–248) 228 (183–260) 202 (160–243) 0.26
Serum creatinine, μmol/L 62–106 76.5 (60–91) 80 (51–89) 74 (60.5–91) 0.53
Aspartate aminotransferase, U/L 0–51 44.3 (30.5- 60.1) 39.7 (31.3–48.2) 45.6 (30.5–61.6) 0.33
Alanine aminotransferase, U/L 0–51 43.8 (23.7–68.8) 37.8 (19.8–66.4) 44.1 (27.4–70.0) 0.53
Lactate dehydrogenase, U/L 135–225 297 (233–411) 405 (260–550) 286 (231–380) 0.13
Creatine kinase, U/L 0–190 118 (41–197) 97.2 (44–262) 127 (44–201) 0.76
Serum ferritin, μg/L 30–400 798 (436–1821) 1354 (695–2271) 762 (400–1596) 0.12
> 300 42 (77) 11 (92) 31 (74) 0.56
Fibrinogen, g/L 2.0–4.0 4.9 (4.3–6.5) 5.2 (4.6–6.6) 4.8 (4.3–6.6) 0.58
D-dimer, μg/mL < 0.5 0.79 (0.48–1.61) 1.63 (0.86–4.94) 0.67 (0.45–1.12) 0.0021
Prothrombin ratio 70–120 88 (79–95) 79 (71–99) 88 (82–94) 0.20
TCA ratio 0.8–1.2 1.00 (0.92–1.09) 1.01 (0.96–1.11) 1.00 (0.91–1.07) 0.43
Imaging features
Time from illness onset to VDU, days 13.0 (11.0–17.5) 17.0 (11.0–22.0) 13.0 (10.0–16.3) 0.06
Chest-CT Scan 46 (64) 14 (88) 32 (58) 0.039
typical pattern of COVID-19 46 (100) 14 (100) 32 (100) 1
Treatments
Prophylactic anticoagulation 70 (99) 16 (100) 54 (99) 1
Antibiotics 65 (92) 16 (100) 49 (89) 0.33
Antiviral treatment 29 (41) 7 (44) 22 (40) 0.78
Corticosteroïds 15 (21) 3 (20) 12 (22) 1
ICU admission 13 (18) 8 (50) 5 (9.1) 0.0008
Invasive mechanical ventilation 8 (11) 6 (37) 2 (4) 0.001

214 M.Artifoni et al.
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patients (21.1%) including 2 (2.8%) symptomatic, 2
(2.8%) proximal and 5 (7.0%) distal. Isolated calf DVT
was found in 7 patients (9.8%), with bilateral calf involve-
ment in five (7.0%). Out of the 71 patients, 7 patients
(9.8%) developed a pulmonary embolism (PE), among
whom 5 had calf DVT, one proximal DVT and one no
DVT. One patient died because of PE. Out of the 71
patients, 34 (48%) underwent angio-CT of whom 7 exhib-
ited pulmonary embolism (21%), which was fatal in 1
case. Among patients with PE 5 (7%) had calf DVT, one
(1.4%) proximal DVT and one (1.4%) no DVT. Demo-
graphics, disease manifestations, comorbidities and base-
line COVID-19 severity were similar in patients with and
without venous thromboembolism (Table1). No signifi-
cant differences were observed with regards to baseline
complete blood counts, inflammatory markers hepatic or
renal parameters.
Predictive value ofD‑dimer
D-dimer level at hospital admission, available in 65 of
the 71 patients, was significantly higher in patients who
developed venous thromboembolism during hospitali-
zation (median: 1.63µg/ml vs 0.63 µg/ml, p = 0.0021)
(Fig.1a). There was no correlation between D-dimer
level and fibrinogen (p = 0.62). The negative predictive
value of a baseline D-dimer level < 1.0µg/ml was 90%
for venous thromboembolism and 98% for pulmonary
embolism (Fig.1b). The positive predictive value for
venous thromboembolism was 44% and 67% for D-dimer
level ≥ 1.0µg/ml and ≥ 3.0µg/ml, respectively. D-dimer
level kinetics, available in 8 out of 16 patients who devel-
oped venous thromboembolism and 7 out of 55 who did
not develop venous thromboembolism (13%), are shown in
Fig.1c. Median time between admission and last D-dimer
level assessment in these 15 patients was 9.0days (IQR,
4.0–9.5days). Taking into account the latest available
D-dimer level prior to venous thromboembolism diagnosis
Fig. 1 correlation between D-dimer levels and venous thrombo-
embolic events in the 65 COVID-19 patients who had a D-dimer
level measurement on admission. (a, top left) Baseline (admission)
D-dimer levels according to thromboembolism events. Stars represent
pulmonary embolism. (b, top right) Risk of deep venous thrombosis
and pulmonary embolism according to baseline D-dimer levels. (c,
bottom, left) D-dimer levels kinetics between baseline and the latest
value before the venous duplex ultrasonography in the 15 patients
with D-dimer levels monitoring. 7 patients with no VTE, median
[IQR] admission D-dimer: 0.62 [0.41–1.34], median [IQR] last-value:
0.66 [0.61–0.89]; 8 patients with VTE, median [IQR] admission
D-dimer: 2.01 [0.62–4.30], median [IQR] last-value: 4.75 [2.98–6.42]
(d, bottom, right) Risk of deep venous thrombosis and pulmonary
embolism according to the latest D-dimer levels. VTE venous throm-
boembolic events, DVT deep venous thrombosis, PE pulmonary
embolism. **p < 0.01

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Systematic assessment ofvenous thromboembolism inCOVID-19 patients receiving…
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enhanced the predictive value of this marker: D-dimer
level < 1.0µg/ml had a 95% and 100% negative predictive
value for venous thromboembolism and pulmonary embo-
lism, respectively. Positive predictive values of a D-dimer
level ≥ 1.0µg/ml and ≥ 3.0µg/ml to predict venous throm-
boembolism were 48% and 80%, respectively (Fig.1d).
In summary, in our study were all patients underwent
low limb venous duplex ultrasonography and were with
thromboprophylaxis, we found a high incidence of throm-
boembolic events (22.5%) and pulmonary embolism
(10%).
In the MEDENOX trial, the incidence of venous throm-
boembolism in patients with acute medical illnesses was
reduced to 5.5% with daily enoxaparin 40mg injection
(3.8% distal thrombosis, 1.7% proximal thrombosis, no pul-
monary embolism) compared to 15% with placebo (9.4%
distal, 4.9% proximal, 0.7% pulmonary embolism) [11]. In
COVID-19, two retrospective cohort studies reported a high
risk of thrombosis in patients hospitalized in intensive care
units [12, 13], with a 25% incidence of venous thromboem-
bolism without thromboprophylaxis [12]. Despite throm-
boprophylaxis in patients in intensive care, a cumulative
incidence of 31% of symptomatic venous and/or arterial
thrombosis was reported [13]. Our study was conducted in
2 medical units were all patients received optimal pharma-
cologic thromboprophylaxis. Our results highlight the high
risk of venous thromboembolism, including pulmonary,
suggesting that standard thromboprophylaxis is insufficient
in COVID-19 inpatients, even if not requiring initial inten-
sive care. Interestingly, D-dimers level measured at hospital
admission predicted venous thromboembolism risk, whereas
other conventional risk factors such as age or body mass
index did not. The negative predictive value of D-dimer
for venous thromboembolism was clinically relevant when
the level was < 1.0µg/ml while patients with high levels
(≥ 3.0µg/ml) had a particularly high risk of venous throm-
boembolism. Our data also suggest that D-dimers monitor-
ing could improve risk estimate. The need for transfer to
intensive care unit and/or for invasive mechanical ventilation
was more frequent in patients who developed venous throm-
boembolism, although baseline clinical characteristics did
not differ from patients who did not develop such event. This
is consistent with the prognostic value of D-dimer levels
in COVID-19 pneumonia, higher levels at admission being
associated with critical presentation [4] and with higher
mortality [3, 4]. Two studies demonstrated that systematic
thromboprophylaxis reduces COVID-19 inpatients mortality
for subjects hospitalized in medical wards [6, 7]. Whether
this finding result from a reduction of fatal thrombotic events
or from an anti-inflammatory of heparin effect is not known
[14] but interestingly we found no correlation between
fibrinogen and D-dimer levels in our study. Finally, the high
frequency of thrombotic events could be explained by the
host inflammatory reaction due to the direct involvement of
endothelial cells by SARS-Cov2 [15].
Our study has some limitations. This was a retrospec-
tive study but it was a cohort of consecutive patients and
screening for DVT was systematically performed. Second,
this study was conducted in two hospital centers with limited
sample size. As such this study may have included dispro-
portionately more patients with poor outcomes.
In summary, venous thromboembolism is a key con-
cern in patients with COVID-19 hospitalized in medi-
cal wards even under thromboprophylaxis. At admission,
D-dimer < 1.0µg/ml has an excellent negative predictive
value for venous thromboembolism whereas the risk of
thromboembolic events is strikingly high in patients with
D-dimer level ≥ 3.0 µg/ml. D-dimer level-guided more
aggressive thromboprophylaxis regimens using higher doses
of heparin should be evaluated in prospective studies and
may improve patients outcome.
Acknowledgments We want to thank Charlotte Biron, Jeanne Brochon,
Marie Chauveau, Jérôme Connault, Colin Deschanvres, Cécile Durant,
Dominique El Kouri, Alexandra Espitia-Thibault, Benjamin Gaborit,
Nicolas Goffinet, Mohamed Hamidou, Ohian Joubert, Amal Kenzi,
Paul Le Turnier, Maeva Lefebvre, Simon Ribes.
Author contributions MA, GD, GG, and PG collected and curated the
data. MA, AN, and RL performed the analysis and wrote the manu-
script. FR, DB,AN and RL critically reviewed the manuscript. All
authors approved the final version.
Funding None.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflicts of
interest.
Ethical approval This retrospective chart review study involving human
participants was in accordance with the ethical standards of the insti-
tutional and national research committee and with the 1964 Helsinki
Declaration and its later amendments or comparable ethical standards.
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