Heart Sci J 2020; 1(3): 10-14
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Heart Science Journal
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Review Article

Venous Thromboembolism Prevention in COVID-19: A Review of
Latest Evidences
Muchammad Dzikrul Haq Karimullah1,2*, Nisa Amnifolia Niazta3, Hiradipta Ardining4
Brawijaya Cardiovascular Research Center, Departement of Cardiology and Vascular Medicine, Faculty of medicine, Universitas Brawijaya, Malang, Indonesia
Department of Cardiology and Vascular Medicine, Kediri District Hospital, Kediri, Indonesia
3
General Practitioner, Kediri District Hospital, Kediri, Indonesia.
4
Internship Doctor, Kediri District Hospital, Kediri, Indonesia.
1
2

ARTI C LE I NFO

AB STR A C T

Keywords:
Venous thromboembolism; Hypercoagulability; Coronavirus; COVID-19; Low
molecular weight heparin

COVID-19 has become major public health problems, with new cases and deaths growing around the world.
COVID-19 has been reported to associate with a hypercoagulable state, which may lead to venous thromboembolism (VTE) formation. This condition is also associated with worse outcomes in COVID-19 patients. It is,
therefore, critical for clinicians to identify this condition and manage accordingly. VTE formation in COVID-19
occurs through several mechanisms, such as inflammatory reaction leading to a hypercoagulable state and
vascular dysfunction and direct vascular injury by the virus. The rate of VTE formation was as high as 31% in
Intensive Care Unit (ICU) patients and 9.2% in general wards patients. It was also associated with poor prognosis.
Thromboprophylaxis with heparin, particularly low molecular weight heparin (LMWH), has been shown to
improve these patients' prognosis. A careful individual assessment is required to determine which patients will
benefit from this therapy. There are still no sufficient prospective trials to establish guidelines for VTE thromboprophylaxis in COVID-19. The assessment includes laboratory parameters such as PT, platelet count, D-dimer,
fibrinogen, and other risk factors incorporated in the PADUA risk assessment model (RAM), versus the risk of
bleeding incorporated in IMPROVE bleeding RAM.

evaluate the risk of VTE formation in COVID-19 patients, and the role
of low molecular weight heparin (LMWH) in preventing this condition.

1. Introduction

In December 2019, a cluster of acute atypical respiratory
disease was found in Wuhan, China, followed by rapid spreading from
Wuhan to other areas. It was later found that a pathogen named severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible
for this disease. This disease, coronavirus disease 2019 (COVID-19),
kept growing as the primary health problem worldwide.1,2 As of 20th
June, this disease has infected 8.148.006 worldwide with total deaths
of 462.691, while in Indonesia, it has infected 45.029 people with
2.429 dead cases. 3,4

2. COVID-19 Pathophysiology: Its Role on Hypercoagulability
State and Thromboembolism Formation

SARS-CoV-2 binds to angiotensin-converting enzyme (ACE)
2 receptors, which are widely expressed in lung epithelial cells, to enter
the host cells.3 Three main components for innate immunity in the
airway; dendritic cells (DCs), alveolar macrophages, and epithelial
cells, fight against viruses until adaptive immunity is activated. Antigen
presentation initiates T cell responses via DCs and macrophages.2

One of the worse prognostic factors in COVID-19 is hypercoagulability state, which can lead to venous thromboembolism (VTE)
formation. According to Zhai et al., severe coagulation abnormalities
were found in 20% of COVID patients. The major coagulation disorder
was found in almost all patients with the condition of severe
COVID-19.5 Cui et al. showed that VTE was found in 25% of severe
COVID-19 patients in ICU, and eventually, 40% of them died.6
Therefore, clinicians should be able to identify this condition and
manage it accordingly. In this review, we will discuss the hypercoagulability state and venous thromboembolism (VTE) formation, how to

The activated immune cells will produce proinflammatory
cytokines, including interleukin (IL) 10, IL-6, IL-8, granulocyte-colony
stimulating factor (G-CSF), tumor necrosis factor (TNF)-α, and macrophage inflammatory protein (MIP)-1α.2 These proinflammatory
cytokines would up-regulate procoagulant factors and down-regulate
the anticoagulant pathway, particularly protein C. This process will
result in the activation of coagulation cascade and inhibition of fibrinolytic reaction, thus stimulating thrombosis. 5,7

*Corresponding author at: Department of Cardiology and Vascular Medicine, Kediri District Hospital, Kediri, Indonesia.
E-mail address: pm.dzikrul@gmail.com (M.D.H. Karimullah).
https://doi.org/10.21776/ub.hsj.2020.001.03.3
Received 9 September 2020; Received in revised form 12 September 2020; Accepted 24 September 2020
Available online 21 October 2020

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M.D.H. Karimullah, et al.

Heart Sci J 2020; 1(3): 10-14

Table 1. Sepsis-induced coagulopathy (SIC) score27

Category

Parameter

0 point

Prothrombin time
Coagulation
Total SOFA*

PT-INR
Platelet count (x109/L)
SOFA four items

≤1.3
≥150
0

1 point
>1.2
<150
1

2 point
>1.4
<100
≥2

Note, *The total Sequential Organ Failure Assessment (SOFA) is the sum of the four items (respiratory SOFA, cardiovascular SOFA, hepatic SOFA,
and renal SOFA; PT-INR, prothrombin time - international normalized ratio
Table 2. SOFA scoring27

SOFA
Score

Respiratory SOFA
PaO2/FiO2 (mmHg)

Cardiovascular SOFA (MAP ±
vasopressors)

Hepatic SOFA (Bilirubin
mg/dl)

Renal SOFA
(Creatinine mg/dl)

0

≥ 400

MAP ≥ 70 mmHg

<1.2

<1.2

+1

< 400

MAP < 70 mmHg

1.2-1.9

1.2-1.9

+2

< 300

Dopamine ≤ 5 μg/kg/min or
dobutamine (any dose)

2.0-5.9

2.0-3.5

+3

< 200 and mechanically
ventilated

Dopamine > 5 μg/kg/min OR
epinephrine ≤ 0.1 μg/kg/min
OR norepinephrine ≤ 0.1
μg/kg/min

6.0-11.9

3.5-4.9

< 100 and mechanically
ventilated

Dopamine > 15 μg/kg/min
OR epinephrine > 0.1
μg/kg/min OR
norepinephrine > 0.1
μg/kg/min

>12.0

>5.0

+4

Note, SOFA, Sequential Organ Failure Assessment; MAP, mean arterial pressure
increased PT, noting a median count DIC 4 days (1-12 days) after
admission.16

Other than through proinflammatory cytokines, it is also
proposed that SARS-CoV-2 directly injures endothelial cells, as
endothelial cells also express ACE2.8 The normal endothelium plays a
significant role in inhibiting thrombosis by producing prostaglandin,
NO, and ectonucleotidase CD39, which have vasodilatory properties
and inhibit platelet aggregation.7 Hence, the dysfunction of endothelial
cells by SARS-CoV-2 will favor thrombosis.

Although ICU patients were found to have a higher risk of
VTE, patients on the general ward were also at increased risk. The
incidences of VTE in ICU patients were 26% (95% CI, 17‐37), 47%
(95% CI, 34‐58), and 59% (95% CI, 42‐72) at 7, 14, and 21 days,
respectively; while for the patients in general wards, the incidences
were 5.8% (95% CI, 1.4‐15), 9.2% (95% CI, 2.6‐21), and 9.2% (2.6‐21)
at 7, 14, and 21 days, respectively.17

SARS-CoV-2 antigens can also activate platelets through IL-8
production. These activated platelets would activate white blood cells
and form a clot to facilitate the pathogen's elimination.9 Besides, hypoxia caused by severe COVID‐19 can cause increased blood viscosity, thus
stimulating thrombosis.10 Immobilization in COVID-19 patients also
contributes to increasing VTE events.11

4. Risk Assessment for Thromboembolism Formation in COVID-19
Patients

In COVID-19, the coagulation disorders seem to be similar to
other coagulopathies due to severe infections, such as DIC and
sepsis-induced coagulopathy (SIC) SIC, an earlier phase sepsis-associated DIC, can be assessed using a category by The International Society
of Thrombosis and Haemostasis (ISTH).10 The SIC scoring system
includes prothrombin time, platelet count, and SOFA score (Table 1
and 2). In a study by Tang et al., it was found that severe COVID-19
patients who meet SIC criteria (≥4) or who have a prominent elevation
of D-dimer (6 times upper limit of normal) have a better prognosis if
they were treated with anticoagulant therapy (mainly with LMWH).10

3. Venous Thromboembolism Formation in COVID-19: the
Incidence and Its Prognostic Significance

Klok et al. found that the rate of thrombotic complications in
COVID-19 patients in ICU was 31%, consisting of pulmonary embolism,
deep vein thrombosis, catheter-related upper extremity thrombosis,
and ischemic stroke.12 Another study suggested that acute pulmonary
embolus was found in 23% of patients with severe COVID-19.13
Furthermore, an autopsy of COVID-19 patients showed microthrombi
in lung microvasculature, suggesting that refractory hypoxemia in these
patients might be caused by ventilation-perfusion mismatch due to the
obstruction of the capillary by these microthrombi. Similar to what
happens in the condition of severe sepsis, activation of coagulation
cascade by cytokines can cause disseminated intravascular coagulation
(DIC), causing multiple organ damage.14 In a study by Tang et al., DIC
was found in 71.4% of nonsurvivors and 0.6% of survivors during their
hospital stay.15 Nonsurvivors were found to have a correlation between
progressive DIC with decreased fibrinogen, increased D-dimer, and

Other than the SIC scoring, the predictor of thromboembolic
formation in COVID-19 is D-dimer, PT, and PTT level. Increased
D‐dimer levels > 1.5 μg/ml (normal range: 0.0–0.5 μg/ml) can predict
VTE with sensitivity 85%, specificity 88.5% and negative predictive
value 94.7%.6 Spontaneous prolongation of the PT by more than 3 s or
PTT by more than 5 s was also found to be an independent predictor for
VTE formation.12

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Heart Sci J 2020; 1(3): 10-14

Table 4. IMPROVE bleeding RAM: score ≥ 7 indicates high bleeding risk.29

Risk Factor

Points

Critically Ill
Inflammatory bowel disease
Active cancer (local or distant metastases and with chemotherapy or radiation in the previous 6
months)
Previous VTE
Reduced mobility (bed rest with bathroom privilage for at least 3 days)
Thrombophilic condition (defects of antithrombin, protein C or S, factor V Leiden, G20210A
prothrombin mutation, or antiphospholipid syndrome)
Recent trauma / surgery (<1 month)
Age ≥ 70 years
Heart or respiratory failure
Acute myocardial infarction or ischemic stroke
Acute infection or rheumatologic disorder
BMI ≥ 30
Ongoing hormonal treatment

4
4
3
3
3
3
2
1
1
1
1
1
1

Note, GFR, glomerular filtration rate; INR, international normalized ratio
thrombocytopenia (HIT). They have higher bioavailability and longer
plasma half-life, making once-daily administration feasible. LMWH also
has a more predictable dose-response compared to unfractionated
heparin (UFH), thus eliminating the need for routine monitoring.7
Furthermore, LMWH also has anti-inflammatory properties that might
be beneficial in COVID-19 by significantly lowering the level of IL-6.22
The reduction of IL-6 level is expected to lessen the cytokine storm
caused by the virus, thus improving the patient's condition.23

A higher score in PADUA risk assessment model (RAM) to
predict VTE (Table 3) has been associated with worse outcomes in
COVID-19.18 Its direct relationship with thromboembolism formation
in COVID-19 has not been studied.

Most patients with severe COVID-19 may have other comorbidities, such as liver dysfunction, that may increase bleeding risk. The
predisposing factors of bleeding should be assessed (i.e. using
IMPROVE bleeding risk assessment model in table 4) and corrected
actively.

Table 5. Standard VTE prophylaxis regimens for patients with high
VTE risk28

5. Preventing Thromboembolism in COVID-19 Patient: When Do
We Need It?

While patients with severe COVID-19 in ICU are at obvious
increased risk for VTE, those in general wards also have significant risk
factors, such as immobilization and infectious disease. Considering that
VTE incidence in non-severe COVID-19 was well above 1% even on
thromboprophylaxis, anticoagulant thromboprophylaxis has been
suggested to be given for all admitted COVID-19 patients by the majority of sources. The ISTH and American Society of Hematology (ASH)
guideline advised prophylactic LMWH in all COVID-19 patients who
meet the requirement of hospitalization if no contraindication (active
bleeding and platelet count < 25 × 109/L).19-21 However, now it is
required in individual patient's evaluation, integrating VTE risk factors
and bleeding risk factors with clinical judgment. There were still no
sufficient prospective trials to establish a guideline for antithrombotic
treatment strategy in COVID-19 patients. Assessment of VTE risk could
be done from laboratory parameters such as PT, platelet count,
D-dimer, and other risk factors incorporated in PADUA risk assessment
model (RAM), while the risk of bleeding can be assessed using
IMPROVE bleeding RAM.

Patient population

VTE prophylaxis regimens

Medical patients

Enoxaparin 40 mg SQ every 24 hours
(Class I, level B)
Or
Heparin 5000 units SQ every 8 to 12
hours (Class I, level B)

Renal impairment
(CrCl < 30 mL/min)
Not on renal
replacement therapy

Enoxaparin 30 mg SQ every 24 hours
(Class IIa, level B)
Or
Heparin 5000 units SQ every 8 to 12
hours (Class I, level B)

Extreme obesity patients
(BMI > 40 kg/M2)

Enoxaparin 40 mg SQ every 12 hours
(Class IIa, level B)

Low body weight
patients
(weight < 50 kg)

Enoxaparin 30 mg SQ every 24 hours
(Class IIb, level C)
Or
Heparin 5000 units SQ every 8 to 12
hours (Class I, level B)

Note, VTE, venous thromboembolism; CrCl, creatinine clearance; BMI,
body mass index

6. The Role of Low Molecular Weight Heparin in Thromboembolism Prevention: Mechanism and Administration

Heparin works by dramatically enhancing the aggregation of
complexes between antithrombin and coagulation factors such as
thrombin (IIa), factors Xia, Xa, and IXa, which will disable these coagulation factors. Furthermore, heparin also compromises platelet
function.7

The current standard dose anticoagulant prophylaxis is
recommended (table 5), rather than intermediate or full treatment
dosing.19 The doses of LMWH for prophylaxis are once-daily subcutaneous doses of 4000 to 5000 units or twice-daily subcutaneously doses of
2500 to 3000 units. The dose is reduced in a patient with renal impairment.24 The drug should be administered for at least 7 to 10 days.5
However, in cases where the patients have a great increase in D-dimers
and severe inflammation, intermediate or therapeutic dosing should be
considered, according to the bleeding risk.4 Ranucci et al. found that
VTE formation still existed with 4000 IU b.i.d LMWH as

Low molecular weight heparin (LMWH) preparations have a
more significant ability to inhibit factor Xa than inhibit thrombin. It also
interacts less with platelets than standard heparin, hence lesser
bleeding side effects and less likely to cause heparin-induced

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M.D.H. Karimullah, et al.

Heart Sci J 2020; 1(3): 10-14

thromboprophylaxis in severe COVID-19 infection. No VTE formation
was found when the dose of LMWH was increased to 6000 IU b.i.d
(8000 IU b.i.d if body mass index > 35).25

References

1. Harapan H, Itoh N, Yufika A, et al. Coronavirus disease 2019
(COVID-19): A literature review. Journal of Infection and Public
Health 2020.

In severe COVID-19 patients, it is recommended to use
mechanical prevention for VTE prevention alternatively to the contraindicated pharmacological thromboprophylaxis due to its high bleeding
risk or active bleeding. Intermittent pneumatic compression (IPC) and
graduated compression stockings (GCS) are the mechanical prevention
that should be given until major bleeding risk factors were removed.
Once the bleeding risk decrease, the pharmacological thromboprophylaxis should be initiated as soon as possible.5

2. Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiology: A
review. Clinical immunology 2020:108427.
3. Coronavirus Breakdown of Deaths and Infections Worldwide. 2020.
at
https://www.euronews.com/2020/06/23/covid-19-coronavirus-breakdown-of-deaths-and-infections-worldwide.)
4. Kompas.com. DATA COVID-19 DI INDONESIA. 2020.

In patients with severe kidney impairment (CrCl <30
mL/min), The use of unfractionated heparin (UFH) is being recommended.5 Up to date, there was no research evaluating the use of direct
oral anticoagulant (DOAC) for VTE prevention in COVID-19. However,
it was known that the use of DOAC in critically ill patients with high
VTE risk did not reduce the risk of VTE and associated with increased
major bleeding.26 Another consideration against DOAC use was DOAC
and COVID-19 medical treatment interaction, (as some of them are
potent inhibitor of CYP3A4). The risk of organ failure and the lack of
an effective reversal agent in some centers also taken as considered
against DOAC use.20

5. Zhai Z, Li C, Chen Y, et al. Prevention and treatment of venous
thromboembolism associated with coronavirus disease 2019
infection: a consensus statement before guidelines. Thrombosis and
haemostasis 2020;120:937.
6. Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.
Journal of Thrombosis and Haemostasis 2020.
7. Hoffbrand AV, Steensma DP. Hoffbrand's essential haematology:
John Wiley & Sons; 2016.

7. Conclusion

8. Huertas A, Montani D, Savale L, et al. Endothelial cell dysfunction:
a major player in SARS-CoV-2 infection (COVID-19)? : Eur Respiratory Soc; 2020.

Patients with COVID-19 are at increased risk of VTE due to
several mechanisms; strong inflammatory reaction leading to hypercoagulability state, vascular injury due to the direct effect of the virus, and
inflammatory reaction. Studies have shown that prophylaxis with
heparin, particularly LMWH, improved the prognosis of these patients.
A rigorous individual patient assessment incorporating VTE risk factors
and bleeding risk factors is required. Assessment of VTE risk with
laboratory parameters such as PT, platelet count, D-dimer, and other
risk factors incorporated in PADUA RAM, versus the risk of bleeding
such as incorporated in IMPROVE bleeding RAM, may aid in determining which patients benefit most with thromboprophylaxis strategy.

9. Giannis D, Ziogas IA, Gianni P. Coagulation disorders in coronavirus
infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons
from the past. Journal of Clinical Virology 2020:104362.
10. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant
treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. Journal of thrombosis
and haemostasis 2020;18:1094-9.

8. Declarations

11. Aryal MR, Gosain R, Donato A, et al. Venous Thromboembolism in
COVID-19: Towards an Ideal Approach to Thromboprophylaxis,
Screening, and Treatment. Current Cardiology Reports
2020;22:1-5.

4.1. Ethics Approval and Consent to participate
Not applicable.
4.2. Consent for publication
Not applicable.

12. Klok F, Kruip M, Van der Meer N, et al. Incidence of thrombotic
complications in critically ill ICU patients with COVID-19. Thrombosis research 2020.

4.3. Availability of data and materials
Data used in our study were presented in the main text.

13. Grillet F, Behr J, Calame P, Aubry S, Delabrousse E. Acute pulmonary embolism associated with COVID-19 pneumonia detected by
pulmonary CT angiography. Radiology 2020:201544.

4.4. Competing interests
Not applicable.

14. Negri EM, Piloto B, Morinaga LK, et al. Heparin therapy improving
hypoxia in COVID-19 patients-a case series. medRxiv 2020.

4.5. Funding source
Not applicable.

15. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are
associated with poor prognosis in patients with novel coronavirus
pneumonia. Journal of thrombosis and haemostasis 2020;18:844-7.

4.6. Authors contributions
Idea/concept: MDHQ. Design: MDHQ. Control/supervision: MDHQ.
Data collection/processing: MDHQ, HA, NAN. Extraction/Analysis/interpretation: MDHQ, HA, NAN. Literature review: HA, NAN. Writing
the article: MDHQ, HA, NAN. Critical review: MDHQ, HA, NAN. All
authors have critically reviewed and approved the final draft and are
responsible for the content and similarity index of the manuscript.

16. Connors JM, Levy JH. COVID-19 and its implications for thrombosis
and anticoagulation. Blood, The Journal of the American Society of
Hematology 2020;135:2033-40.
17. Middeldorp S, Coppens M, van Haaps TF, et al. Incidence of venous
thromboembolism in hospitalized patients with COVID‐19. Journal
of Thrombosis and Haemostasis 2020.

4.7. Acknowledgements
We thank to Brawijaya Cardiovascular Research Center.

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Heart Sci J 2020; 1(3): 10-14

18. Xu J-f, Wang L, Zhao L, et al. Risk assessment of venous thromboembolism and bleeding in COVID-19 patients. 2020.
19. Moores LK, Tritschler T, Brosnahan S, et al. Prevention, Diagnosis,
and Treatment of VTE in Patients With Coronavirus Disease 2019:
CHEST
Guideline
and
Expert
Panel
Report.
Chest
2020;158:1143-63.
20. Tal S, Spectre G, Kornowski R, Perl L. Venous thromboembolism
complicated with COVID-19: what do we know so far? Acta haematologica 2020:1-8.
21. Thachil J, Tang N, Gando S, et al. ISTH interim guidance on
recognition and management of coagulopathy in COVID‐19.
Journal of Thrombosis and Haemostasis 2020;18:1023-6.
22. Jose RJ, Manuel A. COVID-19 cytokine storm: the interplay between
inflammation and coagulation. The Lancet Respiratory Medicine
2020.
23. Shi C, Wang C, Wang H, et al. The potential of low molecular
weight heparin to mitigate cytokine storm in severe COVID-19
patients: a retrospective clinical study. Medrxiv 2020.
24. Zipes D LP. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds. Braunwald's heart disease e-book: A textbook of cardiovascular medicine:
Elsevier Health Sciences; 2011:1822 - 45.
25. Ranucci M, Ballotta A, Di Dedda U, et al. The procoagulant pattern
of patients with COVID‐19 acute respiratory distress syndrome.
Journal of Thrombosis and Haemostasis 2020.
26. Neumann I, Izcovich A, Zhang Y, et al. DOACs vs LMWHs in
hospitalized medical patients: a systematic review and meta-analysis that informed 2018 ASH guidelines. Blood advances
2020;4:1512-7.27.
27. Iba T, Di Nisio M, Levy JH, Kitamura N, Thachil J. New criteria for
sepsis-induced coagulopathy (SIC) following the revised sepsis
definition: a retrospective analysis of a nationwide survey. BMJ
open 2017;7.
28. Philip Trapskin PB. Venous Thromboembolism Prophylaxis – Adult
– Inpatient / Ambulatory – Clinical Practice Guideline: UWHC;
2016.
29. Schünemann HJ, Cushman M, Burnett AE, et al. American Society
of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized
medical patients. Blood advances 2018;2:3198-225.

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