Abstract Page

Title of the article:Mortality in COVID-19 Patients Receiving Systemic Anticoagulant:

A Systematic Review and Meta-Analysis

Abstract
Background: Coronavirus disease (COVID-19) or SARS-CoV-2 is a pandemic disease
which quickly spread throughout the world. There are no definitive therapeutic
recommendation which give benefit results. Recent studies suggest coagulopathy is one of
the complication of COVID-19 which increase the mortality rate in COVID-19 patients either
severe or not. In this systematic review and metaanalysis, we aimed to explore the association
between systemic anticoagulant use and mortality in COVID-19 patients regardless the
clinical condition.

Results: We performed a comprehensive literature from several databases. The anticoagulant

used in this study comprises of systemic anticoagulant such as LMWH or others. The primary
outcome was all cause mortality related anticoagulant use in COVID-19 patients. There were
7064 patients from 7 studies. The metaanalysis showed that systemic anticoagulant use was
related with lower mortality (RR 0.70 [0.51, 0.97], p < 0.03; I 2: 87%, p < 0.00001). The
systematic review shows 4 from 7 studies favor decrease of mortality rate reported.

Conclusions: Systemic anticoagulant use is associated with lower mortality rate in COVID-
19 patients. Further studies are needed for better causation explanation.

Keywords: Systemic anticoagulant, COVID-19, mortality

 Background Coronavirus disease (COVID-19) is a pandemic that was declared by

World Health Organization on March 11, 2020. This pandemic quickly spread throughout the

world1. As the disease spread worldwide in fast manner, therapeutic recommendation is not

clear enough because no definite causation can be taken. Recent autopsies studies suggest

that coagulopathy is one of complication which increase the mortality in COVID-19 patients 2.

The mechanism of thrombus is thought to be related with endothelium damage and

there is evidence in increasing of D-Dimer marker which correlate with the severity of

disease3. Anticoagulant use in COVID-19 is recommended in some evidence but randomized

controlled trial is still in progress (NCT04412304). Low molecular weight heparin (LMWH)

is increasingly popular to be given in COVID-19 but mortality study related the user is still

unclear4,5.

In order to draw conclusions, this writing is expected to be a systematic review and

metaanalysis of systemic anticoagulant use related mortality in addition of management of

COVID-19 in terms of safety and efficacy. This information will help clinicians on

anticoagulant treatment safety and recommendation for daily practice.

 Main Text
METHODS Preferred Reporting Items for Systematic reviews and Meta-Analysis
(PRISMA) were used to accomplished this meta-analysis. We systematically searched
PubMed, SCOPUS, EuropePMC, ProQuest, and Cochrane Central Databases with the search
terms “COVID-19” or “SARS-CoV-2” and “ Systemic Anticoagulant” or “Heparin” that
were published within the year of 2020. Duplicate results were excluded. The remaining
articles were independently screened for relevance by its abstracts with all authors. The full-
text of the selected abstract then were thoroughly read, and those that fulfilled our criteria
were included in the study. The final inclusion of studies was based on the agreements of all
investigators. Any disagreement was resolved by consensus of all authors.

2.1 Article eligibility and selection

The retrieved articles’ titles and abstracts were scanned for potential relevance and

review inclusion eligibility. To be included, the article had to meet strict criteria, as listed in

Table 1, with the search and inclusion criteria primarily targeting published studies

presenting clinical efficacy and/or safety types of evaluations of low molecular weight

heparin or other systemic anticoagulant used in COVID-19 patient infected. Pre-printed and

grey literature journal in this search is also included in the article searched (until 20 th June

2020)

The results of the three independent searches were matched in order to find the

common results and exclude the same article. Among the identified articles meeting the

selection criteria, full versions or pre-proofed journal could used for data analysis and a

secondary search of the listed citations was performed to ensure that all relevant publications

were included. Only articles written or translated into English were included in this

systematic review. The searches were run in the period of January 2020 until June 2020.

Table 1.Article Inclusion and Exclusion Criteria

Inclusion Criteria Exclusion Criteria

Types of Randomized controlled trials evaluating Oral anticoagulant

studies the efficacy of low molecular weight
 heparin or other anticoagulant in COVID-
19 patients regardless of clinical status
Non-randomized, controlled trials
reporting efficacy were allowed provided
that the scope of the research was to
evaluate the effect of low molecular weight
heparin or other anticoagulant in COVID-
19 patients regardless of clinical status

a. Reviews, editorials, opinions, case

All evidence levels, including safety data
were acceptable for safety analysis
inclusion.
Patients (irrespective of age, sex or race)
Types of
with covid-19 infection who had received
Participants
low molecular weight heparin or other
systemic anticoagulant or previous
anticoagulant use
reports, case series, comments, and
letters without original data
b. Non-clinical (i.e., experimental,
animal, or in vitro) studies
c. Clinical trials with major quality
issues and a high risk of bias were
excluded from efficacy analysis, but
could be included in safety analyses
Patients without covid-19 infection
confirmed or based only on rapid test
without RT PCR confirmation

Types of
a. Antiplatelet used reported
intervention Low molecular weight heparin or systemic
b. Reports non regular use of low
anticoagulant molecular weight heparin or
anticoagulant
Types of
Non user of Low molecular weight heparin
comparators
or systemic anticoagulant

Types of Could include (but not limited to):

Efficacy
Outcome a. Single use of low molecular weight
Measures heparin or systemic anticoagulant
b. Combination of systemic anticoagulant
Could include ( but not limited to):

a. Mortality
Safety b. Overall incidence of serious adverse
event (quantitative)
Outcome
c. Overall incidence of adverse events
Measures related to anticoagulant (quantitative)
d. Qualitative assessment of specific
adverse events / serious adverse events
related to use of anticoagulant
regardless of type

2.2 Data Appraisal and Extraction

 Data extracted from the identified publication included: study design and outcome,

number of patients, follow up during intervention, intervention information, efficacy, and

safety of the procedures. We used a table in which each information was written descriptively

(Table 2).

2.3 Quality Assessment

The quality of the studies was appraised independently by two authors using the

Modified Newcastle-Ottawa Scale (NOS)6. A score of 0–9 was allocated toeach study, with

studies having a total scoreof > 7 defined as high quality.Any disagreement in the quality

assessment was resolved by discussion witha third author.

2.4 Statistical Analysis

To perform a meta-analysis, Review Manager (RevMan) 5.4 (Computer program, The

Cochrane Collaboration, London, UK) and Comprehensive Meta-Analysis (CMA) 3.3

(Computer program, New Jersey, USA) were used to perform all statistical analysis.The

heterogeneity was considered significantfor a P-value less than 0.05, and its magnitude

wassubstantial when I2 was greater than 50%. A random-effects model was used to report the

results of heterogeneous data,otherwise a fixed-effects model was used. Dichotomous

variables were analyzed with the Mantel-Haenszel statistical method using risk ratio (RR) as

the summary statistic and reported with 95% confidence intervals (CI).Funnel Plot were used

to screen for publication bias.

RESULTS

Characteristics of included studies

An initial search generated 785 potentially relevant papers, of which 253 were

immediately excluded due to duplication. After the first screening of title and abstracts, 504

papers were excluded. An additional 21 papers were excluded after full-text review, which

resulted in 7 studies included in this systematic review and meta-analysis (figure 2).

Among 7 articles that included 7064 participants, 3 were performed in the United

States (USA)7–9, 1 in China4, 2 in Spain10,11, and 1 in Italy12. All of the studies were

retrospective observational and based on hospital care settings.

The baseline characteristics of the included studies are presented in Table 1. The

mean age of the patients in the included studies was 64 years. Only Paranjpe et al 8 did not

supply the mean age of the patients. Of the 7 included articles, 4 focus on the association

between anticoagulant or heparin and survival of COVID-19 patients4,8,10,11 and one among

them specifically included severe COVID-19 patients only 4; 2 articles reported the possible

risk factors including anticoagulant with clinical outcomes of COVID-19 especially

mortality7,9; and the final article reported about thromboembolic complication in COVID-19

patients12. At final screening, 525 titles were excluded due to one or more of the following:

(1) no full-text available, (2) not written in english, (3) meeting our exclusion criteria (4) not

using LMWH or systemic anticoagulant.

A total of 7 publications were included, all of which are retrospective studies

(evidence level II). Authors of each studies used LMWH such as heparin in different form

and for different purpose. The highest number of patients are 2773 patients in Paranjpe study

with total samples are 7424 participants from all studies included, while the lowest patients
Table 2. Characteristics of the included studies

Author and Study Design Country Quality Characteristic of Age N Mortality Follow up Intervention Efficacy
Year Score participant (mean) (A vsB) (A vs B)

Ayerbeet al, Retrospective Spain 6 Hospitalized COVID- 67.57 1734; 242; During Heparin, detail not mentioned Heparin associated
2020 cohort 19 patients 341 59 hospitalization, 201 with lower mortality
still admitted at the when the model was
time collecting data adjusted for age and
gender
Garibaldi et Retrospective USA 7 Hospitalized COVID- 63 571; 59; During Prophylactic and therapeutic doses Characteristic of
al, 2020 cohort 19 patients 261 54 hospitalization heparin or enoxaparin data and pasien risk
factor for severe
outcome
Gil et al, Retrospective USA 7 Hospitalized COVID- 61.3 178; 57; During Prophylactic or Therapeutic doses of Cause of Mortality
2020 cohort 19 patients 39 13 hospitalization Anticoagulation (LMWH,apixaban, and anticoagulant
UFH, Warfarin, Bivalirudin) was not explained
Gonzales- Retrospective Spain 7 Hospitalized COVID- 72.48 611; 79 153; 45 During Non heparin vs low dose heparin vs high Reduce mortality in
Porras et al, cohort 19 patients hospitalization dose heparin unselected adult
2020 patients
Lodigianiet Retrospective Italy 6 Hospitalized COVID- 68.4 25; 5; During LMWH (enoxaparin 120-160mg/day or - High
al, 2020 cohort 19 patients with 3 2 hospitalization 8000 IU qd, nadroparin 5700 IU – 9600 thromboembolic
thromboembolic IU bid, Fondaparinux 10-30mg), UFH events
complication therapeutic dose No data specifically
for
thrombopropylaxis
user
Paranjpeet al, Retrospective USA 7 Hospitalized COVID- N/A 786; 177; During Systemic anticoagulation Reduced risk of
2020 cohort 19 patients 1987 453 hospitalization overall mortality
Tang et al, Retrospective China 7 Hospitalized severe 65.1 99; 30; 28 days UFH(10000-15000 U/day) or Reduce mortality in
2020 cohort COVID-19 patients 350 104 LMWH(40-60 mg enoxaparin/day) for 7 unselected adult
days or longer patients

A, anticoagulant group; B,control group;COVID-19, coronavirus disease 2019; LMWH,low molecular weight heparin; N/A, not available; UFH, unfractionated heparin.
are 217 patients. There are unfortunately no randomized-controlled trials (RCT) found on our

search.

For quality evaluation through NOS, studies were considered high quality if they

received ascore of 7 stars or more. In this analysis, 5 studies 4,7–9,11 considered high quality,

with the remaining 2 receiving fewer than 7 stars10,12 (Table 2).

Anticoagulant Use and Mortality

To test impact of anticoagulant use on the mortality outcome, we included 7 studies

[4-9] with 7064 participants. The data including anticoagulant use in confirmed COVID-19

patients demonstrate 18% (723/4004) mortality rate compared to patients without

anticoagulant use 24% (730/3060). The data showed that anticoagulant use lower the

mortality rate in COVID-19 patients (RR 0.70 [0.51, 0.97], p < 0.03; I2: 87%, p < 0.00001).

Publication Bias

The funnel plot of this study based on mortality outcome isshown in Figure 2. There was

potential publication bias in mortality withsome studies falling outside the 95% CI of the

funnel plot.

Efficacy, Mortality, and Safety of Anticoagulant Treatment in COVID-19

Anticoagulant use in COVID-19 is uprising but there are still no evidence of safety

and mortality rate related. The direct observation related systemic anticoagulant and mortality

of COVID-19 was conducted by Ayerbe et al10. From 2075 patients viewed, there were 1256

and 819 male and female respecetively with mean age from both of them are 67.57. Among

the 1734 patients who received heparin 242 patients died. There are significant results from

age difference which favor older age (p<0.001) but gender is not associated. From adjustment

analysis, Heparin was associated with lower mortality in both variable with OR (95%CI):

0.55 (0.37-0.82) p=0.003. This study are in line with study from Garibaldi et al7. Garibaldi
reported lower mortality event in COVID-19 patients which were given anticoagulant

compared with those that were not given without significant statistic result.

Another study from Lodigiani et al12, include 388 patients with COVID-19 which

16% of population required ICU. Thromboprophylaxis was used in all ICU subjects and 75%

in non ICU-setting. In conjunction, there is also study that depict the important role of

coagulopathy pathway in COVID-19, depictly by increasing occurence of veno-thrombotic

events or VTE. Lodigiani et al12, in 2020 conducted study about COVID-19 and VTE. They

included 388 patients (median age 66 years, 68% men, 16% requiring intensive care [ICU]).

Thromboprophylaxis was used in 100% of ICU patients and 75% of those on the general

ward. Thromboembolic events occurred in 28 patients, which 25 patients on heparin with

20% mortality rate (5 patients) and 3 patients without heparin 66,7% (2 patients). There are

no possible mechanism of death reported from this study. DIC is one of plausible mechanism

in both subjects. The study report that 8 patients become DIC which VTE imaging shows the

same correlation as pulmonary embolism, stroke and acute coronary syndrome. The exact

patomechanism is not fully understood but coagulation is proven in autopsy of patient with

COVID-19 which so anticoagulant use can be the main target to prevent the thromboembolic

events.13

Tang et al14 perform retrospective study shows 28-day mortality between heparin

users and non related sepsis-induced coagulopathy and D-dimer score were compared. 99 of

the patient received LMWH mostly for 7 days or longer. The correlation shows significant

difference from D-dimer, prothrombin time and age with no significant related to platelet

count. There are also no significant mortality rate in 28 days from overall user (30.3% vs

29.7%, P=0.910). From subgroup analysis, the mortality rate was lower in patients with SIC

score ≥4 (40.0% vs 64.2%, P=0.029). The increase of D-dimer more than 6 fold of upper

limit also shows significant founding in mortality difference (32.8% vs 52.4%, P=0.017).
LMWH is associated with good prognosis in severe COVID-19 from coagulation parameter

and recieved better outcome in this study.

Gil et al,9 in the year of 2020 conducted a study about several parameters of COVID-

19 patients. This study included 270 case series of COVID-19 patients in new epicentre of

COVID-19, which is New York City. In this study they are concluded that therapeutic

anticoagulant was associated with higher mortality compared with prophylactic anticoagulant

in COVID-19 patient, although was not yet proven statistically.

Paranjpe et al8 studied the safety and bleeding event of anticoagulant treatment in

COVID-19 patients. From 786 patients who recieved systemic anticoagulant, there was

22.5% in mortality rate compared to 22.8% without anticoagulant. From subanalysis, patient

with anticoagulant received invasive mechanical ventilation likely (29.8% vs 8.1%, p<0.001).

In patients who required mechanical ventilation (N=395), in-hospital mortality was 29.1%

with a median survival of 21 days for those treated with anticoagulant as compared to 62.7%

with a median survival of 9 days in patients who did not receive anticoagulant. In a

multivariate proportional hazards model, longer duration of anticoagulant treatment was

associated with a reduced risk of mortality (adjusted HR of 0.86 per day, 95% confidence

interval 0.82-0.89, p<0.001).

From Gonzales-Porras study11, the mortality rate total event is noted in 24 patients

which 14 patients associated with high dose anticoagulant. From bleeding cause, only 1

patient is related with fatal bleeding occurrence. The study shows mean age of patient within

72,48 years. The non survivor patients presented with higher levels of INR (1.14 vs 1.09,

p=0.001), D-dimer (2.1 mg/L vs 0.9 mg/L, p<0·001) as well PT (13.3 vs 12.7, p=0.001). The

treatment with LMWH affect the mortality rate in this study which 458 (93%) and 143 (72%)

patients receiving LMWH were in the survivors and non-survivors groups, respectively

(p<0.001). Statistical differences were observed between the three heparin groups in in-
hospital mortality (p<0·.01): in the survivors, 34 (6.9%) patients did not received LMWH,

318 (64.6%) patients received low-dose LMWH and 140 (28.5%) received high-dose

LMWH, while non-survivors, 45 (22.7%) patients did not received LMWH, 104 (52.5%)

patients received low-dose LMWH and 49 (24.7%) received high-dose LMWH.

Among those who did not receive anticoagulant, 38 (1.9%) individuals had bleeding

events, compared to 24 (3%) among those who received anticoagulant (p=0.2). Bleeding

events were more common among patients intubated (30/395; 7.5%) than among non-

intubated patients (32/2378; 1.35%). These findings suggest that systemic anticoagulant may

be associated with improved outcomes among patients hospitalized with COVID-19. The

potential benefits of systemic anticoagulant, however, need to be weighed against the risk of

bleeding and therefore should be individualized. The association of in-hospital anticoagulant

and mechanical ventilation likely reflects reservation of anticoagulant for more severe

clinical presentations. Interestingly, there was an association with anticoagulant and

improved survival after adjusting for mechanical ventilation.

 DISCUSSION

This systematic review and meta-analysis was performed to assess the possible

association between systemic anticoagulant treatment with decreased of mortality rate in

COVID-19 patients. Although there was reduced mortality rate, the result shows significant

difference in reducing death (RR 0.70 [0.51, 0.97], p < 0.03; I 2: 87%, p < 0.00001). Because

all of the data come from retrospective studies and because anticoagulant are more likely to

be given to person with severe conditions, and the dosage use in the included studies in this

meta-analysis were vary within and between studies, although the results are significant, there

is selection bias in this study. However, the result is still essential for consideration in clinical

management for treating COVID-19 patients.

Recently, Coronavirus Disease 19 (COVID-19) is unexpectedly taking the world by

storm as the first pandemic of 21st century. Despite of its contagious and rather lethally

nature, therapeutic recommendation is not clear enough because no definite causation can be

taken. Recent studies based on autopsies by Atallah et al2, shown that coagulopathy is one of

the suggested cause of mortality of COVID-19 patients. Those founding bring the insight

therapy that can alter coagulopathy, such as systemic anticoagulant can bring a promising

addition in the further promising treatment protocol against COVID-19. This study aim to

summarize of systemic anticoagulant use or heparin based related mortality in addition of

management of COVID-19 in terms of safety, efficacy, and mortality rate.

In recent study, coagulopathy allegedly play pivotal role in pathophysiology of

COVID-19. This can be proven by shift of the pro-coagulant pattern to pathological side. D-

dimer levels were significantly elevated in patients admitted to the ICU with severe cases of

COVID-1914. Increasing level of D-dimer above 1 mg/dl was significantly associated with

mortality in COVID-19 patients7. Hospitalized patients with COVID-19 also characterized by

substantial in-hospital mortality and a high rate of thromboembolic complications12. The

alteration of coagulopathy pathway, such as from anticoagulant are expected to bring a good

benefit in COVID-19 patient. This theory supported by study from Ayerbe et al 10 this year

that proved an administration of heparin was associated with lower mortality in patients

admitted with COVID-19.

The 28-days mortality of heparin user in COVID-19 patients with D-dimer level 6-

fold greater than normal range were significantly lower than non-heparin user,as the

activation of coagulation also contributes to compartmentalization of pathogens and reduces

their invasion, therefore, anticoagulant treatment in patients without significant coagulopathy

has potential risk. This may explain the relatively lower mortality of heparin users comparing

to nonusers in patients with D-dimer greater than 6-fold normal level4. From this study we

can learn there is also essential to know the selection criteria of COVID-19 patient that

benefit outweight the risk from anticoagulant treatment.

Study from Paranjpe et al8 shows 177 patients associated with mortality with 24

bleeding events. The study mentioned that from 24 bleeding events, 9 patients had bleeding

before the systemic anticoagulant start and occured often in intubated patients. In this study,

the anticoagulation systemic shows decrease of mortality (95%CI 0,82-0,89; p<0,001). Study

from Gonzaleso-Porras et al11 further divide the anticoagulant heparin used in high dose and

low dose. The study shows that higher anticoagulant dose associated with reduced mortality

but significant bleeding event. On subgroup analysis, severe form of COVID-19 are using

high anticoagulant use. The effect of anticoagulant or severity of disease cannot be

determined in the influence of mortality rate in the study.

Anticoagulant use in ARDS patient receiving anticoagulant found decrease of

pulmonary embolism and venous thromboembolism event15. The mechanism of anticoagulant

decrease mortality in COVID-19 is thought to prevent coagulopathy in alveolar space. The

bronchoalveolar lavage and forensic speciment show there were fibrin and plasma fibrinogen
found16. Anticoagulant shows promising results in many study therefore it may be one of the

mechanism but studies should be conducted to prove this finding.

It must to be accounted that until now, there is no clear evidence about the optimal

dose of anticoagulant to be given for COVID-19 patients. Trinh et al 17 in 2020 by using

Kaplan-meier plot demonstrated that therapeutic dose of anticoagulant has a superiority in the

term of survivability of COVID-19 patients. In contrast, retrospective case study from Gil et

al9 in 2020 stated that prophylactic dose of anticoagulant tend to have greater benefit in

survivability of COVID-19 patients.

Safety of anticoagulant also must be taking into consideration when treated COVID-

19 patient. Major bleeding is most commonly occured side effect when patient was treated by

systemic anticoagulant. Study from Paranjpe et al8 shown that there was slightly increase of

major bleeding event of COVID-19 patient that was treaten by anticoagulant, although it is

not significant. In the future, there must be a criteria that can stratify the need of

anticoagulant in COVID-19 patient so the benefit can exceed the risk of the anticoagulant

treatment.Overall, sum of studies shows the benefit of anticoagulant LMWH systemic is

beneficial to reduce the mortality rate in COVID-19 patients either in severe or non severe

form.

There are some limitations in this study, The studies are only retrospective studies

without RCT trial included. There are 3 undergoing clinical trials admitted but from the day

this study is conducted, recruitment of patients are still on process There are no adjusting age

or other factors contribute in all the studies searches which cannot determine the effect of

systemic anticoagulant in such manner. Other limiting factors are there are still no effective

antiviral treatment, which duration of the treatment course is different and it is hard to

conclude the benefit or anticoagulation itself related to the progression of the disease.

Although significant from meta-analysis result, the extrapolation of these data studies should
be done with some caution because there are no randomized controlled trials involving

systemic anticoagulant or LMWH uses to strengthen this conclusion. Randomized controlled

study are needed to perform the better conclusion.

CONCLUSION

There are association of lowered mortality rate in anticoagulant user in COVID-19

patients regardless the severity of the disease in this study. The lowered mortality rate is

likely due to prevention of coagulopathy in COVID-19 patients.

ABBREVIATIONS

ARDS: Acute Respiratory Distress Syndrome

CMA: Comprehensive Meta-Analysis

COVID-19: Coronavirus Disease-2019

DIC: Disseminated Intravascular Coagulation

ICU: Intensive Care Unit

INR: International Normalized Ratio

LMWH: Low-Molecular Weight Heparin

NOS: Newcastle Ottawa Scale

RCT: Randomized Controlled Trial

RevMan: Review Manager

RT-PCR: Real Time-Polymerize Chain Reaction

VTE: Venous Thromboembolism

SIC: Sepsis-Induced Coagulopathy

REFERENCES

1. Li Q, Guan X, Wu P, et al. Early transmission dynamics in Wuhan, China, of novel

coronavirus-infected pneumonia. N Engl J Med. 2020. doi:10.1056/NEJMoa2001316

2. Atallah B, Mallah SI, AlMahmeed W. Anticoagulation in COVID-19. Eur Hear journal

CardiovascPharmacother. 2020. doi:10.1093/ehjcvp/pvaa036

3. Giannis D, Ziogas IA, Gianni P. Coagulation disorders in coronavirus infected patients:

COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past. J ClinVirol. 2020.

doi:10.1016/j.jcv.2020.104362

4. 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. J

ThrombHaemost. 2020. doi:10.1111/jth.14817

5. Kreuziger L, Garcia D, Cuker A, Cushman M, Connors J. COVID-19 and VTE-

anticoagulation. https://www.hematology.org/covid-19/covid-19-and-vte anticoagulation.

Access June 2020.

6. Wells G, Shea B, O’Connell D, Peterson J. The Newcastle-Ottawa Scale (NOS) for

assessing the quality of nonrandomised studies in meta-analyses. Ottawa, ON: Ottawa

Hospital Research Institute.

7. Garibaldi BT, Fiksel J, Muschelli J, et al. Patient trajectories and risk factors for severe

outcomes among persons hospitalized for COVID-19 in the Maryland/DC region.

medRxiv. 2020. doi:10.1101/2020.05.24.20111864

8. Paranjpe I, Fuster V, Lala A, et al. Association of Treatment Dose Anticoagulation with

In-Hospital Survival Among Hospitalized Patients with COVID-19. J Am CollCardiol.

2020. doi:10.1016/j.jacc.2020.05.001
9. Reyes Gil M, Gonzalez-Lugo JD, Rahman S, et al. Correlation of coagulation parameters

with clinical outcomes in Coronavirus-19 affected minorities in United States:

Observational cohort. medRxiv. 2020. doi:10.1101/2020.05.01.20087932

10. Ayerbe L, Risco C, Ayis S. The association between treatment with heparin and survival

in patients with Covid-19. J Thromb Thrombolysis. 2020. doi:10.1007/s11239-020-

02162-z

11. Gonzalez-Porras JR, Belhassen-Garcia M, Lopez-Bernus A, et al. Low Molecular

Weight Heparin in Adults Inpatient COVID-19. SSRN Electron J. 2020.

doi:10.2139/ssrn.3586665

12. Lodigiani C, Iapichino G, Carenzo L, et al. Venous and arterial thromboembolic

complications in COVID-19 patients admitted to an academic hospital in Milan, Italy.

Thromb Res. 2020. doi:10.1016/j.thromres.2020.04.024

13. Wichmann D, Sperhake JP, Lutgehetmann M, Steurer S, Edler C, et al. Autopsy findings

and venous thromboembolism in patients with covid-19. Annals of Internal Medicine.

2020. https://doi.org/10.7326/M20-2003

14. 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. doi:10.1101/2020.03.28.20046144

15. Barnes GD, Burnett A, Allen A, et al. Thromboembolism and anticoagulant therapy

during the COVID-19 pandemic: interim clinical guidance from the anticoagulation

forum. J Thromb Thrombolysis. 2020. doi:10.1007/s11239-020-02138-z

16. Helms J, Tacquard C, Severac F, et al. High risk of thrombosis in patients with severe

SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med.

2020. doi:10.1007/s00134-020-06062-x
17. Trinh M, Chang DR, Govindarajulu US, et al. Therapeutic Anticoagulation Is Associated

with Decreased Mortality in Mechanically Ventilated COVID-19 Patients. medRxiv.

2020. doi:10.1101/2020.05.30.20117929