REVISIÓN DE LA LITERATURA

COAGULOPATHY AND COVID-19: A REVIEW FOR MEDICAL PRACTICE.

Estrella Porter Jorge

, Del Castillo Arellano Jaime

, Añazco Villarreal Diego

, Ayala Mullo Juan

, Badillo Llerena Alejan-

dro

, Balcazar Medrano Dayanara

, Bolaños Romero Daniel

, Cañizares Quisiguiña Stalin

, Carrera Barriga Gabriela

, Di

Stefano Pelizzo Marco

, Espinosa Maza Jorge

, Espinosa Proaño Isabel

, Guamán Maldonado Lucia

, Guijarro Falcon

Katherine

, Guzmán Cerda Paola

, Iturralde Elena

, Moncayo Intriago Ruben

, Montalvo Silva Paola

, Moya Quitto Gusta-

, Muhammad Mendoza Iqrah

, Noboa Salgado Gabriela

, Ortiz Salazar Doménica

, Puertas Ruiz German

, Pullas Man-

tilla Tatiana

, Salazar Chuquimarca Cinthia

, Sosa Cifuentes Daniela

, Suarez Aguirre Fabian

, Vinueza Erazo Denise

Zambrano Real Esteban

, Zarate Cazorla Susan

, Zurita Salvador Danna

, Di Stefano Ciabatella Marcos

1,2,3

In December 2019, an outbreak of a new coronavirus disease (formally

known as COVID-19) was rst reported in Wuhan, China, and soon spread

around the world. On March 11, 2020, COVID-19 was declared as a

pandemic by the World Health Organization (WHO). So far, COVID-19

has proven to be a disease with multiorgan involvement, affecting the

hematological system as well. Patients with COVID-19, especially those

with moderate to severe disease, frequently experience a coagulopathy

associated with a high incidence of thrombotic events, which leads to poor

outcomes. The pathogenesis of COVID-associated coagulopathy (CAC), is

not fully understood yet, although the host inammatory response to the

infection appears to be a crucial element in the development of CAC.

IL2, IL-6, IL7, G-CSF, PI10, MIP1, and TNF alpha, among other molecules,

act as proinammatory cytokines that stimulate endothelium damage

and alter the coagulation homeostasis. CAC usually manifests as venous

thromboembolisms (VTE). While bleeding can also occur, it is a rare form

of presentation. Inpatients with COVID-19 must receive thromboprophylaxis,

mainly with low-molecular-weight heparin (LMWH); unfractioned

heparin can be accepted under certain circumstances. Patients with a

diagnosis or high suspicion of VTE should receive the complete doses of

anticoagulation treatment and must continue on it for at least three months.

Recommendations regarding prophylaxis and treatment may vary among

institutions and countries. There is not clear evidence for the regular use of

antiplatelet therapy in patients with COVID-19. This review will provide key

insights regarding the pathophysiology, clinical manifestations, diagnosis

and treatment of COVID-19 and its associated coagulopathy.

En diciembre de 2019, un brote de una nueva enfermedad formalmente

conocida como COVID-19 se informó por primera vez en Wuhan, China, y

pronto se extendió por todo el mundo. El 11 de marzo de 2020, el COVID-19

fue declarado pandemia por la Organización Mundial de la Salud - OMS.

Hasta ahora, el COVID-19 ha demostrado ser una enfermedad con

afectación multiorgánica, afectando también al sistema hematológico.

Los pacientes con COVID-19, especialmente aquellos con enfermedad

de moderada a grave, experimentan con frecuencia una coagulopatía

asociada con una alta incidencia de eventos trombóticos, lo que conduce

Revista Médica Vozandes

Volumen 32, Número 1, 2021

Resumen

COAGULOPATÍA Y COVID-19: UNA REVISIÓN PARA LA

PRÁCTICA MÉDICA

Abstract

Palabras clave: COVID-19, coagulopathy, SARS-CoV-2, coagulation, thrombosis.

Forma de citar este artículo: Estrella J,

Del Castillo J, Añazco D, Ayala J, Badillo

A, Balcazar D, et al. Coagulopathy and

COVID-19: a review for medical practice.

Rev Med Vozandes. 2021, 32 (1): 61-70

1 Universidad San Francisco de Quito - USFQ. Colegio

Ciencias de la Salud. Escuela de Medicina. Quito –

Ecuador.

2 Hospital Solón Espinosa Ayala – SOLCA: núcleo Qui-

to. Médico del servicio de Hematología/Citometría/

Biología Molecular. Quito – Ecuador.

3 Hospital de los Valles. Médico del servicio de Hema-

tología. Quito – Ecuador.

ORCID ID:

Estrella Porter Jorge

orcid.org/0000-0001-9773-661X

Del Castillo Arellano Jaime

orcid.org/0000-0003-4922-0066

Añazco Villarreal Diego

orcid.org/0000-0003-1829-7001

Ayala Mullo Juan

orcid.org/0000-0002-4484-5908

Badillo Llerena Alejandro

orcid.org/0000-0001-6264-3333

Balcazar Medrano Dayanara

orcid.org/0000-0003-4661-1109

Bolaños Romero Daniel

orcid.org/0000-0003-1505-3247

Cañizares Quisiguiña Stalin

orcid.org/0000-0003-4706-862X

Carrera Barriga Gabriela

orcid.org/0000-0002-1627-970X

Di Stefano Pelizzo Marco

orcid.org/0000-0002-5950-5340

Espinosa Maza Jorge

orcid.org/0000-0001-5120-6082

Espinosa Proaño Isabel

orcid.org/0000-0002-6060-344X

Guamán Maldonado Lucia

orcid.org/0000-0001-8490-5728

Guijarro Falcon Katherine

orcid.org/0000-0002-5152-4272

Guzmán Cerda Paola

orcid.org/0000-0002-6729-2816

Iturralde Elena

rcid.org/0000-0003-3552-4157

Moncayo Intriago Ruben

orcid.org/0000-0002-8687-7799

Este artículo está bajo una

licencia de Creative Com-

mons de tipo Reconocimien-

to – No comercial – Sin obras

derivadas 4.0 International.

DOI: 10.48018/rmv.v32.i1.5

Revista Médica Vozandes

Volumen 32, Número 1, 2021

Introduction

In late December 2019, a cluster of cases of pneumonia was

rst documented in Wuhan, Hubei Province, China. These

pneumonia cases from unknown etiology were originally

tracked to patients who visited a wet seafood market where

other exotic wildlife animals were sold as well.

(1)

Eventually,

a novel coronavirus was identied as the causative agent

of the disease: named SARS-CoV-2, this is a simple RNA type

beta-coronavirus

(2)

. At rst, the disease was known as “Wuhan

pneumonia”, since it was limited to people who lived in nearby

areas or who worked in that market, and then renamed as

COVID-19

(3)

. Since its discovery, the virus has been causing a

rapid and uncontrolled spread worldwide, leading to outbreaks

in almost every country, which has resulted in more than

114 million conrmed cases, and around 2.5 million deaths,

according to the CSSE at Johns Hopkins University. To this day,

COVID-19, declared a pandemic by the WHO in march 2020

(4)

is still spreading around the globe and due to its lack of specic

treatment and widely available vaccination campaigns in a

majority of countries, this disease stills represents a

big threat to public health

(5)

COVID-19 is a not-only-respiratory but a systemic

disease, with a range of clinical manifestations,

ranging from no symptoms at all to critical illness

and death

(6)

. The most common symptoms include

fever, cough, sore throat, malaise, headache,

muscle pain, nausea, vomiting, diarrhea, loss of

taste and loss of smell

(7)

. According to the NIH from

the United States of America, COVID-19 severity

can be classied as follows: asymptomatic

(individuals with no symptoms at all), mild disease

(individuals who have any of the signs and

symptoms of COVID-19 but who do not present

with difculty in breathing or abnormalities in chest

imaging), moderate illness (individuals who have

evidence of lower respiratory compromise during

clinical assessment or evaluation by imaging

COAGULOPATHY AND COVID-19: A REVIEW FOR

MEDICAL PRACTICE.

Estrella Porter J, et al.

a resultados poco satisfactorios. La patogénesis de la coagulopatía

asociada a COVID - CAC, aún no se entiende completamente,

aunque la respuesta inamatoria del huésped a la infección parece

ser un elemento crucial en el desarrollo del CAC. IL2, IL-6, IL7,

G-CSF, PI10, MIP1 y TNF alfa, entre otras moléculas, actúan como

citoquinas proinamatorias que estimulan el daño del endotelio y

alteran la homeostasis de coagulación. La CAC generalmente

se maniesta como tromboembolismos venosos (VTE). Mientras

que el sangrado también puede ocurrir, es una forma rara de

presentación. Los pacientes hospitalizados con COVID-19 deben

recibir tromboprolaxia, principalmente con heparina de bajo peso

molecular (LMWH); heparina no fraccionada puede ser utilizada

en algunas circunstancias. Los pacientes con un diagnóstico o alta

sospecha de VTE deben recibir las dosis completas anticoagulación

y el tratamiento debe extenderse por al menos tres meses más. Las

recomendaciones relativas a la prolaxis y el tratamiento pueden

variar entre instituciones y países. No hay evidencia clara para el uso

regular de tratamiento antiplaquetarios en pacientes con COVID-19.

Esta revisión proporcionará información clave sobre la siopatología,

las manifestaciones clínicas, el diagnóstico y tratamiento del

COVID-19 y su coagulopatía asociada.

Keywords: COVID-19, coagulopatía, SARS-CoV-2, coagulación, trombosis.

*Corresponding author: Di Stefano Ciabatella Marcos

E-mail: distefano.mt@gmail.com

Received: 6 – Jan – 2021

Accepted: 19 – Feb – 2021

Publish: 01 – Mar – 2021

Article history

Conflict of interest: All authors declared that there are no

conicts of interest.

Financial disclosure: The authors have no nancial relations-

hips relevant to this article to disclose.

Authors’ contribution: All the authors contributed in the

search selection of articles and writing. All the authors reviewed

and approved the nal manuscript.

Montalvo Silva Paola

orcid.org/0000-0002-6766-1271

Moya Quitto Gustavo

orcid.org/0000-0002-5948-4367

Muhammad Mendoza Iqrah

orcid.org/0000-0002-2278-872X

Noboa Salgado Gabriela

orcid.org/0000-0002-7439-2532

Ortiz Salazar Doménica

orcid.org/0000-0002-4646-2361

Puertas Ruiz German

orcid.org/0000-0002-7535-3842

Pullas Mantilla Tatiana

orcid.org/0000-0001-53156170

Salazar Chuquimarca Cinthia

orcid.org/0000-0002-5439-256X

Sosa Cifuentes Daniela

orcid.org/0000-0002-0567-339X

Suarez Aguirre Fabian

orcid.org/0000-0001-9361-050X

Vinueza Erazo Denise

orcid.org/0000-0002-4664-822X

Zambrano Real Esteban

orcid.org/0000-0002-6698-9056

Zarate Cazorla Susan

orcid.org/0000-0002-5670-4547

Zurita Salvador Danna

orcid.org/0000-0002-4813-0491

Di Stefano Ciabatella Marcos

orcid.org/0000-0002-6749-6261

REVISIÓN DE LA LITERATURA

Revista Médica Vozandes

Volumen 32, Número 1, 2021

techniques, and who have SpO2 ≥94% on room air at sea

level), severe illness (for individuals with SpO2 <94% on room

air at sea level, PaO2/FiO2 <300 mmHg, respiratory rate >30

breaths per minute, or lung inltrates compromising >50%)

and critical illness (individuals who have either respiratory

failure, septic shock, and/or multiple organ dysfunction)

(8)

Coagulopathy, an alteration in the normal homeostatic

state of the coagulation system, appears to be related with

COVID-19, especially to patients who develop moderate

to critical COVID-19 cases

(9)

. Several abnormalities related

to coagulation markers have been widely reported in

patients hospitalized with COVID-19, who are the ones who

present at least moderate disease. In fact, coagulopathy

is one of the most signicant prognostic factors in patients

who have COVID-19, as it is related with poor outcomes

(10)

The COVID-associated coagulopathy, CAC, is not yet

fully understood, but it has been associated with specic

markers, such as elevated D-dimer and brinogen levels,

as well as with thrombocytopenia, which tends to be mild,

and with modest prolongations of prothrombin time (PT) or

partial thromboplastin time (PTT), if any, making it different

to other coagulopathies associated to infection, such as

disseminated intravascular coagulation

(11)

. Considering that

CAC can affect as much as 20%-30% of patients with severe

disease, reaching almost 49% prevalence in those admitted

to ICU

(12)

, it is necessary to understand this clinical aspect of

COVID, in order to enhance a more comprehensive clinical

management. For this reason, this study aims to show the

key aspects of the CAC, including its pathophysiology,

diagnosis, evaluation and treatment, based in the state of

the art and the information available to this day.

COVID-19 and coagulation

COVID-19, the relatively new disease caused by the

SARS-CoV-2 virus, has been proved to be associated with

microthrombi formation in lung and other tissues

(13)

. As a

result, the term CAC, COVID-associated coagulopathy,

is now being used for dening mechanisms associated

with coagulopathy in COVID-19 patients

(14)

. There is still

controversy regarding the specic pathways involved in

its pathogenesis

(15)

. It is unclear whether it relies on current

known molecular mechanisms in clot homeostasis or if the

infection triggers a different reaction. For instance, SARS-

Cov2 may enter endothelial cells through the ACE2 receptor

stimulating the coagulation process

(13)

. Apparently, the

infection also causes a cytokine storm in certain patients,

characterized by the release of IL-6, IL-1β, TNF-α, granulocyte

colony stimulating factor (G-CSF), and interferon γ-inducible

protein (IP10) which ultimately enhance the expression

of P-selectin, vWF, TF and VEGF in the endothelial cells

(16)

As a result, vessels proliferate and platelets, which have

increased in number due to trophic cytokines, bind through

adhesion molecules, starting the coagulation cascade

(17)

However, it has also been proposed that, in contrast to other

virus, the interaction of SARS-CoV-2 within the coagulation

cascade may not be as important when compared to

other factors in the clot homeostasis

(18)

. This may interpret

endothelial damage as a result rather than a cause,

as it is well known that hyperviscosity, which is present

in some critical patients, can cause endothelial

damage

(15)

. The resultant systemic inammatory

response might also be independently associated

with thrombo-inammation

(16)

. All in all, it is very likely

that hypercoagulation in the COVID-19 context has

a multifactorial origin, but because of discordant

data, more research is still needed to provide an

accepted and fully proven pathogenic mechanism.

Pathophysiology

The liberation of cytokines as an initial in-

ammatory process

From a pathogenesis point of view, COVID-19

triggers an unrestrained cytokine production, which

contributes to the severity of the disease

(19)

. To start

with, SARS-CoV-2 is recognized via surface receptors

ACE2 and TMPRSS2. Its detection induces pyroptosis

of the infected cells when viral PAMs are recognized

by PRRs. Furthermore, the hosts cells destruction

generates DAMPs, such as ASC and nucleic acids

oligomers, which will be identied by neighboring

alveolar macrophages along with endothelial and

epithelial cells

(20)

. Subsequently, IL6 will be produced,

orchestrating further response. IL6 can activate

two possible pathways, cis and trans signaling. Cis

activation will induce both innate and acquired

immune response, promoting migration of B and T

cells, macrophages, neutrophils and natural killers. On

the other hand, trans pathway will act on endothelial

cells, giving rise to VEGF, MCP-1 (monocyte

chemoattractant protein -1), IL6, IL8 and reduced

E-cadherin

(21)

. Most of the hosts are able to control

the infection and minimize lung damage through

the mechanism previously described. Nevertheless,

some patients undergo an uncontrolled production

of cytokines that exacerbates not only lung damage

but also fosters multiorgan injury, and coagulation

cascade activation

(22)

The mechanism behind the production of a

cytokine storm is not fully understood, but a delayed

type 1 IFN (interferon) response may contribute.

SARS-CoV-1, and possibly SARS-CoV-2, contain

proteins that interrupt an early type 1 IFN response,

facilitating viral replication

(23)

. Thereafter, once

type 1 IFN reaction nally activates, it promotes a

disproportionate inltration of immune cells to the

parenchyma, hence, activating pro inammatory

cytokines such as IL2, IL7, G-CSF, PI10, MIP1, and

TNF alpha, and causing the most severe cases of

infection

(20)

. Undoubtedly, a hyperproduction of

cytokines and a proinammatory context induced

by SARS-CoV-2 links to the severity of the disease,

clinically evidenced by an acute respiratory distress

syndrome in which pulmonary microvascular and

alveolar epithelial cells are damaged, as part of the

pathophysiology of CAC

(24)

Revista Médica Vozandes

Volumen 32, Número 1, 2021

Procoagulating factors in vascular endothelium

Cytokine expression stimulates endothelial activation and

thrombosis, creating a connection between inammatory and

prothrombotic pathways. One explanation of this endothelial

affectation could be that SARS-CoV-2 induces an elevated

angiotensin release

(25)

. Therefore, angiotensin upregulates the

expression of ROS and dysregulates the activation of antioxidant

and vasodilatory pathways such as NOX2 and eNOS causing

endothelial damage. Moreover, ARDS created by a cytokine

storm, promotes pulmonary vasoconstriction and creates an

hypoxic environment which potentiates the cell damage

(23)

The second event is the prothrombotic effect, that is explained

by both, the activation of the intrinsic and extrinsic pathway

within an immunity-inammatory context

(26)

. On one hand, the

overexpression of tissue factor by the injured endothelial cells

and the activated macrophages, leads to the initiation of the

extrinsic pathway. And at the other hand, the intrinsic pathway

is initiated by the activation of factor XII as consequence of

intravascular DAMPS release mediated by NETOSIS

(27)

The third

mechanism associated is increased secretion of Von Willebrand

Factor due to the endothelial damage. Hence, the excessive

amount produces a deciency with ADAMTS13 in response

to viral systemic inammation

(28)

. Finally the excess of VWF

recruits platelets, which when activated produce neutrophils-

platelets complexes that causes micro-thrombogenesis within

microvasculature

(29)

. Another important event is that PROS1

is depleted by the formation of the clot. PROS1 serves as one

of the two activation ligands for the TAM family of the RTKs

receptor, an immunosuppressive activator. Thus, deciencies in

TAM receptor and PROS1 are associated with chronic immune

hyperactivation which leads to endothelial damage

(30)

Hypercoagulability (Thrombosis of microcirculation

and circulation, a systemic effect)

Once the cytokine storm is established following SARS-CoV2

infection and endothelial injury has occurred, an extensive

interplay is present among endothelial cells, monocytes/

macrophages, platelets, neutrophils, and proteins of the

coagulation cascade and complement pathways. The

interaction among all the above-mentioned components

lead to a hypercoagulable state with increased levels of

procoagulant and decrease in anticoagulant factors, and

hypobrinolysis

(23)

. The latter is the result of an imbalance

state between tPA/uPA and an excess of PAI-1, a nding that

may explain the brin deposits in the alveoli and perialveolar

capillary microthrombosis found in some ARDS patients

(31)

As the hyperinammation state expands, the immunothrombosis

process progresses and multiorganic dysfunction sets up

soon. This hypercoagulable state may be amplied by many

factors: hypoxemia because of ARDS (it induces HIF gene

factors expression which boost hypercoagulability through

augmentation of blood viscosity, activation of platelets and

coagulation factors, promoting further imbalance between

tPA/uPA and PAI-1, and inhibition of protein S

(32)

, hyperthermia

(it activates platelets) and/or hypovolemia due to negative

uids balance secondary to ARDS protocols treatment

(33)

Although not completely characterized yet, many studies have

mentioned the importance of antiphospholipid antibodies

(such as, anticardiolipin IgA, anti-β2 glycoprotein and lupus

anticoagulant) in the hypercoagulable state

found in some patients

(34)

Additionally, an aberration of the RAA system

could also explain many of the ndings seen in the

immuno-thrombosis process. As reviewed earlier,

SARS-CoV2 targets ACE2, thus preventing Ang-

II to be metabolized into Ang1-7; Ang-II induces

expression of TF and PAI-1, therefore, it contributes

to the imbalance state between tPA and PAI-1

(23)

Another remarkable nding that in part explains

why COVID-19 is more severe in obese patients, is

because AngII also stimulates PAI-1 release from

adipocytes via AT1 receptors

(35)

. Furthermore,

ACE protein metabolizes bradykinin into inactive

metabolites, consequently, preventing it from

exerting its vasodilation properties and release of

tPA, thus promoting hypobrinolysis

(36)

Clinical Manifestations

The initial clinical manifestations

The spectrum of thromboembolic manifestations of

patients with COVID-19 can be broad and appears

to have variations among different individuals

(37)

The hypercoagulable state that might appear

in individuals with COVID-19 is characterized

by venous and arterial thromboembolism,

although venous thromboembolism appears to

be more common. The most frequent clinical

manifestations are: deep venous thrombosis

(DVT), pulmonary embolism (PE), ischemic and

hemorrhagic stroke, myocardial infarction, and

arterial embolism

(38)

. Symptoms consistent with

DVT, such as asymmetric pain, swelling of the

lower extremities, local swelling of the lateral

limbs after catheterization of the central vein,

hypotension or any unilateral leg symptom,

or with PE like hypoxemia should be taken in

consideration for prevention and treatment of

COVID-associated coagulopathy

(39)

. Severe

COVID-19 patients should be screened for DVT

based on their inammatory markers and clinical

features. For the outpatient, the presence of any

of these symptoms should be highly suspicious for

DVT via telehealth, and if not, close monitoring

should be executed

(14)

Stratication of coagulation state in patients

Patients with COVID-19 infection have worse

prognosis if they develop coagulopathy during

the course of the disease

(40)

. Older age, the

presence of certain comorbidities or underlying

conditions, and some image ndings related to

coagulation abnormalities are also associated

with mortality in COVID-19 infection

(41)

COAGULOPATHY AND COVID-19: A REVIEW FOR

MEDICAL PRACTICE.

Estrella Porter J, et al.

REVISIÓN DE LA LITERATURA

Revista Médica Vozandes

Volumen 32, Número 1, 2021

Table 1. Factors to be considered for the evaluation of

COVID-associated coagulopathy

(42)

Age Older age is related to vascular and

homeostatic changes that increase the

risk of thrombotic complications.

Underlying

conditions

Severe pneumonia, admission to Inten-

sive Care Unit (ICU), Coronary Care Unit

(CCU) setting, Virchow triad

Comorbidities Diabetes, Coronary Artery Disease,

Obesity, Hypertension, Venous trom-

boemolism (VTE) and Cancer are

related to endothelial damage and

alterations in the coagulation cascade.

Other clinical

features

Unexplained sudden deterioration of

pulmonary status, acute lower erythe-

ma or swelling

Coagulation

markers

D-dimer

Prothrombin time

Activated partial thromboplastin time

Platelet count

Fibrinogen

Image ndings Echocardiography: Right ventricular

strain associated with Pulmonary Em-

bolism

Ultrasound: upper and lower limbs: eva-

luate Deep Venous Thrombosis (DVT)

* This table was originally created by the authors of this paper.

Coagulation markers, especially D dimer, are useful

tools for understanding the nature of the coagulopathy

and to classify it according the results, as well as other

factors that might be considered when evaluation

COVID-associated coagulopathy

(42)

(Table 1). The

three stages of COVID-19 Associated Hemostatic

Abnormalities (CAHA), proposed by Thachil and

collaborators, allow clinicians to categorize affected

patients in 3 stages that follow the pathophysiology of

the process, based in clinical aspect, laboratory and

image results, so as to establish a possible treatment for

their condition

(43)

. Table 2 was created to summarize

the 3 proposed stages. Evaluation of a patient with

COVID-19 infection must be done carefully in order

to aid early recognition, prognosis determination

and decision-making about the management of the

coagulopathy.

Diagnosis and Evaluation

Laboratory exams

A signicant proportion of COVID-19 patients

develop important coagulation abnormalities, which

may result in venous and arterial thromboembolic

complications

(44)

and increased mortality rates

(45)

Findings in COVID-19-associated coagulopathy, CAC,

may resemble other coagulopathies associated with

severe infection, such as sepsis induced coagulopathy

(SIC), disseminated intravascular coagulation (DIC),

hemophagocytic syndrome (HPS)/hemophagocytic

Table 2. Stages of COVID-19 Associated Hemostatic Abnormalities (CAHA) *

Stages Clinical aspect Laboratory markers Image studies

I Non-severe symptoms

Outpatient or Hospital

inpatient.

Elevated D-dimer (2 to 3 fold above normal)

Normal PT

Normal PTT

Normal or elevated platelet count

Normal or elevated brinogen

Usually none or missed

ndings on CT nor US for

pulmonary micro-thrombi or

DVT respectively

II Severe symptoms

Critical care support

required

Elevated D-dimer (3 to 6 fold above normal)

Mildly reduced platelet count (100 - 150 x

109)

Minor prolonged PT

Filling defects on CT (pulmo-

nary thrombi or emboli)

Asymptomatic DVT

III Clinically worsening pa-

tient.

Higher-level critical care

support (EMO)

Overt DVT

Multi-organ failure

Ischemia (gut, limbs,

coronary or cerebral

vasculature)

Elevated D-dimer (>6 fold above normal)

Signicant thrombocytopenia

Marked prolonged PT and PTT

Decreased brinogen

Extensive pulmonary throm-

bi that compromises both

lungs.

Systemic thrombosis.

PT: Prothrombin time, PTT: Partial thromboplastin time, CT: Computerized tomography, US: Ultrasound, DVT: Deep

Vein Thrombosis, EMO: Extracorporeal membrane oxygenation

* This table was adapted by the authors of this paper, based on the one created by Thachil and collabora-

tors, 2020

(43)

Revista Médica Vozandes

Volumen 32, Número 1, 2021

lymphohistiocytosis (HLH), antiphospholipid syndrome (APS),

and thrombotic microangiopathy (TMA); however, CAC should

be considered as a separate entity as it does not entirely t

in other coagulopathies

(18)

. The most common pattern found

in patients with CAC is an increased D-dimer value, relative

thrombocytopenia and a slightly prolonged prothrombin time

(PT)

(45)

. D-dimer values tend to be signicantly higher in patients

with CAC, and thrombocytopenia is usually less evident than in

other coagulopathies, such as DIC

(44)

. It is important to consider

that consumptive coagulopathy, which is a classical feature of

DIC and SIC, is not present in early-stage CAC

(12)

. Importantly,

prolongation of PT, degree of thrombocytopenia and D-dimer

elevation have been associated with a higher mortality in patients

with COVID-19

(46)

. Thus, a coagulation prole should be obtained in

hospitalized patients with COVID-19, including PT, activated partial

thromboplastin time (aPTT), D-dimer, platelet count and brinogen,

in order to identify CAC features and establish the prognosis

(47)

As mentioned before, a complex inammation cascade is

triggered in response to SARS-CoV-2 infection. This innate

response may activate the coagulation pathway, in a process

known as thrombo-inammation or immune-thrombosis.

Therefore, the abnormalities in the coagulation biomarkers

are most likely a result of the intense inammatory response,

rather than due to specic pro-coagulant properties of the

virus

(47)

. In severe cases of COVID-19, the hyperactivation of the

inammatory pathway can lead to an overproduction of pro-

inammatory cytokines between day 7 to 14 of the disease(48),

known as a cytokine storm, which may cause the symptoms of

the disease and eventually death

(49)

. The inammatory cytokines

and biomarkers that can potentially determine high risk patients

include interleukin IL-2, IL-6, IL-7, tumor necrosis factor-α (TNF-α),

macrophage inammatory protein 1-α (MIP1-α), granulocyte-

colony stimulating factor (G-CSF), lactate dehydrogenase (LDH),

C-reactive protein (CRP), ferritin, and D-dimer

(50)

The cytokines that are more likely to predict the severity of the

disease are IL-6 and IL-10(51). IL6 is a multifunctional cytokine

and a strong proinammatory effect, also is a key role in the

acute response and it is used as an early biomarker in sepsis

and lung injury and predictive factors of lung disease, organ

dysfunctions and mechanical ventilation

(52)

. IL-10 may be related

to compensatory anti-inammatory response in the severe forms

of the disease, and the reason of secondary infections in non

survivors

(53)

. The CPR, C-reactive protein, is induced by IL-6 in the

liver as a sensitive biomarker of inammation, infection or tissue

damage

(54)

. In COVID-19 patients, elevated levels of CPR in early

stage could reect lung lesions and disease severity

(55)

. On the

other hand, procalcitonin and serum ferritin have shown a poor

clinical prognosis, and a higher serum ferritin was associated

with acute respiratory distress syndrome (ARDS). Elevated

procalcitonin and lactate dehydrogenase can suggest a

secondary bacterial infection complicating the clinical course of

COVID-19 in severe cases

(48)

According to the NIH, in non-hospitalized patients with COVID-19,

there are currently no data to support the routine measurement

of coagulation markers (e.g., D-dimers, PT, aPTT, platelet count,

brinogen). However, in hospitalized patients with COVID-19,

hematologic, coagulation parameters and inammatory

biomarkers are commonly measured, although there are

currently insufcient data to recommend for or against using this

data to guide management decisions

(56)

Imaging and echography

Patients with severe COVID-19 infection

have an increased risk of developing venous

thromboembolism (VTE) and pulmonary

embolism (PE) due to an hypercoagulable

state, endothelial injury and immobilization

(47)

Considering this, a high-level of suspicion for

thromboembolism is warranted, especially if there

is any sign of respiratory deterioration in critically-

ill patients

(39)

. Deep venous thrombosis (DVT)

can be detected through bilateral compression

ultrasonography (CUS) of the legs, while PE

can be detected through echocardiography

or point-of-care ultrasonography (POCUS)

and computed tomography with pulmonary

angiography

(57)

. Table 3 (based in Manna

et. al 2020

(58)

and Torres et al. 2020

(59)

summarizes general ndings of complications

for thromboembolism and pulmonary embolism

found in different imaging device, which could

be helpful for a quicker diagnosis. First, for

ultrasonography, CHEST guidelines suggest a

routine ultrasound screening to detect DVT only

in critically ill (not in asymptomatic) patients or

situations like: suspected pulmonary embolism

(PE), unexplained ventricular dysfunction and a

refractory hypoxemia

(60)

. The utility of ultrasound

is based on its advantages like availability,

rapidity, and safety especially considering that

50-70% patients with PE have an underlying

DVT

(61)

. Second, echocardiography is not useful

as a screening tool due to its low sensitivity

and high rate of false-positive ndings in

diagnosis of PE. Furthermore, it lacks the ability

to visualize the pulmonary vessels

(58)

. Third, initial

routine imaging like chest X-ray do not provide

adequate information to diagnose PE, however,

indirect signs could be helpful (Table 3). Finally,

computed tomographic angiography (CTA) is

a powerful tool to stratify risk and detect PE in

hemodynamically stable patients

(58)

. Its limitations

include its low availability, higher chances of

transmission, difculty venous access, and the use

of contrast in renal impairment or allergy.

Management

When evaluating if there is high risk of

thromboembolism, physicians must consider

certain parameters that could guide the clinical

suspicion such as labored breathing, respiratory

rate >24/min, decreased SpO2 (<90%), elevated

C-reactive protein, rising D-dimers levels and

evaluating brinogen levels

(62)

Outpatient management

Despite the increased risk of coagulopathy

in COVID-19 patients, the NIH gives a strong

recommendation, based on expert opinion,

that for non-hospitalized patients with COVID-19,

anticoagulants and antiplatelet therapy

COAGULOPATHY AND COVID-19: A REVIEW FOR

MEDICAL PRACTICE.

Estrella Porter J, et al.

REVISIÓN DE LA LITERATURA

Revista Médica Vozandes

Volumen 32, Número 1, 2021

should not be initiated for the prevention of VTE or arterial

thrombosis. The only exception is given for patients who have

other indications for the therapy or who are participating in

a clinical trial

(56)

Table 3. General ndings of complications for throm-

boembolism and pulmonary embolism found in different

imaging device*

Imaging device Findings

Ultrasonography Visualization of the thrombus

Absence of color ow

Non-comprensible venous seg-

ment

Increased venous diameter

Echocardiography Right heart thrombus

McConnel sign+

paradoxical interventricular sep-

tal movements

Computed tomogra-

phic angiography

complete arterial occlusion

partial lling defects of the con-

trast

peripheral partial lling defects

forming acute angles with arterial

walls

Chest X-ray Westermark sign

Hampton’s hump

Fleischner’s sign

Palla’s sign

akinesis of the free wall of the right ventricle and hyper-

contractility of the apical wall

focal oligemia

pleural-based wedge shape consolidation because

pulmonary infarction

enlargement pulmonary artery

vascular prominence before arterial occlusion

* This table was originally created by the authors of this paper.

Inpatient management

All hospitalized patients with COVID-19 should receive

prophylactic therapy for venous thromboembolism (VTE)

(56)

. Parenteral anticoagulation is suggested with Low

Molecular Weight Heparin (LMWH), over Unfractionated

Heparin (UFH) and oral anticoagulants, unless there are clear

contraindications (e.g., active bleeding, serious bleeding

in the prior 24-48h, platelet count less than 25,000…)

(63)

. In

cases of renal replacement therapy or creatinine clearance

(CrCl) less than 15 mL/min, unfractioned heparin (UFH) is

recommended

(64)

. In patients with history of heparin-induced

thrombocytopenia, fondaparinux is the drug of choice

(65)

When feasible, it is reasonable to use strategies to minimize

infection risk by medical personal and patient contact (e.g.,

use of daily LMWH rather than thrice-daily UFH injections)

(66)

. This treatment should be continued until symptoms

and infection are resolved. The decision to continue post-

discharge thromboprophylaxis should consider the individual

patient’s risk factors (VTE, recent surgery, trauma or

immobilization), bleeding risks, and feasibility.

(56)

For those patients with COVID who are on therapeutic

anticoagulation for other indications such as atrial

brillation, mechanical cardiac valves, or long term

secondary VTE prevention, it is recommended to

receive full dose or a dose equivalent to their current

doses

(56)

. LMWH or UFH are preferred over direct oral

anticoagulants because their shorter half-lives, ability to

be administered intravenously or subcutaneously, and

fewer drug-drug interactions

(47)

. In patients who do not

have any therapeutic anticoagulation recommended

before admission but develop denitive VTE or

highly suspected VTE where standard conrmatory

testing cannot be performed, myocardial infarction,

clotting of vascular devices, despite prophylactic

anticoagulation, a full dose anticoagulation therapy

should be given unless there are contraindications

for anticoagulation

(56)

. Table 4 summarizes different

anticoagulation regimens based on type of

anticoagulant and different medical conditions.

Patients with conrmed venous thromboembolism

who are discharged from hospital, should continue

anticoagulation for a minimum time of three months

(67)

Intensive Care Unit management

In critically ill patients admitted to ICU the

thromboprophylaxis should be intermediate doses of

LMWH 40-60 mg daily drip to parenteral protocol to

target an active partial thromboplastin time (aPTT)

between 60-85s which are associated with better

outcomes and prognosis

(69)

. It is important to consider

BMI for adjusting doses. In cases of high hemorrhagic

risk, thromboprophylaxis will preferably be performed

with mechanical methods (intermittent pneumatic

compression). In these circumstances, it is suggested

to value the performance of viscoelastic tests as

a complement to the monitoring of hemostasis.

After the discharge of the patient in this condition,

thromboprophylaxis should be continued for up to

14-30 days, where LMWH or OAC can be used

(69)

Full dose anticoagulation for UCI patients should be

administered under the same recommendations as

for non-UCI patients. Patients who suffered VTE/DVT

should continue anticoagulation therapy for at least

3 months

(69)

New proposed approaches

A large NIH multiplatform, adaptive-design trial that

incorporates 3 global studies/networks (REMAP-CAP,

ATTACC and ACTIV-4A) was established to compared

the effectiveness of therapeutic dose anticoagulation

and prophylactic dose anticoagulation in

reducing the need for organ support over 21 days

in moderately ill or critically ill adults hospitalized

for COVID-19

(8)

. The results of the interim analysis,

released at the end of January 2021, suggest that full

dose anticoagulation might be superior to standard

care prophylactic dose anticoagulation (OR 1.5; 1.1

Revista Médica Vozandes

Volumen 32, Número 1, 2021

– 2.2) in lowering the need for organ support and mortality in

moderately ill hospitalized COVID-19 patients, understood as

those patients who required in-hospital management different

to ICU. This same interim analysis suggests the futility of full

dose anticoagulation in reducing the need for organ support

and mortality, compared with usual care prophylactic dose

anticoagulation in patients managed at the ICU, which are

considered to be severe cases

(14)

. Peer review analysis is still

pending. However, we recommend considering this new data

when deciding prophylaxis treatment of COVID-19 associated

coagulopathy in patients with moderate to severe disease.

Treatment of bleeding

Bleeding does not seem to be a major manifestation of patients

with COVID-19

(70)

. However, patients may have bleeding for

other reasons, like trauma and/or anticoagulation therapy. The

approach to bleeding is similar to individuals without COVID-19

and involves anticoagulant reversal and/or discontinuation,

transfusions for thrombocytopenia or hypobrinogenemia, or

specic therapies such as factor replacement

(71)

Role of antiplatelet therapy

The role of antiplatelet agents is currently under

study. Antiplatelet therapy administration is not

recommended outside of standard indications

(71)

It is reasonable to continue antiplatelet therapy

if the individual is already receiving it for another

justied indication

(72)

Conclusion

The link between COVID-19 and a

hypercoagulable state has been well

documented in the previous months, and it is

associated with acute inammatory changes

and particular laboratory ndings that make

it different from those of acute disseminated

intravascular coagulation (DIC). COVID-

associated coagulopathy, CAC, is especially

prevalent in patients with moderate to severe

COAGULOPATHY AND COVID-19: A REVIEW FOR

MEDICAL PRACTICE.

Estrella Porter J, et al.

Table 4. Anticoagulation doses in COVID-19 patients, as recommended by Massachusetts General Hospital

(68)

Enoxaparine Unfractionated Hepa-

rin (UFH)

Fondaparinoux Argatroban Bivalirudin

Standard

dose

1mg/kg SQ q 12h Venous thromboem-

bolism (VTE) or Atrial

brillation (Ab): 80

units/kg bolus + 18

unitis/kg/hr infusion

Acute coronary syn-

drome (ACS): 60 unit/

kg bolus + 12 units/kg/

hr infusion

<50kg: 5mg SQ

q 24h

50-100 kg: 7.5

SQ mg q 24h

>100kg 10 SQ

mg q 24h

0.25 mcg/kg/

min (usual star-

ting dose)

0,15 mg/kg/hr

Renal

Adjustment

CrCl 15-29 ml/min:1

mg/kg SQ q 24h

CrCl ¬<15 ml/min :

consult with phar-

macy and local

protocols

No dose adjustment CrCl < 30 ml/

min Use is not

recommended

No dose ad-

justment

CrCl 30-60 mL/

min: 0.05 mg/

kg/hr

CrCl <30ml/min:

0,025 mg/kg/hr

Hepatic

Adjustment

No dose adjustment No dose adjustment No dose ad-

justment

Moderate

(Child-Pugh B) :

0.5 mcg/kg/min

Severe

(Child-Pugh C):

Use bivalirudin

No dose

adjustment

Obesity

BMI>40 kg/

CrCl >30 ml/min:

0.75 mg/kg q 12h

CrCl < 30 ml/min;

0.75 mg/kg q 24h

>150 kg : Use is not

recommended

Consult with Pharma-

cy and local protocols

>100kg:10 mg

q 24h

Limited Data

Consult local

with Pharmacy

and local pro-

tocols

Limited Data

Consult local

with Pharmacy

and local pro-

tocols

* This table was adapted by the authors of this paper, based on the one created by Massachusetts General Hospital, 2020

(68)

REVISIÓN DE LA LITERATURA

Revista Médica Vozandes

Volumen 32, Número 1, 2021

disease, and certain factor are related with an increased risk

for developing it, like being managed at the ICU, older age

and comorbidities (see Table 1). Among laboratory ndings,

brinogen and D-dimer tend to be increased, with only

modest prolongation of both the prothrombin time (PT) and

the activated partial thromboplastin time (aPTT). Regarding

platelets, mild thrombocytosis or thrombocytopenia are

typically seen. The pathogenesis of these abnormalities is

not fully understood yet, although the host inammatory

response to the infection appears to be a crucial element

in the development of CAC.

Generally, all patients admitted to the hospital with a

diagnosis of COVID-19 should have a laboratory test done,

which must include baseline complete blood count, with

platelet count, PT, aPTT, brinogen, and D-dimer. People

being managed in the outpatient setting do not require

coagulation testing, unless there is another justied indication

for it. Imaging studies might be appropriate when there is a

high-level of suspicion for VTE, which includes deep venous

thrombosis and pulmonary thromboembolism (see Table 3).

A scale based on the stages of CAC can be used to better

understand and classify patients with a hypercoagulable

state related to COVID-19 (see Table 2).

All inpatients must receive thromboprophylaxis unless there

is a clear contraindication, while outpatients should not

receive it unless clearly justied by another reason. New

preliminary data suggests that full dose anticoagulation

might be superior to standard care prophylactic

dose anticoagulation in lowering the need for organ

support and mortality in moderately ill hospitalized

COVID-19 patients; this same new data points out

the futility of full dose anticoagulation in reducing

the need for organ support and mortality in patients

managed at the ICU, compared with usual care

prophylactic dose anticoagulation. Peer review is still

needed before making this recommendation widely

available.

Low molecular weight heparin (LMWH) is generally

preferred to unfractionated heparin or oral

anticoagulants, but unfractionated heparin can

be used if LMWH is not available or if there is severe

renal impairment (see Table 4). Protocols may vary

by institution and country. Full therapeutic dose of

anticoagulation is appropriate when deep vein

thrombosis (DVT) or pulmonary embolism (PE) are

conrmed or highly suspected. This therapy must

be continued for at least three months. For patients

who did not have an episode of venous thrombosis,

thromboprophylaxis after discharge from the

hospital is not recommended. Bleeding is much less

common than thrombosis, and when it occurs, the

management should follow the recommendations

given for patients who do not have COVID-19. There

is no clear role for antiplatelet therapy.

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