Circulation

PERSPECTIVE

Antiplatelet Therapy After Percutaneous

Coronary Intervention in Patients With COVID-19
Implications From Clinical Features to Pathologic Findings

O
n March 11, 2020, the World Health Organization officially declared the Xin Zhou, MD, PhD
novel coronavirus disease 2019 (COVID-19) a global pandemic. Consid- Yongle Li, MD, PhD
ering that ≈5 million percutaneous coronary interventions (PCIs) are per- Qing Yang, MD, PhD
formed worldwide annually, safety concerns exist about the effect of dual anti-
platelet therapy (DAPT) on bleeding complications, especially the risk for diffuse
alveolar hemorrhage, among patients infected with severe acute respiratory syn-
drome coronavirus 2 (SARS-CoV-2).
SARS-CoV-2 and SARS-CoV have a shared cellular target: angiotensin-convert-
ing enzyme 2. When comparing the clinical manifestations of infections with these
viruses, we found that thrombocytopenia (platelet count <150 000/μL), prolonged
thrombin time, and elevated D-dimer levels were observed frequently in both,1,2
suggestive of high likelihood of disseminated intravascular coagulation or pre–
disseminated intravascular coagulation. Diffuse alveolar hemorrhage was reported
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as a common finding in lung pathology in severe acute respiratory syndrome and

COVID-19.3,4
Although incompletely understood, previous findings from influenza pneumo-
nia revealed a mechanistic link between virus infection and the risk for diffuse
alveolar hemorrhage (summarized in the Figure), which starts with virus replica-
tion and dissemination, followed by alveolar endothelial dysfunction, platelet ac-
tivation, generation of neutrophil–platelet aggregates, neutrophil migration, and
fibrin and microthrombus formation; if left uncontrolled, these alterations would
trigger secondary fibrinolysis, coagulation factors depletion, and consequently
disseminated intravascular coagulation and diffuse alveolar hemorrhage. Diffuse
alveolar hemorrhage refers to a distinct form of life-threatening pulmonary hem-
orrhage that originates from pulmonary microcirculation (alveolar arterioles, capil-
laries, and venules) and should be distinguished from other causes of pulmonary
hemorrhage caused by localized abnormalities (bronchiectasis, malignancy, and
tuberculosis). Although alveolar hemorrhage can be localized, there are generally
multiple areas of involvement; therefore, the term “diffuse alveolar hemorrhage”
is preferred. In the rapid progressive and life-threatening form of viral pneumonia,
the underlying pathologic process is often diffuse alveolar hemorrhage. Collec-
tively, the pathologic and clinical features of COVID-19 are mechanistically linked
to high risk for disseminated intravascular coagulation and propensity for diffuse
alveolar hemorrhage.
The opinions expressed in this article are
In addition to thrombosis and hemostasis, emerging evidence supports a puta-
not necessarily those of the editors or
tive role of platelets in the host defense against infections, which adds a greater of the American Heart Association.
layer of complexity in evaluating the role of antiplatelet therapy in the setting of Key Words: coronavirus ◼ COVID-19
viral pneumonia. The following 3 issues should be taken into account when inter-
© 2020 American Heart Association, Inc.
preting the effect of antiplatelet therapy on disease progression. First, the timing
of administration is important. As summarized in the Figure, in the early phase https://www.ahajournals.org/journal/circ

1736 June 2, 2020 Circulation. 2020;141:1736–1738. DOI: 10.1161/CIRCULATIONAHA.120.046988

 Zhou et al Antiplatelet Therapy and COVID-19

FRAME OF REFERENCE
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Figure. The potential pathophysiologic evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in lung tissue and
implications for antiplatelet therapy.
Early antiplatelet therapy, especially P2Y12 antagonists, may be beneficial because of their inhibitory effects on platelet activation and generation of neutrophil–
platelet aggregates, key mechanisms in thrombus formation and pulmonary neutrophil recruitment.

of infection, platelet inhibition may reduce intravascu-
lar fibrin and thrombus formation, thereby preventing
the ensuing consequences. Aspirin use before hospi-
talization, but not after hospitalization, was associated
with lower risk of developing severe acute respiratory
distress syndrome and mortality in patients with com-
munity-acquired pneumonia. Second, the choice of oral
P2Y12 inhibitors deserves consideration. Although all
P2Y12 inhibitors reduce platelet–leukocyte aggregates
and platelet-derived proinflammatory cytokines from
α-granules, ticagrelor is unique in having the only well-
documented additional target of inhibition ENT1 (equili-
brative nucleoside transporter 1), contributing to inhibi-
tion of cellular adenosine uptake. Therefore, ticagrelor
confers more potent anti-inflammatory properties by
inhibiting platelet P2Y12 receptor and ENT1. The XAN-
THIPPE trial (Targeting Platelet–Leukocyte Aggregates in
Pneumonia With Ticagrelor; URL: https://www.clinical-
trials.gov; Unique identifier: NCT01883869), as well as
post hoc analyses of the PLATO study (A Comparison of
Ticagrelor [AZD6140] and Clopidogrel in Patients With
Acute Coronary Syndrome; URL: https://www.clinical-
trials.gov; Unique identifier: NCT00391872) and basic
research, provide evidence demonstrating the clinical
benefit of ticagrelor in the management of pneumonia
by preventing the complications of sepsis and reduc-
ing lung injury. Third, circulating platelet counts are
important. Both primary thrombocytopenia (immune
thrombocytopenia) and secondary thrombocytopenia
(enhanced consumption) are associated with increased
risk of infection (including pneumonia) and worsened
clinical outcomes associated with acute respiratory dis-
tress syndrome. Thrombocytopenia leads to loss of the
ability to deposit fibrinogen and to seal the damaged
pulmonary vasculature. Expert consensus warrants tak-
ing proactive measures or stopping antiplatelet ther-
apy in patients with a platelet count <100 000/μL or
<50 000/μL, respectively.
Emerging evidence suggests DAPT as an important
aggravating factor for diffuse alveolar hemorrhage,

Circulation. 2020;141:1736–1738. DOI: 10.1161/CIRCULATIONAHA.120.046988 June 2, 2020 1737

 Zhou et al
which could be mistaken as pneumonia initially because
FRAME OF REFERENCE
of similarities in clinical manifestations (ie, coughing,
radiographic evidence of mild infiltration, and fever).
Given the high bleeding risk in patients with COVID-19
after PCI, shorter-duration DAPT may be beneficial in
this population.
To counterbalance the increased bleeding risk as-
sociated with DAPT, emerging findings from large ran-
domized controlled trials provide evidence supporting
a net benefit of aspirin-free strategies after PCI for
patients at low, intermediate, and high risk for both
ischemia and bleeding, which is mainly driven by re-
duction in bleeding events. This strategy reduces the
duration of aspirin use (1 to 3 months) and allows for
more prolonged use of potent P2Y12 inhibitors. When
faced with the challenge of the COVID-19 pandemic
with insufficient evidence regarding appropriate anti-
thrombotic regimens for patients after PCI, we must
extrapolate information from related clinical scenarios
to assist in decision making. Among patients on DAPT,
maintaining P2Y12 inhibitor monotherapy (preferably
ticagrelor) may be scientifically reasonable for ≥3
months after PCI. DAPT should not be discontinued
<3 months after PCI. Considering recent experience
from China demonstrating the effectiveness of low-
molecular-weight heparin in reversing disseminated
intravascular coagulation in COVID-19,5 the Interna-
tional Society of Thrombosis and Hemostasis dissemi-
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nated intravascular coagulation scoring system and
platelet counting should be performed daily or more
frequently to identify patients who would benefit from
early low-molecular-weight heparin administration or
from discontinuation of P2Y12 antagonists because of
clinically meaningful thrombocytopenia. The trade-off
between ischemia and bleeding may be challenging
when patients take an oral P2Y12 inhibitor concomi-
tantly with an indication for low-molecular-weight
heparin prophylaxis. An alternative approach in this
setting would involve using an intravenous P2Y12 in-
hibitor such as cangrelor as bridge therapy.
The COVID-19 pandemic presents a unique oppor-
tunity to study key questions concerning the preven-
tive, therapeutic, or aggravating effects of antiplatelet
1738 June 2, 2020
Antiplatelet Therapy and COVID-19
therapy on viral pneumonia on the basis of nonran-
domized real-world data. Clinicians must be cognizant
of the effects of antiplatelet therapy in patients with
COVID-19.
ARTICLE INFORMATION
Correspondence
Qing Yang, MD, PhD, Department of Cardiology, Tianjin Medical University
General Hospital, 154, Anshan Road, Heping District, Tianjin 300052, China.
Email cardio-yq@tmu.edu.cn
Affiliation
Department of Cardiology, Tianjin Medical University General Hospital, China.
Acknowledgments
The authors thank Drs Haonan Sun, Zhijia Wang, Hangkuan Liu, Yifan Guo,
Chunpo Liang, and Chengcheng Wu for literature search and suggestions.
Sources of Funding
This work was supported by the Tianjin Municipal Science and Technology
Commission (18ZXZNSY00290) and the National Natural Science Foundation
of China (81970304).
Disclosures
None.
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Circulation. 2020;141:1736–1738. DOI: 10.1161/CIRCULATIONAHA.120.046988