Pulmonary Thrombosis in Moderate Covid-19 Patients

Based on Contrast Enhanced Conventional Chest Ct : A Case Series

Noni Novisari Soeroso1*, Aziza Ghanie2, Wan Betty Pratiwi1, Rosita Juwita Sembiring3
1
Department of Pulmonology and Respiratory Medicine, Faculty of Medicine Universitas
Sumatera Utara, Universitas Sumatera Utara Hospital, Medan, Indonesia.
2
Department of Radiology, Public Hospital Center Persahabatan, Universitas Pembangunan
Nasional, Jakarta, Indonesia.
3
Department of Clinical Pathology, Columbia Asia Hospital
*Corresponding author : Noni Novisari Soeroso. Department of Pulmonology and
Respiratory Medicine, Faculty of Medicine Universitas Sumatera Utara, Universitas
Sumatera Utara Hospital. Medan, Indonesia. Jl. Dr. T. Mansyur no. 66. Email :
noni@usu.ac.id

ABSTRACT
The primary pathogenesis of COVID-19 disease was associated with hypercoagulation and
pulmonary intravascular coagulation, which was different from sepsis-associated
disseminated intravascular coagulation (DIC) with relatively normal prothrombin time (PT),
fibrinogen levels, and platelet counts, despite markedly elevated D-dimer levels. We reported
a case series of COVID-19 patients with hypercoagulable states characterized by increased
levels of D-Dimer, but no significant increase in PT, APTT, fibrinogen and no significant
levels of platelets and confirmed by the findings of pulmonary artery occlusion in contrast
enhanced conventional chest CT which showed filling defect in pulmonary artery which is
pulmonary thrombosis occurred.
Keywords: COVID-19, hypercoagulopathy, pulmonary thrombosis, contrast enhanced chest
CT.

INTRODUCTION
SARS-CoV2 binds to ACE2 receptors on type II pneumocytes and vascular
endothelial cells, which leads to procoagulant activity and activates fibrin deposit
accumulation in pulmonary microcapillary veins [(1)]. Pathological evidence from series of
autopsies showed main pathogenic mechanism of pulmonary intravascular coagulopathy
(PIC) that triggered local haemostasis activation, driven by the interaction between platelets
and endothelium, initiating microthrombi formation in COVID-19 [(2),(3)]. Thrombus that
locally occurred in the lungs, not an embolism from the peripheral veins, is called Pulmonary
Thrombosis [(4)].

These four case reports are about four patients confirmed to have moderate degree
COVID-19 with hypercoagulopathy and pulmonary thrombosis. The coagulation profiles of
all 4 patients are summarized in Table 1.

Table 1. Patient’s coagulation profiles

Cases D-Dimer ApTT* PT** Fibrinogen Thrombosit
(< 500 (25”- (12”– 18”) (210-456 (150.000-
ng/mL) 35”) mg/dl) 450.000)
1. Male, 77 years old 8.758 39.8 18.7 367 179.000

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 2. Female, 56 years 305.000
814.8 38.4 13.2 627
old
3. Female, 58 years 146.000
801 29.2 14.3 367
old
4. Female, 31 years 175.000
1.475 26.3 12.6 361
old
* ApTT control : 34,0
** PT control : 15,2
Case 1
The first case was a male patient, 77 years old, admitted to the emergency room (ER) with
complaints such as shortness of breath that was not related to any activities, nor the location
and weather, fever, and followed by nausea and vomiting for 4 days before the hospital
admission. The patient had history of pulmonary tuberculosis, hypertension, coronary heart
disease, gout, and drug eruptions. No abnormalities were found in clinical examination. Chest
X-ray (CXR) showed bilateral pneumonia. RT-PCR (Real-Time – Polymerase Chain
Reaction) swab test was positive and the patient was diagnosed with moderate degree
COVID-19. Contrast enhanced chest CT and laboratory tests were performed. Laboratory
results showed hypercoagulopathy, while contrast enhanced chest CT provided an image of
filling defect in the distal right pulmonary artery, descending branch of the right pulmonary
artery, and main pulmonary artery. indicating pulmonary thrombosis.

Figure 1. (A) Axial CT showing a filling defect in the distal right pulmonary artery (white
arrow). (B) Filling defect in the descending branch of the right pulmonary artery (yellow

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arrow) and Right pleural effusion (red arrow) and (C) filing defect in the main pulmonary
artery (black arrow).

Case 2
The second patient was 56-year-old female, admitted to the ER by the family members with
complaints such as shortness of breath that was not related to any activities, nor the location
and weather, cough with phlegm, and fever for 3 days before the hospital admission. The
patient was without comorbidities. Abnormalities were found on thoracic physical
examination, where there were crackles. The patient’s chest X-ray (CXR) showed bilateral
pneumonia. RT-PCR swab test was positive and the patient was diagnosed with moderate
degree COVID-19. Contrast enhanced chest CT and laboratory tests were performed.
Laboratory results showed hypercoagulopathy, while contrast enhanced chest CT provided an
image of filling defects in the right distal main pulmonary artery and right pulmonary artery
due to pulmonary thrombosis.

Figure 2. (A&B) Filling Defects in the right distal main pulmonary artery and right
pulmonary artery due to pulmonary thrombosis (white arrow)

Case 3
The third patient was a female, 46 years old, admitted to the ER with shortness of breath for 3
days before hospital admission that was related to activity. The patient also had complaints
such as cough with phlegm for 3 days. The patient had history of pulmonary tuberculosis and
type 2 diabetes with insulin and OAT treatment course. No abnormalities were found in
clinical examination. Chest X-ray showed bilateral pneumonia image. RT-PCR swab test was
positive and the patient was diagnosed with moderate degree COVID-19. contrast enhanced
chest CT and laboratory tests were performed. Laboratory results showed hypercoagulopathy,
while contrast enhanced chest CT provided an image of filling defect in right main
pulmonary artery and small branch of right pulmonary artery, indicating pulmonary
thrombosis.

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Figure 3. (A) Enhanced CT shows filling defect in right main pulmonary artery (white arrow)
and (B) small branch of right pulmonary artery (white arrow) due to pulmonary thrombosis.

Case 4
The last patient (patient number 4) was a 31-year-old female admitted to the ER with cough
and phlegm, and fever complaints about 2 days. There were also complaints about headaches
and generalized weakness. The patient had no history of diseases. No abnormalities were
found in clinical examination. Chest X-ray showed bronchopneumonia bilateral. RT-PCR
swab test was positive and the patient was diagnosed with moderate degree COVID-19.
contrast enhanced chest CT and laboratory tests were performed. Laboratory results showed
hypercoagulopathy, while contrast enhanced chest CT provided an image of filling defect in
the right pulmonary artery, indicating pulmonary thrombosis.

Figure 4. (A) Filling defect in the right pulmonary artery (red arrow), (B) normal size main
pulmonary artery and right pulmonary artery

All four patients in the above cases were confirmed to have moderate degree COVID-
19 and diagnosed with thrombosis in the pulmonary blood vessels.

DISCUSSION
This case series was created by using data from four COVID-19 patients with
pulmonary thrombosis. All patients in this case had elevated D-dimer levels but no significant
increase in PT, APTT, fibrinogen, no significant levels of platelets. Contrast enhanced

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Conventional chest CT performed showed filling defects that indicated pulmonary
thrombosis.
The lung pathology seen in patients with coronavirus disease 2019 (COVID-19)
shows marked microvascular thrombosis and haemorrhage linked to extensive alveolar and
interstitial inflammation that shares features with macrophage activation syndrome (MAS).
Vascular immunopathology associated with COVID-19 as diffuse pulmonary intravascular
coagulopathy, which in its early stages is distinct from disseminated intravascular
coagulation[(2)]. Interactions between the innate immune system, coagulation activation and
endothelial dysfunction are evident in COVID-19 and as understanding of SARS-CoV-2
increases, it is becoming clear that immunothrombosis plays a pivotal role in the pathogenesis
of severe COVID-19 disease [(5)]. Immunothrombosis is a component of the innate immune
system, triggered by pathogens or cell damage, whereby activation of coagulation occurs
secondary to inflammation, and consequently microthrombi are formed within small vessels
[(6)]
Although the primary pathogenesis was assumed as type II pneumocyte in pulmonary
injury, viral pneumonia, acute respiratory disease syndrome (ARDS), or macrophage
activating, such as ARDS leading to DIC (Disseminated intravascular coagulation), the
pathological evidence from autopsy series showed that the main pathogenic mechanism was
pulmonary intravascular coagulopathy (PIC), which was a type of immune thrombocytopenia
different from classic DIC [(2)].
Endothelial dysfunction in COVID-19 may occur through multiple mechanisms and
precipitating factors. Direct invasion of SARS-CoV-2 into endothelial cells causes cellular
damage that disturbs intercellular junctions and exposes prothrombotic subendothelial
collagen. Internalisation of the ACE2 receptor causes an imbalance of Ang1-7 and AngII, in
favour of the latter. Accumulation of AngII promotes the endothelial expression of P-selectin,
tissue factor (TF) and von Willebrand factor (VWF). Intracellular viral replication within
endothelial cells results in their activation and expression of an array of prothrombotic
proteins. Expression of these prothrombotic proteins activates the extrinsic coagulation
cascade. Simultaneous recruitment of platelets to the site of endothelial injury further
contributes to hypercoagulability [(7)].
Acute EC activation and damage triggers secretion of high molecular weight von
Willebrand factor (VWF) multimers normally stored within Weibel Palade bodies. This
results in high local concentrations of VWF. Large VWF strings anchored on the EC surface
can then tether circulating platelets and recruit neutrophils and monocytes. In addition, WPB
secretion results in externalization of P-selectin to the EC surface where it facilitates
leukocyte and platelet adherence. Enhanced expression of other adhesion molecules,
including VCAM-1, ICAM-1, and E-selectin, further promote neutrophil and monocyte
recruitment. TF expression on EC and monocytes, coupled with NETosis, leads to
coagulation cascade activation. Moreover, normal anti-coagulant pathways on the EC surface
are down-regulated.[(8)]
Additionally, inflammation affects fibrinolysis by promoting local release of tPA and
PAI-1 from EC. Significant amounts of PAI-1 are also secreted from activated platelets, and
TAFI and α2-antiplasmin levels are both increased. Consequently, fibrinolysis is attenuated
in severe COVID-19. Furthermore, EC tight-barrier junctions become disrupted leading to
enhanced permeability and extravasation. The net effect of this dysregulated
immunothrombosis is the generation of platelet- and fibrin-rich thrombi and pulmonary vaso-
occlusion [(8)]. Importantly, intra-alveolar fibrin deposition was also observed post-mortem
and hypothesized to contribute to the increased d-dimer levels [(9)]
Thrombus formation in the microvasculature could be a part of physiological effort to
limit viral load [(3)]. The biochemical features of COVID-19- associated coagulopathy

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include elevated D-dimer, elevated fibrinogen, mildly prolonged/normal pro-thrombin time
and mildly reduced/normal platelet count.[(10)] Tang et al. studied 183 patients with novel
coronavirus and compared the coagulation parameters between survivors and
nonsurvivors;on admission, non-survivors were found to have significantly higher D-dimer,
fibrin degradation products (FDP) levels and a mildly prolonged pro-thrombin time (PT)
compared to survivors.[(11)]
Lately, there were different opinions between pulmonary embolism and pulmonary
thrombosis. There was an increasing acknowledgment that COVID-19 related haemostatic
disorders could cause local thrombosis in the lungs. Two main phenotypes in COVID-19
patients with thrombolytic lung injury could be identified, such as venous thromboembolism
(VTE) and pulmonary microthrombosis (PMT). Since deep venous thrombosis (DVT) or
other VTE sources were not consistently found in COVID-19 patients with pulmonary
embolism, PMT (Pulmonary micro thrombosis) could be the result of local
hypercoagulability rather than secondary to embolization from the lower limbs [(12)]. Post-
mortem studies in COVID-19 have consistently reported the presence of thrombi in both the
micro- and macro-vasculature of the lungs. Composed predominantly of platelets and fibrin,
these thrombi have been identified in precapillary arteries, alveolar capillaries, as well as
postcapillary venules [(13),(14)].
One study questioned whether the pulmonary artery occlusions described in COVID-
19 patients were exclusively caused by pulmonary embolisms. The report stated that
pulmonary artery filling defects detected in CTA (Computed tomography angiography) scan
showed more pulmonary thrombosis cases than pulmonary embolisms because they were not
completely occlusive [(4)]. Dual-energy CT imaging has been used to examine lung
perfusion and investigate for pulmonary embolism/infarction in COVID-19, with some
suggesting that scan appearances are more in keeping with pulmonary thrombosis in situ
rather than pulmonary embolism [(15)].
This observation aligned with the postmortem description of the manifestation of
thrombotic microangiopathy, or thrombo-haemorrhagic, pulmonary artery enlargement that
contained microthrombus. Therefore, thrombus that occurred locally in the lungs and not an
embolism from the peripheral veins was the distinct characteristic of severe COVID-19. The
administration of 40 mg of enoxaparin for thromboprophylaxis in COVID-19 patients was
believed to prevent thrombus in the lungs [(4)].
In conclusion, this case series shows that patients diagnosed with Moderate-grade
COVID-19 have hypercoagulopathy state, characterized by increased levels of D-Dimer, but
no significant increase in PT, APTT, fibrinogen and no significant levels of platelets .
Further, pulmonary artery occlusion might be found on Contrast Enhancement Conventional
Chest CT that shows pulmonary artery occlusion. All these findings suggest that pulmonary
thrombosis has occurred in the course of COVID-19. So thromboprophylaxis using
enoxaparin 40 mg for COVID-19 patients is recommended to prevent pulmonary thrombosis
in COVID-19 patients.

ACKNOWLEDGEMENTS
The authors would like to thank Aziza Ghanie and Rosita Juwita Sembiring for as a clinical
pathologist and their expertise in acquiring the radiological images

COMPETING INTERESTS
The authors declare any actual or potential conflict of interest in this study.

AUTHOR’S CONTRIBUTION

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 The authors confirm their contribution to this paper. The NNS is in charge of
collecting data and interpreting of cases. WBP and AG arranged for the preparation of the
draft manuscript. All authors reviewed the results and approved the final version of the
manuscript.

ETHICAL CONSIDERATIONS
Written consent was obtained for the publication of the case series and accompanying
images.

FUNDING INFORMATION
This research received no specific grant from any funding agency in the public, commercial,
or not-for-profit sectors.

DATA AVAILABILITY
Data sharing is not applicable to this article, as no new data were created or analysed in this
study.

DISCLAIMER
The views and opinions expressed in this article are those of the authors and do not
necessarily reflect the official policy or position of any affiliated agency of the authors.

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