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\begin{document}

\title{Vascular Emergencies -- The New COVID-19 Crisis?}



\author[1]{Pradeep Narayan}%
\author[2]{Gianni Angelini}%
\affil[1]{Rabindranath Tagore International Institute of Cardiac Sciences}%
\affil[2]{Bristol University}%


\vspace{-1em}



  
  \date{March 13, 2025}


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\begin{abstract}
The authors in this manuscript have reported an increase in the number
of vascular emergencies seen during the early phase of the COVID-19
pandemic in the Lombardy region of Italy. A significant increase in the
number of acute limb ischaemia was seen during this phase along with
other vascular emergencies. In this review, we have tried to examine
this association between increase in vascular emergencies and COVID-19
infection. We have also described the differences in presentations,
prognosis and procedural outcomes following operative interventions in
these patients compared to the non-COVID patients. An attempt has been
made to assess the role of adjunctive measures like intravenous heparin
to improve outcomes.%
\end{abstract}%



\sloppy


\textbf{Vascular Emergencies -- The New COVID-19 Crisis?}

Pradeep Narayan FRCS{[}CTh{]}*, Gianni D Angelini FRCS\^{}

*NH Rabindranath Tagore International Institute of Cardiac Sciences,
Kolkata, India

\textbf{Short Title:} Vascular emergencies in the COVID era

\textbf{Word Count} : 1250

\textbf{Corresponding Author:}

Prof GD Angelini, MD,MCh,FRCS, FMedSci

British Heart Foundation Professor of Cardiac Surgery,

Bristol Heart Institute Bristol Royal Infirmary,

Upper Maudlin Street~BS2 8HW

Bristol, UK

G.D.Angelini@bristol.ac.uk

Conflict of Interest: none

Funding: This work was supported by the British Heart Foundation and the
NIHR Biomedical Research Centre at University Hospitals Bristol and
Weston NHS Foundation Trust and the University of Bristol.

Key words: COVID-19, Cardiac Surgery, Vascular emergencies, Acute Limb
Ischemia, DVT

While the main presentation and focus of the Corona Virus Disease 2019
(COVID-19) has been lung injury, many other presentations have been
reported since the start of the pandemic. The authors in this very
pertinent and informative manuscript report the successful
implementation of the ``Hub-and-Spoke'' model of health care delivery
for vascular services in Lombardy, Italy during the early phase of the
pandemic. More importantly they have reported an increase in the number
of vascular emergencies seen in this phase. The authors have further
tried to explore if there is an association between this increase in
vascular cases and the current COVID-19 pandemic.\textsuperscript{1}

The spectrum of vascular involvement experienced in the different
``Hub'' and ``Spoke'' hospital was varied. In the author's own
institution which was a ``Spoke'' hospital, vascular presentation was
mainly for aortic pathology. However, the ``Hub'' hospitals reported a
significantly higher and unusual number of acute limb ischemia and
amputations.\textsuperscript{2,3} Seventeen cases of symptomatic carotid
artery stenosis requiring carotid endarterectomy were also reported over
a 7-week period at another ``Hub'' hospital.\textsuperscript{4} Besides,
an increase in the number of venous thrombosis and thrombo-embolism was
reported as well.\textsuperscript{5,6}

This increase in the number of vascular cases, majority of them
requiring urgent attention, is a very interesting observation and
deserves in-depth examination. Apart from assessing if this increase was
driven by COVID-19 we also must evaluate these cases for any differences
in terms of presentations, pathogenesis, prognosis, and outcomes of
operative interventions compared to non-COVID-19 patients.

While it is tempting to ascribe it to the ``Hub and Spoke'' model of
service delivery for vascular emergencies and argue that the increase in
limb ischemia was secondary to concentration of vascular emergencies at
the ``Hub'' hospitals it is quite likely that there is indeed ``a
vascular story'' as the authors describe it, in COVID-19 patients. When
the number of cases reported at one of the ``Hub'' hospitals was
compared with the preceding year it was seen that the increase was as
high as nine times the volume reported during the same period in the
preceding year. Similar increase was also seen in another ``Hub''
hospital which reported a seven-fold increase in the incidence of limb
threatening ischemia.\textsuperscript{4} This kind of increase is
unlikely to be the effect of the ``Hub and Spoke model'' alone.
Moreover, this is not a phenomenon that is unique to Lombardy but is
getting reported increasingly from other parts of the world too where
different healthcare delivery models exist. There are several reports
from other centres of young, non-atherosclerotic patients with COVID-19
presenting with upper and bilateral lower limb ischemia as well as
large-vessel strokes.\textsuperscript{7, 8}

It is also not the arterial system alone that seems to be affected by
COVID-19. In keeping with the authors' observations, an increase in the
prevalence of deep vein thrombosis (DVT) and venous-thromboembolism
among COVID-19 patients has also been reported
worldwide.\textsuperscript{5,6} DVT has been reported to be as high as
46\% and in the ITU setting, is four times more common in patients with
COVID-19, compared to those without it.\textsuperscript{9,10} Pooled
data from 12 studies have reported the risk of venous thrombo-embolism
to be 38\% in these cases despite prophylactic or therapeutic
anti-coagulation indicating a high risk of thromboprophylaxis
failure.\textsuperscript{11} In a small early autopsy study in COVID-19
deaths, unsuspected deep vein thrombosis was found in 58\% of COVID-19
patients, and pulmonary embolism was the cause of death in one-third of
the patients.\textsuperscript{12}

In fact as evidence grows it is now becoming apparent that the
pathogenesis of organ dysfunction (lungs, kidneys, liver and
gastrointestinal system) in many of these patients was thrombotic in
nature.\textsuperscript{13} And while the initial focus was mainly on
micro-vascular thrombosis it now appears that there is high incidence of
macro-vascular thrombosis as well as in COVID-19. A simple and
clinically relevant explanation for increased thrombogenicity has been
provided using Virchow's triad of hypercoagulability, stasis and
endothelial injury.\textsuperscript{14} The vascular endothelium is the
cornerstone of organ dysfunction and endothelial dysfunction results in
a pro-thrombotic state which can lead to microthrombi formation as well
as occlusion of bigger vessels.\textsuperscript{15} It has now been
suggested that COVID-19 is due to immune-triggered, complement-mediated
microangiopathy.\textsuperscript{13}

The presentation of vascular involvement in COVID-19 as noted in the
manuscript is extremely diverse. Apart from the aorto-iliac thrombosis
and involvement of both proximal and distal limb vessels involvement of
the Coronary artery, Subclavian artery, Cerebral and Carotid arteries,
and mesenteric artery have all been reported. Similarly, apart from DVT,
jugular and subclavian vein thrombosis as well as prostatic plexus
thrombosis has been reported to occur in COVID-19
patients.\textsuperscript{6,8,12,15-17}

What is especially worrying is the fact that limb ischemia is being
reported in previously healthy patients with no co-morbidities or
history of peripheral vascular disease. Not only that, even after
successful thrombo-embolectomy and return of pedal pulses, recurrence of
thrombosis within 2 hours have been reported in the absence of
atherosclerotic disease .\textsuperscript{7} Overall, the picture that
emerges is that of a seriously deranged intravascular coagulation milieu
and further illustrates that COVID-19 is associated with previously
underestimated but an inherently high risk of thrombogenicity.

Need for re-intervention as well as lower than expected successful
revascularization is another concern in management of these
patients.\textsuperscript{2,4} The thrombus burden is significantly
higher in these patients and there is a higher frequency of thromboses
involving proximal vessels. Patients with symptoms of leg ischemia with
concomitant COVID-19 infection are more likely to require amputation.
This association was found to be true even after adjustment for
peripheral vascular disease. The likely hood of death is also
significantly higher in these patients. In presence of leg ischemia and
COVID-19 infection presence of pulmonary or systemic symptoms put them
at higher risk of adverse outcomes.\textsuperscript{16}

Thus, not only has the incidence of acute limb ischemia actually
increases in COVID-19 but the disease severity, prognosis and outcome
following surgical revascularization are also quite different when
compared to patients with limb ischemia without concomitant COVID-19 .

While there is enough evidence available to suggest the presence of an
increased association between COVID-19 infected patients and risk of
venous and arterial thrombosis the understanding of measures to improve
outcomes is currently lacking. There is some suggestion that heparin
usage may be associated with better outcomes as one of the studies
showed that no patient who had received intravenous heparin required
re-intervention after revascularisation. Even though this was a small
study and statistically it was not a significant association it was
suggested that use of systemic heparin might improve surgical treatment
efficacy, limb salvage, and overall survival. The benefit of heparin
could be secondary to its anti-coagulant effect as well as its
anti-inflammatory properties that include inhibitory interactions with
multiple chemokines and complement.\textsuperscript{15, 18} Moreover,
heparin might also have anti-viral properties and prevents viral
attachment by acting on the virus spike
protein.\textsuperscript{19}Apart from anticoagulation the influence of
antiviral treatment, complement inhibition, immune-suppression, plasma
exchange and intravenous immunoglobulins have to be evaluated in future
studies.

The authors in this manuscript have initiated a very relevant discussion
and have raised several important questions. Based on the evidence there
is no doubt that the vascular burden in general and limb ischemia in
particular is significantly increased by COVID-19 infection. However,
many unanswered questions remain, especially those pertaining to the
management of this condition and improvement of outcome. Hopefully,
future studies will help answer some of them.

References:

1. Bissacco D. Is there a vascular side of the story? Vascular
consequences during COVID-19 outbreak in Lombardy, Italy. Journal of
Cardiac Surgery.

2. Bellosta R, Luzzani L, Natalini G, Pegorer MA, Attisani L, Cossu LG,
et al. Acute limb ischemia in patients with COVID-19 pneumonia. J Vasc
Surg {[}Internet{]}. 2020 Apr 29 {[}cited 2020 Sep 9{]}; Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188654/

3. Melissano G, Mascia D, Baccellieri D, Kahlberg A, Bertoglio L,
Rinaldi E, et al. Pattern of vascular disease in Lombardy, Italy, during
the first month of the COVID-19 outbreak. J Vasc Surg. 2020
Jul;72(1):4--5.

4. Mascia D, Kahlberg A, Melloni A, Rinaldi E, Melissano G, Chiesa R.
Single-Center Vascular Hub Experience after 7~weeks of COVID-19 Pandemic
in Lombardy (Italy). Ann Vasc Surg. 2020 Aug 5;

5. Baccellieri D, Apruzzi L, Ardita V, Rinaldi E, Bertoglio L, Melissano
G, et al. The ``venous perspective'' in Lombardia (Italy) during the
first weeks of the COVID-19 epidemic. Phlebology. 2020;35(5):295--6.

6. Lodigiani C, Iapichino G, Carenzo L, Cecconi M, Ferrazzi P, Sebastian
T, et al. Venous and arterial thromboembolic complications in COVID-19
patients admitted to an academic hospital in Milan, Italy. Thromb Res.
2020 Jul;191:9--14.

7. Perini P, Nabulsi B, Massoni CB, Azzarone M, Freyrie A. Acute limb
ischaemia in two young, non-atherosclerotic patients with COVID-19. The
Lancet. 2020 May;395(10236):1546.

8. Oxley TJ, Mocco J, Majidi S, Kellner CP, Shoirah H, Singh IP, et al.
Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young. N
Engl J Med. 2020 May 14;382(20):e60.

9. Zhang Li, Feng Xiaokai, Zhang Danqing, Jiang Chunguo, Mei Heng, Wang
Jing, et al. Deep Vein Thrombosis in Hospitalized Patients With COVID-19
in Wuhan, China. Circulation. 2020 Jul 14;142(2):114--28.

10. Zerwes S, Hernandez Cancino F, Liebetrau D, Gosslau Y, Warm T, M\selectlanguage{ngerman}ärkl
B, et al. {[}Increased risk of deep vein thrombosis in intensive care
unit patients with CoViD-19 infections?-Preliminary data{]}. Chir Z Alle
Geb Oper Medizen. 2020 Jul;91(7):588--94.

11. Hasan SS, Radford S, Kow CS, Zaidi STR. Venous thromboembolism in
critically ill COVID-19 patients receiving prophylactic or therapeutic
anticoagulation: a systematic review and meta-analysis. J Thromb
Thrombolysis. 2020 Aug 3;1--8.

12. Demelo-Rodríguez P, Cervilla-Muñoz E, Ordieres-Ortega L, Parra-Virto
A, Toledano-Macías M, Toledo-Samaniego N, et al. Incidence of
asymptomatic deep vein thrombosis in patients with COVID-19 pneumonia
and elevated D-dimer levels. Thromb Res. 2020;192:23--6.

13. Merrill JT, Erkan D, Winakur J, James JA. Emerging evidence of a
COVID-19 thrombotic syndrome has treatment implications. Nat Rev
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14. Ahmed S, Zimba O, Gasparyan AY. Thrombosis in Coronavirus disease
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2020 Sep;39(9):2529--43.

15. Pons S, Fodil S, Azoulay E, Zafrani L. The vascular endothelium: the
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16. Goldman IA, Ye K, Scheinfeld MH. Lower extremity arterial thrombosis
associated with COVID-19 is characterized by greater thrombus burden and
increased rate of amputation and death. Radiology. 2020 Jul 16;202348.

17. Wichmann D, Sperhake J-P, Lütgehetmann M, Steurer S, Edler C,
Heinemann A, et al. Autopsy Findings and Venous Thromboembolism in
Patients With COVID-19. Ann Intern Med {[}Internet{]}. 2020 May 6
{[}cited 2020 Sep 12{]}; Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240772/

18. Wada H, Matsumoto T, Suzuki K, Imai H, Katayama N, Iba T, et al.
Differences and similarities between disseminated intravascular
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11;16(1):14.

19. Mycroft-West C, Su D, Elli S, Guimond S, Miller G, Turnbull J, et
al. The 2019 coronavirus (SARS-CoV-2) surface protein (Spike) S1
Receptor Binding Domain undergoes conformational change upon heparin
binding. bioRxiv. 2020 Mar 2;2020.02.29.971093.

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