Acute limb ischemia is characterized by a sudden
decrease in blood perfusion that endangers the viability of the limb.[
9] Although hypercoagulability
conditions are rare causes for ALI, the incidence
of thromboembolic complications can be observed
up to 40%, particularly in cases with a COVID-19
infection.[
10] In addition, critically ill patients have
an even higher risk of both venous and arterial
thromboembolism, which is associated with high
mortality.[
11] As we found in the present study,
ALI was associated with an early mortality rate of
27.5% and late mortality rate of 12.5%, although the
reported mortality in non-COVID-19 populations
with ALI ranges from 5 to 9% in the literature.[
12] In
parallel with our current finding, comparative studies
have also shown that the incidence of thrombotic
events, such as stroke, is higher in COVID patients
compared to others.[
13]
Another important point to focus on is whether
the incidence of ALI as a result of COVID-19
varies by age, sex, comorbid factors, and ethnicity.
In the current study, most of our patients admitted
with ALI and COVID-19 were male, and patients
generally had additional comorbidities, such as
hypertension, diabetes mellitus, and coronary artery
disease. Other studies in the literature also reported
cases with similar sex and age distribution and
comorbidities.[6] However, ALI has been reported to
occur in patients suffering from COVID-19 without
known peripheral arterial disease, even in young
patients without comorbidity or previous significant
atherosclerosis.[8,14] Although these new reports
associated with ALI are available, more efforts are
needed to understand the COVID-19 disease due to
the lack of large population-based studies that can
confirm this observation.
The pathophysiology and phenotype of ALI in
COVID-19 are still the subject of research. Severe
acute respiratory syndrome coronavirus 2, like other
members of the coronavirus family, causes isolated
respiratory tract infection. However, in some patients,
inappropriate triggering of the immune system may
cause the release of cytokines and chemokines, leading
to multiple organ failure.[15] Factors causing ischemia
in COVID-19 patients can be considered endothelial
damage, coagulopathy and hypercoagulability
conditions, hyperimmune reaction, and platelet
aggregation. Although myocardial damage and
arrhythmia caused by COVID-19 infection can lead
to thromboembolic events, the virus can also directly
cause vascular endothelial damage.[16] In addition,
complement activation also causes endothelial cell damage, leading to cell death and the release of
thrombogenic basement membrane. It was reported
that more than 70% of patients died from COVID-19-
related disseminated intravascular coagulation.[17]
High D-dimer levels, fibrinogen degradation
products, and prolonged thromboplastin and
prothrombin times in COVID-19 cases have been
associated with higher in-hospital mortality and the
need for mechanical ventilation.[18] High levels of
D-dimer may have predictive value for the occurrence
of arterial thromboembolic events in COVID-19
patients. Monitoring the values of D-dimer and
fibrin breakdown products can help the clinician with
the early diagnosis of severe cases of COVID-19-
related thromboembolism.[19] In our study, the levels
of fibrinogen, D-dimer, and other laboratory markers
at the time of diagnosis of ALI were examined in
all patients. In addition, the effects of preoperative
laboratory markers on early and late mortality in the
study were investigated. There was no association
of D-dimer levels with early and late mortality.
However, white blood cell count, neutrophil count,
C-reactive protein, PRC, IL-6, lactate dehydrogenase,
and median ferritin levels of the group with early
mortality were significantly higher than the group
without early mortality. Fibrinogen median levels of
the group with late mortality were also significantly
higher than the group without late mortality. Due to
the small number of patients, the relevant data may not
be meaningful. However, an optimal cut-off level and
its prognostic value in COVID-19-related ALI cases
are still unknown. In addition, a certain cut-off value
related to markers may be determined by prospective
studies with a large number of patients in terms of
their effects on mortality.
Essentially, COVID-19 patients who develop an
upper or lower limb injury usually have a large clot
burden, which is an anatomically more common
disease and is accompanied by higher amputation
rates.[20] Therefore, it is recommended to perform
complete imaging with CTA from the aortic arch
to the upper and lower extremities in such patients.
Detection of other thromboembolic events, such as
pulmonary thromboembolism, cardiac thrombus,
and aortic thrombus, using whole-body CTA
scan is of great benefit to the clinician. After a
detailed CTA evaluation, the recommendations
in the guidelines should be applied in the initial
management of ALI patients. These include
adequate analgesia, intravenous rehydration, oxygen therapy, and intravenous heparin
administration.[8,21] Therapeutic anticoagulation
with intravenous unfractionated heparin should be
provided following the diagnosis of ALI, unless
there are significant contraindications, such as
active severe bleeding or recent surgery within
48 h. There is no published study that shows the
superiority of a particular anticoagulant.
As an initial strategy, all patients in the current
study were given LMWH during their hospital
stay and for one month after discharge if they
did not have active bleeding or a high-risk profile
for major bleeding. Rivaroxaban treatment as oral
anticoagulation after the procedure was preferred in
long-term follow-up.
The choice of endovascular or surgical methods
after initial treatment may vary depending on
the experience of the clinician and the clinic. In
patients admitted with ALI, treatment should not be
postponed regardless of the severity of COVID-19,
and treatment should be applied urgently according to
current guidelines.[4] Endovascular procedures such
as catheter-mediated thrombolysis and mechanical
thrombectomy may be preferred in selected patients.
Although reported in some publications, systemic
thrombolysis is not recommended as the initial
treatment of ALI in severe COVID-19 patients due
to a lack of supporting evidence.[22] In patients with
a demarcation line and motor loss, the decision on
the timing of major amputation should be made
according to the severity of COVID-19 symptoms. In
our clinical experience and the patient's preference,
surgical methods are preferred for the management
of COVID-19-related ALI cases. Open surgical
treatment using thromboembolectomy remains
the most common revascularization technique in
many countries and centers.[7] We perform surgical
embolectomy using appropriate brachial, femoral,
and popliteal incisions. In contrast, intra-arterial
locoregional thrombolysis using alteplase can be
considered an adjunct to thromboembolectomy,
particularly in patients with residual distal thrombus
and foot ischemia. Regional anesthesia may be
preferred instead of general anesthesia to avoid
any airway manipulation in COVID-19 cases.[23]
Although there is no scientific evidence to support
this theory, we performed our local anesthesia
procedures under sedation whenever possible in our
clinical practice. In addition, a total complication
rate of almost 17.5% and an amputation rate of 7.5% were present in our study, and the majority
of these were major amputations. In comparison to
clinical series previously reported in the literature,
successful revascularization in COVID-19 patients
in our study was disappointingly low.[24] Medical
follow-up in selected comorbid patients may be
superior to surgery in patients with COVID-19-
associated ALI. It is difficult to make a definite
comment on this issue. It would be more accurate
to develop patient-based treatment strategies, and
wider publications may surely shed light on what
should be done.
Although COVID-19, which had a high mortality
rate during the pandemic period, appears to have
decreased, its effects still continue, albeit low, and
should be taken into consideration. Additionally, the
effects on long-term vascular pathologies are still a
matter of research.
There are some limitations to this study. This
study was a single-center retrospective study with a
small sample size. Randomized controlled studies
of larger populations are needed to assess its general
applicability and management strategy.
In conclusion, the choice of patient-based
endovascular or surgical methods to be applied after
appropriate anticoagulation in COVID-19, where
high thrombotic events are observed, is crucial in
terms of reducing morbidity and mortality rates.
In cases of ALI associated with this disease, the
chances of successful revascularization are relatively
less. In some selected comorbid patients, medical
follow-up may be superior to surgery. Development of
patient-based treatment strategies for the treatment
of COVID-19-associated ALI is essential.
Ethics Committee Approval: The study protocol was
approved by the Ankara Bilkent City Hospital Ethics
Committee (date: 19.04.2021, no: E1-21-1747). The study
was conducted in accordance with the principles of the
Declaration of Helsinki.
Patient Consent for Publication: A written informed
consent was obtained from each patient.
Data Sharing Statement: The data that support the
findings of this study are available from the corresponding
author upon reasonable request.
Author Contributions: Idea/concept: A.Ö., G.Y.; Design:
A.Ö., M.Y.; Control/supervision, critical review, references
and fundings: H.Z.İ.; Data collection and/or processing,
materials: A.Y., E.B.G.; Analysis and/or interpretation: G.Y.,
M.Y.; Literature review: A.Ö., G.Y., A.Y., E.B.G.; Writing
the article: A.Ö., G.Y., A.Y.
Conflict of Interest: The authors declared no conflicts
of interest with respect to the authorship and/or publication
of this article.
Funding: The authors received no financial support for
the research and/or authorship of this article.