review article

Patients with chronic venous insufficiency in the

COVID-19 era and thrombotic risk – guidelines for
conservative patient management resulting from the
basics of pathophysiology
Pacjenci z przewlekłą niewydolnością żylną w dobie COVID-19 i ryzyko
zakrzepowe – wskazówki dotyczące leczenia zachowawczego chorych
wynikające z podstaw patofizjologii
Authors’ Contribution:
A – Study Design
Zbigniew Krasiński1ADE, Aleksandra Krasińska2AD, Szymon Markiewicz1EF, Maciej Zieliński1FC
B – Data Collection
C – Statistical Analysis
1
Department of Vascular and Endovascular Surgery, Angiology and Phlebology, Institute of Surgery, Medical University of Poznan,
D – Manuscript Preparation Poland; Head: prof. Zbigniew Krasiński MD PhD
E – Literature Search 2
Chair and Clinic of Ophthalmology, Faculty of Medicine, Poznan University of Medical Sciences, Poland;
F – Funds Collection Head: prof. Jarosław Kocięcki MD PhD

Article history: Received: 15.03.2021 Accepted: 26.04.2021 Published: 27.04.2021

ABSTRACT: The current limitations of surgical treatment, as well as restrictions on professional and sport activities related to COVID-19
pandemic require seeking therapeutic solutions for the vast population of patients with chronic venous insufficiency (CVI,
chronic venous insufficiency). To understand the principles of pharmacotherapy of this disease, the authors used data related
to epidemiology and pathophysiology of CVI. They provided the latest data on venoactive drugs and recommendations that
should be followed and summarized the literature based on the EBM. The article should provide the answer to the question
of how to deal with patients with varicose veins or, more broadly, chronic venous insufficiency during the pandemic.
KEYWORDS: COVID-19, CVI, pharmacotherapy, varicose veins

STRESZCZENIE: Obecne ograniczenia w leczeniu operacyjnym, a także ograniczenia dotyczące aktywności zawodowej i sportowej związane
z pandemią COVID-19, nakazują szukanie rozwiązań w postępowaniu terapeutycznym dla olbrzymiej populacji chorych
z przewlekłą niewydolnością żylną (ang. chronic venous insufficiency; CVI). Dla zrozumienia zasad farmakoterapii tej jednostki
chorobowej autorzy posłużyli się danymi dotyczącymi epidemiologii oraz patofizjologii CVI. Przytoczyli też najnowsze dane
dotyczące leków wenoaktywnych i zaleceń, których należy przestrzegać. Syntetycznie podsumowali dane z piśmiennictwa
oparte na EBM (ang. evidence-based medicine). Ma to być odpowiedź na pytanie: jak postępować w czasie pandemii z chorymi,
którzy mają żylaki lub – szerzej – przewlekłą niewydolność żylną?
SŁOWA KLUCZOWE: COVID-19, farmakoterapia, przewlekła niewydolność żylna, żylaki

ABBREVIATIONS syndrome coronavirus 2; SARS-CoV-2). The fear of infection re-

sults mainly from the extent of the pandemic, high virulence of
ACCP – American College of Chest Physicians the pathogen, but also from ignorance and misinformation of me-
BMI – Body Mass Index dical professionals, especially when they are not involved in ma-
CVI – Chronic Venous Insufficiency nagement of patients with infectious diseases on a daily basis [1].
EBM – Evidence Based Medicine These days it is already known that the consequences of this disease
NLPZ – Non-Steroidal Anti-Inflammatories on our health and life are very significant. Symptoms associated with
PTS – Post-Thrombotic Syndrome chronic venous insufficiency are observed to worsen in patients. Many
VADs – Vaso-Active Drugs patients with COVID-19 develop deep vein thrombosis. One of the
VCSS – Venous Clinical Severity Score risk factors for venous thrombo-embolism (VTE) is varicose veins
VTE – Venous Thrombo-embolism of the lower extremities, which is reflected, for example, in Caprini's
VV – Varicose Veins surgical scale of risk assessment of thromboembolic complications.
WHO – World Health Organization Currently, the American College of Surgeons' COVID-19 guidelines:
Elective Case Triage Guidelines for Surgical Care do not recommend
surgery for varicose veins of the lower extremities [2]. So the qu-
INTRODUCTION estion has arisen, how to deal with patients who have varicose veins
or – more broadly – chronic venous insufficiency in the pandemic
At the beginning of 2020, the world was informed about an outbre- era? To understand the whole issue, reference should be made to the
ak in China caused by a new coronavirus (Severe acute respiratory basics of research on chronic venous insufficiency (CVI) and VTE.

42 DOI: 10.5604/01.3001.0014.8500 WWW.PPCH.PL

 review article

Tab. I. Classification of chronic venous insufficiency – CAEP [10] – modified.

CLINICAL CLASSIFICATION (C)

C0 without subjective symptoms of vein disease

C1 telangectasias and reticular veins

C2 varicose veins

C3 oedema

C4a skin hyperpigmentation or eczema

C4b lipodermatosclerosis or atrophie blanche

C5 healed venous ulcer

C6 active venous ulcer

Adding "S" in the subscript to the above-mentioned indicates presence of symptoms such as pain,
S tenderness, tightness, skin irritation, heaviness, muscle spasms and other symptoms which may be
associated with vein disease.
A Adding "A" in the subscript to the above-mentioned means there are no subjective symptoms.

(A)ETIOLOGY (E)

Ec inherited

Ep primary

Es secondary (post-thrombotic)

En venous aetiology unknown

ANATOMICAL LOCALIZATION (A)

As superficial veins

Ap perforating veins (perforators)

Ad deep veins

An indefinite localization

PATHOPHYSIOLOGY (P)

Pr reflux

Po obstruction

Pr,o reflux and obstruction

Pn without reflux and obstruction

AETIOLOGY AND EPIDEMIOLOGY OF CHRONIC
VENOUS INSUFFICIENCY AND THE RESULTING
THERAPEUTIC GUIDELINES IN CONSERVATIVE
TREATMENT
Chronic venous insufficiency is a wide spectrum of venous diseases
– from telangiectasias (spider veins) and reticular veins, through varico-
se veins (VV), oedema of the lower limbs, to very serious and advanced
forms of venous disorders, including ulcerations. CVI includes symp-
toms such as skin discoloration, eczema, lipodermatosclerosis, atrophie
blanche with healed or active ulcers. Symptoms associated with CVI
are widespread and have a big impact both on the patient's individual
health and on the whole healthcare system. Lower limb varicose ve-
ins occur in about 5–30% of the adult population, although according
to various reports this percentage ranges from 1% to 70% [3]. VV is
more common in industrialized countries. The prevalence (number of
cases reported over a given period) of CVI varies significantly across
POL PRZEGL CHIR 2021: 93 (2): 42-51
different publications. In Framingham’s study, the annual incidence
of varicose veins in the lower limbs was 2.6% among women and 1.9%
among men [4]. A prospective study confirmed the presence of vari-
cose veins in the lower limbs in 19% of men and 25% of women [5].
In other studies, skin changes in the course of CVI were reported
in 3% of men and 3.7% of women, and the prevalence, regardless of
gender, increased significantly with age and was 1.8% in the group
of people aged 30–39 for women (increasing to 20.7% over the age
of 70) and for men – 1.1% (increasing to 24.2% over the age of 70)
[6–8]. The most frequently discussed and best-studied clinical form
of CVI are VVs of the lower limbs. Since 1994, the CAEP classifica-
tion (clinical sings, anatomic distribution, (a)etiologic classification,
pathophysiologic dysfunction) has been used for the assessment
of chronic diseases of veins (Tab. I.). It takes into account clinical
symptoms on a scale from 0 to 6, in which telangiectasias and re-
ticular veins present the first degree of clinical stage, while varico-
se veins present the second degree. Commonly accepted divisions
43
 review article
Varicose
Telangiectasias veins Oedema
Pharmacological
therapy
Sclerotherapy
Compression
therapy
Local treatment
Surgical treatment
Fig. 1. D
 iagram showing the type of recommended treatment depending on the severity of chronic venous insufficiency.
distinguish between: (1) primary varicose veins (95%), occurring
with the normal condition of deep veins and (2) secondary (5%),
which are the result of insufficiency of deep perforating veins or
arteriovenous fistulas [9, 10].
Based on clinical and epidemiological studies, CVI risk factors
have been identified, which include: older age, pregnancy, obe-
sity, genetic predisposition, reduced mobility, chronic standing
or sitting position, constipation. Female gender has always been
considered as a significant risk factor, although recent studies
indicate that these differences are wearing off in industrialized
countries. Other behavioral factors such as smoking, physical
activity and a diet low in fiber may also play a role [7]. The most
advanced form of CVI – venous leg ulceration (active or healed)
– affects approximately 1% of the adult population. Risk factors
for the development of venous ulcers of shins in the first instance
are family history of ulceration on maternal side, physical activity
or previous deep vein thrombosis. Summarizing this fragment
with regard to the situation of patients in the COVID-19 era, it
should be emphasized that restrictions related to mandatory qu-
arantine, repeat lockdowns, movement and travel restrictions,
gym closures can lead to or make worse symptoms of CVI. Follo-
wing the rules of triage, we should not operate on varicose veins,
therefore we should treat patients in such a way as to minimize
the progression of the disease and the risk of complications, the
most dangerous of which is VTE [1, 2] Patients should be cau-
tioned that their CVI symptoms may be worsening at present.
More frequent swelling, night cramps, heavy legs or venous clau-
dication may develop. All who develop these symptoms can be
treated conservatively . It is not without significance that CVI
affects people of working age, i.e. those whose activity is curren-
tly very limited. This shows us the target population for conse-
rvative treatment, i.e. patients with a history of CVI, women on
hormone therapy (contraception or hormone replacement the-
rapy), people working in a sitting position and those working in
warm temperatures. The diagram of factors which have influen-
ce on the development of CVI is shown in Fig. 1.
44
Trophic Healed Active
changes ulceration ulceration
PATHOPHYSIOLOGY OF CHRONIC VENOUS
INSUFFICIENCY AND RESULTING THERAPEUTIC
GUIDELINES IN CONSERVATIVE TREATMENT
Chronic venous insufficiency develops when venous pressure rises
and blood return is disturbed by several mechanisms, primarily due
to insufficiency of valves of superficial or deep axial veins, perforator
valves, venous obstruction or various coexistence of the above pa-
thologies. Dysfunction of the muscle pump or the plantar network
(rete venosum plantare) also contributes to venous pathology. Such
situational dysfunction takes place while studying or working remo-
tely, when people who carry out those tasks for many hours do not
get or stand up. Immobilization of the shin muscles in particular is
the equivalent of CVI in healthy people, which means that even in
people with healthy veins symptoms of insufficiency can be obse-
rved, such as swelling, leg heaviness or restless legs. These mecha-
nisms cause venous hypertension, especially when standing or in
a sitting position. In case of valve insufficiency in the deep veins,
which are the main route for blood outflow from the lower extremi-
ties, there is a significant volume overload associated with normal
arterial blood inflow from the capillary side and pathological veno-
us blood as the result of retrograde inflow (reflux). The dysfunction
or insufficiency of the valves in the superficial venous system may
look similar, leading to reflux and – as a consequence – increased
hydrostatic pressure. The causes of valve insufficiency may be pri-
mary and occur in connection with the pre-existing weakening of
venous wall of vessels or may result from: direct damage, thrombo-
phlebitis (inflammation of superficial veins) or excessive vein wide-
ning due to effect of sex hormones (pregnancy, use of oral contra-
ceptives). Valve insufficiency at the point of contact with the deep
system, especially the sapheno-femoral or the sapheno-popliteal
system, causes the transfer of high pressure from the deep system
to the superficial veins. High pressure can also be transferred from
the deep to the superficial system through insufficient perforators.
In patients with varicose veins of the lower extremities, valve pa-
thology occurs in about 60–70% of saphenous or lesser sapheno-
us veins. In contrast, the most common venous tributaries where
WWW.PPCH.PL

High Hormonal
external factors
temperature
Long-term Increasing
hydrostatic stretch
load of venous wall
Increasing distal
pressure
Organization
Valve damage
Recanalization
Fig. 2. D
 iagram of factors which have influence on development of chronic venous insufficiency.
reflux is found without its presence in the trunk veins are those
of the saphenous (65%), small saphenous (19%) or both (7%). Im-
portantly, the presence of reflux in a single tributary may contri-
bute to disease progression in other superficial or deep veins. In
patients with post-thrombotic syndrome, valve damage and valve
insufficiency as well as chronic deep vein obstruction associated
with venous thrombosis cause persistent hypertension both at
rest and while walking. Again, referring to the current COVID-19
situation in patients who had symptoms of venous insufficiency,
we can expect an exacerbation of their symptoms. The dysfunc-
tion of the muscle pump, also influenced by the restrictions rela-
ted to the pandemic, leads to ineffective venous blood emptying
within limbs. Clinically significant muscle pump disorders often
occur with severe reflux or obstruction. Muscle pump disorders
are a factor contributing to the development/worsening of veno-
us insufficiency and complications associated with venous ulcers.
Haemodynamic disturbances in large veins of the lower extremi-
ties contribute to disturbances at microcirculation level. Moreover,
valve dysfunction at the microcirculation level may play an impor-
tant role and occur independently of dysfunction in the large vein
system. Various mechanisms can lead to the development of chan-
ges in the microcirculation. The most frequently mentioned are
the theories of fibrin cuffs, leukocyte trap and growth factor trap.
Fibrin cuffs resulting from a disturbance of fibrinolysis, deposited
in the pericapillary space, increase diffusion barrier, inhibit repair
and support inflammatory processes. The theory of white blood
cell capture in capillaries (or post-capillary venules) suggests that
this mechanism leads to leukocyte activation and development of
POL PRZEGL CHIR 2021: 93 (2): 42-51
review article
P
Genetic
factors
Normal
vein
varicose
vein
V
Valve
insufficiency
Reflux – superficial Reflux – perforating
veins veins
Varicose veins Hormonal factors
Venous stagnation Hypercoagulability
Thrombosis
inflammation. The related mechanism of capturing of growth fac-
tors makes them inaccessible for tissue repair and healing. Based
on these data, a practical conclusion is the use of drugs that will
raise the venous tone and seal venous walls.
CHRONIC VENOUS INSUFFICIENCY SEVERITY
SCORES
For objective clinical assessment of degree of CVI severity the
Venous Clinical Severity Score (VCSS) was created which is ba-
sed on 10 descriptors/characteristics (identifiers), which include:
pain, varicose veins, swelling, hyperpigmentation, inflammation,
induration, number of ulcers, duration of ulceration, ulcer size and
compression therapy [11]. A scale of 0 to 3 (none, mild, modera-
te, severe) has been used to grade the severity. VCSS seems to be
more useful for assessment of changes and treatment outcomes
than clinical component of the CAEP classification. Both scales
are presented in Tab. I. and II. In the VCSS, a feature that should
be understood broadly is pain, but also symptoms such as: leg he-
aviness, weakness, burning, itching. Abnormal veins were consi-
dered as varicose veins when their diameter was 3 mm or more in
a standing position. Venous oedema should have a venous aetiolo-
gy, which may be indicated by the following symptoms: appearan-
ce of oedema at the end of the day and in the standing position or
presence of varicose veins. Swellings which occur every day sho-
uld be considered as significant. Inflammation means: erythema,
cellulitis, venous eczema and dermatitis. Venous induration refers
45
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Tab. II. Clinical scale of the severity of chronic venous insufficiency – Venous Clinical Severity Score [11] – modified.

Attribute Absent – 0 Mild – 1 Moderate – 2 Severe – 3

Sporadically, does not restrict Daily, has influence on
Pain None Daily, restricting activity
daily activity activity, but does not restrict
Varicose veins None Single varicose veins Limited to calf or thigh Calf and thigh
Above ankles, but limited
Oedema None Limited to foot and ankles to calf Calf and above

Skin pigmentation None or focally Limited, perimalleolar Disseminated, above 1/3 calf Diffuse, above 1/3 calf
Moderate celulitis,
Inflammation None Disseminated, above 1/3 calf Diffuse, above 1/3 calf
perimalleolar ulceration
Induration None Limited, perimalleolar Disseminated, above 1/3 calf Diffuse, above 1/3 calf
Number of ulcers 0 1 2 3 and more
Not healed
Ulcer duration – < 3 months > 3 i < 12 months > 12 miesięcy
Ulcer size – < 2 cm 2–6 cm > 6 cm
Compression therapy Not applied Sometimes Most days All the time

to skin and subcutaneous tissue, including: chronic lesions asso-
ciated with fibrosis, atrophie blanche and lipodermatosclerosis.
The longest lasting active ulcer is taken as the time of ulceration,
while the active ulcer size is the one with the greatest diameter or
surface area in patients with multiple ulcers.
Nowadays most advice is given remotely, so it is difficult to use
scales based on visual assessment of limbs. However, patients can
be asked to measure the circumference of the limb in three pla-
ces, even with a tailor tape measure, i.e. above the ankle, under
the knee and in the middle of the thigh. The patient can also send
visualizations in the form of photographs. Of course, the most
important is to exclude acute venous insufficiency, i.e. deep vein
thrombosis, where the dominant symptoms are: sudden pain,
redness and swelling of the limb. It should be emphasized that
the only form of treatment that can be used in all stages of CVI is
pharmacological therapy. The diagram positioning the drug the-
rapy is shown in Fig. 2.
this method is the ultrasound examination in the B-presentation
combined with the Doppler examination with double imaging, so-
-called duplex testing. It allows to establish anatomical relations in
the venous system and perform a Doppler examination in a strictly
selected part of the vessel, maintaining all the conditions necessary
for the reliability of the result and thus – the assessment of valve
patency and sufficiency. Ultrasound examination of the superfi-
cial system is performed in a standing position. The deep system
can also be tested when lying down, although it seems easier when
patients are standing. By means of Doppler ultrasonography, it is
possible to determine the sufficiency of all valves in the limb and
to determine the degree of reflux in the system of superficial and
deep veins. That reflux can have 4 degrees, that is:
• I – to the mid-thigh level,
• II – to the level of the knee joint,
• III – to the middle of the calf,
• IV – to the level of the medial ankle.

In general recommendations, one should aim at lowering pres-
sure in the venous system by elevating the limbs or improving
motor activity and, in selected cases, reducing body weight. The
use of compression products is obligatory as long as there are no
contraindications for it, the main of which is ischemia of the lo-
wer limbs. Additionally, phlebotropic drugs are included at each
degree of severity. In case of unsatisfactory results, invasive tre-
atment is carried out. The anatomy and pathophysiology as well
as patient's preferences should always be taken into account [11].
DIAGNOSTICS OF CHRONIC INSUFFICIENCY
DURING LIMITED ACCESS TO MEDICAL SERVICES
CVI diagnostics is based on history and physical examination, sup-
plemented by non-invasive and rarely invasive tests. Of course, in
times of limited access to health services, it may be very difficult
to carry out. Currently, the most important non-invasive imaging
technique, which can be considered the reference method, is du-
plex double Doppler examination (USG duplex Doppler). It is cha-
racterized by high sensitivity and non-invasiveness. The basis of
Urgent ultrasound-Doppler examination in patients with suspec-
ted VTE should be pursued, additionally assessing d-dimer level.
VENOUS ULCERS OF CALVES
Venous ulcers of calves, which may also form, reopen or enlar-
ge in the population during the pandemic, should be discussed
separately. Venous ulceration is defined as a chronic skin dama-
ge/defect that does not heal spontaneously and persists for more
than 4 weeks [12]. They account for approximately 70% of all leg
ulcers. They are most often located above the ankles (gaiter area)
and may be accompanied by other symptoms of CVI, such as va-
ricose veins, oedema, discoloration and lipodermatosclerosis.
Venous ulcers develop in patients as the result of chronic venous
hypertension. In industrialized countries, up to 1.5% of the popu-
lation suffer from them. In patients over 65 years of age the inci-
dence of this disease rises to 4%. In the United States, over 500,000
people develop a chronic wound of venous origin [3]. Venous ulcers
are the result of high venous pressure throughout the day, which
may be due to disease of the veins, obesity or low physical activity

46 WWW.PPCH.PL

due to osteoarthritis or old age. Other risk factors include family
history of CVI and history of deep vein thrombosis. Superficial
venous insufficiency can be seen in vast majority of patients with
venous ulcers; it is a correctable cause of venous hypertension
[13]. Venous ulcers have some characteristic features. Most often
they are located just above the ankles (gaiter area). They are usu-
ally relatively painless and surrounded by discolored and/or dry,
itchy and red skin. Approximately 50% of patients develop: visible
varicose veins, pain and leg swelling [14]. The exact pathomecha-
nism of chronic wounds of venous origin is not known. The in-
fluence of haemodynamic changes, such as venous hypertension,
blood stagnation in the venous circulation and the role of shear
forces in blood flow seem to play an important role in stimulating
and sustaining the inflammatory response which, together with
activation of leukocytes, leads to fibrotic, sclerotic skin remode-
ling and subsequent ulceration. The differential diagnosis should
include: arterial ulcers, neurotrophic ulcers (mainly located in
the foot), vasculitis, gangrenous dermatitis, skin ulceration with
neoplastic component such as basal cell carcinoma or squamous
cell carcinoma (Marjolin ulcer) as well as lesions in the course of
rheumatoid arthritis. The medical history and clinical symptoms
of leg ulcers can be confusing and one should remember that abo-
ut 30% of them are not associated with venous system pathology.
The most important factor in differential diagnosis is to exclude
limb ischemia. Therefore, measurement of ankle-brachial index is
an obligatory procedure, especially before starting compression
therapy. In addition, patients with leg ulcers should be screened
for diabetes mellitus. If vasculitis is suspected, a biopsy of the edge
of the ulcer is useful to confirm the diagnosis. In patients who, de-
spite properly conducted therapy, fail to achieve any improvement,
a biopsy should be performed to exclude the presence of a mali-
gnant neoplasm [15].
POST-THROMBOTIC SYNDROME
Post-thrombotic syndrome (PTS) is the most common compli-
cation of deep vein thrombosis. PTS develops in 20–50% of ca-
ses of proximal DVT and 5–10% of patients develop severe PTS,
i.e. the one that significantly worsens the quality of life and gene-
rates high health care expenses. The most important risk factors
for PTS are: the location of deep vein thrombosis and previous
history of thrombosis on the same side. Other predisposing fac-
tors for PTS include:
• proximal thrombosis – obstruction of the venous outflow
from the limb (obstruction of the iliac veins),
• the presence of a residual thrombus in the vein,
• poor control of anticoagulant therapy,
• obesity,
• the presence of varicose veins,
• the presence of venous reflux,
• persistence of limb symptoms associated with thrombosis
for more than a month,
• no recanalization 6 months after an episode of venous
thromboembolism (VTE) [16, 17].
The diagnosis of PTS is based mainly on clinical symptoms, in re-
lation to the presence and severity of characteristic features and
symptoms of venous insufficiency in the same limb where deep
vein thrombosis was previously diagnosed [18]. Treatment options
POL PRZEGL CHIR 2021: 93 (2): 42-51
review article
of PTS are limited. The main task is rather to prevent deep vein
thrombosis with appropriate anticoagulation prophylaxis. In or-
der to prevent recurrence of deep vein thrombosis on the same
side, the optimal duration of anticoagulation therapy should be
followed [19].
VARICOSE VEINS AND DEEP VEIN THROMBOSIS
Varicose veins of lower limbs pose an increased risk of deep vein
thrombosis. A study by Meuller-Buehl U. et al. in 2012 showed
5.6% occurrence of deep vein thrombosis (DVT) episodes in pa-
tients with varicose veins (VV) in the lower extremities compa-
red to 0.9% in patients without varicose veins [20]. Also, the Ca-
prini scale, which describes the risk of venous thrombosis, scores
1 point for the presence of varicose veins. However, this issue is
still controversial among researchers and medical professionals.
This is evidenced by the fact that in the ACCP consensus on anti-
thrombotic prophylaxis, in the VIIth edition, varicose veins were
included as a risk factor for venous thrombosis and in the VIIIth
edition, they were absent [21]. The exact mechanism by which the
coexistence of varicose veins increases the rate of VTE is also unk-
nown. Kreidy et al. found no significant gender difference in the
incidence of VTE associated with varicose veins [22]. However,
they emphasize that the majority of patients with varicose veins
are over 65 and in this case the age of the patient may have a signi-
ficant influence on the occurrence of thrombosis. They compile
their data in opposition to the publications of other authors who
considered varicose veins as an independent risk factor for deep
vein thrombosis, but only among women over 65 years of age.
[23]. Heit et al. demonstrated VV as a factor increasing the risk
of VTE, but emphasized that it is related to the patient's age [24].
There is also evidence of an increased risk of thrombotic compli-
cations in association with VV, oestrogen use, overweight [BMI
(body mass index) > 25 kg/m2] and hyperlipidaemia. This risk in-
creases significantly in immobilized patients – the most at risk are
people after injuries and operations and those hospitalized [25].
The situation is similar in patients with: ischemic heart disease,
symptomatic lower limb ischemia and atherosclerosis of cerebral
vessels. This confirms a significant role of blood stagnation in the
venous circulation in the development of thrombotic complica-
tions [26]. Also, a study by the World Health Organization (WHO)
identified VV as a risk factor of VTE in patients using oral con-
traceptives [27]. It should also be emphasized that patients with
varicose veins may suffer from venous ulcers, which often addi-
tionally reduce their physical activity and as a consequence may
increase the risk of deep vein thrombosis [28]. Mohr et al. confir-
med that the presence of VV is often associated with stagnation
in the venous system of the lower extremities and this stagnation
may be the cause of deep vein thrombosis. Researchers estimated
that 10% of deep vein thromboses are preceded by a stagnation in
the superficial vein system [29].
PHARMACOTHERAPY OF CHRONIC VENOUS
INSUFFICIENCY DURING THE PANDEMIC TIMES
Pharmacological treatment is an important component of the con-
servative treatment of chronic venous insufficiency and there is
no doubt about the indications and benefits of this type of treat-
ment in patients with diseases of the venous system. We are more
47
 review article
and more familiar with the pathophysiology of CVI and therefo-
re we can define the goals of appropriate pharmacological treat-
ment. They include:
• increasing of vein emptying,
• influence on vascular walls and interstitial tissue,
• restoring metabolic balance (acidosis and oxidation),
• reduction of thrombotic readiness in the lymphatic system,
• reducing cell damage.
Among the drugs used in CVI, two groups of drugs are distingu-
ished – one with phlebotropic or venoactive effect (VADs) and the
second group of drugs conventionally referred to as symptomatic
treatment, which include among others: diuretics, non-steroidal
anti-inflammatory drugs (NSAIDs). VDAs, having a prophylactic
and therapeutic effect on the consequences of chronic venous in-
sufficiency, should be used not instead of but as addition to direct
treatment. Their influence on the microcirculation prevents or
reduces the formation of swelling and inflammatory response as
well as the accompanying pain. It often happens that patients are
more compliant taking medications than wearing stockings. It
should be emphasized that this is only a supportive treatment.
Therefore, it cannot replace other CVI treatment methods, so it
should be recommended after careful evaluation of the condition
of the venous system and according to strictly defined indications.
Presently, we can use the current interpretation of the effects of
individual drugs on subjective and objective symptoms published
by Nicloides et al. [30]. The authors of these evidence-based gu-
idelines summarized the meta-analyzes to date successfully ruling
out unreliable studies. As a result, consistent data were obtained
confirming the importance of VADs in the treatment of CVI as
monotherapy in the early stages of the disease or in combination
therapy with interventional procedures used in the advanced sta-
ges of the disease. This update of the guidelines complements the
conclusions presented in the 2014 guidelines that VADs can be
used to relieve symptoms and oedema in the course CVI at all sta-
ges of the disease [31]. Knowledge of the specific effects of parti-
cular drugs on symptoms expands the available treatment options
and strengthens confidence in therapy. Particular attention was
paid to the presentation of new data, not only in terms of statisti-
cal significance, but also in terms of clinical efficacy. Given these
limitations, panel of experts clearly emphasized significant and
unique importance of VADs in the treatment of symptomatic pa-
tients yet in early stages of CVI, for whom compression may be
the only other form of treatment. This should be the basis for re-
commending this group of patients the drugs during times of re-
duced mobility and lack of access to medical services. Moreover,
given low compliance rates for compression therapy, especially
when it is warm (house heating), VADs may be the only available
treatment option [32]. The importance of effective treatment of
patients in stage according to the CEAP classification was empha-
sized in the latest study, in which approximately 20% of all patients
consulted by a general practitioner were diagnosed with CVI class
C0s [33]. In more advanced stages of CVI, VADs can be used in
combination with interventional treatments such as sclerothera-
py, surgery and intravenous therapy. The beneficial effect of com-
bined intervention therapy and VADs has been shown in six pu-
blications, including two randomized ones [34–39]. Only one
study showed no difference in the severity of postoperative pain
and daily activities [40]. There are no data on efficacy of VADs in
combination with other surgical or vascular procedures, among
48
others in procedures on deep veins. The combination of VADs and
compression therapy has been recommended in several reviews
and meta-analyzes showing the effectiveness of this type of com-
bination therapy in the form of accelerated healing of venous ulcers
[30]. Data on the treatment of PTS with VADs were summarized
in a systematic review with meta-analysis, which included 4 ran-
domized trials, involving 520 subjects [41]. The efficacy of rutosi-
des (believed to reduce capillary filtration and microcirculation
permeability), defibrotide (reduces the release of plasminogen ac-
tivator inhibitor 1 [PAI-1], increases the release of prostacyclin,
prostaglandin E2 and thrombomodulin) and hidrosmin (unknown
mechanism of action) was assessed [42, 44]. In a small study by de
Jongste et al. rutosides significantly reduced the sensation of limb
fatigue compared to placebo, only moderately reducing pain, he-
aviness and swelling [43]. Monreal et al. demonstrated that hidro-
smin and rutosides reduce PTS symptoms, the former to a greater
extent [45]. Cochrane systematic review focused on assessment
of the effectiveness of rutosides, highlighting the low or very low
quality of the available data according to GRADE; no data was fo-
und to suggest the advantage of rutosides over placebo or com-
pression therapy in the reduction of PTS symptoms [46]. Signifi-
cant improvement in pain and swelling was found in a study by
Coccheri et al. comparing defibrotide with placebo in a group of
288 patients with PTS stage C2-4 according to the CEAP scale,
but no reduction in claudication, skin pigmentation and lipoder-
matosclerosis was noted [44]. In a study by Frull et al. in the gro-
ups treated with compression therapy, rutosides or combination
of these methods, some patients showed improvement (70%, 65%,
and 63%, respectively) or worsening of symptoms (15%, 23% and
23%). The treatment effects completely subsided during the 6-month
follow-up [42]. The side effects of phlebotropic drugs were usual-
ly mild in intensity and did not differ significantly between the
studied groups: 1. headache, hair loss, finger swelling, erythema,
morning stiffness, light-headedness in 17% of patients treated with
rutosides vs 12% in the placebo group [43]; 2. nausea, vomiting,
syncope in 3% of patients receiving defibrotide (vs. 3% in the pla-
cebo group); laryngeal oedema in 1 patient from the defibrotide
group [44]; 3. epigastric pain in 8% of rutoside users [42]. The low
quality of data on the use of vasoactive drugs in the treatment of
PTS is due to significant inconsistency of the data and lack of pre-
cision. In addition, treatment duration in those studies was usu-
ally short (2–12 months) and the potential effects of long-term
use are unknown. The need for better-methodology studies to as-
sess clinically relevant endpoints including safety, efficacy and
maintenance effects of PTS pharmacotherapy, including quality
of life, is underlined. Due to the quality of research relating to PTS,
it is impossible to formulate unequivocal recommendations for
the use of phlebotropic drugs in this group of patients. However,
pharmacotherapy is one of the recommended treatments for symp-
tomatic patients with chronic venous disease. Current guidelines
on the use of phlebotropic drugs in primary or secondary (inclu-
ding post-thrombotic) venous insufficiency do not clearly specify
indications for pharmacological treatment depending on the cau-
se of chronic venous disease; they mainly focus on patients with
subjective symptoms such as pain, leg heaviness or presence of
oedema. According to the American Venous Forum guidelines,
the use of phlebotropic drugs (diosmin, hesperidin, rutosides, su-
lodexide, micronized purified flavone fraction) is suggested in pa-
tients with pain and swelling of the lower limbs caused by chronic
venous disease in countries where these drugs are available (re-
commendation 2B) [47]. The guidelines of the European Society
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 review article

Tab. III. T he impact of therapy with main types of VADs on individual subjective and objective symptoms and signs [31] – modified table.

Calcium
Subjective/objective symptom MPFF Ruscus Oxerutin HCSE dobesilate
Pain (NNT) A (4.2) A (5) B A (5.1) B (1)
Feeling of heaviness (NNT) A (2.9) A (2.4) B (17) A (1)
Feeling of oedema (NNT) A (3.1) A (4)
Discomfort (NNT) A (3.0) B (4)
Tiredness in legs (NNT) NS B
Cramps (NNT) B (4.8) B/C B
Paresthesia (NNT) B/C (3.5) A (1.8) B (2)
Burning (NNT) B/C NS
Itchiness (NNT) B/C A (6.1)
Feeling of pressure (NNT) NS
Restless leg syndrome (NNT) NS
Leg redness (NNT) B (3.6)
Skin changes (NNT) A (1.6)
Ankle circumference (NNT) B A NS A (4)
Objętość kończyn dolnych lub stóp NS A NS A A
QOL A NS

Level A means data from at least two randomized controlled trials (RCT) based on sound science or systematic reviews and meta-analyzes, the results of
which are clearly defined and have a direct impact on the target population. Level A means that it is very unlikely that further research will change the current
assessment of the subject of the study.
Level B means data obtained from one well-documented RCT or more than one RCT with less consistent results, with limited power or showing other
methodological defects; these data translate directly into the target population; they may also come from RCTs extrapolated to the target population from
a different patient population. Level B means that it is likely that further research may influence the current assessment of the subject of the study and lead to
a change in the current assessment.
Level C represents data from unsatisfactory design studies, observational studies or small case series studies. Level C means that there is a very high probability
that further research will affect the current assessment of the subject of the study and may lead to a change in the current assessment.
NS – irrelevant.

of Vascular Surgery referring to the group of patients with chronic
venous diseases suggest their use as a treatment option in the case
of oedema and pain caused by chronic venous disease [48]. The la-
test document mentioned earlier also recommends an extract from
the rhizome of butcher's broom (Ruscus aculeatus L.) in conserva-
tive treatment. The preparations of the highest recommendation
for most subjective symptoms of CVI and oedema are: micronized
flavonoid fraction and a combination of butcher's broom, hesperi-
din and ascorbic acid. All of the above recommendations unanimo-
usly recommend a clear distinction between drugs and dietary sup-
plements and clearly do not recommend the use of the latter in the
treatment of patients with CVI [30]. The treatment of venous ulcers
is comprehensively described in the guidelines of the expert group
on the healing of venous leg ulcers [15]. The most important gro-
unds for these recommendations are methods accelerating healing,
which include: compression therapy, pharmacotherapy with pen-
toxifylline and sulodexide, and surgical methods of removing su-
perficial veins and closing insufficient connecting veins. Regarding
the prevention of deep vein thrombosis in patients with varicose
veins of the lower extremities, it should be emphasized that, based
on current knowledge, no thesis can be made about the direct in-
fluence of venous drugs on VTE prevention. On the other hand, all
measures and pharmacotherapy that will prevent blood stagnation
in venous system by increasing the tension of its walls or reduce its
viscosity or repair damaged endothelium, can contribute to redu-
cing the risk of varicose vein complications in the form of venous
thromboembolism.
At the end of this publication, based on the guidelines of the Eu-
ropean Venous Forum and the International Union of Angiology,
the table summarizes the level of evidence A or B, determining
the effect of therapy with main types of VADs on individual sub-
jective symptoms, objective signs and QoL with their efficacy. The
NNT value (number of patients to be treated) is also presented to
show benefits for an individual patient. Only randomized placebo-
-controlled trials and meta-analyzes were included [31] (Tab. III.).

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Word count: 7194 Page count: 10 Table: 3 Figures: 2 References: 48

DOI: 10.5604/01.3001.0014.8500 Table of content: https://ppch.pl/issue/13669

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Corresponding author: Szymon Markiewicz MD; Department of Vascular and Endovascular Surgery, Angiology and Phlebology, Institute of
Surgery, Medical University of Poznan; Fredry street 10, 61-701 Poznan, Poland; Phone: +48 61 854 60 00;
E-mail: markiewicz07@gmail.com

Cite this article as: Krasinski Z., Krasinska A., Markiewicz Sz., Zielinski M.: Patients with chronic venous insufficiency in the times of COVID-19
and the risk of thrombus formation – suggestions on conservative treatment of such patients based on the principles of
pathophysiology; Pol Przegl Chir 2021: 93 (2): 42-51

POL PRZEGL CHIR 2021: 93 (2): 42-51 51