Invest Clin 63(2): 163 - 169, 2022 https://doi.org/10.54817/IC.v63n2a06

Corresponding Author. Ersin Çelik. Clinic of Cardiovascular Surgery, Isparta Şehir Hastanesi, Sanayi Mahallesi

Atatürk Bulvarı No:51 Isparta, Turkey. E-mail: dr.ersincelik@gmail.com

Concomitant acute lower extremity arterial

and deep vein thrombosis developing in a

patient under anticoagulant therapy after

COVID 19 infection.

Ersin Çelik and Ahmet Rıfkı Çora

Clinic of Cardiovascular Surgery, Isparta City Hospital, Isparta, Turkey.

Key words: Covid 19; thrombosis; hypercoagulability; thromboprophylaxis.

Abstract. The hypercoagulable state continues after the Coronavirus 2019

(Covid 19) infection and prophylactic anticoagulants are recommended in this

period. However, arterial and venous thromboembolic events can be observed

during the convalescence period after the Covid 19. Here, we present the case

of acute lower extremity arterial and venous thromboembolism developed in

the post-Covid 19 period in a 77-years-old patient, under therapeutic doses of

anticoagulant therapy (enoxparin 1mg/kg of weight every 12 hours). The pa-

tient, who had no previous history of arterial or venous thrombosis, was taken

to emergency surgery with the diagnosis of ALI (acute limb ischemia) due to

acute arterial thrombosis. An arterial thrombectomy was performed with the

help of a 4F Fogarty catheter inserted from the left femoral artery under local

anesthesia. All distal pulses of the patient were palpable in the postoperative

period. After the platelet count became >100,000 mm3, 100 mg of acetylsali-

cylic acid daily was added to the therapeutic dose of enoxaparin sodium treat-

ment. The patient was discharged, uneventfully, except for a minimal diameter

increase secondary to deep venous thrombosis (DVT) on the fifth postoperative

day, with a combination of enoxaparin and acetylsalicylic acid treatment. En-

dothelial injury, chronic immuno-thrombogenicity, and increased platelet ag-

gregation in the post-Covid 19 recovery period can cause major thrombotic

events, even weeks after the recovery. Anticoagulant therapy is recommended

for thromboprophylaxis when the following statuses exist: ≥65 years, critical

illness, cancer, prior VTE, thrombophilia, severe immobility, and elevated D-

dimer. Combination treatment with long-term antiaggregant therapy may be

prudent in thromboembolic events developed under anticoagulant therapy.

164 Çelik and Rıfkı Çora

Investigación Clínica 63(2): 2022

Trombosis arterial aguda y trombosis venosa profunda

concomitantes de extremidad inferior en un paciente bajo

terapia anticoagulante después de infección por COVID 19.

Invest Clin 2022; 63 (2): 163 – 169

Palabras clave: COVID 19; trombosis; hipercoagulabilidad; tromboprofilaxis.

Resumen. El estado de hipercoagulabilidad continúa después de la infec-

ción por Coronavirus 2019 (Covid-19) y la anticoagulación profiláctica se reco-

mienda durante este período. Sin embargo, eventos tromboembólicos arteriales

y venosos se pueden observar durante el período de convalecencia posterior al

Covid-19. Se presenta el caso de trombosis venosa profunda (TVP) y arterial

agudas de una extremidad inferior en una paciente de 77 años, bajo terapia

anticoagulante (enoxparin 1mg/kg de peso, cada 12 horas), en el período post-

Covid 19. La paciente, sin historia previa de trombosis arterial ni venosa, fue

llevada a cirugía de emergencia con el diagnóstico de isquemia aguda de extre-

midades por trombosis arterial aguda. Se le realizó trombectomía arterial con

la ayuda de un catéter Fogarty 4F insertado desde la arteria femoral izquierda

bajo anestesia local. Todos los pulsos distales del paciente fueron palpables en

el periodo postoperatorio. Después de que las plaquetas llegaron a ser mayores

a100.000 mm3, 100 mg de ácido acetilsalicílico diarios se añadieron a la dosis

terapéutica del tratamiento con enoxaparina sódica. La paciente fue dada de

alta sin incidencias, excepto por un mínimo aumento de diámetro secundario

a la TVP, al quinto día postoperatorio con la combinación de enoxaparina y

ácido acetilsalicílico. La lesión endotelial, la inmunotrombogenicidad crónica

y la agregación plaquetaria aumentada en el período de recuperación posterior

a Covid-19 pueden causar eventos trombóticos importantes incluso semanas

después de la recuperación. La combinación con terapia antiagregante a largo

plazo puede ser prudente en los casos de eventos tromboembólicos desarrolla-

dos en pacientes con terapia anticoagulante.

Received: 20-02-2022 Accepted: 20-03-2022

INTRODUCTION

Due to Coronavirus 2019 (Covid 19)

infection, mostly pulmonary and cardiovas-

cular complications develop. It has been

demonstrated that patients with Covid 19 in-

fection are in a hypercoagulable state, which

causes arterial and venous thrombosis1. The

hypercoagulable state continues after Co-

vid 19, and long-term anticoagulant therapy

is recommended for its treatment 2. Acute

limb ischemia (ALI) and venous thrombo-

embolism are among the most common

vascular complications seen after Covid 19

infection 1,3. Especially in the patients that

develop ALI, high amputation and mortality

rates are reported 3.

Here, we present a case of concomitant

lower extremity arterial and venous throm-

bosis that developed under anticoagulant

therapy in the early period after Covid 19

infection. A written informed consent was

Acute arterial and venous thrombosis, post COVID 19 165

Vol. 63(2): 163 - 169, 2022

obtained from the patient for the report of

the details and images related to her case.

CASE REPORT

On September 27, 2021, a 77-year-old

female patient was referred to us from the

emergency department of the Isparta City

Hospital with complaints of tightness and

swelling in the left leg that had been pres-

ent for a day, and sudden coldness, pallor,

and severe pain below the knee for the last

two hours. As a result of physical examina-

tion, signs of coldness, pallor, prolongation

of capillary refill time, tightness, increase in

diameter and Homans sign were found in the

left lower extremity (Fig. 1). While all pulses

were palpable in the right lower extremity,

only the femoral pulse was palpable in the

left lower extremity. Monophasic flow pat-

tern was determined with manual Doppler in

the popliteal artery, but flow could not be

determined with manual Doppler in the dis-

tal pulses. An electrocardiogram revealed si-

nus tachycardia at a rate of 105 per minute.

Urgent blood test results were found as fol-

lows: white blood cell 10,720/mm3 (normal

range <10,000), lymphocyte 680/mm3 (nor-

mal range 800-4,000), eosinophil 10/mm3

(normal range 20-50), platelet 84,000/mm3

(normal range 100,000-400,000), hemoglo-

bin 9.5 g/dL (normal range 12-16), D-dimer

value 0.92 mg/L (normal range 0-0.55), pro-

thrombin time 12.4 seconds (normal range

10.5-14.5), activated partial thromboplastin

time 21.6 seconds (normal range 21.6-35),

and international normalized ratio 1.11

(normal range 0.8-1.2). Other biochemical

parameters were found normal. A computed

tomography angiogram (CTA) taken on the

patient revealed an intraluminal thrombus

extending from the distal part of the left su-

perficial femoral artery to the tibioperoneal

trunk (Figs. 2a, 2b). In addition, calibration

increases were observed in the main and su-

perficial femoral veins (Fig. 2c). Acute deep

venous thrombosis (DVT) extending from

the popliteal vein to the external iliac vein

was determined by venous Doppler ultra-

sound.

Fig. 1. Significant increase in the diameter and cyanotic areas in patches in the left lower extremity.

166 Çelik and Rıfkı Çora

Investigación Clínica 63(2): 2022

In the patient’s medical history,

there was a diagnosis of Covid 19 pneu-

monia confirmed by reverse transcription-

polymerase chain reaction test and chest

computed tomography 36 days before the

thrombotic event. After 21 days of inten-

sive care and 11 days of chest diseases ser-

vice follow-up, the patient was discharged

from the hospital a with therapeutic dose

of enoxaparin sodium treatment (1mg/

kg of weight every 12 hours) (Fig. 3). D-

dimer value was found as 0.78 mg/L (nor-

mal range 0-0.55) and platelet was found

as 202,000 mm3 (normal range 100,000-

400,000) at discharge. The patient had

not been vaccinated against Covid 19 in-

fection prior to the event.

The patient, who had no previous his-

tory of arterial or venous thrombosis, was

taken to emergency surgery with the diag-

nosis of ALI due to acute arterial throm-

bosis. An arterial thrombectomy was

performed with the help of a 4F Fogarty

catheter inserted from the left femoral ar-

tery under local anesthesia. The catheter

was introduced to a 70 cm distal length.

Abundant and fresh thrombus material

was removed. All distal pulses of the pa-

tient were palpable in the postoperative

period. After the platelet count became

>100,000 mm3, 100 mg of acetylsalicylic

acid daily was added to the therapeutic

dose of enoxaparin sodium treatment.

Leg elevation was applied. The patient

was discharged from the cardiovascular

surgery service uneventfully on the fifth

postoperative day with the combination of

enoxaparin and acetylsalicylic acid, except

for a minimal diameter increase second-

ary to DVT.

Fig. 2. Computed tomography angiogram a) and b) acute thrombus material in the left superficial femoral

artery c) Calibration increase in the left common femoral vein due to acute thrombus material.

Acute arterial and venous thrombosis, post COVID 19 167

Vol. 63(2): 163 - 169, 2022

DISCUSSION

Apart from pulmonary involvement, co-

agulopathy and cardiovascular effects, which

cause significant increases in morbidity and

mortality rates due to Covid 19 infection,

are relatively common 4. As detected in our

case, increased fibrin degradation products,

as well as high D-dimer and low platelet lev-

els, may be an indicator of thrombotic com-

plications that develop or may develop 5.

ALI is less common than venous throm-

bosis in patients with Covid 19. ALI due to

arterial thrombosis can be seen after Covid

19 infection as well as during the acute in-

fection period. Borrelli et al. reported cases

of arterial thrombosis that developed 15-45

days after respiratory symptoms in the pa-

tients whose Covid 19 treatment was com-

pleted and nasopharyngeal swab test was

negative 6, and Bozzani et al reported cases

of arterial thrombosis that developed after

41-149 days in the patients with the same

conditions 7. In our case, the swab test was

negative during the convalescence, and arte-

rial and venous acute thrombosis was detect-

ed under therapeutic dose of anticoagulant

therapy on the 19th day.

Virchow’s classic triad for thrombosis

consist of stasis, endothelial injury, and a

hypercoagulable state. Hypercoagulability

and stasis particularly affect acute throm-

bogenesis. This may play a lesser role in the

arterial and venous events seen in conva-

lescent Covid 19 patients. The most impor-

tant mechanism here may be endothelial

injury and dysfunction. The multisystem

inflammatory syndrome, which includes

myocarditis and inflammatory vasculopa-

thy and seen in the recovery period after

Covid 19 in children, is an indicator of en-

dothelial dysfunction and injury 8. Chronic

immuno-thrombogenicity, which develops

and accumulates especially after mild or

asymptomatic Covid 19 infection, may also

cause major thrombotic events even weeks

later 2. Another cause of thrombogenicity

may be increased platelet aggregation. Zaid

et al showed severe acute respiratory syn-

drome coronavirus 2 RNAs and high plate-

let-associated cytokine levels in platelets

in their 115 cases studied. In this study as

well, platelet aggregation occurred at lower

concentrations of thrombin than it was ex-

pected 9.

There is no consensus on long-term

thromboprophylaxis following Covid 19 in-

fection. Guidelines for COVID 19 are de-

rived from recommendations in medically

ill populations. Although therapeutic doses

of low molecular weight heparin (LMWH)

have been recommended for the patients

with Covid 19 and standard thromboprophy-

laxis, by taking the high incidence of venous

thromboembolism (VTE) into consider-

ation, the American College of Chest Phy-

sicians recommends standard prophylactic

LMWH due to the lack of clinical trial data

10. On the other hand, the International So-

ciety on Thrombosis and Hemostasis (ISTH)

Fig. 3. Timeline of patient of this article.

168 Çelik and Rıfkı Çora

Investigación Clínica 63(2): 2022

guidelines recommend thromboprophylaxis

with LMWH and a direct oral anticoagulant

(DOAC) in patients with low bleeding and

high VTE risks. ISTH has identified as high-

risk factors the age older than 65 years,

critical illness, cancer, prior VTE, throm-

bophilia, severe immobility, and elevated

D-dimer. The ISTH suggests a duration of

14 to 30 days for post discharge thrombo-

prophylaxis, although optimal duration re-

mains unclear 11. Although prophylaxis was

initiated with a therapeutic dose of LMWH

treatment in our case, who was considered

with high risk due to high D-dimer level

and advanced age, antiaggregant agent was

added to the treatment in the postopera-

tive period, considering possible increased

platelet aggregation due to the simultane-

ous occurrence of arterial and VTE.

More systematic, randomized controlled

studies on Covid 19-related thrombosis are

needed. Results of ongoing clinical trials,

such as the ACTIV-4 trial (NCT04498273),

which have specifically evaluated prophylac-

tic antiaggregant and anticoagulant therapy,

are awaited.

In conclusion, anticoagulant agents

and thromboprophilaxis should be consid-

ered especially in high-risk patients after

Covid 19 infection. The combination of an-

ticoagulant and antiaggregant prophylaxis

should also be kept in mind in patients with

low bleeding risk. It may be rational to add

a long-term antiaggregant to the treatment,

especially in thromboembolic events devel-

oped under anticoagulant therapy.

Funding

The authors received no financial sup-

port for the research and/or authorship of

this article

Declaration of conflicting interests

The authors declared no conflicts of in-

terest with respect to the authorship and/or

publication of this article.

Author’s ORCID numbers

• Ersin Çelik:

0000-0002-0015-3280

• Ahmet Rıfkı Çora:

0000-0002-4892-9463

REFERENCES

1. Tan BK, Mainbourg S, Friggeri A, Berto-

letti L, Douplat M, Daraud Y, Grange C,

Lobbes H, Provencher S, Lega JC. Arte-

rial and venous thromboembolism in CO-

VID-19: a study-level meta-analysis. Thorax

2021;76:970-979.

2. Fan BE, Cheung C. Post COVID-19 ar-

terial thromboembolism: a clear and

present danger. Semin Thromb Hemost

2022;48(01):112-114.

3. Sanchez JB, Alcalde JDC, Isidro RR, Luna

CZ, Cubas WS, Charres AC, Gutierrez JE,

Ochoa JD, Arias PF. Acute limp ischemia

in a Peruvian cohort infected by COVID-19.

Ann Vasc Surg 2021;72:196-204.

4. Clerkin KJ, Fried JA, Raikhelkar J, Sa-

yer G, Griffin JM, Masoumi A, Jain SS,

Burkhoff D, Kumaraiah D, Rabbani L,

Schwartz A, Uriel N. Coronavirus Disease

2019 (COVID-19) and cardiovascular disea-

se. Circulation 2020;141:1648-1655.

5. Del Castillo-García S, Minguito-Carazo C,

Echarte JC,Santamarta MR, Gonzalez TB,

Seara ST, Gonzalez LM, Fernandez-Vaz-

quez F. A case report of arterial and venous

thromboembolism in a patient with severe

COVID-19 pneumonia. Eur Heart J Case

Rep 2020;4(6):1-6.

6. Borrelli MP, Buora A, Scrivere P, Sponza

M, Frigatti P. Arterial thrombotic sequa-

lae after Covid-19: mind the gap. Ann Vasc

Surg 2021;000:1.e1-1.e8.

7. Bozzani A, Arici V, TavazziG, Mojoli F, Bru-

no R, Sterpetti AV, Ragni F. Acute throm-

bosis of lower limbs arteries in the acute

phase and after recovery from COVID19.

Ann Surg 2021;273:159–160.

8. Jiang L, Tang K, Levin M, Irfan O, Morris

SK, Wilson K, Klein JD, Bhutta ZA. CO-

VID-19 and multisystem inflammatory syn-

drome in children and adolescents. Lancet

Infect Dis 2020;20(11):e276–288.

Acute arterial and venous thrombosis, post COVID 19 169

Vol. 63(2): 163 - 169, 2022

9. Zaid Y, Puhm F, Allaeys I, Naya A, Oudghi-

ri M, Khalki L, Limani Y, Zaid N, Sadki

K, El Haj RB, Mahir W, Belayachi L, Bele-

fquih B, Benouda A, Cheikh A, Langlois

MA, Cherrah Y, Flamand L, Guessous F,

Boilard E. Platelets can associate with

SARS-Cov-2 RNA and are hyperactivated in

COVID-19. Circ Res 2020;127:1404-1418.

10. Moores LK, Tritschler T, Brosnahan S, Ca-

rrier M, Collen JF, Doerschug K, Holley

AB, Jimenez D, LeGal G, Rali P, Wells P.

Prevention, diagnosis and treatment of ve-

nous thromboembolism in patients with

COVID-19: CHEST Guideline and Expert

Panel Report. Chest 2020;158:1143-1163.

doi:10.1016/j.chest.2020.05.559.

11. Spyropoulos AC, Levy JH, Ageno W, Con-

nors JM, Hunt BJ, Iba T, Levi M, Samama

CM, Thachil J, Giannis D, Douketis JD;

Subcommittee on perioperative, critical

care thrombosis, haemostasis of the scien-

tific, standardization Committee of the

International Society on Thrombosis and

Haemostasis. Scientific and Standardiza-

tion Committee communication: Clinical

guidance on the diagnosis, prevention, and

treatment of venous thromboembolism

in hospitalized patients with COVID-19. J

Thromb Haemost 2020;18(8):1859-1865.

doi:10.1111/jth.14929.