Official Title
Investigating the Involvement of ACE and Angiotensinogen Genes' Polymorphism Along With Other Thrombophilic Genotypes in Severe Forms of COVID-19 With/Without Thrombotic Events
Brief Summary

An estimated 22% of the global population is at an increased risk of a severe form of COVID-19, while one in four coronavirus patients admitted to intensive care unit will develop a pulmonary embolism. A major public health question remains to be investigated: why COVID-19 is mild for some, critically severe for others and why only a percentage of COVID-19 patients develop thrombosis, despite the disease's proven hypercoagulable state? Patients' intrinsic characteristics might be responsible for the deep variety of disease forms. Our study aims to assess the validity of the hypothesis according to which underlining genetic variations might be responsible for different degrees of severity and thrombotic events risks in the novel coronavirus disease. Moreover, we suspect that prothrombotic genotypes occuring in the genes that encode angiotensin-converting enzyme (ACE-DEL/INS) and angiotensinogen (AGT M235T) are involved in the unpredictable evolution of COVID-19, both in terms of severity and thrombotic events, due to the strong interactions of SARS-CoV-2 with the renin-angiotensin-aldosterone system (RAAS). Therefore, we also aim to assess the validity of the theory according to which there is a pre-existing atypical modulation of RAAS in COVID-19 patients that develop severe forms and/or thrombosis. Our hypothesis is based on various observations. Firstly, there is a substantial similarity with a reasonably related condition such as sepsis, for which there is a validated theory stating that thrombophilic mutations affect patients' clinical response. Secondly, racial and ethnic genetic differences are responsible for significant dissimilar thrombotic risks among various nations. Thirdly, an increase in stroke incidence has been reported in young patients with COVID-19, without essential thrombosis risk factors, favoring the idea that a genetic predisposition could contribute to increase the thrombotic and thromboembolic risk. Fourthly, the plasminogen activator inhibitor (PAI)-1 4G/5G inherited mutation was found to be responsible for a thrombotic state causing post-SARS osteonecrosis.

Detailed Description

The study's protocol will cover the following steps:

• Collected data from COVID-19 patients at admission will include:

- Descriptive general demographic data

- Previous pathologies and thrombosis risk factors

- Routine biological data (the blood routinely collected will also be used for SARS-Cov-2 specific RT-PCR exam)

Complete thrombophilic profile testing by multiplex PCR and reverse hybridization of DNA to assess the presence of prothrombotic genotypes:

- Factor V Leiden

- Factor V 4070 A G (Hr2)

- Factor II G20210A

- Methylenetetrahydrofolate reductase (MTHFR) C677T

- MTHFR A1298C

- Cystathionine β-synthase (CBS) 844ins68

- PAI-1 4G/5G

- Glycoprotein IIIa T1565C (HPA-1a/b)

- ACE-DEL/INS

- Apolipoprotein E (ApoE)

- AGT M235T

- Angiotensin II type 1 receptor (ATR-1) A1166C

- Fibrinogen - 455 G A

- Factor XIII Val34Leu SpO2, respiratory rate, PaO2/FiO2 RAAS components

- Imagistic procedures (chest X-ray or CT)

- All patients with a positive SARS-CoV-2 PCR test will be included

- Patients will be divided into three groups depending on disease severity and the presence of thrombotic state:

- 1st group includes COVID-19 patients with proved

- venous thrombosis (deep vein thrombosis, pulmonary embolism or venous thrombosis occurring in more atypical places such as in the veins of the brain, liver, kidney, mesenteric vein and the veins of the arms)

- or arterial thrombosis (heart attacks, strokes)

- 2nd group encompasses asymptomatic patients and those with mild or moderate disease, according to current guidelines, without thrombosis: no symptoms or evidence of lower respiratory disease by clinical assessment or imaging and a SpO2 ≥ 94%

- 3rd group includes severe disease, according to current guidelines, without thrombosis: respiratory frequency > 30 breaths per minute, SpO2 < 94%, PaO2/FiO2 < 300 mmHg, or lung infiltrates >50%

- Statistical methods will be employed to check for significant differences between prothrombotic mutations frequency and RAAS components levels for the three groups

Recruiting
COVID19
Corona Virus Infection
Thrombosis
ARDS
Thrombophilia
Thromboses, Intracranial
Thromboses, Deep Vein
RAAS

Genetic: Complete thrombophilic profile testing by multiplex PCR
Complete thrombophilic profile testing by multiplex PCR and reverse hybridization of DNA to assess the presence of prothrombotic genotypes:
Factor V Leiden
Factor V 4070 A>G (Hr2)
Factor II G20210A
Methylenetetrahydrofolate reductase (MTHFR) C677T
MTHFR A1298C
Cystathionine β-synthase (CBS) 844ins68
PAI-1 4G/5G
Glycoprotein IIIa T1565C (HPA-1a/b)
ACE-DEL/INS
Apolipoprotein E (ApoE)
AGT M235T
Angiotensin II type 1 receptor (ATR-1) A1166C
Fibrinogen - 455 G>A
Factor XIII Val34Leu
Asymptomatic COVID-19 & those with mild or moderate disease
COVID-19 patients with proved venous thrombosis
Severe disease, according to Guidelines, without thrombus

Eligibility Criteria

Inclusion Criteria:

- All hospitalized patients with cough, fever, myalgia - with confirmed COVID-19 infection • All patients with a positive SARS-CoV-2 PCR test

Exclusion Criteria:

- Patient refusal

- Uncertain tests results

- Children

Eligibility Gender
All
Eligibility Age
Minimum: 18 Years
Countries
Romania
Contacts

Alexandru Burlacu, MD, PhD
00407444488580
alexandru.burlacu@umfiasi.ro

Radu Crisan-Dabija, MD, PhD
radu.dabija@umfiasi.ro

Adrian Covic, Professor
Study Chair
Gr T Popa University of Medicine and Pharmacy Iasi ROMANIA

Grigore T. Popa University of Medicine and Pharmacy
NCT Number
Keywords
Covid-19
COVID-19 severity
thrombosis
Thrombophilia
thrombophylic profile
Renin-angiotensin-aldosterone system alterations
MeSH Terms
Coronavirus Infections
Severe Acute Respiratory Syndrome
Intracranial Thrombosis
Thrombosis
Venous Thrombosis
Thrombophilia