The Angiotensin Converting Enzyme Deletion/Deletion Genotype Is a Risk Factor for Severe COVID-19: Implication and Utility for Patients Admitted to Emergency Department

Background and objective: Insertion/deletion polymorphisms of angiotensin-converting enzyme (ACE) have been previously described in association with adult respiratory distress syndrome (ARDS) and correlated to outcome. The ACE deletion/deletion(D/D)genotype represents a marker of thrombosis in subjects apparently without predisposing factors and/or traditional thrombophilic alterations and increases the risk of venous thromboembolism in subjects in whom a thrombogenic condition occurs. Thrombosis seems to play a role very early in the disease caused by SARS-CoV-2, in particular in those with severe COVID-19 pneumonia. The counterbalance between angiotensin-converting enzyme (ACE) and ACE2 activities in COVID-19 disease may play a crucial role in the thrombo-inflammatory process. We hypothesised that a genetic predisposition could condition the severity and complications of SARS-CoV-2 infection. Materials and methods: We conducted a spontaneous, single centre observational study in the Sub-Intensive Care Unit of A.O.R.N. Ospedali dei Colli, Cotugno Hospital, Naples (Italy). In this study, we performed genetic screening for ACE D/D genotype and other thrombophilic mutations in 20 patients affected by ARDS related to COVID-19 pneumonia, compared to 19 age- and sex-matched healthy controls. Results: All tested patients had multiple polymorphisms and, in particular, a significantly higher prevalence of ACE D/D polymorphism in severe COVID-19 patients Conclusion: We found that the majority of patients who tested positive for ACE D-D genotype and who were not associated with other risk factors for VTE showed an evolution to ARDS. This finding could have a predicting role in the selection of patients more prone to developing severe COVID-19 during clinical observation in emergency department.

Role of Inherited Thrombophilia Risk Factors in Patients with CKD-5 Receiving Haemodialysis

<b><i>Background:</i></b> The inherited thrombophilic mutations of the factor V gene (FVG1691A Leiden-FVL), prothrombin gene (PTG20210A), and the methylenetetrahydrofolate reductase gene C677T (MTHFR C677T) are risk factors for thromboembolic events and are related to the pathogenesis of vascular diseases. <b><i>Objectives:</i></b> The main objective of this study was to explore the role of these factors in the pathogenesis of chronic kidney disease (CKD) and survival of patients with CKD-5 receiving haemodialysis. <b><i>Methods:</i></b> A cohort of 395 patients with CKD-5 on haemodialysis, from 6 dialysis units in Crete, Greece were recruited based on their medical records and were followed for 5 years. We collected data on CKD-5 aetiology, thrombophilic gene expression, vascular access thrombosis, time of death, and causes of death. <b><i>Results:</i></b> The mutated genes just as prevalent in patients with CKD-5 as they were in a control group with no renal disease (<i>p</i> &#x3e; 0.05). FVL heterozygosity was significantly more prevalent (11.4 vs. 5.7%; <i>p</i> = 0.036) in patients presented with CKD of unknown aetiology, compared to CKD secondary to known aetiologies. The survival of patients with CKD-5 receiving haemodialysis was not affected by the presence of any thrombophilic mutation. This held true for the whole cohort and for the cohort that included only lethal vascular events. Most patients with MTHFR C677T heterozygosity, and all patients with MTHFR C677T homozygosity, died from vascular events during the follow-up period. <b><i>Conclusion:</i></b> The FVL mutation may act as a risk factor for CKD. This study increases our understanding of molecular mechanisms in the pathogenesis of CKD of unknown aetiology. Τhe presence of thrombophilic mutations did not affect the overall survival of patients with CKD-5. This finding probably reflects the effect of medical care on patient outcomes.

Hyperbaric oxygen treatment results in a group of Turkish central retinal artery occlusion patients with a combined presence of thrombophilic mutations

Background: Central retinal artery occlusion (CRAO) is a rare ocular-ischemic syndrome causing irreversible blindness. Its pathophysiology has not been clarified, and no targeted therapies are available yet. Hyperbaric oxygen (HBO2) therapy is an approved therapy for CRAO and has been shown to improve the visual acuity of CRAO patients safely. However, further clinical data are required to classify HBO2 therapy as a type-I general agreement for CRAO. Materials and Methods: Eleven patients with non-arteritic CRAO were enrolled. Patient demographics, medical history, detailed eye examinations, HBO2 therapy results, pre-/post- HBO2 therapy visual acuity measurements and genotypes for common thrombophilic mutations (Factor V G1691A Leiden, Factor II G20210A, MTHFR A1298C, MTHFR C677T, and PAI-1-675 4G/5G) were obtained. Results: Six patients (54%) responded to HBO2 therapy compared to five non-responders (46%). Patients admitted before 12 hours responded well to HBO2 therapy. No systemic diseases nor advanced age were statistically correlated to CRAO. A combination of mutations rather than single mutations for each patient could be seen as responsible for CRAO. No Factor V G1691A Leiden mutations and only one FII G20210A mutation were observed. Eight patients (72%) had MTHFR 677T allele, five patients (45%) had MTHFR 1298C allele, and 10 patients (91%) had the PAI-1-675 4G allele. Conclusion: Not a single mutation but a combination of mutations and other unknown factors probably lead to CRAO, and if intervention is timely, HBO2 therapy offers improvement in visual acuity safely.

Sociodemographic characteristics and thrombophilic mutations in women with in vitro fertilization failure – initial results from case control study

There are many factors for in vitro fertilization (IVF) failure, and hereditary thrombophilia has been mentioned as one of them in the last few years. Thrombophilia is a condition of predisposition to thromboembolism. The aim of the study was to evaluate the sociodemographic characteristics and to examine the representation of thrombophilic mutations in women with IVF failure. Material and methods: In a retrospective-prospective case-control study we evaluated 52 women, divided in two groups. Twenty-twowomen with at least three IVF failures were included in the examined group (EG). Thirty women, age matched, who gave birth to at least one healthy child without obstetric complications were included in the control group. Presence of gene mutations for factor II Prothrombin (G20210A), factor V Leiden (FVL) and methylentetrahydrofolate reductase (MTHFR C677T) was examined in both groups. Sociodemographic data, data from personal, family and obstetric anamnesis was collected with standard questionnaire. Results: Representation of nationality in both groups roughly corresponds to the national structure in Republic of Macedonia. In both groups the most prevalent age was from 30 to 34 years (40% in the CG and 50% in the EG). According to the degree of education, homogeneity between the two groups was registered. In most of the EG, MTHFR heterozygous was 63.6% vs. 56.7% in the CG, followed by the FV Leiden heterozygous with 13.6% vs. 3.3% in the CG, MTHFR homozygous with 9.1% vs. 6.7% in CG, factor II Prothrombin (G20210A) heterozygous with 4.5% vs. 6.7 in CG. 72.7% of women in the EG and 60% in the CG had one thrombophilic mutation, and 9.1% of women in EG and 6.7% in CG had two thrombophilic mutations. 18.2% of women in EG and 33.3% in CG did not have any mutations. Conclusion: The sociodemographic profile of women with IVF failure is a woman aged between 30 and 34 years with a university degree, with at least one thrombophilic mutation. Thrombophilic mutation has not been registered in only a small percentage of women with failed IVF.

Role of inherited thrombophilic profile on survival of patients with sepsis

The existence of various coagulation and/or fibrinolytic system disorders (such as inherited thrombophilia) in patients with sepsis could possibly modify host response to infection as well as patient outcome. The aim of the study is to investigate inherited thrombophilic profile in patients with sepsis. Eighty-three patients with sepsis admitted at the Department of Internal Medicine of the University General Hospital of Patras, Greece were included. Thrombophilic profile (factor V G1691A (Leiden), factor V H1299R (R2), prothrombin G20210A, MTHFR C677T, MTHFR A1298C, factor XIII V34L, β-fibrinogen-455 G-A and plasminogen activator inhibitor (PAI)-1 4G/5G) was evaluated using the cardiovascular diseases (CVD) StripAssay based on DNA isolation, PCR and reverse hybridisation. Data were collected from patients’ chart reviews. Seventy patients (84.3%) of the 83 enrolled had at least one thrombophilic mutation. The most common mutations were heterozygous for β-fibrinogen-455 G-A (43.4%), heterozygous for factor XIII V34L (32.5%), PAI-1 4G/4G (26.5%), homozygous MTHFR C677T (22.9%), heterozygous factor V H1299R (R2) (13.3%) and homozygous MTHFR A1298C (12.0%). A 30-day mortality was 14.5%. Multivariate analysis revealed that mortality was independently associated with Simplified Acute Physiology Score II score on admission, pneumonia and fibrinogen on admission. Nine patients (10.8%) developed septic shock. Coagulation disorders on admission, bacteraemia and PAI-1 genotype 5G/5G were independently associated with development of septic shock. The presence of thrombophilic mutations in patients with sepsis may affect their clinical response, and future studies are needed in order to elucidate the role of isolated thrombophilic mutations in patients with sepsis or septic shock.