The relationship between thromboembolic conditions and hereditary thrombophilia in COVID-19 patients

Authors

Abstract

AimCOVID-19 has spread rapidly worldwide, becoming a major cause of morbidity and mortality. This study investigates the relationship between this thrombosis-related disease and hereditary thrombophilia.
MethodsThis single-center retrospective study included patients with hereditary thrombophilia (Factor V Leiden, Factor II, methylenetetrahydrofolate reductase (MTHFR) A1298C, plasminogen activator inhibitor-1 (PAI-1), and Factor XIII gene mutations) who presented to the emergency department during the pandemic. Demographic, clinical, and laboratory data were analyzed, with significance set at p<0.05.
ResultsA total of 203 cases were included. Thromboembolism (TE) was significantly higher in patients with Factor V and MTHFR A1298C mutations, while no such association was found for Factor II, Factor XIII, or PAI mutations. Homozygous mutations in any of the studied genes (Factor V, Factor II, Factor XIII, MTHFR A1298C, and PAI-1) were associated with a significantly higher incidence of TE compared to heterozygous or mutation-free cases. D-dimer levels and hospitalization rates were also elevated in TE cases.
In patients with positive COVID-19 polymerase chain reaction (PCR) tests, TE was significantly more frequent in those with MTHFR A1298C and Factor XIII mutations, a pattern not observed in PCR-negative cases. Homozygous mutations in any of the studied genes were again associated with increased TE risk in COVID-19-positive cases. Elevated D-dimer levels were particularly prominent in TE cases among COVID-19-positive patients. No significant differences were observed among other groups.
ConclusionCOVID-19 significantly increases thrombotic complications in patients with hereditary thrombophilia, highlighting the need for close monitoring in this population.

Keywords

Introduction

COVID-19 disease, a SARS-CoV-2 infection, emerged in Wuhan, China, in December 2019 and was declared a pandemic by the World Health Organization in March 2020. The spectrum of COVID-19 disease is very wide; it can be asymptomatic or cause severe respiratory failure and even death.¹ Since its emergence, the COVID-19 disease has caused both deaths and many complications, including thrombotic events, worldwide. It was confirmed that COVID-19 disease has been seen in approximately 500 million cases and caused more than 6 million deaths in 2022.²
Hereditary thrombophilia is an inherited disease that causes thromboembolic (TE) events at young ages, leading to miscarriages and sudden deaths due to cerebral or coronary artery occlusion. Factor V Leiden mutation, methylene tetrahydrofolate gene mutation (MTHFR) (C677T, A1298C), plasminogen activator inhibitor-1 (PAI-1) (4G-5G), and FXIII gene mutations are among the common mutations and are found as the underlying cause in patients with hereditary thrombophilia. Few studies have examined the relationship between hereditary thrombophilia and increased thrombotic activity in COVID-19 patients.^3,4,5
Prophylactic anticoagulant and antiaggregant treatment are started in patients with hereditary thrombophilia. However, venous or arterial TE events can still occur.^6,7 Studies are reporting that COVID-19 disease could trigger thrombotic events in patients and may worsen the progression of the disease in patients with hereditary thrombophilia.^8,9 Again, in these studies, it is reported that the frequency of TE increases even in COVID-19 patients whose symptoms are mild enough to be followed up without hospitalization.⁹
Protein fragments originate from the breakdown of fibrin bonds in the final stage of coagulation. This protein fragment is D-Dimer, and the increase in D-Dimer level in blood indicates that the coagulation and fibrinolytic systems are working actively.¹⁰
In our study, we aimed to investigate the effect of COVID-19 status on TE events in patients with hereditary thrombophilia and to contribute to the literature by doing so.

Materials and Methods

Study Setting and Study PopulationThis retrospective, single-center study was conducted in a tertiary education and research hospital. Patient data were retrieved from hospital records and the electronic medical system. The study population consisted of individuals with confirmed hereditary thrombophilia gene mutations (Factor V Leiden, Factor II, MTHFR, PAI-1, and Factor XIII) who presented to the hospital’s genetics clinic and met the inclusion criteria. These patients were monitored during the COVID-19 pandemic.
Eligible participants were adults (≥18 years) with a prior diagnosis of hereditary thrombophilia who were admitted to the emergency department during the pandemic, with complete clinical data available. Exclusion criteria included age under 18, pregnancy, incomplete records, absence of hospital admission during the pandemic, uncertain thrombophilia diagnosis, history or active treatment of malignancy, unknown outcomes, or unavailable medical history. COVID-19 infection was confirmed using real-time polymerase chain reaction (RT-PCR) testing of nasopharyngeal swab samples.
Data CollectionPatients' admission to hospital during the pandemic period, COVID-19 RT-PCR test results, TE status, TE type, hospitalization status, and outcomes were evaluated.
Deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE) were diagnosed by the radiologist; cerebrovascular accident (CVA) was diagnosed by a neurologist and radiologist, and acute myocardial infarction (AMI) was evaluated and diagnosed by a cardiologist.
It was learned that all patients included in the study had at least two doses of BioNTech-Pfizer or CoronaVac vaccine before. All hospitalized patients were started on a prophylactic enoxaparin treatment of 40 mg per day.
Ethical ApprovalThis study was approved by the Ethics Committee of Basaksehir Çam and Sakura City Hospital (Date: 02.09.2021, Decision No: 2021.09.200).
Statistical AnalysisStatistical analysis was performed using the SPSS 26.0 for Windows statistical program (IBM Inc., Chicago, IL, USA). Number, percentage, mean, standard deviation, median, minimum, and maximum values were used in the presentation of descriptive data. The conformity of the data to the normal distribution was evaluated with the Kolmogorov-Smirnov Test. Pearson’s chi-square test and Fisher's Exact test were used to compare categorical data. The T-Test was used to compare two independent numerical data, and the Kruskal Wallis Test was used to compare three numerical data. Post Hoc analysis was also used to compare the three numerical data sets with each other.
Results were considered significant at p<0.05, with a 95% confidence interval.
Reporting GuidelinesThis study is reported in accordance with the STROBE guideline.

Results

Our study was carried out with 203 cases. The study population had a mean age of 40.2 ± 12.3 years, with a nearly equal gender distribution (47.8% male and 52.2% female). Regarding genetic mutations, Factor V Leiden was absent in the majority of patients (81.8%), while 3.0% were homozygous and 15.3% heterozygous carriers. Factor II mutation was absent in 91.6% of cases, with 2.0% homozygous and 6.4% heterozygous mutations. For MTHFR A1298C, 47.8% showed no mutation, whereas 14.8% were homozygous and 37.4% heterozygous. PAI-1 mutation was absent in 43.3% of patients, while 15.8% were homozygous and 40.9% heterozygous. Factor XIII mutation analysis revealed that 30.0% had the 5G/5G genotype, 20.7% were homozygous (4G/4G), and 49.3% heterozygous (4G/5G).
During the COVID-19 pandemic, 48.3% of patients tested positive, while 51.7% were negative. Homozygous mutations were present in 46.3% of cases. Mortality was observed in only 1.0% of patients, whereas hospitalization was required in 46.3%.
Thrombosis was found in 17.7% of the cases (acute TE during the pandemic period). When these thrombosis conditions were classified, it was observed that there was DVT in 38.9%, PTE in 36.1%, CVA in 11.1%, and AMI in 13.9% of the patients. Laboratory findings showed a mean platelet count of 280.39 ± 96.65 ×10³/mm³, prothrombin time of 12.38 ± 4.66 seconds, activated partial thromboplastin time of 24.46 ± 11.83 seconds, international normalized ratio (INR) of 1.04 ± 0.62, and D-dimer levels averaging 1319.34 ± 2115.79 µg/L.
The relationship between demographic, clinical, and laboratory data was evaluated according to the presence of TE in the cases, and no correlation was found between TE status and age, gender, or mortality. When the mutation states are examined, TE was found to be significantly higher in cases with Factor V Leiden and MTHFR A1298C mutations, while no relationship was detected in cases with Factor II, Factor XIII, and PAI mutations. Again, the presence of TE was found to be significantly higher in cases with homozygous mutations in any of the genes, including Factor V Leiden, Factor II, Factor XIII, MHTFR A1298C, and PAI-1, than in cases with no mutations or heterozygous mutations. Hospitalization was significantly higher in patients with the non-TE group. When the relationship between laboratory data and TE is examined, D-Dimer was found to be significantly higher in cases with TE. There was no significant correlation between other laboratory results and TE (Supplementary Table 1).
When the thrombosis status of the cases was evaluated according to COVID-19 RT-PCR results, it was observed that 28.6% of 98 patients with COVID-19 RT-PCR positive had TE, whereas 71.4% did not. Also, TE was observed in 7.6% of 105 cases with negative COVID-19 RT-PCR test, while 92.4% did not have TE. There was no significant relationship between age and TE presence as well as COVID-19 status (p>0.05). Among COVID-19 positive cases, TE was significantly higher in cases with MTHFR A1298C, and Factor XIII mutations (p = 0.007 and p = 0.015, respectively). This was not the case for negative COVID-19 cases. Again, the presence of TE was found to be significantly higher in cases with homozygous mutations in any of the Factor V Leiden, Factor II, Factor XIII, MHTFR A1298C and PAI-1 mutations than in cases with no mutations or heterozygous mutations (p = 0.030). This relationship was not detected for COVID-19 (-) cases. Among both the COVID-19 (+) and COVID (-) cases, hospitalization was significantly higher in cases with TE. When the laboratory results are examined, D-Dimer was significantly higher in cases with TE for both COVID-19 (+) and COVID (-) cases. This relationship was not significant in platelet (PLT), PT, activated partial thromboplastin time (aPTT), and INR values (Supplementary Table 2).
The association of cases with DVT, PTE, CVA, and AMI with gene mutations causing hereditary thrombophilia was examined, and no gene mutations were found to be associated with a specific TE type (p>0.05 for all TE types).
In our study, the differences in D-dimer levels were examined according to the gene mutation types, and it was observed that the D-dimer level was significantly higher in cases with Factor XIII gene mutations (p=0.035). In the post hoc analysis performed for this gene mutation, D-dimer level was found to be significantly higher in cases with homozygous gene mutation (4G/4G) as well as in cases with heterozygous gene mutation (4G/5G) compared to cases without Factor XIII gene mutation (p=0.010 [95% CI: 266.91-1917.17] and p = 0.038 [95% CI: 40.75-1377.88] respectively). This difference in terms of D-dimer was not observed in cases with Factor V Leiden, Factor II, MHTFR A1298C, and PAI-1 mutations.
Cases were grouped according to COVID-19 RT-PCR results (+/-) and TE status (+/-), and the relationship between those statuses and D-dimer levels was examined. It was determined that D-dimer differed significantly according to COVID-19 results and TE status (Z = 51.89; p<0.001). According to the post hoc analysis results, it was observed that D-dimer was significantly higher in COVID-19 (+) and TE (+) cases than in other groups. There was no significant difference between the other groups (Supplementary Table 3).

Discussion

In our study, TE was found to be significantly higher in COVID-19 RT-PCR positive cases with MTHFR A1298C and Factor XIII gene mutations compared to COVID-19 negative cases. This relationship was not detected in other hereditary thrombophilia gene mutations. Again, in cases with homozygous mutations in any of Factor V Leiden, Factor II, Factor XIII, MHTFR A1298C, and PAI-1 mutations, TE was found to be significantly higher than in cases with no mutations or heterozygous mutations.
There are studies investigating the relationship between thrombotic events and hereditary thrombophilia in cases of mortality due to COVID-19 disease.⁵ Abdullaev et al. evaluated the relationship between FV (506R/Q), MTHFR (223A/V), F2 (20210G/A), PAI-1 (4G/5G) mutations and COVID-19 and reported that MTHFR 223A/V heterozygous and PAI-1 (4G/5G) heterozygous genotype incidence was higher in cases with COVID-19 and thrombotic conditions whereas the incidence of heterozygous FV (506R/Q), MTHFR (223A/V), F2 (20210G/A) was lower. However, they reported a larger number of patients was necessary to come to a certain conclusion.^4,5 Again, in the studies by Khan S. and Han et al., it was reported that there is a strong relationship between PAI-1 and thrombotic complications of COVID-19.^3,11 In the study of Burlacu et al., they investigated the hereditary thrombophilia in a COVID-19 positive male case with stroke and they reported the presence of MTHFR A1298C, Factor XIII, angiotensin-converting enzyme (ACE) D/I, Argentina (e3/e4) and angiotensinogen (AGT) M235T gene mutations.¹² In the study by Cappadona et al., it has been reported that COVID-19 has a poor prognosis in cases with MTHFR and methionine synthase (MTR) gene mutations.¹³ Ponti et al. reported an increased incidence and severity of COVID-19 disease in patients with MTHFR gene mutations.¹⁴
Also, in the study of de la Morena-Barrio et al., the relationship between hereditary thrombophilia and thrombotic events due to COVID-19 was examined, and they reported that there was no interaction.¹⁵ The results of this study differ from the results of the studies by Khan S, Han et al., and de la Morena-Barrio et al. However, they support the results of the studies by Burlacu et al, Ponti et al., and Cappadona et al.
D-dimer is a fibrin degradation product, reflecting pathological activation of hemostatic pathways in COVID-19 patients. In our study, the relationship between gene mutations and D-dimer levels was evaluated. We found that D-dimer was significantly higher in the presence of Factor XIII mutation. This association was not seen in Factor V Leiden, Factor II, MHTFR A1298C, and PAI-1 mutations. In the cohort study by Köse et al., it was found that D-dimer was significantly higher in patients with Factor V Leiden mutation.¹⁶ In the study of Chaireti et al., they reported that D-dimer levels in patients with TE who had either homozygous or heterozygous Factor V Leiden mutations were significantly higher than the control group (without Factor V Leiden mutation).¹⁷ According to the results of this study, unlike the literature, no significant relationship between Factor V Leiden mutation and D-dimer was found. We think that this may be due to the low number of patients with the Factor V Leiden mutation in our study.
Studies report that mortality in COVID-19 is associated with high D-dimer levels. We wanted to compare this relationship in patients with hereditary thrombophilia, but it is hard to make any claims considering the low mortality rate in this study. Nevertheless, we found that the D-dimer level in cases with COVID-19 and with TE was significantly higher than in cases with negative COVID-19 (Supplementary Table 3). Tang et al. reported that D-dimer levels in patients who died from COVID-19 were significantly higher than in those who survived.¹⁸ According to Kampouri et al., D-dimer was significantly higher in COVID-19 positive cases with venous TE.¹⁹ In the study by Brosnahan et al., it was stated that the D-dimer level of COVID-19 positive cases with TE is significantly higher than that of COVID-19 negative cases with TE.²⁰ In this context, our study supports the literature data.

Limitations

The study has several limitations. The first of these is the risk of data loss and errors in the data that may occur due to the retrospective nature of our study. Secondly, the number of patients we followed up in this study was low because the cases were referred to other hospitals or moved to other hospitals with similar conditions. The third limitation is that we do not have the opportunity to look at all gene mutations associated with hereditary thrombophilia. However, we think that these limitations are not at a level to affect our study results.

Conclusion

In the results of our study, we found that COVID-19 disease increased thrombotic complications in patients with hereditary thrombophilia. In addition, we think that anticoagulant and antiaggregant treatments in patients with hereditary thrombophilia can reduce both COVID-19-related and thrombotic complications.

Declarations

Abbreviations

ACE: Angiotensin-converting enzyme
AGT: Angiotensinogen
AMI: Acute myocardial infarction
aPTT: Activated partial thromboplastin time
COVID-19: Coronavirus disease 2019
CVA: Cerebrovascular accident
DVT: Deep vein thrombosis
F2: Factor ii
FXIII: Factor xiii
INR: International normalized ratio
MTHFR: Methylenetetrahydrofolate reductase
MTR: Methionine synthase
PAI-1: Plasminogen activator inhibitor-1
PCR: Polymerase chain reaction
PLT: Platelet
PTE: Pulmonary thromboembolism
RT-PCR: Real-time polymerase chain reaction
SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2
STROBE: Strengthening the reporting of observational studies in epidemiology
TE: Thromboembolism

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About This Article

Received:

February 13, 2026

Accepted:

April 24, 2026

Published Online:

April 29, 2026