Abstract
Background
Plasminogen activator inhibitor-1 (PAI-1) is an important inhibitor of plasminogen activator, but the role of the PAI-1 4G/5G polymorphism in deep vein thrombosis (DVT) has been contradictory. In this study, we investigated the distribution of the PAI-1 4G/5G genotype in Chinese patients with DVT compared with healthy controls and the association between the PAI-1 4G/5G genotype and the persistence of residual venous occlusion (RVO) after different treatments.
Methods
The PAI-1 4G/5G genotype was determined by fluorescence in situ hybridization in 108 patients with unprovoked DVT and 108 healthy controls. The patients with DVT were treated with catheter-based therapy or anticoagulation only. RVO was assessed by duplex sonography during the follow-up.
Results
Thirty-two patients (29.6%) were homozygous for 4G (4G/4G), 62 patients (57.4%) were heterozygous for 4G/5G, and 14 patients (13%) were homozygous for 5G (5G/5G). No significant difference in genotype frequency was found between patients with DVT and controls. A total of 86 patients completed follow-up of ultrasound examination with a mean follow-up of 13.4 ±7.2 months. The results of patients with RVO were significantly different between homozygous 4G carriers (76.9%), heterozygous 4G/5G (58.3%), and homozygous carriers of 5G (33.3%) (P <.05) at the end of follow-up. Catheter-based therapy showed a better result in patients who were noncarriers of 4G (P = .045).
Conclusions
The PAI-1 4G/5G genotype was not a relevant predictor for DVT in Chinese patients, but is a risk factor for persistent RVO after idiopathic DVT.
Keywords: Deep vein thrombosis, Plasminogen activator inhibitor 1, Genetic polymorphisms, Fibrinolytic disorders, Anticoagulant agents, Percutaneous mechanical thrombectomy
Article Highlights.
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Type of Research: Single-center, retrospective cohort study
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Key Findings: The plasminogen activator inhibitor-1 4G/5G genotype was studied in 108 patients with unprovoked deep vein thrombosis (DVT) and 108 healthy controls. No significant difference in genotype frequency was found between patients with DVT and controls. The results of patients with residual venous occlusion were significantly higher in 4G carriers at the end of follow-up.
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Take Home Message: The plasminogen activator inhibitor-1 4G/5G genotype was not a relevant predictor for DVT in Chinese patients. The carriers of 4G (homozygous for the 4G genotype and heterozygous for the 4G/5G genotype) is a risk factor for persistent residual venous occlusion after idiopathic DVT. Noncarriers of 4G (homozygous for the 5G genotype) had a lower rate of residual venous occlusion if catheter-based therapy was applied.
Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism, is common. Among them, the incidence rate for DVT ranges from 88 to 112 per 100,000 person-years and is mostly observed in older patients.1,2 VTE is also potentially fatal owing to life-threatening pulmonary embolism and is easily recurrent, with a recurrence rate of more than 20% within 10 years after the initial event.3,4
Traditional risk factors for VTE and DVT include surgery, trauma, cancer, chemotherapy, prolonged immobilization, and acute medical illness. In addition, a recent study found that DVT is a polygenic disease.5,6 Genetic predisposition plays an important role in the occurrence and development of VTE, and the presence of Factor V Leiden or prothrombin 20210 G-A mutation are the most extensively studied factors.7,8 Otherwise, the plasminogen activator inhibitor (PAI)-1 4G/5G genotype may lead to a functional imbalance between the coagulation system and fibrinolytic system and play a role in the pathogenesis and course of DVT.5 Recent studies have proven that the 4G/5G polymorphism of the PAI-1 gene promoter region is related to the plasma and activity levels of PAI-1 and is significant in dissolving blood clots by inhibiting fibrinolytic activators tissue plasminogen activator and urokinase-type plasminogen activator as negative feedback to fibrinolysis.6,9,10
Meanwhile, the persistence of residual vein occlusion can lead to recurrence and post-thrombotic syndrome (PTS).9 The 4G/5G polymorphism may be associated with the inhibition of thrombus resolution and result in complications such as recurrent DVT or PTS.10 However, these conclusions remain controversial.
Thus, we hypothesized that the distribution of genotypes and frequency of alleles of the 4G/5G polymorphism of the PAI-1 gene were predictors for the development of thrombosis and persistence of residual vein occlusion.
Methods
This study was an institutional review board-approved study evaluating the association between the 4G/5G polymorphism and thrombosis and the persistence of residual vein occlusion. The study protocol was approved by the Ethics Committee of the Beijing Friendship Hospital in accordance with the Declaration of Helsinki, and written informed consent was obtained from all study participants. A single-institutional procedural database was queried for all consecutive cases of DVT treated with surgery from March 2021 to August 2022.
The inclusion criteria were the presence of DVT of the lower limb. The exclusion criteria were DVT secondary to predisposing factors, including surgery, trauma, immobilization, and bed rest; complicated with cancer, malignant hematological diseases, thrombophilia, or the presence of antiphospholipid antibodies, the presence of factor V Leiden or prothrombin 20,210 G-A mutation, and a clinical history of previous episodes of VTE. The presence of the factor V Leiden and the 20210 G-A mutation for the prothrombin gene was excluded by means of the same method used for the 4G/5G polymorphism.
The control group consisted of 108 unrelated and apparently healthy subjects showing no evidence of venous thrombosis.
In the enrolled patients, we analyzed the PAI-1 promoter polymorphism 4G/5G using fluorescence in situ hybridization according to the manufacturer's protocol. In brief, 2 to 3 mL of peripheral venous blood was collected from the enrolled patients, and white blood cell suspension was obtained from the peripheral blood. The suspension was added to the corresponding commercial test kit (Huaxia Times Gene Technology Development Ltd., Beijing, China), and a Fluotec 48E micro fluorescence detector (Tianlong Technology Ltd., Xi'an, China) was used for testing. The signal intensity was examined using fluorescence in situ hybridization and the PAI-1 (rs1799889) genotype was analyzed.
All patients were treated with low-molecular-weight heparin (nadroparin calcium or enoxaparin sodium) at a dosage of 90 IU/kg body weight, given in two administrations daily (except for those with contraindications to anticoagulation). Retrievable inferior vena cava filter insertion was performed for patients with proximal DVT and contraindications to anticoagulation or those with pulmonary embolism despite therapeutic anticoagulation.
Patients with symptomatic proximal DVT involving the femoral, common femoral, or iliac veins were considered for catheter-directed thrombolysis (CDT) or percutaneous mechanical thrombectomy (PMT). CDT was performed using a multiple-side hole infusion catheter (Multi-Sideport, Cook Medical, Bloomington, IN) embedded within the thrombosed vein for continuous infusion of urokinase. The urokinase was diluted in 500 mL of normal saline solution and infused at approximately 50,000 IU/h. PMT was performed with an AngioJet Rheolytic Thrombectomy System (Boston Scientific, Marlborough, MA) and then to infuse urokinase and balloon venoplasty if residual thrombus was present. These treatments were consistent with published guidelines and carried out by certified physicians.11
After discharge, patients received anticoagulant therapy consistent with published guidelines, including warfarin sodium (therapeutic target international normalized ratio of 2 to 3) after initial treatment with low-molecular-weight heparin and the option of factor Xa inhibitors (rivaroxaban and edoxaban).
Color duplex ultrasound examination and compression ultrasound examination were performed 3, 6, and 12 months after the initial event and at the end of the follow-up. The definition of venous recanalization is the same as in previous studies.12 In detail, the persistence of residual venous occlusion (RVO) was diagnosed if the veins were 2.0 mm larger in diameter at maximal compression on a single test or 3.0 mm larger in diameter on two consecutive tests according to the most recent result of compression ultrasound examination. The RVO was scanned from iliac vein to calf vein and the most proximal segment was recorded and displayed.
All analyses were performed using SPSS 24.0 software (SPSS Inc., Chicago, IL). Data are expressed as proportions for dichotomous variables and as the mean ± standard deviation or median and interquartile range (25th-75th percentiles) for continuous variables. Genotypic and allelic frequencies were determined by gene counting. The distribution of genotypes and alleles between the study group and controls and the relationship between the PAI-1 4G/5G genotype and the presence of RVO were analyzed by univariate chi-square tests. Risk assessment was performed by calculating odds ratios (ORs) with 95% confidence intervals (CIs). A P value of less than 0.05 was considered to be statistically significant.
Results
During the study period, 108 consecutive patients with idiopathic DVT were included. The results of genotype frequency in these patients and controls are illustrated in Table I. They had a median age of 67 years (interquartile range, 55-77 years), with 32 patients (29.6%) homozygous for the 4G (4G/4G) genotype, 62 patients (57.4%) heterozygous for the 4G/5G genotype, and 14 patients (13%) homozygous for the 5G (5G/5G) genotype. The genotype frequencies of the controls were 31.2% for 4G/4G, 51.4% for 4G/5G, and 16.5% for 5G/5G. Hardy-Weinberg equilibrium was observed in both the control group and the group with DVT. No significant difference in genotype frequency was found between patients with DVT and controls.
Table I.
Comparison of genotypes of the PAI-4G/5G polymorphism in the patient group and controls
| Patients with DVT (%) | Controls (%) | P value | |
|---|---|---|---|
| Male sex | 65 (60.2) | 68 (63.0) | .228 |
| Age, years | 67 (55-77) | 68 (55-77) | .744 |
| Genotypes | |||
| 4G/4G | 32 (29.6) | 34 (31.5) | .229 |
| 4G/5G | 62 (57.4) | 56 (51.8) | |
| 5G/5G | 14 (13) | 18 (16.7) |
A P value of <.05 was considered statistically significant.
Values are number (%) or median (interquartile range).
The statistical analysis of clinical and laboratory characteristics and the extent of thrombosis in different genotypes are shown in Table II. In general, iliac veins were involved in 27 patients (25%), thrombosis extended to the femoral veins in 54 patients (50%), and popliteal veins and calf veins were involved in 27 patients (25%). None of these characteristics were significantly different between carriers.
Table II.
Clinical and laboratory characteristics and extent of initial thrombosis of the overall study population and different genotypes of the PAI-4G/5G polymorphism
| Overall | 4G/4G (n = 32) | 4G/5G (n = 62) | 5G/5G (n = 14) | P valuea | |
|---|---|---|---|---|---|
| Age, years | 67 (55-77) | 66 (57-76) | 68 (53-77) | 65 (56-79) | .961 |
| Male sex | 65 (60) | 23 (72) | 32 (52) | 10 (71) | .115 |
| Smoking | 27 (25) | 5 (16) | 16 (26) | 6 (43) | .152 |
| Platelet count, × 109/L | 179 (144-243) | 166 (140-244) | 195 (146-242) | 178 (160-261) | .867 |
| Erythrocyte count, × 1012/L | 4.4±0.8 | 4.6±0.8 | 4.3±0.7 | 4.4±0.6 | .193 |
| Leukocyte count, y × 109/L | 7.1 (5.8-9.0) | 6.8 (5.9-7.9) | 7.4 (5.7-9.3) | 7.2 (5.7-8.4) | .307 |
| d-Dimer, mg/L | 3.8 (2.1-6.9) | 5.0 (2.3-6.9) | 3.2 (1.4-7.1) | 4.1 (2.3-7.2) | .982 |
| Extent of thrombosis | |||||
| Iliac vein | 27 (25) | 10 (31.3) | 14 (22.6) | 3 (21.4) | .665 |
| Femoral vein | 54 (50) | 16 (50) | 32 (51.6) | 6 (42.9) | .839 |
| Popliteal vein and calf vein | 27 (25) | 6 (18.8) | 16 (25.8) | 5 (35.7) | .434 |
Values are number (%), median (interquartile range), or mean ± standard deviation.
A P value of <.05 is considered statistically significant.
Denotes comparisons between different genotypes of the PAI-4G/5G polymorphism.
A total of 86 patients completed follow-up of ultrasound examination with a mean follow-up of 13.4 ±7.2 months. There were 22 patients who did not undergo duplex ultrasound examination; two of them died of septic shock and myocardial infarction in 3 months and the rest of patients refused to undergo duplex ultrasound examination because they lived far away. The results of follow-up in different genotypes are shown in Tables III and IV. At the end of the follow-up, 52 patients (60.5%) had RVO, and 4 patients (4.6%) had a recurrence of DVT. The results of patients with RVO were significantly different between homozygous 4G carriers (76.9%), heterozygous 4G/5G (58.3%), and homozygous carriers of 5G (33.3%) (P <.05) at the end of follow-up.
Table III.
Extent of initial thrombosis and residual venous occlusion (RVO) in different genotypes of the PAI-4G/5G polymorphism
| Overall (n = 86) | 4G/4G (n = 26) | 4G/5G (n = 48) | 5G/5G (n = 12) | P valuea | |
|---|---|---|---|---|---|
| Extent of initial thrombosis | |||||
| Iliac vein | 18 (20.9) | 5 (19.2) | 10 (20.8) | 3 (25) | .871 |
| Femoral vein | 45 (52.3) | 16 (61.5) | 25 (52.1) | 4 (33.3) | .292 |
| Popliteal vein and calf vein | 23 (26.7) | 5 (19.2) | 13 (27.1) | 5 (41.7) | .382 |
| Extent of RVO at the end of follow-up | |||||
| Iliac vein | 4 (4.7) | 2 (7.7) | 2 (4.2) | 0 (0) | .788 |
| Femoral vein | 28 (32.6) | 12 (46.2) | 14 (29.2) | 2 (16.7) | .176 |
| Popliteal vein and calf vein n | 20 (23.3) | 6 (23.1) | 12 (25) | 2 (16.7) | .937 |
| With RVO n | 34 (39.5) | 20 (76.9) | 28 (58.3) | 4 (33.3) | .039 |
Value are number (%).
Comparisons between different genotypes of the PAI-4G/5G polymorphism.
Table IV.
Number of patients with residual venous occlusion (RVO) at the end of follow-up in different genotypes and allelic frequencies of the PAI-4G/5G polymorphism
| With RVO | Without RVO | P value | OR (95% CI) | |
|---|---|---|---|---|
| Genotypes | ||||
| 4G/4G | 20 | 6 | 0.039 | |
| 4G/5G | 28 | 20 | ||
| 5G/5G | 4 | 8 | ||
| Dominant model | ||||
| 4G/4G+4G/5G | 48 | 26 | 0.047 | 3.692 (1.015-13.435) |
| 5G/5G | 4 | 8 | ||
| Recessive model | ||||
| 4G/4G | 20 | 6 | 0.044 | 2.917 (1.027-8.283) |
| 4G/5G+5G/5G | 32 | 28 |
CI, Confidence interval; OR, odds ratio.
Moreover, more frequencies of RVO were shown in 4G carriers (4G/4G and 4G/5G; 64.9%) than in noncarriers of 4G (5G/5G; 33.3%) (OR, 3.692; 95% CI, 1.015-13.435; P = .0.047). The recessive model (4G/4G vs 4G/5G+5G/5G) also showed a significant association with RVO (OR, 2.917; 95% CI, 1.027-8.283; P = .0044).
Sixty-three patients had thrombosis involving the femoral vein or above and were considered for aggressive treatment, such as CDT or PMT treatment; 31 patients (49.2%) received catheter-based therapy and anticoagulation. The circumstances of RVO in patients with thrombosis involved in the femoral vein or above in different genotypes of the PAI-4G/5G polymorphism are shown in Table V. Catheter-based therapy and anticoagulation showed a better result of RVO in patients who were noncarriers of 4G (P = .045). For patients who received anticoagulation only, 50% of patients in the 4G/4G group had no decrease in the extent of thrombus, higher than the rest of the patients (4G/5G+5G/5G), with only 25% having no decrease in the extent of thrombus; however, no statistically significant difference was seen (P = .25).
Table V.
The circumstances of residual venous occlusion (RVO) in patients with thrombosis involved in the femoral vein or above in different genotypes of the PAI-4G/5G polymorphism
| Overall | 4G/4G | 4G/5G | 5G/5G | P valuea | |
|---|---|---|---|---|---|
| Anticoagulation alone | |||||
| RVO | 22 (68.7) | 9 (75) | 12 (70.6) | 1 (66.7) | .406 |
| RVO level with no decrease | 11 (34.4) | 6 (50) | 4 (23.5) | 1 (33.3) | .359 |
| Catheter-based therapy and anticoagulation | |||||
| RVO | 22 (71.0) | 9 (100) | 11 (61.1) | 2 (50) | .045 |
| RVO level with no decrease | 7 (22.6%) | 2 (22.2) | 5 (27.8) | 0 (0) | .384 |
Values are number (%).
Comparisons between different genotypes of the PAI-4G/5G polymorphism.
Discussion
In recent decades, substantial progress has been made in the diagnosis and management of DVT, and many etiological factors have been well-documented, such as deficiencies in protein C, protein S, antithrombin III, and mutations in factor V Leiden and prothrombin G20210 A.13 PAI-1 may be one of the factors as a fast-acting serpin that regulates the fibrinolytic system through the inhibition of tissue plasminogen activator and urokinase-type plasminogen activator, and it has been recognized as a pivotal protein in the progression of vascular events such as myocardial infarction, stroke, and DVT.14, 15, 16 The 4G/5G polymorphism in the PAI-1 gene promoter region is related to the plasma and activity level of PAI-1, and the single deletion of a guanosine residue (4G) allele could bind to a transcription activator, enhancing messenger RNA transcription, increasing the level of PAI-1 and increasing thrombotic risk.13,17
Based on these results, the distribution of genotypes and frequency of alleles of the 4G/5G polymorphism of the PAI-1 gene were studied extensively. In our study, we found no association between the PAI-1 gene polymorphism and DVT, which is in agreement with other studies in Austria and Turkey.5,18 However, many published studies suggested the impact of the PAI-1 4G/5G polymorphism on the occurrence of unprovoked DVT, and the results varied greatly in different studies.6,12,19 The genotype frequencies of homozygosity for 4G ranged from 4.0% to 73.7% in patients with DVT and 0% to 58.0% in controls, and 4G/5G ranged from 17.7% to 66.7% in patients with DVT and 12.7% to 59.0% in controls. The relationship between the 4G allele and DVT remains controversial and inconclusive.6,20, 21, 22 We think these studies produced contradictory results owing to sample selection, race, and region; hemostatic metabolism is also influenced by nongenetic factors.
The same controversy was seen in the extension of thrombosis. In our study, a greater prevalence of iliac vein involvement was seen in 4G/4G patients, but the difference was not statistically significant. These findings are not in agreement with previously published data. Ferrara et al22 reported a relationship between the progression of thrombosis and the 4G/5G polymorphism, and carriers of the 4G allele experienced a more marked extension than noncarriers. These different data differences may be explained by the limited number of cases involved in our study.
RVO and a greater RVO burden have been linked previously with the promotion of recurrent VTE and other serious complications such as PTS, and RVO information could potentially be used to estimate the risk of DVT recurrence and to guide the duration of anticoagulation.23,24 Our study showed that the presence of the 4G/5G polymorphism could be related to the persistence of thrombosis, and this difference was also found in the dominant model or recessive model. Similar to our study, Incalcaterra et al10 found an association of the PAI-1 4G/5G genotype with PAI-1 plasmatic activity and RVO in patients with postoperative DVT of the legs. In addition, their study demonstrated a significantly increased PAI-1 activity in carriers of the 4G allele and experienced more PTS than noncarriers of 4G during the follow-up. The progression of RVO may be partially associated with decreased fibrinolytic activity related to the 4G/5G polymorphism.22 Conversely, Giurgea et al5 investigated patients with acute idiopathic DVT of the lower limb and showed that the PAI-1 4G/5G genotype was not a relevant predictor of RVO. This discrepancy may be due to differences in race, region, and number of cases, because only 43 patients were included in their study.
More important, the relationship between the PAI-1 4G/5G genotype and RVO may influence the management and treatment of DVT in carriers of the 4G polymorphism. Although the use of anticoagulant therapy may decrease the morbidity of thrombus extension, recurrence, and PTS, this complication develops within 2 years in approximately one-half of the patients with proximal DVT.4,25 During the past decade, there has been significant evolution in the methods of endovascular thrombus removal, and large-scale studies have shown that thrombolysis or PMT may decrease PTS.11,26 Therefore, catheter-directed fibrinolysis with or without mechanical thrombectomy was considered in our patients with iliofemoral obstruction, severe symptoms, and a low risk of bleeding as recommended.4 Sixty-three patients had thrombosis above the iliac, common femoral, or femoral veins, and nearly one-half of them received CDT with or without PMT (49.2%). It seems that most patients remained with RVO regardless of whether catheter-based therapy was applied, but the patients who were noncarriers of 4G had a lower rate of RVO (P = .045). Moreover, the effect of anticoagulation only seems to be insufficient in patients homozygous for 4G, with 50% of them having no decrease in the extent of thrombus, higher than the rest of the patients (4G/5G+5G/5G), with only 25% having no decrease in the extent of thrombus; however, no statistically significant difference was seen (P = .25). If the poor effect of anticoagulation alone in patients homozygous for 4G can be confirmed by further studies, there will be significant clinical practice implications for management and treatment. As we mentioned elsewhere in this article, the 4G/5G polymorphism is not rare in the general population, and the frequency of homozygosity for 4G is more than one-quarter of the population in our study and other surveys.18,27,28 The use of anticoagulants only seems to be inadequate in preventing the progression of thrombosis in these patients, and more aggressive treatment may need to be considered to decrease the residual thrombus.
The limitations of this study deserve mention. First, owing to the short follow-up time, the occurrence of PTS was not studied, and the relationship between the 4G/5G polymorphism of the PAI-1 gene and PTS or recurrence may not be clear in such a short period. Second, the relationship between the 4G/5G polymorphism and plasma levels of PAI-1 activity may vary in different populations, and we did not detect PAI-1 levels in patients with DVT or controls. Last, this study is inherently subject to its relatively small sample size, and the loss to follow-up poses a potential threat to validity as well; these results should be validated in large-scale studies. Despite these limitations, this study is the first to evaluate the effectiveness of different treatments for patients with DVT with the 4G/5G polymorphism of the PAI-1 gene.
In conclusion, the 4G/5G PAI-1 polymorphism was not over-represented in patients with unprovoked DVT compared with healthy controls, but it is a predictor of RVO in patients with acute idiopathic DVT.
Author Contributions
Conception and design: WL, HF
Analysis and interpretation: SC, BL
Data collection: WL, ZZ, ZL
Writing the article: WL, SC, BL
Critical revision of the article: ZZ, ZL, HF
Final approval of the article: WL, SC, BL, ZZ, ZL, HF
Statistical analysis: WL
Obtained funding: Not applicable
Overall responsibility: FH
Footnotes
Author conflict of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest.
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