Prevalence and risk factors of deep venous thrombosis of hospitalizations in plateau: A cross-section analysis

doi:10.21203/rs.3.rs-3133945/v1

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Prevalence and risk factors of deep venous thrombosis of hospitalizations in plateau: A cross-section analysis

https://doi.org/10.21203/rs.3.rs-3133945/v1

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Background: To elucidate the prevalence of and associated risk factors for deep venous thrombosis (DVT) in hospitalized patients in plateau areas.

Methods: We enrolled patients who were hospitalized in three grade III-a hospitals in Qinghai Province, China, between January 2020 and October 2020. The demographic and clinical data and laboratory results were collected at admission. Simultaneously, we performed ultrasonography of the bilateral lower extremities, and the length of hospital stay was collected before discharge.

Results: In total, 3432 patients were enrolled; of them, 159 were diagnosed with DVT (4.60%). The total length of hospital stay of patients with DVT was longer than that of those without DVT (16.40 ± 7.66 vs. 14.77 ± 8.55 days). Age of >50 years (OR = 1.969, 95% CI: 1.192–3.252, P = 0.008), residence altitude of ≥3000 m (OR = 2.344, 95% CI: 1.238–4.438, P = 0.009), D-dimer level of ≥0.5 mg/L (OR = 2.53, 95% CI: 1.813–3.529, P < 0.001), comorbidities (OR = 1.906, 95% CI: 1.365–2.662, P < 0.001),history of varicose veins (OR = 2.202, 95% CI: 1.096–4.425, P = 0.027), and current medications (OR = 2.591, 95% CI: 1.857–3.616, P < 0.001) were identified as risk factors for DVT in plateau areas.

Conclusion: The prevalence of DVT in hospitalized patients in plateau areas was 4.60%. We recommend considering individualized risk stratification (age > 50 years, residence altitude ≥ 3000 m, history of varicose veins, D-dimer level ≥ 0.5 mg/L, current medications, and comorbidities) for patients at admission.

deep venous thrombosis

plateau

prevalence

risk factors

Deep venous thrombosis (DVT) is a venous return disorder caused by abnormal blood clotting in deep veins, usually occurring in the lower extremities. Loss of thrombus can cause pulmonary embolism (PE) [1, 2], which can significantly affect the quality of life and even lead to death [3–5]. The incidence of DVT is 88–112/100 000 person-years [6], and the annual incidence of the first episode of symptomatic DVT is 50–100/100 000 population in the adult population [7]. The most serious complication of DVT is PE, which is associated with 50,000–200,000 deaths every year [4, 8]. Therefore, DVT has become a serious public health issue that threatens human health and economic development [9].

Approximately 500 million people worldwide live at high altitudes [10]. At such altitudes, the air is thin, oxygen partial pressure is low, and the body is in an obvious state of hypoxia. Therefore, the prevalence of DVT is significantly higher in these areas than in plain areas [11, 12]. A study has reported that lowlanders living at high altitudes have a 30–44 times higher risk of presenting to hospitals with DVT than those living at low altitudes [13]; however, data on the prevalence of DVT in high-altitude hospitalized patients are lacking.

The main causes of DVT are damage to venous stasis, vessel wall injury, and hypercoagulability [4]. The established risk factors include a history of DVT, presence of a malignant transformation, increasing age, cigarette smoking, obesity, prolonged bed rest, trauma or fracture, surgery, pregnancy and puerperium, oral contraceptives and hormone therapy, and general anesthesia [5, 7, 14]. Exposure to high altitudes and hypoxia are the recognized predisposing factors for venous thrombosis [2, 4, 5, 15]. Further, increased red blood cell and blood viscosity [10, 16], platelet aggregation and coagulation activation [5, 17, 18], and vascular endothelial cell damage [19, 20] caused by hypoxia increase the risk of thrombosis in high-altitude hospitalized patients [2, 4, 11, 16–18]; this suggests that there are other risk factors in plateau areas and that further research is warranted.

Qinghai province is located in the Qinghai–Tibet Plateau and has an average elevation of approximately 3500 m above sea level. It is a multiethnic region; in addition to the Han nationality, many ethnic minorities such as Tibetan, Hui, Salar, Tu, and Mongolian are present. The people’s diet is mainly high in salt and fat. At present, no studies have determined whether there are differences in the prevalence of DVT among different nationalities and residence altitudes and whether special diet cultures affect DVT formation. Therefore, it is important to understand the effect of ethnic characteristics, different altitudes, and special diet culture on DVT formation in plateau areas. The present study aimed to investigate the prevalence of DVT in hospitalized patients in plateau areas and analyze its risk factors to provide a basis for DVT prevention in plateau areas and establish a risk assessment system for DVT in plateau areas.

Participants

In this cross-sectional study, we enrolled patients who were hospitalized between January 1, 2020, and December 31, 2020 in three third-class A hospitals in the Qinghai-Tibet Plateau. The inclusion criteria were as follows: (1) patients residing in Qinghai for ≥ 10 years, (2) those who were ≥ 18 years of age, and (3) those who voluntarily agreed to participate after providing written informed consent. The exclusion criteria were as follows: (1) patients who had difficulty in language communication or understanding, (2) those with disturbance of consciousness and who were unable to communicate effectively; further, their caregivers were unable to provide effective information, and (3) patients who were in emergency treatment and died within 24 h after admission. All patients in this study provided written informed consent. The study was approved by the ethics committee of Qinghai Provincial People’s Hospital (2020-48). All procedures involving human participants were conducted according to the ethical standards of the institutional and/or national research committee and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Sample size

According to the empirical criteria, the sample size for logistic regression analysis should be 10–15 times the covariates numbers. This study considered 26 covariates; therefore, the sample size should be 260–390. Considering 20% of sample shedding, the sample size should not be < 468.

DVT diagnosis

Duplex ultrasonography (DUS) was performed to diagnose DVT. All participants underwent DUS of bilateral lower extremities at admission. The diagnostic criteria for DVT were noncompressed veins, lumen obstruction or filling defect, lack of respiratory vibration above the knee vein segment, and inadequate flow augmentation to the calves [21]. DUS included the common femoral vein, superficial femoral and deep femoral, popliteal, anterior tibial, posterior tibial, and common fibular veins. Blood clots located in the intermuscular veins (i.e., the gastrocnemius and soleal veins) were not included.

Data collection

The data collected were demographic variables (age/sex/nationality/residence/body mass index), history of smoking or drinking alcohol, diet consumption (boiled tea/ghee/beef/ mutton), activity ability, diagnoses, comorbidities, family history of DVT, history of varicose veins, current medications, lower limb edema, laboratory examination results (red blood cell count/platelet count/prothrombin time/thrombin time/activated partial thromboplastin time/fibrinogen/D-dimer/fibrinogen degradation products [FDPs]), and total length of hospital stay.

Statistical analysis

Data analysis was performed using SPSS23.0 (IBM, Armonk, New York, United States). Demographics and measured variables were characterized using descriptive statistics (i.e., mean ± SD, quartile median, and proportions). Continuous variables were analyzed using the Student’s t-test for independent samples or the Mann–Whitney U test for non-normal distribution variables. Categorical variables were analyzed using the chi-squared test. Multivariate logistic regression analysis was performed to identify the risk factors. The odds ratio (OR) and 95% confidence interval (CI) were used to express the strength of the correlations. A P-value of < 0.05 was considered statistically significant.

1 Patient characteristics

In total, 3432 patients were enrolled in this study; of them, 159 (4.60%) patients were diagnosed with DVT. Table 1 lists the characteristics of the study participants.

Table 1

Patients characteristics
Particulars	Mean (SD)	Median (P25, P75)	n (%)
Age (year)	59.94 ±15.55
Residence (year)	56.34 ±17.60
Body mass index BMI (kg/m²)	24.21 ±3.89
*Red blood cell count (10¹²/L)**	4.42 ±2.86
*Platelet count (10**⁹)	24.81 ±20.43
Prothrombin time (PT) (s)	11.32 ±4.56
Thrombin time TT (s)	16.56 ±3.07
Activated partial thromboplastin time APTT (s)	28.53 ±6.43
Fibrinogen, FIB (g/L)		2.00 (2.00, 3.00)
D-Dimer (mg/L)		0.00 (0.00, 1.00)
Fibrinogen degradation products FDP (mg/L)		2.00 (1.00, 6.00)
Gender
Male			1875(52.3)
Female			1557(43.2)
Nationality
Han			2686
Hui			414
Zang			269
Others			63
Residence attitude
༜3000 m			3281
≥ 3000 m			151
Smoking history
No			2486
Yes			946
Alcohol consumption
No			2618
Yes			814
Boil tea consumption
Never			692
Occasionally			2193
Sometimes			249
Frequently			298
Ghee consumption
Never			2665
Occasionally			489
Sometimes			107
Frequently			171
Beef and mutton consumption
Never			97
Occasionally			722
Sometimes			1913
Frequently			700
Activity ability
Paralysis			5
Immobilization			41
Bedridden ≥ 3 days			313
Wheelchair			191
Limited activity requires help from Others			327
Walking aid			158
Autonomic activities			2397
Diagnosis
Endocrine, nutritional, metabolic, and immune diseases			872
Neurological			129
Respiratory			288
Digestive			67
Circulation			570
Genitourinary			63
Hematological			12
Musculoskeletal system and connective tissue			612
Trauma and toxicosis			674
Neoplastic			56
Others			89
Comorbidities
No			2294
Yes			1138
DVT family history
No			3392
Yes			40
History of varicose veins
No			3339
Yes			93
Current medications
No			2547
Yes			885
Lower Limb Edema
No			137
Yes			3075

2 Differences in the characteristics of patients with and without DVT

Compared with patients without DVT, those with DVT had a longer total length of hospital stay (16.40 ± 7.66 vs. 14.77 ± 8.55, P < 0.05). Tables 2 and 3 present the comparison results of the characteristics of the patients with and without DVT. Significant differences were observed in 11 variables: D-dimer levels, FDPs, sex, age, residence altitude, alcohol drinking, activity ability, diagnosis, comorbidities, history of varicose veins, and current medications.

Table 2

Comparison between non-DVT and with-DVT in all collected variables
	Non-DVT	With-DVT	t/Z	P
Total of hospital stay (days)	14.77 ± 8.55	16.40 ± 7.66	-2.609	0.01
BMI (kg/m²)	24.22 ± 3.87	24.06 ± 4.40	0.465	0.643
Red blood cells	4.42 ± 2.83	4.39 ± 3.44	0.118	0.906
Platelets	24.82 ± 20.42	24.64 ± 20.60	0.111	0.912
PT (s)	11.31 ± 4.63	11.48 ± 2.57	-0.75	0.454
TT (s)	16.55 ± 2.95	16.67 ± 4.74	-0.329	0.743
APTT (s)	28.51 ± 6.43	28.93 ± 6.26	-0.832	0.406
FIB (s)	2.00 (1.00, 5.00)	5.00 (1.75, 12.25)	-1.246	0.213
D-Dimer (mg/L)	0.00 (0.00, 1.00)	1.00 (0.00, 4.00)	-5.866	༜0.001
FDP (mg/L)	2.00 (2.00, 3.00)	3.00 (2.00, 3.00)	-4.626	༜0.001
BMI body mass index, RBC Red blood cell, PT Prothrombin time, TT thrombin time, APTT activated partial thromboplastin time, FIB fibrinogen, FDP fibrinogen degradation product

Table 3

Comparison between non-DVT and with-DVT in all collected variables
		Non-DVT N(%)	With-DVT N(%)	X²	P
Gender	Male	1801(96.05)	74(3.95)	4.405	0.036
	Female	1472(94.54)	85(5.46)
Age (years)	≤ 50	806	19	13.343	< 0.001
	> 50	2467	140
Nationality	Han	2559	127	4.972	0.174
	Hui	402	12
	Zang	254	15
	Others	58	5
Residence Attitude (m)	< 3000 m	3134	147	3.927	0.048
	≥ 3000 m	139	12
Smoking history	No	2362	124	2.574	0.109
	Yes	911	35
Alcohol drinking	No	2485	133	5.000	0.025
	Yes	788	26
Boil tea	Never	663	29	0.693	0.875
	Occasionally	2091	102
	Sometimes	237	12
	Frequently	282	16
Ghee	Never	2545	120	6.671	0.083
	Occasionally	470	19
	Sometimes	97	10
	Frequently	161	10
Beef and mutton	Never	94	3	3.024	0.388
	Occasionally	687	35
	Sometimes	1817	96
	Frequently	675	25
Activity ability	paralysis	5	0	30.341	<0.001
	Immobilization	35	6
	Bedridden ≥ 3 days	295	18
	Wheelchair	179	12
	Limited activity Requires help from others	298	29
	Walking aid	151	7
	Autonomic activities	2310	87
Diagnosis	Endocrine, nutritional, metabolic, and immune diseases	840	32	19.499	0.034
	Neurological	126	3
	Respiratory	262	26
	Digestive	62	5
	Circulation	547	23
	Genitourinary	59	4
	Hematological	11	1
	Musculoskeletal System and connective tissues	584	28
	Trauma and Toxicosis	642	32
	Neoplastic	55	1
	Others	85	4
Comorbidities	No	2217	77	25.506	༜0.001
	Yes	1056	82
DVT family history	No	3236	156	0.753	0.386
	Yes	37	3
History of varicose veins	No	3190	149	8.103	0.004
	Yes	83	10
Current medications	No	2466	81	47.175	༜0.001
	Yes	807	78
Lower Limb Edema	No	126	11	4.3	0.116
	Yes	2939	136

3 Multivariate analyses of risk factors associated with DVT in hospitalizations in plateau

The 11 variables were entered into the multivariate analysis, and the variables assignment are listed in Table 4. age (༞50 years), residence attitude (≥ 3000 m), D-dimer level (≥ 0.5 mg/L), comorbidities, history of varicose veins, and current medications acted as independent risk factors of the DVT in high altitude, and patients with-DVT influenced the total hospital stay duration (Table 4).

Table 4

Multivariate analyses of risk factors associated with DVT in hospitalizations in plateau
	B	Standard error	Wald X²	P	OR	95% CI
						lower	upper
Constant	-5.037	0.297	287.296	0	0.006
Age (༞50 years)	0.678	0.256	7.007	0.008	1.969	1.192	3.252
Residence attitude (≥ 3000 m)	0.852	0.326	6.835	0.009	2.344	1.238	4.438
D-dimer (≥ 0.5 mg/L)	0.928	0.17	29.815	0	2.53	1.813	3.529
Comorbidities	0.645	0.17	14.318	0	1.906	1.365	2.662
History of varicose veins	0.79	0.356	4.921	0.027	2.202	1.096	4.425
Current medications	0.952	0.17	31.357	0	2.591	1.857	3.616
Total hospital stay duration (day)	0.49	0.176	7.786	0.005	1.632	1.157	2.302

In our study, the prevalence of DVT in hospitalized patients residing in plateau areas was 4.6%; this was much higher than the findings of Loffredo et al.(0.25%) [22], Sun et al.(1.65%) [23], and Law et al.(0.03%) [24]. In 2010, a 9-month prospective study in China revealed that the incidence of DVT in China was 0.9%. The 25 hospitals included in this study were all located in plain areas, further confirming that the special plateau environment plays an important role in DVT formation. Hypoxia can lead to vascular wall damage, dysfunction of vascular endothelial cells covering the surface, and increased D-dimer and activated protein c resistance; further, the body exhibits a state of promoting coagulation [25]. On the other hand, it induces the secretion of Weibel–Palade bodies in vascular endothelial cells [2], which store various thrombus formation-related components [26, 27]. Stimulation of hypoxia can lead to changes in blood composition, including increased red blood cell count and hemocytosis, resulting in increased blood viscosity and decreased blood flow [10, 28–31], and promote hypercoagulability.

We observed that the incidence of DVT in inpatients residing at altitudes of ≥ 3000 m was considerably higher than that of those residing in altitudes of ≤ 3000 m (7.95% vs, 4.48%). Tibetans, an ethnic group living in the Tibetan Plateau, mostly reside in altitudes of > 3000 m. In the present study, the incidence of DVT in hospitalized Tibetan patients was higher than that of other ethnic groups (Tibetan, 5.58%; Han, 4.73%; and Hui, 2.90%); this may be one of the reasons for the high incidence of DVT in patients residing at altitudes of ≥ 3000 m. Deng et al. [32] compared the blood components of 222 patients who had been hospitalized in plateau areas and found that Hb concentration, Hct, and RBC count in the blood of the patients increased with an increase in altitude.

We also observed that the incidence of DVT in patients > 50 years was significantly higher than that in patients < 50 years (5.37% vs. 2.30%); this is consistent with the findings of Nordstrom et al [33]. The risk of blood clots is strongly associated with aging [33, 34]. Hb concentration, Hct, and RBC count in the blood of permanent residents in high-altitude areas increased with age [31, 35]; further, the D-dimer level increased with age [6, 36, 37]. All these factors may increase the risk of DVT in people > 50 years.

The diagnostic value of D-dimer for thrombus was confirmed in the Guidelines for Diagnosis and Treatment of Acute Pulmonary Embolism in 2019 issued by the European Society of Cardiology [38]; it was further verified in the present study. We found that when patients’ D-dimer level is ≥ 0.5 mg/L, attention should be paid to evaluating the presence of DVT symptoms. The D-dimer level increases with age, leading to a decrease in the specificity of DVT diagnosis in elderly patients [6]. Righini et al. [39] suggests adjusting the D-dimer threshold for patients > 50 years to improve the specificity of DVT diagnosis; this has been verified in related studies [39, 40]. Medical staff should not only pay attention to the D-dimer index of patients but also apply the age-adjusted D-dimer strategy to improve the diagnostic specificity for patients > 50 years [40].

This study indicates that comorbidity is an independent risk factor for DVT in hospitalized patients. Some studies [41–43] have also reported that complications increase thrombosis risk. This study included 33.16% of patients with complications, and the incidence of DVT was as high as 7.21%. A meta-analysis by Tang et al. [44] revealed that the risk of DVT in patients with stroke and complications of diabetes, coronary heart disease, atrial fibrillation, and heart failure increased by 1.63, 2.31, 1.55, and 1.96 times, respectively. Wei B et al. [45] and Wang S et al. [46] reported that patients with spinal diseases and hypertension, diabetes, and heart disease exhibited an increased risk of postoperative DVT. In patients with renal insufficiency, the risk of thrombosis was reported to increase by 5.5 times [47]. A prospective registry of 5451 patients with DVT by Goldhaber SZ et al. [48] reported that 50% of these patients had hypertension. Therefore, the medical staff should take active and effective preventive measures to minimize the onset of complications. For patients with complications, effective preventive measures for DVT should be taken while strengthening observation and evaluating factors to reduce DVT risk.

The results of this study suggest that varicose vein history is an independent risk factor for DVT in hospitalized patients. Varicose veins are common in the lower extremities of patients and are among the manifestations of venous insufficiency of the lower extremities. Several studies have reported that venous insufficiency of the lower extremities is a secondary risk factor for DVT [49]. A total of 2.71% of patients had varicose veins in this study, and the incidence of DVT was as high as 10.75%. The incidence of chronic mountain sickness among residents living at altitudes > 2500 m was reported to be 5–10% [50, 51], including varicose veins. Gao et al. [52] studied 218 individuals living at an altitude of 3300–5400 m in 2019, and the findings revealed that the incidence of varicose veins in areas of high altitude was as high as 11.47%. For patients with varicose veins, it is necessary to understand the extent of varicose veins. Lower limb vascular Doppler examination should be conducted when necessary to understand clearly the valve function of the veins and whether regurgitation along with the degree of regurgitation, so as to perform targeted diagnosis and treatment. During patient hospitalization, relevant health instructions were provided according to the patient’s condition, including elevating the affected limb while lying flat, and regular ankle and calf movements to relieve venous hypertension and increase the venous return of the lower limb. Elastic stockings, inflatable pressure treatment, and elastic bandages can be used as pressure treatment to promote venous return and relieve limb stasis.

Current medications were found to be an independent risk factor for DVT in hospitalized patients. In this study, the proportion of patients taking medications was 25.79%, and the incidence of DVT was as high as 8.81%. Various drugs are clinically used. Drugs that have been proven to be likely to cause thrombosis include sedation, dehydration, and vasopressin drugs. These drugs cause hemodynamic changes and vascular damage in patients, among which vasopressin also leads to the reduction of the vascular lumen, increasing the risk of thrombosis.

Antibiotics are commonly used to prevent and control infection and are very common in clinical settings. Timp et al. [53] revealed that with the use of antibiotics, the risk of VTE was 4.5 times higher and the risk of DVT was 3.2 times higher than that without the use of antibiotics. A population-based case-control study by Schmidt et al. [54]revealed a nearly three-fold increase in the risk of DVT after community antibiotic treatment. Therefore, medical staff should improve antibiotic-related awareness regarding the risk of thrombosis. Furthermore, they should rationally use antibiotics based on the results of drug sensitivity tests and reduce the administration of unnecessary antibiotics to reduce the risk of thrombosis.

The total length of hospital stay of patients with DVT in this study was longer than that of patients without DVT (16.40 ± 7.66 days vs. 14.77 ± 8.55 days). With an extended hospital stay, the economic burden of patients, hospitals, and society correspondingly increases and also brings more risks. Therefore, the prevention and treatment of DVT are particularly important. Thus, we can combine the characteristics of the plateau to build a VTE prevention and management system in the plateau areas, improve patient prognoses, improve the quality of medical treatment, and guarantee the medical safety of inpatients to reduce the VTE-related disease and economic burden.

Currently, the prevalence of DVT in inpatients on the Tibetan Plateau in China is limited. Our study provides a basis for DVT prevention and treatment in the Tibetan Plateau in the future. Therefore, medical staff should use an appropriate DVT evaluation model to assess DVT risk and occurrence. Based on the outcomes, targeted preventive measures along with plateau characteristics can be used to reduce DVT incidence. During hospitalization, patients should focus on assessing the conditions of their lower extremities.

deep venous thrombosis

DVT

Duplex ultrasonography

DUS

fibrinogen degradation products

FDPs

odds ratio

confidence interval

Prothrombin time

Thrombin time

Activated partial thromboplastin time

APTT

Fibrinogen

FIB

Ethics approval and consent to participate

All patients in this study provided written informed consent. The study was approved by the ethics committee of Qinghai Provincial People’s Hospital (2020-48). All procedures involving human participants were conducted according to the ethical standards of the institutional and/or national research committee and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All patients in this study provided written informed consent.

Consent for publication

Not applicable

Availability of data and materials

The datasets generated and analyzed during the present study are available from the corresponding author on reasonable request.

Conflict Interest

The authors declare that they have no conflict of interest.

Funding

This work was supported by Key project of Qinghai Provincial Health Commission (2019-wjzd-01).

Authors' contributions

Conceptualization：Lijuan Sun, Shiqin Pan;

Data curation: Limei Wang, Cuo Yong, Hongmei Ma;

Formal analysis;

Funding acquisition: Yuemei Li;

Investigation: Xiaofang, Hongmei Li, Lijuan Sun;

Methodology: Shiqin Pan, Jingni Zhang;

Project administration: Yuemei Li, Mingqin Luo;

Roles/Writing - original draft: Lijuan Sun, Shiqin Pan;

Writing - review & editing: Yuemei Li, Mingqin Luo.

Acknowledgements

Not applicable

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No competing interests reported.

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Prevalence and risk factors of deep venous thrombosis of hospitalizations in plateau: A cross-section analysis

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Abstract

Background

Methods

Participants

Sample size

DVT diagnosis

Data collection

Statistical analysis

Results

1 Patient characteristics

2 Differences in the characteristics of patients with and without DVT

3 Multivariate analyses of risk factors associated with DVT in hospitalizations in plateau

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

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