Abstract
Background
Individuals aged 80 and older face a notably increased risk of venous thromboembolism (VTE) and mortality after SARS-CoV-2 infection. Clinical guidelines recommend routine pharmacological thromboprophylaxis, yet its application in oldest-old patients remains insufficiently studied.
Aims
To assess the efficacy and safety of low-molecular-weight heparin (LMWH) thromboprophylaxis in hospitalized COVID-19 patients aged 80 years and older.
Methods
We conducted a multicenter, prospective cohort study enrolling in-hospital COVID-19 patients aged ≥ 80 years from six tertiary hospitals in China between December 2022 and January 2023. The clinical outcomes were VTE, all-cause mortality and bleeding events. Patients were followed up for 3 months after discharge. Multivariate Cox regression models were used to identify risk factors and evaluate the impact of LMWH prophylaxis on clinical outcomes.
Results
Among 1526 patients aged ≥ 80 years, 41.6% received LMWH prophylaxis. LMWH prophylaxis significantly reduced VTE risk by 50% (HR 0.50, 95% CI 0.33–0.75) and mortality risk by 20% (HR 0.80, 95% CI 0.65–0.99), without increasing bleeding risk (HR 0.90, 95% CI 0.60–1.34). Male, history of stroke, critical illness on admission and hemoglobin < 90 g/L were identified as risk factors of bleeding. LMWH prophylaxis remained effective in preventing VTE and demonstrated favorable safety particularly in male patients and patients with hemoglobin < 90 g/L.
Discussion and conclusion
LMWH may be safe and effective for thromboprophylaxis in the oldest-old COVID-19 patients, even in patients with high bleeding risk. Further studies are needed to verify our findings.
Supplementary Information
The online version contains supplementary material available at 10.1186/s40001-025-03041-0.
Keywords: Thromboprophylaxis, VTE, COVID-19, Older people
Introduction
The COVID-19 epidemic has resulted in significant global consequences [1, 2], with particular vulnerability observed in older adults over 80 years who face a more than 20-fold increased risk of COVID-19-related mortality compared to younger populations [3]. Growing evidence showed a significantly increased risk of venous thromboembolism (VTE) following SARS-CoV-2 infection [4, 5], which was associated with poor outcomes among these patients [6, 7]. Demographic projections estimate that the global population aged ≥ 80 years will triple from 143 million in 2020 to 426 million by 2050 [8], underscoring the urgent need for evidence-based strategies to reduce VTE risk and improve clinical outcomes in hospitalized older adults with COVID-19.
In the population aged 80 years and older, the high prevalence of multimorbidity [9], upregulated pro-inflammatory profile of plasma cytokines and endothelial dysfunction collectively contribute to an increased susceptibility to VTE [10, 11]. Additionally, age-related pharmacokinetic changes, including reduced renal clearance [12], raise concerns about the accumulation of low-molecular-weight heparins (LMWHs), which are primarily eliminated renally, thereby increasing the risk of bleeding [13].
Current clinical guidelines strongly recommend routine pharmacological prophylaxis, for hospitalized COVID-19 patients without contraindications [14–17]. However, critical knowledge gaps remain regarding its safety and efficacy in the oldest-old population, as individuals aged ≥ 80 years have been underrepresented in randomized controlled trials (RCTs) on thromboprophylaxis. Many trials predominantly included younger patients, often excluding those over 80 years or those at high risk of bleeding [18–21]. Consequently, the potential benefits and risks of prophylactic anticoagulation in this vulnerable group remain unclear.
Therefore, the aim of the present study was to explore the efficacy and safety of pharmacological VTE prophylaxis in hospitalized COVID-19 patients aged 80 years and older. Since LMWHs are the first-line anticoagulant for COVID-19 patients according to guidelines, we mainly assessed the prophylaxis with LMWH in our cohort.
Methods
Study design
This study consecutively enrolled patients hospitalize with COVID-19 from six tertiary hospitals between December 1, 2022, and January 31, 2023, during the Omicron pandemic in China. It adhered to the Declaration of Helsinki and received approval from the institutional review boards and ethics committees (approval no. 2016-SSW-7). Adults were consecutively enrolled if they had a confirmed COVID-19 diagnosis upon admission or during hospitalization, with a hospital stay exceeding 24 h. COVID-19 infection was confirmed using a polymerase chain reaction (PCR) assay on nasal or pharyngeal swab specimens. Exclusion criteria included diagnosis of VTE within 24 h of admission; pregnancy or incomplete critical data on anticoagulant therapy; having recent bleeding events. Patients aged over 80 years old were included in the final analysis. Physicians decided whether to administer thromboprophylaxis based on institutional treatment guidelines, personal clinical judgments, and evaluation of the patient’s risks of thrombosis and bleeding. For patients with endogenous creatinine clearance rate (Ccr) < 30 mL/min, the doses were halved in accordance with local guidelines and medication instruction. The enrolled patients received regular follow-up at 30 days and 90 days after discharge, either through standardized clinic evaluations or structured telephone interviews.
Data collection
Demographics, comorbidities, prescriptions, other laboratory data and follow-up information were collected using case report forms (CRFs). The physicians at each institution were responsible for data entry into the electronic case report form. In addition, data were manually double-checked for missing or contradictory inputs and values outside the expected ranges at the research-based office.
Definitions
The illness severity of COVID-19 was defined according to the diagnosis and treatment protocol for novel coronavirus pneumonia (version 10), published by the National Health Commission of China as follows: (1) moderate: fever and respiratory symptoms, with evidence of pneumonia on radiologic imaging; (2) severe: any of the following symptoms and signs: respiratory distress with respiratory rate ≥ 30 breaths/min, SpO2 ≤ 93% at rest, PaO2/FiO2 ≤ 300 mmHg (1 mmHg = 0.133 kPa); (3) critical: any of the following conditions: respiratory failure requiring mechanical ventilation, shock, or other organ failure requiring admission to the intensive care unit (ICU). Prophylactic anticoagulation was defined as VTE prophylaxis with LWMHs for more than 3 days during hospitalization. Definitions of comorbidities were shown in eMethod 1 in Supplementary file.
Clinical outcomes
The primary outcome was symptomatic VTE during hospitalization and within 3 months after discharge, including deep vein thrombosis (DVT) and pulmonary embolism (PE) confirmed by imaging examinations (ultrasound, contrast-enhanced computed tomography, ventilation-perfusion lung scintigraphy, pulmonary angiography, or contrast venography). The secondary outcome were all-cause mortality and bleeding events including major bleeding (MB), clinically relevant non-major bleeding (CRNMB) and minor bleeding. MB consisted of a reduction in the hemoglobin level by at least 2 g/dL, transfusion of at least 2 U of blood, or symptomatic bleeding in a critical area or organ according to the International Society of Thrombosis and Hemostasis (ISTH) [22]. CRNMB consisted of any sign or symptom of hemorrhage (e.g., more bleeding than would be expected for a clinical circumstance, including bleeding found by imaging alone) that does not fit the criteria for the ISTH definition of major bleeding but does meet at least one of the following criteria: i. requiring medical intervention by a healthcare professional; ii. leading to hospitalization or increased level of care; iii. prompting a face to face (i.e., not just a telephone or electronic communication) evaluation [23].
Statistical analysis
Baseline characteristics are reported as mean with standard deviation (SD) for continuous variables and total number with percentage for categorical variables. Comparisons were performed using Fisher Exact Test, student’s t test or Chi-square test as appropriate. Missing values were imputed using multiple imputations (eMethod 2 in Supplementary file). To investigate clinical outcomes during the first 3 months after infection, we calculated the cumulative incidences of VTE, all-cause death and major bleeding. A stepwise multivariate Cox proportional hazards model was employed to evaluate the contribution of candidate covariates to the risk of these outcomes. Variables were selected based on clinical and statistical significance. Further subgroups analysis was performed according to bleeding risk. Crude and adjusted hazard ratios (HRs) and corresponding 95% confidence intervals (Cis) were estimated for each outcome. Sensitivity analysis was carried out by excluding patients with contraindications to anticoagulation. All statistical analyses were performed using the R software (version 4.2.2) with statistical significance at a p-value < 0.05.
Results
Patient characteristics
Among 4443 enrolled patients, the current analysis included 1526 patients 80 years and older (547 females [35.8%]; 979 males [64.2%]). Patients who received LMWH prophylaxis during hospitalization accounted for 41.6% (Fig. 1).
Fig. 1.
Flowchart. VTE, venous thromboembolism, LMWH, low-molecular-weight heparin
The baseline characteristics of the study population, stratified by thromboprophylaxis, were presented in Table 1. The average age of the entire population was 86.3 ± 4.6 years, without significant difference between the two groups. There were no significant differences in body mass index (BMI) or comorbidities between patients with and without prophylaxis. Disease severity at admission differed significantly (P < 0.001), with a higher proportion of severe cases (34.3% vs. 25.0%) and critical cases (12.8% vs. 11.2%) in the prophylaxis group. The Prophylaxis group also had a higher proportion of patients with platelet counts ≥ 300*109/L (12.3% vs. 7.5%, P = 0.003). As for treatment, significant differences were observed in the use of antiviral drugs and corticosteroids, both of which were more frequently used in the prophylaxis group (both P < 0.001). The incidence of VTE was significantly lower in the prophylaxis group (7.2% vs. 10.4%, P = 0.033). No significant differences were found in mortality (29.4% vs. 29.0%, P = 0.835) or bleeding events (6.3% vs. 7.5%, P = 0.357) among the two groups. The mean length-of-stay was longer in the prophylaxis group (15 ± 10 days vs. 13 ± 9 days, P = 0.010). Among those receiving LMWH prophylaxis, the daily dosage was 4000 IU (interquartile range (IQR): 3000-5000 IU), with a median prophylactic duration of 8 days (IQR: 5-12 days). Detailed site-specific strategies for LMWH thromboprophylaxis were provided in supplementary Table 1.
Table 1.
Baseline characteristics of patients with and without low-molecular-weight heparin prophylaxis
| Characteristic | Overall N = 1526 | No Prophylaxis N = 891 | Prophylaxis N = 635 | P-value |
|---|---|---|---|---|
| Age | 86.3 ± 4.6 | 86.5 ± 4.6 | 86.1 ± 4.4 | 0.075 |
| Sex | 0.298 | |||
| Female | 547 (35.8%) | 329 (36.9%) | 218 (34.3%) | |
| Male | 979 (64.2%) | 562 (63.1%) | 417 (65.7%) | |
| BMI (Kg/m2) | 0.924 | |||
| 18.5–28 | 753 (82.1%) | 465 (81.7%) | 288 (82.8%) | |
| < 18.5 | 104 (11.3%) | 66 (11.6%) | 38 (10.9%) | |
| ≥ 28 | 60 (6.5%) | 38 (6.7%) | 22 (6.3%) | |
| Cardiovascular disease | 1126 (73.8%) | 657 (73.7%) | 469 (73.9%) | 0.958 |
| Respiratory disease | 378 (24.8%) | 231 (25.9%) | 147 (23.1%) | 0.216 |
| Gastrointestinal Disease | 163 (10.7%) | 102 (11.4%) | 61 (9.6%) | 0.251 |
| Chronic kidney disease | 213 (14.0%) | 127 (14.3%) | 86 (13.5%) | 0.693 |
| Stroke | 359 (23.5%) | 211 (23.7%) | 148 (23.3%) | 0.865 |
| Metabolic syndrome | 503 (33.0%) | 282 (31.6%) | 221 (34.8%) | 0.196 |
| Hematological diseases | 44 (2.9%) | 26 (2.9%) | 18 (2.8%) | 0.924 |
| VTE history | 50 (3.3%) | 29 (3.3%) | 21 (3.3%) | 0.955 |
| Active cancer | 61 (4.0%) | 40 (4.5%) | 21 (3.3%) | 0.245 |
| Disease severity at admission | < 0.001 | |||
| Moderate | 904 (59.2%) | 568 (63.7%) | 336 (52.9%) | |
| Severe | 441 (28.9%) | 223 (25.0%) | 218 (34.3%) | |
| Critical | 181 (11.9%) | 100 (11.2%) | 81 (12.8%) | |
| PLT (*109/L) | 0.003 | |||
| 100–300 | 1202 (81.1%) | 708 (81.8%) | 494 (79.9%) | |
| ≥ 300 | 141 (9.5%) | 65 (7.5%) | 76 (12.3%) | |
| < 100 | 140 (9.4%) | 92 (10.6%) | 48 (7.8%) | |
| HGB (g/L) | 0.786 | |||
| ≥ 120 | 850 (57.3%) | 489 (56.4%) | 361 (58.5%) | |
| 90–120 | 515 (34.7%) | 310 (35.8%) | 205 (33.2%) | |
| 60–90 | 110 (7.4%) | 63 (7.3%) | 47 (7.6%) | |
| < 60 | 9 (0.6%) | 5 (0.6%) | 4 (0.6%) | |
| d-dimer (mg/L) | 0.296 | |||
| < 0.5 | 137 (9.9%) | 84 (10.6%) | 53 (8.9%) | |
| ≥ 0.5 | 1246 (90.1%) | 706 (89.4%) | 540 (91.1%) | |
| eGFR (mL/min/1.73m2) | 0.431 | |||
| ≥ 90 | 138 (9.0%) | 75 (8.4%) | 63 (9.9%) | |
| 60–89 | 847 (55.5%) | 493 (55.3%) | 354 (55.7%) | |
| 30–59 | 379 (24.8%) | 220 (24.7%) | 159 (25.0%) | |
| < 30 | 162 (10.6%) | 103 (11.6%) | 59 (9.3%) | |
| Antiviral drug | 274 (18.0%) | 113 (12.7%) | 161 (25.4%) | < 0.001 |
| Corticosteroids | 816 (53.5%) | 418 (46.9%) | 398 (62.7%) | < 0.001 |
| Anti-platelet drugs | 109 (7.1%) | 64 (7.2%) | 45 (7.1%) | 0.943 |
| VTE | 139 (9.1%) | 93 (10.4%) | 46 (7.2%) | 0.033 |
| Death | 445 (29.2%) | 258 (29.0%) | 187 (29.4%) | 0.835 |
| All bleeding | 107 (7.0%) | 67 (7.5%) | 40 (6.3%) | 0.357 |
| Minor bleeding | 70 (4.6%) | 48 (5.4%) | 22 (3.5%) | |
| CRNMB | 29 (1.9%) | 15 (1.7%) | 14 (2.2%) | |
| Major bleeding | 8 (0.5%) | 4 (0.4%) | 4 (0.6%) | |
| Length of stay (days) | 14 ± 9 | 13 ± 9 | 15 ± 10 | 0.010 |
BMI, body mass index; VTE, venous thromboembolism; PLT, platelet; HGB, hemoglobin; eGFR, estimated glomerular filtration rate; IU, International Unit; CRNMB, clinically relevant non major bleeding
Clinical outcomes of COVID-19 patients 80 years and older with and without prophylaxis
Figure 2 showed the cumulative incidence of VTE in 3 months, death in 3 months and all bleeding events in 14 days since COVID-19 diagnosis in patients aged ≥ 80 years with and without LMWH prophylaxis. Patients receiving LMWH prophylaxis during hospitalization had a significantly lower cumulative incidence of VTE (Fig. 2a) (P = 0.026) but showed no significant difference in death (Fig. 2b) (P = 0.905) or bleeding (Fig. 2c) (P = 0.789) as compared to patients without LMWH prophylaxis.
Fig. 2.
Efficacy and safety outcomes of low-molecular-weight heparin thromboprophylaxis. Cumulative incidences are shown for VTE in 3 months (A), death in 3 months (B), bleeding in 14 days (C). Bleeding events include major bleeding, clinically relevant non-major bleeding and minor bleeding. VTE, venous thromboembolism
Risk factors of VTE, all-cause mortality and bleeding events in COVID-19 patients 80 years and older
Results of the multivariable analysis are reported in Table 2, with detailed results of the univariate analysis presented in Supplementary Table 2–4. The following factors were associated with VTE: the history of VTE (HR 3.34, 95% CI 1.59–6.98), severe (HR 1.83, 95% CI 1.20–2.79) and critical (HR 1.99, 95% CI 1.12–3.55) disease severity at admission, elevated platelet counts (≥ 300 × 10⁹/L) (HR 1.95, 95% CI 1.13–3.36), low hemoglobin levels (< 90 g/L) (HR 1.93, 95% CI 1.03–3.62), and elevated d-dimer levels (≥ 2 mg/L) (HR 2.97, 95% CI 1.30–6.83). Notably, prophylactic anticoagulation with LMWH significantly reduced VTE risk by 50% (HR 0.50, 95% CI 0.33–0.75), while the use of antiviral drugs was associated with an increased VTE risk (HR 1.78, 95% CI 1.13–2.80).
Table 2.
Multivariable model assessing risk factors of VTE, all-cause death and bleeding events in the oldest-old COVID-19 patients. Results expressed as hazard ratios (95% confidence intervals)
| VTE | Death | Bleeding | |
|---|---|---|---|
| Male gender | – | – | 2.04 (1.30, 3.32)† |
| Cardiovascular disease | – | 1.50 (1.17, 1.93) ‡ | – |
| Gastrointestinal Disease | 1.71 (1.00, 2.92) | – | – |
| Stroke | – | 1.37 (1.10, 1.71)† | 1.59 (1.03, 2.40)* |
| VTE history | 3.34 (1.59, 6.98)‡ | – | – |
| Disease severity at admission | |||
| moderate | Reference | Reference | Reference |
| severe | 1.83 (1.20, 2.79)† | 3.13(2.43, 4.02) ‡ | 1.54(0.97, 2.45) |
| critical | 1.99(1.12, 3.55)* | 8.06(6.09, 10.66) ‡ | 3.21(1.90, 5.40) ‡ |
| PLT 100–300 (*109/L) | Reference | Reference | Reference |
| ≥ 300 | 1.95(1.13, 3.36)* | 0.71(0.47, 1.07) | – |
| < 100 | 0.86(0.43, 1.73) | 1.40(1.03, 1.90)* | – |
| HGB ≥ 120 (g/L) | Reference | Reference | Reference |
| 90–120 | 1.14(0.76, 1.72) | – | 1.03 (0.65, 1.61) |
| < 90 | 1.93 (1.03, 3.62)* | – | 2.92 (1.60, 5.22)‡ |
| D-dimer < 2 (mg/L) | Reference | Reference | Reference |
| ≥ 2 | 2.97 (1.30, 6.83)* | 3.22 (1.94, 5.33) ‡ | – |
| eGFR ≥ 90 (mL/min/1.73m2) | Reference | Reference | Reference |
| 60–89 | – | 1.45 (0.93, 2.27) | – |
| 30–59 | – | 1.75 (1.10, 2.79)* | – |
| < 30 | – | 3.09 (1.90, 5.04) ‡ | – |
| Prophylaxis | 0.50 (0.33, 0.75) ‡ | 0.80 (0.65, 0.99)* | 0.90 (0.60, 1.34) |
| Antiviral drugs | 1.78 (1.13, 2.80)* | – | – |
Abbreviation: VTE, venous thromboembolism; PLT, platelet; HGB, hemoglobin; eGFR, estimated glomerular filtration rate
*P < 0.05; †P < 0.01; ‡P < 0.001
For all-cause mortality, multivariable analysis implicated that cardiovascular disease (HR 1.50, 95% CI 1.17–1.93) and stroke (HR 1.37, 95% CI 1.10–1.71) were independent risk factors. Severe (HR 3.13, 95% CI 2.43–4.02) and critical (HR 8.06, 95% CI 6.09–10.66) disease severity markedly increased mortality risk. Elevated d-dimer levels (≥ 2 mg/L) and reduced estimated glomerular filtration rate (eGFR) were also associated with increased mortality. Prophylactic anticoagulation shows a protective effect, reducing mortality risk by 20% (HR 0.80, 95% CI 0.65–0.99).
Male gender (HR 2.04, 95% CI 1.30–3.32), stroke (HR 1.59, 95% CI 1.03–2.40), critically ill patients at admission (HR 3.21, 95% CI 1.90–5.40), and low hemoglobin levels (< 90 g/L) (HR 2.92, 95% CI 1.60–5.22) were identified as significant risk factors for bleeding events. Prophylactic anticoagulation does not significantly increase the risk of bleeding (HR 0.90, 95% CI 0.60–1.34). Sensitivity analyses were conducted in 1461 patients without contraindications to anticoagulation, defined as platelet counts > 50*109/L and eGFR > 15 mL/min/1.73m2 (shown in Supplementary Table 5). The results remained similar after excluding patients with severe thrombocytopenia or severe renal failure. Prophylactic anticoagulation with LMWH significantly reduced VTE risk (HR 0.52, 95% CI 0.35–0.78), without significant increase in mortality or bleeding.
The influence of LMWH prophylaxis in subgroups of high bleeding risk
After identifying the risk factors associated with bleeding events in elderly hospitalized COVID-19 patients, we further investigated the impact of prophylactic anticoagulation with LMWH on clinical outcomes in subgroups at high risk of bleeding, including male, stroke, critically ill and low hemoglobin levels.
After adjusting for d-dimer levels and usage of antiviral drugs, the overall effect of LMWH prophylaxis was associated with a 37% reduction in VTE risk (adjusted HR (aHR: 0.63, 95% CI 0.44–0.91). In males, LMWH prophylaxis exhibited a significant reduction in VTE risk (aHR: 0.59, 95% CI 0.38–0.93), whereas showed a non-significant trend in female. There was no significant reduction in VTE risk with LMWH prophylaxis in patients with history of stroke (aHR: 0.50, 95% CI 0.24–1.04). Patients with hemoglobin levels less than 90 g/L benefited significantly from LMWH prophylaxis (aHR: 0.22, 95% CI 0.07–0.68). LMWH prophylaxis shows no significant effect on VTE in critically ill patients (aHR: 0.75, 95% CI 0.31–1.79) (Fig. 3).
Fig. 3.
Subgroup analysis of venous thromboembolism risk in COVID-19 patients aged ≥ 80 years with and without LMWH thromboprophylaxis. d-dimer level at baseline and the use of antiviral drugs were adjusted as covariates. LMWH, low-molecular-weight heparin; HGB, hemoglobin; aHR, adjusted hazard ratios; CI, confidence intervals
In these subgroups, no significance of LMWH prophylaxis on mortality and bleeding events was observed in patients with high bleeding risk. (Supplementary Figs. 1 and 2).
Discussion
Our study provides critical evidence on the efficacy and safety of LMWH prophylaxis in COVID-19 patients aged 80 and older based on real-world data. Generally, LMWH prophylaxis was associated with significantly decreased risk of VTE and all-cause mortality, without increasing the risk of bleeding. Male gender, history of stroke, critical illness on admission, and hemoglobin levels below 90 g/L were identified as independent risk factors for bleeding events in the oldest-old COVID-19 patients. Notably, LMWH prophylaxis remained effective in preventing VTE and demonstrated favorable safety even in subgroups with a high risk of bleeding. These findings underscore the benefits of prophylactic anticoagulation in this vulnerable population while identifying specific subgroups with potential risks, providing valuable guidance for individualized anticoagulation strategies in clinical practice.
Despite RCTs rarely include a representative number of patients over 80 years old, a few cohort studies have examined prophylactic anticoagulation in this population. The CLOT-COVID study from Japan, which included 196 patients over 80 years old, showed that 47% of the patients received pharmacological thromboprophylaxis with unfractionated heparin (UFH). The reported incidences of thrombosis, major bleeding and all-cause death were 1.5, 2.0 and 16.8% respectively [24]. However, the study did not evaluate the relationships between UFH and clinical outcomes in elderly patients. Other studies on nursing home residents (NHRs) with COVID-19 suggested that antithrombotic therapies could reduce the risk of 30-day mortality [25–27]. However, most studies in NHRs focused on chronic anticoagulation initiated prior to COVID-19 infection for other conditions. The efficacy and safety of initiating thromboprophylaxis post-infection in elderly patients without prior anticoagulation remains uncertain. Differences in care settings further limit the applicability of NHR-based findings to hospitalized patients, as NHRs typically continue chronic anticoagulation with oral anticoagulants, while hospitalized patients are commonly treated with LMWHs. Thus, evidence from NHR-based studies cannot be directly extrapolated to elderly inpatients. Our study could provide real-world evidence to address these important gaps.
In subgroups with high bleeding risk, LMWH prophylaxis was particularly beneficial in males and those with hemoglobin levels < 90 g/L, significantly reducing the risk of VTE. However, its protective effect was not significant in critically ill patients, potentially due to the small sample size and the complexity of their clinical conditions. Previous studies have shown that male COVID-19 patients tend to exhibit greater inflammation and delayed antibody responses [28, 29], which could exacerbate hypercoagulability. Our findings suggest that prophylactic anticoagulation should be prioritized in elderly male patients. However, differences in comorbidities and concomitant medications between male and female patients should be further explored to refine individualized anticoagulation strategies. In patients with risk factors of bleeding within our cohort, the potential survival benefit of thromboprophylaxis may have been outweighed by a higher prevalence of comorbidities and the risk of bleeding, which further offset the impact of anticoagulation.
The overall incidence of bleeding events was 7% in our cohort, with the rate of major bleeding lower than that reported in the Japanese study [24]. This discrepancy may be attributed to the predominant use of UFH in Japan, as UFH is associated with a higher risk of bleeding compared to LMWH [30]. We observed that most bleeding events occurred within 14 days after the COVID-19 diagnosis. This aligns with previous research suggesting that bleeding tends to occur early on, as anticoagulation may unveil pre-existing lesions prone to bleeding in the gastrointestinal tract and central nervous system [31–33]. Meanwhile, current guidelines do not recommend pharmacological prophylaxis after discharge for COVID-19 patients [14, 34, 35], making long-term bleeding outcomes less relevant to anticoagulants.
The present study has significant strengths. The multicenter and prospective design could enhance the representativeness and generalizability of our findings across patients aged 80 and older. Moreover, by utilizing real-world data, we provide clinically relevant evidence on LMWH prophylaxis in the underrepresented population, offering guidance for clinicians in balancing efficacy and safety. The sub-group analysis in patients with high bleeding risk further reinforces the safety of LMWH prophylaxis in the oldest-old population.
Our study also has some limitations. First, the observational design may lead to selection bias, as physicians choose patients for thromboprophylaxis based on subjective judgment. Nevertheless, given the evidence from RCTs were scant, large-scale and multicenter observational studies remained the best available approach to provide real-world evidence. Second, we focused solely on LMWH and did not compare its efficacy and safety with other anticoagulants. However, since LMWH is the first-line anticoagulant recommended by guidelines for hospitalized COVID-19 patients, our results remained highly relevant for clinical practice. Third, we could only observe symptomatic VTE because of limited diagnostic resources during the COVID-19 outbreak. The true incidence of thrombosis might be underestimated. Lastly, the generalizability of our findings might be limited due to the ongoing emergence of SARS-CoV-2 variants. However, the oldest-old population remains particularly vulnerable to COVID-19. Our study provided valuable insights into the use of thromboprophylaxis in this high-risk group. Future research should focus on conducting RCTs to evaluate the efficacy and safety of anticoagulants in elderly COVID-19 patients using more rigorous study designs.
Conclusion
The efficacy and safety of LMWH prophylaxis were promising in COVID-19 patients aged 80 and older in 3 months after discharge. In general, the routine use of prophylactic anticoagulation in this vulnerable group may be recommended. However, our results and special consideration for specific subgroups with high bleeding risk were warranted in further studies, especially RCTs.
Supplementary Information
Acknowledgements
We appreciate great contributions and continuous support from Qiong Hu, Yuanyuan Wu (Guizhou Provincial People’s Hospital), Nan Shao (The First Affiliated Hospital of Fujian Medical University), Juanxia Chen (The First People’s Hospital of Yinchuan), Jinliang Meng, Cheng Chen, Suya Li, Tingting Zhang (First People’s Hospital of Yunnan Province), Xiaobo Li (Taizhou First People’s Hospital).
Author contributions
(I) Conception and design: FY Xu, GH Fan, DY Wang, C Wang, ZG Zhai; (II) Administrative support: Chen Wang, ZG Zhai; (III) Data collection and follow-up of patients: FY Xu, J Han, YZ Tao, LY Chen, YH Zhang, BL Wang, CS Deng; (IV) Data analysis and interpretation: FY Xu, DY Wang, GH Fan, S Zhang, YX Zhang, Z Zhang, WM Xie, YM Wang, WB Wu; (V) Manuscript writing: All authors; (VI) Final approval of manuscript: All authors.
Funding
This work was supported by National Key Research and Development Program of China (No.2023YFC2507201); Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (2023-I2M-C&T-A-014); Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS)(No. (2021-I2M-1-001; 2021-I2M-1-049); Elite Medical Professionals. Project of China-Japan Friendship Hospital (No. ZRJY2023-QM20).
Data availability
Readers can access the data by contacting the corresponding authors to acquire permission.
Declarations
Ethics approval and consent to participate
It adhered to the Declaration of Helsinki and received approval from the institutional review boards and ethics committees of China-Japan Friendship hospital (approval no. 2016-SSW-7).
Competing interests
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Feiya Xu, Guohui Fan and Jing Han: Joint first author.
Change history
9/9/2025
The original online version of this article was revised”: Affiliation has been updated.
Contributor Information
Dingyi Wang, Email: wg_snake@163.com.
Chen Wang, Email: cyh-birm@263.net.
Zhenguo Zhai, Email: zhaizhenguo2011@126.com.
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