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Abstract

Multimorbidity defined as the co-occurrence of two or more chronic comorbidities, is becoming increasingly burdensome and is a big challenge for healthcare systems all over the world. Venous thromboembolism (VTE) is a potentially lethal disease and is the third most common cardiovascular disease. Multimorbidity is closely associated with VTE, and the VTE risk is approximately fourfold higher in individuals with multimorbidity compared to those without. Notable and consistent evidences show a significant association between multimorbidity and VTE. Plausible mechanisms for the observed associations between multimorbidity and VTE have been outlined, including higher prevalence of identified VTE risk factors, organ function and coagulation function disorders, reduced physical activity, older age, low cognitive level of VTE, and complications following the multimorbidity. Worse therapeutic and prophylactic anticoagulation efficacy, and safety are suggested by the studies, and the VTE recurrence and bleeding risk are higher in patients with multimorbidity compared to those without. Management of the therapeutic and prophylactic anticoagulation for VTE in patients with multimorbidity is difficult, and a balanced and detailed evaluation of the risks of VTE and bleeding is needed, and antiplatelet medications, increased doses or alternative direct oral anticoagulants (DOACs), thromboelastography (TEG), and physical activity may be helpful.

Keywords

multimorbidity venous thromboembolism epidemiology prophylaxis therapy anticoagulation efficacy and safety

Introduction

Multimorbidity, commonly defined as the co-occurrence of two or more chronic comorbidities, affects the majority of elderly persons.^1-3 Studies show that patients with multimorbidity are becoming increasingly common. 65% of the general population aged 65-84 years are multimorbid, and the prevalence rises to 82% in those aged over 85 years.¹ People are living longer, but more of their lives are spent with comorbidities, and individuals experiencing four or more diseases are estimated to reach 17% by 2035.⁴

Multimorbidity does not only affect the elderly.⁵ A Scottish cross-sectional study reported a 23.2% prevalence of multimorbidity in individuals who are not elderly.¹ Multimorbidity now, is a heavy global burden and a big challenge for healthcare systems worldwide.^6,7

Venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a potentially lethal disease and is the third most common cardiovascular disease.^8,9 The incidence of VTE ranges from 104 to 183 events per 100,000 person-years⁹ and increases with age, with an incidence of 0.001% in children and 1% per year in patients above 70 years of age.¹⁰ VTE not only causes lower limb swelling and pain, which affects prognosis and recovery,¹¹ but also results in significant morbidity and mortality, contributing to impaired quality of life and high healthcare costs.^12,13,14 PE, which is caused by a mobile thrombus, is fatal, and mortality from PE is significant, with a recent noted up-trend among younger patients (25-64 years old).^15,16,17 Even after active treatment, the fatality rate of PE is as high as 11%.¹⁸ The overall mortality rate for VTE is around 5% within 90 days,¹⁹ and over 20% of people with VTE die in the first year after diagnosis.²⁰

Multimorbidity is closely associated with VTE, and VTE risk is approximately fourfold higher in individuals with multimorbidity compared to those without.²¹ Multimorbidity has also been proven to be a risk factor for more severe VTE, with a higher proportion of PE over isolated DVT and a higher mortality rate.^16,22,23 Recently, more and more studies have focused on multimorbidity and VTE,^21,24 and subsequent research has significantly improved the knowledge of the relationship between multimorbidity and VTE. Here, we review the epidemiological evidence for the association between multimorbidity and VTE, the pathophysiology of multimorbidity-associated VTE, and the efficacy, safety, and difficulties of prophylactic and therapeutic anticoagulation for VTE in patients with multimorbidity.

The Evidences for the Associations of Multimorbidity and VTE

Notable and consistent evidences suggest the significant associations between multimorbidity and VTE.

A Swiss prospective multicenter cohort study including 991 patients aged ≥65 years with acute VTE, demonstrated that 708 (71%) patients were multimorbid. And, the most common comorbid conditions were arterial hypertension, anemia, and obesity. Comorbidity was measured using modified, unweighted Charlson Comorbidity Index (mCCI), and the overall mean mCCI score (standard deviation) was 2.7 (1.8) points.²⁵ This indicates that multimorbidity is significantly associated with VTE.

An extended cross-sectional Swedish study (1997-2015) of 2,694,442 individuals indicated a strong association between VTE and different multimorbidity diseases. The adjusted odds ratios (OR) for VTE in the first three clusters were as follows: cardiometabolic diseases 3.44 (95%CI 3.24-3.65); mental disorders 2.25 (95%CI 2.14-2.37); and digestive system disease 4.35 (95%CI 3.63-5.22). For the individual diseases comprising the multimorbidity, the strongest associations were found for atherosclerosis (OR = 7.66, 95%CI7.02-8.35), heart failure (OR = 5.02, 95%CI 4.47-5.63),bronchiectasis (OR = 4.309, 95%CI 2.77-6.69),and cancer (OR = 3.76, 95%CI 3.57-3.95). Multimorbidity score is a health status assessment tool for multimorbid patients, capable of evaluating both the number and severity of comorbid diseases. There was an increasing association between VTE and multimorbidity scoring and severity.²⁴ The adjusted OR for VTE was 1.94 (95% CI: 1.86 to 2.02) for one disease, 2.93 (95% CI: 2.80 to 3.08) for two diseases, 4.07 (95% CI: 3.85 to 4.31) for three diseases, 5.46 (95% CI: 5.10 to 5.85) for four diseases, and 9.08 (95% CI: 8.56 to 9.64) for five or more diseases. And the association between multimorbidity and VTE was stronger in males (OR 3.45, 95% CI:3.29 to 3.62) than in females (OR 2.91, 95% CI:2.77 to 3.04).²¹

Similarly, a cross-sectional analysis of 439 women in the Genes & Health British-South Asian cohort aimed to clarify how the intersection of multimorbidity contributes to the cumulative risk of VTE, also showed that multimorbidity is an independent risk factor for VTE, and the prevalence of VTE increases with the number of the diseases, with ORs as follows: one disease, OR = 1.6 (95% CI 1.2-2.0, p = .001); two diseases, OR = 2.7 (95% CI 2.0-3.7, p < .001); three diseases, OR = 5.3 (95% CI 3.8-7.4, p < .001); and four co-occurring diseases, OR = 8.1 (95% CI 4.9-13.0, p < .001).²⁶

In China, 710 patients from 10 primary care areas were included in analysis to explore the risk factors for VTE and to determine which diseases are more likely to promote VTE among patients with multimorbidity. Results showed that the coexistence of multiple diseases (χ²= 61.347,P < .001) was the main risk factor for VTE. Diabetes mellitus (OR = 1.636,95%CI 1.030-2.599, P = .037), cerebral infarction (OR = 8.484, 95% CI 4.615-15.597, P < .001), coronary heart disease (OR = 2.987, 95% CI 1.699-5.252, P < .001), intracerebral hemorrhage (OR = 15.130, 95% CI 4.707-48.630, P < .001), respiratory diseases (OR = 3.470, 95% CI 1.428-8.43, P = .006)and malignant tumors (OR = 4.576, 95% CI 1.85-11.315, P = .001) were independent risk factors for VTE, and the risks from high to low were cerebral hemorrhage > cerebral infarction > malignant tumor > respiratory system disease > coronary heart disease > diabetes.¹¹

Stroke is a strong risk factor for VTE, and a population-based cohort study showed that during the first three months after stroke, multimorbidity accounted for 15% to 33% of the VTE rates. Non-metastatic solid tumors and metastatic disease accounted for most of the observed interactions with stroke, representing 41% and 56% of attributable three-month VTE rates, respectively. Comorbidity, particularly cancer, increased the risk of VTE within three months following stroke.²⁷

For the pediatric VTE, a study by the Kids’ Inpatient Database 2006 which included over 4500 children showed that underlying chronic illnesses were associated with most VTE cases (76.2%), and the most common multiple diseases were cardiovascular (18.4%), malignancy (15.7%), and neuromuscular disease (9.9%).²⁸

Mechanisms for the Association of Multimorbidity and VTE

The co-occurrence of multiple diseases increases the risk of acute cardiovascular and cerebrovascular events, as well as respiratory or circulatory failures, and these events and failures have been identified as powerful predisposing risk factors for VTE for many years.^11,29,30,31 The increased use of drugs due to multiple diseases will lead to decreased liver and kidney function, coagulation disorders, and increased blood viscosity, all of which significantly promote the incidence of VTE.¹¹

Multiple diseases obviously increase the bedridden time of patients and reduce physical activity, and a sedentary lifestyle contributes to the risk of VTE,.^11,32,33,34 In line with this, it has been shown that prolonged sitting or sedentary time causes vein compression,³⁵ and can inhibit the venous blood returning from the lower limbs, furtherly promote venous stasis.^36,37 Sitting for a long time can also weaken muscle contraction, affecting metabolism and blood vessel health, all of which lead to the development of VTE.³⁸ On the other hand, prolonged sitting can increase the circulating inflammatory factors levels and hemostatic parameters, which promote VTE, especially DVT.³⁹ Limb muscle movement can decrease venous pressure, elevate venous flow, and reduce edema, consequently, physical activity may lower the VTE risk.^40,41,42 Moreover, evidences prove that physical activity can modify both the hemostatic and fibrinolytic systems to reduce the incidence of VTE.^43,44 The population-based, prospective Venous thromboembolism In Northern Sweden (VEINS) cohort study, which included 108,025 participants, showed that physical activity had a protective effect against VTE, and increased physical activity was significantly associated with a lower risk of first-time VTE.⁴⁵ From another UK Biobank study with 85,116 participants, higher levels of physical activity of any intensity were associated with a lower risk of new-onset VTE.⁴⁶

Patients with multimorbidity are more likely to be older than patients without,² and age is an important risk factor for VTE. Several age-related physiological changes, including hypercoagulation and vascular endothelial dysfunction⁴⁷ are associated with a higher VTE risk in patients with multimorbidity.

In addition, it has been proved in China that the cognitive level of VTE is low in patients with multimorbidity currently, at the same time, the reduction in cognitive level has a negative impact on the effectiveness of VTE prevention,¹¹ which may make VTE more widespread among the patients with multimorbidity.

Complications following multimorbidity also make significant contributions to the increased VTE risk. Prolonged immobilization, infection, and fractures after stroke,^48,49 the synergistic effect of frailty after cancer, and combined therapies such as the use of central venous catheters,⁵⁰ may explain the observed increased VTE risk in patients with multimorbidity.

Therapeutic and Prophylactic Anticoagulation Efficacy, and Safety of VTE in Multimorbidity

The efficacy and safety of anticoagulation for the prophylaxis and treatment of VTE in patients with multimorbidity have been investigated in many clinical trials and secondary analyses, with generally worse results.

The Swiss prospective multicenter cohort study, which examined whether multimorbidity was associated with lower anticoagulation quality in patients with VTE by unfractionated heparin (UFH), low molecular weight heparins (LMWH), fondaparinux, danaparoid, and vitamin K antagonists, demonstrated that multimorbid patients not only had lower anticoagulation quality but also a higher incidence of adverse clinical bleeding events.²⁵ Consistent with the Swiss prospective multicenter cohort study, a retrospective cohort study of 928 consecutive patients receiving 1103 courses of warfarin, found that multimorbidity was an independent predictor of a first episode of serious bleeding (RR, 1.4 [CI, 1.1 to 2.5]).⁵¹ Moreover, the risk of short- and long-term mortality increases with the cumulative number of comorbid conditions in multimorbid patients with VTE.^52,53

A multicenter cohort study examined whether multimorbidity was associated with lower anticoagulation quality in patients with VTE treated with UFH, LMWH, fondaparinux, danaparoid, and vitamin K antagonists, and results also demonstrated that multimorbid patients had a higher 3-year cumulative incidence of recurrent VTE (16.8 vs 10.8%; P = .056) and major bleeding (18.7 vs 9.0%; P = .001) than non-multimorbid patients.²⁵

Regarding the prophylactic anticoagulation of VTE, patients with multimorbidity admitted to the Italian internal medicine wards participating in the REPOSI registry were analyzed to investigate the association between pharmacological thromboprophylaxis (TP) and VTE, bleeding in hospital, and during the 3-month post-discharge follow-up, and results showed that the rate of TP was relatively low in the medical patients, and less than one-fifth of the patients with multimorbidity admitted to 70 internal medicine wards in Italy were prescribed TP in hospital. Moreover, patients receiving TP had more frequent fatal and non-fatal bleeding events during the 3 months of post-discharge follow-up compared to those not receiving TP.⁵⁴

In recent years, beyond the “traditional coagulation cascade,” the roles of platelet in VTE initiation and propagation have garnered increasing attention.⁵⁵ Platelet hyperactivity is widely observed in numerous diseases and conditions, including cancer, diabetes, and pregnancy. This hyperactivity is a very important cause of hypercoagulation,^56,57,58 which significantly increases the VTE risk. Inhibiting platelet hyperactivity may therefore limit VTE.⁵⁶ Multimorbidity is associated with platelet hyperactivity.⁵⁹ A cohort study of 277 patients indicates that multimorbidity is significantly associated with an increase in platelet volume indices, and the mean platelet volume values increase with the number of comorbid conditions.⁶⁰ Compared to anticoagulants, aspirin is believed to be associated with a lower risk of bleeding and infectious complications.⁶¹ The adoption of aspirin has increased in VTE treatment and prophylaxis, especially in the orthopedic literature, where numerous published studies suggest that antiplatelet is an effective medication for VTE.^{61,62,63,64,65} Consequently, antiplatelet medications should also be considered for the VTE prevention and treatment in multimorbid patients to individualize the treatment, especially when platelet hyperactivity has been identified as the cause of hypercoagulation.

Moreover, patients’ responsiveness to anticoagulants is another important point. For multimorbid patients, the responsiveness to anticoagulant drugs may vary among patients due to differences in comorbidities and drug interactions. Some patients may be medication non-responders, and in this case, increased doses or alternative DOACs may be needed.

For future research, thromboelastography (TEG) should be considered as an objective measure of hypercoagulability and treatment effectiveness for VTE in patients with multimorbidity. TEG is a hypercoagulability marker and, in a clinical retrospective study, TEG was used to measure blood coagulability changes in patients with nephrotic syndrome of different etiologies, as well as in patients with VTE. Multivariate logistic regression analysis revealed that TEG variables were independent risk factors for VTE.⁶⁶ In a study of cancer patients undergoing chemotherapy, TEG was used to determine whether it could inform VTE risk assessment. The results proved that TEG parameters, such as maximum amplitude and clotting index, can assess VTE risk.⁶⁷ In the fields of orthopedics, burns, trauma, and many others, TEG has also been proved to be helpful in identifying and predicting VTE events, and in guiding the use anticoagulants, eventually reducing the occurrence of VTE events.^68,69,70

Reasons for the Difficulties of Therapeutic and Prophylactic Anticoagulation of VTE in Multimorbidity

Evidences suggest that it is difficult to manage the therapeutic and prophylactic anticoagulation of VTE in multimorbidity, and the reasons may be as follows:

The quality of oral anticoagulation was assessed in 821 of 991 (83%) patients who received vitamin K antagonists, and multimorbid patients spent significantly less time within the therapeutic range (2.0-3.0) and significantly more time in the supratherapeutic international normalized ratio (INR) range (>3.0) than non-multimorbid patients.²⁵ Another study also suggests that patients with a greater burden of multimorbidity appear to spend less time within the therapeutic INR range,⁷¹ resulting in a lower quality of anticoagulation therapy. With increasing numbers of comorbid conditions, patients spent less time in and more time above and below the therapeutic INR range, and patients with a mCCI score ≥4 spent the least time in the therapeutic INR range and were more likely to be over- or under-anticoagulated.²⁵ These may be important reasons for the higher risk of VTE recurrence and bleeding events of therapeutic and prophylactic anticoagulation for VTE in patients with multimorbidity.

Moreover, several comorbid conditions of multimorbidity are originally risk factors for recurrent VTE, such as inflammatory bowel disease and obesity.^72,73 Chronic renal and liver diseases are risk factors for anticoagulation-related bleeding, and active cancer is a risk factor for both recurrent VTE and bleeding.⁷⁴

Age is another significant reason, and all the registries clearly show that advanced age is also a risk factor for bleeding during therapeutic or prophylactic anticoagulation.^75,76 Multimorbid patients are usually elderly, and are older than patients without multimorbidity. A population-based study comparing efficacy and safety of the anticoagulation treatment practices for VTE including UFH, LMWH, other parenteral anticoagulants, and warfarin, between subjects ≥ 65 years and younger patients, showed that the rates of mortality and major bleeding in older patients with VTE are also two times higher than those in younger patients.⁷⁷ Furthermore, elderly patients with VTE are less likely to complain of typical symptoms and frequently have high D-dimer levels at baseline,⁷⁸ making the diagnostic process more difficult, which may also affect the anticoagulation efficacy and safety. Age-related physiological changes that affect drug pharmacokinetics/-dynamics also make older persons more vulnerable to anticoagulation-related complications.⁷⁹

Multimorbidity is strongly associated with polypharmacy, leading to drug interactions, less stable INR levels, and increased bleeding risk.^80,81 Direct oral anticoagulants (DOACs) including dabigatran, rivaroxaban, apixaban, and edoxaban are becoming the most commonly prescribed drugs for the VTE treatment and prevention.⁸² Prevalence of polypharmacy is very high in patients with multimorbidity, and the combination of multiple treatments can cause relevant drug-drug interactions (DDIs) by affecting the exposure or the pharmacological activities of DOACs.⁸³ DDI between DOACs and antiarrhythmic drugs results in higher bleeding risk and higher bioavailability.⁸⁴ The interaction of DOACs with antiplatelet drugs are of clinical importance with 3- to 4-fold increased risk of bleeding complications.⁸⁵ DDIs between DOACs and nonsteroidal anti-inflammatory drugs (NSAIDs)⁸⁶ and other medications–such as antibiotics and antifungal drugs,⁸⁷ antineoplastic and immune-modulating agents,⁸⁸ and antiviral agents⁸⁹ have also been proven to increase bleeding risk.

Conclusions

In summary, there are notable and consistent evidences of a significant association between multimorbidity and VTE. Multimorbidity is a strong risk factor for VTE, and the more severe the multimorbidity, the higher the risk of VTE. Plausible mechanisms for the observed associations between multimorbidity and VTE have been outlined in this review, including higher prevalence of identified VTE risk factors, organ function and coagulation function disorders, reduced physical activity, older age, low cognitive level of VTE, and complications following the multimorbidity. Worse therapeutic and prophylactic anticoagulation efficacy, and safety are suggested by the studies, and the VTE recurrence and bleeding risk are higher in patients with multimorbidity compared to those without.

Management of the therapeutic and prophylactic anticoagulation of VTE in patients with multimorbidity is of a lot of difficulties, and a balanced and detailed evaluation of the risks of VTE and bleeding is needed. Antiplatelet medications, increased doses or alternative DOACs, and TEG potentially can enhance the VTE prevention and treatment in multimorbidity. Exercise is safe in patients with acute DVT and may help reduce acute symptoms.¹⁷ Physical activity has been proved that it can modify both the hemostatic and fibrinolytic systems to reduce the incidence of VTE, and increasing physical activity may lower the VTE risk.^45,46 Further research is necessary to fully elucidate the management of the therapeutic and prophylactic anticoagulation for VTE in patients with multimorbidity and to assess the effect of physical activity.

Footnotes

ORCID iDs

Feng Liang

Min Chao

Rui-Dong Cheng

Jing-Jing Ren

Ethical Considerations

Our institution does not require ethical approval for reporting this review.

Informed Consent

Informed consent for patient information to be published in this article was not obtained because our institution does not require informed consent for reporting this review.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by grants from the Medical and Health Science and Technology Project of Zhejiang Province (Grant No. 2023KY470).

This study was supported by grants from the Medical and Health Science and Technology Project of Zhejiang Province (Grant No. 2025KY629).

Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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Multimorbidity and Venous Thromboembolism: Epidemiological Evidence,Pathophysiology,Prophylactic and Therapeutic Anticoagulation Efficacy,Safety,and Difficulties. A Review

Abstract

Keywords

Introduction

The Evidences for the Associations of Multimorbidity and VTE

Mechanisms for the Association of Multimorbidity and VTE

Therapeutic and Prophylactic Anticoagulation Efficacy, and Safety of VTE in Multimorbidity

Reasons for the Difficulties of Therapeutic and Prophylactic Anticoagulation of VTE in Multimorbidity

Conclusions

Footnotes

ORCID iDs

Ethical Considerations

Informed Consent

Funding

Conflicting Interests

References