This longitudinal cohort study identified significant associations between DVT and MALEs including major amputation and severe wound conditions (ulcer and gangrene) in patients with type 2 diabetes. To the best of our knowledge, this is the first study to show that a history of prior DVT was independently associated with a 1.6-fold higher risk of MALEs and 1.4-fold higher risk of major amputation. These critical events may contribute to functional disability, future mortality, and insurance costs for long-term diabetic care.
In this study, more than 21% of the enrolled diabetic patients with DVT were very elderly (age > 75 years) and had a history of PAD and various comorbidities, both of which tend to be risk factors for MALEs (25). Female patients have also previously been reported to have worse outcomes after revascularization, however male sex was shown to independently increase the risk of PTS ulcers in the RIETE registry (26). During long-term follow-up (5.2 years), the average 5-year mortality rate in the current study was 38.1%, which is higher than that in the study of Chang et al. (17.97% at 5 years) (16). The proportion of patients with diabetes in Chang’s study was 18.43% lower than in our study; however, they found that male patients with diabetes and unprovoked VTE had a higher risk of mortality. Our results suggest that DVT increased the incidence of lower limb complications, arterial thrombosis, and amputation, thereby contributing to poor survival in our patients with type 2 diabetes.
Factors reported to contribute to major limb amputation include wound infection, microvascular dysfunction (3), and recurrent arterial thrombosis with chronic luminal occlusion (8, 9). Our findings indicate that DVT also has a significant influence on foot ulcer and gangrene in patients with diabetes. The EUCLID trial showed reported an overall rate of major amputation of 8.4% in patients with critical limb ischemia (4), while the rate of amputation in the DVT group was 2.5% in our study. The rate of revascularization for PAD is low in patients with diabetes and DVT because advanced endovascular interventions are increasingly being used in Taiwan (27). The COMPASS and VOYAGER studies (6,7) concluded that thrombosis should not be ignored in PAD, because the addition of anticoagulants can successfully reduce MALEs and mortality. Therefore, systemic thromboembolism may be a major risk factor for MALEs as supported by our results. Even though there were more below the knee amputations than above the knee amputations (38 vs. 17 in the DVT group), the risk of incidental above the knee amputations was still significantly higher (1.97-fold) in the DVT group. Mao et al. reported a high incidence of above the knee amputations in patients with atrial fibrillation receiving PTA, and they concluded that intra-cardiac or up-stream intra-arterial thrombus was the major source (28). In addition, the patients receiving above the knee amputations had a poor survival rate because of poor limb salvage, functional disability, and ambulance, which is compatible with our analysis. Therefore, DVT may increase the risk of incidental above the knee amputations and mortality in patients with diabetes.
Several studies have reported associations between VTE and cardiovascular disease with cardiovascular risk burden (10) and arterial thrombosis (11). However, the influence of DVT on ischemic stroke and myocardial infarction may be inconsistent due to previous studies focusing on unprovoked VTE or pulmonary embolism (16), in contrast to our study population (diabetic patients with DVT). A 20-year cohort study with a large number of patients reported that DVT and pulmonary embolism were risk factors for acute arterial cardiovascular events; however, the relative risk decreased during 1 ~ 5 years (11). Consuelo et al. further reported that VTE was not associated with subsequent acute myocardial infarction but death (29). Furthermore, the severity of diabetes, proteinuria, and other CVD-associated risk factors (dyslipidemia and hypertension) have been reported to be major risk factors for future MACEs and cardiac dysfunction. Heart failure is also a known risk factor for DVT (32), increasing atrial fibrillation burden (31), physical inactivity and impaired tissue perfusion due to lower cardiac output. Nevertheless, incidental heart failure hospitalizations and cardiovascular events were not prevalent in our DVT group. Taken together, we suggest that the association between DVT and all-cause mortality is closed related to MALEs and systemic thromboembolism rather than traditional cardiovascular risk factors and MACEs. Moreover, our findings suggest that MALEs are mainly due to DVT-associated pathomechanisms, a prothrombotic state and systemic thromboembolism.
Venous thrombosis can induce recurrent thromboembolism, peripheral edema, and inflammation as well as accelerated diabetic atherosclerosis. Those patients with DVT had 2.7 ~ 7.1% PTS for 1 ~ 3 years observation, and diabetes is also a risk factor of PTS (2.3-fold) (26). Residual thrombus venous hypertension has been shown to play a central pathogenetic role in PTS, and in turn to cause dilatation of the capillaries and increased endothelial permeability to plasma, proteins, and erythrocytes (32). The consequences of PTS can result in valve insufficiency, chronic edema, inflammation, hyperpigmentation of the skin, and stasis dermatitis, or even the development of a venous ulcer. Persistent edema has been shown to affect wound healing (33) and induce an inflammatory cascade as evidenced by increasing levels of CRP (C-Reactive Protein), platelet aggregation (34), endothelial dysfunction (35), coagulation disturbance and cytokine activation.
Strengths and Limitations
DVT is less prevalent in Asia than in European countries, and the NHIRD is a good resource for such investigations. However, retrospective surveys have inherent limitations including a lack of data on DVT/PTS severity, echo reports, laboratory findings, body weight, lifestyle habits (such as smoking), infected wound condition and physical activity. The RIETE registry observed that the characteristics of obesity and DVT treatment (duration or drugs) failed to predict the risk PTS after acute DVT (26). Hyperglycemia affects diabetic vascular complications, however, A1c level is not a predictor associated with amputation (5) or recurrent VTE (36). Inadequate self-care, living alone without family support, lower social-economic status, and infection with a high white blood cell count have also been shown to be independent risk factors for adverse outcomes in long-term wound care. This may also suggest that we underestimated ulcer/gangrene and severity because less severe foot cases may have been treated at clinics. However, in-hospital records of ulcer and gangrene may be considered to be critical limb events. Thrombophilia and hyperhomocysteinemia have been reported to contribute to both venous and arterial thrombosis (37). Many factors involving hypercoagulation status are likely to be lost in general practice. We excluded patients with malignancy and autoimmune diseases associated with unprovoked DVT to decrease the effects of hypercoagulation status and recurrent DVT under inadequate therapy.
In conclusion, we found independent associations between DVT and MALE outcomes including major limb amputation, systemic thromboembolism, and mortality in patients with type 2 diabetes. The impact of a history of DVT highlights the importance of thrombotic prevention in diabetic foot care. We needed a further large-scale randomized control trial to prove the relationship.