The interaction effect of transfusion history and previous stroke history on the risk of venous thromboembolism in stroke patients: a prospective cohort study

Venous thromboembolism (VTE), consisting of deep vein thrombosis (DVT) and pulmonary embolism (PE), is one of the common but preventable complications of stroke patients [1]. VTE is characterized by a high incidence rate, high mortality, and heavy economic health­care burden despite advances in diagnosis and treatment [2]. The incidence of VTE in stroke patients can be as high as 21.1%-28.5%, 40% of stroke patients can develop VTE in the first 3 weeks, and the mortality even can be up to 16.70% within 30 days [3‐5].

Previous studies have shown that a transfusion history (TH) could increase the risk of VTE [6, 7]. Transfused red blood cells have been proposed to modulate the inflammatory cascade [8]. This could result from a direct immune response to the blood transfusion or oxidative stress related to the storage of red blood cells and consequently surface damage resulting in a pro-coagulative state [9]. Besides, a history of transfusion was included as a risk factor in the Caprini score of 2013 version [10].

Additionally, previous studies have also confirmed that patients with a previous stroke history (PSH) were more likely to have provoked VTE than those without stroke, and patients with VTE who had a prior stroke were more than twice as likely to die while hospitalized and within 30 days of VTE diagnosis compared to those without previous stroke [11]. Patients with a prior stroke may be more prone to thrombosis due to the impairment of limb movement and hypercoagulability [12].

According to the pathophysiology and Virchow’s triad theory of thrombosis, the blood was hypercoagulable in patients with a history of stroke and transfusion [13]. Therefore, it is reasonable to speculate that coagulation abnormalities arising from two distinct acquired sources could increase the risk of VTE. Previous interaction studies in the field mainly focused on the effect of gene-gene interaction on thrombosis [14, 15]. The interaction effect between genetics and environmental factors on VTE incidence has also been shown [16]. A few studies have explored the joint effect of individual factors including obesity, smoking, cancer and other factors that were associated with an increased VTE risk [17, 18]. However, the interaction effect between transfusion history and prior stroke history on VTE in stroke patients is unclear. Exploring and understanding the possible associations between the two risk factors are of great significance for thromboprophylaxis in stroke patients.

Therefore, our study aims to evaluate whether there is an interaction effect between the history of blood transfusion and prior stroke on VTE in a large prospective cohort of Chinese stroke patients.

Previous research on the joint effect of TH and PSH on VTE is very limited. However, the independent effect of TH and PSH on VTE is supported by substantial evidence. Several studies have demonstrated that acute transfusions are associated with the risk of VTE, which are consistent with our findings. A retrospective cohort study suggested that postoperative blood transfusions may be associated with an increased risk of postoperative VTE, independent of confounders [6]. Acuña et al. [22] found that the receipt of a postoperative transfusion was relevant to an increased risk of VTE in 333, 463 patients with total knee arthroplasty. Furthermore, another single-center retrospective cohort study also confirmed that the risk of VTE following total joint arthroplasty increased by approximately three-fold when blood transfusions were prescribed [7]. Patients often receive acute transfusion during the perioperative period. Increasing evidence suggests the role of red blood cells and platelet in physiological hemostasis and pathologic thrombosis [9, 23]. Studies have shown that plasma transfusion can lead to a significant increase in fibrinogen and soluble clotting factors (II, V, VII, IX, X) and caused hypercoagulability [24]. In addition, red blood cells are associated with inflammatory cascade, altered tissue perfusion, impaired vasoregulation and storage lesions, all of which may promote prothrombogenic [25]. Due to the close relationship between hypercoagulability and inflammation, the proinflammatory and immunomodulatory abilities of red blood cells transfusion may further accelerate the hypercoagulable status [26]. Additionally, studies have revealed that red blood cells could participate in thrombosis by increasing platelet reactivity and mediating platelet adhesion to the intact endothelial surface [27].

Established evidence has stated a correlation between prior transfusion and VTE risk. A case-crossover study [28] found that a history of transfusion during one year or earlier was a significant predictor of VTE, with an incidence rate ratio of 2.57 (P=0.018) after adjustment for covariates. A multicentre propensity score matching study showed that transfusion had a negative impact on long-term survival in patients with early stages of perihilar cholangiocarcinoma treated after curative resection [29]. Worse long-term survival may be associated with infection and immobility, which are risk factors of VTE. In addition, patients with multiple blood transfusions were chronically exposed to foreign antigens, which may be associated with abnormalities of immunologic function [30]. Previous evidence also indicated that immune cells and inflammatory processes are involved in VTE initiation [31]. Therefore, it is reasonable to speculate that blood transfusion may have long-term effects on cell and coagulation states in the body. The adverse reactions of transfusion, such as immune inflammatory reactions and antibodies, can remain in the patient’s body and be activated at any time. Their ability to affect coagulation is multifactorial. It may depend on their mechanical properties potentially affecting vascular endothelium, molecular signaling via microvesicles and surface proteins, including blood group antigens, immunomodulation, altered tissue perfusion, impaired vasoregulation, and participation in nitric oxide metabolism [32]. There is evidence that the transfused blood cells have stronger adhesion to endothelial cells and exacerbate microvascular pathology [33]. In summary, both prior and acute blood transfusions may be associated with VTE risk. However, we did not collect data on composition and frequency of blood transfusion, the number of transfused red blood cells, platelets or plasma, which will be the focus of our future research.

Evidence also supports the association between prior stroke and VTE. Neurological deficits following stroke frequently contribute to immobility and predispose to common complications such as VTE [34]. A population-based study of 2483 central Massachusetts residents in America suggested that patients with a history of prior stroke were more likely to have provoked VTE than those without stroke (P<0.001) [11]. The underlying mechanism may be owing to the hypercoagulation status of blood and paralysis associated with the sequelae in prior stroke patients [11, 12].

The potential mechanism behind such interaction is still unclear. However, as both TH and PSH are associated with hypercoagulability and inflammatory response. One might speculate that the observed excess VTE risk could be related to increased blood viscosity and inflammation [7, 35, 36]. Thus, it is likely to speculate that a biological interaction between TH and PSH on the risk of VTE could be mediated via procoagulant changes arising from two sources. Moreover, PSH is also associated with subsequent dysfunction of extremities, such as paralysis and long-term bed rest, which are common risk factors of VTE, and potentially lead to increased risk of VTE [37]. However, the specific mechanism remains unclear, further study is still warranted.

Interestingly, several studies suggested that VTE appears to occur more frequently in non-smokers and non-drinkers, which supports the results of our study. A large cohort study with 144,952 participants indicated that smoking was associated with increased VTE risk in cancer subjects, but not in non-cancer subjects [17]. A recent meta-analysis of ten prospective studies (1 441,128 individuals) also showed that compared with the lowest group, the highest consumption of alcohol was not associated with the VTE risk (P=0.293) [38]. Interestingly, a large case-control study indicated that alcohol consumption was associated with a reduced risk of VTE [39]. However, further studies with larger samples are needed to validate the results.

In subgroup analyses, the interaction effect measured in the multiplicative and additive scale was significant for severe stroke patients with NIHSS score > 5 points. The possible explanation is that severe stroke patients may have higher blood viscosity, which further aggravates the hypercoagulability of blood caused by TH and PSH [24]. Besides, limb dysfunction and prolonged immobility associated with severe stroke may further increase this association.

Considering the strong and synergistic interaction between TH and PSH on VTE in stroke patients, it is essential to implement measures to prevent and treat VTE in those patients. The combination of TH and PSH could aid in the screening process to identify high-risk populations before VTE and may contribute to more effective prevention of VTE in clinical practice. For stroke patients with TH and PSH, health education on VTE prevention was necessary for them and their families. Additionally, clinicians can give corresponding physical intervention, such as intermittent pneumatic compression and thrombus elastic stocking, and anticoagulant therapy to those patients.

The current study has several strengths. First, our participants were derived from a large prospective Chinese stroke cohort and the data can also be linked to electronic health records, which was accurate and reliable. Second, both multiplicative and additive interactions were evaluated, and the results were consistent in theory, which provided strong support for the main conclusion. Additionally, our study for the first time implicated the interaction effect between TH and PSH towards VTE in stroke patients, which may provide a new perspective and reference for thromboprophylaxis in stroke patients.

Meanwhile, there are still several limitations to our study. First, we can only provide a clue for the synergistic interaction between TH and PSH towards VTE, but the causality of the association between the synergistic interaction and VTE still needs more prospective studies to verify. Second, our findings were derived from Chinese stroke subjects, which may not be generalized to other ethnic populations. Thirdly, we did not collect data on composition and frequency, number of blood transfusions, and the quantity number of transfused red blood cells, platelets or plasma, the variables associated with pre-stroke disability such as the Rankin score or Barthel score, which should be paid attention to in future research. In addition, patients in some subgroups were too few, which may reduce the statistical power of the interaction. The results of this study still need to be validated in a larger sample size prospective cohort study. Finally, as in any observational study, we cannot exclude the potential presence of unrecognized residual confounding and inevitable selection bias. However, patients with prior stroke and prior transfusion were not prioritized for investigation. Therefore, extensive studies with more potential moderators are warranted.

In conclusion, our study suggested a significant interaction effect between TH and PSH on the risk of VTE in stroke patients. A substantial proportion of VTE was attributable to the interaction. Besides, the percentage of VTE incidence explained by interaction increased with the severity of stroke. Overall, these findings will provide valuable evidence for the combined effects of TH and PSH in predicting VTE in Chinese stroke patients. Future studies are warranted to verify our findings and explore the specific biological mechanisms of interaction.