VTE is closely related to the length of hospital stay and prognosis, and has become the second leading cause of death in tumor patients. ICU patients are considered to be at high risk for VTE even after routine prophylactic anticoagulant therapy (upper and lower extremity venous thrombosis; about 10%) [16, 17]. In recent years, numerous studies have evaluated the risk factors related to VTE from the aspects of patient factors, tumor factors, and treatment factors [4, 6-10, 12, 13], thus developing the thrombosis evaluation scale and model for out-patient and inpatient patients to predict the risk of thrombosis [14, 15]. Recently, an ICU-VTE scale was created for ICU inpatients to assess the risk of thrombosis in critically ill patients . Until now, there has been no validated VTE risk assessment tool that can be applied to medical and surgical critically ill patients with tumors.
This retrospective study evaluated the risk of thrombosis in 560 ICU patients during hospitalization from the aspects of patient factors, tumor factors, and treatment factors, as well as using the ICU VTE scale, and found that multiple factors were closely associated with thrombosis in critical patients with tumors. 79% of our study population received thromboprophylaxis, and the in-hospital VTE occurrence rate in our cohort was 55.7%, while lower VTE frequency (about 10%) was obtained in previous researches [16-18]. The median interval from ICU admission to VTE diagnosis was 8 days and most events occurred within the first 2 weeks of ICU admission, which is consistent with previous studies [6, 18, 19].
Patient factors that increase the risk of VTE include female sex, previous VTE history, advanced age, obesity, and ABO blood type [6-10]. A study of 44 656 patients undergoing surgery for solid tumors elucidated other risk factors of VTE after cancer surgery with a 1.6% overall risk of VTE, such as tumor type, metastatic disease, congestive heart failure, ascites, thrombocytosis, hypoproteinemia, and operation duration >2 hours . Other researchers found that baseline analysis of high-density lipoprotein cholesterol levels might be of clinical value in predicting VTE in cancer outpatients treated with anticancer drugs . We got the same conclusion that age ≧65 yrs, prior VTE, and higher PLT counts contributed to VTE occurrence, while higher TC levels trend to be a novel VTE risk factor but turned to no statistic difference after adjustment. Another study of 43,808 patients undergoing cancer surgery confirmed the effect of co-existing disease on the risk of postoperative VTE, they found that longer hospital stays (>1 week) and postoperative complications (wound infection, re-intubation, cardiac arrest, and sepsis) were more likely to lead to VTE . This study explains our results laterally that patients admitted to ICU for acute medical problems had a 1.3 times higher risk of VTE than postoperative patients (OR, 1.56; 95% CI, 1.03-2.36, P = 0.037).
We also found that the length of ICU stay and hospital stay in tumor patients treated for acute medical diseases were significantly higher than those in the surgery group (ICU duration, median 8.0 days, IQR, 4.0-14.0 days vs. median 3.0 days, IQR, 1.0-5.0 days, P < 0.001; LOS, median 22.0 days, IQR, 16.0-34.0 days vs. median 20.0 days, IQR, 13.0-33.0 days, P = 0.02; not shown in table), which partly explains the higher incidence of VTE in this group. We thought there was a process of mutually affecting, promoting, and positive interaction.
The link between Hb and VTE remained contradictory results in previous studies [6, 23], Chi G confirmed that anemia was independently associated with higher VTE incidence among acutely ill medical patients despite the provision of thromboprophylaxis in an APEX trial substudy including 7513 hospitalized medical patients . We also found the similar trend that patients developed VTE had lower Hb levels during admission (median 79.5 g/L, IQR, 69.0-95.0 g/L vs. median 82.0 g/L, IQR, 70.8-101.0 g/L, P = 0.029). One possible explanation is that anemia may contribute to endothelial dysfunction, blood stasis, and/ or hypercoagulable state, which in turn lead to a greater risk of VTE [25-27]. Anemia, on the other hand, is often indicative of a number of conditions that can lead to VTE, such as inflammation, surgery, malnutrition, and bone marrow suppression after chemotherapy [1, 10, 11, 22]. Thus our study offered supporting evidence for hemoglobin measurement as a wildly available and useful method of VTE risk assessment.
In recent years, a number of studies have shown that tumor type, stage, and histopathological grade were closely related to VTE [1, 9-12]. Tumor cells may express the procoagulant activity and induce thrombin production, while non-cancerous tissues of patients may also express the procoagulant activity under the influence of tumors . Blood-derived tissue factors in microparticles may play a role in the pathogenesis of hypercoagulability associated with cancer . Some tumors increase the risk of VTE either through external compression or direct invasion of large vessels [30, 31]. One study included 8 million patients older than 65 yrs who were hospitalized in the United States between 1988 and 1990 found that patients with a diagnosis of malignancy had a higher incidence of VTE during initial hospitalization, and the malignancies with the highest incidence of VTE included ovarian, brain, pancreatic and lymphoma . Another large cohort study with 57,591 patients hospitalized for cancer indicated that high tumor stage was associated with increased risk of VTE (incidence rate, 27.7, 95% CI, 24.0-32.0) . In addition, the CATS study included 740 patients with solid tumors confirmed high tumor grade (G3-4) to be a significant risk factor of VTE (hazard ratio, 2.0, 95% CI, 1.1-3.5) . In this study, we did not find significant differences in the incidence of VTE among patients with different tumor types and stages, while histological grade was proved to be a risk factor of VTE (G3-4 vs. G1-2, 63.4% vs. 50.3%, OR, 1.80; 95% CI, 1.24-2.62, P = 0.002).
It has been found that thromboprophylaxis can reduce the risk of VTE in inpatients of internal medicine and surgery, and other studies have found that thromboprophylaxis can reduce the risk of death in surgical patients , but VTE prevention cannot eliminate the risk of VTE or VTE-related death in inpatients. A post-hoc analysis of 3746 critically ill patients in a randomized trial found that the incidence of VTE was 8% (DVT 5%, PE 2%, and both 1%) . The preferred method for VTE prevention is primary prophylaxis, which include mechanical methods (IPC, and GCS) and drugs (low dose unfractionated heparin, low molecular weight heparins, low molecular weight heparin (LMWH), fondaparinux, oral factor Xa or direct thrombin inhibitors) [13, 34]. In this study, all patients admitted to ICU received physical prophylaxis (IPC or GCS), 63.4% of the cohort population received drug prophylaxis during hospitalization, of which 349 patients (98.3%) received the recommended dose of LMWH anticoagulant, and 6 patients (1.7%) received oral prophylaxis such as rivaroxaban or dabigatran. We concluded that drug prophylaxis significantly reduced the incidence of VTE in ICU inpatients (OR, 0.55; 95% CI, 0.37-0.81, P = 0.002), validly confirming previous studies.
Invasive mechanical ventilation was proved to be a significant risk factor of VTE because of activity limitation and reduced venous return from positive airway pressure [6, 35], but no significant difference was found in this study. It is worth mentioning that only 9 individuals did not receive ventilation treatment during their hospitalization, the difference would be meaningful if we get a larger sample size. Meanwhile, we got the same conclusion with prior studies that a longer duration of mechanical ventilation, as well as prolonged immobilization and longer hospitalization, resulted in higher VTE occurrence .
Several prior researches confirmed that CVC increased VTE incidence by local vessels injury and blood flow stasis [6, 35, 36], 293 (56.0%) patients with CVC in our study developed VTE, slightly higher than those without CVC (19, 51.4%), but no visible correlation was found.
Blood transfusion was wildly used in tumor operation and myelosuppression after chemotherapy as an alternative treatment in cancer patients, both red blood cell (RBC) and platelet transfusions were identified to be predictive variables of VTE (RBC: OR, 1.60; 95% CI, 1.53-1.67; platelets: 1.20; 1.11-1.29; P < 0.001) and in-hospital mortality (RBCs: OR, 1.34; 95% CI, 1.29-1.38; platelet: 2.40; 2.27-2.52; P < 0.001) in a retrospective cohort study with 504 208 hospitalizations of patients with cancer between 1995 and 2003 at 60 US medical centers . Some other studies also yielded similar conclusion . Several possible mechanisms might be related to this phenomenon: transfusion can improve blood stasis by increasing the circulating red cell mass; severe shortage of nitric oxide in stored red cells might cause vasoconstriction in turn leading to vascular rheologic changes and rising risk of thrombosis; plentiful pro-inflammatory and pro-thrombotic soluble mediators such as sCD40L, platelet microparticles, and activated platelets are contained in blood conduct, could contribute to the prothrombotic state in cancer patients [39-41]. In our cohort, patients treated with blood transfusion got higher VTE occurrence (56.1% vs. 49.2%), a significant difference was found in patients who received FFP transfusion after multivariate analysis (OR, 1.63; 95% CI, 1.13-2.37, P = 0.010). Few previous researches reported the relationship between VTE and plasma transfusion, further studies are needed to confirm this association.
The ICU-VTE Scores
At last, we quoted the ICU-VTE score as a new VTE risk assessment model for ICU patients with tumors, which included six proven independent predictors (chosen from patient characters and treatment factors), and results verified the feasibility of this model. Firstly, we found that individuals developed VTE got significantly higher scores than the others (median 11.0, IQR, 9.0-12.0 vs. median 9.0, IQR, 7.0-11.0, P < 0.001) when examining the observed VTE rates across the full range of ICU-VTE scores from 0 to 18, which was consistent with prior research . Secondly, when grouping by scores, low-risk patients (131, 23.4% of the total cohort) with scores of 0–8 have an overall 33.6% rate of VTE, and intermediate-risk patients (412, 73.6% of the study cohort) with scores of 9–14 have an overall 60.9% rate of VTE, while all members of high-risk group (17, 3.0% of the study cohort) with 15-18 scores experienced in-hospital VTE and the rate was 1.8 times the risk of VTE among all patients. Thirdly, tumor patients of intermediate-high risk group with 9-18 scores had statistically significant higher rates of VTE after adjustment (62.5% vs. 33.6%, OR, 3.13; 95% CI, 2.01-4.85, P < 0.001). At last, our analysis of ROC curves showed that an ICU-VTE score of > 10 was a significant predictor of in-hospital VTE, almost consistent with the cut-off ICU-VTE score presented by Viarasilpa T.
The relatively higher VTE rates, when compared with prior studies, might be related to disease feature (all patients were diagnosed with tumor), ethnicity, and the majority of our study population were treated with surgery (523, 93.4%), CVC (523, 93.4%), and invasive mechanical ventilation (551, 98.4%) in hospital, which were proven to be independent risk factors of VTE in prior studies [6, 20, 35, 36]. Moreover, due to it being a retrospective study, not all of the patients hospitalized in ICU received VTE-related screening, and data on VTE events after hospitalization were unable to be obtain, which lead to relatively small sample size, incomplete information, and skewed distribution of study population. Finally, other potential effects like chemotherapy was not included in this study. These limitations may cause the obtained results correspondingly short of conviction.