In a nationwide cohort of 15,183 veterans with CLD, we found a 4.4% annual incidence of non-variceal hemorrhage, and we identified clinical and laboratory predictors of non-variceal hemorrhage in this population.
We analyzed risk of hemorrhage associated with laboratory parameters that predict severity of liver disease in the MELD [28] and Child Pugh Classifications [27]. We chose the cut-offs of these laboratory parameters (bilirubin, albumin and creatinine clearance) based on the definitions used in the MELD and Child-Pugh classifications. We chose the cut-off for INR based on recent literature showing uniform elevation in risk of hemorrhage at all INR values above 1.5 [17]. All these laboratory abnormalities predicted higher risk of hemorrhage suggesting that the severity of liver disease at diagnosis correlates with the risk of non-variceal hemorrhagic complications in the following year. While low albumin represents severe liver disease, this could also affect the risk of hemorrhage by creating an inflammatory milieu [32, 33]. The association between hypoalbuminemia and hemorrhage should be explored further in future studies. Ascites and hepatic encephalopathy, although components of Child-Pugh classification, did not predict hemorrhage in this study. The lack of association between ascites and hemorrhage could be due to non-specific coding of ascites, which may or may not be a consequence of CLD, as suggested by other administrative database studies [21]. Hepatic encephalopathy was coded in less than 1% of our study cohort, which made it hard to find a putative association with hemorrhage. Our analysis however, found a 2.5-fold increase in the risk of hemorrhage in people with “dementia”, which could represent episodes of hepatic encephalopathy in patients with CLD.
The results from this study support prior preclinical research addressing hemostasis in patients with CLD. For example, patients with CLD did not experience a higher risk of hemorrhage with thrombocytopenia. This lack of association supports the preclinical studies demonstrating rebalancing of hemostasis in CLD patients with thrombocytopenia by elevated vWF levels [18, 37]. We found 2.5-fold risk of hemorrhage with recent infection in this analysis, which supports the preclinical finding that infections can promote hemorrhage in CLD by producing heparin like effect, detectable on heparinase-modified thromboelastography [30, 38].
Some of the risk factors for hemorrhage in this cohort of CLD patients concur with the risk factors for hemorrhage observed in a general non-CLD population e.g., anemia, alcohol abuse, and antiplatelet therapy [14–16]. Dementia predicted a higher risk of hemorrhage likely due to compromised self-care and an increased risk of falls [34]. Other risk factors for hemorrhage in a general non-CLD population e.g., age and hypertension [14–16] did not predict hemorrhage in CLD patients. The lack of association between age and hemorrhage could be due to survivorship bias where patients with severe liver disease do not live long enough [35] to experience hemorrhage. The restricted age range of our study population with few veterans older than 75 years also makes it harder to find this association. Patients with severe liver disease are more likely to have hypotension than hypertension [36], and this may explain the lack of association between hypertension and hemorrhage in this cohort. Moreover, we identified non-Caucasian race to be at a higher risk of non-variceal hemorrhage, which represents a novel finding.
The most frequent site of non-variceal hemorrhage in patients with CLD was upper gastrointestinal tract (60%). This was followed lower gastrointestinal tract (19.3%) and intracranial (9.9%) sites (Table 3). Patients with liver disease are pre-disposed to vascular ectasias [39] and peptic ulcer disease [40], which could explain the higher risk of upper gastrointestinal hemorrhage.
We utilized the VHA database to conduct this study as it provides access to patient charts, vital signs, laboratory parameters and pharmacy data from both inpatient and outpatients encounters. This is helpful for an unbiased determination of risk factors for hemorrhage as outcomes associated with parameters observed during hospitalization alone could be confounded by the reason for hospitalization and interventions performed during hospitalization e.g., transfusions. Moreover, we assessed vital signs, laboratory parameters and medication as time-dependent variables and utilized all values during the study period to determine temporal association of these variables with hemorrhage. We used previously validated methods to identify study population and outcomes [21–25].
This study has several limitations. We relied on ICD-9 and − 10 codes for identification of hemorrhage, so inclusion of events was contingent on accuracy of coding. The coding provider may have misclassified variceal hemorrhage as “non-variceal”. Moreover, we were unable to capture any events outside of the VHA system. VHA database underrepresents females, and thus results should be confirmed in a cohort more inclusive of females. While retrospective analysis establishes association, it is hard to elucidate causation. For example, anemia and prescription for proton pump inhibitors likely represent consequences of hemorrhage rather than “causes” for hemorrhage. Despite these limitations, this study provides a comprehensive assessment of the clinical and laboratory predictors of non-variceal hemorrhage in a national cohort of CLD patients. This study has the potential to guide physicians in risk-stratifying patients for hemorrhage at the time of CLD diagnosis and encourage them to perform a careful assessment of the risk versus benefit of certain interventions like antiplatelet therapy that predispose to hemorrhage. This study will also generate rationale for future research for example, development of a risk-prediction model for hemorrhage specific to patients with CLD.
In summary, non-Caucasian race, severity of liver disease, anemia, alcohol abuse, antiplatelet therapy, chronic kidney disease, dementia, infections, and prescriptions for proton pump inhibitors are associated with a higher risk of non-variceal hemorrhage in the first year after CLD diagnosis. Knowledge of risk factors for hemorrhage in CLD can inform management of this patient population (e.g., avoidance of anti-platelet therapy without a clear indication) and increase patient awareness regarding possible complications of their disease.