Bleeding and Liver Transplant Outcomes in Hemophilia
Authors: Mehta Kathan Dilipbhai , Ragni Margaret V. 
Published: October 2019

Background: Orthotopic liver transplant (OLTx) is increasingly being performed in hemophilia patients with cirrhosis or hepatocellular carcinoma (HCC). Previous studies on outcomes of OLTx are limited by small sample size or incomplete data. In this study, we investigated the epidemiology and outcomes of OLTx in hemophilia patients in the U.S. from 1993 to 2012.
Methods: This was a retrospective database analysis using the Nationwide Inpatient Sample (NIS), a 20% sample of discharges of all U.S. hospitals participating in the Healthcare Cost and Utilization Project (HCUP), excluding rehabilitation and long-term acute care hospitals. Males undergoing OLTx were identified by ICD9 procedure code 50.59. Hemophilia patients were identified by ICD9 diagnosis codes 286.0 and 286.1. Female patients and those undergoing non-liver transplants were excluded. The primary outcome was in-hospital mortality. Secondary outcomes were in-hospital transplant complications, length of stay (LOS), and total charges: the latter was adjusted for inflation by consumer price index data. Severity of co-morbid conditions was defined by Deyo's modification of the Charlson co-morbidity index. Using SAS 9.2, SURVEY procedures with STRATA, CLUSTER and WEIGHT statements were used for all analyses to adjust for the stratified cluster design of NIS.
Results: Of 11,267 (weighted N = 54,691) patients undergoing OLTx in the period 1993-2012, 44 (0.4%) (weighted N = 213) had hemophilia. The latter had a significantly higher incidence of HIV (24.8% vs. 0.5%, p<0.005), hepatitis B (16.2% vs. 7.9%, p=0.04) and vitamin K deficiency (2.1% vs. 0.02%, p<0.001) as compared to non-hemophilia patients. Trend analysis showed that among hemophilia patients undergoing OLTx, the prevalence of HCC is increasing (0% in 1993-1997 vs. 36.7% in 2008-2012, p<0.001), while the prevalence of HIV and HCV are unchanged, and alcoholism is decreasing (25.7% in 1993-1997 vs. 0% in 2008-2012, p<0.001). Although there was no difference in in-hospital mortality between hemophilic and non-hemophilic patients (6.8% vs. 6.2%, p=0.9), the former were more likely to have bleeding complications (45.3% vs. 31.5%, p=0.009), including lower gastrointestinal bleeding (2.1% vs. 0.1%, p=0.0002) and hypovolemic shock (7.0% vs. 1.1%, p<0.0001). A higher proportion of patients with hemophilia received clotting factor infusion (13.7% vs. 1.3%, p<0.0001) and shed-autologous blood (2.2% vs. 0.2%, p=0.0007). In multivariate logistic regression, bleeding complications in hemophilia increased the risk of in-hospital mortality by more than 10-fold (p<0.0001). Moreover, disseminated intravascular coagulation and sepsis increased the risk of bleeding complications by greater than 10-fold in patients with hemophilia (p<0.0001). In multivariate linear regression analysis, in patients with hemophilia, coagulation factor transfusion reduced the total charges by greater than $90,000 (p=0.04). Excluding those who died during hospitalization, there was no difference in LOS between patients with and without hemophilia (17.1 days vs. 20.8 days, p=0.10).
Conclusion: These data constitute one of the largest samples of hemophilia patients undergoing OLTx. Bleeding complications increase the risk of hypovolemic shock and death in those with hemophilia, even more so when accompanied by DIC and sepsis. Clotting factor replacement reduces total hospital charges, likely by reducing OLTx complication rates. Aggressive correction of coagulation defects in those with hemophilia may be an economically and medically sound approach to reduce complications and mortality associated with liver transplantation.

Disclosures
Ragni: Pfizer: Research Funding; SPARK: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tacere Benitec: Membership on an entity's Board of Directors or advisory committees; Ferring Pharmceuticals: Research Funding; Vascular Medicine Institute: Research Funding; Biomarin: Research Funding; Alnylam: Research Funding; Genentech Roche: Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Foundation Women Girls Blood Disorders: Membership on an entity's Board of Directors or advisory committees; Biogen: Research Funding; Bristol Myers Squibb: Research Funding; Dimension Therapeutics: Research Funding; CSL Behring: Research Funding; Medscape, Web MD: Honoraria; National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees.