Intracranial Hemorrhage in Patients with Hemophilia in the Prophylaxis Era.
Authors: Witmer Char , Pressley Rodney , Kulkarni Roshni , Soucie J. Michael , Manno Catherine Scott 
Published: October 2019

Objective: With a mortality rate of 20%, intracranial hemorrhage (ICH) accounts for the highest number of deaths from bleeding in patients with hemophilia and is a common cause of long-term disability. We performed a nested case-control study within a cohort of males with hemophilia enrolled in the Centers for Disease Control and Prevention (CDC) Universal Data Collection (UDC) project. The study objective was to identify rates and risk factors associated with ICH in the modern era of prophylaxis.

Patients and methods: Study participants were males with hemophilia A or B, enrolled in the CDC UDC project, 2 years or older, who had an initial visit, and at least one follow up event between May 1998 and March 2008. Patients were followed from the initial visit until their study termination event, defined as an ICH reported during a subsequent annual visit, death, or the latest annual visit held during the study period. Cases were patients who after UDC enrollment either had an ICH or whose cause of death was from an ICH. The following clinical factors were examined for an association with ICH: hemophilia type, severity level, prior ICH, presence of an inhibitor, treatment with prophylaxis, HIV status, chronic hepatitis B, hepatitis C, alcohol abuse, elevated prothrombin time, ethnicity and age. Data analysis was conducted using SAS 9.2 (SAS Institute, Cary, NC). Factors associated with ICH were identified using a nested case control design. Interaction effects were assessed using the Breslow-Day Test for homogeneity of the odds ratios. The independent association between prophylaxis and ICH was assessed using logistic regression. All hypothesis testing was two tailed with odds ratios and confidence intervals reported.

Results: During the study period 10,262 patients were identified who met the inclusion criteria. Of these, 199 (1.9%) experienced an ICH. Based on patient follow up time (mean 4.9 +/−2.46 years) the incidence rate was 3.9 per thousand patient years. Thirty-nine of the 199 ICH cases died from the event, resulting in a mortality rate of 19.6%. In 148 (74%) of the ICH cases, the subjects had severe hemophilia. See table 1 for univariate analysis of all patients.

Table 1: Clinical factors associated with ICH for all patients in the cohort, N=10,262 (univariate analysis)

Clinical Factors Odds Ratio (95% CI) P-Value *Reference group White (non-Hispanic). **Reference group age 10–15 years. Prior ICH 3.62 (2.66–4.92) <0.001 Severe Hemophilia 3.25 (2.01–5.25) <0.001 High Titer Inhibitor 4.01 (2.40–6.71) <0.001 Hepatitis C 1.73 (1.30–2.29) <0.001 Black (non-Hispanic)* 2.07 (1.46–2.96) <0.001 Age 2-9 years** 1.85 (1.14–2.99) 0.01 Age >41 years** 2.17 (1.34–3.50) 0.001

For the entire cohort, prophylaxis use was not associated with a statistically significantly reduced risk of ICH (0.83 (0.61–1.15) p=0.26). However, further analysis (see table 2), restricted to patients with severe hemophilia, demonstrated a protective effect of prophylaxis use that was limited only to patients who did not have an inhibitor and who were not infected with HIV.

Table 2: Clinical factors independently associated with ICH among 5,485 patients with severe hemophilia (multivariate analysis)

Clinical Factors Odds Ratio (95% CI) P-Value **Reference group age 10–15 years. Prophylaxis no inhibitor 0.50 (0.32–0.77) 0.002 Prophylaxis no HIV 0.52 (0.34–0.81) 0.004 Prior ICH 3.24 (2.27–4.64) <0.0001 Chronic Hepatitis B 2.99 (1.03–8.63) 0.043 Age 2–9 years** 1.92 (1.05–3.51) 0.034

Conclusion: This study demonstrates that patients with severe hemophilia who use prophylaxis and are not HIV positive and do not have an inhibitor experience a 50% risk reduction for ICH. This study confirms the previously identified risk factors for ICH including severity of disease, prior ICH, young age and the presence of an inhibitor. The strongest predictor for ICH was a history of ICH before enrollment in the UDC. Unfortunately even in the age of widely available prophylactic therapy, the mortality rate from ICH remains quite high at 19.6%.