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Hemophilia A is a rare inherited bleeding disorder characterized by a deficiency in factor VIII. The evolution of currently approved prophylaxis therapy in hemophilia A will be reviewed, including the clinical value of prophylaxis, real-world experience with prophylaxis, and patient quality-of-life factors that must be considered when choosing treatment options for these patients.

Characteristics of inhibitors identified by prospective screening may differ from those detected clinically. In a prospective study at 17 hemophilia centers with central inhibitor measurement by Nijmegen-Bethesda assay, 23 (2.8%) of 824 hemophilia A patients had new inhibitors detected: nine high-titer inhibitors (HTI: 7 ≥ 5.0 NBU plus 2 of 2.6 and 3.4 NBU at immune tolerance induction initiation) and 14 low-titer inhibitors (LTI: 0.5-1.9 NBU). HTI occurred at an earlier age (median 2 years, range 1-18, vs. median 11 years, range 2-61, P = 0.016). Both HTI (22%) and LTI (43%) occurred in non-severe patients. All HTI, but only 64% of LTI, were found to be FVIII-specific by chromogenic Bethesda assay or fluorescence immunoassay (FLI), indicating a high rate of false-positive LTI. Repeat specimens confirmed all HTI, 7/9 LTI, and 7/7 FVIII-specific LTI. FLI results were similar between HTI and FVIII-specific LTI; all included IgG1 and IgG4 subclasses. A comparable prospective study conducted from 1975 to 1979 at 13 U.S. centers found 31 (2.4%) new inhibitors among 1,306 patients. In both studies, one-third of inhibitors occurred in non-severe patients and one-quarter after 150 exposure days (ED). Significant differences were seen in the age at which inhibitors occurred (median 16 years in the older study vs. 5 years currently, P = 0.024) and in ED before inhibitor development, 10% in the older study and 43% currently study occurring within 20 ED, suggesting a temporal change in inhibitor development. Prospective screening detects inhibitors in patients of all severities, ages, and ED. Some LTI, however, are false positives.

Elevated factor VIII (FVIII) has been linked with higher risk of vascular events. We aimed to determine the relationship between FVIII and hypertension in patients with acute ischemic stroke.FVIII levels and transthoracic echocardiogram reports were reviewed in patients with acute ischemic stroke who presented to our stroke center between July 2008 and September 2011. Presenting systolic and diastolic blood pressure, history of hypertention, left ventricular hypertrophy, diastolic dysfunction, and depressed left ventricular function (ejection fraction50%) were compared in patients with normal and elevated FVIII levels.No differences in presenting blood pressure or frequency of hypertension history were found based on FVIII level. Patients with elevated FVIII had demonstrated a statistically significant higher frequency of diastolic dysfunction (64.8 vs. 43.6%, p=0.042) and a trend towards higher frequency of left ventricular hypertrophy (18.5 vs 5.1%, p=0.073). Median FVIII was significantly higher in patients with left ventricular hypertrophy (194.4 vs 152.9%, p=0.042) and diastolic dysfunction (180.5 vs 149.3%, p=0.031) than patients without these findings.Among patients with acute ischemic stroke, FVIII levels were higher when there was evidence of hypertensive heart disease. Synthesis of FVIII may be augmented by the ongoing presence of shear stress and could contribute to the higher risk of vaso-occlusive events in patients with elevated FVIII.

Background and Purpose: Recent studies have demonstrated that elevated levels of coagulation factor VIII (FVIII), a risk factor for stroke, may persist independent of the acute-phase response; however, this relationship has not yet been investigated in the context of acute ischemic stroke (AIS). We sought to determine 1) the proportion of AIS patients with acutely elevated serum FVIII levels who had persistently elevated FVIII levels in the outpatient setting and 2) the characteristics at baseline predictive of persistently elevated FVIII levels. Methods: From our stroke registry, patients diagnosed with AIS between 07/2008-05/2014 were included if the initial FVIII level was elevated and a repeat FVIII level was obtained. A score was developed to predict which patients are at the greatest odds of remaining persistently elevated at both the 150% and 200% thresholds. Results: Among 1,616 AIS cases, 106 patients had initially elevated FVIII levels and repeat FVIII levels obtained. A total of 82.7% of patients had persistent elevation at the 150% threshold and 75.7% had persistent elevation at the 200% threshold. Time from initial FVIII measurement to second FVIII measurement was not different between the two groups (p=0.054). According to the models developed, for every one-point increase in the score, an individual is at ten-fold increased odds to have persistently elevated FVIII at both the 150% threshold (OR=10.43, 95% CI 1.63-66.9, p=0.0134) and 200% threshold (OR=10.2, 95% CI 1.82-57.5, p=0.0083). Conclusions: Persistent elevation in FVIII is common and in most AIS patients likely represents a constitutional risk factor. Persistent elevation in FVIII can be predicted by baseline characteristics in the setting of AIS, potentially proving useful in identifying patients at high risk for developing subsequent stroke.

Background: Elevated factor VIII (FVIII) is an independent risk factor for thromboembolic events and acute ischemic stroke (AIS). Laboratory reference ranges categorize levels >150% and >200% activity as elevated and severely elevated, respectively. We sought to identify the upper limit of FVIII activity with the most clinical relevance for outcomes after AIS. Methods: From our stroke registry, patients admitted with AIS between 07/2008 to 10/2013 were included if FVIII levels were measured during admission. Logistic regression, was used to assess differences in baseline, in-hospital, and outcome variables in patients with FVIII elevation as compared to those with normal levels. The primary outcome was poor modified Rankin Scale (mRS) score on discharge, defined as mRS>2. Serial dichotomized FVIII levels using a 5-point incremental analysis of levels were analyzed with respect to poor outcome. The threshold yielding the largest area under the curve (AUC) was determined. Results: Among 1,453 cases in our registry, inclusion criteria were met for 267 patients. In our sample, in a comparison of normal FVIII levels vs. elevation >150%, and elevation >200%, patients differed significantly according to race (p=0.0017), history of diabetes (p=0.0001), and history of congestive heart failure (p=0.0401). FVIII elevation threshold of 150% was the best predictor of poor mRS on discharge (OR 3.7, 95% CI 1.77-8.05, p=0.0006) with an AUC of 0.618. Conclusions: FVIII elevation greater than 150% is the most clinically useful threshold for the prediction of poor clinical outcomes in the setting of AIS based on data from our center.

Many persons with hemophilia were infected with hepatitis C and B viruses (HCV, HBV) and HIV, but the consequences of these transfusion-acquired infections are poorly defined. We estimated the risk of HCV-related end-stage liver disease (ESLD) and the associations of age, HBV, and HIV with that risk. All 1816 HCV-seropositive hemophilic patients at 16 centers were followed for up to 16 years. Of these, 624 were HIV(-) and 1192 were HIV-coinfected; 135 had persistent HBV surface antigenemia, 1374 had resolved HBV infection, and 287 were HBV-uninfected. ESLD was defined as bleeding esophageal varices, hepatic encephalopathy, persistent ascites, or death excluding nonhepatic causes of these conditions. Competing risk models were used to estimate the annual hazard rate and cumulative incidence of ESLD. Proportional hazards models were used to estimate relative hazards of ESLD with covariates. ESLD developed in 127 of the HCV/HIV-coinfected participants, with an estimated 16-year cumulative incidence of 14.0% (95% confidence interval [CI], 11.6%-16.4%). Without HIV, 10 HCV-infected participants developed ESLD, for a significantly lower cumulative incidence of 2.6% (95% CI, 1.0%-4.3%, P.0001). ESLD risk increased steeply with age in both groups. With HIV, ESLD risk was increased 8.1-fold (95% CI, 1.9-35.2) with HBV surface antigenemia, 2.1-fold (95% CI, 1.3-3.3) with fewer than 0.2 x 10(9)/L (200/microL) CD4(+) lymphocytes, and 1.04-fold (95% CI, 1.03-1.06) per year of age. Thus, HIV is associated with a markedly increased risk of HCV-related ESLD for persons with hemophilia, particularly with HBV infection, low CD4(+) lymphocytes, or older age.