Ischemic Heart Disease Mortality and Coronary Atherosclerosis in Hemophilia.
Authors: Ragni Margaret V. , Nichols Lawrence A. 
Published: October 2019

Abstract
Mortality in individuals with hemophilia is 2.7-fold higher than the general population. By contrast, ischemic heart disease mortality in this group is 60% lower than in the general population. The reason for these differences is not known. While high VIII:C is associated with thrombotic risk, and low VIII:C is associated with bleeding risk, it remains unproven whether low VIII:C is protective against atherosclerosis or cardiovascular morbidity or mortality. We, therefore, conducted a case-control study to compare coronary atherosclerosis at autopsy in 14 hemophilic men who died between 1983 and 1992, on whom autopsies were available, and 42 HIV-negative age-, gender-, and race-matched non-hemophilic controls. The mean age at death in hemophilic cases was 40 ± 4 yr (19–74), as compared with 41 ± 2 yr (18 to 75) in the controls, p > 0.25. The cause of death in cases was AIDS in 7 (50.0%), hepatitis C liver disease in 4 (28.6%), CNS bleeding in 2 (14.3%), and cancer in 1 (7.1%). The cause of death in controls was cardiopulmonary disease in 14 (33.3%), infection in 13 (30.9%), cancer in 4 (9.5%), organ failure in 4 (9.5%), and other in 7 (16.7%). None (0%) of the hemophilia cases had coronary disease symptoms vs. 2 (4.8%) of the controls, p = 0.559. Ten (71.4%) of the cases were HIV-infected, but none had received HAART therapy. Twelve cases had severe hemophilia (VIII < 0.01 U/ml), one moderate disease (VIII = 0.01–0.04 U/ml), and one mild disease (VIII ≥ 0.05 U/ml). None of the cases had diabetes or hypercholesterolemia (> 220 mg/dl); five (35.7%) were smokers, five (35.7%) were hypertensive (systolic > 140 and/or diastolic > 80 mm Hg), and three (21.4%) were obese (body mass index > 25 kg/m2). Body mass index, mean 23.84 ± 0.84 kg/m2, and blood pressure, mean systolic, 129 ± 6 mm Hg, and mean diastolic, 82 ± 3 mm Hg, increased with age, r = 0.439, r = 0.488, r = 0.209, respectively, but not significantly so, p > 0.05. Intraluminal coronary stenosis was assessed by a semi-quantitative scoring system, with 0 = minimal (< 25%), 1= mild (≥ 25%), 2 = moderate (≥ 50%), and 3 = severe (≥ 75%). Coronary stenosis was detected in 11 of 14 (78.6%) hemophilic cases and in 25 of 42 (59.5%) controls, p = 0.118. There was no difference in the proportion with > 75% narrowing, 2 of 14 (14.3%) cases vs. 9 of 42 (21.4%) controls, respectively, p = 0.272. The overall mean stenosis score in hemophilic cases was 1.1 ± 0.2, not different from that in non-hemophilic controls, 1.2 ± 0.2, p > 0.25. The degree of intraluminal narrowing increased with age in cases, r = 0.773, p < 0.01, and in controls, r = 0.694, p < 0.01. There was no difference between age and coronary narrowing between groups, p = 0.928. In conclusion, the prevalence of coronary atherosclerosis in hemophilic men is comparable to that in age-, gender-, and race-matched non-hemophilic controls. Although factor VIII:C does not appear to promote atherogenesis, it is possible, although not proven, that low or missing VIII:C in hemphilia may be protective against thrombotic occlusion of atherosclerotic vessels by interfering with fibrin formation, thereby affording protection from ischemic heart disease mortality.