Aging in Haemophilia: Getting to the heart of the matter

As a result of safer blood products and more effective treatments for human immunodeficiency virus (HIV) and hepatitis C infection (HCV), the life expectancy of those with haemophilia is approaching that of the general population. This was predicted over 20 years ago by Dutch epidemiologists who assessed the mortality of haemophilic men, after controlling for HIV and HCV infections (1). Thus, if trends in haemophilia follow the world population, 20% will be over 60 years of age by the year 2050 (2). To meet the challenges of the aging haemophilia population, it will be critical to plan for the treatment and prevention of diseases previously uncommon in haemophilia, but not uncommon in the general population, chief among which is the major cause of morbidity and mortality in Western society, atherosclerotic heart disease (ASHD). This may seem counter-intuitive, given the well-known 50% to 80% lower ASHD mortality in men with haemophilia than in the general population (1, 3, 4). The protection against ASHD mortality is attributed to hypocoagulability, that is, low factor VIII or IX, which reduces thrombus formation on a ruptured atherosclerotic plaque and fatal myocardial infarction (5, 6). Yet, whether hypocoagulability is protective against development of ASHD the disease, and whether ASHD will increase as the haemophilia population ages is controversial. What is the evidence that haemophilic men may be at risk for ASHD? At a molecular level, atherosclerosis is a chronic inflammatory response directed at the arterial wall, at specific sites where fatty streaks have progressed to lipid plaques, with lipid accumulation in macrophages, so-called macrophage foam cells, and foam cell trapping within the arterial intima (2, 7). In animal models, in fact, it is mice deficient in regulators of lipid trafficking, not those with haemophilia or von Willebrand disease, that are protected against atherosclerosis. Specifically, hyperlipidaemic mice deficient in CD36, a scavenger receptor that modulates migration of macrophages and traps oxidised LDL in arterial intima (2), are protected from lipid atheroma, but atherosclerotic-prone apolipoprotein E – factor VIII knockout mice (8) and pigs with von Willebrand disease (9) develop atherosclerotic plaques indistinguishable from unaffected animals. Thus, hypocoagulability in animals does not appear to protect against ASHD. Is this true for the aging man with haemophilia? Evidence has been increasing that both atherosclerosis and atherosclerotic risk factors are not uncommon or new in haemophilia. First, the frequency of pathogenic coronary atherosclerosis was recently shown to be similar to that in the general population. In an autopsy study of men with haemophilia, most of whom died of HIV or hepatitis, the degree of intraluminal coronary stenosis was similar to that in age-, sex-, race-matched controls (10). Cardiovascular risk factors, including hypertension, smoking, diabetes, and hyperlipidaemia, in those cases were similar to controls (10). These findings were further supported by a statewide analysis of inpatient ASHD discharge data in haemophilic men showing disease prevalence and cardiovascular risk factors are similar to controls (11). Further, a six-state CDC (Centres for Disease Control) study of hospitalised haemophilic men found that 15% over age 60 had ischaemic heart disease, independently associated with traditional risk factors, as well as factor infusion and HIV disease Correspondence to: Margaret V. Ragni, MD, MPH University of Pittsburgh, Department of Medicine Division Hematology/Oncology Director, Haemophilia Center of Western PA 3636 Boulevard of the Allies Pittsburgh, PA 15213–4306, USA Tel.: +1 412 209 7288, Fax: +1 412 209 7281 E-mail: ragni@pitt.edu