Atherosclerotic heart disease (ASHD) is the most common cause of morbidity and mortality in Western society. Among individuals with hemophilia, there is increasing interest in defining the scope of ASHD, now that their survival is approaching that of the normal population with the availability of safer clotting factor concentrates and effective treatment for blood-borne pathogens HIV and hepatitis C [1–3]. A CDC study reported that as many as 15% of hemophilic men over 60 years of age have clinical ASHD [4]. While their mortality is 2.7-fold higher than the general population, due to hepatitis C and AIDS, the mortality from ischemic heart disease is 60% lower [3, 5–7]. Elevated circulating factor VIII [8], fibrinogen [9], and von Willebrand factor [10] levels are known risk factors for cardiovascular disease, but whether low factor VIII or IX, i.e. hypocoagulability, protects against ASHD remains an area of debate. In a recent case-control study we found that risk factors for ischemic heart disease (hypertension, smoking, diabetes, hyperlipidemia) and degree of intraluminal coronary stenosis at autopsy in hemophilic men are similar to those in the general population [11]. This suggests that while risk for cardiovascular disease is similar, the risk for cardiovascular mortality is lower in individuals with hemophilia than the general population, despite improving lifespan, and this may be related to hypocoagulability [11, 12]. Few data, however, exist on the prevalence and predictors of ASHD in hospitalized hemophilia patients as compared with the general population. While some studies describe a lower frequency of lipid elevation in those with hemophilia than controls [13], others studies report no difference [14, 15], suggesting differences in age, viral infection, obesity, or other confounders between these groups [16]. We, therefore, reviewed statewide inpatient ASHD discharge data for ASHD from the Pennsylvania Health Care Cost Containment Council (PHC4) to determine the prevalence and characteristics of ASHD in hospitalized hemophilia patients in Pennsylvania.

De-identified discharge data for the five-year period 2001–2006 were obtained from the Pennsylvania Health Care Cost Containment Council (PHC4). This independent agency collects inpatient hospital discharge data and outpatient procedure records from hospitals and ambulatory surgery centers in the state of Pennsylvania to monitor health care cost [17]. Data for analysis were limited to Pennsylvania residents hospitalized between 2001 and 2006, excluding female patients. Discharges were analyzed by age, race, year, severity of illness, length of stay, and vital status including in-hospital deaths [17, 18]. Coronary disease data were classified by diagnostic ICD-9 codes [19] for atherosclerotic heart disease (ICD-9 414), myocardial infarction (ICD-9 412), angina (ICD-9 413), and other ischemic heart disease (ICD-9 411). Cardiac diagnostic procedure codes were classified by procedure codes, including cardiac catheterization, EKG, angiography, and nuclear procedures. Co-morbidities were also assessed, including hypertension (ICD-9 401–405), hyperlipidemia (ICD-9 272.4); diabetes (ICD-9 250), obesity (ICD-9 278), and HIV (ICD-9 042). Primary admission diagnoses were classified as circulatory system (ICD-9 390–460), blood-forming organs (ICD-9 280–290), respiratory system (ICD-9 460–520), digestive system (ICD-9 520–580), and injury/trauma (ICD-9 800–999). Three groups of hospitalized patients were identified for comparisons: 1) individuals with hemophilia A and ASHD; 2) those with hemophilia A and no ASHD; and 3) individuals without hemophilia A but with ASHD, based on the presence or absence of these two diseases in the primary or secondary diagnoses (admissions categorization). The study was approved by the University of Pittsburgh Institutional Review Board (IRB) by exempt review.

As the hemophilia population is now aging, a number of studies have established that while cardiovascular mortality is three times more common as a cause of death [20], cardiovascular disease [3, 6, 7, 12, 21, 22], pathologic coronary artery atherosclerosis [11], and endothelial dysfunction [14] do not differ between individuals with hemophilia and the general population. Further, the prevalence of ASHD is not uncommon in older individuals in normal, nonhemophilia groups. However, there is controversy regarding whether those with hemophilia have similar cardiovascular risk factors to those in the general population. Some of the difficulties with studies to date include small cohort size, few cardiovascular events, and differing age, decade of study, and proportion HIV infected or on antiretroviral therapy.

This study utilized hospital discharge data to establish that, as compared with non-hemophilic men with ASHD, hemophilic men with ASHD have similar cardiovascular risk factors with the exception of hyperlipidemia, and they also have similar primary admitting (non-hemophilic) diagnoses. Further, they have similar cardiovascular ICD-9 codes for myocardial infarction and angina pectoris, a similar severity of illness, and a similar proportion who undergo cardiovascular diagnostic procedures. It is of note that the trend to fewer undergoing coronary angiography, although not significant, is possibly related to fear of bleeding, not only by persons with hemophilia, but by the cardiologists caring for them.

The findings of this study suggest that cardiovascular procedures should be part of standard medical care for individuals with hemophilia, just as for the general population. There are, however, important caveats to consider in this approach. Anticoagulation or anti-platelet therapy, whether for myocardial infarction or surgical procedures, e.g. coronary stent placement, may increase the risk of life-threatening bleeding in the individual with hemophilia. Further, the risk of bleeding may be even greater in the presence of other concomitant coagulation defects, e.g. thrombocytopenia or Vitamin K deficiency, not uncommon in hemophilic men with chronic hepatitis C liver disease. Thus, before initiating anticoagulation or platelet inhibitor therapy in the individual with hemophilia, careful coagulation assessment before and during anticoagulation or anti-platelet therapy is critical to avoid unforeseen bleeding. It is of note that no safety recommendations or evidence-based guidelines exist to guide anticoagulation or anti-platelet therapy in hemophilic men. This is, in part, because potential bleeding risk excludes hemophilic men them from participation in cardiovascular prevention trials. In the absence of evidence, wide-ranging approaches to anticoagulation and anti-platelet therapy for cardiovascular disease and/or procedures have been proposed, including short-term anticoagulation anti-platelet therapy only with concomitant factor infusion, low dose anticoagulation or anti-platelet therapy, or avoidance of such agents altogether [23]. The lack of hemophilia-specific guidelines for anticoagulation management of ischemic cardiovascular disease suggests the need for prospective clinical trials, which would likely require international collaboration for sufficient sample size to achieve significant findings.

There are several limitations of this study. First, the use of a hospital discharge database may miss healthier outpatients not requiring admission; however, traditionally patients with acute myocardial infarction and angina pectoris, the ICD-9 codes we reviewed, are hospitalized, and, thus, we believe few potential subjects were missed. Further, an advantage of an inpatient database is the availability of severity of illness and in-hospital mortality data, not previously reported in hemophilic men. Secondly, because these are administrative data collected for another purpose, it is not possible to verify that all patients with an ICD-9 for hemophilia actually had hemophilia, nor is it possible to establish hemophilia severity, although previous studies suggest no difference in ASHD risk by hemophilia severity [11]. Further, these data do not include clinical history of smoking, laboratory values,, e.g. lipid levels, or treatment medications for hypertension or hyperlipidemia, which may result in identification of fewer individuals with hyperlipidemia or at risk for cardiovascular disease. Thirdly, these data are limited to the state of Pennsylvania which, although unlikely, may not be representative of the nation and miss geographic differences. Fourthly, as expected, HIV infection was more common among ASHD inpatients with hemophilia than in those without hemophilia, yet the prevalence was low, in only 2.7% of patients with hemophilia. The reason for this is not known, but it is possible this reflects the advanced age of the patient population, and/or limitations of hospital discharge coding.

To summarize, the presence of atherosclerotic heart disease among adult men with hemophilia is not rare (6–10% of admissions). Cardiovascular risk factors, severity of illness and in-hospital mortality are similar in hemophilia men with ASHD compared to the general population of men with ASHD. These findings are consistent with the previous demonstration that pathologic coronary atherosclerosis [11] and endothelial dysfunction [14] in those with hemophilia are similar to the general population, and underscore the importance of a cardiovascular risk prevention strategy in adults with hemophilia, similar to that in the general population. Such a strategy will require ongoing clinical studies to define the safety of anticoagulation and anti-platelet therapy in this group.