Endothelial dysfunction in haemophilia patients

Abstract

Haemophilia patients may develop cardiovascular diseases, suggesting that their clotting defect does not protect them completely from atherosclerosis and its complications. We aimed to evaluate cardiovascular risk factors and, for the first time, the presence of endothelial dysfunction in middle-aged haemophilia patients. We studied 40 patients with haemophilia A and B (24 with moderate-severe disease and 16 with mild disease), and 40 healthy controls. Flow-mediated dilation (FMD), carotid ultrasound (US) intima media thickness (IMT), arterial blood pressure, body mass index (BMI), cholesterol, triglycerides, glucose, insulin, lipoprotein(a) and homocysteine levels were measured, and PAI-1 and t-PA levels before and after venous occlusion (VO), and antibodies to HIV, HBV and HCV were assayed. At least one cardiovascular risk factor was detected in 87.5% of patients, and 2 or more in 47.5% of cases. At US exam, none of the patients had significant carotid stenosis or significant differences in IMT compared to controls. In contrast, all the patients had a significant FMD impairment, associated with a reduced t-PA release after VO in 70% of cases. PAI-1 levels significantly correlated with BMI, triglycerides and insulin values. Fifteen haemophilia patients with chronic viral hepatitis and/or HIV infection showed a significantly lower FMD than patients without active infection. We found an endothelial dysfunction with impaired FMD and t-PA release in our haemophilia patients, usually associated with cardiovascular risk factors. Other pathogenic mechanisms, such as chronic viral infections, are likely to be involved in this endothelial damage, however.

Cardiovascular risk in patients with hemophilia

“…25 In humans, several earlier studies analyzed the presence of subclinical atherosclerosis by measuring the carotid and femoral intima media thickness (IMT) in patients with hemophilia or von Willebrand disease. [26][27][28][29] Overall, there was no difference in the mean IMT of either the carotid artery (0.75 mm vs 0.74 mm) or femoral artery (0.75 mm vs 0.79 mm) in patients and age-matched healthy controls. 8 Recently, 2 studies investigated whether hypocoagulability is associated with decreased atherogenesis by evaluating subclinical atherosclerosis and endothelial function in hemophilia patients and in matched unaffected controls.…”

Coronary Artery Calcification in Hemophilia A

“…[17][18][19][20][21] Srámek et al 21 and Sartori et al 20 found no differences in IMT, whereas 3 other studies [17][18][19] did show a lower IMT, fewer atherosclerotic plaques, or both in hemophilia patients. In these studies, patients were relatively young; mean age ranged from 40 to 58 years.…”

“…A major disadvantage in most studies is the heterogeneous study population, combining patients with severe, moderate, and mild hemophilia A or B or von Willebrand disease. 17,18,20,21 Clotting factors VIII and IX and von Willebrand factor play different roles in the development of atherosclerosis. 12,34 Combining these disorders in 1 study might result in masking a possible relationship between 1 of the disorders and atherosclerosis.…”

“…Moreover, comparison groups were not well chosen and, in some, not well described. [17][18][19][20][21] In addition, confounding was not accounted for in the analyses. These factors make interpretation of the results difficult.…”

“…16 Conflicting results have also been reported by studies comparing intima-media thickness (IMT) between hemophilia patients and nonhemophilic subjects. [17][18][19][20][21] This could be due to heterogeneous study populations including patients with other bleeding disorders than hemophilia, low mean ages, not well chosen or not well defined comparison populations, and variability in tests and outcome parameters.…”