ORIGINAL ARTICLE Laboratory investigation Endothelial dysfunction in haemophilia patients M. T. SARTORI, F. BILORA, E. ZANON, C. VARVARIKIS, G. SAGGIORATO, E. CAMPAGNOLO, A. PAGNAN and G. CELLA 2nd Chair Internal Medicine, Department of Medical and Surgical Sciences, University of Padua, Padova, Italy Summary. Haemophilia patients may develop car- diovascular 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 moder- ate–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 mea- sured, 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. Keywords: atherosclerosis, endothelial dysfunction, fibrinolysis, flow-mediated dilation, haemophilia, viral infection Introduction After von Willebrand disease, haemophilia A and B are leading congenital bleeding disorders with clin- ical signs strongly correlating with the degree of factor VIII or IX deficiency. The median survival of haemophiliacs has improved thanks to the safe implementation of substitutive therapy, without the risk of blood-transmitted infection, and patients with mild-moderate disease have much the same sur- vival rate as the non-haemophiliac population [1]. Whether the coagulation factor defect protects against atherosclerosis and thrombotic risk is a matter of debate [2,3]. Previous case–control studies by our group showed that patients with von Willebrand disease and haemophilia had fewer atherosclerotic carotid pla- ques and less carotid stenosis than sex- and age- matched controls, and ultrasound (US) evaluation of several arterial districts demonstrated a significantly lower asymptomatic atherosclerosis in patients with moderate and severe haemophilia A [4,5]. Cardiovascular events have rarely been described in haemophilia patients [6–8], although haemophiliacs are susceptible to common cardiovascular risk fac- tors, e.g. arterial hypertension, smoking, high choles- terol levels, diabetes mellitus and obesity. Venous thrombosis has also been reported in patients with haemophilia, especially in the presence of other prothrombotic conditions such as neoplastic disease, central venous lines, or major surgery [9–11]. Clotting defect (over)correction with factor concentrate infu- sions has frequently, but not unequivocally, been assumed to cause or contribute to thrombosis [12,13]. The coexistence of thrombophilic defects, such as the Correspondence: Maria Teresa Sartori, MD, 2nd Chair Internal Medicine, Department of Medical and Surgical Sciences, Via Giustiniani 2, 35128 Padova, Italy. Tel.: +39 0498212653; fax: +39 0498218731; e-mail: mtsart@unipd.it Accepted after revision 5 June 2008 Haemophilia (2008), 14, 1055–1062 DOI: 10.1111/j.1365-2516.2008.01808.x Ó 2008 The Authors Journal compilation Ó 2008 Blackwell Publishing Ltd 1055