Haemorrhagic symptoms in patients with combined factors V and VIII deficiency in north-eastern Iran H. MANSOURITORGABEH,* Z. REZAIEYAZDI,  A. A. POURFATHOLLAH,* J. REZAI à and H. ESAMAILI§ *Experimental Hematology and Blood Banking Group, Medical Sciences School, Tarbiat Modarres University (TMU), Tehran;  Department of Internal Medicine, Mashhad University of Medical Sciences, Mashhad; àAzad Medical University, Mashhad; and §Biostatic and Social Medicine Department, Mashhad Medical Sciences University, Mashhad, Iran Summary. Of the six types of dual coagulation factors deficiency, combined factors V and VIII are the most common type, a few cases of this disease have been reported in different populations. This accounts for the relatively low number of cases reported so far. Our report, which included 19 patients, is the second largest group that has been reported from one centre in north-eastern Iran. The most frequent spontaneous bleeding symptoms were epistaxis and haemarthrosis, and the most frequent traumatic bleeding symptoms were bleeding after dental extraction and bleeding after cutting any part of the body. It seemed that dual coagulation FV and FVIII deficiency is as severe as single coagulation factor (V or VIII) deficiency. Keywords: combined factors V and VIII deficiency, haemorrhagic symptoms Introduction Six types of combined hereditary coagulation factors have been reported to date [1]. Combined deficiency of factors V and VIII was reported in 1954 by Oeri et al. [2]. This inherited disorder is a rare bleeding diathesis that has been reported in 106 cases from 62 families throughout the world until 2000 [3]. Most patients are from the Mediterranean region including Israel [4], Iran [5] and Italy [6]. Additional families have been reported from India [7], Japan [8], North America and Europe [6]. In genetic defects of single coagulation factors, the relationship of severity of clinical symptoms with the plasma factor level is evaluated. However, the data available from published reports show wide vari- ation with regard to clinical manifestations in cases of combined FV and FVIII deficiency [9]. Many mechanisms have been proposed to explain this mysterious dual deficiency. In 1980, Marlar and Griffen reported an apparent deficiency of protein C inhibitor as the underlying mechanism for this disorder [10]. This intriguing model was based on the observation that four unrelated patients with combined deficiency FV and FVIII had no protein C inhibitor in their blood [11]. Despite this attractive hypothesis, subsequent studies failed to confirm it in these patients [12–14]. Genetic linkage studies in affected families mapped the responsible gene for combined FV and FVIII deficiency to the long arm of chromosome 18 [15]. Positional cloning studies led to the identification of endoplasmic reticulum Golgi intermediate compartment (ERGIC-53) as a respon- sible gene newly named LMAN1 [16–18]. It has been shown that 18 distinct REGIC-53 mutations can cause complete loss of ERGIC-53 protein expression. FV and FVIII contain heavily glycosylated B domain that may interact with ERGIC-53. This molecule may function as a sorting receptor for transporting FV and FVIII from ER to Golgi. Nearly in 30% of affected patients no ERGIC-53 protein has been detected by Western blot analysis. In some families lack of linkage to the ERGIC-53 locus has been noted [15,17]. Further research revealed a second gene, called MCFD2 (that is short for multi-coagu- lation factor deficiency 2). Researchers identified seven distinct mutations in the MCFD2 gene. MCFD2 is localized to ERGIC-53 through a direct, calcium-dependent interaction with LMAN1. There are still families who have the bleeding disorder, but without mutation in either the LMAN1 or MCFD2 genes, so there may or may not be a third gene involved in this coagulation disorder [18,19]. It is Correspondence: Z. Rezaieyazdi, Internal Medicine Department, Ghaem Hospital, Mashhad. Iran. E-mail: rezaieyazdi-z@mums.ac.ir. Accepted after revision 6 February 2004 Haemophilia (2004), 10, 271–275 DOI: 10.1111/j.1365-2516.2004.00890.x Ó 2004 Blackwell Publishing Ltd 271