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Factor V and FVIII deficiency in a young Czech woman

Combined deficiency of factor V and factor VIII is a rare autosomal recessive bleeding disorder characterized by concomitantly low levels (usually between 5% and 20%) of two coagulation factors [1]. Oeri et al. first described this deficiency in 1954 [2]. The molecular mechanism was discovered in 1998 [3,4], when Nichols et al., using the positional cloning method, described the cause of the deficiency, which is associated with null mutations in the gen now called LMAN1. In 2003, the second cause of F5F8D was identified as mutations in a novel gene that was named MCFD2 (multiple coagulation factor deficiency gene 2) [5]. The LMAN1 is a mannose-specific lectin that cycles between the endoplasmic reticulum (ER) and the ER-Goldi intermediate compartment. MCFD2 is an EF-hand domain protein that forms a calcium-dependent heteromeric complex with LMAN1 in cells. Missense mutations in the EF-hand domains of MCFD2 abolish the interaction with LMAN1.The LMAN1-MCFD2 complex may serve as a cargo receptor for the ER-to-Goldi transport of FV and FVIII [6]. The incidence is very rare (estimated to be 1:1 000 000 in the general population) [7]. A comprehensive review (including clinical and molecular features and treatment strategy) was recently published [8]. No case in the Czech population has been described in the literature yet. In 2008, a 19-year-old white Caucasian woman (T.B) was referred to our Department with a history of bleeding and prolongation of prothrombin time (PT) and activated partial thromboplastin time (aPTT). There was no family history of bleeding diathesis (in the mother, father or brother), even when exposed to multiple surgeries (tonsillectomy in mother, both elbows and total knee replacement in father). This young woman was suffering from bilateral nose bleeds since early childhood and experienced easy bruising and haematomas formation. She does not have menorrhagia. In 2007, she suffered head injury with bleeding from the site of injury after falling of a bicycle. She immediately visited the district hospital. The CT of head excluded intracranial haemorrhage and a couple of stitches were inserted. In spite of this routine procedure, bleeding persisted and resulted in rupture of the stitches. A global coagulation test showed prolongation of PT (control 14.2, patient 24 s) and aPTT (control 32.8, patient 80.7 s). Other tests (thrombin time, fibrinogen were normal), the number of platelets was also within the normal range. The fresh-frozen plasma was administered in a dose of 10–15 mL kg of body weight over two successive days and had a very good effect on bleeding. After full recovery, detail coagulation work-up has been done in the hospital haemophilia centre. The results are summarized in the Table 1. The further tests (platelet aggregation, PFA-100, platelets 195.10 L) were within physiological range as well. The diagnosis of combined FV and FVIII deficiency was established. The genetic examination (LMAN1 and MCFD2) is not available in our centre. Her parents were also tested with normal results (FV 105% and FVIII 75% in the mother, respectively FV 106% and FVIII 73% in the father). We made recommendations to the patients regarding the further management of bleeding and the interventional procedures (surgery etc.). She was also advised about the necessity of observation in case of pregnancy and requirement of having any delivery in our centre. We described the first case of combined FV and FVIII deficiency in Czech population with typical activity of FV and FVIII. The case was revealed after head injury.