Combined deficiency of Factor V (FV) and Factor VIII (FVIII) (F5F8D; Online Mendelian Inheritance in Man® [OMIM] # 227300 and # 613625, accessed September 2018) is an autosomal recessive bleeding disorder characterized by concomitantly low levels of these two coagulation factors. This condition was first described by Oeri et al. in 1954.1 The molecular mechanism of the association of the two factor deficiency had not been understood until Nichols et al.2,3 discovered that the cause of the deficiency was associated with null mutations in the ERGIC-53 gene, now called LMAN1 (lectin mannose binding protein). LMAN1 encodes an endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC) marker protein. Approximately 70% of affected patients have mutations in LMAN1.
In 2003, Zhang et al.4 identified a second locus associated with the deficiency in about 15% of affected families with no mutation in LMAN1: the MCFD2 (multiple coagulation factor deficiency 2) gene encoding a cofactor for LMAN1.5 Biochemical studies to date have failed to identify additional components of the LMAN1-MCFD2 receptor complex,5 supporting the theory that F5F8D might be limited to the LMAN1 and MCFD2 genes.6
The LMAN1-MCFD2 complex functions as a cargo receptor to transport FV and FVIII from the endoplasmic reticulum to the Golgi for eventual secretion. FV and FVIII are essential coagulation factors that circulate in plasma as precursors to the activated proteins. These proteins exhibit cofactor activities in the activation of FX and prothrombin by FIXa and FXa, respectively, ultimately leading to clot formation.
At the end of the coagulation process the intravascular clots have to be dissolved and removed to avoid thrombosis: inactivation of procoagulant factors is therefore needed. Inactivation of FVa and FVIIIa is accomplished through several proteolytic cleavage events at distinct sites by activated protein C in the presence of protein S and phospholipids.7
LMAN1 is a 53 kDa non-glycosylated type 1 transmembrane protein with homology to leguminous lectin proteins.8 LMAN1 displays different oligomerization states – monomer, dimer, and hexamer – that have been implicated in its exit/retention within the ER. LMAN1 is believed to bind correctly-folded glycosylated cargo proteins, including FV and FVIII, in the ER. LMAN1 recruits cargo for packaging into coat protein complex II (COPII)-coated vesicles and subsequently transports this cargo first to the ERGIC and ultimately to the Golgi.9
Efficient transport of coagulation FV and FVIII along the secretory pathway requires the integrity of the heavily-glycosylated FV and FVIII B-domains, as well as a functional LMAN1 protein.5,10 MCFD2 is a small soluble protein of 16 kDa (146 residues) that bears a signal sequence that mediates translocation into the ER; it contains two C-terminal EF-hand motifs that may bind Ca2+ ions. MCFD2 forms a Ca2+-dependent 1:1 stoichiometric complex with LMAN1, with the complex serving as a cargo receptor for coagulation FV and FVIII during efficient ER-to-Golgi transport of these factors during secretion.4
The three-dimensional structure of the complex between MCFD2 and LMAN1 was determined in 2009, and the structural information gained suggested that MCFD2 is converted into the active form upon complex formation with LMAN1, allowing FV and FVIII binding. The coagulation factors bind the LMAN1 oligomer in the ER but are released upon arrival in acidic post-ER compartments, as binding of the FV and FVIII sugar moieties by LMAN1 is pH-dependent.11 Recent structural studies by Zheng et al. have provided new insight into the endoplasmic reticulum export of FV and FVIII by the LMAN1-MCFD2 complex.12
To date, more than 50 mutations in LMAN1 and MCFD2 genes have been described, with almost 70% of these mutations being located on LMAN1. Mutations in LMAN1 and MCFD2 are associated with indistinguishable phenotypes.4 Zhang et al.13 performed a genotype-phenotype analysis to evaluate whether mutations in the two genes are associated with differences in the FV and FVIII plasma levels. Results from this study revealed that the mean FV and FVIII levels in patients with MCFD2 mutations were significantly lower than the corresponding levels in patients with LMAN1 mutations.
Congenital F5F8D is estimated to be extremely rare (1:1,000,000) in the general population.14 However, this disorder was reported to be particularly prevalent in some Middle Eastern areas,15 probably due to, at least in part, to the high incidence of consanguinity. Other cases were also reported from continents across the world: Europe, Asia, Africa, and the Americas.16
The World Federation of Hemophilia (WFH) global survey and the European Network of Rare Bleeding Disorders (EN-RBD) project indicate that the worldwide prevalence of F5F8D patients is about 2-3% (5-6% in the above-mentioned Middle Eastern areas) of the total number of patients affected by rare coagulation disorders (http://www1.wfh.org/publications/files/pdf-1690.pdf and www.rbdd.eu, accessed September 2018). This figure suggests that F5F8D is one of the rarest of coagulation disorders. Nonetheless, F5F8D may be significantly underdiagnosed because of the often-mild bleeding symptoms associated with this condition.
Rare Coagulation Disorders Resource Room, an extension of the RBDD Registry (eu.rbdd.org), was developed in collaboration with the Indiana Hemophilia & Thrombosis Center (www.innovativehematology.org).
The Resource Room serves as a platform to promote international collaboration to increase knowledge of these very rare disorders and to improve the care of affected individuals. The international RBDD mission, under the leadership of Dr. Peyvandi, will continue to be expanded over time.
The Resource Room thanks all contributing authors of the website articles that have made this valuable information available to the global community of both individuals affected with rare coagulation disorders and their healthcare providers.
