Combined Deficiency of Coagulation Factors V and VIII: An Update

Abstract

Combined deficiency of factor V (FV) and FVIII (F5F8D) is an autosomal recessive bleeding disorder characterized by simultaneous decreases of both coagulation factors. This review summarizes recent reports on the clinical presentations, treatments, and molecular mechanism of F5F8D. Genetic studies identified LMAN1 and MCFD2 as causative genes for this disorder, revealing a previously unknown intracellular transport pathway shared by the two important blood coagulation factors. LMAN1 and MCFD2 form a Ca2+-dependent cargo receptor complex that functions in the transport of FV/FVIII from the endoplasmic reticulum (ER) to the Golgi. Disrupting the LMAN1-MCFD2 receptor, complex formation is the primary molecular defect of missense mutations leading to F5F8D. The EF-hand domains of MCFD2 are necessary and sufficient for the interactions with both LMAN1 and FV/FVIII. Similarly, the carbohydrate recognition domain of LMAN1 contains distinct and separable binding sites for both MCFD2 and FV/FVIII. Therefore, FV and FVIII likely carry duel sorting signals that are separately recognized by LMAN1 and MCFD2 and necessary for the efficient ER-to-Golgi transport. FV and FVIII likely bind LMAN1 through the high-mannose N-linked glycans under the higher Ca2+ conditions in the ER and dissociate in the lower Ca2+ environment of the ER–Golgi intermediate compartment.

Rare bleeding disorders: diagnosis and treatment

“…A comparison of the most and least common symptoms among those with severe deficient RBDs is shown in Table 2. [9][10][11][12][13][14][15][16] Heterozygous individuals commonly do not manifest a bleeding tendency. Mucocutaneous and surgical associated bleeding were reported in 20% of patients, whereas post-traumatic hemarthrosis and hematomas are rarely reported in FVII and FX deficiencies.…”

“…Combined FV and FVIII deficiency (F5F8D) 12,39 is characterized by concomitantly low levels (usually 5-20%) of both coagulant activity and antigen. Interestingly, the concomitant deficiency of these 2 coagulation factors does not enhance the hemorrhagic tendency observed in each separate defect.…”

Postanalytical considerations that may improve the diagnosis or exclusion of haemophilia and von Willebrand disease

“…Another, albeit potentially rarer event, except perhaps in some geographies, would be misdiagnosis of haemophilia in patients with combined FVIII/FV deficiency, reflecting a rare bleeding disorder due to genetic mutations in genes ( LMAN1 , MCFD2 ) responsible for intracellular transport of FVIII and FV. Failure in this transport mechanism leads to low plasma levels of both these clotting factors . Naturally, preanalytical issues also need to be excluded here.…”

Combined deficiency of factors V and VIII by chance coinheritance of parahaemophilia and haemophilia A, but not by mutations of either LMAN1 or MCFD2, in a Japanese family

“…2 Although the prevalence of F5F8D in the general population is estimated to be rare (1 in 1 000 000 births), an increased frequency has been observed in regions where consanguineous marriage is practised. …”