Page 2164 - Williams Hematology ( PDFDrive )

2138 Part XII: Hemostasis and Thrombosis Chapter 124: Inherited Deficiencies of Coagulation Factors II, V, V+VIII, VII, X, XI, and XIII 2139

THERAPY type 1 transmembrane nonglycosylated protein with homology to legu-
118
Patients with epistaxis and gingival bleeding may respond to tranex- minous lectin proteins. It displays different oligomerization states—
amic acid (1 g four times daily), and local hemostatic measures may monomer, dimer, and hexamer—which have been implicated in its exit/
suffice for minor lacerations. Menorrhagia can also be managed directly retention within the endoplasmic reticulum (ER), and is thought to
using oral contraceptives, progestin-containing intrauterine devices, bind correctly folded glycosylated cargo proteins, including factors V
endometrial ablation, or hysterectomy. If these measures fail, severe and VIII in the ER, recruiting the cargo for package into coat protein
spontaneous bleeding occurs, or surgery is performed, treatment option complex II (COPII)–coated vesicles and to transport them first to the
is limited to FFP replacement as no specific factor V concentrate is yet ERGIC and then to the Golgi. MCFD2 is a small (146 residues) solu-
available on the market and factor V is not present in cryoprecipitate ble protein of 16 kDa with a signal sequence mediating translocation
2+
or PCCs. However, a new factor V concentrate has been developed for into the ER and two EF-hand motifs that may bind Ca ions in the
119
2+
clinical use in patients deficient in factor V and preclinical studies are C-terminal region. MCFD2 forms a Ca -dependent 1:1 stoichiomet-
currently being performed for the orphan drug designation applica- ric complex with LMAN1, which works as a cargo receptor for efficient
tion to the European Medicine Agency (EMA) and the Food and Drug ER–Golgi transfer of coagulation factors V and VIII during their secre-
Administration (FDA) so as to make it available on the market as soon tion. Although several proteins have been identified as cargo of LMAN1
as possible. (factor V, factor VIII, cathepsin C, cathepsin Z, nicastrin, and α -antit-
1
rypsin), 120–123 MCFD2 is only known to be required for transport of the
blood coagulation factors, suggesting a possible role for MCFD2 as a
124
COMBINED DEFICIENCY OF specific recruitment factor for this subset of LMAN1 cargo proteins.
The three-dimensional structure of the complex between MCFD2 and
FACTORS V AND VIII the carbohydrate recognition domain (CRD) of LMAN1 was deter-
mined and a model of functional coordination between the two pro-
DEFINITION AND HISTORY teins was proposed: MCFD2 is converted into the active form upon
Combined deficiency of factors V and VIII (F5F8D) is completely sep- complex formation with LMAN1, thereby becoming able to capture
arate from factor V deficiency and factor VIII deficiency. The latter polypeptide segments of factors V and VIII. The coagulation factors
two are transmitted with different patterns of inheritance (autosomal bind the LMAN1 oligomer in the ER, but are released upon arrival in
recessive for factor V, X-linked for factor VIII) and involve proteins the acidic post-ER compartments because the sugar-binding of ERGIC-
encoded by two different genes (F5 gene and F8 gene). F5F8D was first 53 is pH-dependent. 125
described in 1954 ; however, the molecular mechanism of the associ-
111
ation of the combined factor deficiency was not understood until late GENETICS
1990s, 112,113 when null mutations in the endoplasmic reticulum–Golgi Homozygosity mapping and positional cloning in nine unrelated Jew-
intermediate compartment (ERGIC)-53 gene, now called the LMAN1 ish families demonstrated that the LMAN1, composed of 13 exons,
gene, were determined to be causative. In 2003, a second locus associ- localizes on the long arm of chromosome 18. 112,113,126 Using a similar
ated with the deficiency in approximately 15 percent of affected families approach in other families with the combined factors V and VIII defi-
26
with no mutation in LMAN1 was identified : the MCFD2 gene encod- ciency identified the short MCFD2, made up of four exons on the short
ing for a cofactor for LMAN1. Even if a debate were carried out on the arm of chromosome 2. Thirty-four mutations identified in LMAN1
26
possible existence of other loci involved in the intracellular transport predicted either a truncated protein product or no protein at all, being
of factors V and VIII and associated with the disease, until now previ- more than 90 percent deletion/insertion, null, or splicing mutations.
ous biochemical studies failed to identify additional components of the In contrast, of the 22 mutations identified in the MCFD2, 11 are mis-
114
LMAN1–MCFD2 receptor complex, supporting the idea that F5F8D sense and 11 are null mutations. Missense mutations are located at the
might be limited to the LMAN1 and MCFD2 genes. The disorder EF-2 domains, giving rise to defective binding to LMAN1. A distinct
115
127
has been detected in many populations, but a relatively high frequency founder haplotype was found in patients belonging to six unrelated
116
occurs among Tunisian and Middle Eastern Jews residing in Israel families of Tunisian-Jewish origin bearing a donor splice-site mutation
and among Iranians. 117 in intron 9 of LMAN1. 112,127 All six families originated from an ancient
Jewish community that has resided on the island of Djerba for more
PROTEIN than 2 millennia. A survey of this community, which presently lives in
Factors V and VIII are essential coagulation factors that circulate in Israel, disclosed that the mutation is prevalent at an allele frequency of
0.0107. Another founder effect for a G insertion in exon 1 of LMAN1
128
plasma as precursors. Upon limited proteolysis by thrombin or fac- was observed in eight unrelated Jewish families of Middle Eastern ori-
tor Xa and in concert with negatively charged phospholipid surfaces, gin. 112,127 A Met to Thr mutation in LMAN1 has been detected in several
factors VIIIa and Va exhibit profound cofactor activities for activation unrelated Italian families, implying another founder effect. 127
of factor X by factor IXa and for activation of prothrombin by factor
Xa, respectively. Inactivation of factors Va and VIIIa is accomplished
by activated protein C in the presence of protein S and phospholipids CLINICAL MANIFESTATIONS
through several proteolytic cleavages at distinct sites. Factor V and fac- Symptoms of F5F8D are generally mild. Comparison of relatively
tor VIII have similar domain organizations with partial homology (see large cohorts of F5F8D in India, Iran, and Israel indicates that bleed-
“Factor V Deficiency” above). ing from trauma/surgery is the most frequently reported clinical man-
The pathogenesis of combined deficiency of factors V and VIII ifestation. 116,117,129,130 This observation likely reflects the fact that often
puzzled investigators for more than 40 years. The enigma was resolved F5F8D is brought to the attention of physicians following excessive
by the finding that the disease stems from the deficiency of either one bleeding during and after trauma, surgery, and labor. Homozygous
of two interacting proteins, LMAN1 and MCFD2, which play a role in patients exhibit spontaneous and posttraumatic bleeding. Menorrha-
the intracellular transport of factors V and VIII. LMAN1 is a 53-kDa gia, epistaxis, easy bruising, hemarthrosis and gingival hemorrhage

Kaushansky_chapter 124_p2133-2150.indd 2139 17/09/15 3:41 pm