An autosomal recessive bleeding disorder in which plasma coagulation factor V and factor VIII are reduced together, usually to 5-30% of normal. It is not caused by variants in F5 or F8. Instead, biallelic loss-of-function variants in LMAN1 (ERGIC-53) or MCFD2 disrupt a two-subunit, calcium-dependent cargo receptor that carries both factors from the endoplasmic reticulum to the ER-Golgi intermediate compartment, so less of each is secreted. LMAN1 is a hexameric transmembrane mannose-binding lectin and MCFD2 a small soluble EF-hand protein. Missense variants in either gene act mainly by disrupting formation of the LMAN1-MCFD2 complex, and the two genetic types are clinically indistinguishable, so they are curated as subtypes of one entry with one pathograph. Patients with MCFD2 variants have on average somewhat lower factor levels than patients with LMAN1 variants, with wide overlap. Bleeding is mild to moderate: excessive bleeding after trauma, surgery, dental extraction, circumcision or childbirth is the most common presentation, with epistaxis, gingival bleeding, bruising and menorrhagia as the common spontaneous symptoms. Hemarthrosis, gastrointestinal bleeding, hematuria and intracranial hemorrhage are uncommon. Screening shows prolongation of both the prothrombin time and the activated partial thromboplastin time. There is no factor V concentrate, so treatment combines fresh frozen plasma (the only source of factor V) with factor VIII concentrate or desmopressin, plus antifibrinolytics, mostly on demand or around procedures.
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Conditions with similar clinical presentations that must be differentiated from Combined Factor V and Factor VIII Deficiency:
name: Combined Factor V and Factor VIII Deficiency
creation_date: "2026-10-31T18:30:00Z"
category: Mendelian
synonyms:
- F5F8D
- combined deficiency of factor V and factor VIII
- combined factor V and VIII deficiency
- familial multiple coagulation factor deficiency I
description: >-
An autosomal recessive bleeding disorder in which plasma coagulation factor V
and factor VIII are reduced together, usually to 5-30% of normal. It is not
caused by variants in F5 or F8. Instead, biallelic loss-of-function variants
in LMAN1 (ERGIC-53) or MCFD2 disrupt a two-subunit, calcium-dependent cargo
receptor that carries both factors from the endoplasmic reticulum to the
ER-Golgi intermediate compartment, so less of each is secreted.
LMAN1 is a hexameric transmembrane mannose-binding lectin and MCFD2 a small
soluble EF-hand protein. Missense variants in either gene act mainly by
disrupting formation of the LMAN1-MCFD2 complex, and the two genetic types are
clinically indistinguishable, so they are curated as subtypes of one entry
with one pathograph. Patients with MCFD2 variants have on average somewhat
lower factor levels than patients with LMAN1 variants, with wide overlap.
Bleeding is mild to moderate: excessive bleeding after trauma, surgery,
dental extraction, circumcision or childbirth is the most common
presentation, with epistaxis, gingival bleeding, bruising and menorrhagia as
the common spontaneous symptoms. Hemarthrosis, gastrointestinal bleeding,
hematuria and intracranial hemorrhage are uncommon. Screening shows
prolongation of both the prothrombin time and the activated partial
thromboplastin time.
There is no factor V concentrate, so treatment combines fresh frozen plasma
(the only source of factor V) with factor VIII concentrate or desmopressin,
plus antifibrinolytics, mostly on demand or around procedures.
disease_term:
preferred_term: combined deficiency of factor V and factor VIII
term:
id: MONDO:0018175
label: combined deficiency of factor V and factor VIII
parents:
- Rare bleeding disorder
- Inherited blood coagulation disorder
has_subtypes:
- name: Type 1
display_name: Type 1 (LMAN1-related)
subtype_term:
preferred_term: factor V and factor VIII, combined deficiency of, type 1
term:
id: MONDO:0009206
label: factor V and factor VIII, combined deficiency of, type 1
classification: genetic
description: >-
Caused by biallelic LMAN1 variants, most of them null alleles
(insertion/deletion, nonsense and splice-site). Accounts for roughly 70% of
genotyped families. Founder alleles include LMAN1 c.89insG in Iranian/Iraqi
Jewish families and c.2T>C (M1T) in Italian families.
genes:
- preferred_term: LMAN1
term:
id: hgnc:6631
label: LMAN1
evidence:
- reference: PMID:9546392
reference_title: "Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "DNA sequence analysis identified two different mutations, accounting for all affected individuals in nine families studied."
explanation: >-
The positional-cloning study that identified ERGIC-53 (LMAN1) variants as
the cause of the disorder.
- reference: PMID:39209292
reference_title: "Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "The testing should start with LMAN1, because in 70% of cases, mutations are found in this gene, followed by MCFD2 if no mutations are identified in LMAN1."
explanation: Supports the approximate share of families explained by LMAN1.
- reference: PMID:39209292
reference_title: "Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Some mutations, such as c.89insG and c.2T > C (M1T) in LMAN1, which are prevalent in Iranian/Iraqi Jewish and Italian populations, may represent founder effects."
explanation: Supports the founder alleles named in this subtype.
- name: Type 2
display_name: Type 2 (MCFD2-related)
subtype_term:
preferred_term: factor 5 and Factor VIII, combined deficiency of, 2
term:
id: MONDO:0013331
label: factor 5 and Factor VIII, combined deficiency of, 2
classification: genetic
description: >-
Caused by biallelic MCFD2 variants, which include more missense alleles than
LMAN1 does; all reported MCFD2 missense variants abolish binding to LMAN1.
Clinically indistinguishable from type 1, though mean plasma factor V and
factor VIII levels are somewhat lower.
genes:
- preferred_term: MCFD2
term:
id: hgnc:18451
label: MCFD2
evidence:
- reference: PMID:12717434
reference_title: "Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here we show that inactivating mutations in MCFD2 cause F5F8D with a phenotype indistinguishable from that caused by mutations in LMAN1."
explanation: >-
Identifies MCFD2 as the second causal gene and states that the phenotype
matches LMAN1-related disease, which is why the two are lumped here.
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Disease requires two defective alleles of the same gene, LMAN1 or MCFD2.
Heterozygous carriers are usually asymptomatic. Consanguinity is common
among reported families.
evidence:
- reference: PMID:39209292
reference_title: "Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "The disease has an autosomal recessive mode of inheritance and therefore occurs with an equal incidence among males and females. Heterozygous mutation carriers usually do not have clinical manifestations."
explanation: States the recessive inheritance and the asymptomatic carrier state.
pathophysiology:
- name: Biallelic LMAN1 Loss-of-Function Variants
biological_scale: MOLECULAR
subtypes:
- Type 1
description: >-
Homozygous or compound heterozygous LMAN1 variants on chromosome 18q21. Most
are null alleles that abolish LMAN1 protein expression; the rare missense
variants (W67S, C475R) produce unstable protein or defective mannose and
MCFD2 binding.
genetic_context:
variant_origin: GERMLINE
functional_impact_category: LOSS_OF_FUNCTION
genes:
- preferred_term: LMAN1
term:
id: hgnc:6631
label: LMAN1
downstream:
- target: LMAN1-MCFD2 Cargo Receptor Complex Disruption
causal_link_type: DIRECT
evidence:
- reference: PMID:9546392
reference_title: "Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Immunofluorescence and Western analysis of immortalized lymphocytes from patients homozygous for either of the two mutations demonstrate complete lack of expression of the mutated gene in these cells."
explanation: Shows that the founder LMAN1 alleles are null, abolishing expression.
- reference: PMID:23852824
reference_title: "Combined deficiency of coagulation factors V and VIII: an update."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Only two missense mutations have been identified in LMAN1, including W67S and C475R."
explanation: Names the rare LMAN1 missense variants described in this node.
- name: Biallelic MCFD2 Loss-of-Function Variants
biological_scale: MOLECULAR
subtypes:
- Type 2
description: >-
Homozygous or compound heterozygous MCFD2 variants on chromosome 2p21,
including null alleles, a large 5' regulatory deletion, and missense or
C-terminal truncating variants that disrupt the calcium-dependent EF-hand
fold MCFD2 needs to bind LMAN1.
genetic_context:
variant_origin: GERMLINE
functional_impact_category: LOSS_OF_FUNCTION
genes:
- preferred_term: MCFD2
term:
id: hgnc:18451
label: MCFD2
downstream:
- target: LMAN1-MCFD2 Cargo Receptor Complex Disruption
causal_link_type: DIRECT
evidence:
- reference: PMID:18391077
reference_title: "Genotype-phenotype correlation in combined deficiency of factor V and factor VIII."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We show that a novel MCFD2 missense mutation identified here (D81Y) and 2 previously reported mutations (D89A and D122V) abolish MCFD2 binding to LMAN1."
explanation: Patient MCFD2 missense variants abolish complex formation with LMAN1.
- reference: PMID:17971482
reference_title: "Deletion of 3 residues from the C-terminus of MCFD2 affects binding to ERGIC-53 and causes combined factor V and factor VIII deficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Biochemical and structural analysis of the DeltaSLQ mutant demonstrated impaired binding to ERGIC-53 due to modification of the 3-dimensional structure of MCFD2."
explanation: A patient-derived C-terminal MCFD2 truncation also impairs binding to LMAN1 (ERGIC-53).
evidence:
- reference: PMID:12717434
reference_title: "Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here we show that inactivating mutations in MCFD2 cause F5F8D with a phenotype indistinguishable from that caused by mutations in LMAN1."
explanation: Establishes inactivating MCFD2 variants as the lesion in type 2.
- reference: PMID:17971482
reference_title: "Deletion of 3 residues from the C-terminus of MCFD2 affects binding to ERGIC-53 and causes combined factor V and factor VIII deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a large deletion of 8.4 kb eliminating the 5'UTR of the gene and a nonsense mutation resulting in the deletion of only 3 amino acids (DeltaSLQ) from the C-terminus of MCFD2"
explanation: Documents the large 5' regulatory deletion and the C-terminal truncation in an MCFD2 patient.
- name: LMAN1-MCFD2 Cargo Receptor Complex Disruption
biological_scale: MOLECULAR
description: >-
LMAN1 and MCFD2 form a calcium-dependent cargo receptor that cycles between
the endoplasmic reticulum and the ER-Golgi intermediate compartment. The
LMAN1 carbohydrate recognition domain holds separable binding sites for
MCFD2 and for high-mannose glycans on factor V and factor VIII, and the
MCFD2 EF-hand domains bind both LMAN1 and the cargo. Loss of either
subunit, or any missense variant that prevents the two from associating,
removes a functional receptor.
cell_types:
- preferred_term: hepatocyte, the site of factor V synthesis
term:
id: CL:0000182
label: hepatocyte
- preferred_term: endothelial cell, the site of factor VIII synthesis
term:
id: CL:0000115
label: endothelial cell
molecular_functions:
- preferred_term: cargo receptor activity
modifier: DECREASED
term:
id: GO:0038024
label: cargo receptor activity
cellular_components:
- preferred_term: ER-Golgi intermediate compartment
term:
id: GO:0005793
label: endoplasmic reticulum-Golgi intermediate compartment
genes:
- preferred_term: LMAN1
term:
id: hgnc:6631
label: LMAN1
- preferred_term: MCFD2
term:
id: hgnc:18451
label: MCFD2
downstream:
- target: Impaired ER-to-Golgi Export of Factor V and Factor VIII
causal_link_type: DIRECT
evidence:
- reference: PMID:16304051
reference_title: "Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2."
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: BACKGROUND
snippet: "LMAN1 and MCFD2 form a protein complex that functions as a cargo receptor ferrying FV and FVIII from the endoplasmic reticulum to the Golgi."
explanation: Links the receptor complex to the transport step it performs.
- target: Hepatocyte ER Retention of Alpha-1-Antitrypsin
causal_link_type: DIRECT
evidence:
- reference: PMID:23852824
reference_title: "Combined deficiency of coagulation factors V and VIII: an update."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Disrupting the LMAN1-MCFD2 receptor, complex formation is the primary molecular defect of missense mutations leading to F5F8D."
explanation: States that loss of complex formation is the shared molecular defect.
- reference: PMID:20817851
reference_title: "Molecular basis of LMAN1 in coordinating LMAN1-MCFD2 cargo receptor formation and ER-to-Golgi transport of FV/FVIII."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Thus, the CRD of LMAN1 contains distinct, separable binding sites for both its partner protein (MCFD2) and the cargo proteins (FV/FVIII)."
explanation: Supports the receptor architecture described in this node.
- reference: PMID:20007547
reference_title: "EF-hand domains of MCFD2 mediate interactions with both LMAN1 and coagulation factor V or VIII."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Our results suggest that the EF-hand domains of MCFD2 contain separate binding sites for LMAN1 and FV/FVIII that are essential for cargo receptor formation and cargo loading in the ER."
explanation: Supports the role of the MCFD2 EF-hand domains in the receptor.
- reference: PMID:20142513
reference_title: "Structural basis for the cooperative interplay between the two causative gene products of combined factor V and factor VIII deficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The interaction is independent of sugar-binding of ERGIC-53 and involves most of the missense mutation sites of MCFD2 so far reported in F5F8D."
explanation: >-
The crystal structure places most patient MCFD2 missense sites at the
LMAN1 (ERGIC-53) binding interface.
- name: Impaired ER-to-Golgi Export of Factor V and Factor VIII
biological_scale: CELLULAR
description: >-
Without the cargo receptor, newly made factor V (in hepatocytes) and factor
VIII (in endothelial cells) leave the endoplasmic reticulum
inefficiently, so less of each is secreted. Export is reduced rather than
abolished, which is why plasma levels fall to roughly 5-30% of normal
rather than to zero.
cell_types:
- preferred_term: hepatocyte
term:
id: CL:0000182
label: hepatocyte
- preferred_term: endothelial cell
term:
id: CL:0000115
label: endothelial cell
biological_processes:
- preferred_term: ER to Golgi transport of factor V and factor VIII
modifier: DECREASED
term:
id: GO:0006888
label: endoplasmic reticulum to Golgi vesicle-mediated transport
- preferred_term: secretion of factor V and factor VIII
modifier: DECREASED
term:
id: GO:0009306
label: protein secretion
genes:
- preferred_term: F5
term:
id: hgnc:3542
label: F5
- preferred_term: F8
term:
id: hgnc:3546
label: F8
downstream:
- target: Reduced Plasma Factor V and Factor VIII
causal_link_type: DIRECT
evidence:
- reference: PMID:12717434
reference_title: "Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "These findings suggest that the MCFD2-LMAN1 complex forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins."
explanation: Frames the disorder as a cargo-specific ER export defect.
- reference: PMID:21795745
reference_title: "Mice deficient in LMAN1 exhibit FV and FVIII deficiencies and liver accumulation of α1-antitrypsin."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Levels of plasma FV and FVIII, and platelet FV, are all reduced to ∼ 50% of wild-type in Lman1(-/-) mice, compared with the 5%-30% levels typically observed in human F5F8D patients."
explanation: >-
LMAN1 knockout mice reproduce the coordinate reduction, confirming that
loss of the receptor reduces export of both factors in vivo.
- name: Reduced Plasma Factor V and Factor VIII
biological_scale: ORGANISM
description: >-
Plasma factor V and factor VIII activities fall together, usually to 5-30%
of normal (typically 10-20%). Mean levels are lower in MCFD2-related than in
LMAN1-related disease. Bleeding severity correlates poorly with factor
levels, and two simultaneous deficiencies do not bleed more than a single
factor V or factor VIII deficiency of similar degree.
biological_processes:
- preferred_term: blood coagulation
modifier: DECREASED
term:
id: GO:0007596
label: blood coagulation
downstream:
- target: Reduced Platelet Factor V
causal_link_type: DIRECT
description: >-
Platelet factor V is taken up from plasma by megakaryocytes, so the
platelet pool falls with plasma factor V.
evidence:
- reference: PMID:39209292
reference_title: "Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "In humans, plasma FV is synthesized by hepatocytes and platelet FV is derived from plasma FV via endocytosis by megakaryocytes."
explanation: Platelet factor V derives from the plasma pool, which is why it falls with plasma factor V.
- target: Prolonged prothrombin time
- target: Prolonged activated partial thromboplastin time
- target: Reduced factor V activity
- target: Reduced factor VIII activity
- target: Bleeding after surgery
- target: Bleeding after trauma
- target: Prolonged bleeding after dental extraction
- target: Bleeding after circumcision
- target: Epistaxis
- target: Gingival bleeding
- target: Easy bruising
- target: Menorrhagia
- target: Postpartum hemorrhage
- target: Hemarthrosis
- target: Gastrointestinal bleeding
- target: Hematuria
- target: Muscle hematoma
- target: Intracranial hemorrhage
evidence:
- reference: PMID:23852824
reference_title: "Combined deficiency of coagulation factors V and VIII: an update."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Diagnosis is made on laboratory findings of decreased FV and FVIII levels in plasma, usually in the range of 5 to 30% of normal (typically 10–20%). No correlations of bleeding severity and the levels of FV and FVIII have been observed in F5F8D patients."
explanation: States the typical factor range and the weak level-severity correlation.
- reference: PMID:23852824
reference_title: "Combined deficiency of coagulation factors V and VIII: an update."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Recent reports also confirmed the previous observation that defects of two factors do not lead to more severe bleeding symptoms than single defect of FV or FVIII of similar degree."
explanation: Supports the statement that the double deficiency is not more severe.
- reference: PMID:18391077
reference_title: "Genotype-phenotype correlation in combined deficiency of factor V and factor VIII."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Although there is considerable overlap, the mean levels of plasma FV and FVIII in patients with MCFD2 mutations are significantly lower than the corresponding levels in patients with LMAN1 mutations."
explanation: Supports the gene-level difference in mean factor levels.
- name: Reduced Platelet Factor V
biological_scale: CELLULAR
description: >-
About a fifth of circulating factor V is stored in platelet alpha-granules
and is derived from plasma factor V by megakaryocyte endocytosis. In this
disorder the platelet pool is reduced to the same degree as plasma factor V.
cell_types:
- preferred_term: platelet
term:
id: CL:0000233
label: platelet
evidence:
- reference: PMID:18391077
reference_title: "Genotype-phenotype correlation in combined deficiency of factor V and factor VIII."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Measurement of platelet factor V (FV) levels in 7 F5F8D patients (4 with LMAN1 and 3 with MCFD2 mutations) demonstrated similar reductions to those observed for plasma FV."
explanation: Direct measurement of reduced platelet factor V in patients.
- name: Hepatocyte ER Retention of Alpha-1-Antitrypsin
biological_scale: CELLULAR
description: >-
The LMAN1-MCFD2 receptor also exports alpha-1-antitrypsin. Knockout mice
and knockout hepatoma cells accumulate it in the hepatocyte endoplasmic
reticulum and secrete less of it. No liver or lung consequence has been
reported in patients, so this node has no clinical downstream.
cell_types:
- preferred_term: hepatocyte
term:
id: CL:0000182
label: hepatocyte
cellular_components:
- preferred_term: endoplasmic reticulum
term:
id: GO:0005783
label: endoplasmic reticulum
evidence:
- reference: PMID:29735583
reference_title: "Analysis of MCFD2- and LMAN1-deficient mice demonstrates distinct functions in vivo."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Comparable accumulation of AAT was observed in hepatocyte ER of singly and doubly deficient mice, demonstrating a role for LMAN1 and MCFD2 in efficient ER exit of AAT."
explanation: Shows hepatocyte ER retention of AAT in LMAN1- and MCFD2-deficient mice.
- reference: PMID:35322856
reference_title: "LMAN1-MCFD2 complex is a cargo receptor for the ER-Golgi transport of α1-antitrypsin."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Here, we report that LMAN1 and MCFD2 knockout (KO) HepG2 and HEK293T cells display reduced AAT secretion and elevated intracellular AAT levels due to a delayed ER-to-Golgi transport of AAT."
explanation: Cell-line evidence that the receptor exports AAT.
phenotypes:
- category: Hematologic
name: Bleeding after surgery
description: >-
Excessive bleeding during and after surgery is, together with
trauma-related bleeding, the most frequently reported manifestation and is
often how the disorder comes to medical attention.
phenotype_term:
preferred_term: Prolonged bleeding after surgery
term:
id: HP:0004846
label: Prolonged bleeding after surgery
evidence:
- reference: PMID:23852824
reference_title: "Combined deficiency of coagulation factors V and VIII: an update."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Comparison of relatively large cohorts of F5F8D in India, Iran, and Israel indicates that bleeding from trauma/surgery is the most frequently reported clinical manifestation."
explanation: Identifies trauma- and surgery-related bleeding as the most common manifestation.
- category: Hematologic
name: Bleeding after trauma
description: >-
Excessive bleeding after injury; with surgical bleeding, the most frequently
reported manifestation.
phenotype_term:
preferred_term: Persistent bleeding after trauma
term:
id: HP:0001934
label: Persistent bleeding after trauma
evidence:
- reference: PMID:23852824
reference_title: "Combined deficiency of coagulation factors V and VIII: an update."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Comparison of relatively large cohorts of F5F8D in India, Iran, and Israel indicates that bleeding from trauma/surgery is the most frequently reported clinical manifestation."
explanation: Identifies trauma- and surgery-related bleeding as the most common manifestation.
- category: Hematologic
name: Prolonged bleeding after dental extraction
phenotype_term:
preferred_term: Prolonged bleeding after dental extraction
term:
id: HP:0006298
label: Prolonged bleeding after dental extraction
evidence:
- reference: PMID:39209292
reference_title: "Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "The most typical were menorrhagias (49%), epistaxis (34%), ecchymoses (19%), postoperative (17%) and posttraumatic hemorrhages (15%), bleeding after tooth extraction (11%), and ovulatory hemorrhages (4%)."
explanation: Reports bleeding after tooth extraction in women with the disorder.
- category: Hematologic
name: Bleeding after circumcision
description: Frequently reported in males where circumcision is common practice.
phenotype_term:
preferred_term: Prolonged bleeding following circumcision
term:
id: HP:0030137
label: Prolonged bleeding following circumcision
evidence:
- reference: PMID:23852824
reference_title: "Combined deficiency of coagulation factors V and VIII: an update."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "In males, bleeding due to circumcision is frequently reported in regions where it is commonly practiced."
explanation: Supports post-circumcision bleeding.
- category: Hematologic
name: Epistaxis
phenotype_term:
preferred_term: Epistaxis
term:
id: HP:0000421
label: Epistaxis
evidence:
- reference: PMID:23852824
reference_title: "Combined deficiency of coagulation factors V and VIII: an update."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Common spontaneous bleeding symptoms include epistaxis, gum bleeding, easy bruising, and menorrhagia."
explanation: Lists epistaxis among the common spontaneous bleeding symptoms.
- category: Hematologic
name: Gingival bleeding
phenotype_term:
preferred_term: Gingival bleeding
term:
id: HP:0000225
label: Gingival bleeding
evidence:
- reference: PMID:23852824
reference_title: "Combined deficiency of coagulation factors V and VIII: an update."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Common spontaneous bleeding symptoms include epistaxis, gum bleeding, easy bruising, and menorrhagia."
explanation: Lists gum bleeding among the common spontaneous bleeding symptoms.
- category: Hematologic
name: Easy bruising
phenotype_term:
preferred_term: Bruising susceptibility
term:
id: HP:0000978
label: Bruising susceptibility
evidence:
- reference: PMID:23852824
reference_title: "Combined deficiency of coagulation factors V and VIII: an update."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Common spontaneous bleeding symptoms include epistaxis, gum bleeding, easy bruising, and menorrhagia."
explanation: Lists easy bruising among the common spontaneous bleeding symptoms.
- category: Hematologic
name: Menorrhagia
description: Found in a majority of affected women in every reported series.
frequency: FREQUENT
phenotype_term:
preferred_term: Menorrhagia
term:
id: HP:0000132
label: Menorrhagia
evidence:
- reference: PMID:23852824
reference_title: "Combined deficiency of coagulation factors V and VIII: an update."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "In females, menorrhagia is found in a majority of patients in all reported studies."
explanation: Supports menorrhagia in most affected women.
- category: Hematologic
name: Postpartum hemorrhage
phenotype_term:
preferred_term: Post-partum hemorrhage
term:
id: HP:0011891
label: Post-partum hemorrhage
evidence:
- reference: PMID:39209292
reference_title: "Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "The authors describe 19 pregnancies in 18 women: there were no miscarriages, and bleeding during childbirth was registered in 32% of the patients."
explanation: Reports bleeding during childbirth in a series of pregnancies.
- category: Hematologic
name: Hemarthrosis
description: Less frequent than mucocutaneous bleeding.
phenotype_term:
preferred_term: Joint hemorrhage
term:
id: HP:0005261
label: Joint hemorrhage
evidence:
- reference: PMID:23852824
reference_title: "Combined deficiency of coagulation factors V and VIII: an update."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Less frequently reported are hemarthroses, gastrointestinal bleeding, hematuria, and intracranial bleeding."
explanation: Records hemarthrosis as a less common manifestation.
- category: Hematologic
name: Gastrointestinal bleeding
phenotype_term:
preferred_term: Gastrointestinal hemorrhage
term:
id: HP:0002239
label: Gastrointestinal hemorrhage
evidence:
- reference: PMID:23852824
reference_title: "Combined deficiency of coagulation factors V and VIII: an update."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Less frequently reported are hemarthroses, gastrointestinal bleeding, hematuria, and intracranial bleeding."
explanation: Records gastrointestinal bleeding as a less common manifestation.
- category: Hematologic
name: Hematuria
phenotype_term:
preferred_term: Hematuria
term:
id: HP:0000790
label: Hematuria
evidence:
- reference: PMID:23852824
reference_title: "Combined deficiency of coagulation factors V and VIII: an update."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Less frequently reported are hemarthroses, gastrointestinal bleeding, hematuria, and intracranial bleeding."
explanation: Records hematuria as a less common manifestation.
- category: Hematologic
name: Muscle hematoma
phenotype_term:
preferred_term: Intramuscular hematoma
term:
id: HP:0012233
label: Intramuscular hematoma
evidence:
- reference: PMID:39209292
reference_title: "Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Hemarthroses, muscle hematomas, hematuria, gastrointestinal bleeding, and hemorrhages in the central nervous system occur in rare cases."
explanation: Records muscle hematomas as a rare manifestation.
- category: Neurological
name: Intracranial hemorrhage
description: Rare, but reported.
phenotype_term:
preferred_term: Intracranial hemorrhage
term:
id: HP:0002170
label: Intracranial hemorrhage
evidence:
- reference: PMID:23852824
reference_title: "Combined deficiency of coagulation factors V and VIII: an update."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Less frequently reported are hemarthroses, gastrointestinal bleeding, hematuria, and intracranial bleeding."
explanation: Records intracranial bleeding as a less common manifestation.
- category: Laboratory
name: Prolonged prothrombin time
phenotype_term:
preferred_term: Prolonged prothrombin time
term:
id: HP:0008151
label: Prolonged prothrombin time
evidence:
- reference: PMID:39209292
reference_title: "Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "In F5F8D, according to a screening coagulogram, prolongation of activated partial thromboplastin time (aPTT) and prothrombin time (PT) is typical."
explanation: Prolonged PT is a typical screening finding.
- category: Laboratory
name: Prolonged activated partial thromboplastin time
phenotype_term:
preferred_term: Prolonged activated partial thromboplastin time
term:
id: HP:0003645
label: Prolonged partial thromboplastin time
evidence:
- reference: PMID:39209292
reference_title: "Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "In F5F8D, according to a screening coagulogram, prolongation of activated partial thromboplastin time (aPTT) and prothrombin time (PT) is typical."
explanation: Prolonged aPTT is a typical screening finding.
- category: Laboratory
name: Reduced factor V activity
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Reduced coagulation factor V activity
term:
id: HP:0003225
label: Reduced coagulation factor V activity
evidence:
- reference: PMID:39209292
reference_title: "Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Congenital combined deficiency of FV and FVIII is characterized by decreased activities of both FV and FVIII in plasma, usually to 5 to 30% of normal."
explanation: Reduced factor V activity is a defining laboratory feature.
- category: Laboratory
name: Reduced factor VIII activity
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Reduced factor VIII activity
term:
id: HP:0003125
label: Reduced factor VIII activity
evidence:
- reference: PMID:39209292
reference_title: "Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Congenital combined deficiency of FV and FVIII is characterized by decreased activities of both FV and FVIII in plasma, usually to 5 to 30% of normal."
explanation: Reduced factor VIII activity is a defining laboratory feature.
genetic:
- name: LMAN1
gene_term:
preferred_term: LMAN1
term:
id: hgnc:6631
label: LMAN1
relationship_type: CAUSATIVE
variant_origin: GERMLINE
subtype: Type 1
gene_disease_validity:
- validity_classification: DEFINITIVE
classified_by: CLINGEN
external_id: CGGV:assertion_31792b8d-aca4-4832-b7f7-1993611777d7-2019-11-27T170000.000Z
subtype: Type 1
evidence:
- reference: CGGV:assertion_31792b8d-aca4-4832-b7f7-1993611777d7-2019-11-27T170000.000Z
reference_title: "LMAN1 / factor V and factor VIII, combined deficiency of, type 1 (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "LMAN1 | HGNC:6631 | factor V and factor VIII, combined deficiency of, type 1 | MONDO:0009206 | AR | Definitive"
explanation: ClinGen's Hemostasis/Thrombosis GCEP classifies LMAN1 in type 1 disease (AR) as Definitive.
notes: >-
LMAN1 is on chromosome 18q21.32 and has 13 exons. Most pathogenic alleles are
null; an adenine mononucleotide repeat in exon 8 is a mutational hotspot.
evidence:
- reference: PMID:16304051
reference_title: "Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Combined with our previous reports, we have identified LMAN1 or MCFD2 mutations as the causes of F5F8D in 71 of 76 families."
explanation: LMAN1 and MCFD2 together explain nearly all genotyped families.
- reference: PMID:39209292
reference_title: "Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "A string of mononucleotide repeat of nine adenines from nucleotide 904 to 912 in exon 8 of LMAN1 appears to be another mutation hotspot"
explanation: Supports the exon 8 adenine-repeat hotspot named in the notes.
- name: MCFD2
gene_term:
preferred_term: MCFD2
term:
id: hgnc:18451
label: MCFD2
relationship_type: CAUSATIVE
variant_origin: GERMLINE
subtype: Type 2
gene_disease_validity:
- validity_classification: DEFINITIVE
classified_by: CLINGEN
external_id: CGGV:assertion_afa4ae2a-c40d-4f25-affe-852a67144cdd-2020-06-24T160000.000Z
subtype: Type 2
evidence:
- reference: CGGV:assertion_afa4ae2a-c40d-4f25-affe-852a67144cdd-2020-06-24T160000.000Z
reference_title: "MCFD2 / factor 5 and Factor VIII, combined deficiency of, 2 (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "MCFD2 | HGNC:18451 | factor 5 and Factor VIII, combined deficiency of, 2 | MONDO:0013331 | AR | Definitive"
explanation: ClinGen's Hemostasis/Thrombosis GCEP classifies MCFD2 in type 2 disease (AR) as Definitive.
notes: >-
MCFD2 is on chromosome 2p21 and has 4 exons. c.149+5G>A and c.407T>C are
recurrent across populations.
evidence:
- reference: PMID:12717434
reference_title: "Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here we show that inactivating mutations in MCFD2 cause F5F8D with a phenotype indistinguishable from that caused by mutations in LMAN1."
explanation: Establishes MCFD2 as a causal gene.
- reference: PMID:39209292
reference_title: "Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Other mutations, such as the c.149 + 5G > A and c.407T > C in MCFD2, are recurrent mutations found in multiple populations."
explanation: Supports the recurrent MCFD2 alleles named in the notes.
- reference: PMID:39209292
reference_title: "Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "The MCFD2 gene is situated on the short arm of chromosome 2 (2p21) and contains four exons"
explanation: Supports the MCFD2 location and exon count in the notes.
prevalence:
- population: Worldwide
measure_type: POINT_PREVALENCE
prevalence_class: BAND_1_9_PER_1000000
rate_per_100000: 0.1
rate_denominator: POPULATION
notes: >-
Estimated at about 1 in 1,000,000, higher where consanguineous marriage is
common (Middle East, Mediterranean, South Asia).
evidence:
- reference: PMID:39209292
reference_title: "Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "The prevalence of this disease in the general population is estimated to be 1:1,000,000 and is significantly higher in regions where consanguineous marriages are permitted, such as the Mideast and South Asia."
explanation: States the worldwide prevalence estimate normalised in this record.
diagnosis:
- name: Coagulation screen
description: >-
Prolonged prothrombin time and prolonged activated partial thromboplastin
time together, which correct on mixing with normal plasma, prompt
factor-specific assays.
diagnosis_term:
preferred_term: coagulation screening blood test
term:
id: NCIT:C217390
label: Diagnostic Blood Testing
evidence:
- reference: PMID:39209292
reference_title: "Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "In F5F8D, according to a screening coagulogram, prolongation of activated partial thromboplastin time (aPTT) and prothrombin time (PT) is typical."
explanation: States the screening abnormalities that prompt factor assays.
- reference: PMID:39209292
reference_title: "Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Tests involving mixing with normal plasma can correct aPTT and PT, thereby ruling out the presence of inhibitors."
explanation: States the mixing study that rules out an inhibitor.
- name: Factor V and factor VIII activity assays
description: >-
The diagnosis rests on finding factor V and factor VIII activity reduced
together, usually to 5-30% of normal, which separates this disorder from
isolated factor V deficiency and from hemophilia A.
diagnosis_term:
preferred_term: coagulation factor activity assay
term:
id: NCIT:C217390
label: Diagnostic Blood Testing
measurements:
- preferred_term: factor V activity
term:
id: LOINC:3193-0
label: Coagulation factor V activity actual/normal in Platelet poor plasma by Coagulation assay
- preferred_term: factor VIII activity
term:
id: LOINC:3209-4
label: Coagulation factor VIII activity actual/normal in Platelet poor plasma by Coagulation assay
evidence:
- reference: PMID:23852824
reference_title: "Combined deficiency of coagulation factors V and VIII: an update."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Diagnosis is made on laboratory findings of decreased FV and FVIII levels in plasma, usually in the range of 5 to 30% of normal (typically 10–20%)."
explanation: States that the diagnosis is made on combined reduction of factor V and factor VIII.
- name: LMAN1 and MCFD2 sequencing
description: >-
Confirms the diagnosis and assigns the subtype. LMAN1 is tested first
because it explains about 70% of families, then MCFD2.
diagnosis_term:
preferred_term: LMAN1 and MCFD2 genetic testing
term:
id: NCIT:C15709
label: Genetic Testing
evidence:
- reference: PMID:39209292
reference_title: "Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "The testing should start with LMAN1, because in 70% of cases, mutations are found in this gene, followed by MCFD2 if no mutations are identified in LMAN1."
explanation: States the order of molecular testing.
differential_diagnoses:
- name: Congenital factor V deficiency with type 1 von Willebrand disease
description: >-
Coinherited factor V deficiency and type 1 von Willebrand disease also lower
both factor V and factor VIII, because low von Willebrand factor shortens
factor VIII survival. Normal von Willebrand factor separates combined
factor V and factor VIII deficiency.
disease_term:
preferred_term: congenital factor V deficiency
term:
id: MONDO:0009210
label: congenital factor V deficiency
evidence:
- reference: PMID:23852824
reference_title: "Combined deficiency of coagulation factors V and VIII: an update."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "FV deficiency (parahemophilia) combined with type 1 von Willebrand disease can also present with decreases in FV and FVIII levels, due to the indirect effect of von Willebrand factor deficiency on FVIII stability."
explanation: Names this combination as a mimic of combined factor V and factor VIII deficiency.
- name: Coinherited factor V deficiency and hemophilia A
description: >-
Chance coinheritance of the two single-factor deficiencies would produce the
same laboratory picture but is extremely unlikely given how rare each is.
disease_term:
preferred_term: hemophilia A
term:
id: MONDO:0010602
label: hemophilia A
evidence:
- reference: PMID:23852824
reference_title: "Combined deficiency of coagulation factors V and VIII: an update."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Although chance coinheritance of parahemophilia and hemophilia A is a possibility, it is extremely unlikely due to the low frequency of both disorders in general population"
explanation: Records coinheritance as a theoretical but unlikely differential.
treatments:
- name: Fresh frozen plasma
description: >-
The only available source of factor V, since no factor V concentrate exists.
Used for bleeding episodes and to cover surgery, typically targeting factor V
activity of about 15%. Plasma alone does not raise factor VIII enough, so it
is combined with factor VIII concentrate or desmopressin.
therapeutic_modality: PROTEIN_REPLACEMENT
treatment_term:
preferred_term: Fresh Frozen Plasma Transfusion
term:
id: NCIT:C116475
label: Fresh Frozen Plasma Transfusion
target_mechanisms:
- target: Reduced Plasma Factor V and Factor VIII
treatment_effect: RESTORES
description: Donor plasma supplies factor V (and some factor VIII).
evidence:
- reference: PMID:19141160
reference_title: "Combined FV and FVIII deficiency."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Treatment of bleeding episodes requires a source of both FV and FVIII; replacement of FV is achieved through the use of fresh frozen plasma, and that of FVIII by desmopressin or specific FVIII concentrates, plasma-derived or recombinant FVIII products."
explanation: Fresh frozen plasma is the means of replacing factor V.
- reference: PMID:39209292
reference_title: "Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "However, there are no available FV concentrates in clinical practice."
explanation: Explains why plasma remains the only factor V source.
- reference: PMID:39209292
reference_title: "Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "In case of bleeding or planned surgery, the therapeutic goal is to achieve a FV activity of 15% based on treatments of FV deficiency63,70,71 and a FVIII activity of at least 50% of the norm."
explanation: Supports the factor V and factor VIII treatment targets.
- name: Factor VIII concentrate
description: >-
Plasma-derived or recombinant factor VIII, given with fresh frozen plasma for
significant bleeding or surgery, because plasma alone cannot restore factor
VIII to haemostatic levels.
therapeutic_modality: PROTEIN_REPLACEMENT
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: antihemophilic factor
term:
id: NCIT:C81122
label: Antihemophilic Factor Human
target_mechanisms:
- target: Reduced Plasma Factor V and Factor VIII
treatment_effect: RESTORES
description: Replaces the factor VIII half of the deficiency.
evidence:
- reference: PMID:23852824
reference_title: "Combined deficiency of coagulation factors V and VIII: an update."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "the recommended therapy includes fresh frozen plasma (FFP), which provides FV, and FVIII concentrate, which compensates for the shorter half-life of plasma FVIII."
explanation: Supports factor VIII concentrate alongside plasma.
- name: Desmopressin
description: >-
Releases stored factor VIII and von Willebrand factor from endothelial
Weibel-Palade bodies; in one reported patient it roughly doubled factor VIII
for 1-2 hours. Can replace
factor VIII concentrate for minor procedures in patients whose baseline
factor VIII is above about 15%; not suitable for long-term use because the
stores deplete.
therapeutic_modality: PEPTIDE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: desmopressin
term:
id: CHEBI:4450
label: desmopressin
target_mechanisms:
- target: Reduced Plasma Factor V and Factor VIII
treatment_effect: RESTORES
description: Transiently raises plasma factor VIII; it does not raise factor V.
evidence:
- reference: PMID:23852824
reference_title: "Combined deficiency of coagulation factors V and VIII: an update."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "In patients whose FVIII levels are at the higher end of the range (> 15% of normal), DDAVP could be used in lieu of FVIII concentrate for preventing bleeding in tooth extraction, labor, or other minor surgeries."
explanation: Supports desmopressin in place of factor VIII concentrate for minor procedures.
- reference: PMID:39209292
reference_title: "Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Desmopressin is not recommended for long-term use due to the depletion effect."
explanation: Supports the caution against long-term desmopressin use.
- reference: PMID:39209292
reference_title: "Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "The mechanism of action of this drug involves a release of the stored VWF and FVIII from WPB and consequently an increase in the plasma levels of these coagulation factors."
explanation: Supports the Weibel-Palade body release mechanism.
- reference: PMID:23852824
reference_title: "Combined deficiency of coagulation factors V and VIII: an update."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "was shown to increase the FVIII level by more than twofold over 60 to 120 minutes in a patient with F5F8D"
explanation: Supports the roughly twofold, 1-2 hour rise in factor VIII, observed in a single patient.
- name: Antifibrinolytic therapy
description: >-
Tranexamic acid or aminocaproic acid, given orally, intravenously or
topically for mucocutaneous bleeding and as an adjunct around procedures.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: tranexamic acid
term:
id: CHEBI:48669
label: tranexamic acid
- preferred_term: aminocaproic acid
term:
id: CHEBI:16586
label: 6-aminohexanoic acid
target_mechanisms:
- target: Menorrhagia
treatment_effect: MODULATES
description: Inhibits fibrinolysis so clots at mucosal bleeding sites hold.
- target: Epistaxis
treatment_effect: MODULATES
description: Inhibits fibrinolysis so clots at mucosal bleeding sites hold.
- target: Gingival bleeding
treatment_effect: MODULATES
description: Inhibits fibrinolysis so clots at mucosal bleeding sites hold.
evidence:
- reference: PMID:39209292
reference_title: "Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "The following hemostatic agents can be highlighted: fibrinolysis inhibitors (tranexamic acid and aminocaproic acid) are prescribed for oral, intravenous, and topical administration."
explanation: Supports antifibrinolytic use in this disorder.
- name: Recombinant activated factor VII
description: >-
Off-label bypass therapy reported for surgical bleeding that did not respond
to plasma and factor VIII concentrate; it avoids plasma volume overload, but
its safety in this disorder is not established.
therapeutic_modality: OTHER
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: recombinant activated factor VII (eptacog alfa)
term:
id: NCIT:C81125
label: Eptacog Alfa
target_mechanisms:
- target: Reduced Plasma Factor V and Factor VIII
treatment_effect: BYPASSES
description: >-
Activated factor VII drives thrombin generation on the platelet surface
without needing the missing factor V and factor VIII cofactors.
evidence:
- reference: PMID:23852824
reference_title: "Combined deficiency of coagulation factors V and VIII: an update."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "In a case of F5F8D with persistent abdominal hematoma following surgery that combined FFP and FVIII concentrate infusions failed to control, FVIIa was successfully used to stop the bleeding complications."
explanation: Reports successful rFVIIa use for refractory surgical bleeding.
- reference: PMID:23852824
reference_title: "Combined deficiency of coagulation factors V and VIII: an update."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "However, the safety of off-label use of FVIIa in treating F5F8D remains to be established."
explanation: Records rFVIIa as off-label with unestablished safety.
animal_models:
- name: Lman1 knockout mouse
species: Mouse
genotype: Lman1 -/- (gene trap)
publication: PMID:21795745
description: >-
Plasma factor V, factor VIII and platelet factor V fall to about 50% of
wild type, a milder reduction than in patients, with hepatocyte ER
accumulation of alpha-1-antitrypsin and strain-dependent partial perinatal
lethality.
modeled_mechanisms:
- target: Impaired ER-to-Golgi Export of Factor V and Factor VIII
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
limitations: >-
Factor levels fall to about half of normal rather than the 5-30% seen in
patients, and the strain-dependent perinatal lethality has no human
counterpart.
evidence:
- reference: PMID:21795745
reference_title: "Mice deficient in LMAN1 exhibit FV and FVIII deficiencies and liver accumulation of α1-antitrypsin."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Levels of plasma FV and FVIII, and platelet FV, are all reduced to ∼ 50% of wild-type in Lman1(-/-) mice, compared with the 5%-30% levels typically observed in human F5F8D patients."
explanation: Reports the coordinate but milder factor reduction in the knockout.
- target: Hepatocyte ER Retention of Alpha-1-Antitrypsin
relationship: RECAPITULATES
fidelity: UNKNOWN
limitations: >-
The node itself rests on mouse and cell-line data; no corresponding
finding has been reported in patients, so fidelity to human disease
cannot be judged.
evidence:
- reference: PMID:21795745
reference_title: "Mice deficient in LMAN1 exhibit FV and FVIII deficiencies and liver accumulation of α1-antitrypsin."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "However, the ER in Lman1(-/-) hepatocytes is slightly distended, with significant accumulation of α1-antitrypsin and GRP78."
explanation: Reports hepatocyte ER accumulation of AAT in the knockout.
- name: Mcfd2 knockout mouse
species: Mouse
genotype: Mcfd2 -/-
publication: PMID:29735583
description: >-
Plasma factor V and factor VIII are reduced further than in Lman1 knockout
mice, mirroring the gene-level difference in patients, with normal survival.
modeled_mechanisms:
- target: Impaired ER-to-Golgi Export of Factor V and Factor VIII
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
limitations: >-
Doubly deficient mice have the higher Lman1-null factor levels, implying
an alternative export route whose relevance to patients is unknown.
evidence:
- reference: PMID:29735583
reference_title: "Analysis of MCFD2- and LMAN1-deficient mice demonstrates distinct functions in vivo."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We now report that MCFD2-deficient mice generated by gene targeting also demonstrate reduced plasma FV and FVIII, with levels lower than those in LMAN1-deficient mice, similar to previous observations in LMAN1- and MCDF2-deficient humans."
explanation: The knockout reproduces the reduced factor levels and the gene-level difference.
notes: >-
The two genetic types (MONDO:0009206, LMAN1; MONDO:0013331, MCFD2) are lumped
as has_subtypes because the genes encode the two subunits of one cargo
receptor and the phenotype is indistinguishable. No mechanism module in
kb/modules covers cargo-receptor-dependent ER export, so no conforms_to is
declared. Isolated factor V deficiency is curated separately as
Congenital_Factor_V_Deficiency. No GeneReviews chapter covers this disorder
(Bookshelf index snapshot 2026-09-10), so the phenotype baseline rests on the
2013 and 2025 reviews cited here.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Create: Combined Factor V and Factor VIII Deficiency · 2026-10-31T20:11:31Z · View source
New entry for combined deficiency of factor V and factor VIII (MONDO:0018175), lumping type 1 (LMAN1, MONDO:0009206) and type 2 (MCFD2, MONDO:0013331) as has_subtypes because the two genes encode the subunits of one ER-to-Golgi cargo receptor and PMID:12717434 reports an indistinguishable phenotype. Both stubs retired. Causal chain: biallelic LMAN1 or MCFD2 loss -> LMAN1-MCFD2 complex disruption -> impaired ER export of FV/FVIII -> reduced plasma FV and FVIII (and platelet FV) -> bleeding and laboratory phenotypes; a model-only alpha-1-antitrypsin ER retention branch is recorded without clinical downstream. Evidence was gathered from 14 PubMed records fetched directly plus two ClinGen gene-validity records (both Definitive). Deep research: falcon was requested but had no API key; run with --fallback, it was produced by openscientist (research/Combined_Factor_V_And_Factor_VIII_Deficiency-deep-research-openscientist.md). Its 39 references all resolved; its 3 unmatched quotes are elided versions of real abstract sentences. It was used as a cross-check and agreed with the entry; its suggestion of HP:0005261 for trauma bleeding was not taken because that term is Joint hemorrhage. No GeneReviews chapter exists (just check-genereviews, NO_CHAPTER). A fresh-context self-review led to: generic endothelial cell (CL:0000115) instead of an unsourced hepatic-sinusoid binding, the platelet FV edge moved to the plasma node, IN_VITRO/BACKGROUND grading on two mechanistic quotes, desmopressin as PEPTIDE, rFVIIa as OTHER, inferred PT/aPTT frequencies removed, and uncited prose facts given evidence. Validated with just validate, validate-terms, count-verified-snippets (64/64), check-entity-refs, check-causal-targets, check-snippet-grading and the other offline gates.
F5F8D is a rare autosomal-recessive coagulopathy characterized by the simultaneous, coordinate reduction of two clotting factors — FV and FVIII — that are otherwise genetically and structurally normal. The defect lies in a shared intracellular transport receptor, making F5F8D a paradigm of a "secretory-pathway cargo-receptor disease" rather than a classic single-factor deficiency.
Key identifiers:
| Resource | Identifier |
|---|---|
| MONDO | MONDO:0018175 |
| OMIM | 227300 (F5F8D1, LMAN1); 613625 (F5F8D2, MCFD2) |
| Orphanet | ORPHA:35909 |
| ICD-10 | D68.2 (hereditary deficiency of other clotting factors) |
| ICD-11 | 3B12 (hereditary deficiency of other coagulation factors) |
| MeSH | Factor V deficiency / Factor VIII deficiency (combined) |
| Genes (HGNC) | LMAN1 (HGNC:6631; OMIM 601567); MCFD2 (HGNC:18451; OMIM 607788) |
Synonyms: F5F8D; FV and FVIII combined deficiency; combined deficiency of factor V and factor VIII; familial multiple coagulation factor deficiency; DF5F8.
Source of information: The knowledge base entry is derived from aggregated disease-level resources (OMIM, Orphanet, review literature) combined with individual-patient case reports and small case series (e.g., Saudi, Turkish, Tunisian, Iranian, Pakistani, Indian cohorts). There is no large EHR-derived dataset; because of rarity, the evidence base is dominated by case reports, founder-population series, and molecular/structural studies.
Primary cause — genetic. F5F8D is caused by biallelic (homozygous or compound heterozygous) loss-of-function mutations in LMAN1 or MCFD2. Positional cloning first mapped the locus to chromosome 18q21 and identified ERGIC-53/LMAN1 as the causal gene, with two mutations "accounting for all affected individuals in nine families studied" (PMID: 9546392). A second gene, MCFD2 on 2p21, accounts for LMAN1-negative families.
Genetic risk factors: The only established risk factor is inheritance of two pathogenic LMAN1 or MCFD2 alleles. Consanguinity sharply increases risk in endogamous populations. Founder alleles (see §9) elevate carrier frequency regionally.
Environmental risk factors: None established as causal. Because the phenotype is provoked, environmental/situational triggers of bleeding (surgery, trauma, dental procedures, childbirth, antiplatelet/anticoagulant drugs) convert a latent defect into a clinical event, but they do not cause the disease.
Protective factors: No genetic or environmental protective modifiers are established. Mechanistically, residual LMAN1 expression acts in a dose-dependent protective manner — hypomorphic alleles retaining partial function predict milder phenotypes (mouse data, §6).
Gene–environment interactions: Not formally characterized. The practical interaction is between the genetic secretion defect and hemostatic challenges (surgery, parturition), which determine when bleeding manifests.
F5F8D produces a mild-to-moderate bleeding diathesis. Phenotypes are both laboratory abnormalities (the defining concordant FV/FVIII reduction with dual PT/aPTT prolongation) and clinical bleeding signs/symptoms.
| Phenotype | Type | HPO term | Frequency / characteristics |
|---|---|---|---|
| Prolonged PT and aPTT | Lab abnormality | HP:0008151 (prolonged PT), HP:0003645 (prolonged aPTT) | Universal; both correct on mixing |
| Reduced factor V activity | Lab abnormality | HP:0003225 (reduced factor V activity) | ~5–20% in most patients |
| Reduced factor VIII activity | Lab abnormality | HP:0003125 (reduced factor VIII activity) | ~5–20%, concordant with FV |
| Epistaxis | Sign | HP:0000421 | Common |
| Gingival/oral bleeding | Sign | HP:0000225 | Common |
| Easy bruising / ecchymoses | Sign | HP:0000978 (bruising susceptibility) | Common |
| Menorrhagia | Sign | HP:0000132 | Common in affected women |
| Prolonged bleeding after surgery/procedure | Sign | HP:0004846 (post-surgical bleeding) | Characteristic; circumcision, dental extraction |
| Postpartum hemorrhage | Sign | HP:0011891 | Risk during delivery |
| Prolonged bleeding after trauma | Sign | HP:0005261 (abnormal bleeding) | Characteristic |
Onset: Congenital (defect present from birth), but recognition is frequently delayed to childhood or adulthood because symptoms are mild; many cases surface at the first hemostatic challenge or incidentally. Severity: mild-to-moderate, variable. Progression: stable, non-progressive, lifelong. Frequency among affected individuals: mucocutaneous bleeding predominates; hemarthrosis and life-threatening CNS/GI bleeds are uncommon.
Characteristic factor levels and severity are summarized in the literature: F5F8D "is characterized by concomitantly low levels (usually between 5% and 20%) of both FV and FVIII, and is associated with a mild to moderate bleeding tendency" (PMID: 19141160). A pediatric case documented gum bleeding leading to diagnosis (PMID: 38912355), and multiple reports describe incidental detection in asymptomatic individuals on preoperative screening (PMID: 38659545; PMID: 41040772).
Quality-of-life impact: Generally modest given the mild phenotype, but women bear a disproportionate burden through menorrhagia and reproductive-tract bleeding, which can affect quality of life and employment (rare-bleeding-disorder cohort, PMID: 39958127). Bleeding severity can be quantified with standardized tools (ISTH-BAT; EN-RBD bleeding score), with bleeding score inversely correlated with factor activity (PMID: 27855295).
Causal genes:
| Gene | Locus | Protein | OMIM (disease) | Share of families |
|---|---|---|---|---|
| LMAN1 (ERGIC-53) | 18q21.3-q22 | Hexameric type-1 transmembrane mannose-specific lectin | 227300 | ~70% |
| MCFD2 | 2p21 | Soluble EF-hand protein | 613625 | ~15–30% |
Pathogenic variants: - LMAN1 alleles are overwhelmingly null — splice-site, frameshift insertions/deletions, nonsense, and start-codon loss (PMID: 10090934). Reported examples include a nonsense C→T transition in exon 9 and a frameshift deletion in a Turkish family (PMID: 20460353); a homozygous c.604C>T in a Saudi child (PMID: 38659545); and a homozygous c.822G>A in Saudi siblings (PMID: 36116005). - MCFD2 harbors both null and missense variants; most reported missense substitutions cluster at the LMAN1-binding interface (see §6), which explains their pathogenicity (PMID: 20142513). - Structural variants matter: a heterozygous large deletion in MCFD2 can mimic a homozygous substitution and requires dosage analysis to resolve (PMID: 38764219).
Variant classification: Reported disease alleles are predominantly pathogenic/likely pathogenic under ACMG/AMP criteria (null variants = PVS1-supported; recurrent founder alleles with segregation).
Allele frequency: Pathogenic alleles are extremely rare in gnomAD generally, but founder alleles reach appreciable carrier frequencies regionally (e.g., ~0.011 for the Djerba Tunisian LMAN1 intron-9 allele; §9).
Origin: Germline, biallelic. No somatic contribution.
Functional consequence: Loss of function of the cargo receptor → failure of efficient ER-to-Golgi export of FV and FVIII. The defect is in transport, not synthesis.
Modifier genes: The two causal genes modify each other's phenotype — MCFD2 mutations generally yield lower FV/FVIII than LMAN1 mutations: "Though clinically indistinguishable, MCFD2 mutations generally exhibit lower levels of FV and FVIII than LMAN1 mutations" (PMID: 19183188). Residual LMAN1 dose is itself a quantitative modifier (§6). No external modifier loci are established.
Epigenetic information / chromosomal abnormalities: None described as relevant to F5F8D.
F5F8D is a purely monogenic disorder with no environmental, lifestyle, or infectious etiology. No toxins, radiation, occupational exposures, dietary factors, or pathogens cause or trigger the disease. Environmental factors only matter as bleeding precipitants (surgery, trauma, parturition) and through drugs that impair hemostasis (antiplatelets, anticoagulants, NSAIDs), which should be used cautiously. Infectious agents: not applicable.
(Branch: whether the lesion is in LMAN1 or MCFD2 converges on the same complex failure; MCFD2 defects tend to lower factor levels more. Inferred step: the exact quantitative link between residual LMAN1 and human phenotype severity is extrapolated from mouse dose-response data.)
The cargo-receptor complex. LMAN1 (ERGIC-53) is a hexameric type-1 transmembrane mannose-specific lectin that cycles between the ER and the ER-Golgi intermediate compartment (ERGIC). Its luminal carbohydrate-recognition domain (CRD) contains separable binding sites: one for its partner MCFD2 (on the N-terminal β-sheet) and one for mannose/cargo. "The CRD of LMAN1 contains distinct, separable binding sites for both its partner protein (MCFD2) and the cargo proteins (FV/FVIII)," and LMAN1 oligomerization is necessary for receptor function (PMID: 20817851). Structural work pinpointed His178 and Gly251/252 as critical cargo-binding residues (PMID: 23709226).
MCFD2 is the FV/FVIII-specific adaptor. MCFD2 is a soluble EF-hand (calcium-binding) protein. Crystallography shows a 1:1 ERGIC-53-CRD : MCFD2 complex, and "the interaction is independent of sugar-binding of ERGIC-53 and involves most of the missense mutation sites of MCFD2 so far reported in F5F8D" (PMID: 20142513). Critically, MCFD2 is not required for transport of the receptor's other cargoes: "ERGIC-53 can bind cargo glycoproteins in an MCFD2-independent fashion and … MCFD2 is a recruitment factor for blood coagulation factors V and VIII" (PMID: 17010120). This is why F5F8D patients lack lysosomal or other cargo phenotypes — only the FV/FVIII arm is affected. MCFD2 binds a 10-amino-acid segment of the FVIII B-domain (PMID: 32170195).
Division of labor. Cell-line studies indicate that MCFD2 performs cargo binding/transport while LMAN1 acts as a shuttle carrier of MCFD2: overexpression of MCFD2 alone rescues FV/FVIII secretion in LMAN1-deficient cells, and N-glycan binding by LMAN1 is not strictly essential for transport (PMID: 36490287).
pH/Ca²⁺-triggered cargo cycle. Cargo capture in the ER is Ca²⁺-dependent at neutral pH; a conserved CRD histidine acts as a pH/Ca²⁺ sensor so that mild acidification and lower Ca²⁺ in the ERGIC trigger glycoprotein release: "Acidification of cells inhibited the association of ERGIC-53 with the known cargo … and dissociation of this glycoprotein in the ERGIC was impaired by organelle neutralization" (PMID: 14718532).
Broader cargo repertoire. The LMAN1–MCFD2 receptor also exports cathepsin C and cathepsin Z (PMID: 15849265; PMID: 17010120), alpha-1-antitrypsin (PMID: 18283111), and Mac-2BP/LGALS3BP (PMID: 23550150). Because MCFD2 is dedicated to FV/FVIII, humans with MCFD2 mutations lose only FV/FVIII transport; the other cargoes are handled MCFD2-independently.
Cell types and tissues. FVIII is synthesized primarily by endothelial cells, not hepatocytes — conditional-knockout mouse studies "demonstrate that endothelial cells are the primary biosynthetic source of murine FVIII and that hepatocytes make no significant contribution to the plasma FVIII pool" (PMID: 24719406). FV is produced by hepatocytes and megakaryocytes (platelet FV).
LMAN1 or MCFD2 biallelic null mutation
│ (loss of function)
▼
No functional LMAN1–MCFD2 cargo receptor in ER
│
▼
FV & FVIII not captured → not loaded into COPII vesicles
│ (ER→Golgi export fails; Ca2+/pH-gated cycle broken)
▼
↓ Secretion of FV (hepatocytes/megakaryocytes) & FVIII (endothelium)
│
▼
Plasma FV ≈ FVIII ≈ 5–20% of normal
┌────────────┴────────────┐
▼ ▼
↓ Prothrombinase (FVa) ↓ Tenase (FVIIIa)
│ │
▼ ▼
Prolonged PT Prolonged aPTT
└────────────┬────────────┘
▼
Mild–moderate mucocutaneous / provoked bleeding
Suggested GO / CL terms: GO:0006888 (ER-to-Golgi vesicle-mediated transport); GO:0030134 (COPII-coated ER-to-Golgi transport vesicle); GO:0005537 (mannose binding); GO:0007596 (blood coagulation); GO:0005509 (calcium ion binding). CL:0000182 (hepatocyte); CL:0000115 (endothelial cell); CL:0000556 (megakaryocyte). UBERON:0002107 (liver); UBERON:0001981 (blood vessel). CHEBI:29108 (calcium(2+)); CHEBI:4208 (D-mannose).
UBERON terms: UBERON:0002107 (liver); UBERON:0001981 (blood vessel/vasculature); UBERON:0000178 (blood); UBERON:0000344 (mucosa); UBERON:0002097 (skin of body).
Epidemiology: Estimated prevalence ~1 in 1,000,000 in the general population; F5F8D constitutes roughly 3% of rare coagulation disorders. "The prevalence of this disease in the general population is estimated to be 1:1,000,000 and is significantly higher in regions where consanguineous marriages are permitted, such as the Mideast and South Asia" (PMID: 39209292).
Inheritance: Autosomal recessive. Heterozygotes are asymptomatic. Equal sex incidence (though women are more often symptomatic due to menstrual/reproductive bleeding).
Penetrance/expressivity: High penetrance of the biochemical phenotype (low FV/FVIII) in biallelic carriers; variable expressivity of bleeding severity. No genetic anticipation (not a repeat-expansion disorder). Germline mosaicism not a recognized feature.
Founder effects and consanguinity: Strong. Documented founder alleles include an LMAN1 intron-9 donor-splice mutation prevalent among Tunisian Djerba Jews (carrier allele frequency ~0.011) and an exon-1 G insertion among Middle Eastern/Iraqi Jews: "a thymidine (T) to cytosine (C) transition in intron 9 at a donor splice site among Tunisian families. For each mutation, haplotype analysis revealed a founder effect" (PMID: 15166951). High prevalence is reported in consanguineous cohorts in Iran (PMID: 27894217; PMID: 23632381) and Pakistan (PMID: 28388959).
Population demographics: Enriched in Mediterranean, Middle-Eastern, and South-Asian populations where endogamy is common. Geographic distribution of variants tracks founder haplotypes. Sex ratio ~1:1.
Diagnostic algorithm: 1. Screening coagulation tests: simultaneously prolonged PT and aPTT, both fully corrected by 1:1 mixing (indicates factor deficiency, not an inhibitor). 2. Specific factor assays: concordant reduction of FV:C and FVIII:C to ~5–20%, with normal levels of other coagulation factors and normal von Willebrand factor antigen/activity. This pattern distinguishes F5F8D from isolated hemophilia A (normal PT), isolated FV deficiency (normal FVIII), and type 2N/3 von Willebrand disease. Illustrative case: "a combined deficiency of factors V and VIII at 12.4% … and 9.1%, respectively, whereas other coagulation factor levels remained within the normal range, including the antigenic activity of von Willebrand" (PMID: 40296097). 3. Molecular confirmation: targeted LMAN1/MCFD2 sequencing, a rare-bleeding-disorder gene panel, or whole-exome sequencing (which identified a novel homozygous LMAN1 c.604C>T, PMID: 38659545). Dosage/copy-number analysis is needed because a heterozygous large MCFD2 deletion can masquerade as a homozygous substitution (PMID: 38764219).
Biomarkers: FV:C and FVIII:C are the defining biomarkers; reduced platelet FV supports the diagnosis. vWF is normal (key discriminator).
Clinical/bleeding assessment: Standardized bleeding-assessment tools (ISTH-BAT; EN-RBD bleeding score) quantify symptom burden, with bleeding score inversely correlated with factor activity (PMID: 27855295).
Differential diagnosis: hemophilia A (isolated FVIII, normal PT); isolated FV deficiency (normal FVIII); combined vitamin-K-dependent factor deficiency; von Willebrand disease types 2N/3; rare digenic coincidental F5 + F8 mutations (PMID: 41040772).
Screening: Carrier and cascade testing within affected consanguineous families; no population newborn screening exists given rarity and mild phenotype. Imaging/electrophysiology/biopsy are not diagnostic for this disorder.
LOINC concepts: PT (5902-2), aPTT (3173-2/14979-9), Factor V activity (3192-2), Factor VIII activity (3209-4), von Willebrand factor antigen (5088-1).
Prognosis is excellent with normal life expectancy. F5F8D is a milder rare bleeding disorder than FXIII, FX, or FVII deficiencies: "patients with factor XIII, factor X and factor VII more commonly presented severe life-threatening bleeding, while patients with combined factor V and factor VIII presented a milder phenotype" (PMID: 27894217).
Core principle: replace BOTH factors. Because no clotting-factor gene is defective but two factor proteins are low, therapy must raise both FV and FVIII. "Treatment of bleeding episodes requires a source of both FV and FVIII; replacement of FV is achieved through the use of fresh frozen plasma, and that of FVIII by desmopressin or specific FVIII concentrates, plasma-derived or recombinant FVIII products" (PMID: 19141160).
| Modality | Purpose | Notes / NCIT |
|---|---|---|
| Fresh frozen plasma (or SD/virus-inactivated plasma) | Sole practical FV source | No FV concentrate exists: "only prothrombin and FV deficiencies still remain without a specific product" (PMID: 27913544). NCIT:C681 (plasma) |
| FVIII concentrate (plasma-derived or recombinant) | Raise FVIII | NCIT:C1947 (Coagulation Factor VIII) |
| Desmopressin (DDAVP) | Transiently raise FVIII for minor bleeds/procedures | NCIT:C29066 (Desmopressin) |
| Antifibrinolytics (tranexamic acid) | Mucosal/minor bleeds, menorrhagia, dental work | NCIT:C47720 (Tranexamic Acid) |
| Local hemostatic measures | Epistaxis, dental | Adjunctive |
Management is tailored to the setting — surgery, spontaneous bleeding, pregnancy/delivery, and the neonate — per UKHCDO guidelines (PMID: 15357789). Broader reviews confirm the dual-replacement strategy and the absence of a dedicated FV product (PMID: 19141160; PMID: 27913544).
Pregnancy/peripartum: A documented F5F8D pregnancy (FV 29%, FVIII 21%; aPTT 78s) was managed with a protocol-based multidisciplinary plan: 2000 IU FVIII at onset of labor raising FVIII to 36% and FV to 38%, then 12-hourly tapering doses keeping FVIII >50% for 5 days — delivery with no bleeding: "An infusion of 2000IU of FVIII was implemented over 5 minutes; soon thereafter, PT was 17 seconds, aPTT patient/control ratio had decreased to 1.9 and FV and FVIII reached 38% and 36% respectively" (PMID: 24161289). Because the defect persists through pregnancy, planned cover prevents postpartum hemorrhage (PMID: 19298378).
Pharmacogenomics / gene / cell / targeted therapies: None approved or required; F5F8D is managed with replacement and antifibrinolytics. (Of note, the LMAN1–MCFD2 axis is being explored in the opposite direction as an anticoagulant target — GalNAc-siRNA knockdown of LMAN1/MCFD2 lowers FVIII and prolongs aPTT in mice, PMID: 39222205 — which conceptually validates the pathway but is not a treatment for the deficiency.)
Treatment strategy: On-demand replacement for bleeds/procedures; prophylaxis is rarely needed given the mild phenotype; antifibrinolytics first-line for menorrhagia and mucosal bleeding.
Mouse is the principal model.
| Model | Phenotype | Key insight | PMID |
|---|---|---|---|
| Lman1⁻/⁻ knockout | Plasma/platelet FV and FVIII ~50% (milder than human ~5–30%); distended hepatocyte ER with accumulation of α1-antitrypsin and GRP78; partially penetrant, strain-dependent perinatal lethality | Confirms LMAN1 as cargo receptor; implicates additional unidentified cargoes; identifies A1AT as a co-cargo | PMID: 21795745 |
| Lman1^cgt/cgt hypomorph (~6–8% mRNA) | Intermediate FV/FVIII ~70% | Dose-dependent effect of residual LMAN1: "these results show a dose-dependent effect of residual LMAN1 on the secretion of its cargo proteins … human subjects with hypomorphic LMAN1 mutations might present with mild bleeding phenotypes" | PMID: 33196840 |
| Lman1 conditional (tissue-specific) KO | Endothelial, not hepatocyte, FVIII loss | "Endothelial cells are the primary biosynthetic source of murine FVIII … hepatocytes make no significant contribution to the plasma FVIII pool" | PMID: 24719406 |
| Mcfd2⁻/⁻ vs Lman1⁻/⁻ | Distinct in vivo functions | Dissects separable roles of the two subunits | PMID: 29735583 |
Cellular / in-vitro models: HEK293T, HepG2, and HCT116 LMAN1- and MCFD2-deficient lines reveal cell-type-dependent secretion requirements and allow functional pathogenicity assays for candidate variants; MCFD2 overexpression rescues FV/FVIII secretion in LMAN1-null cells, establishing MCFD2 as the cargo-engaging subunit and LMAN1 as its shuttle (PMID: 36490287). Structural models (crystallography, NMR) defined the CRD–MCFD2 interface and the FVIII B-domain binding peptide (PMID: 20142513; PMID: 23709226; PMID: 32170195).
Model limitations: Mouse knockouts underrecapitulate human factor-level reduction (≈50% vs ≈5–20%), likely due to species redundancy; partially penetrant lethality and additional cargoes complicate interpretation. Cell lines capture transport biology but not whole-organism bleeding phenotypes.
F5F8D is best understood as a trafficking disease masquerading as a coagulation-factor deficiency. The single unifying lesion — loss of the LMAN1–MCFD2 cargo receptor — explains every clinical observation: (1) why two unrelated factors fall together (they share a transporter); (2) why the factors are structurally normal (synthesis is intact, export is not); (3) why levels sit near 5–20% rather than zero (bulk-flow and residual secretion provide a floor, and residual-LMAN1 dose modulates it); (4) why the phenotype is mild and non-progressive (partial, stable secretion defect); and (5) why MCFD2 defects tend to be slightly more severe (MCFD2 is the dedicated FV/FVIII adaptor, so its loss more directly cripples their recruitment while sparing other cargoes). The MCFD2-is-a-recruitment-factor finding is the linchpin that reconciles the broad cargo repertoire of LMAN1 (cathepsins, α1-antitrypsin, Mac-2BP) with the narrow, FV/FVIII-only clinical picture of F5F8D.
| PMID | Contribution | Finding |
|---|---|---|
| 9546392 | Identified ERGIC-53/LMAN1 as first causal gene | F001 |
| 10090934 | LMAN1 mutation spectrum uniformly null (35 families) | F001 |
| 20817851 | Separable MCFD2 vs cargo binding sites; oligomerization required | F002 |
| 23709226 | His178, Gly251/252 cargo-binding residues | F002 |
| 20142513 | 1:1 CRD–MCFD2 crystal structure; missense sites at interface | F002, F004 |
| 17010120 | MCFD2 = FV/FVIII recruitment factor; MCFD2-independent cargo binding | F009 |
| 14718532 | pH/Ca²⁺-triggered cargo release in ERGIC | F009 |
| 36490287 | MCFD2 carries cargo; LMAN1 shuttles MCFD2 | F002 |
| 19183188 | MCFD2 mutations give lower FV/FVIII than LMAN1 | F003 |
| 19141160 | Factor levels 5–20%, mild-moderate bleeding; dual replacement | F003, F005 |
| 39209292 | Prevalence 1:1,000,000; consanguinity enrichment | F004 |
| 15166951 | Founder mutations in Jewish populations | F004 |
| 27913544 | No specific FV concentrate exists | F005 |
| 33196840 | Dose-dependent residual LMAN1 effect (mouse) | F006 |
| 21795745 | Lman1⁻/⁻ ~50% factors; A1AT accumulation | F006 |
| 24719406 | Endothelium is FVIII source | F006 |
| 29735583 | Distinct MCFD2 vs LMAN1 in-vivo roles | F006 |
| 24161289 | Peripartum FVIII protocol | F007 |
| 19298378 | Defect persists in pregnancy; PPH risk | F007 |
| 40296097 | Defining lab pattern with normal vWF | F008 |
| 38764219 | Large deletion mimics homozygous substitution | F008 |
| 27855295 | EN-RBD bleeding score; inverse correlation with factor activity | F008 |
| 27894217 | F5F8D milder than FXIII/FX/FVII | F010 |
| 38912355 | Pediatric gum-bleeding presentation | F010 |
| 39222205 | LMAN1/MCFD2 knockdown as anticoagulant — pathway validation | Context |
All findings are supported by multiple independent lines of evidence (human clinical case series, structural/biochemical studies, and mouse and cell-line genetics). No contradictory findings were identified; the main tension is the quantitative mismatch between mouse (~50%) and human (~5–20%) factor levels, attributed to species redundancy.
Report compiled from a 5-iteration autonomous investigation: 10 confirmed findings across 45 reviewed papers. Evidence spans human clinical case series, structural/biochemical studies, and mouse and cell-line genetics.
Checked with linkml-reference-validator 0.4.0.
| Outcome | Count |
|---|---|
| References checked | 39 |
| Resolved | 39 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 15 |
| Quoted claims found in source | 12 |
| Quoted claims not found in source | 3 |
| References weighed for topical relevance | 39 |
| On topic | 20 |
| Off topic | 0 |
Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:
Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.
PMID:17010120 (abstract only): "ERGIC-53 can bind cargo glycoproteins in an MCFD2-independent fashion and … MCFD2 is a recruitment factor for blood coagulation factors V and VIII"PMID:14718532 (abstract only): "Acidification of cells inhibited the association of ERGIC-53 with the known cargo … and dissociation of this glycoprotein in the ERGIC was impaired by organelle neutralization"PMID:40296097 (abstract only): "a combined deficiency of factors V and VIII at 12.4% … and 9.1%, respectively, whereas other coagulation factor levels remained within the normal range, including the antigenic activity of von Willebrand"Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 36 |
| Resolved | 32 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 1 |
| Unverifiable | 3 |
| Terms whose name was checked | 29 |
| Terms named correctly | 10 |
| Terms named as a different term | 10 |
| Terms whose name is worth a second look | 9 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:0018175 (2 mentions) - the report calls it "MONDO"; MONDO calls it combined deficiency of factor V and factor VIIIHP:0000421 (1 mention) - the report calls it "Sign"; HP calls it EpistaxisHP:0000225 (1 mention) - the report calls it "Sign"; HP calls it Gingival bleedingHP:0000132 (1 mention) - the report calls it "Sign"; HP calls it MenorrhagiaHP:0011891 (1 mention) - the report calls it "Sign"; HP calls it Post-partum hemorrhageHP:0005261 (1 mention) - the report calls it "abnormal bleeding"; HP calls it Joint hemorrhageNCIT:C681 (1 mention) - the report calls it "plasma"; NCIT calls it Opiate AntagonistNCIT:C1947 (1 mention) - the report calls it "Coagulation Factor VIII"; NCIT calls it Organic OxoacidsNCIT:C29066 (1 mention) - the report calls it "Desmopressin"; NCIT calls it Gamma Interferon-SCHNCIT:C47720 (1 mention) - the report calls it "Tranexamic Acid"; NCIT calls it Sodium AcetateThese terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:
NCIT:C29066 (Gamma Interferon-SCH) (1 mention)The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
HP:0003225 (1 mention) - the report calls it "reduced factor V activity"; HP calls it Reduced coagulation factor V activity, and lists "Reduced factor V activity" among its other namesHP:0004846 (1 mention) - the report calls it "post-surgical bleeding"; HP calls it Prolonged bleeding after surgery, and lists "Protracted bleeding after surgery" among its other namesGO:0006888 (1 mention) - the report calls it "ER-to-Golgi vesicle-mediated transport"; GO calls it endoplasmic reticulum to Golgi vesicle-mediated transport, and lists "ER to Golgi vesicle-mediated transport" among its other namesGO:0030134 (2 mentions) - the report calls it "COPII-coated ER-to-Golgi transport vesicle", "COPII vesicles"; GO calls it COPII-coated ER to Golgi transport vesicle, and lists "COPII vesicle" among its other namesGO:0005537 (1 mention) - the report calls it "mannose binding"; GO calls it D-mannose binding, and lists "mannose binding" among its other namesCL:0000182 (2 mentions) - the report calls it "hepatocyte", "Tissue/cell level: hepatocytes"; CL calls it hepatocyte**UBERON:0001981 (2 mentions) - the report calls it "blood vessel", "blood vessel/vasculature"; UBERON calls it blood vesselCHEBI:4208 (1 mention) - the report calls it "D-mannose"; CHEBI calls it D-mannopyranose, and lists "D-Mannose" among its other namesGO:0005793 (1 mention) - the report calls it "ER-Golgi intermediate compartment/ERGIC"; GO calls it endoplasmic reticulum-Golgi intermediate compartment, and lists "ER-Golgi intermediate compartment" among its other namesThe report gives these identifiers more than one name of its own:
GO:0030134 - called "COPII-coated ER-to-Golgi transport vesicle", "COPII vesicles"CL:0000182 - called "hepatocyte", "Tissue/cell level:** hepatocytes"UBERON:0001981 - called "blood vessel", "blood vessel/vasculature"Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.