Table 3. [Inherited Bleeding Disorders with Low Factor VIII Clotting Activity]. - GeneReviews®

Gene(s)	Disorder	MOI	Clinical Features	Laboratory Findings / Comment
VWF	Type 1 von Willebrand disease (VWD)	AD	Mucous membrane bleeding incl epistaxis, bleeding w/dental extractions, heavy menstrual & postpartum bleeding, & spontaneous bruises. Also may have trauma & procedure-related bleeding.	Partial quantitative deficiency of VWF (low VWF antigen, low factor VIII clotting activity, & low VWF activity). VWF levels can differentiate mild hemophilia A from VWD (persons w/hemophilia A have a normal VWF antigen level).
Type 2A & 2B VWD	AD	Type 2A: Bleeding as in Type 1 VWD or may be more severe. Type 2B: Bleeding as in Type 1 VWD or may be more severe. Also may have thrombocytopenia.	Qualitative deficiency of VWF w/↓ of high molecular-weight multimers (more loss in type 2A). Measures of VWF platelet or collagen binding activity are ↓, while VWF antigen & factor VIII clotting activity may be low-normal to mildly ↓.
Type 2M VWD	AD	Bleeding as in type 2A VWD	Qualitative deficiency of VWF w/similar ↓ in function as seen in type 2A; but assoc w/normal multimer pattern.
Type 2N VWD	AR	Clinically indistinguishable from mild/moderate hemophilia A	VWF platelet binding is completely normal. Type 2N VWD is biochemically indistinguishable from mild hemophilia A. Mild hemophilia A can be distinguished from type 2N VWD by molecular genetic testing or measuring binding of factor VIII to VWF using ELISA or column chromatography.
Type 3 VWD	AR	Frequent episodes of mucous membrane bleeding; joint & muscle bleeding similar to that seen in hemophilia A but usually w/more mucosal bleeding symptoms.	Complete or near-complete quantitative deficiency of VWF. VWF level is often <1% & factor VIII clotting activity is most commonly 2%-8%.
LMAN1 MCFD2	Combined factor V & factor VIII deficiency (OMIM 613625 & 227300)	AR	Very rare disorder w/mucocutaneous & bleeding w/trauma & surgery	Low factor VIII & factor V clotting activity levels (usually 10%-20%); prolonged PT & aPTT (Mild hemophilia A does not result in prolonged PT.)

Gene(s)

Disorder

MOI

Clinical Features

Laboratory Findings / Comment

VWF

Mucous membrane bleeding incl epistaxis, bleeding w/dental extractions, heavy menstrual & postpartum bleeding, & spontaneous bruises. Also may have trauma & procedure-related bleeding.

Partial quantitative deficiency of VWF (low VWF antigen, low factor VIII clotting activity, & low VWF activity). VWF levels can differentiate mild hemophilia A from VWD (persons w/hemophilia A have a normal VWF antigen level).

Type 2A & 2B VWD

Type 2A: Bleeding as in Type 1 VWD or may be more severe.
Type 2B: Bleeding as in Type 1 VWD or may be more severe. Also may have thrombocytopenia.

Qualitative deficiency of VWF w/↓ of high molecular-weight multimers (more loss in type 2A). Measures of VWF platelet or collagen binding activity are ↓, while VWF antigen & factor VIII clotting activity may be low-normal to mildly ↓.

Type 2M VWD

Bleeding as in type 2A VWD

Qualitative deficiency of VWF w/similar ↓ in function as seen in type 2A; but assoc w/normal multimer pattern.

Type 2N VWD

Clinically indistinguishable from mild/moderate hemophilia A

VWF platelet binding is completely normal. Type 2N VWD is biochemically indistinguishable from mild hemophilia A. Mild hemophilia A can be distinguished from type 2N VWD by molecular genetic testing or measuring binding of factor VIII to VWF using ELISA or column chromatography.

Type 3 VWD

Frequent episodes of mucous membrane bleeding; joint & muscle bleeding similar to that seen in hemophilia A but usually w/more mucosal bleeding symptoms.

Complete or near-complete quantitative deficiency of VWF. VWF level is often <1% & factor VIII clotting activity is most commonly 2%-8%.

LMAN1
MCFD2

Combined factor V & factor VIII deficiency (OMIM 613625 & 227300)

Very rare disorder w/mucocutaneous & bleeding w/trauma & surgery

Low factor VIII & factor V clotting activity levels (usually 10%-20%); prolonged PT & aPTT (Mild hemophilia A does not result in prolonged PT.)

From: Hemophilia A

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Adam MP, Feldman J, Mirzaa GM, et al., editors.

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