Table 3. [Inherited Bleeding Disorders with Normal Factor IX Clotting Activity]. - GeneReviews®

Gene(s)	Disorder	MOI	Clinical Features	Laboratory Findings / Comment
F11	Factor XI deficiency (OMIM 612416)	AR AD	Both compound heterozygotes & homozygotes may exhibit bleeding similar to that seen in mild or moderate hemophilia B.	Heterozygotes have factor XI coagulant activity 25%-75% of normal; homozygotes have activity <1%-15%. ¹ A specific factor XI clotting assay establishes the diagnosis.
F12 KLKB1 KNG1	Factor XII (OMIM 234000), prekallikrein (OMIM 612423), or high molecular-weight kininogen deficiencies (OMIM 228960)	AR	Not assoc w/clinical bleeding	Can cause prolonged aPTT
F13A1 F13B	Factor XIII deficiency (OMIM 613225, 613235)	AR	Umbilical stump bleeding in >80% of persons. Intracranial bleeding that occurs spontaneously or following minor trauma in 30% of persons. Subcutaneous hematomas, muscle hematomas, defective wound healing, & recurrent spontaneous abortion are also seen. Joint bleeding is rare.	All coagulation screening tests are normal; a screening test for clot solubility or a specific assay for factor XIII activity can confirm the diagnosis. Bleeding symptoms are reported in persons w/levels <13% by quantitative assay. ²
F2 F5 F7 F10	Prothrombin (factor II) (OMIM 613679), factor V (OMIM 227400), factor X (OMIM 227600), & factor VII (OMIM 227500) deficiencies	AR	Rare bleeding disorders. Persons may have easy bruising & hematoma formation, epistaxis, heavy menstrual bleeding, & bleeding after trauma & surgery. Hemarthroses are less common. Spontaneous intracranial bleeding can occur.	Factor VII deficiency should be suspected if the PT is prolonged & aPTT is normal. Persons w/deficiency of factors II, V, or X usually have prolonged PT & aPTT, but specific coagulation factor assays establish the diagnosis.
F8	Hemophilia A	XL	Clinically indistinguishable from hemophilia B	Diagnosis is based on a factor VIII clotting activity level <40% in the presence of a normal VWF level.
FGA FGB FGG	Afibrinogenemia (OMIM 202400), hypofibrinogenemia (OMIM 616004), dysfibrinogenemia (OMIM 616004)	AR AD ³	Afibrinogenemia is assoc w/manifestations similar to hemophilia B except that bleeding from minor cuts is prolonged due to lack of fibrinogen to support platelet aggregation. Hypofibrinogenemia & dysfibrinogenemia can be assoc w/mild-to-moderate bleeding symptoms. Rarely persons w/dysfibrinogenemia are at risk for thrombosis.	In dysfibrinogenemia there is discordance between functional & antigenic levels, w/latter usually in normal range. For all fibrinogen disorders thrombin & reptilase times are almost always prolonged & functional measurements of fibrinogen are ↓.
GP1BA GP1BB GP9 ITGA2B	Platelet function disorders incl Bernard-Soulier syndrome (OMIM 231200) & Glanzmann thrombasthenia (OMIM 273800)	AR	In Bernard-Soulier syndrome, Glanzmann thrombasthenia, & storage pool & nonspecific secretory defects: skin & mucous membrane bleeding, recurring epistaxis, GI bleeding, heavy menstrual bleeding, & excessive bleeding during or immediately after trauma & surgery. Joint, muscle, & intracranial bleeding is rare.	Diagnosis is established using platelet aggregation assays, flow cytometry, & platelet electron microscopy.
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). (Persons w/hemophilia B have a normal VWF level & a normal factor VIII activity.)
Type 2A & 2B VWD	AD	in type 2A, bleeding as in Type 1 VWD or may be more severe. In 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 hemophilia B	VWF platelet binding is completely normal. Biochemically, type 2N VWD is indistinguishable from hemophilia B; however, hemophilia B can be distinguished from type 2N VWD by molecular genetic testing.
Type 3 VWD	AR	Frequent episodes of mucous membrane bleeding. Joint & muscle bleeding similar to that seen in hemophilia B.	Complete or near-complete quantitative deficiency of VWF. VWF level is often <1% & factor VIII clotting activity is most commonly 2%-8%.

Gene(s)

Disorder

MOI

Clinical Features

Laboratory Findings / Comment

F11

Factor XI deficiency (OMIM 612416)

AR
AD

Both compound heterozygotes & homozygotes may exhibit bleeding similar to that seen in mild or moderate hemophilia B.

Heterozygotes have factor XI coagulant activity 25%-75% of normal; homozygotes have activity <1%-15%. ¹ A specific factor XI clotting assay establishes the diagnosis.

F12
KLKB1
KNG1

Factor XII (OMIM 234000), prekallikrein (OMIM 612423), or high molecular-weight kininogen deficiencies (OMIM 228960)

Not assoc w/clinical bleeding

Can cause prolonged aPTT

F13A1
F13B

Factor XIII deficiency (OMIM 613225, 613235)

Umbilical stump bleeding in >80% of persons. Intracranial bleeding that occurs spontaneously or following minor trauma in 30% of persons. Subcutaneous hematomas, muscle hematomas, defective wound healing, & recurrent spontaneous abortion are also seen. Joint bleeding is rare.

All coagulation screening tests are normal; a screening test for clot solubility or a specific assay for factor XIII activity can confirm the diagnosis. Bleeding symptoms are reported in persons w/levels <13% by quantitative assay. ²

F2
F5
F7
F10

Prothrombin (factor II) (OMIM 613679), factor V (OMIM 227400), factor X (OMIM 227600), & factor VII (OMIM 227500) deficiencies

Rare bleeding disorders. Persons may have easy bruising & hematoma formation, epistaxis, heavy menstrual bleeding, & bleeding after trauma & surgery. Hemarthroses are less common. Spontaneous intracranial bleeding can occur.

Factor VII deficiency should be suspected if the PT is prolonged & aPTT is normal. Persons w/deficiency of factors II, V, or X usually have prolonged PT & aPTT, but specific coagulation factor assays establish the diagnosis.

Hemophilia A

Clinically indistinguishable from hemophilia B

Diagnosis is based on a factor VIII clotting activity level <40% in the presence of a normal VWF level.

FGA
FGB
FGG

Afibrinogenemia (OMIM 202400), hypofibrinogenemia (OMIM 616004), dysfibrinogenemia (OMIM 616004)

AR
AD ³

Afibrinogenemia is assoc w/manifestations similar to hemophilia B except that bleeding from minor cuts is prolonged due to lack of fibrinogen to support platelet aggregation. Hypofibrinogenemia & dysfibrinogenemia can be assoc w/mild-to-moderate bleeding symptoms. Rarely persons w/dysfibrinogenemia are at risk for thrombosis.

In dysfibrinogenemia there is discordance between functional & antigenic levels, w/latter usually in normal range. For all fibrinogen disorders thrombin & reptilase times are almost always prolonged & functional measurements of fibrinogen are ↓.

GP1BA
GP1BB
GP9
ITGA2B

Platelet function disorders incl Bernard-Soulier syndrome (OMIM 231200) & Glanzmann thrombasthenia (OMIM 273800)

In Bernard-Soulier syndrome, Glanzmann thrombasthenia, & storage pool & nonspecific secretory defects: skin & mucous membrane bleeding, recurring epistaxis, GI bleeding, heavy menstrual bleeding, & excessive bleeding during or immediately after trauma & surgery. Joint, muscle, & intracranial bleeding is rare.

Diagnosis is established using platelet aggregation assays, flow cytometry, & platelet electron microscopy.

VWF

Type 1 von Willebrand disease (VWD)

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). (Persons w/hemophilia B have a normal VWF level & a normal factor VIII activity.)

Type 2A & 2B VWD

in type 2A, bleeding as in Type 1 VWD or may be more severe. In 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 hemophilia B

VWF platelet binding is completely normal. Biochemically, type 2N VWD is indistinguishable from hemophilia B; however, hemophilia B can be distinguished from type 2N VWD by molecular genetic testing.

Type 3 VWD

Frequent episodes of mucous membrane bleeding. Joint & muscle bleeding similar to that seen in hemophilia B.

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

From: Hemophilia B

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

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