Table 4.

Inherited Bleeding Disorders with Normal Factor VIII Clotting Activity

Gene(s)DisorderMOIClinical FeaturesLaboratory Findings / Comment
F9 Hemophilia B XLClinically indistinguishable from hemophilia ADiagnosis is based on factor IX clotting activity <40%.
F11 Factor XI deficiency (OMIM 612416)AR
AD		Compound heterozygous & homozygous persons may exhibit bleeding similar to mild/moderate hemophilia A. Some heterozygotes have mucocutaneous bleeding symptoms.Heterozygotes have factor XI coagulant activity 25%-75% of normal; homozygotes have activity <1%-15%. 1 A specific factor XI clotting assay establishes diagnosis.
F12
KLKB1
KNG1 		Factor XII (OMIM 234000), prekallikrein (OMIM 612423), & high molecular-weight kininogen deficiencies (OMIM 228960)ARNot assoc w/clinical bleedingCan cause long aPTT
F2
F5
F7
F10 		Prothrombin (factor II) (OMIM 613679), factor V (OMIM 227400), factor X (OMIM 227600), & factor VII (OMIM 227500) deficienciesARRare 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 PT is prolonged & aPTT normal. Persons w/deficiency of factors II, V, or X usually have prolonged PT & aPTT, but specific coagulation factor assays establish diagnosis. 2
FGA
FGB
FGG 		Afibrinogenemia
(OMIM 202400), hypofibrinogenemia (OMIM 202400), dysfibrinogenemia (OMIM 616004)		AR
AD 3		Afibrinogenemia is assoc w/manifestations similar to hemophilia A 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 level, w/latter usually in normal range. For all fibrinogen disorders thrombin & reptilase times are almost always prolonged & functional measurements of fibrinogen ↓.
F13A1
F13B 		Factor XIII deficiency (OMIM 613225, 613235)ARUmbilical 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 specific assay for factor XIII activity can confirm diagnosis. Bleeding symptoms are reported in persons w/levels <13% by quantitative assay. 4
GP1BA
GP1BB
GP9
ITGA2B 		Platelet function disorders: Bernard-Soulier syndrome (OMIM 231200) & Glanzmann thrombasthenia (OMIM 273800)ARIn 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.

AD = autosomal dominant; aPTT= activated partial thromboplastin time; AR = autosomal recessive; GI = gastrointestinal; MOI = mode of inheritance; PT = prothrombin time

1.
2.

Combined (multiple) deficiencies are usually acquired disorders, although a few families have hereditary deficits of the vitamin K-dependent factors, often resulting from deficiency of gamma-carboxylase.

3.

Afibrinogenemia is inherited in an autosomal recessive manner. Hypofibrinogenemia can be inherited in either an autosomal dominant or an autosomal recessive manner. Dysfibrinogenemia is inherited in an autosomal dominant manner.

4.

From: Hemophilia A

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