Factor Deficiencies, Uncommon
Factor Deficiencies, Uncommon
Clinical Background
Inherited deficiencies of factors II, V, VII, X, XI, XII and XIII, high molecular weight kininogen (HMWK), prekallikrein and fibrinogen deficiency are uncommon.
Epidemiology
- Incidence
- Factors II, V, X, XI, XII, XIII – 1/1-2,000,000
- Factor XI deficiency is rare in general population, but more common in Ashkenazi Jewish population
- Factor VII – 1/500,000
- Age – may be discovered in adulthood
- Sex – M:F, equal
Inheritance – all disorders have autosomal recessive inheritance
Pathophysiology
- Most factor deficiencies are due to either quantitative or qualitative abnormalities in the proteins
- Factor II (prothrombin)
- Activated to thrombin by prothrombinase complex (factor Xa and factor Va)
- Thrombin converts fibrinogen to fibrin and is a potent platelet activator
- Factor V
- Factor V is activated by thrombin
- Activated factor V acts as a cofactor in the conversion of prothrombin (factor II) to thrombin (factor IIa) by activated factor X
- Factor VII
- Activated FVII binds to tissue factor and initiates the extrinsic pathway of coagulation by converting factor X to factor Xa
- Factor X
- Factor X is activated by either the “intrinsic tenase complex” (factor IXa and factor VIIIa) or the “extrinsic tenase complex” (factor VIIa and tissue factor)
- Activated factor X and activated factor V (cofactor) convert prothrombin (factor II) to thrombin (factor IIa)
- Factor XI
- Activated by thrombin and through other mechanisms
- Activated factor XI converts factor IX to factor IXa
- Factor XII (Hageman factor), HMWK (Fitzgerald factor) and prekallikrein (Fletcher factor)
- Involved in initiation of the intrinsic pathway of coagulation through contact with negatively charged or hydrophobic surfaces
- The contact factors initiate the coagulation cascade in the partial thromboplastin time (aPTT) test, but are not necessary for coagulation in vivo (deficiency not associated with bleeding)
- Factor XIII
- Activated to factor XIIIa by thrombin
- Factor XIIIa is a transglutaminase that covalently crosslinks fibrin, resulting in a clot that resists mechanical and enzymatic degradation
- Fibrinogen
- Fibrinogen is converted to fibrin by factor IIa (thrombin)
- Deficiency varies from hypo- to afibrinogenemia
Clinical Presentation
- The bleeding phenotype ranges from mild to severe, depending on the defect (a variety of different mutation types have been reported for most factor deficiencies) and whether multiple abnormalities are present
- Combined inherited deficiencies, such as deficiency of all vitamin K-dependent factors (II, VII, IX, and X), are rare
- Factor II
- Extent of bleeding does not always correlate with factor II activity
- Mild to moderate mucocutaneous and soft tissue bleeding
- May include hemarthrosis and intracranial bleeding in patients with very low activity
- Factor V
- May be associated with combined inherited deficiency of factor V and factor VIII
- Mild, moderate, and severe forms exist
- Patients with severe deficiency present in childhood with umbilical stump bleeding, easy bruising, and epistaxis
- Factor VII
- May be associated with combined inherited deficiency of factor VII and factor X
- Poor correlation between extent of bleeding and factor VII activity
- Severe bleeding in patients with very low activity may resemble bleeding seen in hemophilia A or B
- Factor X
- May be associated with combined inherited deficiency of factor X and factor VII
- Bleeding may be mild, moderate, or severe, depending on the mutation
- Severe bleeding in patients with very low activity may resemble bleeding seen in hemophilia A or B
- Factor XI
- Extent of bleeding does not always correlate with factor XI activity
- Symptoms are generally milder than in patients with hemophilia A or B
- Some patients are asymptomatic
- Can be associated with excessive bleeding, usually related to surgical procedures or trauma (tooth extraction, tonsillectomy, nasal surgery)
- Factor XII, HMWK, and prekalikrein
- Asymptomatic; deficient individuals have no bleeding tendency despite markedly prolonged partial thromboplastin times (often >100 seconds)
- Factor XIII
- Umbilical stump bleeding at birth, delayed post-surgical or post-traumatic bleeding, intracranial hemorrhage, poor wound healing, and recurrent abortion
- Fibrinogen
- Afibrinogenemia usually presents in childhood and is associated with bleeding of variable severity (often severe)
- Hypofibrinogenemia is associated with bleeding of variable severity
Diagnosis
- Indications for testing
- Bleeding history suggestive of an inherited factor deficiency and more common deficiencies (factors VIII and IX) have been excluded
- Prolonged routine clotting times (PT and/or PTT may be prolonged, depending on which factor is deficient)
- 1:1 mixing studies demonstrate correction of the prolonged clotting time in most cases of factor deficiency
- Laboratory testing
- Elevated PTT (PTT 1:1 mixing study demonstrates correction), normal PT
- Exclude factor VIII and IX deficiencies
- Test for factor XI, factor XII, HMWK, and prekallikrein deficiency
- For patients who present with bleeding, focus on relevant disorders and skip testing for disorders not associated with bleeding (FXII, prekallikrein, HMWK)
- Other factors – test selection is based on clinical presentation, family history, and results of routine clotting times (PT, PTT) and mixing studies
- Factor VII deficiency is associated with an isolated prolonged PT that demonstrates correction in a 1:1 mixing study
- Deficiencies of fibrinogen and factors II, V, and X can prolong both the PT and the PTT
- PT and PTT are normal in patients with factor XIII deficiency
Differential Diagnosis
- Other coagulation factor deficiencies
- FVIII
- FIX
- von Willebrand disease (vWD) (vWD factor is a carrier for factor VIII, factor VIII may be decreased in patients with vWD)
- Platelet disorders
- Dysfibrinogenemia
- Abnormalities of fibrinolysis
Pharmacogenetics and Therapeutic Drug Monitoring
Indications for Laboratory Testing
- Tests generally appear in the order most useful for common clinical situations
- Click on number for test-specific information in the ARUP Laboratory Test Directory
| Test Name and Number |
Recommended Use |
Limitations |
Follow Up |
| Inhibitor Assay, PTT with Reflex to PTT 1:1 Mix 2-Hour Incubation 0030169 Method: Electromagnetic Mechanical Clot Detection |
Initial testing for rare coagulation factor deficiencies |
|
|
| Inhibitor Assay, PT with Reflex to PT 1:1 Mix 2-Hour Incubation 0030161 Method: Electromagnetic Mechanical Clot Detection |
Initial testing for rare coagulation factor deficiencies |
|
|
| High Molecular Weight Kininogen 0093002 Method: Clotting |
Evaluate the cause of an isolated prolonged PTT in a patient without bleeding |
Heparin will interfere with test results Lupus anticoagulants may interfere with test results |
Referral test |
| Prekallikrein Factor, Activity 0099043 Method: Clotting |
Evaluate the cause of an isolated prolonged PTT in a patient without bleeding |
Heparin will interfere with test results Lupus anticoagulants may interfere with test results |
|
| Factor II, Activity (Prothrombin) 0030007 Method: Clotting |
Evaluate possible factor II deficiency |
|
|
| Factor V, Activity 0030075 Method: Clotting |
Evaluate possible factor V deficiency |
|
|
| Factor VII, Activity 0030080 Method: Clotting |
Evaluate possible factor VII deficiency |
|
|
| Factor X, Activity 0030105 Method: Clotting |
Evaluate possible factor X deficiency |
|
|
| Factor XI, Activity 0030110 Method: Clotting |
Evaluate possible factor XI deficiency |
Heparin will interfere with test results Lupus anticoagulants may interfere with test results |
|
| Factor XII, Activity 0030115 Method: Clotting |
Evaluate the cause of an isolated prolonged PTT in a patient without bleeding |
Heparin will interfere with test results Lupus anticoagulants may interfere with test results |
|
| Factor XIII, Qualitative 0030120 Method: Solubility |
Qualitative screening test for initial evaluation of possible factor XIII deficiency |
Abnormal results only occur in samples with severe factor XIII deficiency Quantitative factor XIII testing is recommended for confirmation of abnormal results |
|
| Fibrinogen 0030130 Method: Electromagnetic Mechanical Clot Detection |
Determine if fibrinogen deficiency is a potential cause of bleeding
|
|
|
Additional Tests Available
Click the plus sign to expand the table of additional tests.
| Test Name and Number | Comments |
| Fibrinogen Antigen 0030135 Method: Radial Immunodiffusion |
|
General References
References from the ARUP Institute for Clinical and Experimental Pathology®
Comprehensive Review: February 2010
Last Update: February 2010