Factor Deficiencies, Uncommon

Diagnosis

Indications for Testing

  • Bleeding history suggestive of an inherited factor deficiency after more common deficiencies (FVIII, FIX, and von Willebrand disease) have been excluded
  • Prolonged routine clotting times (PT or PTT may be prolonged, depending on which factor is deficient)

Laboratory Testing

  • Perform PTT and PT – if elevated, perform PTT 1:1 mixing study
    • If mixing study demonstrates corrections, factor deficiency is likely; consider the following (after excluding more common FVIII and FIX deficiencies)
      • FXI, FXII, high-molecular-weight kininogen (HMWK), and prekallikrein deficiency
    • If patient presents with bleeding, focus on relevant disorders and skip testing for disorders not associated with bleeding (FXII, prekallikrein, HMWK)
    • If no bleeding but random discovery, perform testing for FXII, prekallikrein, and HMWK
  • Testing for acquired FXIII deficiency not practical if patient involved in trauma – test when patient recovers
    • Use FXIII test with 1:1 mix
  • Other factors – test selection is based on clinical presentation, family history, and results of routine clotting times (PT, PTT) and mixing studies
    • Expected laboratory result for factor deficiency

      Expected Laboratory Result for Factor Deficiency

      Prolonged PT
      Normal PTT

      Prolonged PTT
      Normal PT

      Prolonged PT
      Prolonged PTT

      FVII

      Vitamin K

      FVIII

      FIX

      FXI

      Contact factors

      FI

      FII

      FV

      FX

      Vitamin K

      Normal PT and PTT with FXIII deficiency

      *Corrects with 1:1 mixing study

Differential Diagnosis

Clinical Background

Uncommon inherited factor deficiencies include II, V, VII, X, XI, XII, XIII, high-molecular-weight kininogen (HMWK), prekallikrein, and fibrinogen.

Epidemiology

  • Incidence
    • Factors II, V, XII, XIII – 1/1 million
    • Factor XI deficiency – rare in the general population (1/100,000-1/1 million)
      • More common in the Ashkenazi Jewish population (1/200)
    • Factors VII, X – 1/500,000
    • Factor IX – 1/100,000
  • 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 of the proteins
  • Factor II (FII) – 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 (FV)
    • FV is activated by thrombin
    • Activated FV acts as a cofactor in the conversion of prothrombin (FII) to thrombin (FIIa) by activated FXa
  • Factor VII (FVII)
    • Activated FVII binds to tissue factor and initiates the extrinsic pathway of coagulation by converting factor X to factor Xa
  • Factor X (FX)
    • FX is activated by either the intrinsic tenase complex (FIXa and FVIIIa) or the extrinsic tenase complex (FVIIa and tissue factor)
    • Activated FX and activated FV (cofactor) convert prothrombin (FII) to thrombin (FIIa)
  • Factor XI (FXI)
    • Activated by thrombin and through other mechanisms
    • Activated FXI converts FIX to FIXa
  • Factor XII (FXII or 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 (PTT) test but are not necessary for coagulation in vivo (deficiency not associated with bleeding)
  • Factor XIII (FXIII)
    • Activated to FXIIIa by thrombin
    • FXIIIa is a transglutaminase that covalently crosslinks fibrin, resulting in a clot that resists mechanical and enzymatic degradation
  • Fibrinogen
    • Fibrinogen is converted to fibrin by FIIa (thrombin)
    • Deficiency varies from hypo- to afibrinogenemia

Clinical Presentation

  • Bleeding phenotypes range from mild to severe, depending on the mutation (a variety of different mutation types have been reported for most factor deficiencies) and whether multiple abnormalities are present
  • Combined inherited deficiencies are rare, such as deficiency of all vitamin K-dependent factors (FII, FVII, FIX, FX)
    • FII
      • Extent of bleeding does not always correlate with FII activity
      • Mild to moderate mucocutaneous and soft tissue bleeding
      • May include hemarthrosis and intracranial bleeding in patients with very low activity
    • FV (Owren disease or parahemophilia)
      • May be associated with combined inherited deficiency of FV and FVIII
      • Mild, moderate, and severe forms exist
      • Patients with severe deficiency present in childhood with umbilical stump bleeding, easy bruising, and epistaxis
      • In severe deficiency – resembles hemophilia with hemarthroses
    • FVII
      • May be associated with combined inherited deficiency of FVII and FX
      • Poor correlation between extent of bleeding and FVII activity
      • Severe bleeding in patients with very low activity may resemble bleeding seen in hemophilia A or B
    • FX
      • May be associated with combined inherited deficiency of FX and FVII
      • 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
    • FXI
      • Extent of bleeding does not always correlate with FXI 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)
    • FXII, HMWK, and prekallikrein
      • Asymptomatic; deficient individuals have no bleeding tendency despite markedly prolonged partial thromboplastin times (often >100 seconds)
    • FXIII
      • Umbilical stump bleeding at birth, delayed post-surgical or post-traumatic bleeding, intracranial hemorrhage, poor wound healing, recurrent miscarriages
      • May also be acquired due to cardiopulmonary bypass or inflammatory disease
    • Fibrinogen
      • Afibrinogenemia usually presents in childhood and is associated with bleeding of variable severity (often severe)
      • Hypofibrinogenemia is associated with bleeding of variable severity

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, with Reflex to 1-Hour Incubation 2003266
Method: Electromagnetic Mechanical Clot Detection

Initial screen for inhibitor in plasma

   
Inhibitor Assay, PT with Reflex to PT 1:1 Mix 2003260
Method: Electromagnetic Mechanical Clot Detection

Initial screen for inhibitor in plasma

   
Bleeding Disorders (Uncommon) with Reflex to Factor XIII 1:1 Mix and/or Fibrinogen Antigen 2003947
Method: Electromagnetic Mechanical Clot Detection/Solubility/Radial Immunodiffusion

Test for uncommon bleeding disorders (factors II, V, VII, X, and dysfibrinogenemia)

Screen for FXIII deficiency/inhibitor

Clot lysis occurs only in samples with <1% of normal FXIII activity

 
High Molecular Weight Kininogen (HMWK) 2007578
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 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 Activity 2006182
Method: Chromogenic Assay

First-line test to diagnose FXIII deficiency (acquired or congenital)

Monitor therapy

Confirm abnormalities identified by qualitative testing

   
Factor XIII, Qualitative, with Reflex to Factor XIII 1:1 Mix 2002819
Method: Qualitative Solubility

Most useful for acquired or severe FXIII deficiency

Abnormal results should be confirmed with quantitative testing

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Fibrinogen Antigen 0030135
Method: Radial Immunodiffusion
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

Fibrinogen 0030130
Method: Electromagnetic Mechanical Clot Detection

Determine if fibrinogen deficiency is a potential cause of bleeding