Factor Deficiencies, Uncommon

Diagnosis

Indications for Testing

  • Bleeding history suggestive of an inherited blood coagulation factor deficiency and the most common deficiencies (eg, FVIII, FIX, and von Willebrand disease) have been excluded
  • Prolonged clotting times discovered by routine screening tests (prothrombin time [PT] or partial thromboplastin time [PTT])
  • Normal clotting times do not exclude a factor deficiency (eg, FXIII, or milder factor deficiencies)

Laboratory Testing

  • Elevated PT/PTT – perform PT/PTT 1:1 mixing study
    • If mixing study demonstrates corrections of PT/PTT – quantitative factor deficiency is likely
      • Pursue factor deficiency evaluation
    • If mixing study does not demonstrate correction in PT/PTT – inhibitor or antibody is likely
      • Factor assays are still necessary but should evaluate for presence of inhibitors
    • If patient has abnormal bleeding history – focus on disorders associated with bleeding and skip testing for disorders that are not associated with bleeding
    • If no abnormal bleeding history is present – perform testing for FXII, prekallikrein, and high-molecular-weight kininogen (HMWK) deficiencies
  • Factor XIII deficiency suspected (bleeding tendency with normal PT/PTT) – type of testing depends on whether deficiency is suspected to be inherited or acquired
    • Do not evaluate trauma patient for at least 4-6 weeks, or evaluate after recovery
    • Acquired FXIII deficiency
      • Start with functional assay to detect deficiency
      • If severe deficiency is identified, follow with FXIII test with 1:1 mix to evaluate for inhibitor pattern
    • Inherited FXIII deficiency
      • Functional activity assay is preferred
    • Expected laboratory result for factor deficiency

      Expected Laboratory Result for Factor Deficiency*

      Normal PT

      Normal PTT

      Prolonged PT

      Normal PTT

      Normal PT

      Prolonged PTT
       

      Prolonged PT

      Prolonged PTT

      FXIII

      Hypo-/dysfibrinogenemia

      Other mild factor deficiencies

      FVII

      Vitamin K/warfarin

      FVIII

      FIX

      FXI

      Contact factors

      FI (hypo-/, a-/, or /dysfibrinogenemias)

      FII

      FV

      FX

      Multiple factor deficiencies due to

      • Vitamin K deficiency
      • Vitamin K combined factor deficiency (VKCFD)
      • Warfarin therapy
      • Liver disease
      • Disseminated intravascular coagulation

      *Corrects with 1:1 mixing study

Differential Diagnosis

  • Other, more common coagulation factor deficiencies
    • FVIII (hemophilia A)
    • FIX (hemophilia B)
    • von Willebrand disease (vWD)
      • vWD factor is a carrier for factor VIII
      • Factor VIII may be decreased or normal in patients with vWD
  • Platelet disorders (eg, Hermansky-Pudlak syndrome)
  • Abnormalities of fibrinolysis

Clinical Background

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

Epidemiology

  • Incidence
    • FVII – most common (1/500,000)
    • Factors II, V, XII, XIII – least common (1-2/million)
  • Age – usually discovered before adulthood
  • Sex – M:F, equal
  • Ethnicity
    • FXI deficiency – most common in Ashkenazi Jews (1/200-450)

Inheritance 

  • Inheritance – most disorders autosomal recessive
  • Dysfibrinogenemia and FXI deficiency
    • Inheritance – autosomal dominant
    • Heterozygotes – asymptomatic
    • FXI deficiency – variable penetrance

Pathophysiology

  • Thirteen proteins (factors) are involved in forming clots that stop bleeding
  • Diminished or absent activity of a protein may lead to abnormal bleeding
    • Can occur later in life (eg, if antibodies form against clotting factors [deemed acquired])
    • Combined inherited deficiencies (eg, deficiency of all vitamin K-dependent factors [FII, FVII, FIX, FX]) are rare
  • Pathophysiology of blood coagulation factors

    Pathophysiology of Blood Coagulation Factors

    Factor

    Activated by

    Function

    Pathway (Intrinsic, Extrinsic, Common)

    FI (fibrinogen)

    Thrombin

    Converted to fibrin by FIIa (thrombin)

    Forms initial structure of blood clot

    Common

    FII (prothrombin)

    Prothrombinase complex (factor Xa and factor Va) to form thrombin

    Thrombin converts fibrinogen to fibrin and is a potent platelet activator

    Common

    FV

    Thrombin

    Activated FV acts as a cofactor in the conversion of prothrombin (FII) to thrombin (FIIa) by activated FXa

    Common

    FVII

    Tissue factor

    Activated FVII binds to tissue factor and initiates the extrinsic pathway of coagulation by converting FX to FXa

    Extrinsic

    FX

    Either the intrinsic tenase complex (FIXa and FVIIIa) or the extrinsic tenase complex (FVIIa and tissue factor)

    Activated FX and activated FV (cofactor) convert FII to FIIa

    Common

    FXI

    Thrombin and other mechanisms

    Activated FXI converts FIX to FIXa

    Reinforces intrinsic pathway by activation of factor IX after its triggering by thrombin

    Intrinsic

    FXII (Hageman factor); high-molecular-weight kininogen (HMWK); and kallikrein (Fletcher factor)

    Binds to exposed collagen at site of vessel wall injury

    However, activation not clinically important and deficiencies in these contact factors do not result in a bleeding disorder

    Involved in initiation of intrinsic pathway through contact with negatively charged or hydrophobic surface

    Intrinsic

    FXIII

    Thrombin to form FXIIIa, which crosslinks fibrin clot

    Is a transglutaminase that covalently cross-links fibrin, resulting in a clot that resists mechanical and enzymatic degradation

    Not applicable

Clinical Presentation

  • Bleeding phenotypes range from mild to severe, depending on
    • Gene mutation
    • Number of deficiencies present
    • Factor activity
  • Most common bleeding in mild cases – mucosal or postoperative bleeding
  • Most common bleeding in severe cases – intracranial or umbilical cord bleeding
  • Clinical presentation of coagulation factors

    Clinical Presentation of Coagulation Factors

    Coagulation Factor

    Bleeding Severity

    Correlation of Factor Deficiency with Extent of Bleeding

    Sites of Bleeding

    Other

    FI (Fibrinogen)

    Mild, moderate, and severe forms

    Good

    Umbilical stump after birth

    Excessive bleeding after trauma or surgery

    Afibrinogenemia usually presents in childhood

    May present with thrombosis in afibrinogenemia and dysfibrinogenemia

    FII

    Mild to moderate

    Good

    Mucocutaneous and soft tissue bleeding

    May include hemarthrosis and intracranial bleeding if FII levels are very low

    FV (Owren disease or parahemophilia)

    Mild, moderate, and severe forms

    Poor 

    Severe deficiency resembles hemophilia

    • Umbilical stump after birth
    • Epistaxis and easy bruising in childhood
    • Hemarthrosis

    May be associated with combined inherited deficiency of FVIII

    • No apparent cumulative bleeding effect due to dual defect

    FVII

    Asymptomatic, minor bleeder, and major bleeder forms

    Poor

    Minor bleeder

    • Epistaxis, easy bruising, hematuria, bleeding gums

    Major bleeder

    • Hemarthrosis
    • Similar to hemophilia A or B

    May be associated with combined inherited deficiencies of FVII and FX

    FX

    Mild, moderate, and severe forms

    Good

    Severe form similar to hemophilia A or B

    • May also experience mucocutaneous bleeding

    Rare combined deficiency of FII, FVII, FIX, and FX causes severe bleeding and skeletal abnormalities (called vitamin K combined factor deficiency [VKCFD])

    May be associated with combined inherited deficiency of FVII

    Non-coagulation abnormalities

    • Mitral valve prolapse
    • Hypertrophic cardiomyopathy
    • Hypercholesterolemia
    • Thrombocytopenia – absent radius syndrome

    FXI

    Asymptomatic to mild

    Poor

    Excessive bleeding, usually related to surgical procedures or trauma

    No spontaneous bleeding in neonatal period reported

    Milder bleeding than hemophilia A or B

    FXII, HMWK, prekallikrein

    Asymptomatic

    Poor

    No bleeding tendency despite markedly prolonged partial thromboplastin time (Often >100 seconds)

    FXIII

    Severe

    Good

    • Umbilical stump after birth
    • Defective wound healing
    • Delayed post-surgical or post-traumatic bleeding
    • Intracranial hemorrhage
    • Recurrent miscarriages

    May also be acquired

    • Cardiopulmonary bypass
    • Inflammatory disease

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

   
High Molecular Weight Kininogen (HMWK) 2007578
Method: Enzyme Immunoassay

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: Electromagnetic Mechanical Clot Detection

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: Electromagnetic Mechanical Clot Detection

Evaluate possible factor XI deficiency

Heparin will interfere with test results

Lupus anticoagulants may interfere with test results

 
Factor XII, Activity 0030115
Method: Electromagnetic Mechanical Clot Detection

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: Electromagnetic Mechanical Clot Detection

Evaluate possible factor II deficiency

Factor V, Activity 0030075
Method: Electromagnetic Mechanical Clot Detection

Evaluate possible factor V deficiency

Factor VII, Activity 0030080
Method: Electromagnetic Mechanical Clot Detection

Evaluate possible factor VII deficiency

Factor X, Activity 0030105
Method: Electromagnetic Mechanical Clot Detection

Evaluate possible factor X deficiency

Fibrinogen 0030130
Method: Electromagnetic Mechanical Clot Detection

Determine if fibrinogen deficiency is a potential cause of bleeding