Factor Deficiencies, Uncommon

  • Diagnosis
  • Background
  • Lab Tests
  • References
  • Related Content

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

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

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

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

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

Factor XII, Activity 0030115
Method: Electromagnetic Mechanical Clot Detection

Limitations

Heparin will interfere with test results

Lupus anticoagulants may interfere with test results

Factor XIII Activity 2006182
Method: Chromogenic Assay

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

Factor XI, Activity 0030110
Method: Electromagnetic Mechanical Clot Detection

Limitations

Heparin will interfere with test results

Lupus anticoagulants may interfere with test results

Prekallikrein Factor, Activity 0099043
Method: Electromagnetic Mechanical Clot Detection

Limitations

Heparin will interfere with test results

Lupus anticoagulants may interfere with test results

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

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

Limitations

Heparin will interfere with test results

Lupus anticoagulants may interfere with test results

Follow Up

Referral test

Inhibitor Assay, PTT with Reflex to PTT 1:1 Mix, with Reflex to 1-Hour Incubation 2003266
Method: Electromagnetic Mechanical Clot Detection

Additional Tests Available

Factor X, Activity 0030105
Method: Electromagnetic Mechanical Clot Detection

Comments

Evaluate possible factor X deficiency

Fibrinogen 0030130
Method: Electromagnetic Mechanical Clot Detection

Comments

Determine if fibrinogen deficiency is a potential cause of bleeding

Factor VII, Activity 0030080
Method: Electromagnetic Mechanical Clot Detection

Comments

Evaluate possible factor VII deficiency

Factor V, Activity 0030075
Method: Electromagnetic Mechanical Clot Detection

Comments

Evaluate possible factor V deficiency

Factor II, Activity (Prothrombin) 0030007
Method: Electromagnetic Mechanical Clot Detection

Comments

Evaluate possible factor II deficiency

Fibrinogen Antigen 0030135
Method: Radial Immunodiffusion

General References

Acharya S. Rare bleeding disorders in children: identification and primary care management. Pediatrics. 2013; 132(5): 882-92. PubMed

Bolton-Maggs P. The rare inherited coagulation disorders. Pediatr Blood Cancer. 2013; 60 Suppl 1: S37-40. PubMed

Girolami A, Scandellari R, Scapin M, Vettore S. Congenital bleeding disorders of the vitamin K-dependent clotting factors. Vitam Horm. 2008; 78: 281-374. PubMed

Lippi G, Favaloro E, Montagnana M, Manzato F, Guidi G, Franchini M. Inherited and acquired factor V deficiency. Blood Coagul Fibrinolysis. 2011; 22(3): 160-6. PubMed

National Hemophilia Foundation for all bleeding disorders. Other Factor Deficiencies. National Hemophilia Foundation. New York , NY [Accessed: Jan 2016]

Rare Coagulation Disorders Resource Room. Rare Bleeding Disorders. Indiana Hemophilia & Thrombosis Center, and Rare Coagulation Disorders Subcommittee of the National Hemophilia Foundation. [Accessed: Sep 2015]

Venkateswaran L, Yee D. Rare bleeding disorders in young women. J Pediatr Adolesc Gynecol. 2010; 23(6 Suppl): S38-42. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Kling S, Jones K, Rodgers G. A second case of prothrombin Puerto Rico I in the United States. Am J Hematol. 2007; 82(7): 661-2. PubMed

Rodgers G. Prothrombin complex concentrates in emergency bleeding disorders. Am J Hematol. 2012; 87(9): 898-902. PubMed

Rodgers G. Role of antithrombin concentrate in treatment of hereditary antithrombin deficiency. An update. Thromb Haemost. 2009; 101(5): 806-12. PubMed

Rondina M, Markewitz B, Kling S, Nohavec R, Rodgers G. The accuracy of activated partial thromboplastin times when drawn through a peripherally inserted central catheter. Am J Hematol. 2007; 82(8): 738-9. PubMed

Medical Reviewers

Last Update: January 2016