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

Epidemiology

• Incidence
  • Factors II, V, XII, XIII – 1/1,000,000
  • Factor XI deficiency is rare in the general population (1/100,000-1,000,000), but more common in the Ashkenazi Jewish population (1/200)
  • Factor VII, X – 1/500,000
  • Factor IX, XI – 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
    • 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
  • 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, and recurrent abortion
    • 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 Testing

• Bleeding history suggestive of an inherited factor deficiency after more common deficiencies (FVIII and FIX) 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 prolonged clotting time in most cases of factor deficiency

Laboratory Testing

• Perform PTT and PT; if elevated perform PTT 1:1 mixing study
  • If mixing study demonstrates corrections, factor deficiency likely; consider for the following deficiencies (initially excluding more common FVIII and FIX deficiencies)
    • FXI, FXII, 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
• 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

• FVII deficiency associated with an isolated prolonged PT that corrects in 1:1 mixing study
• Deficiencies of fibrinogen and FII, FV, and FX can prolong both the PT and the PTT

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

Tests generally appear in the order most useful for common clinical situations

General

• Asahina T, Kobayashi T, Takeuchi K, Kanayama N. Congenital blood coagulation factor XIII deficiency and successful deliveries: a review of the literature. Obstet Gynecol Surv. 2007; 62 (4) :255-260.PubMed
• Girolami A, Ruzzon E, Tezza F, Allemand E, Vettore S. Congenital combined defects of factor VII: a critical review. Acta Haematol. 2007; 117 (1) :51-56.PubMed
• Girolami A, Ruzzon E, Tezza F, Scandellari R, Scapin M, Scarparo P. Congenital FX deficiency combined with other clotting defects or with other abnormalities: a critical evaluation of the literature. Haemophilia. 2008; 14 (2) :323-328.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
• Girolami A, Scarparo P, Scandellari R, Allemand E. Congenital factor X deficiencies with a defect only or predominantly in the extrinsic or in the intrinsic system: a critical evaluation. Am J Hematol. 2008; 83 (8) :668-671.PubMed
• Iyengar SS, Olitsky SE, Neville KA. Diagnosis of Factor XI deficiency following congenital cataract extraction. J AAPOS. 2008; 12 (3) :297-298.PubMed
• Martin-Salces M, Jimenez-Yuste V, Alvarez MT, Quintana M, Hernandez-Navarro F. Review: Factor XI deficiency: review and management in pregnant women. Clin Appl Thromb Hemost. 2010; 16 (2) :209-213.PubMed
• Muszbek L, Bagoly Z, Bereczky Z, Katona E. The involvement of blood coagulation factor XIII in fibrinolysis and thrombosis. Cardiovasc Hematol Agents Med Chem. 2008; 6 (3) :190-205.PubMed
• Schmaier AH. The elusive physiologic role of Factor XII. J Clin Invest. 2008; 118 (9) :3006-3009.PubMed
• Schroeder V, Durrer D, Meili E, Schubiger G, Kohler HP. Congenital factor XIII deficiency in Switzerland: from the worldwide first case in 1960 to its molecular characterisation in 2005. Swiss Med Wkly. 2007; 137 (19-20) :272-278.PubMed
• Seligsohn U. Factor XI in haemostasis and thrombosis: past, present and future. Thromb Haemost. 2007; 98 (1) :84-89.PubMed

ARUP Institute for Clinical and Experimental Pathology®

• Kling SJ, Jones KA, Rodgers GM. A second case of prothrombin Puerto Rico I in the United States. Am J Hematol. 2007; 82 (7) :661-662.PubMed
• Rodgers GM. Role of antithrombin concentrate in treatment of hereditary antithrombin deficiency. An update. Thromb Haemost. 2009; 101 (5) :806-812.PubMed
• Rondina MT, Markewitz B, Kling SJ, Nohavec R, Rodgers GM. The accuracy of activated partial thromboplastin times when drawn through a peripherally inserted central catheter. Am J Hematol. 2007; 82 (8) :738-739.PubMed

Acute Phase Proteins
Antiphospholipid Syndrome
Fibrinolytic Disorders
Functional Platelet Disorders
Hemophilia
Hereditary Hemorrhagic Telangiectasia
Hypercoagulable States
Venous Thromboembolism