Clotting Factors


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Subject: Clotting Factors

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  • Clotting factors are circulating plasma proteins. The final coagulation product, the clot, results from the interaction of clotting factors through an enzymatic cascade. In vivo, many of these interactions take place on lipid surfaces, the most abundant of which are provided by platelets. In contrast, in vitro, the cascade can be dissected into three pathways: intrinsic, extrinsic, and common. Although to some extent artificial, this distinction remains useful for performing and understanding the tests of coagulation. For instance, PT reflects the extrinsic and common pathway, whereas PTT reflects the intrinsic and common pathway. Fibrinogen, the penultimate step in the generation of clots, is the target of the common pathway, being changed by thrombin into fibrin; finally, fibrin is consolidated by factor XIII to generate a stable clot, essential for achieving hemostasis through clotting. (Primary hemostasis through activation of platelets and the von Willebrand factor is discussed separately.)

  • Properties of individual clotting factors:

    • Factor II (prothrombin): Synthesized in the liver; becomes active only after carboxylation by vitamin K. It is converted to thrombin (factor IIa). Its deficiency results in prolonged PT and PTT.

    • Thrombin (factor IIa): A major coagulant that converts fibrinogen into fibrin; has multiple functions, including as an anticoagulant, by binding to thrombomodulin on endothelial cell surfaces to convert protein C into its active form.

    • Factor V: Synthesized in the liver; 20% is released from platelets. Cofactor in the conversion of factor II to IIa. Vitamin K has no effect on its activity. Proteolyzed by the protein C/S complex.

    • Factor VII: Synthesized in the liver. Becomes activated in a complex with tissue factor. Factor VII requires carboxylation by vitamin K for its activity. Shortest half-life of all clotting factors (4 hours) reflected in the initial rapid elongation in PT (elevation of INR) in patients started on vitamin K antagonists. Recombinant factor VIIa is used therapeutically.

    • Factor VIII (antihemophilic factor): Synthesized in the liver and endothelial cells of others organs (principally the spleen). It is unaffected by liver failure or vitamin K deficiency. Principal cofactor in the intrinsic pathway of coagulation. PT (INR) not affected by deficiency of factor VIII. PTT becomes prolonged when factor VIII decreases to <40%. Serves as substrate for proteolysis by the protein C/S complex. Purified or recombinant factor VIII preparations are used therapeutically.

    • Factor IX (also known as Christmas factor): Synthesized in the liver. Requires vitamin K to become active in coagulation. Principal factor in the intrinsic pathway of coagulation. PT (INR) not affected by deficiency of factor IX. PTT becomes prolonged when factor IX decreases to <40%. Purified and recombinant factor IX are used therapeutically.

    • Factor X: Synthesized in the liver. Requires vitamin K to become active in coagulation. Principal factor in the common pathway of coagulation where it converts factor II into IIA (thrombin). Both PT (INR) and PTT affected in marked deficiencies.

    • Factor XI: Synthesized in the liver and megakaryocytes. Activates factors XII and IX in the intrinsic pathway. If markedly decreased, it may prolong PTT but not PT.

    • Factor XII (Hageman factor): Synthesized in the liver. Activated by collagen, disrupted basement membranes, activated platelets, and high molecular weight kininogen and prekallikrein in conjunction with factor XI. PTT (but not PT) is prolonged in severe deficiency. No bleeding diathesis associated with its congenital deficiency.

    • High molecular weight kininogen and prekallikrein (Fletcher factor): Clotting factors that activate the early phase of the intrinsic pathway and the complement system. May prolong PTT (not PT) when decreased. No bleeding diathesis associated with their congenital deficiencies.

    • Factor XIII (fibrin-stabilizing factor): Synthesized in the liver; also present in platelets. Stabilizes polymerized fibrin in the presence of calcium. Its deficiency does not affect PT (INR) or PTT. In its absence, clots are soluble in 5-molar urea.

  • Normal ranges:

    • Factors based on PT reagent:

      • Factor II: 70–120%

      • Factor V: 70–150%

      • Factor VII: 70–150%

      • Factor X: 70–150%

    • Factors based on PTT reagent:

      • Factor VIII: 70–150%

      • Factor IX: 70–120%

      • Factor XI: 60–120%

      • Factor XII: 60–150%

      • Prekallikrein: 55–207%

      • High molecular weight kininogen: 59–135%


  • Quantitation of clotting factors can be achieved through assays specific for each factor, whether chromogenic or, more commonly, automated clotting tests. A plasma deficient in each factor is purchased and used to find out whether it corrects the patient's plasma. When there is correction, the patient's defect has been identified and can be quantitated using a reference curve obtained with dilutions of normal pooled plasmas.

  • A plasma deficient in any factor(s) active in the extrinsic and common pathway (VII, V, X, and II) results in a prolonged PT. These four factors are quantitated in assays that use PT reagents as activators. Plasma deficient in factors active in the intrinsic (and common) pathway (high molecular weight kininogen, prekallikrein, and factors XII, XI, IX, and VIII) prolongs the PTT and is assayed with PTT reagents.

  • When to use clotting factor tests:

    • When a discrete congenital clotting deficiency (most commonly factors VIII and IX) is suspected

    • Occasionally, to separate the effect of oral anticoagulants (decrease in factors II, VII, IX, and X but not V or VIII) from liver disease (deficiencies of all these clotting factors, including factor V, but not factor VIII)

    • To measure blood heparin (factor Xa inhibition) and possibly when therapeutic inhibitors of factor X are used therapeutically


Increased In

  • Factor II: The genetic mutation G20210A predisposes to thromboembolism.

  • Factor VII: Pregnancy and oral contraceptive use. An increase in factor VII has been linked to thrombophilia in some studies.

  • Factor VIII: Acute-phase reactant (acute inflammatory conditions), pregnancy, and the use of oral contraceptives. If markedly increased, it may predispose to thromboembolism.

  • Factor IX: Pregnancy and use of oral contraceptives. Very elevated values have been associated with a tendency to thromboembolism.

  • Factor X: Pregnancy and use of oral contraceptives.

Decreased In

  • Factor II

    • Congenital deficiency (recessive inheritance): Bleeding of various severities in homozygotes

    • Acquired deficiency: Liver disease, DIC, pathologic fibrinolysis, vitamin K deficiency, or warfarin therapy

  • Factor V

    • Congenital: inherited autosomal deficiency; bleeding in homozygotes

    • Acquired: liver disease, DIC, or pathologic fibrinolysis

  • Factor VII

    • Congenital deficiency: manifested by variable bleeding in homozygotes

    • Acquired: liver disease, vitamin K deficiency, vitamin K antagonist therapy

  • Factor VIII

    • Congenital: hemophilia A in male patients and in some female carriers of the hemophilia gene (usually mild decrease); von Willebrand disease, especially if moderate to severe

    • Acquired: Acquired anti–factor VIII autoantibodies in previously unaffected individuals; acquired anti–factor VIII alloantibodies in multiply transfused hemophilia A patients; DIC and pathologic fibrinolysis

  • Factor IX

    • Congenital: hemophilia B:X-linked transmission

    • Acquired: liver disease, vitamin K deficiency or use of vitamin K antagonists, nephrotic syndrome, amyloidosis, autoantibodies to factor IX in previously healthy individuals (extremely rare), alloantibodies in hemophilia B patients treated with factor IX infusions

  • Factor X

    • Congenital: rare autosomal recessive defect. Homozygotes may have a bleeding diathesis.

    • Acquired: severe liver disease; vitamin K deficiency or use of vitamin K antagonists, DIC, amyloidosis

  • Factor XI

    • Congenital: autosomal recessive inheritance; mild bleeding diathesis if markedly decreased

  • Factor XIII

    • Congenital: severe bleeding in homozygous state; impaired wound healing

    • Acquired: liver disease; acute promyelocytic leukemia; autoantibodies against factor XIII


  • Improperly filled test tubes or the use of different anticoagulants than recommended (3.2% sodium citrate as provided in blue top tubes).

  • Improperly stored plasma.

  • Hyperlipidemic, hemolyzed, or icteric blood may affect the results with some coagulation instruments.

  • Contamination with heparin or dilution of the collected blood if indwelling catheters are used.