Factor IX Assay 

Updated: Jan 17, 2014
  • Author: Bishnu Prasad Devkota, MD, MHI, FRCS(Edin), FRCS(Glasg), FACP; Chief Editor: Eric B Staros, MD  more...
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Reference Range

Factor IX (plasma thromboplastin component [PTC]) is produced in the liver. It is a single-chain zymogen with a molecular weight of 57 kd and a plasma half-life of 18-24 hours. It binds effectively to collagen not only in vitro [1] but also, apparently, in vivo, and this may account for the finding that when factor IX is infused into hemophilia B patients, recovery is only 50% of what was expected.

The reference range for factor IX is between 70% and 120% of normal values. [2]

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Interpretation

Elevated factor IX concentrations are linked with an increased risk of thromboembolism. The following are associated with increases in factor IX:

  • Pregnancy
  • Use of oral contraceptives

The following are associated with decreases in factor IX [2] :

  • Hemophilia B
  • Liver disease
  • Use of vitamin K antagonists (eg, warfarin) or vitamin K deficiency
  • Amyloidosis
  • Nephrotic syndrome
  • Alloantibodies in hemophilia B patients treated with factor IX infusions
  • Autoantibodies to factor IX in previously healthy individuals (extremely rare)
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Collection and Panels

Collection approach and panels for factor IX are as follows:

  • Specimen: Plasma
  • Container: Blue-top vacuum tube
  • Collection method: Routine venipuncture
  • Packing: To comply with Occupational Safety and Health Administration (OSHA) safety standards, samples must be sent in a leakproof sealed container labeled with a biohazard sticker
  • Panels: Quantitative functional assays of coagulation factors
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Background

Description

Factor IX is produced in the liver. It circulates as a single-chain zymogen with a molecular weight of 57 kd and a plasma half-life of 18-24 hours. It binds effectively to collagen not only in vitro [1] but also, apparently, in vivo, and this may account for the finding that when factor IX is infused into hemophilia B patients, recovery is only 50% of what was expected. [3] The physiologic relevance of this finding is not yet clear; there is some evidence that factor IX mutants lacking collagen-IV binding may exhibit greater recovery but may be associated with a mild bleeding tendency. [4, 5]

Either activated factor XI (XIa) or the activated factor VII (VIIa)–tissue factor complex may activate factor IX. Activated factor IX (IXa), complexed with activated factor VIII (VIIIa) on a phospholipid membrane surface, activates factor X, and activity normally expressed on the surface of activated platelets. Platelets express a receptor/binding protein for factor IXa that promotes assembly of the IXa/VIIIa complex. [6]

Antithrombin (AT) is the primary inhibitor of factor IXa. Such inhibition, though notably slower than the inhibition of thrombin by AT, is enhanced in the presence of heparin.

The gene for factor IX is found on the X chromosome (on the tip of the long arm), [7] indicating that factor IX deficiency is sex-linked. [6] Christmas disease (hemophilia B) is caused by the deficiency of factor IX [8] and is treated with factor IX replacement. Products available on the market include prothrombin complex concentrates (PCCs), which contain prothrombin, factors VII and X, and proteins C and S in addition to factor IX. PCCs may also contain small amounts of factors VIIa, IXa, and Xa. [9] They may be less expensive than purified factor IX products.

Thromboembolism related to PCC use derives from contamination with activated components. In factor IX-deficient patients with liver dysfunction, inability of the diseased liver to clear the activated factors may lead to thrombosis. [6] Large PCC doses have led to reports of deep vein thrombosis (DVT) and disseminated intravascular coagulation (DIC) in some cases. The preparations now available, however, are less likely to give rise to these complications. As a general rule, if PCCs are to be used for replacement therapy, factor IX levels should not exceed 50% of normal.

Some highly purified factor IX products are derived from human plasma. Although factor IX products synthesized via recombinant DNA technology prevent transmission of prion disease, they are generally associated with lower intravascular recovery of factor IX than purified factor IX products prepared from plasma are. [10] Recombinant factor IX products appear not to give rise to thrombosis. [9] With regard to transmission of hepatitis B and C viruses and HIV, currently available factor IX concentrates are safe, though transmission of these viruses may have occurred in patients treated before 1985. [9]

Inhibitors may develop in factor IX –deficient patients exposed to factor concentrates early in life. In hemophilia B patients undergoing surgical procedures, tranexamic acid may help reduce the risk of perioperative bleeding. [11]

Indications/applications

Factor IX testing is indicated in the following situations:

  • Hemophilia B is suspected
  • The clinician needs to differentiate the effects of oral anticoagulants from those of liver disease

Considerations

Of the more than 100 factor IX gene mutations that have been identified, many cause bleeding diatheses, though some do not give rise to significant symptoms; a few may result in thromboembolism. [12]

Factor IX deficiency does not affect the prothrombin time (PT) appreciably; however, it does prolong the partial thromboplastin time (PTT) when the factor IX level falls to less than 40% of the normal value. [2]

The following factors may decrease the accuracy of the PT [2] :

  • Partial clotting of specimens, resulting from improper mixture of the anticoagulant (3:2 sodium citrate, as per the manufacturer’s blue-top tube)
  • Overfilling or underfilling of test tubes, either of which alters the blood-to-anticoagulant ratio (9:1)
  • Analytical errors (eg, lipemic, icteric, or hemolyzed plasma), which may interfere with photoelectric measuring instruments
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