What is factor IX?

Updated: Feb 04, 2020
  • Author: Bishnu Prasad Devkota, MD, MHI, FRCS(Edin), FRCS(Glasg), FACP; Chief Editor: Eric B Staros, MD  more...
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Answer

Answer

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. [4] 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. [5, 6]

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. [7]

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), [8] indicating that factor IX deficiency is sex-linked. [7] Christmas disease (hemophilia B) is caused by the deficiency of factor IX [9] 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. [10] 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. [7] 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. [11] Recombinant factor IX products appear not to give rise to thrombosis. [10] 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. [10]

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. [12]

Gene therapy employing adeno-associated viral (AAV) vectors has emerged as a treatment for hemophilia B, with the use of hyperactive factor IX variant R338L (Padua) having been found to ameliorate the problem of liver toxicity linked to high vector doses. A study by Samelson-Jones et al indicated that without factor VIIIa activity, hyperactivity is ablated for recombinant factor IX R338L and for factor IX R338L expressed via the AAV-mediated transgene. [13, 14]


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