Factor XII

Factor XII is a coagulation factor that initiates the intrinsic (contact) coagulation system. It is for this reason that it is also known as contact factor. It was described in 1955 in a patient John Hageman and hence it is also known as Hageman’s factor. It does not have a role in normal coagulation but may provide a link between inflammation and coagulation. It may have a role in pathological thrombosis.

 

Gene

The Gene for factor XII is situated on chromosome 5 (5q33-qter). The gene is 12 kilobases in length and contains 13 introns and 14 exons. It has an oestrogen responsive element in it’s promoter.

 

Biochemistry of Factor XII

Factor XII is a 596 amino acid single chain β-globin zymogen with a molecular weight 80kDa. It is primarily produced in the liver. Factor XII is 17% glycosylated. The plasma concentration of factor XII is 40 μg/ml (500 nmol/L) and it has a half-life of 2 to 3 days.

 

It is the following domains (from the N-terminal to the C terminal)

  1. N-terminal fibronectin domain type II (exons 3,4)
  2. Epidermal-growth-factor like domain (exon 5)
  3. Fibronectin domain type I (exon 6)
  4. Epidermal growth factor like domain (exon 7)
  5. Kringle domain (exon 8 and 9),
  6. Proline rich region
  7. The catalytic domain (exon 10-14) at the COOH end.

Kallikrein splits the bond between Val352 and Arg353 activating factor XII to XIIa (see activation). activation converts factor XII into a two chain structure held together by a disulfide bond between Cys340-Cys367.  The heavy chain is responsible for binding of factor XIIa to anionic surfaces (52 kDa) and a light chain (28 kDa) that has the enzymatic activity.

 

Activation

Factor XII can be activated to XIIa by the following

  1. Contact with negatively charged surfaces: Factor XII is activated by contact with negatively charged surfaces e.g. glass, kaolin, dextran sulphate, ellagic acid and bismuth subgallate. This rection forms the basis of the activated partial thromboplastin test. As none of these activators are encountered under physiological circumstances it is not the mechanism by which factor XII is activated in vivo for normal haemostasis. It has been hypothesized that contact with anionic surfaces provided by polyphosphates results in a conformational change and activation of factor XII. The mechanism of this activation is not clear.
  2. Activation of By Kallikrein: Factor XII, prekallikrein and high molecular weight kininogen can form a complex on anionic phospholipids of membranes. This, as discussed above, leads to a conformational change in factor XII leading to it’s activation. XIIa splits kallikrein from prekallikrein that in turn activates factor XII leading to a mutual activation loop. Activation involves a cleavage of the peptide bond between Arg 353-Val354 that converts a single chain factor XII to a two chain factor XIIa that are connected by a single disulphide bond between Cys340-Cys367.

 

 

Actions of Activated Factor XIIa

Factor XIIa activates coagulation by the intrinsic pathway by activating factor XI. The ability of factor XIIa to split prekallikrein to kallikrein links it to inflammation and fibrinolysis. Kallikrein is converts plasminogen to plasmin, pro-u-PA to u-PA and cleaves high-molecular weight kininogen to give bradykinin. Factor XII is pro-inflammatory and promotes thrombolysis by these actions.

 

 

Regulation

The principle inhibitor of factor XIIa is C1-inhibitor. Antithrombin, α1-antitrypsin, α1-antiplasmin and α2-macroglobulin are the other inhibitors of factor XIIa

 

Role of Factor XII in Haemostasis

Patients with factor XII deficiency do not suffer bleeding following trauma or surgery despite having a prolonged aPTT. The role of factor XII in haemostasis is complex and unclear. There are many divergent pieces of evidence from experimental and epidemiological studies. These include:

  1. Deficiency in factor XII in mice has been shown to protect against thrombosis induced by injury.
  2. Anti-factor XII monoclonal antibody has been shown to reduce fibrin formation in collagen coated tubes perfused by human blood.
  3. The same antibody has been shown to reduce platelet and fibrin deposition in a baboon graft model
  4. Epidemiological studies have shown an inverse relation between factor XII levels from between all cause mortality and factor XII levels for factor XII levels between 10-100% but no increase in patients with factor levels ≤10%.

Factor XII and Disease

Mutations in factor XII have been associated with type III hereditary angioedema (HE) type III. Unlike patients of type I and II HE who have a defect of C1 inhibitor, patients of Type III HE have point mutation in factor XII resulting in substitution of threonine at position 309 with arginine or lysine.

 

 

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