Factor XII

• OMIM: 234000
• UniProt: P00748
• MGI: 1891012

The Hageman factor (factor XII ) is an enzyme involved in blood clotting and belongs to the group of serine proteases. He also belongs to the β - globulins and is represented in the blood plasma as a monomer at a concentration of 15-45 mg / l. Its molecular mass is 80 kDa. In addition to its function for thrombus formation factor XII brings the kallikrein - kinin system in transition, leading to the formation of the inflammatory mediator bradykinin. Factor XII is mainly of liver cells (hepatocytes ) and synthesized by cleavage of the propeptide as an inactive form of the enzyme ( zymogen ) secreted into the plasma.

Genetics

The gene of the Hageman factor in humans is on chromosome 5 locus q33 - qter.

Function

Factor XII is activated on the surface of procoagulant platelets. Platelet polyphosphates set free ( long-chain polymers of phosphate subunits) that activate factor XII efficiently. Active factor XII is then its substrate factor XI of the intrinsic blood coagulation cascade the impetus leading to fibrin formation.

Does the Hageman factor to negatively charged surfaces ( in vivo: polyphosphates, collagen, cell fragments, bacterial endotoxin, and in vitro: glass, kaolin, asbestos, uric acid crystals, long-chain fatty acids), it is pre-activated. This pre-activated form catalyzes the conversion of prekallikrein ( Fletcher Factor) to kallikrein. This now converts high molecular weight kininogen to ( Fitzgerald factor) to kinin. Kallikrein and kinin in turn convert the Hageman factor to its activated form; it is referred to as factor XIIa. This is done by limited proteolysis cleavage of a single peptide bond and there is a two-chain form. Both subunits are not covalently linked by a disulfide bond. Activated Hageman factor activated by proteolysis plasma thromboplastin antecedent (factor XI) and plasminogen.

Diseases

A severe deficiency of Hageman factor occurs as a rare genetic disease with an incidence of 1:1,000,000, but with a slight accumulation in Asians. The deficiency causes no increased risk of bleeding, since the launched of Factor XII Fibrin in vessels has no meaning for hemostasis ( hemostasis ). In genetically modified mouse models, in which the gene has been inactivated for Factor XII, the thrombus is broken and this factor XII deficient mice are protected in a significant extent prior to the brain damage caused by stroke. Therefore, a pharmacological blockade of this factor offers to block thrombus formation, without this being purchased with an increased bleeding tendency, which is the case with current anticoagulants ( heparin, warfarin ). Both in humans and in mice a lack of factor XII leads to a massive increase in the partial thromboplastin time.

Factor XII is polyphosphates, which are secreted by platelets, activated ( contact phase activation). The polyphosphate -mediated factor XII activation combines primary hemostasis (formation of a platelet aggregate ) with the secondary hemostasis ( plasmatic coagulation cascade ). Defects of the polyphosphates -mediated factor XII activation reduce the stability of thrombi and thus increase the one hand, the risk of venous embolism and on the other hand in the arterial system, the formation of clots.

In addition to its function for thrombus formation factor XII starts the kallikrein - kinin system, which leads to the formation of the inflammatory mediator bradykinin. A single point mutation in the factor XII leads to a rare inherited disease swelling, the hereditary angioedema type III.

History of Research

The Hageman factor was first in 1955 when a 37 -year-old patient named John Hageman discovered when it was noticed during a routine blood test before surgery that the coagulation time of his blood was increased in the test tube, without that he had hemorrhagic symptoms. Hageman was then examined by Oscar Ratnoff, who noted the lack of a hitherto undiscovered clotting factor. Ratnoff later discovered in the investigation of relatives that this deficiency is inherited in an autosomal recessive manner.