Hageman factor

Factor XIIa
	Existing structure data : 4BDW , 4BDX , 4XDE , 4XE4
Properties of human protein
Mass / length primary structure	596 = 353 + 243 amino acids
Precursor	Factor XII
Identifier
Gene names	F12 ; HAF
External IDs	OMIM : 234000 ; UniProt : P00748 ; MGI : 1891012 ;
Enzyme classification
EC, category	3.4.21.38 , serine protease
MEROPS	S01.211
Substrate	Arg - + - Ile in factor VII / XI
Products	Factor VIIa / XIa
Occurrence
Homology family	Trypsin
Parent taxon	Creature
	Orthologue

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

genetics

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

function

Factor XII is activated on the surface of procoagulant platelets. Platelets release polyphosphates (long-chain polymers made up of phosphate subunits), which efficiently activate factor XII. Active factor XII then triggers the intrinsic blood coagulation cascade via its substrate factor XI, which leads to fibrin formation.

Meets the Hageman factor on negatively charged surfaces ( in vivo : polyphosphates , collagen , cell fragments , bacterial endotoxins, in vitro : glass, kaolin , asbestos , monosodium urate crystals , long chain fatty acids ), it is prior activated. This pre- activated form catalyzes the conversion of prekallikrein (Fletcher factor) to kallikrein . This now converts high-molecular kininogen (Fitzgerald factor) to kinin . Kallikrein and Kinin in turn convert the Hageman factor into its activated form; it is referred to as factor XIIa. A single peptide bond is cleaved by limited proteolysis and a two-chain form is created. Both subunits are still covalently linked by a disulfide bridge. Activated Hageman factor activates plasma thromboplastin antecedent (factor XI) and plasminogen by proteolysis .

Diseases

A severe deficiency of Hageman factor occurs as a rare hereditary disease with a frequency of 1: 1,000,000, but with a slight increase in Asians. The deficiency does not cause an increased tendency to bleeding, since the fibrin formation in vessels started by factor XII is of no importance for hemostasis. In genetically modified mouse models in which the gene for factor XII has been inactivated, the thrombus formation is defective and these factor XII-deficient animals are protected to a considerable extent from brain damage after a stroke. A pharmacological blockade of this factor is therefore advisable in order to block the formation of thrombus without this having to be paid for with an increased tendency to bleed, which is the case with current anticoagulants (heparins, coumarins). The deficiency of factor XII leads to a massive increase in the partial thromboplastin time in both humans and mice .

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

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 factor XII leads to a rare hereditary swelling disorder, hereditary angioedema type III.

multiple sclerosis

A higher than normal amount of factor XII was found in the blood of the patients in the blood serum of patients with active multiple sclerosis . FXII could regulate the immune response in this inflammatory disease. In mice with experimental encephalomyelitis, factor XII blockade could reduce inflammation and symptoms.

Research history

Hageman factor was first discovered in 1955 in a 37-year-old patient named John Hageman when, during a routine blood test before an operation, it was noticed that his blood had increased clotting time in the test tube without any hemorrhagic symptoms. Hageman was then examined by Oscar Ratnoff , who found the lack of a previously undiscovered coagulation factor. Ratnoff later discovered while examining relatives that this deficiency is inherited as an autosomal recessive trait.

Web links

Hageman factor. In: Online Mendelian Inheritance in Man . (English)

swell

↑ Renné T, Pozgajová M, Grüner S, et al : Defective thrombus formation in mice lacking coagulation factor XII . In: J. Med.. . 202, No. 2, July 2005, pp. 271-81. doi : 10.1084 / jem.20050664 . PMID 16009717 . PMC 2213000 (free full text).
↑ Müller F, Mutch NJ, Schenk WA, et al : Platelet Polyphosphates are Proinflammatory and Procoagulant Mediators in vivo . In: CELL . 139, No. 6, December 2009, pp. 1143-56. doi : 10.1016 / j.cell.2009.11.001 . PMID 20005807 . PMC 2796262 (free full text).
↑ K. Göbel, S. Pankratz u. a .: Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells. In: Nature Communications . Volume 7, 2016, p. 11626, doi : 10.1038 / ncomms11626 , PMID 27188843 .
↑ RATNOFF OD, MARGOLIUS A: Hageman trait: an asymptomatic disorder of blood coagulation . In: Trans. Assoc. At the. Physicians . 68, 1955, pp. 149-54. PMID 13299324 .
↑ MARGOLIUS A, RATNOFF OD: Observations on the hereditary nature of Hageman trait . In: Blood . 11, No. 6, June 1956, pp. 565-9. PMID 13315514 .

[1] Renné T, Pozgajová M, Grüner S, et al : Defective thrombus formation in mice lacking coagulation factor XII . In: J. Med.. . 202, No. 2, July 2005, pp. 271-81. doi : 10.1084 / jem.20050664 . PMID 16009717 . PMC 2213000 (free full text).

[2] Müller F, Mutch NJ, Schenk WA, et al : Platelet Polyphosphates are Proinflammatory and Procoagulant Mediators in vivo . In: CELL . 139, No. 6, December 2009, pp. 1143-56. doi : 10.1016 / j.cell.2009.11.001 . PMID 20005807 . PMC 2796262 (free full text).

[PMID27188843-3] K. Göbel, S. Pankratz u. a .: Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells. In: Nature Communications . Volume 7, 2016, p. 11626, doi : 10.1038 / ncomms11626 , PMID 27188843 .

[4] RATNOFF OD, MARGOLIUS A: Hageman trait: an asymptomatic disorder of blood coagulation . In: Trans. Assoc. At the. Physicians . 68, 1955, pp. 149-54. PMID 13299324 .

[5] MARGOLIUS A, RATNOFF OD: Observations on the hereditary nature of Hageman trait . In: Blood . 11, No. 6, June 1956, pp. 565-9. PMID 13315514 .