Coagulation factor XII, also known as Hageman factor, is a plasma protein. It is the zymogen form of factor XIIa, an enzyme (EC 188.8.131.52) of the serine protease (or serine endopeptidase) class. In humans, factor XII is encoded by the F12 gene.
|, HAE3, HAEX, HAF, coagulation factor XII|
Human Factor XII is 596 amino acids long and consists of two chains, the heavy chain (353 residues) and light chain (243 residues) held together by a disulfide bond. It is 80,000 daltons. Its heavy chain contains two fibronectin-type domains (type I and II), two epidermal growth factor-like domains, a kringle domain, and a proline-rich region, and its light chain contains the protease domain. Recently, the structure of the FnI-EGF-like tandem domain of coagulation factor XII was solved by x-ray crystallography.
Factor XII is part of the coagulation cascade and activates factor XI and prekallikrein in vitro. Factor XII itself is activated to factor XIIa by negatively charged surfaces, such as glass. This is the starting point of the intrinsic pathway. Factor XII can also be used to start coagulation cascades in laboratory studies.
In vivo, factor XII is activated by contact to polyanions. Activated platelets secrete inorganic polymers, polyphosphates. Contact to polyphosphates activates factor XII and initiates fibrin formation by the intrinsic pathway of coagulation with critical importance for thrombus formation. Targeting polyphosphates with phosphatases interfered with procoagulant activity of activated platelets and blocked platelet-induced thrombosis in mice. Addition of polyphosphates restored defective plasma clotting of Hermansky–Pudlak syndrome patients, indicating that the inorganic polymer is the endogenous factor XII activator in vivo. Platelet polyphosphate-driven factor XII activation provides the link from primary hemostasis (formation of a platelet plug) to secondary hemostasis (fibrin meshwork formation).
Factor XII deficiency is a rare disorder that is inherited in an autosomal recessive manner. Unlike other clotting factor deficiencies, factor XII deficiency is totally asymptomatic and does not cause excess bleeding. Mice lacking the gene for factor XII, however, are less susceptible to thrombosis. The protein seems to be involved in the later stages of clot formation rather than the first occlusion of damages in the blood vessel wall.
Factor XII does play an important role in clot formation during in vitro measurements of the partial thromboplastin time, which causes these measurements to be markedly prolonged in patients with factor XII deficiency, usually well beyond even what is seen in hemophilia A, hemophilia B, or factor XI deficiency. As a result, the main concern related to factor XII deficiency is the unnecessary testing, delay in care, worry, etc. that may be prompted by the abnormal lab result. All of this, including the mechanism of inheritance, also holds true for the other contact factors, prekallikrein (Fletcher factor) and high molecular weight kininogen.
Excess levels of factor XII can predispose individuals towards greater risk of venous thrombosis due to factor XII's role as one of the catalysts for conversion of plasminogen to its active fibrinolytic form of plasmin.
Hageman factor was first discovered in 1955 when a routine preoperative blood sample of the 37-year-old railroad brakeman John Hageman (1918) was found to have prolonged clotting time in test tubes, even though he had no hemorrhagic symptoms. Hageman was then examined by hematologist Oscar Ratnoff, who found that Hageman lacked a previously unidentified clotting factor. Ratnoff later found that the Hageman factor deficiency is an autosomal recessive disorder, after examining several related people who had the deficiency. Paradoxically, pulmonary embolism contributed to Hageman's death after an occupational accident in 1968. Since then, case studies and clinical studies identified an association between thrombosis and Factor XII deficiency. Hepatocytes express blood coagulation factor XII.
Activated clotting time (ACT), also known as activated coagulation time is a test of coagulation.The ACT test can be used to monitor anticoagulation effects, such as high-dose heparin before, during, and shortly after procedures that require intense anticoagulant administration, such as cardiac bypass, cardiac angioplasty, thrombolysis, extra-corporeal membrane oxygenation (ECMO) and continuous dialysis. It measures the seconds needed for whole blood to clot upon exposure to an activator of an intrinsic pathway by the addition of factor XII activators. The clotting time is based on a relative scale and requires a baseline value for a point of comparison due to inconsistencies between the source and formulation of the activator being used. It is usually ordered in situations where the partial thromboplastin time (PTT) test may take an excessive amount of time to process or is not clinically useful. Prolongation of the ACT may indicate a deficiency in coagulation factors, thrombocytopenia or platelet dysfunction. Clotting time measurements can be affected by other drugs that such as Warfarin, aprotinin and GPIIb/IIIa inhibitors and may also be affected by physical perturbations to the body such as hypothermia, hypervolemia or hypovolemia.Angioedema
Angioedema is an area of swelling of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which are swelling within the upper skin. Onset is typically over minutes to hours.The underlying mechanism typically involves histamine or bradykinin. The version related to histamine is due to an allergic reaction to agents such as insect bites, foods, or medications. The version related to bradykinin may occur due to an inherited problem known as C1 esterase inhibitor deficiency, medications known as angiotensin converting enzyme inhibitors, or a lymphoproliferative disorder.Efforts to protect the airway may include intubation or cricothyroidotomy. Histamine related angioedema can be treated with antihistamines, corticosteroids, and epinephrine. In those with bradykinin related disease a C1 esterase inhibitor, ecallantide, or icatibant may be used. Fresh frozen plasma may be used instead. In the United States the disease affects about 100,000 people a year.Anti-apolipoprotein antibodies
In autoimmune disease, anti-apolipoprotein H (AAHA) antibodies, also called anti-β2 glycoprotein I antibodies, comprise a subset of anti-cardiolipin antibodies and lupus anticoagulant. These antibodies are involved in sclerosis and are strongly associated with thrombotic forms of lupus. As a result AAHA are strongly implicated in autoimmune deep vein thrombosis.
Also, it was proposed that AAHA is responsible for lupus anticoagulant. However, antiphospholipid antibodies bind phospholipids at sites similar to sites bound by anti-coagulants such as PAP1 sites and augment anti-coagulation activity.
This contrasts with the major, specific, activity of AAHA, defining a subset of anti-cardiolipin antibodies that specifically interacts with Apo-H. AHAA only inhibits the anti-coagulation activity in the presence of Apo-H and the AAHA component of ACLA correlates with a history of frequent thrombosis. This can be contrasted with lupus anticoagulant which inhibits agglutination in the presence of thrombin. A subset of AHAA appear to mimic the activity of lupus anticoagulant and increase Apo-H binding to phospholipids. These two activities can be differentiated by the binding to Apo-H domains, whereas binding to the 5th domain promotes that anti-coagulant activity binding to the more N-terminal domains promotes lupus anticoagulant-like activities.
AAHA interferes with factor Xa inhibition by Apo-H increasing factor Xa generation. However, like Apo-H the Lupus anticoagulant inhibits factor Xa generation.AAHA also inhibited the autoactivation of factor XII while at high AAHA concentrations, factor XIIa activation increases at levels comparable to Apo-H that cause inhibition of factor XIIa activation. A synchronized inhibition of factor XII autoactivation by Apo-H and AHAA has been suggested.CD93
CD93 (Cluster of Differentiation 93) is a protein that in humans is encoded by the CD93 gene. CD93 is a C-type lectin transmembrane receptor which plays a role not only in cell–cell adhesion processes but also in host defense.Contact activation system
In the contact activation system or CAS, three proteins in the blood, factor XII (FXII), prekallikrein (PK) and high molecular weight kininogen (HK), bind to a surface and cause blood coagulation and inflammation. FXII and PK are proteases and HK is a non-enzymatic co-factor. The CAS can activate the kinin–kallikrein system and blood coagulation through its ability to activate multiple downstream proteins. The CAS is initiated when FXII binds to a surface and reciprocal activation of FXII and PK occurs, forming FXIIa and PKa. FXIIa can initiate the coagulation cascade by cleaving and activating factor XI (FXI), which leads to formation of a blood clot. Additionally, the CAS can activate the kinin–kallikrein system when PKa cleaves HK to form cHK, releasing a peptide known as bradykinin (BK). BK and its derivatives bind to bradykinin receptors B1 and B2 to mediate inflammation.Factor XI
Factor XI or plasma thromboplastin antecedent is the zymogen form of factor XIa, one of the enzymes of the coagulation cascade. Like many other coagulation factors, it is a serine protease. In humans, Factor XI is encoded by the F11 gene.Factor XII deficiency
Factor XII deficiency (also Hageman factor deficiency) is a deficiency in the production of factor XII (FXII), a plasma glycoprotein and clotting factor that participates in the coagulation cascade and activates factor XI. FXII appears to be not essential for blood clotting, as individuals with this condition are usually asymptomatic and form blood clots in vivo. FXII deficiency tends to be identified during presurgical laboratory screening for bleeding disorders.The condition can be inherited or acquired.Fibronectin type II domain
Fibronectin type II domain is a collagen-binding protein domain.
Fibronectin is a multi-domain glycoprotein, found in a soluble form in plasma, and in an insoluble form in loose connective tissue and basement membranes, that binds cell surfaces and various compounds including collagen, fibrin, heparin, DNA, and actin. Fibronectins are involved in a number of important functions e.g., wound healing; cell adhesion; blood coagulation; cell differentiation and migration; maintenance of the cellular cytoskeleton; and tumour metastasis. The major part of the sequence of fibronectin consists of the repetition of three types of domains, which are called type I, II, and III.Type II domain is approximately sixty amino acids long, contains four conserved cysteines involved in disulfide bonds and is part of the collagen-binding region of fibronectin. Type II domains occur two times in fibronectin. Type II domains have also been found in a range of proteins including blood coagulation factor XII; bovine seminal plasma proteins PDC-109 (BSP-A1/A2) and BSP-A3; cation-independent mannose-6-phosphate receptor; mannose receptor of macrophages; 180 Kd secretory phospholipase A2 receptor; DEC-205 receptor; 72 Kd and 92 Kd type IV collagenase (EC 184.108.40.206); and hepatocyte growth factor activator.Glycoprotein Ib-IX-V Receptor Complex
The GPIb-IX-V complex is a profuse membrane receptor complex originating in megakaryocytes and exclusively functional on the surface of platelets. It primarily functions to mediate the first critical step in platelet adhesion, by facilitating binding to von Willebrand factor (VWF) on damaged sub-endothelium under conditions of high fluid shear stress. Although the primary ligand for the GPIb-V-IX receptor is VWF, it can also bind to a number of other ligands in the circulation such as thrombin, P-selectin, factor XI, factor XII, high molecular weight kininogen as well as bacteria. GPIb-IX-V offers a critical role in thrombosis, metastasis, and the life cycle of platelets, and is implicated in a number of thrombotic pathological processes such as stroke or myocardial infarction.Hemostatic dressing
Hemostatic dressing, such as QuikClot, is a wound dressing that contains an agent that promotes blood clotting.Hereditary angioedema
Hereditary angioedema (HAE) is a disorder that results in recurrent attacks of severe swelling. The swelling most commonly affects the arms, legs, face, intestinal tract, and airway. Itchiness does not typically occur. If the intestinal tract is affected abdominal pain and vomiting may occur. Swelling of the airway can result in its obstruction. Attacks, without preventive treatment, typically occur every couple of weeks and last for a few days.There are three main types of HAE. Type I and II are caused by a mutation in the SERPING1 gene that makes the C1 inhibitor protein while type III is often due to a mutation of the factor XII gene. This results in increased amounts of bradykinin which promotes swelling. The condition may be inherited from a person's parents in an autosomal dominant manner or occur as a new mutation. Triggers of an attack may include minor trauma or stress, but often occurs without any obvious preceding event. Diagnosis of type I and II is based upon measuring C4 and C1-inhibitor levels.Management involves efforts to prevent attacks and the treatment of attacks if they occur. During an attack supportive care such as intravenous fluids and airway support may be required. The medication C1 inhibitor can be used for both prevention and treatment. Ecallantide and icatibant can be used to treat acute attacks.This disorder affects approximately one in 50,000 people. The condition is typically first noticed in childhood. Type I and II affected females and males equally. Type III affects females more often than males. When the airway is involved, without treatment, death occurs in about 25%. With treatment outcomes are generally good. The condition was first described in 1888 by William Osler.High-molecular-weight kininogen
High-molecular-weight kininogen (HMWK or HK) is a circulating plasma protein which participates in the initiation of blood coagulation, and in the generation of the vasodilator bradykinin via the kallikrein-kinin system. HMWK is inactive until it either adheres to binding proteins beneath an endothelium disrupted by injury, thereby initiating coagulation; or it binds to intact endothelial cells or platelets for functions other than coagulation.Hypotensive transfusion reaction
A Hypotensive transfusion reaction or HTR is a rare condition that presents with low blood pressure associated with administration of blood products. The low blood pressure quickly resolves when the transfusion is stopped.
HTRs are caused by the production of bradykinin produced through Factor XII activation by negatively charged surfaces such as filters. When mechanisms for the degradation of bradykinin are impaired, the peptide builds up and causes hypotension. Angiotensin converting enzyme (ACE) is primarily responsible for its degradation (75%) but can be inhibited by administration of blood pressure medications called ACE inhibitors. Polymorphisms in ACE or aminopeptidase P (APP), another enzyme responsible for bradykinin degradation (20%) may also contribute to HTRs.Kininogen
Kininogens are proteins that are defined by their role as precursors for kinins, but that also can have additional roles. Kinins are biologically active peptides, the parent form is bradykinin.
The two main kininogen types are:
High-molecular-weight kininogen, which is produced mostly by the liver but is synthesized in endothelial cells and is present in platelets and neutrophils. It acts as a cofactor for prekallikrein, factor XI, and factor XII in the coagulation and inflammation systems. It has no intrinsic enzymatic activity. These high molecular weight kininogens are cleaved into bradykinin and kallidin by tissue and plasma kallikreins.
Low-molecular-weight kininogen, which is produced locally by numerous tissues, and secreted together with tissue kallikrein.They are both spliced from the same precursor.
A third type, T-kininogen, is found in rats but not humans.Closely related proteins include cystatin.Oscar Ratnoff
Oscar Davis Ratnoff (August 23, 1916 – May 20, 2008) was an American physician who conducted research on the process of coagulation and blood-related disorders. Ratnoff discovered the substance later known as factor XII and was one of the primary contributors to the delineation of the exact sequence that makes up the clotting cascade. He also made notable research contributions to the understanding of the complement system and to the detection and treatment of hemophilia.
Ratnoff was a professor at the Case Western Reserve University School of Medicine, served as president of the American Society of Hematology, and was elected to the National Academy of Sciences. He remained active in research at Case Western Reserve until he was 85 and he died in Cleveland a few years later.Polyphosphate
Polyphosphates are salts or esters of polymeric oxyanions formed from tetrahedral PO4 (phosphate) structural units linked together by sharing oxygen atoms. Polyphosphates can adopt linear or a cyclic ring structures. In biology, the polyphosphate esters ADP and ATP are involved in energy storage. A variety of polyphosphates find application in mineral sequestration in municipal waters, generally being present at 1 to 5 ppm. GTP, CTP, and UTP are also nucleotides important in the protein synthesis, lipid synthesis, and carbohydrate metabolism, respectively.Prekallikrein
Prekallikrein (PK), also known as Fletcher factor, is an 85,000 Mr serine protease that complexes with high-molecular-weight kininogen. PK is the precursor of plasma kallikrein, which is a serine protease that activates kinins. PK is cleaved to produce kallikrein by activated Factor XII (Hageman factor).Purpura
Purpura is a condition of red or purple discolored spots on the skin that do not blanch on applying pressure. The spots are caused by bleeding underneath the skin secondary to platelet disorders, vascular disorders, coagulation disorders, or other causes. They measure 0.3–1 cm (3–10 mm), whereas petechiae measure less than 3 mm, and ecchymoses greater than 1 cm.Purpura is common with typhus and can be present with meningitis caused by meningococci or septicaemia. In particular, meningococcus (Neisseria meningitidis), a Gram-negative diplococcus organism, releases endotoxin when it lyses. Endotoxin activates the Hageman factor (clotting factor XII), which causes disseminated intravascular coagulation (DIC). The DIC is what appears as a rash on the affected individual.Vroman effect
The Vroman effect, named after Leo Vroman, is exhibited by protein adsorption to a surface by blood serum proteins. The highest mobility proteins generally arrive first and are later replaced by less mobile proteins that have a higher affinity for the surface. A typical example of this occurs when fibrinogen displaces earlier adsorbed proteins on a biopolymer surface and is later replaced by high molecular weight kininogen. The process is delayed in narrow spaces and on hydrophobic surfaces, fibrinogen is usually not displaced. Under stagnant conditions initial protein deposition takes place in the sequence: albumin; globulin; fibrinogen; fibronectin; factor XII, and HMWK.
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|Sources:Amigo / QuickGO|
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