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  1. Exposure of blood or plasma to negatively charged surfaces results in activation of the plasma proteins factor XII and prekallikrein (PK) by a process termed contact activation. These reactions require the cofactor high-molecular-weight-kininogen (HK). Contact activation triggers fibrinolysis, kinin formation, and blood coagulation through activation of factor XI.

  2. The cDNAs for human factor XI, factor XII, PK, and HK have been cloned, and the amino acid sequences and domain structures of the proteins have been determined. Factor XI, factor XII, and PK are zymogens of serine proteases containing C-terminal trypsin-like catalytic domains and N-terminal domains that bind other macromolecules. Factor XI is a homodimer of 80-kDa polypeptides structurally similar to PK. Factor XI and PK circulate as noncovalent complexes with HK. HK is a multifunctional 110-kDa protein with domains for binding to cells, factor XI, PK, and negatively charged surfaces, and two domains that inhibit cysteine proteases. HK is a source of the potent vasodilatory nanopeptide bradykinin.

  3. Genes for factor XI, factor XII, PK, and HK have been characterized and their chromosomal locations determined. Mutations causing hereditary deficiency states have been identified for each protein except PK. The genes, cDNAs, and amino acid sequence for factor XI and PK are very similar, which suggests that they are the products of a duplication event involving a common ancestral gene.

  4. Deficiency of factor XI (mim 264900) results in excessive bleeding following trauma or surgery indicating that this protein is essential for normal coagulation. In contrast, deficiencies of factor XII (mim 234000), PK (mim 229000), HK (mim 228960) are not associated with clinical abnormalities. These observations suggest that factor XI is activated in vivo by processes other than contact activation.

  5. Factor XI deficiency is common in Ashkenazi Jews, in whom the carrier frequency has been estimated to be 5 to 13 percent. Two distinct point mutations account for the majority of abnormal alleles in this group. The type II mutation results in early termination of the protein, while the type III mutation causes greatly reduced protein secretion from the liver.

  6. While deficiencies of factor XII, PK, or HK are not associated with an abnormal phenotype, inappropriate activation of these proteins may contribute to pathologic processes in several clinical conditions such as sepsis, inflammation, and hereditary angioedema.

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