Three proteins – factor XII, prekallikrein (PK), and high-molecular- weight kininogen (HK) – comprise the contact system, currently referred to as the plasma kallikrein-kinin system (KKS) (Table 49–1). HK was originally identified as a substrate (1) that yields a bioactive peptide, bradykinin (BK), when cleaved. BK in vivo stimulates microvascular permeability and arteriolar vasodilation, resulting in hypotension. Two enzymes are required for the hydrolysis of HK. In 1955, factor XII was discovered by Oscar Ratnoff in a study of a patient, John Hageman, who lacked the protein and had a very prolonged coagulation time (2). Prekallikrein (PK) was first purified from human plasma as the activated enzyme, kallikrein, after being identified by Hathaway in 1965, in a subject with modestly prolonged activated partial thromboplastin time (aPTT) (3). Factor XII autoactivates to factor XIIa, which cleaves plasma PK to kallikrein. Kallikrein then feeds back to cleave factor XII to factor XIIa. Plasma kallikrein and factor XIIa (to a lesser extent) both hydrolyze HK to form cleaved HK (HKa) and BK. The importance of HK was first apparent when three different research groups described patients deficient in HK with prolonged aPTT. One such patient, Williams (4), was identified by our laboratory to have absent BK, even in the urine. All three proteins – factor XII, PK, and HK– were cloned in the mid-1980s.

FACTOR XII

Factor XII is encoded by a single gene of 12 kb that maps to chromosome 5, comprising 13 introns and 14 exons (5). A putative signal peptide sequence on the NH2 terminus of the zymogen is located on the first exon, followed by a region of unknown homology encoded by the second exon.