Contact system: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes.

and increased microvessel permeability. In 1975, three indiHigh Molecular Weight Kininogen (Williams, Fitzgerald viduals were described with deficiency of high molecular Factor) weight kininogen (HK), a precursor of BK, all of whom had Gene expression and regulation. The two forms of a prolonged activated partial thromboplastin time (APTT), plasma kininogens, HK and low molecular weight kininogen a surface-activated coagulation protein screening test. De(LK), are the products of a single gene. This gene maps spite the fact that none of these individuals had a hemorto 3q26-qter, the location of the homologous a2HS-glycoprorhagic state, studies on the plasma kallikrein-kinin system tein and histidine-rich glycoprotein. The single kininogen focused on defining the procoagulant property of HK. In gene of 11 exons consisting of 27 kb produces a unique fact, it was already known that deficiency of the two zymomRNA for HK and LK by alternative splicing (Fig 1). HK gens, factor XII and prekallikrein, required for the enzymatic and LK share the coding region of the first nine exons, a cleavage of HK, also did not lead to bleeding. These plasma part of exon 10 containing the BK sequence, and the first proteins together were grouped as the contact system because 12 amino acids after the carboxy-terminal sequence of BK. they required contact with artificial, negatively charged surExon 11 codes for a unique 4-kD light chain of LK. The faces for zymogen activation. Over the last 20 years, these complete exon 10 contains the full coding sequence for the proteins have been shown to have little influence on hemounique 56-kD light chain of HK. A novel mechanism for stasis. However, examination of their molecular, biochemialternative RNA processing has been characterized in the rat cal, biologic, and physiologic properties has shown that these kininogen gene. Splicing efficiency is controlled by the proteins interact with a number of physiologic and pathointeraction of U1 small nuclear ribonucleoproteins and the physiologic systems. Cloning and delineation of their strucU1 small nuclear RNA (snRNA)-complementary repetitive ture-function relationships have shown new activities of sequences of the kininogen pre-mRNA. The mRNA for LK these proteins such as protease inhibition, antithrombin funcand HK are 1.7 and 3.5 kb, respectively. tion, and antiadhesive properties. Their specific interactions The molecular basis for one example of homozygous total with biologic membranes of endothelial cells, platelets, neukininogen deficiency, Williams trait, has been determined. trophils, and monocytes indicate that assembly and activaA C to T transition at nucleotide 587 occurred, changing a tion of this system takes place in a physiologic milieu, indeCGA (Arg) codon to TGA (Stop) mutation in exon 5 and pendent of negatively charged surfaces. In fact, it is correct to resulting in prevention of synthesis of both HK and LK. say that the so-called elusive physiologic, negatively charged The phenotype of this defect is similar to that seen in Brownsurface for contact system activation is actually the assembly Norway, Katholiek strain rats that have absent plasma kininof these proteins on cell membranes. In vivo, a negatively ogens, but the defect in the rats is due to a single point charged surface is not needed for activation. One may argue mutation, Ala163 to Thr, which results in defective secretion that the term contact activation is a misnomer to describe from the liver. Little is known about what regulates gene this system. The proteins of the plasma contact system have expression of kininogens. In the rat, ovariectomy results in anticoagulant, profibrinolytic, antiadhesive, and proinflama reduction of kininogen transcripts in the liver, whereas matory functions. This review presents a revitalized view of