COAGULATION FACTORS AND THE ROLE OF SURFACE IN THEIR ACTIVATION *

A critical moment in the development of knowledge concerning mammalian blood coagulation was the observation of Bordet and Gengou' that the clotpromoting property of glass was exerted, at least in part, by an action upon cell-poor plasma. Over the years, many attempts were made to localize the effect of glass to one or another component of plasma, Borrowing methods that had been developed by Margolis 2 and by Shafrir and deVries,:{ we were able to demonstrate that the clot-promoting effect of glass was related to an action upon Hageman factor (factor X U ) , an agent deficient in the plasma of an asymptomatic individual, Mr. John Hageman:I. Since then, a large number of insoluble agents have been discovered that appear to initiate the clotting process through an action upon Hageman factor, including, for example, kaolin, diatomaceous earth, and talc." All of these substances have the property of adsorbing Hageman factor from plasma. After suitable washing, these solids with their adsorbed Hageman factor can then correct the defective clotting of individuals deficient in Hageman factor, as if the adsorbed Hageman factor had been converted from an inert to an activated form. How the activation of Hageman factor comes about is only partially understood. Hubbard and Lucas demonstrated that a wide variety of substances that initiated coagulation bore, on their surfaces, a negative ionic charge. A reasonable assumption, then, is that such substances activate Hageman factor by reacting in some unknown way with amino acid residues of the Hageman factor molecule that are positively charged. Analysis of purified preparations of human Hageman factor demonstrate that each molecule contains approximately 27 arginine, 23 lysine, and 23 histidine residues,h any of which might be affected by negative charges. Takahashi !' reported that under appropriately mild conditions, phenylglyoxal hydrate would react specifically with arginine residues, Using his conditions, we found that this compound would so alter Hageman factor that it could no longer be activated by kaolin. If the Hageman factor had first been adsorbed to kaolin, however, this inhibitory property of phenylglyoxal hydrate was no longer manifest.Io These experiments do not tell us the way in which clot-promoting surfaces activate Hageman factor, nor even if these residues are the only sites upon which charged surfaces act, but they do suggest a rational basis for further studies.