766 XII. VITAMINS K 



cumarolized chicks which was capable of accelerating the clotting of 

 vitamin K-deficient plasma. This new factor was called the 5-factor.'^* 

 It differed from factor V, from prothrombin, and from factor k. 



It is assumed that, during blood coagulation, thromboplastin does not 

 act directly on prothrombin, but on proconvertin, and that it activates 

 the latter to converthi.^-^ Convertin transforms prothrombin into throm- 

 bin, aided by accelerin, which is formed from proaccelerin.^-'^ The latter 

 is believed to consist of several factors. Dam'-^ reviewed this subject in 

 1953. 



(^) In Counteracting Hemorrhagic Conditions due to Dicwnarol 



The understanding of the mode of action and source of some of the 

 natural hemorrhagic agents constitutes one of the brilliant discoveries of 

 recent years. It was recognized by Roderick'-^ that the disease occurring 

 in cattle as a result of feeding on spoiled sweet clo\'er was associated with 

 a prothrombin deficiency. Approximately twelve to twenty-four hoin-s 

 elapse after the feeding of spoiled sweet clover before the hypoprothrom- 

 binemia is established. It is believed that this period of time is required 

 to cataboUze the prothrombin present at the time of the feeding. ^''^•'^" 

 Since no new prothrombin is synthesized after the toxic agent is ingested, 

 the blood prothrombin falls as that present becomes exhausted. Ap- 

 parently the animal requires a continuous supply of new prothrombin to 

 replace that being used, since no storehouse exists for this protein.''^ 



Campbell and Link'''*'- and Stahmann ct al.^^^ were the first to establish 

 the identity of the toxic agent in spoiled sweet clover as "dicoumarin" 

 (dicumarol), which chemically is 3,3'-methylenebis(4-hydroxycumarin). 

 When this compound was administered to vai'ious species of animals, it 

 was found to reduce blood prothrombin, especially when the vitamin K 

 intake was low. It was demonstrated that the hypoprothrombinemia 

 caused by dicumarol could be reversed b.y vitamin K.'^"^ Since dicumarol 



126 0. S0rbye, I. Kruse, and H. Dam, Acta Chem. Scand., 5, 487-488 (1951 ). 



1" H. Dam, Vitamins and Antivitamin-s in Blood Coagulation, Consiglio Nazionale 

 delle Ricerche, Convegno sulle Vitamine, Milan, April 12-16, 1953, pp. 1-11. 



»28 L. M. Roderick, Am. J. Physiol., 96, 413-424 (1931). 



1" K. P. Link, R. S. Overman, W. R. Sullivan, C. F. Huebner, and L. D. Scheel, J. 

 Biol. Chem., U?, 463-474 (1943). 



130 M. Stefanini and A. V. Pisciotta, Science, 111, 364 (1950). 



"1 J. R. Carter, G. H. Chambers, and E. D. Warner, Proc. Soc. Exptl. Biol. Med., 72 

 52-57(1949). 



132 H. A. Campbell and K. P. Link, J. Biol. Chem., 138, 21-33 (1941 ). 



1" M. A. Stahmann, C. F. Huebner, and K. P. Link, /. Biol. Chem., 138, 513-527 

 (1941). 



1'^ A. J. Quick and M. Stefanini, J. Biol. Chem., 175, 945-952 (1948). 



