VII. EFFECTS OF DEFICIENCY 427 



the lack of prothrombin or the lengthenmg of clot time;*^^ however, large 

 doses of vitamin K before exposure of animals to chloroform are reported 

 to be hepatoprotective.^* A practical application is the evaluation of hypo- 

 prothrombinemia of uncertain origin; if parenteral vitamin K analogs are 

 not corrective, hepatic function is presumed to be subnormal (vitamin K 

 tolerance test).^^ Clotting studies suggest that mild hepatic insufficiency 

 results from fever,"" anesthesia,''^ or simple manipulation of the liver.^- 



(2) Anticoagulant Drugs. In contradistinction to such substances as chlo- 

 roform, carbon tetrachloride, and phosphorus, which depress a variety of 

 hepatic activities, including the synthesis of prothrombin and fibrinogen, 

 a class of chemicals has been developed within the past decade, primarily 

 by Link's group,^^ which has found wide clinical use: the anticoagulant 

 coumarins, which include dicoumarol,^^ hydrocoumarol,^^ tromexan,^^ phen- 

 ylindanedione," and anticoagulant "63."^^ These chemicals are adminis- 



" S. J. Wilson, Proc. Soc. Exptl. Biol. Med. 41, 559 (1939) ; F. J. Pohle and J. K. Stew- 

 art, J. Clin. Invest. 19, 365 (1940) ; II. Kark and A. W. Souter, Lancet I, 1149 (1940). 



68 M. A. Pessagno Espora, Dia med. 22, 1264 (1950). 



69 P. N. Unger, S. Shapiro, and S. Schwalb, /. Clin. Invest. 27, 39 (1948) ; P. N. Unger, 

 M. Weiner, and S. Shapiro, Am. J. Clin. Path. 18, 835 (1948). 



70 R. K. Richards, Science 97, 313 (1943). 



" S. C. Cullen, S. E. Ziffren, R. B. Gibson, and H. P. Smith, J. Am. Med. Assoc. 115, 



991 (1940). 

 72 J. W. Lord, Jr., Surgery 6, 896 (1939). 

 " K. P. Link, Harvey Lectures 39, 162 (1943-1944). 

 '^ 3,3'-Methylenebis(4-hydroxycouniarin); dicumarin, dicoumarin, dikumarin, di- 



cumarol, "A. P.," bishydroxycoumarin (Formula 10); R. S. Overman, M. A. 



Stahmann, W. R. Sullivan, C. F. Huebner, H. A. Campbell, and K. P. Link, /. 



Biol. Chem. 142, 941 (1942) ; H. R. Butt, E. V. Allen, and J. L. Bollman, Proc. Staff 



Meetings Mayo Clinic 16, 388 (1941); Council on Pharmacy and Chemistry, J. Am. 



Med. Assoc. 137, 1533 (1948); 145, 644, (1951); H. Dyckerhoff, Biochem. Z. 316, 



397 (1944). 

 '5 3,3'-Methylenebis(3,4-hydro, 4-h3^droxycoumarol) (Formula 11); F. Ericksen, E. 



Jacobsen, and C. M. Plum, Acta Pharmacol. Toxicol. 1, 379 (1945). 

 '6 3,3'-Carboxymethylenebis(4-hydroxycoumarin) ethyl ester or 4,4'-dioxydicou- 



maryl ethj-l acetate; pelentan, "B.O.E.A.," ethyl biscoumacetate (Formula 12); 



K. N. von Kaulla and R. Pulver, Schweiz. med. Wochschr. 78, 806 (1948); R. Delia 



Santa, ibid. 79, 195 (1949); C. Solomon, H. J. McNeile, and R. Lange, J. Lab. Clin. 



Med. 36, 19 (1950) ; G. E. Burke and I. S. Wright, Conf. on Blood Clotting and Allied 



Problems, New York 3, 57 (1950). 

 "Phenyl-2-indanedione-l,3; "P.I.D."; "danilone"; "hedulin" (Formula 13); P. 



Meunier, C. Mentzer, and D. Molho, Coinpt. rend. acad. sci. U.R.S.S. 224, 1666 



(1947); J. P. Soulier and J. Gudguen, Rev. hematol. 3, 180 (1948); N. W. Barker, 



J. E. Estes, Jr., and F. D. Mann, Proc. Staff Meetings Mayo Clinic 26, 162 (1951); 



L. B. Jaques, E. Lepp, and E. Gordon, Conf. on Blood Clotting and Allied Problems, 



New York 3, 11 (1950). 

 7« 2-Methyl-2-methoxy-4-pheuyl-5-oxodihydropyrano(3,2-C) (l)-benzopyran; cou- 



mopyran; M. Ikawa, M. A. Stahmann, and K. P. Link, J. Am. Chem. Soc. 66, 902 



