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A Cause of Delayed Hemorrhage after Tooth Extraction
A CA U SE OF DELAYED H EM O R R H A G E AFTER TO OTH EXTRACTION Gustav William Rapp, Ph.D., C hicago
p r o b le m o f d e la y e d h e m o r r h a g e a f t e r to o t h e x t r a c t io n o r o t h e r o r a l s u r g ic a l o p e r a tio n s h a s p la g u e d t h e d e n t a l p r a c t it io n e r f o r a lo n g tim e . T h i s t y p e o f h e m o r r h a g e p r e s e n t s it s e l f u p t o t w o o r th re e d a y s a fte r th e o p e r a tiv e p r o c e d u r e , w h i c h i n m o s t in s t a n c e s a p p e a r s t o be> u n e v e n t f u l . I t o c c u r s o c c a s io n a lly e v e n w h e n s e e m in g ly a d e q u a te p r e o p e r a tiv e m e d ic a t io n w it h s u c h s u b s ta n c e s as v it a m in K , v it a m in D a n d c a l c i u m a n d p h o s p h a t e h a s b e e n in s t ig a t e d . T h e m e th o d o f p r e v e n tin g h e m o rrh a g e n o w se e m s to b e k n o w n , b u t it w a s o n ly t h r o u g h th e c o in c id e n c e o f a lo n g a n d a p p a r e n t l y u n r e l a t e d s e r ie s o f e v e n t s t h a t t h e s o l u t i o n t o t h is p e r p l e x i n g a n d a n n o y in g p r o b le m b e c a m e o b v io u s .
to b e c o m e t h r o m b in , th e e n z y m e w h ic h a c ts o n f ib r in o g e n t o f o r m t h e b lo o d c lo t. I t c a n b e s e e n t h a t b lo o d d e f ic ie n t in p r o t h o m b in w ill c lo t s lo w ly ; th e re fo re b le e d in g w ill b e p r o lo n g e d a n d a f r a g ile c lo t w ill b e p r o d u c e d .
T he
Hypoprothrombinemia
D u r i n g t h e i r s t u d ie s o n t h e h e m o r r h a g i c s w e e t c l o v e r d is e a s e i n c a t t l e , L i n k a n d h is a s s o c ia t e s 1 d i s c o v e r e d t h a t d i c o u m a r in , a s u b s ta n c e in th e c lo v e r, lo w e re d th e p r o t h r o m b in c o n te n t o f th e b lo o d , th u s p r e c ip ita tin g th e fa ta l h e m o r r h a g e . T h e y s h o w e d s u b s e q u e n tly th a t d i c o u m a r i n is c h a n g e d b y t h e b o d y i n t o s a l i c y l i c a c i d a n d t h a t i t is t h i s l a t t e r s u b s ta n c e w h ic h ca u se s h y p o p r o t h r o m b in e m ia . S in g e r ,2 o f V ie n n a , w h o jo in e d th e U .S . A r m y M e d ic a l C o rp s , m a d e th e re m a r k a b le o b s e r v a t io n t h a t t h e h i g h in c i d e n c e o f h e m o r r h a g e f o llo w in g to n s il le c t o m y in A m e r ic a as c o n t r a s te d t o th e
Physiology
T h e s im p le s t a n d p e r h a p s m o s t n e a r ly c o r r e c t w a y o f e x p la in in g th e s e q u e n c e o f e v e n t s i n t h e c l o t t i n g o f b l o o d is i l l u s t r a te d in th e a c c o m p a n y in g d ia g r a m . V i t a m i n K n o r m a l l y s t im u la t e s th e f o rm a tio n o f a n a d e q u a te q u a n tity o f p r o t h r o m b i n , w h ic h c ir c u la te s in t h e n o r m a l b lo o d s tre a m . U n d e r o r d in a r y c o n d i t i o n s w h e n b l o o d is n o t s h e d o r w h e n t is s u e s a r e n o t i n j u r e d , h e p a r i n , p r e p a r e d b y t h e l i v e r a n d a ls o c i r c u l a t i n g in th e b lo o d , p re v e n ts a n a c t iv a t io n o f p r o t h r o m b i n b y c a l c i u m io n s t o f o r m t h r o m b in . H o w e v e r , w h e n p la te le ts a re r u p t u r e d , c e p h a l i n is r e l e a s e d . C e p h a l i n , h a v in g a n e x t r e m e a f f in ity f o r h e p a r in , re m o v e s th e c h e c k f ro m p ro th ro m b in , w h i c h c a n n o w r e a c t w i t h c a l c i u m io n s
VITAMIN K-------- ► PROTHROMBIN
CALCIUM
IONS
HEPARIN
CEPHALIN
Schem atic diagram of blood clotting phenom enon. Interruption of a line indicates that in hibition w ill take place when that substance is present
From the Department of Research, Chicago College of Dental Surgery, Loyola University. 4*4
1 . Link, K . P.; and others, Studies on Hemorrhagic Sweet Clover Disease; Hypoprothrombinemia in Rat Induced by Salicylic Acid. / . Biol. Chem. 147:463 (February) 1943. 2. Singer, Rudolph, Acetylsalicylic Acid, Probable Cause for Secondary Post-Tonsillectomy Hemorrhage; Preliminary Report. Arch. Qtolaryng. 4 2 :19 (July) »945*
R app
J.A.D.A., Vol. 34, A p ril I, 1947 . . . 485
r e la tiv e ly lo w in c id e n c e in E u r o p e c o u ld b e a s c r ib e d t o t h e f a c t t h a t t h e E u r o p e a n p o s t o p e r a t i v e a n a l g e s i c is a l m o s t a l w a y s a m in o p y rin e (P y r a m id o n ) w h ile in A m e r i c a t h e c h o i c e is a c e t y l s a l i c y l i c a c i d (a s p ir in ) a lo n e o r in c o m b in a t io n w it h o th e r d ru g s . I t w a s n o w p o s s ib l e t o s h o w t h a t a c e t y l s a l i c y l i c a c i d is c a p a b l e o f p r o d u c i n g h y p o p r o t h r o m b in e m i a i n h u m a n b e in g s 3 a n d t h a t t h is s u p p r e s s i o n o f a n a d e q u a t e p r o t h r o m b i n c o n t e n t is r e v e r s i b l e b y t h e a d m in is t r a t io n o f m e n a d io n e , a s y n th e tic s u b s t a n c e p o s s e s s in g v i t a m i n K a c t i v i t y . 4 T h i s c o n c o m it a n t a c e ty ls a lic y lic a c id a n d v ita m in K th e ra p y seem s to h a v e n o e ffe c t o n t h e a n a lg e s ic a c t iv it y o f a c e t y l s a lic y lic a c id .5 T h e p u r p o s e o f t h is p a p e r is t o p r e s e n t th r e e o b s e r v a tio n s w h i c h w e r e m a d e as a r e s u l t o f m y s t u d ie s . F i r s t , a n a n a l g e s i c p r e p a r a t io n o f a ty p e p r e s c r ib e d b y m a n y d e n t a l p r a c t it io n e r s , c o n s is d n g o f a c e ty l s a lic y lic a c id , a c e t o p h e n e t id in a n d c a f fe in e c itra te (c o m m o n ly r e f e r r e d to as A P G ta b le ts , E m p i r i n c o m p o u n d o r A n a c in 6) , causes h y p o p ro th ro m b in e m ia in n o r m a l h u m a n b e in g s . S e c o n d , h y p o p r o t h r o m b i n e m i a c a u s e d i n t h i s w a y is p r e v e n ta b le b y th e a d m in is t r a t io n o f a d e q u a te d o s e s o f s y n th e tic v it a m in K . T h i r d , case re c o rd s in d ic a te t h a t th e in c id e n c e o f d e la y e d p o s te x tra c tio n h e m o r r h a g e s is d i r e c t l y r e l a t e d t o t h e a c e t y ls a lic y lic a c id a n d v i t a m i n K in t a k e o f p a tie n ts . Results o f Studies
I n o r d e r to d e te r m in e w h e t h e r th e m ix t u r e o f a c e ty ls a lic y lic a c id , a c e to p h e n e t i d i n a n d c a f f e in e c i t r a t e p r o d u c e s h y p o p r o th r o m b in e m ia , 4 0 a p p a r e n tly 3. Meyer, O. O ., and Howard, B., Production of Hypoprothrombinemia and Hypocoagulability of Blood with Salicylates. Proc. Soc. Exper. Biol. & Med. 5 3:234 (June) 19434. Neivert, H ., Late Secondary Tonsillar Hemorrhage; Studies of Prothrombin and Vitamin K . Arch. Otolaryng. 4 2 :14 (July) 1945. 5. William, R . G., Personal communication to the author. 6 . None of these products is accepted by the Council on Dental Therapeutics of the American Dental Association.
n o r m a l s tu d e n ts w e re s e p a ra te d in t o f o u r g ro u p s o f 10 e a c h a n d g iv e n th e f o llo w in g m e d i c a t i o n s f o r t w o s u c c e s s iv e d a y s (T a b le i ) : G r o u p A : E i g h t t a b le t s e a c h c o n t a i n in g 2 5 0 m g . o f a c e ty ls a lic y lic a c id , 1 6 0 m g . o f a c e to p h e n e tid in a n d 2 0 m g . o f c a f f e in e c it r a t e , o n e t a b le t b e in g t a k e n e ve ry h o u r. G r o u p B : E i g h t s i m i l a r t a b le t s , t w o b e in g ta k e n e v e ry f o u r h o u rs . G r o u p C : E i g h t s im ila r ta b le ts a n d e ig h t ta b le ts c o n t a in in g 1 m g . o f m e n a d io n e (s y n t h e t ic v it a m in K ) , o n e o f e a c h b e in g t a k e n a t t w o h o u r in t e r v a ls . G ro u p D : S a m e as g ro u p C , tw o ta b le ts o f e a c h b e in g t a k e n e v e r y f o u r h o u rs . New and Nonofficial Remedies, 1946,7 s ta te s t h a t t h e d o s e o f m e n a d io n e “ s h o u ld n o t e x c e e d 2 m g . a d a y a n d s h o u ld n o t b e c o n t in u e d a t 2 m g . a d a y f o r a p e r io d e x c e e d i n g f o u r w e e k s ,” t h e i n f e r e n c e b e in g t h a t la r g e r d o se s c o u ld b e to x ic . A la r g e r d a ily d o s e c o u ld le a d to h y p e r p ro th ro m b in e m ia w h ic h , in t u r n , m ig h t p re d is p o s e th e p a t ie n t to t h ro m b o s is . H o w e v e r , t h is c h a i n o f e v e n t s is n o t lik e ly in c o m b in e d t h e r a p y s u c h as t h a t u s e d i n t h e s e s t u d ie s , s in c e t h e m e n a d i o n e m u s t o v e r c o m e t h e h y p 'o p r o t h r o m b i n e m i a p r o d u c e d b y t h e s a l ic y l a t e s . I t is , o f c o u rs e , a s s u m e d th a t b o th d ru g s a re a b s o r b e d a n d p r o d u c e t h e ir e ffe c ts a t c o m p a ra b le ra te s in a ll p e rs o n s . T h i s i m p o r t a n t p o i n t is n o w u n d e r i n v e s t i g a tio n . P h a r m a c o lo g ic a lly s p e a k in g , m e d ic a m e n ts c o n t a in in g a c e ty ls a lic y lic a c id s h o u ld b e g iv e n a t in t e r v a ls o f t w o h o u rs in s te a d o f t w ic e t h e d o s e a t f o u r h o u r i n t e r v a l s . H o w e v e r , s in c e m o s t p r a c t i t i o n e r s s t ill p r e s c r i b e i n t h e s e c o n d w a y , t h e te s ts f o r G r o u p s A a n d B w e r e b o t h n e c e s s a ry . J u s t b e fo re a n d a t o n e d a y in te r v a ls f o r s ix d a y s a f t e r t h e a d m i n i s t r a t i o n o f t h e f ir s t te s t s u b s t a n c e s , d e t e r m i n a t i o n s 7. New and ^ Nonofficial Remedies, 1946. Chicago: American Medical Association, 1946.
The Journal o f the A m erican Dental A sso ciatio n
486
Table I.— Effects of menadione and a mixture of acetylsalicylic acid, acetophenetidin and caffeine citrate on prothrombin time
Group A, prothrombinf
Group B, prothrombin
Group C, prothrombin
Group D, prothrombin
Day*
1 ....................... 2 ....................... 3 ....................... 4 ............. : . . . . 5 ....................... 6 .......................
Seconds
Per cent
Seconds
18 + 1 .2 19 33 28 25 25
109 103 60 73 79 79
19 + 1.3 19 34 30 26 24
Per cent
103 103 58 66
76 82
Seconds
Per cent
Seconds
Per cent
19 + 1.5 19 18 18 • 19 18
103 103 109 109 103 109
19 + 1.8 18 17 18 19 19
103 109 115 109 103 103
^Medications were administered only on the first and second days. fProthrombin time in seconds and percentage of normal.
of prothrombin time8 were made on all subjects. From these determinations the prothrombin concentrations in percent age of the usual value were calculated. It must be realized that there is a linear agreement between the prothrombin time and clotting time of blood. T h e average prothrombin time for this series of test subjects was 19 .6 3d ! 1.2 seconds. This value was considered as 100 per cent. A n inverse linear relation between the pro thrombin-clotting time and the pro thrombin content was assumed.9 It is of interest to note that the two methods of administering the mixture containing acetylsalicylic acid, aceto phenetidin and caffeine citrate were equally effective in causing hypoprothrombinemia. I t is equally significant that hypoprothrombinemia did not occur in those patients to whom menadione was administered. I also inspected the dental records of a relatively large group of persons who had been receiving experimental quan tities of menadione as a medication accompanied by a suitable control group who received no menadione (Table 2, 8. Page. R . C .; De Beer, E. J ., and Orr, M . L ., Prothrombin Studies Using Russell Viper Venom; Relation of Clotting Time to Prothrombin Concentra tion in Human Plasma. J. Lab. & Clin. Med. 2 7 :19 7 (November) 1941. 9. Fullerton, H . W., Estimation of Prothrombin; Simplified Method. Lancet 2 :19 5 (August 17) 1940.
Groups 1, 2 and 3 ) . Since all were in mates of an institution, their preopera tive and postoperative care was identical. T h e postoperative medication consisted of two of the previously described analge sic tablets every four hours, sixteen tab lets in all. Complete dental records and biweekly determinations of prothrombin time were available. Another institution which used only aminopyrine for postoperative analgesia allowed the perusal of its clinical records (Table 2, Group 4 ) . Finally, a so-called mixed control was obtained by inspection of the clinical records of the dental clinic at Loyola University (Table 2, Group 5 ) . It may be assumed that a considerable number of these patients, who were selected be cause no postoperative medication was definitely prescribed, had used home remedies of their own choice or through advertising insistence. Some of these self administered medications most certainly had contained acetylsalicylic acid in one form or another. In the compilations for Table 2, the extraction of more than one tooth at one time was considered a single operation.
Comment Although it may be argued that the number of cases is not sufficient to w ar
R ap p
.
J.A.D.A., Vol. 34, A p ril I, 1947 . . . 487
Table 2.— Incidence of hemorrhage after tooth extraction
Group
Cases
Postoperative medication
Menadione, mg. daily
Prothrombin time, seconds
Postoperative hemorrhages Number
Per cent
1
132
Analgesic tablets,* 2 every 4 hr. (total 16)
0
19 + 3f 34 + 4Î
18
13.6
2
112
Same as Group 1
3
18 ± 2 f 23+4Î
5
4.5
3
127
Same as Group 1
6
17 ± 2 f 19 ± 1|
2
1.6
4
90
300 mg. aminopyrine every 4 hr.
0
No data
1
1.1
5
200
**
No data
7
3.5
No data
♦Acetylsalicylic acid, 250 m g.; acetophenetidin, 160 m g.; caffeine citrate, 20 mg. fO ne day preoperatively. JThree days postoperatively. ** It is presumed that no menadione was administered.
r a n t d e f in it e c o n c lu s io n s , t h e d a t a a r e u n e q u iv o c a l in d e m o n s tr a tin g t h a t ( i ) p a t ie n ts w i t h a p r o lo n g e d p r o t h r o m b i n tim e c a n b e e x p e c te d to h a v e p o s to p e ra t iv e h e m o r r h a g e s ; ( 2 ) th e a d m in is tra tio n o f t h é m ix t u r e c o n t a in in g a c e ty ls a lic y lic a c id , a c e t o p h e n e t id in a n d c a f f e in e c it r a t e f o r p o s t o p e r a t iv e a n a lg e s ia p r o d u c e s h y p o p r o t h r o m b i n e m i a , a n d ( 3 ) t h is h y p o p r o t h r o m b i n e m i a is n o t f o u n d w h e n m e n a d i o n e is a d m i n i s t e r e d . C o n c u r r e n t l y w it h th e a b se n c e o f h y p o p r o t h r o m b in e m i a t h e r e is a r e l a t i v e i n f r e q u e n c y o f d e la y e d p o s t o p e r a t iv e b le e d in g . I t s e e m s lik e ly t h a t th o s e p a tie n ts w h o h a v e p r o lo n g e d b le e d in g tim e w h e n th e y p r e s e n t th e m s e lv e s f o r o r a l s u r g ic a l o p e r a t io n s m a y h a v e c o n s u m e d a c e t y ls a lic y lic a c id in s o m e f o r m a n d th e re b y p r o d u c e d h y p o p r o t h r o m b in e m ia . T h i s c o n d it io n s h o u ld b e a m e n a b le to v it a m in K th e ra p y .
Conclusions
1. A c u t e h y p o p r o t h r o m b in e m ia c a n b e p r o d u c e d i n n o r m a l h u m a n b e in g s b y th e in g e s tio n o f a m i x t u r e w h ic h c o n ta in s a c e ty ls a lic y lic a c id . 2. T h is h y p o p r o th r o m b in e m ia be co m e s e v id e n t o n e a n d a h a lf to tw o d a y s a f t e r in g e s tio n o f a c e ty ls a lic y lic a c id . 3 . T h e c l o t t i n g t i m e i n t h e s e c a s e s is n e a r ly d o u b le th e u s u a l t im e . 4 . H y p o p r o th r o m b in e m ia ca u se d b y i n g e s t i o n o f a c e t y l s a l i c y l i c a c i d p e r s is t s f o r lo n g e r t h a n f iv e d a y s . 5 . T h e h y p o p r o t h r o m b i n e m i a is p r e v e n t a b le b y in g e s tio n o f 1 o r 2 m g . o f m e n a d io n e w i t h e a c h a n a lg e s ic t a b le t c o n t a in in g a c e ty ls a lic y lic a c id . 6 . I t m a y be assum ed th a t h y p o p ro t h r o m b in e m ia a lr e a d y e x is t in g as a re s u lt o f a c e ty ls a lic y lic a c id t h e r a p y c a n b e c o r re c te d w it h th e p r o p e r d o s a g e o f s y n th e tic v i t a m i n K . — / 7 5 7 West Harrison Street.
p r o b le m o f d e la y e d h e m o r r h a g e a f t e r to o t h e x t r a c t io n o r o t h e r o r a l s u r g ic a l o p e r a tio n s h a s p la g u e d t h e d e n t a l p r a c t it io n e r f o r a lo n g tim e . T h i s t y p e o f h e m o r r h a g e p r e s e n t s it s e l f u p t o t w o o r th re e d a y s a fte r th e o p e r a tiv e p r o c e d u r e , w h i c h i n m o s t in s t a n c e s a p p e a r s t o be> u n e v e n t f u l . I t o c c u r s o c c a s io n a lly e v e n w h e n s e e m in g ly a d e q u a te p r e o p e r a tiv e m e d ic a t io n w it h s u c h s u b s ta n c e s as v it a m in K , v it a m in D a n d c a l c i u m a n d p h o s p h a t e h a s b e e n in s t ig a t e d . T h e m e th o d o f p r e v e n tin g h e m o rrh a g e n o w se e m s to b e k n o w n , b u t it w a s o n ly t h r o u g h th e c o in c id e n c e o f a lo n g a n d a p p a r e n t l y u n r e l a t e d s e r ie s o f e v e n t s t h a t t h e s o l u t i o n t o t h is p e r p l e x i n g a n d a n n o y in g p r o b le m b e c a m e o b v io u s .
to b e c o m e t h r o m b in , th e e n z y m e w h ic h a c ts o n f ib r in o g e n t o f o r m t h e b lo o d c lo t. I t c a n b e s e e n t h a t b lo o d d e f ic ie n t in p r o t h o m b in w ill c lo t s lo w ly ; th e re fo re b le e d in g w ill b e p r o lo n g e d a n d a f r a g ile c lo t w ill b e p r o d u c e d .
T he
Hypoprothrombinemia
D u r i n g t h e i r s t u d ie s o n t h e h e m o r r h a g i c s w e e t c l o v e r d is e a s e i n c a t t l e , L i n k a n d h is a s s o c ia t e s 1 d i s c o v e r e d t h a t d i c o u m a r in , a s u b s ta n c e in th e c lo v e r, lo w e re d th e p r o t h r o m b in c o n te n t o f th e b lo o d , th u s p r e c ip ita tin g th e fa ta l h e m o r r h a g e . T h e y s h o w e d s u b s e q u e n tly th a t d i c o u m a r i n is c h a n g e d b y t h e b o d y i n t o s a l i c y l i c a c i d a n d t h a t i t is t h i s l a t t e r s u b s ta n c e w h ic h ca u se s h y p o p r o t h r o m b in e m ia . S in g e r ,2 o f V ie n n a , w h o jo in e d th e U .S . A r m y M e d ic a l C o rp s , m a d e th e re m a r k a b le o b s e r v a t io n t h a t t h e h i g h in c i d e n c e o f h e m o r r h a g e f o llo w in g to n s il le c t o m y in A m e r ic a as c o n t r a s te d t o th e
Physiology
T h e s im p le s t a n d p e r h a p s m o s t n e a r ly c o r r e c t w a y o f e x p la in in g th e s e q u e n c e o f e v e n t s i n t h e c l o t t i n g o f b l o o d is i l l u s t r a te d in th e a c c o m p a n y in g d ia g r a m . V i t a m i n K n o r m a l l y s t im u la t e s th e f o rm a tio n o f a n a d e q u a te q u a n tity o f p r o t h r o m b i n , w h ic h c ir c u la te s in t h e n o r m a l b lo o d s tre a m . U n d e r o r d in a r y c o n d i t i o n s w h e n b l o o d is n o t s h e d o r w h e n t is s u e s a r e n o t i n j u r e d , h e p a r i n , p r e p a r e d b y t h e l i v e r a n d a ls o c i r c u l a t i n g in th e b lo o d , p re v e n ts a n a c t iv a t io n o f p r o t h r o m b i n b y c a l c i u m io n s t o f o r m t h r o m b in . H o w e v e r , w h e n p la te le ts a re r u p t u r e d , c e p h a l i n is r e l e a s e d . C e p h a l i n , h a v in g a n e x t r e m e a f f in ity f o r h e p a r in , re m o v e s th e c h e c k f ro m p ro th ro m b in , w h i c h c a n n o w r e a c t w i t h c a l c i u m io n s
VITAMIN K-------- ► PROTHROMBIN
CALCIUM
IONS
HEPARIN
CEPHALIN
Schem atic diagram of blood clotting phenom enon. Interruption of a line indicates that in hibition w ill take place when that substance is present
From the Department of Research, Chicago College of Dental Surgery, Loyola University. 4*4
1 . Link, K . P.; and others, Studies on Hemorrhagic Sweet Clover Disease; Hypoprothrombinemia in Rat Induced by Salicylic Acid. / . Biol. Chem. 147:463 (February) 1943. 2. Singer, Rudolph, Acetylsalicylic Acid, Probable Cause for Secondary Post-Tonsillectomy Hemorrhage; Preliminary Report. Arch. Qtolaryng. 4 2 :19 (July) »945*
R app
J.A.D.A., Vol. 34, A p ril I, 1947 . . . 485
r e la tiv e ly lo w in c id e n c e in E u r o p e c o u ld b e a s c r ib e d t o t h e f a c t t h a t t h e E u r o p e a n p o s t o p e r a t i v e a n a l g e s i c is a l m o s t a l w a y s a m in o p y rin e (P y r a m id o n ) w h ile in A m e r i c a t h e c h o i c e is a c e t y l s a l i c y l i c a c i d (a s p ir in ) a lo n e o r in c o m b in a t io n w it h o th e r d ru g s . I t w a s n o w p o s s ib l e t o s h o w t h a t a c e t y l s a l i c y l i c a c i d is c a p a b l e o f p r o d u c i n g h y p o p r o t h r o m b in e m i a i n h u m a n b e in g s 3 a n d t h a t t h is s u p p r e s s i o n o f a n a d e q u a t e p r o t h r o m b i n c o n t e n t is r e v e r s i b l e b y t h e a d m in is t r a t io n o f m e n a d io n e , a s y n th e tic s u b s t a n c e p o s s e s s in g v i t a m i n K a c t i v i t y . 4 T h i s c o n c o m it a n t a c e ty ls a lic y lic a c id a n d v ita m in K th e ra p y seem s to h a v e n o e ffe c t o n t h e a n a lg e s ic a c t iv it y o f a c e t y l s a lic y lic a c id .5 T h e p u r p o s e o f t h is p a p e r is t o p r e s e n t th r e e o b s e r v a tio n s w h i c h w e r e m a d e as a r e s u l t o f m y s t u d ie s . F i r s t , a n a n a l g e s i c p r e p a r a t io n o f a ty p e p r e s c r ib e d b y m a n y d e n t a l p r a c t it io n e r s , c o n s is d n g o f a c e ty l s a lic y lic a c id , a c e t o p h e n e t id in a n d c a f fe in e c itra te (c o m m o n ly r e f e r r e d to as A P G ta b le ts , E m p i r i n c o m p o u n d o r A n a c in 6) , causes h y p o p ro th ro m b in e m ia in n o r m a l h u m a n b e in g s . S e c o n d , h y p o p r o t h r o m b i n e m i a c a u s e d i n t h i s w a y is p r e v e n ta b le b y th e a d m in is t r a t io n o f a d e q u a te d o s e s o f s y n th e tic v it a m in K . T h i r d , case re c o rd s in d ic a te t h a t th e in c id e n c e o f d e la y e d p o s te x tra c tio n h e m o r r h a g e s is d i r e c t l y r e l a t e d t o t h e a c e t y ls a lic y lic a c id a n d v i t a m i n K in t a k e o f p a tie n ts . Results o f Studies
I n o r d e r to d e te r m in e w h e t h e r th e m ix t u r e o f a c e ty ls a lic y lic a c id , a c e to p h e n e t i d i n a n d c a f f e in e c i t r a t e p r o d u c e s h y p o p r o th r o m b in e m ia , 4 0 a p p a r e n tly 3. Meyer, O. O ., and Howard, B., Production of Hypoprothrombinemia and Hypocoagulability of Blood with Salicylates. Proc. Soc. Exper. Biol. & Med. 5 3:234 (June) 19434. Neivert, H ., Late Secondary Tonsillar Hemorrhage; Studies of Prothrombin and Vitamin K . Arch. Otolaryng. 4 2 :14 (July) 1945. 5. William, R . G., Personal communication to the author. 6 . None of these products is accepted by the Council on Dental Therapeutics of the American Dental Association.
n o r m a l s tu d e n ts w e re s e p a ra te d in t o f o u r g ro u p s o f 10 e a c h a n d g iv e n th e f o llo w in g m e d i c a t i o n s f o r t w o s u c c e s s iv e d a y s (T a b le i ) : G r o u p A : E i g h t t a b le t s e a c h c o n t a i n in g 2 5 0 m g . o f a c e ty ls a lic y lic a c id , 1 6 0 m g . o f a c e to p h e n e tid in a n d 2 0 m g . o f c a f f e in e c it r a t e , o n e t a b le t b e in g t a k e n e ve ry h o u r. G r o u p B : E i g h t s i m i l a r t a b le t s , t w o b e in g ta k e n e v e ry f o u r h o u rs . G r o u p C : E i g h t s im ila r ta b le ts a n d e ig h t ta b le ts c o n t a in in g 1 m g . o f m e n a d io n e (s y n t h e t ic v it a m in K ) , o n e o f e a c h b e in g t a k e n a t t w o h o u r in t e r v a ls . G ro u p D : S a m e as g ro u p C , tw o ta b le ts o f e a c h b e in g t a k e n e v e r y f o u r h o u rs . New and Nonofficial Remedies, 1946,7 s ta te s t h a t t h e d o s e o f m e n a d io n e “ s h o u ld n o t e x c e e d 2 m g . a d a y a n d s h o u ld n o t b e c o n t in u e d a t 2 m g . a d a y f o r a p e r io d e x c e e d i n g f o u r w e e k s ,” t h e i n f e r e n c e b e in g t h a t la r g e r d o se s c o u ld b e to x ic . A la r g e r d a ily d o s e c o u ld le a d to h y p e r p ro th ro m b in e m ia w h ic h , in t u r n , m ig h t p re d is p o s e th e p a t ie n t to t h ro m b o s is . H o w e v e r , t h is c h a i n o f e v e n t s is n o t lik e ly in c o m b in e d t h e r a p y s u c h as t h a t u s e d i n t h e s e s t u d ie s , s in c e t h e m e n a d i o n e m u s t o v e r c o m e t h e h y p 'o p r o t h r o m b i n e m i a p r o d u c e d b y t h e s a l ic y l a t e s . I t is , o f c o u rs e , a s s u m e d th a t b o th d ru g s a re a b s o r b e d a n d p r o d u c e t h e ir e ffe c ts a t c o m p a ra b le ra te s in a ll p e rs o n s . T h i s i m p o r t a n t p o i n t is n o w u n d e r i n v e s t i g a tio n . P h a r m a c o lo g ic a lly s p e a k in g , m e d ic a m e n ts c o n t a in in g a c e ty ls a lic y lic a c id s h o u ld b e g iv e n a t in t e r v a ls o f t w o h o u rs in s te a d o f t w ic e t h e d o s e a t f o u r h o u r i n t e r v a l s . H o w e v e r , s in c e m o s t p r a c t i t i o n e r s s t ill p r e s c r i b e i n t h e s e c o n d w a y , t h e te s ts f o r G r o u p s A a n d B w e r e b o t h n e c e s s a ry . J u s t b e fo re a n d a t o n e d a y in te r v a ls f o r s ix d a y s a f t e r t h e a d m i n i s t r a t i o n o f t h e f ir s t te s t s u b s t a n c e s , d e t e r m i n a t i o n s 7. New and ^ Nonofficial Remedies, 1946. Chicago: American Medical Association, 1946.
The Journal o f the A m erican Dental A sso ciatio n
486
Table I.— Effects of menadione and a mixture of acetylsalicylic acid, acetophenetidin and caffeine citrate on prothrombin time
Group A, prothrombinf
Group B, prothrombin
Group C, prothrombin
Group D, prothrombin
Day*
1 ....................... 2 ....................... 3 ....................... 4 ............. : . . . . 5 ....................... 6 .......................
Seconds
Per cent
Seconds
18 + 1 .2 19 33 28 25 25
109 103 60 73 79 79
19 + 1.3 19 34 30 26 24
Per cent
103 103 58 66
76 82
Seconds
Per cent
Seconds
Per cent
19 + 1.5 19 18 18 • 19 18
103 103 109 109 103 109
19 + 1.8 18 17 18 19 19
103 109 115 109 103 103
^Medications were administered only on the first and second days. fProthrombin time in seconds and percentage of normal.
of prothrombin time8 were made on all subjects. From these determinations the prothrombin concentrations in percent age of the usual value were calculated. It must be realized that there is a linear agreement between the prothrombin time and clotting time of blood. T h e average prothrombin time for this series of test subjects was 19 .6 3d ! 1.2 seconds. This value was considered as 100 per cent. A n inverse linear relation between the pro thrombin-clotting time and the pro thrombin content was assumed.9 It is of interest to note that the two methods of administering the mixture containing acetylsalicylic acid, aceto phenetidin and caffeine citrate were equally effective in causing hypoprothrombinemia. I t is equally significant that hypoprothrombinemia did not occur in those patients to whom menadione was administered. I also inspected the dental records of a relatively large group of persons who had been receiving experimental quan tities of menadione as a medication accompanied by a suitable control group who received no menadione (Table 2, 8. Page. R . C .; De Beer, E. J ., and Orr, M . L ., Prothrombin Studies Using Russell Viper Venom; Relation of Clotting Time to Prothrombin Concentra tion in Human Plasma. J. Lab. & Clin. Med. 2 7 :19 7 (November) 1941. 9. Fullerton, H . W., Estimation of Prothrombin; Simplified Method. Lancet 2 :19 5 (August 17) 1940.
Groups 1, 2 and 3 ) . Since all were in mates of an institution, their preopera tive and postoperative care was identical. T h e postoperative medication consisted of two of the previously described analge sic tablets every four hours, sixteen tab lets in all. Complete dental records and biweekly determinations of prothrombin time were available. Another institution which used only aminopyrine for postoperative analgesia allowed the perusal of its clinical records (Table 2, Group 4 ) . Finally, a so-called mixed control was obtained by inspection of the clinical records of the dental clinic at Loyola University (Table 2, Group 5 ) . It may be assumed that a considerable number of these patients, who were selected be cause no postoperative medication was definitely prescribed, had used home remedies of their own choice or through advertising insistence. Some of these self administered medications most certainly had contained acetylsalicylic acid in one form or another. In the compilations for Table 2, the extraction of more than one tooth at one time was considered a single operation.
Comment Although it may be argued that the number of cases is not sufficient to w ar
R ap p
.
J.A.D.A., Vol. 34, A p ril I, 1947 . . . 487
Table 2.— Incidence of hemorrhage after tooth extraction
Group
Cases
Postoperative medication
Menadione, mg. daily
Prothrombin time, seconds
Postoperative hemorrhages Number
Per cent
1
132
Analgesic tablets,* 2 every 4 hr. (total 16)
0
19 + 3f 34 + 4Î
18
13.6
2
112
Same as Group 1
3
18 ± 2 f 23+4Î
5
4.5
3
127
Same as Group 1
6
17 ± 2 f 19 ± 1|
2
1.6
4
90
300 mg. aminopyrine every 4 hr.
0
No data
1
1.1
5
200
**
No data
7
3.5
No data
♦Acetylsalicylic acid, 250 m g.; acetophenetidin, 160 m g.; caffeine citrate, 20 mg. fO ne day preoperatively. JThree days postoperatively. ** It is presumed that no menadione was administered.
r a n t d e f in it e c o n c lu s io n s , t h e d a t a a r e u n e q u iv o c a l in d e m o n s tr a tin g t h a t ( i ) p a t ie n ts w i t h a p r o lo n g e d p r o t h r o m b i n tim e c a n b e e x p e c te d to h a v e p o s to p e ra t iv e h e m o r r h a g e s ; ( 2 ) th e a d m in is tra tio n o f t h é m ix t u r e c o n t a in in g a c e ty ls a lic y lic a c id , a c e t o p h e n e t id in a n d c a f f e in e c it r a t e f o r p o s t o p e r a t iv e a n a lg e s ia p r o d u c e s h y p o p r o t h r o m b i n e m i a , a n d ( 3 ) t h is h y p o p r o t h r o m b i n e m i a is n o t f o u n d w h e n m e n a d i o n e is a d m i n i s t e r e d . C o n c u r r e n t l y w it h th e a b se n c e o f h y p o p r o t h r o m b in e m i a t h e r e is a r e l a t i v e i n f r e q u e n c y o f d e la y e d p o s t o p e r a t iv e b le e d in g . I t s e e m s lik e ly t h a t th o s e p a tie n ts w h o h a v e p r o lo n g e d b le e d in g tim e w h e n th e y p r e s e n t th e m s e lv e s f o r o r a l s u r g ic a l o p e r a t io n s m a y h a v e c o n s u m e d a c e t y ls a lic y lic a c id in s o m e f o r m a n d th e re b y p r o d u c e d h y p o p r o t h r o m b in e m ia . T h i s c o n d it io n s h o u ld b e a m e n a b le to v it a m in K th e ra p y .
Conclusions
1. A c u t e h y p o p r o t h r o m b in e m ia c a n b e p r o d u c e d i n n o r m a l h u m a n b e in g s b y th e in g e s tio n o f a m i x t u r e w h ic h c o n ta in s a c e ty ls a lic y lic a c id . 2. T h is h y p o p r o th r o m b in e m ia be co m e s e v id e n t o n e a n d a h a lf to tw o d a y s a f t e r in g e s tio n o f a c e ty ls a lic y lic a c id . 3 . T h e c l o t t i n g t i m e i n t h e s e c a s e s is n e a r ly d o u b le th e u s u a l t im e . 4 . H y p o p r o th r o m b in e m ia ca u se d b y i n g e s t i o n o f a c e t y l s a l i c y l i c a c i d p e r s is t s f o r lo n g e r t h a n f iv e d a y s . 5 . T h e h y p o p r o t h r o m b i n e m i a is p r e v e n t a b le b y in g e s tio n o f 1 o r 2 m g . o f m e n a d io n e w i t h e a c h a n a lg e s ic t a b le t c o n t a in in g a c e ty ls a lic y lic a c id . 6 . I t m a y be assum ed th a t h y p o p ro t h r o m b in e m ia a lr e a d y e x is t in g as a re s u lt o f a c e ty ls a lic y lic a c id t h e r a p y c a n b e c o r re c te d w it h th e p r o p e r d o s a g e o f s y n th e tic v i t a m i n K . — / 7 5 7 West Harrison Street.