JOUR. D . D . VOLUME 9 APRIL, 1942 NUMBER 4

The Serum Coagulation Reaction: Its Clinical Significance+ By

MANFRED KRAEMER, M.D. .~ NEWARK, NEW JERSEY

I N 1935 I (1) studied Weltmann's (2, 3) Serum Coagulation Reaction in 25 cases of liver disease

and concluded that the test might be of value in differ- ent ia t ing between obstructive and parenchymatous jaundice. The results reported by me at that t ime were inaccurate in tha t the proper technique of read- ing the test was not employed. The cases used in tha t first study were all of advanced disease and when the test was applied in early jaundice, no different iat ing values were found.

Disappointed, I ceased work with the test. No fu r the r American art icles appeared until those of Levinson in 1937 (4) and 1939 (5.) Af te r reading Levinson's first paper I was encouraged to restudy Weltmann's phenomenon. In 1940 Susan Dees (6, 7) presented her extensive studies. Her last paper should be read by all those interested in the theory and chemistry of the serum coagulation reaction. The two papers by Dr. Dees brought the l i t e ra ture on the test up to date.

DESCRIPTION OF THE TEST

If blood serum is diluted in distilled water 1:50 and boiled, coagulation of the blood serum protein fails to occur. However, if a small amount of electrolyte (sodium chloride, calcium chloride, or bar ium chloride) is added to the diluted serum, coagulation of the serum protein takes place.

Weltmann determined that, in a boiling 1:50 di- lution of normal blood serum, the lowest concentration of calcium chloride solution in which coagulation of the serum protein takes place is from .03 to .04 per cent. I f 0.1 cc. of normal blood serum is added to 5 cc. of .04% calcium chloride solution and boiled, the serum protein coagulates. However if added to .02~ solution of calcium chloride it fails to coagulate.

Inflammatory and exudative processes like pneu- monia changed the blood serum so that the protein was coagulated in only the more highly concentrated (.08%) solutions of boiled calcium chloride. On the other hand, disease of the parenchyma of the liver, cardiac decompensation with stasis and fibrous forms of tuberculosis so changed the blood serum that the protein was coagulated in much lower dilutions of boiled calcium chloride, e .g . .02%.

TECHNIQUE EMPLOYED

In stock is kept 500 cc. of .1% solution of calcium chloride CaC12 . 6H20. Ten test tubes are placed in a row on a rack. The tubes are numbered 1 to 10 from left to r ight . 5 cc. of the .1% solution are added to tube one, 4.5 cc. to tube two and so on in diminishing quanti ty so tha t .5 cc. are added to tube ten. Sufficient distilled water is then added so tha t each tube will

?From the Presbyterian Hospital, Deioartraent of Gastro-Enterology. ~Miss Jacqueline Shepherd, B.S., M.T., assisted with the technical

procedures. Submitted June 30, 1941.

eontain a total of 5 cc. of solution. Thus 4.5 cc. of water are added to tube ten, 4.0 cc. to tube nine and so on in diminishing amounts to .5 cc. for tube two. Final ly tube one will contain .1% solution of an- hydrous calcium chloride, tube two .09% and so on down to tube ten which contains .01% solution. (I have discontinued using a tube containing .045% so- lution which Weltmann suggested placing between 6 and 7.)

To each test tube 0.1 cc. of the blood serum to be tested is added, this serum having been collected as for a Wassermann test. The tubes are then shaken and placed in a boiling water bath for exactly fifteen minutes. Af te r removal from the bath, the number of tubes in which coagulation or flocculation of the serum has taken place is recorded. Coagulation is always noted in the tubes of higher concentration (tubes 1-6) and tends not to occur in tubes of lower concentration (7-10.) I f there is coagulation in any tube there will be coagulation in all of the tubes of grea ter concen- t rat ion. Thus if there is coagulation in tube 6 there must also be coagulation in tubes 1 to 5. The number of the tube containing the weakest solution in which coagulation occurs gives the reading for the test. For instance, if coagulation occurs in the first five tubes, the reading for the test is five (C.B. 5 or Weltmann 5.) This reading is called the coagulation band (C.B.) and we would report the test as C.B. 5. Care must be taken to read only the tubes in which coagulation oc- curs, and to d is regard those with only clouding or turbidi ty . Clouding usually occurs in 2 or 3 tubes more dilute than the last in which true coagulation is noted. In normal serum, coagulation usually occurs in the first six tubes (C.B. 6.) If the C.B. is less than six, the C.B. is said to shif t to the left, or to be shortened: if more than six, it is said to have shif ted to the r ight or to be lengthened (Fig . 1.) Weltmann showed tha t in inflammatory or exudative processes, there was a shif t to the left or shortening of the band and in fibrous processes and parenchymatous diseases of the liver the band was lengthened (shif t to r ight . )

CLINICAL MATERIAL

The test was executed over a period of two years on every pr ivate pat ient examined. To date 1200 tests have been performed on about 1100 patients. The test was repeated on several of the patients. In addition, 75 supposedly healthy factory executives were tested at the t ime of the i r periodic health examinations.

In addition to the Weltmann test, most of the pat ients had diagnostic X-ray and laboratory studies, including at least a urinalysis, Wassermann test, complete blood count and sedimentat ion ra te (Cutler.) All but a few of the pat ients were ambulant. The normal range of the coagulation band is 5 to 7. This paper wilI concern i tself only with those cases of the

129

130 AMERICAN JOURNAL OF DIGESTIVE DISEASES V O L U M E 9 NUMBER 4

4371 4 6 M. 49 4351 '4 12 M. 38 4401 4 6 M. 54 4408 4 9 R. 32 44~ 4 II F. 5

4412 4 1O F. 33 4424 3 65 F . 14

6 15 4426 4 1B F. B7 4481 4 13 F . 68 4440 4 ~9 F. 51 4451 4 21 F. 38 4468 3 30 M. 54 4477 4 12 M. 66 4476 3 21 R. 40 4481 I 27 F. 67 4492 4 6 M. 45 4504 8 2~ M. 57 4505 2 25 M. 44 45~7 4 IB R. 46

4577 24 ~. 28 8 25

4596 4 21 R. 52 4568 4 24 . M. 67 461d Z 20 F �9 44

6 7 4622 2 27 M. 62 4627 4 25 F. 61 4626 4 22 M. ~w 4429 4 24 M. 57 4650 0 4 F �9 35

8 ~I 4733 3 29 P. 42

7 S 4784 4 16 F. 53 4738 4 28 M. 50 474~ 0 25 M. 55 4751 4 18 F. 50 4753 2 28 M* [~ 4778 4 8 F. 48 4779 4 8 M. 88 478~ 4 16 M. 5O 4795 3 25 F. 26

7 S

TABLE I

87 P a t i e n t s ~ t Whmt t h e C.B. was, 4 e r l e a s t ~ i Cer re s~ond ia~ S e 4 ~ e n t a t i e n R a t e (S.R.) ( C u t l e r )

~ b e r C,B. S*R. S~x A~�9 Di~osis 2'~41 4 27 Po 6~ ~ e e r a t i v e C o l i t i s 2222 7 :;~1 M. 16

4 2B S091 4 5 M. 33 ~ 1 ~ 3 23 M. 48 3121 4 23- P. 38 3~07 3 86 ' F. 65

5 18 3311 4 16 F. 50 5708 ' 4 27 M. 75 3793 4 I0 P. 31 8632 4 26 M. 47 4128 4 12 F, 37 4157 4 ~2 F. 62 4809 4 22 F. 68

5 20 4227 4 - 5 F. 60 4g17 4 20 F. 58 4~'67 4 15 P. 57 4339 4 25 F. 51. C h o l e c ~ s t i t i s and c h o l e l l t h i a s i a ~ O p e r . ) 4~40 4 22 M. 39 Gastric s~ohill$. Wassermann 3 plus. Healing with a r s p h e n ~ I n e . 4347 4 18 F. 37 Acute a l l e r g i c u l c e r a t i v e colitis ~ P r o o t o s c o ~ ) 4357 4 18 F. 28 7 /87 /88 M i g r a i n e

B 8 9/13/.39 S~mptom free 4858 8 15 M. 57 7/89"/38 penetratln~ gastric u l e e r -

5 9 6/6/40 I a p r eve=ea t (X- ray ) 43d5 4 27" M. 68 L~aphasarcon~ o f esophasua (Biopsy)" 4368 8 25 M. 42 Appendiceal ablceSl toper.)

Incompletel~ s t u d i e d . Re d ta~nos i~ made. P~lorle ulcer (X-ray) - - , , Duodenal ulcer (X-ray) P~elitl8 Rot o~etely studied.

E z d ~ e t r i t t s (E~a t e r e c t ~ a y ) 10/4/~ Acute p l e u r t s y w ~ effusion.

Chromic s a J p ~ n ~ I t i s , Recta l S t r i c t u r e ( P r o c t o s e o p ~ - - p e l v i o e~a~. ) Dub.legal diverticula ~X-ray) Cholee~stitis (X-ra~, Biliar~ Drainage) Inoce~letel~ s t u d i e d . No d i a g n o s i s . P~elitis Penetratin Duodenal ulcer, Antral ~astritis (Oper.) Inco=~lete~ studied Diverticulitis cell, Cholec~stitis Incom~letel~ studied. Possible diabetes Net c ~ l e t e l ~ s t u d i e d . Histor~ of peptle ulcer. Cholecyatltix (non-visuallze~ ~all bladder, no "8" bile) 1/50/4~ G a s t r i c u l c e r (0per.) 4 / 8 / 4 0 A f t e r resection. = 2/7/40 Gi~rdial d y s e n t e r y with jeJunitis and ileitis (X-ray) 2 / 2 5 / 4 0 l ~ r o v e m e n t i n symptoms. Pene%rati~ duodenal ulcer Oper.) " S u p p u r a t i v e bile duct carcinoma o f liver (6iops~) 3/3/40 Acute rhe~atoid arthritis. 5/7/40 All s~mptc~s ~one. Ulceratin~ posterior wall carcinoma of stomach toper.) P a p i l l a r ~ adeno -ca r c inoma of I t ~ a c h (Oper.) Divertloulltis cell (X-ray) Diverticulitis cell [X-re() 4/8/40 Ulcerative colitis, i1/28/40 8~mptom f r e e . 6/7/40 Ulcerating squamous cell carcinoma of rectum (Biopsy) 10/80/40 After resection and apparent cure. H~er tensive Cardiac. Epileps[. Cholsc~stitis (X-ra~) (Noa-vlsualized ~ a l l b l a d d e r ) Lobar Pne~onia (X-ra~) Cholec~stitis and cholelithiasis (X-ra~) Ca~cinc~a of si~old (Oper.) Uterine fibroid. B~pertensive cardiac. Cholec~stitis (X- ra~ and b i l l a r ~ d r a i n a g e ) Ulcerative colitis. 8/7/40 Ulcerative cO] !tis. 1 / 8 / 4 1 A r r e s t e d proctologioally.

4808 4 82 F �9 B7 4824 4 10 M. 38

6 8 4842 1 25 M. 66 4847 4 C l e t t e ~ . 64 486B 8 14 F. 21

5 4877 4 18 F. 6B 4878 4 Clotte~. 70 4894 4 20 F. 68 4898 8 19 F. B8 4910 4 ~5 F. 88 4920 4 12 M. 61 4927 4 23 F. 68 4967 B 17 M. 20 4"643 2 24 M. 2~ 4944 3 7 M. 51

7 12 4948 4 3 M. 50 4962 4 17 M. 88 4957 2 84 M. iO 4688 3 28 T. $3 4978 3 88 M, 47

5 Z5 4988 4 25 R. 42 4987 4 18 M. 27 5005 4 II F. 85

7 9 5007 2 27 F. 67 5032 3 26 M. 65 5089 4 27 P. 60

8/'9/40 U l c e r a t i v e Coliti, I n a c t i v e 12/50/4o Aotiv. Diabetes, Duodenal Dloer P e n e t r a t i n ~ Gas ' t r io U l c e r (Rupture~ w h i l e a w a i t i n g 0 p e r a t i ~ n ) E~pertenelve Card iac , Sinusitis 8/~4/ '39 G a s t r i c ~ l v e r t i c u l m a , Acu'te e n d o m e t r i t l s ( S p a r . ] 8/7/4o s~pto= free H~pertenslve Card iac Re comple te s tud~ p@rmittud I n c a r c e r a t e d i n g u i n a l h e r n i a w i ~ p e r i t o n e a l i r r i t a t i o n (Op=er.) PsoasAcute A~ece'ssa pendi@itis.(T.B.)Chronic s u p p u r a t i v e cholec~stltl$, chol.ellthiasis (Oper.)

Chronlo eupptwative eholeo~stlti8 ~ad oholellthiasi$ loper.) Duodenal U l c e r , R ~ e r t e n s i v e " C a r d i ~ ( B u t t e r f l ~ cap) 7/16/59 Diabetes, 6roast abscess 7 /11 /40 S ~ p t o m free ~osarco~uL of Uterus, R~er~ensive'Cardlac ~Oper.) H ~ e r t e n ~ i v e C a r d i a c . " Inc(mpletel~. s tud~ed . Inverted T Lead 4 o f E.R.G. Duodenal Diver ticulul

Diver tieulltis cell. ~/i0/40 gnoleoystltls. Antral gastritis. 16/50/40 I~rove~ent in s~pt~. CLrein~ os eolea with hepatic m e t a e t a s i , .~O~er.) CsrelnmR nf co lon (X- ra~) 1 0 / 2 5 / 4 0 I r r i t a b l e c o l o n . P o s s i b l e acute c o l i t i s . lO/2d/dO Choleli~hlasis and cholec~stltis. S~hilltic ~aatritis. Wasseri~um 4 plUS. CaroinoBa p o s t e r i o r ~ a s t r l r m i l l (X - ra~ ) . C h o l e l i t h i a s i e , oholee~stitis, PJncreatitis (Oper.) Xdenoca rc lnoaa o f r e c t a , ( (}per , ) Carcinoma of si o l d . Choleli~hia~ is ~X-Cra~) " Regional enteritis (Resection) Regional enteritis (Resection) 122727/42740 Duodenal ulcer. 1/20/41 A f t e r hospital . . . . t ~ e n t . Duodenal u l c e r (X- ra~) C ~ o l a o = a of fu.dus (Ope.r.) Re~ioaal e n t e r i t i s , Acute cholec~stitis ~nd cholellChlasla (0?or.) 1/25/41 Ma~i=al ulcer. 2/8/41 A f t e r t r e a t m e n t . P o s t e r i o r wall g a s t r i c u l c e r ( 0 p e r . ) Not c e m p l e t e l ~ s t u d i e d , T~p ica l u l c e r h i s to ry% 2/15/41 G a s t r i c u l c e r . 8/20/41 After dlsappe~ace of niche.

Rheu~atoidN~ ooapletalar~rltis.studied. Acute phex~itls. ~rippe.

U l c e r a t i v e colitis.

4 Supposed n o . a l l i n Whom the C.8 . was 4 or less and Corresponding Bed i=en ta t i on Rates

R. 17 0 14 M. 48 8 14

R. 19 4 4 M. 88 5

R. 32 3 4 R. 88 6 3

R. 43 4 14 M. 39 7 4

6/22/40 Diabetes. Gingivitis. 10/29/40 A f t e r treatment. 5/24/40 Not completely wormed up. Vague occasional abdominal cramps. lVl2/4o 6r.p . . . . . . o . 8/2/408 Asympto~tic myocarditls, Q.R.S. conduction delay. 11/22/40 Nor~l electrocardlo~r~. 7/22/40 Pyelitis. Ii/27/40 Urine clear.

Use magnifyin~ glass.

1100 studied which had a C.B. of four or less. A more extens ive analysis of the 1100 cases will appear in a subse- quent article. There were 87 pat ients with a C.B. of four or less. Of the 75, supposedly healthy factory execu- t ives , four had a C.B. of four or less. A f t e r compar ing the C.B. wi th the sedimentat ion rate, I conclude that the former has f ewer variables and f ewer false pos i t ive reactions. I con- sidered a sed imentat ion rate of less than 12 in one hour as normal. In seeming ly healthy people a C.B. of less than four will be definite evidence of the presence of an inf lammatory process of the exudat ive type even in the absence of any s y m p t o m s or physical s igns of disease. Such evi- dence may not be found by any other laboratory procedures now at our dis- posal.

By reference to the accompanying table it wil l be noted that diseases re- ducing the C.B. usually cause an in- crease in the sed imentat ion rate. How- ever, in many instances, there is a reduction in the C.B. before the sedi- mentat ion rate is altered. In many cases when healing sets in or cure is accomplished, the C.B. returns to normal while the increase in sedi- mentat ion rate still falsely shows evi- dence of active inflammation.

Examinat ion of the table reveals f e w and possibly no false posi t ives . In every case sufficiently studied in which the Wel tmann was four or less evidence of an exudat ive or mal ignant process could be found. While the test is not a lways pos i t ive for ma- l ignaney those tumors of the s tomaeh or colon which are ulcerated will a lways show a reduction in the C.B. In cases 3311, 4317, 4357, 4371, 4411, 4451, 4478, 4492, 4504, 4734, 4987, and R 19, no definite d iagnos is of an inf lammatory process could be made. However , of these cases, numbers 3311, 4371, 4411, 4451, 4478, 4492, 4504 and 4987 were seen in the office but once.

The urine in case 4492 reduced Benedict 's solution. Further s t u d y may have proven the presence of dia- betes w i th an inf lammatory compli- cation.

Cases 4504 and 4987 gave typical h is tor ies of act ive peptic ulcer.

Case R 19 was not complete ly studied but on May 11, 1940, when the C.B. was four, he was complaining of some abdominal cramps. On No- vember 12, 1940, when the Weltmann was five, the cramps had ceased. He

JouR. D.D. K R A E M E R - - T H E SERUM COAGULATION REACTION 131 APRIL, 1942

may have suffered some mild en t e r i t i s at the t ime of the f i rs t examina t ion .

Case 4317 had p robab ly had a recent co ronary o c c l u s i o n wi thou t symptoms.

I n c a s e 4 3 5 7 a d i a g n o s i s o f m i g r a i n e was made when seen 7/27/39 wi th a We l tmann of four . On 9/13/39 when the Wel tmann was six, he r head- ache had ceased. This was poss ib ly a case of s inus i t i s w h i c h improved. T h a t a n undisclosed in f l ammato ry process was improv ing is also evi- denced in the decl ine of the sedi- men ta t ion rate .

No in f l ammatory process was dis- covered in case 4734, a l though ex- tens ive d iagnos t ic p rocedures w e r e employed.

As has been f r equen t ly descr ibed in the l i t e r a t u r e and as we found in th is s tudy the s ed imen ta t ion r a t e gives numerous fa lse posi t ives . The m a n y var iab les of the s ed imen ta t ion ra te a re not inheren t to the Wel t - mann test .

A C.B. of four or less cannot be. d i s r ega rded . A case to po in t is R 32. This young man was in a p p a r e n t good hea l th and had no previous h i s t o r y of disease. His We l tmann was three. An E.C.G. (F ig . 2) t aken on 6/28/40 showed e v i d e n c e o f delayed con- duct ion t h r o u g h the ventr ic les . H e cont inued a t work wi thou t symptoms . On r e e x a m i n a t i o n 11/22/40 the Wel t - mann was six and the E.C.G. normal . Th is man most l ikely suffered an a s y m p t o m a t i c acute myocard i t i s .

The most s igni f icant f inding in th i s r epor t is the constancy wi th which the t es t was posi t ive in u lcera t ive and in f l ammato ry processes o f t h e di- ges t ive t rac t . This fac t is self ev ident i f the table is analyzed. Whi le the re were n u m e r o u s cases of duodenal ulcer wi th a normal Wel tmann every act ive gas t r i c ulcer had a C.B. of four or less. I i n t e r p r e t a C.B. of f ou r or less wi th duodenal u lcer as evidence of pene- t r a t ion . E v e r y case of u lcera t ive coli t is w i th symptoms and every case of reg iona l i le i t is had a W e l t m a n n of fou r or less. The constancy of a reduced C.B. in carci- noma of the s tomach and colon and in pos t e r io r wall ga s t r i c u lcer has s t imu la t ed me to r e i nves t i ga t i on of all suspic ious cases wi th nega t ive roentgenologic find- ings. Cholecys t i t i s a lmost a lways gave a reduct ion in the C.B. D ive r t i cu l i t i s of the colon and duodenum caused a reduc t ion in the C.B. A s y m p t o m a t i c di- ver t icu los i s caused no reduct ion.

P R O G N O S T I C V A L U E OF T H E C.B.

As hea l ing of an u lcera t ive process proceeds the re is a p r o m p t r e t u r n of the C.B. to normal . The C.B. t h e r e f o r e becomes a valuable p rognos t i c aid. F ig . 3

Fig. 1

(case 5005) shows the change in the C.B. accompanied the hea l ing of a lesser cu rva tu r e ulcer.

In case 4824 the re was a h i s t o ry of an a t t a c k of acute cholecys t i t i s . The C.B. on S e p t e m b e r 10, 1940, was four. A f t e r a ser ies of b i l i a r y d ra inages , the pa t i en t became a lmost symp tom f ree and pus cells d i s appea red f rom the bile. The C.B. on December 30, 1940, was no rma l (6.)

Case 4577 shows the improvemen t of the C.B. f rom 0 to 3 in the course of t r e a t m e n t of a case of G i a r d i a l dysen te ry . Cases 3207, 4424, 4650, 4733, 4863, 4978, and R 32 all demons t r a t e how the s ed imen ta t i on r a t e r e t u r n s to normal as symptoms improve.

C O M P A R I S O N W I T H S E D I M E N T A T I O N R A T E

Cases 3795, 4128, 4358, 4408, 4424, 4477, 4779, 4824, 4920, 5005, and R32 had ex tens ive i n f l ammato ry or m a l i g n a n t diseases. In all of these cases the sed imen-

132 A M E R I C A N J O U R N A L OF D I G E S T I V E D I S E A S E S VOLUME 9 NUMBER 4

Fig. 2

Fig. 3

r a t ion r a t e was no rma l while the C.B. had sh i f t ed to the left"

Cases 4650 and 4944 show t h a t the s ed imen ta t ion r a t e may not become increased unt i l hea l ing sets in ; when the C.B. has a l r e a d y r e t u r n e d to normal .

S U M M A R Y A N D C O N C L U S I O N S

1. The W e l t m a n n tes t is a valuable office procedure . 2. A reduc t ion of the C.B. to fou r is a lmos t ce r t a in

evidence of the presence of an exuda t ive or m a l i g n a n t process.

3. The Wel tmann tes t has p rognos t i c s ignif icance in t h a t a r e t u r n t o w a r d norma l ind ica tes heal ing.

4. F o r genera l use the d e t e r m i n a t i o n of the coagu- la t ion band is of g r e a t e r value than the s ed imen ta t ion

r a t e of the red blood cells. The W e l t m a n n reac t ion occurs e a r l i e r in the course of the disease. I t does not have as many var iab les as the s ed imen ta t i on ra te .

R E F E R E N C E S 1. Kramer, M.: Weltmann Test in Diseases of the Liver. Am. J. Dig.

Dis. and Nutrit., 2:14, 1935. 2. Weltmann, 0 . : Uber die Spiegelung exudatibetzundlicher : und

fibroser Vorgang in Blutserum. Med. Klin., 2S :240, 1939. 3. Weltmann, O. and Medvei, C. V . : The Coagulation Band and I ts

Place in the Clinic. Wien. klin. Wch~chr . , 12:1919, 1933. 4. Levinson, S. A., Klein, R. I. and Rosenblum, P . : The Weltmann

Serum Coagulation Reaction. Jr. Lab. and Clin. Mvd., 23:53, 1937.

5. Levinson, S. A. and Klein, R. I . : The Value of the Wel tmann Serum Coagulation Reaction as a Laboratory Diagnostic Aid; Comp.~.rison with the Sedimentation Rate. Ann. Int. Med., 12:1948, 1939.

6. Dees, S. C.: A Clinical Study of the Wel tmann Serum Coagulation Reaction. J. Ped., 17:44, July, 1940.

7. Ib id : An ]Experimental Study of the Wel tmann Serum Coagulation Reaction. Ibid, p. 53.