Prothrombin time during the postoperative period

Prothrombin

Time

during Period

the Postoperative

LUDWIG STRAUSS, M.D., Los Angeles, Calijornia, MAX W. BAY, M.D., Los Angeles, AND ALFRED D. KATZ, M.D., Bufalo, New York

From the Surgical Service Cedars of Lebanon Hospital,

of Drs. Buy and Strauss, Los Angeles, Culifornia.

vasoconstrictor which causes a proIongec1 Iocalized state of vasoconstriction, reducing blood loss and helping the fibrin clot to anchor. The thrombopIastin, calcium, plasma labile factor (AC globulin) and plasma stable factor

discussing prothrombin time it is necessary to have a clear understanding of the clotting mechanism. Today, blood coagulation, X3 many of us see it, is a confusing mass of terms and diagrams with each authority having his own synonyms. During the Iast fifteen years a great deal of progress has been made in the study of bIood coagulation as a separate branch of hematoIogy. For instance, new clotting factors have been identified and only recentIy has it been shown that the following refer to a single protein clotting factor or its modified form in the serum: AC gIobuIin, XXII; stabIe factor, xX111; pIasma co-factor, XXIV; factor v, xxv; PPCF, XXVI. RecentIy the existence of factor VII has been suggested and DeNicoIa believes that this factor varies more and earlier during anticoagulation therapy than the modification of prothrombin. Increased factor VII activity has also been observed in thromboemboIic disease. In Figure IA to C we have broken the coaguIation process down to perhaps a much too simplified state and use the more famiIiar terms, borrowing from Quick, Stefanini [I], DeNicoIa [2] and Seegers [J]. Stefanini in a recent articte [4] reviewed all the recent conceptions of the mechanism of bIood clotting. He incIudes in his paper the theories of Owren [6], Quick, Seegers, Tocantis and Stefanini (71 as compiled by Dr. Everret C. Albritton, editor of the Handbook of Biological Data. Salibi [T] has also written an excellent review. Nearly a11 men agree that agglutination of pIateIets represents the initial step. It liberates thrombopIastinoginase, which reacts with pIasma thrombopIaitinogen to form thrombopIastin. The plateIets aIso suppIy a

I

California,

N

A

SLOW

PHASE Lysis

of

qlatelets

Thromboplastin 4

Prothrombin +Co”‘,

plasma stable

Plasma

B Thrombin iin small

B

in amounts

AC globulin

omts.)

4 Serum

c

Thrombin small

AC globulin component

AC globulin

Thiomboplostin Prothrqmbin

+ Co”,

> Serum stable

Thrombin in large amounts

Ac’globulin component

Fibrinogen------+ FIG.

I.

A to C, blood

Fibrin

clotting.

form smaI1 amounts of thrombin or what is known as the sIow phase of Stefanini. (Fig. I A.) Thrombin then activates pIasma AC gIobuIin to serum AC gIobuIin, starting the accelerated phase. Prothrombin, calcium, stabIe component and serum AC gIobuIin interact to form thrombin with increasing speed. Enough throm95

American

Journal

of Surgery.

Volvnre

93. January,

,997

Strauss,

Bay

and Katz cases of malignant disease. Nasilowski [I I] found the most marked lowering in patients \vho had lo\\,erecl prothrombin activity- prior to surger\-. Quick found prolonged prothrombin time in the cord and infant’s blood if the mother did not receive vitamin K. Shapiro [IO] and Warren [ r9] found a decrease in platelet count during the early postoperative period also. All avaiIabIe information on postoperative changes in the clotting mechanism has been summarized recently by Warren [zr]. A rather interestmg finding of Steinberger [23] was the increased thrombin in thrombotic states incIuding thrombosed hemorrhoids, coronary occlusion, postoperative thrombosis, but aIso in biliary disease without jaundice. Olwin [24] reported a rise in AC gtobulin in cases of thromboembolic disease. It was not cIear if this was cause or effect. Cook, Pearl and Harris [25] in a clinical study of 165 non-jaundiced patients showed a high incidence of unsuspected low blood prothrombin content. It was suggested that there was a relationship of Iow IeveIs of bIood prothrombin to postoperative complications such as hemorrhage and deficient wound heaIing. Of the 165 patients twenty-one or 13 per cent had a prothrombin on admission under 50 per cent. Ten of these or 67 per cent had comphcations. In 146 patients with prothrombin time over 50 per cent, four or 3 per cent had complications. Experiments on rats gave added evidence that hypoprothrombinemia may contribute to impaired wound healing. Levy-SoIaI and Argent [26] concluded that physioIogic hypercoagulabiIity of blood does not pIay an important part in pathogenesis of postpartum thrombophlebitis. Low prothrombin time has also been reported in myocardia1 infarction. Peery et al. [27] in a series of 136 cases of myocardial infarction reported initial prothrombin time before dicumarol of less than 50 per cent in sixty--one cases (45 per cent). This was determined prothrombin time using the diIute (12.5 per cent) pIasma prothrombin test. These patients with myocardia1 infarction had a mean prothrombin time of 32.29 seconds as compared to that in normal subjects of 38.6 seconds. This was considered significant. Since the surgica1 patient is subjected to great stress during surgery, it was thought that perhaps patients receIvrng

bin is formed to activate fibrinogen to fibrin. Thrombin aIso causes clumping and disintegration of platelets, thus continuing the cycle. (Fig. I B and C.) The process of coagulation is an unstable balance \vith negative and positive factors. Antithromboplastin and antithrombin are present with perhaps many more as yet unidentified factors. Fibrin, pIaying an active roIe, absorbs thrombin on its surface and thereby checks rapid formation of this enzyme. It aIso Iyses pIateIets. The major dispute stiII rages as to whether the reactions are enzymatic or stoichiometric. According to Quick [8] hemorrhagic disease can be roughly cIassified into two main hypothrombopIastinemias and hypogroups: prothrombinemias. Quick [3~,36] states that prothrombin is synthetized by an enzyme which consists of two parts, an apoenzyme (AE) and vitamin K which serves as the prosthetic group. According to this, hypoprothrombinemia faIIs into three groups: (I) Lack of vitamin K; organism has enough AE but cannot form AEK, that is, hemorrhagic disease of newborn and bleeding due to obstructive jaundice; cured by giving vitamin K in smaII amounts. (2) Lack of vitamin by antivitamin K; compounds AED formed (D = dicumarol) ; therapy consists of Iarge doses of vitamin K to repIace D, AED plus K, AEK pIus D. (3) Apoenzyme is lacking due to congenita1 defect or liver injury; therap consists of prothrombin replacement with plasma or blood transfusion. However, Warren believes that three day old blood is low in prothrombin and high in acceIerators. Rhoads [37] writes that prothrombin is destroyed in the Iung. AvaiIabIe evidence points to a rapid disappearance of prothrombin from circuIation and concurrent formation mainIy, if not exclusively, in the liver. He aIso showed that not all patients with hypoprothrombinemia could be helped with vitamin K, onIy those patients with vitamin K deficiency. Many authors have reported on prothrombin IeveIs in the postoperative state [9-r5,17,19]. Most of them found a Iowered prothrombin activity in an appreciabIe number of their cases. There was, however, no consistent modification of the norma levels. Changes in the opposite direction were aIso observed by some of the investigators [9,r3] especially in 96

Prothrombin

Time during

ACTH and cortisone therapy would give a simifar picture. [29] found h)-percoagufabifit? Beaumont almost always in cases of myocardial infarction during the initial twenty-four to forty-eight hours. On the second or third day spontaneous secondary h?-pocoagufabilit2; occurs as shown by tests ancf fasts about seven daj:s. Starting ahout the eighth clay h!-percoagufahlfity recurs. Beaumont suggests that after initial heparin, no anticoagulants be given unless frequent tests show increasing clotting. Similar stages of hypercoagufabilit\were founcf in pufmonar>and cerebral embolism. According to Cosgriff, Diefenbach and Vogt 1301 eight of ten patients receiving ACTH or cortisone showed considerable shortening of venous clotting time. The heparin retarded venous clotting time was decreasecf in four of six patients. These authors state that there is no consistent change to a state of hyper- or hy!oprothrombinism. Won-ever, patients recerving ACTH or cortisone are unusually sensitive to dicumarof. Cosgriff [ 3I] flefieves that thromboembof ic phenomena are one of the serious complications of the h,vperadrenaf state. Napofitano et al. [?2] treated patients who had phfebothromhosis or thromhophfebitis with ACTH and observed remarkabfe improvement. During their study these authors showed that prothrombin time \\‘as prolonged ant1 prothrombin fevef reduced. Protamine Ievef at the same time increased. They felt that protamine increase was tfue to release of heparin from mast ceffs under stress. Napofitano et al. put forth the possibility that epinephrine released under stress acts as a catafyst to after the circulating profibrinolysin into active enzyme, fibrinolysin. Tflis later agent has the capacity of Inactivating the and fibrinogen and I?-sing the prothrombin fifjrin clot.

Postoperative

Period

duct, four; misceffaneous (including t\vo radical mastectomies), eight. Prothrombin times were taken one day preoperatively ancf on the first, second antf third postoperative clay routinely. Additional tests were made in cases of complications and very

I 30 i

FIG. 2. Prothrombin time-percentage operative: preoperative.

change. Post-

marked and proIonged drops in the prothrombin time. The first surprising observation was that only 74.6 per cent of the patients hatf prothrombin time of 70 per cent or over, wflich 1l.e arbitrarily considered as normal. In the postoperative period the postoperative to preoperative percentage change is shown in Figure 2. Thirty-four patients had Ig per cent; nineteen had 20 to 30 per cent; nineteen had 30 to 40 per cent; eighteen hacJ 40 to 50 per cent and eight had $0 per cent or greater drop. In four patients the postoperative prothrombin was higher than preoperative. None of the latter had evidence of phIebitis. In these one hundred four cases there were six complications; there \vere four CBSCS of phlebitis, one case of evisceration folIowing vagotomy and one case of duodena1 stump leakage folfo\ving gastrectomy. In fortj--four of these patients eosinophil counts rvere taken. Thirty-eight were good responses and six were poor. In two of the patients with compfications eosinophif counts were made [Ed]; both responses were good. In the thirty-tw.0 cases of cofectomy 35 per cent of the patients had an admissron prothrombin time of 60 per cent or beJow. However, the postoperative drop was not greater

FINDINGS

In our study, using the one-stage prothrombin test as cfescribed previousfy, both preoperative and postoperative prothrombin times were taken in 104 unsefected patients from our private service. The types of cases are as foffow : cofectomg, thirty-two; hysterectomy, eighteen; gastrectomv, twenty-two; choIecystectomy, nine; resection of smaff howef, six; abdominoperineaf, five; expforation of common 97

Strauss, Bay and Katz than time.

in the cases with norma prothromhin This finding is contrary to Nasilowski’s

The third patient also had gastrectomy with compIications, namely, duodenal stump Ieakage. This drop in prothrombin time postoperatively is shown in Figure 5. Figure 6 shon-s prothrombin time in two patients n-ith phlebitis following hysterectomy.

Irrl.

Figure 3 illustrates the case that started the investigation. This patient had a subtotal gastric resection for duodena1 ulcer. Phlebo-

100

‘0’

c

’

I

I

I

/

I

I

I

I

0

2

4

6

8

IO

12

14

16

onrs

FIG. 3. Gastrectomy. second postoperative

FIG. 4. Vagotomy and pyIoropIasty obstruction at pylorus.

Patient treated with heparin on day. Eosinophil response good.

100

L

with postoperative

\ \

80

20

0

Frc. 6. Hysterectomy.

Two patients

with phIebitis.

FIG. 5. Gastrectomy; duodenat stump leakage on twelfth day. Eosinophil response good.

The interesting observation to us was that these patients were among the group that had the greatest drop in prothrombin time. Figures 7 and 8 show the exceIIent response to vitamin K of a Iow postoperative prothrombin time. One patient had jaundice (Fig. 7) and the other had an ileostomy and colectomy for ulcerative coIitis. (Fig. 8.) This response does not necessariIy suggest lack of vitamin K. The response to vitamin K couId aIso be explained on the basis of a re-establishment of a disturbed enzymatic equation. Figure g shows the marked sensitivity to dicumaro1 in a case of postoperative phIebitis.

thrombosis and an emboIus deveIoped about fifty-four hours postoperativeIy and at that time the patient had a prothrombin time of 40 per cent. He was treated with heparin, and the prothrombin time during the foIIowing fourteen days varied between 21 and 30 per cent without his having received any dicumarol. Figure 4 iIIustrates a case in which evisceration and pyIoric obstruction deveIoped after vagotomy and pyIoropIasty and the patient had a prothrombin time of 20 per cent. His prothrombin time became norma during the following week without vitamin K.

98

Prothrombin

Time during

This patient only needed 375 mg. of dicumarol to keep flis prothrombin time at the desired IeveI. In another case of severe post-traumatic ifeofemoral thrombosis 300 mg. of dicumarol in the presence of a norma prothrombin time 100

-

60

-

Postoperative

Period

nutrition and vitamin K may be only barely in balance. We beIieve that miIk and cream diet does not suppIy optimum protein nutrition for the adult and that many comp1ication.s following

20 -

0'

I

I

I

I

I

I

2

3

4

5

Jo

-ODdY------

FIG. 7. Data on patient with jaundice.

necessitated the administration of vitamin because the prothrombin time dropped dangerous IeveIs.

FIG. 8. Ikostomy and coIectomy for ulcerative coIitis. Preoperative therapy, antibiotics (oral and parcnteral).

K to

CONCLUSIONS I. Variations occur in norma prothrombin time vaIues. A further study of heaIthy outpatients is being ContempIated. 2. There seems to be no correlation between the eosinophi1 response and our compIications. Marked drop in prothrombin time appeared to be present in these cases; however, the same degree of prolonged prothromhin time occurred in cases without complications. 3. We do not believe that prothrombin level drop postoperativeIy is due to loss of acceIerator factors in every or an?- case, but that a multitude of variants are invoIved in every case. 4, Changes in prothrombin activity may he due to one of the folIowing factors: (I j iiver damage [14], (2) Jack of suppIy of vitamin K, (3) Iack of absorption of vitamin K [16], (4) increased use of vitamin K, (5) inadequate protein nutrition and (6) response to stress. In our patients one or severa of these factors pIay a part. For instance, some of these patients received ora antibiotics which changed intestinal flora and vitamin K absorption. Others have had no ora intake because of gastrointestinal suction. Because of diets some patients are probabIy not in optima1 protein

ObYS

FIG. 9. BiInteraI femora1 vein ligation anesthesia for phlebitis with cmbolus after ventral hcrniorrhaphy.

under Ioc:tT four weeks

surgery for chronic peptic uIcer are clue to impaired protein nutrition. Four of our patients with marked drop in prothrombin time had cIinica1 phIebitis. This drop may actually be a sign of increased cIotting and increased use of avaiIabIe prothrombin. Warren and BeIko [zo] found increased consumption. We think that in the presence of suggestive evidence of phIebitis a proIonged prothrombin time is corroborating evidence. We believe that prothrombin time is only one factor in determining normaI, decreased or increased coagulability of the bloocl. 99

Strauss,

Bay

and Katz 14. AL.LE~, I. G. ancf L~vrs!c;sroh~, II. Postopcr:ttivc hypof_“otllron~~~ineI~~i~~:\ncf nnrsthcsi:l. Arch. Sure., 42: 522, I’)42.

Li’c agree with IIogben [42] that prothromhin time does not afford certainty in the prediction of hemorrhage nor, we think, in the prediction of clotting. Thus Sandrock [9] and LVitz :mcf Stufxr [22], found hyperprothrombin time prior to the onset of clinical evidence of thrombosis Jvhereas our finclings anti those of Ochsner [ 121 were just the opposite. We therefore think a profongetf prothrombin time during the postoperative periotf shoultf not lx vielved with alarm nor shouftf an urgent order for vitamin K be given. I$‘e &o cl0 not fxfiel-c that fargc doses of dicumarol shoufcf Ix ordered in cases of susDected DostoDerativc Dhfebitis even in the bresence’of a Aormal pr&hrombin time because of the increased sensitivity to dicumarof cfuring this period.

20. U’ARKEN, R. :!ncI BEI.KO, J. S. Dcficicncy of prothrombin conversion ;Icccfcrators in postoperxtivr st:ltc with :I description of ;I simple method Al CSSAY. Hid, 6: 544m55 I 195 I. 2 I. \VAKIIES, K. Postoperntivc thrombophili:l. Ne,c, l:n&nul J. Med., 249: 99, 107, 1953. 22. \VIX, J. :ind ST~.HEK, A. \I. Applicxtions cn chirurgie du test dc toI&r:rncc 6 I’h&p:\rinc “in ritro.” Presse &xl., ho: 4 j, 1952. 23. SIXIS~EK~R, I.. A. Preliminary clinic:If cv:ifuation ol’ thrombin recovery test. J. A. M. A., I 50: I59--1 jQ3, 1952. 24. OI.\~IU, J. 11. and FAIIEY, J. I.. AC globulin Icvcls in thronlbo-cmbofism. Ann. Surp., I 32: 443 -449, 1950. 25. COOK, 0. S., PPKL, \I. T. nnd ~IAKHIS, F. I. The signific:rncc of hypoprothrombincmi:t in Sur,cery, 27: 208~.2 I 5, the nonj:luncficcd patirnt.

REFERENCES I. SI.EUASI>I, M. hlechanism of blood conguhction in norm:d :lnd pathofogicnl conditions. Am. J. Med., 14: 64-86, ‘953. 2. DENICOLA, P. Texrs report on biology :tncl mediCiTlC, VOI. 2, pp. 3-17, 1953. 3. \I'ARE, A. G., GUEST, hf. Al. and SEEGF.KS, iv. H. A fuctor in ph~sma which nccehxntcs the xtivation of prothrombin. J. Riol. c‘+ Cbem., 169: 23 r-232, ‘947. 4. STEFAWNl, h,I. Recent ndv;lnccs in the theory of the mechanism of blood congufxtion. J. !Mr. Sinai Hosp., 19: 610-638, 1953: 5. SALTBI, R. S. The mechanism of bIoocl co:Lgul:rtion. &rg., Gq.?‘ec. (‘+ Ohst., 95: 108, 1952. 6. Ox-I~EK, P. A. The co;Lgulntion of blood. Investigation on :L new clotting factor. Actu med. Srandinm. (SuppI.), p. 194, 1947. 7. STEFANINI, hl. Annlytical review conversion factors and nccelerntors in the formation of thrombin. Mood, 6: 84-93, 195 I. 8. QL:IW, A. J. P:lthologic:rI physiology of hcmorrhngic conditions. Bul/. Neu, lhrk Ad. ;Cled., 29: 226, 1953. 9. SAPIDROCK,R. S. :rnd I\~AIIOKEY,E. B. Prothrombin :lctivity. Ann. Surg., 128: 43, 521, 1948. IO. SHAWRO, S., SHERWIN, B. nnd GORDIMER, I I. Postopcrutivc thrombocmbofizntion. Ann. Surq., I I 6: ‘75, ‘942. I I. NASIWWSKI, \V. Z. Polski tygodnik lek., 41 ‘4: 423m424, 1949. 12. O~HS~ER, A. Venous thrombosis. J. A. M. A., 132: 827, ,946; IDEM. Venous thrombosis. J. A. M. A., 142: 535. ‘950. 73. FONTAINE, R., ~~ANDEL, P. et ~1. Rcsultnts de I:t d&tcrmination de In prothrombinc et dcs temps dc d&grad&on de fu thrombinc dl\ns diverses nfl‘cctions chirurgicafes et Icurs vnriutions sous f’influrnce de I’actr op&toire. L>,on chir., 46: 169~184, 1951.

l)jO. 26.

27.

28.

29.

30.

31.

32.

33.

IO0

LEVY-SOLAL, E. xncf AR(;EUT, J. Iivolution de I:I prothrolllbini~ruic et dcs fxcteurs thromboplastiques dnns Ies suites clc couches. G!-n&c. et &St., so: 448, 1951. PEEHY, T. hl., ~III.I.EI<, l-. N., JR. :~nd RIILLIS, I. Signific:~ncc of low prothrombin concentmtion prior to dicumnrol therxpy, in myocnrdi;d inftrrction. Af. .471n. District of Colonhia, 2I: 303-306, 1952. OYEHMAN, I<. :lncf \\KIG~I-I.,1. S. Prothrombin time determinntion on p:lticnts with myocartfi:\l inf:irctions. J. A. :21. A., 147: 227-229, 1951. BEA~;MO~T, J. I>. Studies on spontxneous varintions in blood co:lgul:tbifity immcdiatef,y following myocnrdinl inf:lrction. Am. Heart J., 45: 756m 768, 1953. COSGHIFF, S. I\‘., DIEI.KKH.ACH, A. F. nnd VOGT, L\‘. J. Hyperco:~guIability of blood :rssoci:tted with ACTH ;tncf cortisone thcr:\py. Am. J. Med., 0: 752-756, 1950. COS(;RII;I:, S. \I’. Thronrboembolic compficntions ~tssocinted with ACT11 nncf cortisone thernpy. J. A, 114. A., 14:: 924-926, 1951. NAPOLITANO, L. and PIERSANTI, F. Studio defl:l varinzoni dell:1 co:lguI;tbiIitn sanguina in corsu di thcrapia con ormonc :lclrcnocortico tropo tipo fisctrio. Progr. med., 8: 166169, 1952. SMITII, R. \I’., \IAIKI LIS, R. R., BRIXWMY, hl. J. und hIoNTo, R. \%‘. In~lucnce of ACTfI xncf cortisone on certain factors of blood coagulation. S&We, 112: 295-297, 195”.

Prothrombin

Time during

34. A~CGKAW, A. B., MARCULIS, R. R. and BRUSH, B. E. TwofoId effect of ACTW on bIood cIotting and its comphcntions in surgery. Arch. SW-~., 65: 81-87, 1952. 35. QUICK, A. .J. ProbIem of defective hemostasis in surgery. .4m. J. Surp., 84: 614 616, 1952. 36. QUrcK, A. J. On the construction of protfrrombin. Am. J. l’l]J-siol., 140: 212-220, 1943. 37. Rnosns, J. E. Pfrysiologicnl f:lctors reguhiting the level of pIasm:r prothrombin. Ann. Surg., 112: 568-594, 1940. 38. QuI~;K, A. J. The nature of bleeding in jzrundicc. J. A. M. A., 110: 1658, 1938. 30. QuI(:K, A. J. :rnd STEFAWUI, hf. Nature of the :tction of the Inbile factor in the form:rtion ol thrombin. Am. J. I’trJrsiol., 160: 57.2, 195o.

Postoperative

Period

40. QUICK, A. J. New concept of venous thrombosis. Surg., GJwc. e*?Ohst., 91: 296-300, 1950. 41. SCHILLING, F. J. and DE NATALE, A. Natur;tIIy occurring nnticoxgulants and nccelerator substance in humnn blood. Am. J. ,14.SC., 218: 70 -73, ‘949. 42. ~IOGREK, C. A. LZI. xnd ALLEY, I?. V. The reIationship between prothrombin nnd bIceding in the clinic:rI use of dicumnro1 :rfter operxtion. Circul&m, 2: 369, 1952. 43. \I’RIC.HT, L. T. :rnd ROTHMAN, M. Deaths from dicumnrol. Ad. Surg., 62: 23, 1951. 44. SCHOEN, I., STRAUSS, L. ;ind BAY, RI. IV. An cvnlmrtion of the eosinophi1 count in patients undergoing major surgery. Suw., Gynec. 1~ Obs~, 96: 4033408, 1953.

IO1