Groth, CG

Pechet, L

Starzl, TE

English

PubMed

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Coagulation during and after orthotopic transplantation of the human liver

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Reprinted from the Archives of Surgery January 1969, Volume 98 Copyright 1969, American Medical Association /13 Coagula tion During and After Orthotopic Transplantation of the HUlllan Liver Carl G. Groth, MD; Liberto Pechet, MD; and Thomas E. Starzl, MD, Denver I n earlier reports from this insti-tution1 ,2 changes in hemostasis were described in five patients treated with orthotopic homotrans-plantation of the liver. There was an intraoperative bleeding diathesis at the same time as fibrinolysis and hypofibrinogenemia developed. In four of the cases, the hemorrhage was eventually controlled after the administration of epsilon aminocap-roic acid (EACA) , fibrinogen, and fresh blood. Subsequently, three of the four survivors formed thrombi at or near femoral venotomy sites which had been used fOl" the inser-tion of external bypass catheters; in all three, the eventual result was multiple pulmonary embolization. Appreciation of the seriousness of these problems prompted a number of investigations to be performed in dogs and pigs2-5 to more fully char-acterize the clotting abnormalities of liver transplantation and to learn If a succeeding period of hyperco-agulability was an inherent part of the picture. It has been established from these studies that hepatic homo-Submitted for pUblication May 18, 1968, From the departments of pathology and medicine (Dr. Pechet) and surgery (Drs. Groth and Starzl) , the University of Colo-rado School of Medicine and Veterans Ad-ministration Hospital, Denver (Drs. Pechet and Starzl). Dr. Groth is currently an In-ternational Postdoctoral Research Fellow of the Public Health Service in Stockholm. Reprint requests to Department of Sur-gery, University of Colorado Medical Cen-ter, 4200 E Ninth Ave, Denver 80220 (Dr. Starzl). Arch Surg/Vol 98, Jan 1969 transplantation can cause fibrinoly-sis, thrombocytopenia, and depres-sion of various clotting factors; that the extent of these changes are prog-nostic inasmuch as they are propor-tional to the magnitude of liver injury; and that the depression of clotting is not necessarily succeeded by hypercoagulability if thrombo-genic agents are not administered. The present report, based on expe-rience with ten more recent cases of clinical orthotopic transplantation, will show that the same conclusions apply in man. Methods The diseased recipient livers were removed and replaced with orthotopic homografts; splenectomy was concomi-tantly carried out in all but two cases. External bypasses, to decompress the occluded splanchnic and inferior vena caval beds during the anhepatic phase, were not used. The ten patients were 13 months to 43 years old. In the first two cases, organs were used that had sustained a severe ischemic injury as judged by high postoperative rises in the recipient serum transaminases, poo'r hepatic function from the outset including rapidly progressive jaundice, and death of the patients seven days and ten days later from combined he-patic and renal failure. The next eight patients benefited from more discriminating donor selec-tion and from the application of an effective technique for interim preser-vation of the homografts.6 The liver lllJury was mild to moderate by the above criteria, and all patients had satisfactory early homograft function. Five patients with jaundice cleared their hyperbilirubinemia. In the three others, normal preoperative bilirubin levels remained unchanged, at least until the onset of rejection. All these eight recipients survived for at least orie month, and four are still alive after one to ten months with liver function that ranges from good to ex-cellent. The details of these cases including the regimen of immuno-suppreSsion have been reported elsewhere.7,B In seven of the ten patients coagula-tion was studied several times during operation and, in all, the blood was examined at regular intervals thereaf-ter. The battery of examinations and the techniques of analyses were the same as in a recent study of the same problem in dogs<!; the details of metI1-odology will not be repeated here. The tests could be divided as follows on the basis of what tI1ey measure: A. Clotting Factors Known or Thought to be Produced by the Liver. -These included factors I (fibrino-gen) , II (prothrombin), V (accelerator globulin), VII (proconvertin), IX (Christmas), and X (Stuart). Except for fibrinogen which was quantitated in mg/1oo cc, the results were ex-pressed in percent of normal. In a few instances, the less specific Quick pro-thrombin time was obtained. B. Extrahepatic Elements of Clot-ting.-Factor VIII (antihemaphilic globulin) and platelets were measured. C. Indicators of Fibrinolysis.-The presence of plasmin (fibrinolysin) was Coagulation and Liver Transplant/Groth et al 31 assayed directly with the heated fibrin plate method. Indirect evidence of fibrinolysis was sought with several methods. The latter involved tests to detect or to measure or both plasmino-gen (which is low with fibrinolysis), plasminogen activators (determined with the unheated fibrin plate method or with euglobulin lysis times), and the products of partial fibrinogen de-gradation (fibrinogen split products, FSP). D. Antithrombin Activity.-This was assayed by determining the thrombin time; in some samples with prolonged thrombin time the level of plasma heparin was measured. Results Severe Liver Injury.-These two patients were first studied in the postoperative period, at which time profoUnd coagulation abnormalities were present. In a 13-month-old child, whose original diagnosis was biliary atresia, the liver-produced factors II, V, IX, and X were all less than 15% of normal; fibrinogen was never higher than 125 mg/100 cc (Fig 1). The Quick prothrombin time and the thrombin time were both extremely prolonged. In con-trast, factor VIII was supernormal for the entire ten postoperative days (Fig 1). There was a progressive thrombocytopenia despite daily platelet infusions. Euglobulin lysis times (ELT) were prolonged. Hem-orrhage was not troublesome until gastrointestinal bleeding became continuous during the last two days of life. A 28-year-old man with a hepato-ma had similar but widely fluctuat-ing changes. Bleeding was, however, a far more significant problem. Dur-ing the operation and the seven postoperative days he received 33 liters of blood and 3.5 liters of fibrinogen solution. Moderate or Mild Liver Injury. -Early: All the seven recipients in which intraoperative studies were obtained had similar changes which varied only in degree from case to case. None received thrombogenic agents. The courses of the two pa-tients with the most and least pro-found changes respectively are shown in Fig 2 and 3. The factors synthesized by the liver, which be-gan to fall during the hepatectomy, decreased further during the anhe-patic phase and reached a nadir shortly after the homograft was re-vascularized. Factors V and IX were usually the most severely affected; factors II, VII, and X next; and fibrinogen the least. The altera-tions in factor VIII, which is not produced in hepatic tissue, varied from profound depression (Fig 2) in some cases to a moderate de-crease in others (Fig 3). The plate-lets were transiently depressed in five of the seven patients. Following the anhepatic phase all patients had a marked activation of the fibrinolytic system as shown by Fig l.-Measures of coagulation and fibrinolysis in a 13· month·old child who never had satisfactory function of his orthotopic liver homograft. Note that factor VIII remained supernormal while all the liver·based coagulation factors were severely depressed. Euglobulin lysis time (ELT) was infinite. Fig 2.-lntraoperative and early postoperative coagulation changes in a 16·month·old child with life sustaining but im-paired immediate homograft function. All coagulation factors studied were depressed below 50% of normal. These grad-ually returned toward normal. FSP, Fibrinogen split products (see text). !IOO 50 I - EibrinoQen l"o--v--.. -------------_~ ~ ------- .. _---.. )2OO.l ~~~ 200 . ----.\\ ~ 100 ... '. _--,Platelet. ~-- '" , ' .... ---........................ ---... -.. ~ ............ 0 :~ - _J;mmoo--omuoo--60 ~"> .............. 0 o 2 4 6 8 10 :---r--r~r--r-"D"":!::fl--:fOr- I ! 5 DAYS 1------ -------il I--DAYS---I 32 Arch Surg/Vol 98, Jan 1969 Coagulation and Liver Transplant/Groth et al the occurrence of lysis on heated plates, decreases in plasminogen levels, and shortening of the ELT. Concomitantly fibrinogen split prod-ucts appeared in the serum. Prolongation of the thrombin time occurred after revasculariza-tion of the homograft in all cases. In the patient with the most pro-found changes in hemostasis meas-urable amounts of plasma heparin (47 ,ug/ml) occurred at this time. Three other patients studied had no. detectable heparin in their plasma in spite of prolonged thrombin times. Two hours after revascularization of the homografts, a restitution of the clotting factors toward normal had generally begun. By this time, the studies of fibrinolysis also showed improvement (Fig 2 to 4). During the ensuing week the major-ity of hemostatic parameters re-turned to essentially normal levels. Exceptions were the platelets and plasminogen levels which usually remained subnormal for several weeks. There was little or no evi-dence of delayed hypercoagula-bility. Abnormal intraoperative bleeding was encountered only in the patient with the most profound alterations in hemostasis (Fig 2). The hemor-rhagic state in this case was, how-ever, transient. Late: The later postoperative course was studied in the eight best cases. The clotting values were closely correlated to the quality of homograft function as measured by standard liver function tests. The· patient with the longest survival (ten months) has had good liver function and essentially normal co-agulation and fibrinolysis through-out. Two patients who died of pro-gressive liver failure 4Jf2 and 6 months after transplantation had slowly declining levels of the clot-ting factors synthesized by the liver as well as decreases in plasminogen (Fig 4). During this course, factor VIn remained unaffected. Comment Several mechanisms apparently account for the sudden decrease in clotting factors during orthotopic liver transplantation. The most im-portant are probably consumption Fig 3.-Changes in a 14·month·old child with satis· factory immediate liver function. All coagulation factors studied were transiently but only minimally depressed. FSP, Fibrinogen split products. Fig 4.-Postoperative changes in a 20lh·month· old patient. Early homograft function was satis· factory but progressive liver failure due to chronic rejection subsequently developed. During the late course, factor VIII remained supernormal while the liver· based II and V and plasminogen ultimately declined. 150 ANHEFIlTIC STAGE ,/". ..... _ ..___ X ___________ ....... _______ "'" ........ ,. ...... .." • ~KK IbriIotIn ~2.01d l!.!lld ! ... ~ ~!Ko .. r • ~lK!lld I ~ 0 Ii: ll20J ~ III 0 j i I!! --". I' i~i zELT ............ ~~~~KKKK . ~ggmo •• •••••• ~~4 24681012 135 I------HOURS I t--DAYS---i Arch Surg/Vol 98, Jan 1969 a 0 a 0 0 20 '10 60 80 100 120 140 DAYS Coagulation and Liver Transplant/Groth et al 33 of the coagulation factors due to intravascular coagulation,4 and counterregulatory fibrinolysis. Tem-porary cessation of hepatic synthe-sis is presumably a contributory fac-tor. The precise mechanism of these changes has been discussed else-where.1-4 In only one case could prolongation in thrombin time be related to the occurrence of plasma heparin as suggested by Stremple9 ; the trace quantities could have been due to the heparin solutions used to perfuse and flush the grafts.5.7 In the others, the antithrombic activity was attributable to the occurrence of fibrinogen split products.10 In a recent laboratory study,4 it was shown that the severity of the hemostatic breakdown after ortho-topic liver transplantation in dogs was related to the quality of the homografts. The conclusion was the same in the human cases herein reported. The two patients who re-ceived livers badly damaged by is-chemia developed profound and per-sistent abnormalities in clotting while the recipients of well-preserved homografts had only minor or mod-erate changes which were reversible. None of the latter patients required administration of clot promoting or antifibrinolytic agents. Moderate bleeding such as experienced in one of these patients should not neces-sarily be regarded with alarm nor treated pharmacologically since spontaneous improvement can be expected. The avoidance of pharma-cologic manipulation of hemostatis and omission of an external decom-pressing bypass in the venous sys-34 Arch Surg/Vol 98, Jan 1969 tern undoubtedly helped prevent postoperative thromboembolism such as that seen in earlier cases.1 If treatment should become necessary for a hemorrhagic diathesis, it should be guided by frequent meas-ures of clotting parameters. Although most of the clotting fac-tors analyzed in this study are known to be synthesized in hepatic tissue, the origin of factor VIII (an-tihemophilic globulin) remains ob-scure. In several of the patients, who had also had splenectomy, fac-tor VIII remained normal or super-normal as the other factors declined concomitant with acute or chronic hepatic failure; in one such case, the recipient was essentially anhepatic (Fig 1). It thus appears that nei-ther the spleen nor functional liver tissue are essential for the mainte-nance of adequate levels of anti-hemophilic globulin. Summary Orthotopic liver homotransplan-tation in humans was accompanied by acute depression in multiple coagulation factors, thrombocyto-penia, and pathologic fibrinolysis. Two patients with poor homograft function had severe and persistent changes; eight subsequent recipients with satisfactory immediate liver function developed only minor or moderate derangements which were reversible and did not require thera-py with thrombogenic agents. Later in the course coagulation was nor-mal except with the advent of chronic hepatic failure when depres-sion occurred of the coagulation fac-tors synthesized by the liver. This study was supported by Public Health Service grants AM-06344, HE-07735, AM-07772, AI-04152, FR-00051, FR-00069, F05-'IW-1154, AM-12148, AI-AM-08898, and CA-08804. References 1. Starzl, T.E., et al: Homotransplan-tation of the Liver in Humans, Surg Gynec Obset 117:659-676 (Dec) 1963. 2. Von Kaulla, K.N., et al: Changes in Blood CoagUlation Before and After Hepa-tectomy or Liver Transplantation in Dogs and Man, Arch Surg 92:71-79 (Jan) 1966. 3. Hutchison, D.E., et al: Platelet Changes Following Clinical and Experi-mental Hepatic Homotransplantation, Arch Surg 97:27-33 (July) 1968. 4. Pechet, L.; Groth, e.G.; and Daloze, P.M.: Changes in CoagUlation and Fibri-nolysis After Orthotopic Canine Liver Ho-motransplantation, J Lab Clin Med, to be published. 5. Blecher, T.E.; Terblanche, J.; and Peacock, J.H.: Orthotopic Liver Homo-transplantation, Arch Surg 96:331-339 (March) 1968. 6. Brettschneider, L., et al: The Use of Combined Preservation Techniques for Extended Storage of Orthotopic Liver Homografts, Surg Gynec Obstet 126:263-274 (Feb) 1968. 7. Starzl, T.E., et al: Extended Survival in 3 Cases of Orthotopic Homotransplan-tation of the Liver, Surgery 63:549-563 (April) 1968. 8. Starzl, T.E., et ale Orthotopic Homo-transplantation of the Human Liver, Ann Surg 168:392-415 (Sept) 1968. 9. Stremple, J.F.; Hussey, C.V.; and El-lison, E.H.: Study of Clotting Factors in Liver Homotransplantation, Amer J Surg 111:862-869 (June) 1966. 10. Kowalski, E.: Fibrinogen Derived Inhibitors of Blood Coagulation, Thromb Diath Haemorrh, suppl ad, 4:211-223, 1960. Coagulation and Liver Transplant/Groth et al Printed and Published in the United States of America 

Coagulation During and After Orthotopic Transplantation of the Human Liver

Carl G. Groth

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Archives of Surgery

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Coagulation During and After Orthotopic Transplantation of the Human Liver

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