Duquesnoy, R

Esquivel, CO

Kang, YG

Marino, IR

Starzl, TE

Weber, T

English

Duquesnoy, RJ

Name not available

HLA alloimmunization and blood requirements in orthotopic liver transplantation

D-Scholarship@Pitt

HLA Alloimmunization and Blood Requirements in Orthotopic Liver Transplantation Ignazio R. Marino, Thomas Weber, Yoo Goo Kang, Carlos O. Esquivel, Thomas E. Starzl, and Rene Duquesnoy ORTHOTOPIC LIVER transplantation (OL T) is often accompanied by massive blood loss due to portal hypertension, difficult dissection as a result of previous abdominal surgery. and coagulation abnormalities. Major alterations of the coagulation factors such as prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT). decreased fibrinogen levels and thrombocyto-penia have already been documented in patients undergoing OLT. I•3 Moreover, problems like fibrinolysis and consump-tion coagulopathy have been demonstrated to play an impor-tant role in blood coagulation system alterations during such an operation;4.5 these factors often necessitate large quanti-ties of blood products during OL T, despite recent adva nces. 2.6-8 Packed red blood cells (RBC), fresh frozen plasma (FFP), platelets (PL T) and cryoprecipitate (CRY) represent the different blood fractions commonly transfused during OL T. The relation between massive blood use in 0 L T, morbidity9 and mortalitylO.1I has already been described. We have investigated the role of HLA alloimmunization in intraoperative blood transfusion requirements during OL T. Alloimmunization can result from previous exposure to HLA antigens through transfusion, transplantation and pregnancy and is usually detected by serum screening for lymphocytotoxic antibodies. HLA plays a significant role in blood transfusions espe-cially those involving platelets. It is well known that PL T express class I HLA antigens and specific alloimmunization to these antigens is a major cause of refractoriness in thrombocytopenic patients to platelet transfusions. 12·14 Our results demonstrate that HLA alloimmunization has a major effect on blood transfusion requirements during aLT. Intraoperative blood use was significantly increased in alloimmunized liver transplant recipients. This retrospective study indicates that pre-transplant screening of liver candi-dates is useful in estimating blood transfusion requirements duringOLT. PATIENTS AND METHODS Between March 1980 and December 1986, 1053 OL Ts were performed in the Departments of Surgery of the University of Pittsburgh and the Baylor Medical Center in Dallas. The case series includes first (821 ), second and third OLTs. Two groups of adult patients were selected from our liver transplant file on the basis of panel reactive antibody (PRA) of pre-transplant serum as determined by lymphocytotoxic-ity testing with a panel of 45-60 HLA typed donors as previously described. 15 One group of highly alloimmunized patients (n = 25) had PRA values greater than 70% and the second group of nonsensitized patients (n = 26) had PRA values of 0%. Patients who had undergone major surgery immediately prior to transplantation and patients with intra-operative bleeding due to technical reasons were excluded. Both groups of patients were randomly selected except for PRA. All cases were first transplants and there were no significant age, weight and pathology differences between the two groups (Table I). Heparin was never used pre-and / or intraoperatively. Intraoperative blood replacement was determined by thromboelastrographic monitoring as previously described.2 Intraoperative infusion of RBC, PL T, FFP and CRY was retrospectively analyzed, in each group. Statistical analysis was done by Student's t and Mann Whitney U test. Data are shown in mean values ± standard error. RESULTS Highly sensitized patients (70% PRA group) received intra-operatively 21.1 ± 3.7 units of RBC and 17.7 ± 3.2 units of PL T, significantly more than nonsensitized patients (0% PRA group) who received 9.8 ± 0.8 units of RBC and 7.5 ± 1.5 units of PL T (RBC: p = 0_002; PLT: p = 0.003) (Fig. 1). In addition, transfusion of FFP and CRY was significantly higher in the 70% PRA group than in the 0% PRA group (FFP: 20.4 ± 4.2 vs 9.2 ± 6.0, p = 0.006; CRY: 8.3 ± 2.5 vs 3.6 ± 1.2, p = 0.026) (Fig I). Despite the larger PL T substitution in the 70% PRA group, as shown in Figure 1, PL T counts dropped from 106,826 ± 13,714/mm3 preoperatively to 71,043 ± 7,816/ mm3 postoperatively (p = 0.006). In contrast, the 0% PRA group had similar pre- (119,600 ± 18,688/mm3) and postop-erative (114,000 ± 14,617/mm3) PLTcounts (p = 0.55). PT, APTT, hematocrit, and fibrinogen level showed no significant differences between both groups (data not shown). From the University Health Center of Pittsburgh, University of Pittsburgh, and the Veterans Administration Medical Center, Pittsburgh, Pennsylvania, USA. Drs Marino. Esquivel. and Starzl from the Department of Surgery; Drs Weber and Duquesnoy from the Division of Clinic Immunopathology; and Dr Kang from the Department of Anesthesia. Address reprint requests to Ignazio R. Marino. MD. Corso Italia 29.00198 Rome. Italy. Supported in part by research grants from the Veterans Admin-istration and Project Grants HL ·35069 and AM 29961 from the National Institutes of Health. Bethesda. Maryland. USA. @) 1989 by Appleton & Lange. Inc. 0041-1345/89/$3.00/ +0 Transplantation Proceedings. Vol 21. No 1 (February), 1989: pp 789-791 789 790 30 20 units 10 p=0.OO2 Redbbod cells p=0.OO6 Platelets Fresh frozen Cryoprecipitates plasma Intraoperative transfusion o 70% PRA group • 0% PRA group Fig 1. Intraoperative transfusions of red blood cells, plate-lets, fresh frozen plasma, and cryopreclpltates In 25 highly sensitized (70% PRA group) and 26 non-sensitized (0% PRA group) patients. DISCUSSION Management of bleeding represents one of the most important aspects of OL T. Often OL T candidates have severe coagulation disturbances and the frequent presence of portal hypertension makes surgical hemostasis exceedingly difficul t. 3,6 In several other reports the number of RBC un tis was used as a variable to evaluate intraoperative bleeding.9- 11 In our previous series of 87 OL Ts, the range for RBC units was very large, from 3 to 251, with a median of 24 and a mean of 43 units;11 consequently, many attempts have been made to prevent the causes of bleeding during OL T. In addition to the importance of meticulous care in checking and suturing each potential source of bleeding during the operation,3.6 in the last years many efforts have been made to develop devices and strategies to aid in managing intraoperative bleeding. The veno-venous by-pass equipped with heparin coated tubes, inhibiting clot formation without causing generalized heparinization, has been very effective in reducing portal and caval hypertension and consequently blood loss during the an hepatic phase. 16 The infra-red sapphire-headed coagulator has been effective in reducing bleeding from difficulty man-aged sites.3 Intraoperative monitoring by thrombelastography in the last four years has reduced blood infusion volume by 33% and increased blood coagulation stability without adding blood products.2 Also, the appropriate use of epsilon-amino-caproic acid in patients undergoing OL T 17,18 is very effective in treating fibrinolysis and associated generalized oozing. Despite advances, bleeding problems are still one of the major concerns in OL T, During OL T a generalized oozing may develop from all the cut surfaces, a phenomenon not related to mechanical trauma. This lengthens hemostasis time and necessitates larger amounts of blood products. The quantity of blood used correlates negatively (p = 0.0005) with survival as demonstrated in our previous investiga-tions, 10, II MARINO, WEBER, KANG ET AL Table 1. Patient Population In the Non-Alloimmunized Group (0% PRA) and in the Highly-Alloimmunized Group (70% PRA) Patient %PRA 70% PRA Population Group Group Age (years) 44.1 ± 8.9 44.3 ± 10.8 Weight (Kg) 67.5 ± 16.2 63.1 ± 16.1 Primary biliary cirrhosis 6 6 Chronic active hepatitis 7 9 Laennec's disease 6 3 Fulminant hepatitis 2 1 Antitrypsin deficiency 3 Others 4 3 In this study we present evidence suggesting that lympho-cytotoxic antibodies in OL T patients are associated with increased intraoperative blood transfusion requirements. Highly sensitized patients with PRA values equal to or greater than 70% received greater quantities of RBC, PL T, CRY and FFP intraoperatively than did the 0% PRA patients. Lymphocytotoxic antibodies are generally specific for HLA antigens. HLA alloimmunization is a major cause of platelet refractoriness in thrombocytopenic patients requir-ing transfusions. Such refractory patients respond poorly to random ABO compatible platelets. 14 Our data suggest that platelet transfusions are also less effective in correcting the bleeding problems of highly sensitized patients undergoing OL T, This is more apparent from our findings that although the 70% PRA patients received larger quantities of PLT, they had significantly lower PL T counts postoperatively. This lower PL T count might be due to the "innocent bystander" effect whereby the patient's own PL T become involved in the immune clearance of incompatible PLTY Thus, in certain alloimmunized patients, random PL T trans-fusions would not only be ineffective, but might also worsen the bleeding problems during surgery. Our data also show a close correlation between the amounts of transfused PL T and RBC in the 70% PRA group, but not in the 0% PRA group. This can be explained by the possibility that PLT tranfusion in the 70% PRA is not effective in correcting intraoperative bleeding, leading to increased RBC substitution in the 70% PRA group. The decreased coagulation status in the 70% PRA patients is indicated by the different requirement for plasma replace-ment and substitution with concentrated fractions of coagu-lations factors. The 70% PRA group needed significantly higher substitution with FFP and CRY than the 0% PRA group. In conclusion, our findings suggest that routine screening for HLA alloimmunization should be done in every OL T candidate as well as in all patients undergoing major surgical treatments who may require intraoperative PL T transfu-sions. Highly sensitized patients are at risk of developing refractoriness to intraoperative PL T transfusions with subse-quent uncontrollable bleeding. These patients might benefit from transfusions of histocompatible PL T to achieve suffi-cient hemostasis. HLA ALLOIMMUNIZATION AND BLOOD REQUIREMENTS REFERENCES I. Groth CG, Pechet L, Starzl TE: Arch Surg 98:31, 1969 2. Kang YG, Martin DJ, Marquez J, et al: Anesth Analg 64:888, 1985 3. CaIne RY: in Liver Transplantation, CaIne RY (ed). ed 2, London, Grune & Stratton, p 247, 1987 4. Groth CG: in Experience in Hepatic Transplantation, Starzl TE (ed). Philadelphia, WB Saunders, p 159, 1969 5. Pechet L, Groth CG, Daloze PM: J Lab Clin Med 73:91, 1969 6. Starzl TE, Iwatsuki S, Esquivel CO, et al: Semin Liver Dis 5(4):349,1985 7. Sassano JJ: in Hepatic Transplantation: Anesthetic and Preop-erative Management, Winter PM and Kang YG (eds). New York, Praeger, p 120, 1986 8. Kang YG, Lewis JH, Navalgund A, et al: Anesthesiology 66:766,1987 791 9. Lewis JH, Bontempo FA, Cornell F, et al: Transfusion 27(3), 222,1987 10. Shaw BW Jr, Wood PR, Gordon RD, et al: Semin Liver Dis 5( 4), 385, 1985 II. Bontempo FA, Lewis JH, Van Thiel DH, et al: Transplanta-tion 39(5), 532, 1985 12. Heal JM, Blumberg N, Masel D: Blood 70(1). 23,1987 13. Duquesnoy RJ: in The Blood Platelet in Tranfusion Therapy Greenwalt TJ and Jamieson GA (eds). New York, Alan R Liss Inc, 229, 1978 14. Dutcher JP, Schiffer CA, Aisner J, et al: Blood 57(3):395, 1981 15. lwatsuki S, Rabin BS, Shaw BW Jr, et al: Transplant Proc 16:1427,1984 16. Shaw BW Jr, Martin DJ, Marquez JM, et al: Ann Surg 200:524, 1984 17. Flute PT, Rake MO, Williams R, et al: Br Med J 3:20, 1969 

HLA alloimmunization and blood requirements in orthotopic liver transplantation.

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HLA alloimmunization and blood requirements in orthotopic liver transplantation.

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