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Keywords:

  • Biliary complication;
  • donation after cardiac death;
  • ischemic-type biliary stricture;
  • liver transplantation;
  • thrombolysis;
  • tissue plasminogen activator

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

Ischemic-type biliary stricture (ITBS) occurs in up to 50% after liver transplantation (LT) from donation after cardiac death (DCD) donors. Thrombus formation in the peribiliary microcirculation is a postulated mechanism. The aim was to describe our experience of tissue plasminogen activator (TPA) administration in DCD-LT. TPA was injected into the donor hepatic artery on the backtable (n = 22). Two recipients developed ITBS including one graft failure. Although excessive postreperfusion bleeding was seen in 14 recipients, the amount of TPA was comparable between those with and without excessive bleeding (6.4 ± 2.8 vs. 6.6 ± 2.8 mg, p = 0.78). However, donor age (41 ± 12 vs. 29 ± 9 years, p = 0.02), donor BMI (26.3 ± 5.5 vs. 21.7 ± 3.6 kg/m2, p = 0.03), previous laparotomy (50% vs. 0%, p = 0.02) and lactate after portal reperfusion (6.3 ± 4.6 vs. 2.8 ± 0.9 mmol/L, p = 0.005) were significantly greater in recipients with excessive bleeding. In conclusion, the use of TPA may lower the risk of ITBS-related graft failure in DCD-LT. Excessive bleeding may be related to poor graft quality and previous laparotomy rather than the amount of TPA. Further studies are needed in larger population.


Abbreviations: 
BMI

body mass index

CIT

cold ischemia time

DBD

donation after brain death

DCD

donation after cardiac death

HAT

hepatic artery thrombosis

HTK

Histidine-Tryptophan-Ketoglutarate

ITBS

ischemic-type biliary stricture

LT

liver transplantation

MELD

Model for End-Stage Liver Disease

OPO

organ procurement organization

PNF

primary nonfunction

TPA

tissue plasminogen activator

UW

University of Wisconsin

WIT

warm ischemia time

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

Shortage of available organs has led to the use of extended criteria donors including donors from donation after cardiac death (DCD) in liver transplantation (LT) (1–4). In recent years, the number of DCD-LT has increased steadily, accounting for 5% of the total number of LT in the United States (5). Although DCD is an important resource to expand the donor pool, aggressive use of DCD donors has been tempered by a high risk of unfavorable outcome such as primary nonfunction (PNF), hepatic artery thrombosis (HAT)/stenosis and biliary complications (6,7). There are several reports with favorable outcomes from high volume centers (8–12). Analysis of national data, however, has revealed that the outcome of DCD-LT is inferior to that of donation after brain death (DBD) donors (2,6,7). Specifically, ischemic-type biliary stricture (ITBS), or ischemic cholangiopathy, is related to a high risk of graft failure and retransplantation and its incidence has been reported as high as 33–50% after DCD-LT (13–16). Because there is a paucity of effective management of the biliary system in DCD-LT, it is imperative to develop a new strategy to lower the risk of this life-threatening complication.

In procuring DCD livers, a mandated period of warm ischemia is imposed from an agonal phase to cold perfusion after withdrawal of life support. This mandatory warm ischemia time (WIT) leads to stasis of blood and may promote clot formation in the peribiliary microcirculation whose blood is supplied solely by the hepatic artery (17,18). Our hypothesis is that microcirculatory disturbances in the peribiliary vascular plexus by microthrombi may be a mechanism contributing to biliary ischemia in DCD-LT (Figure 1). In this setting, the use of thrombolytic agents may be of benefit to resolve this problem.

image

Figure 1. Schematic diagrams of our hypothesis. (A) The blood supply to the human biliary system depends solely on the hepatic artery via the peribiliary vascular plexus. (B) The postulated mechanism of the development of ischemic-type biliary stricture in DCD-LT. Formation of microthrombi in the peribiliary vascular plexus during a mandated period of warm ischemia may contribute to biliary ischemia.

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Tissue plasminogen activator (TPA) is a protein involved in fibrinolysis of an established blood clot. The efficacy and safety of recombinant TPA has been extensively investigated and has been used clinically in ischemic stroke (19). The clinical application of recombinant TPA, however, has never been reported in the setting of human LT. The aim of this study was to describe our initial experience with the use of recombinant TPA in DCD-LT.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

Study population

From August 2005 to July 2009, our protocol was applied to 22 recipients who underwent primary LT from DCD donors at our institution. The data were collected retrospectively from donor and recipient charts. The follow-up period ranged from 7 to 54 months (mean, 27 months). The Model for End-Stage Liver Disease (MELD) score was calculated with only laboratory data and did not include exception points that were given for liver cancers and medical conditions. This study was approved by our Institutional Review Board (#09-299).

Organ procurement

In all DCD donors, life support was withdrawn in the operating room or intensive care unit. Recovery surgeons were not involved in this process or declaration of death. After withdrawal of life support, vital signs and oxygen saturations were recorded every minute and reported to the recovery surgeons every 5 min. Organ procurement was started after an additional 5 min of mandatory observation after the declaration of death. Heparin was administered systemically prior to withdrawal of life support if the policies of the organ procurement organizations (OPO) or donor hospitals permitted it. If not given prior to withdrawal of life support, 30 000 units of heparin were given along with the initial bag of preservation solution. The distal aorta or common iliac artery was cannulated to allow for the initiation of cold perfusion immediately upon entry into the abdominal cavity. The inferior mesenteric vein was not used for cold perfusion. The thoracic aorta was cross-clamped after a midline sternotomy. All livers were flushed again on the backtable through the portal vein with cold Histidine–Tryptophan–Ketoglutarate (HTK) solution (Custodiol®, Essential Pharmaceuticals, PA, USA) and subsequently preserved in this solution. The bile duct was flushed with cold HTK solution on the backtable. Donor WIT was defined as the time from the withdrawal of life support to in situ cold perfusion. Cold ischemia time (CIT) was defined as the time from cold perfusion to reperfusion of the portal vein.

Recipient operation

After completing recipient hepatectomy, a graft implantation was performed with conventional caval interposition technique (n = 5) or piggyback technique (n = 17). Before reperfusion, liver grafts were flushed with one litter of room temperature saline followed by 400 mL of blood through the portal vein (20). Hepatic artery anastomosis was performed after reperfusion of the portal vein. No recipient had simultaneous reperfusion of the hepatic artery and the portal vein. Veno-venous bypass was used in two recipients. Biliary reconstruction was done with a duct-to-duct anastomosis in all cases.

TPA administration

As a new center protocol since 2005, TPA was administered into the donor hepatic artery in DCD-LT. Briefly, 1 mg/mL of TPA (Activase®, Genetech Inc., CA, USA) was injected into the donor hepatic artery on the backtable before implantation. The protocol dose of TPA was determined based on weight of the organ (0.5 mg/100 gram of graft). When the risk of postreperfusion bleeding was estimated to be high, the dose was reduced at a surgeon's discretion (0.2–0.4 mg/100 gram of graft) based on multiple factors including donor age, previous laparotomy, donor WIT, CIT and MELD score. The dose used in this study ranged from 3 to 10 mg/graft. Among 22 grafts, the protocol dose of TPA was used in 12 grafts and reduced dosing from the protocol dose was used in 10 grafts. Before reperfusion of the portal vein, liver grafts were flushed with saline and blood through the portal vein to minimize the systemic introduction of TPA spilling out of hepatic artery into the portal vein and the hepatic vein. The hepatic artery was kept clamped until 10–15 min after reperfusion of the portal vein. The artery was then unclamped to allow excess TPA to back-bleed and the effluent was discarded.

Excessive postreperfusion bleeding

We defined excessive postreperfusion bleeding as intraoperative bleeding due to either coagulopathy, fibrinolysis or thrombocytopenia, which required more than 2 h to obtain adequate hemostasis after portal reperfusion and before proceeding with bile duct anastomosis. The recipients were divided into two groups based on the presence or absence of excessive bleeding. Group 1 included those with excessive bleeding and group 2 included those without excessive bleeding. The mean time interval from portal reperfusion to bile duct anastomosis was 198 ± 46 min (146–287 min) in group 1 and 80 ± 22 min (49–110 min) in group 2 (p = 0.0001). The donor and recipient characteristics were compared between the groups to identify the risk factors for excessive bleeding. Serial lactate levels in arterial blood samples were used to compare the quality of liver graft between the groups (21).

Statistical analysis

Data were expressed as mean ± standard deviation. The comparisons were performed with the Mann-Whitney U-test for numerical data and the Chi-square test for categorical data. Survival rates were estimated with the Kaplan–Meier method. A p-value less than 0.05 was considered to be significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

Donor and recipient characteristics

Table 1 shows the baseline donor and recipient characteristics. The mean donor age was 37 ± 13 years (15–57 years). Sixteen donors were male and six were female. The mean body mass index (BMI) of donors was 24.6 ± 5.3 kg/m2 (17.4–37.4 kg/m2). The causes of brain injury were as follows: head trauma in 10 (45%), anoxia in 9 (41%) and cerebrovascular accident in 3 (14%). Fourteen donors (64%) required at least one vasopressor to maintain hemodynamic stability. The peak serum sodium level was 153 ± 9 mEq/dL (140–167 mEq/dL). In 11 donors (50%), heparin was given systemically prior to withdrawal of life support. In the remaining 11 donors (50%), heparin was not allowed to be given prior to withdrawal due to the regulations by the local OPO or donor hospitals. The HTK solution was used in 20 donors (91%) and University of Wisconsin (UW) solution was used in two donors (9%) as the initial flush solution. However, all livers were flushed immediately on the backtable with the HTK solution at donor hospitals and preserved subsequently in the same solution. The mean CIT was 422 ± 96 min (268–590 min). The mean donor WIT in organ procurement was 21 ± 7 min (12–42 min). Five grafts (23%) were procured by other transplant centers and imported to our center.

Table 1.  Baseline donor and recipient characteristics
  1. 1Data are presented as mean ± standard deviation.

  2. 2 Donor warm ischemia time is the time from the withdrawal of life support to in situ cold perfusion during organ procurement.

  3. UW = University of Wisconsin; HTK = Histidine–Tryptophan–Ketoglutarate; MELD = Model for End-Stage Liver Disease.

Donor age (years)37 ± 13 (15–57)1  
Donor sex (male)16 (73%)
Donor body mass index (kg/m2)24.6 ± 5.3 (17.4–37.4)1
Cause of brain injury 
 Head trauma10 (45%)
 Anoxia 9 (41%)
 Cerebrovascular accident 3 (14%)
Use of vasopressors14 (64%)
Peak serum sodium (mEq/dL)153 ± 9 (140–167)1
No heparin before withdrawal11 (50%)
Initial flush solution (UW/HTK)2/20
Cold ischemia time (min)422 ± 96 (268–590)1
Donor warm ischemia time (min)221 ± 7 (12–42)1
Imported livers 5 (23%)
Recipient age (years)56 ± 8 (38–68)1
Recipient sex (male)14 (64%)
Recipient diagnosis 
 Hepatitis C cirrhosis10 (45%)
 Alcoholic cirrhosis 4 (18%)
 Cryptogenic cirrhosis 4 (18%)
 Nonalcoholic steatohepatitis1 (5%)
 Hepatitis B cirrhosis1 (5%)
 Hemochromatosis1 (5%)
 Fulminant hepatic failure1 (5%)
History of upper abdominal surgery 7 (32%)
MELD score18.1 ± 9.0 (7–40)1
Concomitant hepatocellular carcinoma 9 (41%)

The mean recipient age was 56 ± 8 years (38–68 years). Fourteen recipients (64%) were male and eight (36%) were female. Indications for LT were hepatitis C cirrhosis in 10 (45%), alcoholic cirrhosis in four (18%), cryptogenic cirrhosis in four (18%), nonalcoholic steatohepatitis in one (5%), hepatitis B cirrhosis in one (5%), hemochromatosis in one (5%) and fulminant hepatic failure in one (5%). Seven recipients (32%) had a history of upper abdominal surgery. MELD score was 18.1 ± 9.0 (7–40). Nine recipients (41%) had concomitant hepatocellular carcinomas.

Graft failure and retransplantation

The graft survivals at 1 month, 6 months, 1 year and 3 years after LT were 96%, 86%, 81% and 81%, respectively (Figure 2). During the study period, four grafts were lost. The causes of graft loss were PNF, ITBS, sepsis unrelated to biliary complications and recurrent hepatitis C. The times of graft loss were postoperative day 4, 117, 124 and 350, respectively. The recipients with ITBS and PNF were salvaged with retransplantation from a DBD donor.

image

Figure 2. Graft survival after DCD-LT assessed by the Kaplan–Meier method.

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Biliary complications

Six recipients (27%) experienced biliary complications during the study period (Table 2). Two recipients had ITBS (9%) without evidence of HAT or stenosis of arterial anastomosis. One of these recipients had a diffuse-type ITBS causing graft failure, which was diagnosed at 117 days after LT by endoscopic retrograde cholangiography. This recipient was a 61-year-old female with hepatitis C cirrhosis and hepatocellular carcinoma. The donor was a 23-year-old male with 473 min of CIT and 12 min of donor WIT. Ten mg of TPA (0.5 mg/100 gram of graft) was used, but heparin was not given prior to withdrawal of life support in organ procurement. Although retransplantation was performed from a DBD donor, the second graft failed due to recurrent hepatitis C and she expired at 660 days after DCD-LT. The other recipient had a focal-type ITBS diagnosed at 115 days after LT. This recipient was a 56-year-old male with alcoholic cirrhosis. The donor was a 45-year-old male with 393 min of CIT and 25 min of donor WIT. Three mg of TPA (0.2 mg/100 gram of graft) was used, and heparin was used prior to withdrawal of life support. Although a focal biliary stricture was found at the confluence, this was managed with multiple biliary stents and did not cause graft failure.

Table 2.  Characteristics of six cases with biliary complications
No.TypesGraftDonorRecipientHeparin1Dose of tissue plasminogen activator
Age (years)BMI (kg/m2)WIT2 (min)CIT (min)Age (years)MELD(mg/graft)(mg/100 gram of graft)
  1. 1Heparin administered prior to withdrawal of life support.

  2. 2Warm ischemia time is the time from the withdrawal of life support to in situ cold perfusion during organ procurement.

  3. ITBS = ischemic-type biliary stricture; AS = anastomotic stricture; BMI = body mass index; WIT = warm ischemia time; CIT = cold ischemia time; MELD = Model for End-Stage Liver Disease score.

1ITBSFailed2321.2124736111No100.5
2ITBSFunctioning4532.2253935618Yes 30.2
3ASFunctioning5721.0264893840No100.5
4ASFunctioning3919.8354236312Yes 70.4
5ASFunctioning3524.3155765633No 80.5
6ASFunctioning5129.8193755915No 30.3

Four recipients (18%) experienced biliary anastomotic strictures, which were treated with biliary stents (Table 2). Heparin was not used in three out of four donors. Reduced dosing of TPA was used in two grafts. None of these had graft failure due to biliary complications and each graft is currently stent-free. Two recipients (9%) developed stones in the bile duct, which coincided with ITBS and anastomotic stricture.

Excessive postreperfusion bleeding

Excessive postreperfusion bleeding was seen in 14 recipients (64%). This was managed by standard blood product administration and surgical hemostasis. No medication was used to reverse fibrinolysis. Table 3 shows intraoperative data regarding blood products transfused after reperfusion of the portal vein. The units of blood products given intraoperatively were significantly greater in group 1 (total red blood cells; 14 ± 4 units in group 1 vs. 4 ± 2 units in group 2 [p = 0.0001], packed red blood cells; 7 ± 3 units in group 1 vs. 2 ± 2 units in group 2 [p = 0.001], autologous red blood cells; 8 ± 3 units in group 1 vs. 3 ± 1 units in group 2 [p = 0.002], fresh frozen plasma; 7 ± 6 units in group 1 vs. 2 ± 3 units in group 2 [p = 0.02] and platelets; 5 ± 3 units in group 1 vs. 1 ± 1 units in group 2 [p = 0.01]). There were five recipients who had a laparotomy for bleeding after LT. Among them, three recipients were in group 1 and two recipients were in group 2. Four recipients were found to have surgical bleeding except one recipient in group 1. None of the recipients experienced extra-abdominal bleeding intraoperatively or postoperatively.

Table 3.  Intraoperative blood usage after reperfusion of the portal vein
Blood productsPostreperfusion excessive bleedingp-Value
Yes (n = 14) Group 1No (n = 8) Group 2
  1. Data are presented as mean ± standard deviation.

  2. 1Total red blood cells = packed red blood cells + autologous red blood cells.

  3. 2Autologous blood salvaged by an autotransfusion device and transfused during liver transplantation.

Total red blood cells (units)114 ± 4 (9–23) 4 ± 2 (3–8)  0.0001
 Packed red blood cells (units)7 ± 3 (2–12)2 ± 2 (0–6) 0.001
 Autologous red blood cells (units)28 ± 3 (1–14)3 ± 1 (0–4) 0.002
Fresh frozen plasma (units)7 ± 6 (1–21)2 ± 3 (0–6)0.02
Platelets (units)5 ± 3 (0–10)1 ± 1 (0–2)0.01
Cryoprecipitate (units)10 ± 15 (0–40)0 ± 0 (0) 0.06

As shown in Table 4, the amount of TPA used was comparable between the groups (6.4 ± 2.8 mg in group 1 vs. 6.6 ± 2.8 mg in group 2; p = 0.78). Among 14 recipients in group 1, the protocol dose of TPA (0.5 mg/100 gram of graft) was used in eight recipients (57%). In the remaining six recipients (43%), reduced dosing (0.2–0.35 mg/100 gram of graft) was used. In group 2, reduced dosing (0.2–0.4 mg/100 gram of graft) was used in four recipients (50%). The donor age in group 1 (41 ± 12 years) was significantly greater than that of group 2 (29 ± 9 years, p = 0.02). The donor BMI in group 1 (26.3 ± 5.5 kg/m2) was significantly greater than that of group 2 (21.7 ± 3.6 kg/m2, p = 0.03). Seven recipients (50%) in group 1 had a history of upper abdominal surgery before LT, but no recipients had previous laparotomy in group 2 (p = 0.02). The CIT, donor WIT, peak serum sodium level, use of vasopressors, use of heparin prior to the withdrawal of life support, preservation solution, the number of imported livers, recipient age, recipient sex and MELD score were comparable between the groups.

Table 4.  Donor and recipient characteristics by postreperfusion excessive bleeding
 Postreperfusion excessive bleedingp-Value
Yes (n = 14) Group 1No (n = 8) Group 2
  1. 1Data are presented as mean ± standard deviation.

  2. 2Donor warm ischemia time is the time from the withdrawal of life support to in situ cold perfusion during organ procurement.

  3. UW = University of Wisconsin; HTK = Histidine–Tryptophan–Ketoglutarate; MELD = Model for End-Stage Liver Disease; TPA = tissue plasminogen activator.

Donor age (years) 41 ± 12129 ± 910.02
Donor sex (male)10 (71%)6 (75%)0.99
Donor body mass index (kg/m2)26.3 ± 5.5121.7 ± 3.610.03
Peak sodium level (mEq/dL)153 ± 101154 ± 810.73
Use of vasopressors9 (64%)5 (63%)0.63
No heparin before withdrawal8 (57%)3 (38%)0.99
Initial flush solution (UW/HTK)0/142/60.12
Cold ischemia time (min)439 ± 971392 ± 9310.28
Donor warm ischemia time (min)221 ± 7120 ± 810.52
Imported liver3 (21%)2 (25%)0.99
Recipient age (years)56 ± 7158 ± 910.43
Recipient sex (male)8 (57%)6 (75%)0.65
History of upper abdominal surgery7 (50%)0 (0%)0.02
MELD score17.6 ± 5.51 19.0 ± 13.610.58
Dose of TPA (mg) 6.4 ± 2.81 6.6 ± 2.810.78
Use of reduced dosing of TPA6 (43%)4 (50%)0.99

To compare the quality of graft, lactate levels in arterial blood sample were compared between the groups. As shown in Figure 3, lactate levels in group 1 were significantly higher than those in group 2 at 2 h (6.3 ± 4.6 mmol/L in group 1 vs. 2.8 ± 0.9 mmol/L in group 2, p = 0.005) and at 6 h (7.1 ± 6.1 mmol/L in group 1 vs. 2.6 ± 1.0 mmol/L in group 2, p = 0.02) after reperfusion of the portal vein. In contrast, no significant difference was found in lactate levels at 24 h after reperfusion (2.4 ± 1.2 mmol/L in group 1 vs. 2.0 ± 1.1 mmol/L in group 2, p = 0.45).

image

Figure 3. Lactate levels in arterial blood after reperfusion of the portal vein. Lactate levels were significantly higher in group 1 at 2 and 6 h after reperfusion. No significant difference was found at 24 h; (a) p = 0.005 and (b) p = 0.02. Data are presented as mean ± standard deviation.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

One of the current issues in DCD-LT is a high incidence of biliary complications, in particular, ITBS is considered the Achilles heel of using DCD donors because of increased morbidity and mortality without any available preventive strategies (22). To help augment the use of DCD donors, reducing the risk of ITBS is imperative. Possible preventive strategies include minimizing CIT and WIT, simultaneous arterial revascularization with portal vein, avoiding old donor, and in situ biliary flush to minimize bile-induced epithelial damage (15,23). Avoiding DCD-LT for unstable recipients is another consideration (2,24). It is, however, unclear if these are effective because of the lack of data to support these approaches.

Because patients with ITBS behave like those with HAT clinically as well as radiologically, it is possible that they can have a similar underlying ischemic etiology. The development of HAT is related to the high risk of subsequent biliary ischemia because the blood supply to the human biliary system depends solely on the hepatic artery via a vascular plexus to ensure its viability (17,18). The utility of thrombolytic therapy for the treatment of HAT was demonstrated to rescue livers with a surprisingly low incidence of ITBS (25). In DCD organ procurement, mandatory WIT leads to stasis of blood and may lead to the formation of microthombi in the peribiliary vascular plexus resulting in biliary ischemia. This is a postulated mechanism contributing to the development of ITBS after DCD-LT (Figure 1). If this is the case, the use of thrombolytic agents may be of benefit to resolve this problem.

The effect of thrombolytic agents in DCD donors has been reported in the experimental (26–28) as well as clinical transplantation (29) of various organs. The common finding in previous reports was that pretreatment with thrombolytic agents improved graft viability with better perfusion. To the best of our knowledge, however, this is the first clinical study to examine the effectiveness of a thrombolytic agent in human LT for prevention of ITBS in DCD livers.

The extent and severity of ITBS after LT determines the prognosis and management. Unless recipients have multifocal or diffuse strictures, they can have a good prognosis with no need for retransplantation (30). In this study, an overall incidence of ITBS was 9% but ITBS-related graft failure was observed in only one recipient who was salvaged by retransplantation. Although the other recipient had a focal stricture, he currently has a functioning graft. Although the use of TPA is not able to totally eradicate the risk of ITBS, it is worthy to note that the risk of ITBS-related graft failure could be minimized or made equal to that in LT from DBD donors (11,16,31). On the other hand, the development of anastomotic biliary strictures (18%) is similar to that seen in our DBD duct-to-duct population and considered a technical complication (32).

A major concern in this approach is the risk of transferring TPA activity from the donor liver to the recipient. In ischemic stroke, while far larger dose of TPA (up to 90 mg/body) is administered directly into the systemic circulation, the risk of bleeding is very low (19). In this study, 3–10 mg of TPA solution was injected into the donor hepatic artery before implantation, not into the systemic circulation. To minimize the systemic introduction of TPA, two important steps were adapted during LT. First, livers were flushed with saline followed by blood through the portal vein to remove excess TPA spilling out of the hepatic artery into the portal vein and the hepatic vein. Second, the hepatic artery was back-bled before revascularization of the hepatic artery to discard TPA in the main branch of the hepatic artery. Theoretically, only a small amount of TPA in the small arterial branches is released into the systemic circulation after reperfusion of the hepatic artery. In addition, donor age, donor BMI and recipient lactate levels after portal reperfusion were significantly greater in recipients with excessive bleeding. Further, 50% of recipients with excessive bleeding had a previous laparotomy before LT, whereas no recipients without excessive bleeding had a previous laparotomy. Taken together, our results indicate that the risk of excessive bleeding may be determined by graft quality and a history of laparotomy rather than the amount of TPA used. However, because coagulopathy, fibrinolysis and thrombocytopenia are very common in liver transplant recipients, especially early after graft reperfusion, the risk of bleeding should not be underestimated even with a small amount of TPA.

The dose of TPA was determined based on graft weight. The protocol, however, was not strictly followed in this study due to unknown risks of bleeding and the lack of previous studies in determining an optimal dose of TPA. Thus, the dose was reduced to 0.2–0.4 mg/100 gram of graft in 10 grafts based on multiple factors including donor age, previous laparotomy, donor WIT, CIT and MELD score. Even with the experience with 22 recipients, it is still unclear how much TPA is needed and whether the dose of TPA influences the risk of ITBS. To establish a safe and effective protocol, these issues need to be addressed.

The major limitation of this study is the lack of the control group. Although this weakens the strength of this study, our risk of graft loss due to ITBS is lower than that in the previous reports (13–16). However, a prospective randomized study is warranted to determine whether our approach can reduce the risk of ITBS and its life-threatening complications. Another limitation of this study is the lack of thromboelastography data and plasma level of TPA that would help differentiate the causes of excessive bleeding. In our future study, these crucial pieces of information will be included.

It should be noted that the situation of DCD used in this study was quite extreme, as the use of heparin prior to start of warm ischemia was prohibited in half of the donors. This was due to OPO regulations stemming from jurisdictional legal regulations. In this study, the single ITBS leading to graft failure was in a donor where heparin was not given antemortem. The majority of OPOs in the United States, however, allow the use of heparin prior to initiation of life support withdrawal. Preservation solution is the other issue. Although HTK solution is favored over UW solution in our center, it is still controversial which solution is superior in DCD-LT (22,33). The impact of preservation solution on the risk of ITBS is also unknown and needs to be determined.

Based on our preliminary data, our approach of administering TPA into the donor hepatic artery appears to lower the risk of life-threatening complications due to ITBS. Although recipients may experience an increased risk of intraoperative blood loss, excessive bleeding appears to be related to poor graft quality and previous laparotomy rather than the amount of TPA used. Nevertheless, given the morbidity and mortality associated with ITBS, the impact of this approach should be validated by additional study of a larger group of patients.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

This study was supported by a grant from the HRSA, R38OT15491: Clinical Interventions to Increase Organ Procurement.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References