AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• History and Background
• Bleeding During Liver Transplantation
• Transfusion Requirements
• Alternatives To Transfusion
• Special Diagnoses and Patient Populations
• Outcomes, Complications, and Costs
• Conclusion
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• History and Background
• Bleeding During Liver Transplantation
• Transfusion Requirements
• Alternatives To Transfusion
• Special Diagnoses and Patient Populations
• Outcomes, Complications, and Costs
• Conclusion
• References

Liver transplantation has emerged as an increasingly successful treatment for patients with end-stage liver disease (ESLD). Orthotopic liver transplantation (OLT) is the replacement of a diseased liver with a healthy liver in the normal anatomic position. The operative procedure is extensive, complex, and technically challenging with multiple vascular transections and anastomoses. In addition, the liver is an extremely vascular organ and extensive bleeding can occur in patients with portal hypertension due to ESLD.

Historically, significant blood loss at the time of liver transplantation has been treated with large autologous transfusions of packed RBCs (PRBCs), fresh frozen plasma (FFP), platelets, cryoprecipitate, and other drugs that assisted in restoring balance to metabolic and coagulation abnormalities. Because of many transfusion-related complications, especially those from large-volume transfusion, alternative therapies and approaches to transfusion are being investigated in transplantation and other surgical fields. Transfusion-related complications include infection, transfusion reaction, drug overdose, graft rejection or graft death, and patient death.

The outcomes of several operative therapies have been correlated with transfusion requirements. Increased blood requirements are associated with a more frequent occurrence of sepsis, a prolonged stay in the intensive care unit, a higher rate of severe cytomegalovirus infection, and higher rates of graft failure and patient mortality. However, whether these differences in outcome are related to the transfusion as an independent risk factor or whether the transfusion is a marker for a technically more difficult surgery remains unclear.

The foci of this article are factors associated with bleeding during OLT, transfusion requirements, predictive factors for bleeding and transfusion requirements, prevention of bleeding, special populations of OLT patients, and alternatives to transfusion. For excellent patient education resources, visit eMedicine's Liver, Gallbladder, and Pancreas Center and Hepatitis Center. Also, see eMedicine's patient education articles Cirrhosis and Liver Transplant.

HISTORY AND BACKGROUND

Section 3 of 10  

• Authors and Editors
• Introduction
• History and Background
• Bleeding During Liver Transplantation
• Transfusion Requirements
• Alternatives To Transfusion
• Special Diagnoses and Patient Populations
• Outcomes, Complications, and Costs
• Conclusion
• References

In 1963, Starzl and colleagues performed the first liver transplantation procedure. This patient, along with the next 4, died from bleeding. To define the operative technique, many practice operations were performed on animals, but the surgical team was unprepared for the technical difficulties of liver explantation in the presence of advanced portal hypertension.

Starzl et al performed the first successful human liver transplantation in 1967. Initial survival rates were poor, with only 24% of adults and 33% of children surviving the first year after liver transplantation through the 1970s. Many factors have contributed to improvements in the mortality rates since that time, including improved operative techniques and experience, improved preoperative and postoperative care, and other factors beyond the scope of this article. Aspects addressed herein are the risk for perioperative death as a result of massive blood loss and coincidental complications, analyses of preoperative conditions, review of the assessment of coagulopathy, and risk factors for bleeding. Specific advances, including autologous transfusion with cell saver–washed erythrocytes, venovenous bypass, and argon-beam coagulation, have contributed to liver transplantation success. The procedure can now be performed in as little as 4 hours, often with no or minimal transfusion.

BLEEDING DURING LIVER TRANSPLANTATION

Section 4 of 10  

• Authors and Editors
• Introduction
• History and Background
• Bleeding During Liver Transplantation
• Transfusion Requirements
• Alternatives To Transfusion
• Special Diagnoses and Patient Populations
• Outcomes, Complications, and Costs
• Conclusion
• References

Contributing factors to blood loss during liver transplantation can be categorized based on factors related to preoperative, intraoperative, and postoperative periods.

Preoperative factors

Preoperative factors associated with blood loss during liver transplantation include liver failure, cirrhosis, cholestasis, and splenomegaly. Many complex derangements of hemostasis are associated with ESLD.

Patients with acute or chronic liver failure do not synthesize normal amounts of clotting factors II (prothrombin), VII, IX, and X. Decreased production of these factors may lead to a coagulopathy, which is typically identified by a prolonged prothrombin time (PT). Patients with severe deficiencies also may exhibit a prolonged activated partial thromboplastin time (aPTT). Cholestasis leads to decreased synthesis of vitamin K–dependent clotting factors (II, VII, IX, and X), further contributing to abnormal clotting. However, in advanced liver failure, this abnormality may not be correctible, even with oral or parenteral vitamin K administration.

Thrombocytopenia is another common problem in cirrhotic patients. The cause of thrombocytopenia is multifactorial. The liver is the primary site of thrombopoietin synthesis, and thrombopoietin deficiency due to cirrhosis leads to low platelet production. In addition to the decreased formation of platelets, splenomegaly caused by portal hypertension leads to platelet sequestration and destruction. Thrombocytopenia is sometimes reversed in patients who undergo OLT, although occasional patients have severe, persistent thrombocytopenia after OLT and require splenectomy.

Besides low levels of coagulation factors and platelets, some patients with ESLD demonstrate increased fibrinolytic activity, which results in a low-grade disseminated intravascular coagulation–like picture.

Intraoperative factors

Liver transplantation may be divided into 3 stages. Stage I (preanhepatic period) begins with dissection of the inflow and outflow vascular structures of the liver is performed and ends with removal of the diseased organ. Stage II (anhepatic phase) begins with implantation of the donor liver and ends with reperfusion of the new organ. Stage III (reperfusion and postreperfusion period) begins with reperfusion of the grafted liver and ends with completion of the surgery.

Blood loss in stage I occurs mainly from transection of the fragile collaterals that develop from the portal hypertension. In addition, extensive bleeding may occur from raw areas remaining after liver explantation. Preexisting abnormalities of clotting, platelets, and fibrinolysis compound the problem. Therefore, the anesthesiologist must aggressively attempt to correct the international normalized ratio and platelet count by transfusing plasma and platelets early in the operative procedure—this is crucial. Furthermore, coagulation factors, especially factors V and VIII, may be degraded during transplantation as a result of enhanced proteolysis, and the degree of degradation correlates with the transfusion requirements during OLT.

Transplantation of a healthy liver usually restores the patient's clotting function in the operating room. However, a dysfunctional graft may not immediately produce clotting factors. In severe cases, this may lead to nonfunction of the primary graft, which mandates retransplantation. However, in some patients this is temporary and the graft recovers and function improves.

Besides the standard coagulation tests (ie, PT, aPTT, fibrinogen level), the thromboelastogram and coagulation and platelet function analyzer (eg, Sonoclot) are used in the evaluation of coagulation during liver transplantation. The thromboelastogram is used to monitor coagulation, fibrinolysis, and bleeding time. It assesses clot formation and monitors clotting until an endpoint of clot lysis or retraction is determined. The thromboelastogram is performed using whole blood, and it analyzes the interactions of plasma coagulation proteins with platelets and fibrinogen. Specific details regarding the interpretation of results from this test are beyond the scope of this article, but thromboelastogram findings have been correlated with intraoperative hemorrhage and coagulopathy and can assist the anesthesiologist in treating intraoperative bleeding by helping identify the cause.

Fibrinolysis may be a problem during the anhepatic or postanhepatic phase of OLT. The cause of fibrinolysis is most likely diminished uptake of tissue plasminogen activator (t-PA), accumulation of fibrinolytic activators, and enhanced release of t-PA from the donor liver (after reperfusion). Additionally, alpha-2 antiplasmin, the principal inhibitor of plasmin and plasminogen activity during this phase, is decreased.

In addition to fibrinolysis, the bleeding that occurs during the postanhepatic phase also may be related to disseminated intravascular coagulation and platelet trapping. Platelet trapping has been documented by simultaneous measurement of arterial and venous platelet counts. Decreases as large as 55% have been described in the absence of any thrombus in the graft. One study described extravasation of platelets into the Disse space and the sinusoids and phagocytosis by Kupffer cells. Additionally, many platelets that remained were found to be degranulated or nonfunctional. Disseminated intravascular coagulation has been correlated with ischemic damage of the graft liver. Antithrombin III administration has not been shown effective for reversing reperfusion disseminated intravascular coagulation.

Drugs to control bleeding are discussed under Drugs that minimize blood loss. Other potential causes of bleeding after reperfusion include the release of heparinlike factors from the allograft, release of preservative solution into the systemic circulation, and dysfunction of the graft.

Postoperative factors

Postoperative bleeding is not common, but it can occur from leaks at vascular suture lines or bleeding from the cut surfaces at bowel anastomoses. Most of these causes appear to be related to clot lysis or technical failures. Failure of the graft to function will contribute to postoperative bleeding, causing coagulopathy. In addition, graft versus host disease (GVHD) may occur from the transfer of donor-derived passenger lymphocytes; GVHD often manifests as hemolysis. This type of GVHD is generally limited to the first 4-6 weeks after transplantation and can be controlled by transfusion of donor-specific RBCs.

Less commonly, thrombocytopenia following liver transplantation causes bleeding, and this is associated with platelet consumption, platelet-associated immunoglobulin M and immunoglobulin A (IgA) antibody production, sequestration, and thrombin generation. Other causes of thrombocytopenia include viral infection, cytomegalovirus-induced hematophagic histiocytosis, treatment with antiviral therapy, and ABO-incompatible GVHD.

TRANSFUSION REQUIREMENTS

Section 5 of 10  

• Authors and Editors
• Introduction
• History and Background
• Bleeding During Liver Transplantation
• Transfusion Requirements
• Alternatives To Transfusion
• Special Diagnoses and Patient Populations
• Outcomes, Complications, and Costs
• Conclusion
• References

Historically, liver transplantation was associated with massive blood loss. More recent reports show a trend toward decreased mean blood loss, and several reports describe liver transplantation without the use of blood products. In the past, the volume of blood loss has been inversely associated with outcome; therefore, efforts have been made to determine predictors of transfusion requirements.

Predictors of transfusion requirements

Important variables affecting transfusion requirements include the severity of disease or Child classification, preoperative PT, history of abdominal operations, and factor V levels. Other factors identified as independent predictors of transfusion include the preoperative hematocrit value, use of the piggyback transplantation method, and operative time.

The Child classification is a measure of disease severity that includes assessments of ascites, encephalopathy, and muscle wasting and measurements of serum bilirubin and albumin. In a retrospective study, Motschman and colleagues found that the presence of ascites and a preoperative PT greater than 15 seconds were predictive of intraoperative blood loss during OLT. This study also reported a statistically significant difference in non-PRBC blood product use among 3 diagnostic groups undergoing liver transplantation. Patients with chronic active hepatitis had more advanced disease and required more blood products than patients with primary sclerosing cholangitis or primary biliary cirrhosis.

The predictive value of the PT is unclear. The PT was correlated with blood loss in children undergoing OLT only with univariate analysis; the multivariate analysis performed to eliminate confounding factors failed to demonstrate that preoperative PT was a significant predictor of blood loss. A retrospective study of 300 liver transplantation procedures reported no correlation among preoperative platelet count, aPTT, PT, thrombin time, fibrinogen, or antithrombin III and intraoperative blood loss or transfusion requirements. A retrospective review of 263 adult OLT patients found a significant correlation between intraoperative median PT and aPTT (5 min before reperfusion) and median volume of blood transfused within the first 70 minutes after reperfusion.

Portal vein hypoplasia and decreased donor liver size were predictive of blood loss in a series of 95 consecutive pediatric liver transplantation patients. The presence of portal vein hypoplasia is a technical challenge for the surgeons and a correlate of coexisting congenital abnormalities (eg, polysplenia syndrome). Use of a partial liver graft, as in living-donor liver transplantation, creates a graft with a raw surface that can bleed after reperfusion.

Both severity of disease and PT/aPTT were compared with blood requirements during OLT. One retrospective study of 263 patients found a correlation between aPTT or/and PT and blood requirements in persons with alcoholic liver disease, chronic active hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis. Laboratory analysis of coagulation factors was not helpful for predicting blood loss in retransplantation patients. A retrospective review of 205 transplantation patients revealed 41 patients who required more than 10 units of transfused PRBCs.

Independent analysis was performed on many variables, including fulminant hepatic failure, previous portosystemic shunt, and complete ABO mismatch. Multivariate analysis identified an elevated serum creatinine level, low platelet counts, and an elevated aPTT as risk factors for large transfusion requirements, with a sensitivity of 60% and a specificity of 69%. Because of the great variability of transfusion requirements, the authors concluded that preoperative factors were not helpful in predicting large-volume loss and large transfusion requirements; however, large transfusion requirements were predictive of outcome, as previously discussed.

ALTERNATIVES TO TRANSFUSION

Section 6 of 10  

• Authors and Editors
• Introduction
• History and Background
• Bleeding During Liver Transplantation
• Transfusion Requirements
• Alternatives To Transfusion
• Special Diagnoses and Patient Populations
• Outcomes, Complications, and Costs
• Conclusion
• References

Operative Techniques that Minimize Blood Loss

During surgery, technical factors are associated with bleeding and transfusion requirements. Established and innovative surgical techniques to minimize blood loss include the use of venovenous bypass, autologous blood transfusion, volume expansion, and a cell saver.

Surgeons can attend to many technical details in order to minimize blood loss during OLT. The use of split or reduced-size liver grafts results in the successful transplantation of partial adult livers into infants, and, at times, expands the number of recipients who can receive cadaveric grafts. The experience of the surgical team impacts blood loss, transfusion requirements, and the morbidity of patients undergoing liver transplantation. Additionally, modifications in surgical technique, including the use of cautery, and medical therapy have reduced morbidity during the learning curve of living-donor liver transplantation, as reported for right-lobe living-donor liver transplantation.

OLT involves the explantation of the native liver and replacement with the donor liver. This requires either the use of bypass or clamping of the inferior vena cava and portal vein. A variation of this technique is called piggyback transplantation, whereby the inferior vena cava is preserved and venovenous bypass can be avoided. Several studies have failed to show a benefit in the piggyback technique regarding blood loss or use.

Portosystemic shunting has been used in patients with liver failure in order to decrease preoperative complications associated with portal hypertension (eg, bleeding varices, ascites, sepsis). Traditionally, surgery was the only option to create a shunt, but a transhepatic intraoperative portosystemic shunt is now available. This procedure is designed to decompress the portal system in order to decrease the risk of variceal rebleeding and minimize ascites. Patients with a previously performed shunt (transhepatic intraoperative portosystemic shunt vs surgical shunt) were compared with regard to outcome after liver transplantation. The findings demonstrated a benefit for the transhepatic intraoperative portosystemic shunt patients when compared with surgical portosystemic shunts. The benefits noted were decreased blood requirements, shorter operative time, shorter intensive care unit stay, and shorter hospital stay.

Central venous pressure (CVP) monitoring is an important aspect of OLT. Patients frequently undergo volume expansion prior to hepatic resection to prevent bleeding complications, but expansion increases CVP. Deliberate lowering of the CVP during liver resection assists in bleeding control by decreasing the blood pressure gradient over which bleeding occurs during dissection. Melendez and coworkers showed that this anesthesia maneuver decreased median estimated blood loss, morbidity, length of intensive care unit stay, and hospital stay when used with vascular occlusion. Renal failure directly attributable to low CVP was not observed. In a prospective study of 100 hepatic resections, subjects were analyzed for blood loss according to CVP. Blood loss was significantly less in the low-CVP group, and blood transfusions were significantly less frequent (2 vs 25 patients), with no reported increases in morbidity.

Massicotte and colleagues¹ showed that maintenance of a low CVP prior to the anhepatic phase in 100 patients was associated with a decrease in RBC transfusions during liver transplantation. In this group, the mean number of intraoperative RBC units transfused was 0.4 ± 0.8, and no plasma, platelets, albumin, or cryoprecipitate were transfused.

A small pilot study investigated recombinant factor VIIa (rFVIIa) during OLT. Six adult ESLD subjects were prospectively enrolled in the study. Subjects were given 80 mcg/kg of rFVIIa 10 minutes preoperatively (and intraoperatively if the estimated blood loss exceeded the subject's estimated blood volume). Subjects were matched to OLT controls and then evaluated for estimated blood loss and transfusion requirements. Significant decreases in transfused PRBCs, FFP, and platelets were noted in subjects who received the rFVIIa treatment. The results of this small study indicate that rFVIIa may be an innovative therapy, but further investigation is required.

Kalicinski and colleagues² at the Warsaw Children's Hospital have studied the impact of rFVIIa treatment in children undergoing liver transplantation. In a retrospective study, they compared 2 groups of recipients of primary cadaveric liver transplantation. Group I consisted of 28 patients with preoperative risk of high intraoperative blood loss, including severe uncorrected coagulopathy. This group was given a bolus of rFVIIa just before transplantation. Group II (control group) included 61 patients without a particular risk for increased intraoperative blood loss. These patients were not given rFVIIa.

Patients from the study group (I) had significantly worse coagulation parameters than patients in the control group (II) at the start of the surgical procedure. However, after administration of a bolus of rFVIIa, immediate correction of coagulation occurred in all recipients. No significant differences in intraoperative blood transfusions were observed between study and control groups (1980 ± 311.4 mL vs 1527 ± 154.2 mL, respectively), operating time (8.7 h vs 8.9 h) or ICU and hospital stay (7.03 d vs 6.15 d and 40.89 d vs 41.1 d). Re-exploration because of bleeding was performed in 3 patients from group I (10.7%) and in 7 patients (11.5%) from group II. No single case of vascular thrombosis was observed in the study group, while 3 hepatic artery thromboses, 2 portal vein thromboses, and 1 hepatic vein thrombosis were reported in the control groups. The study group concluded that rFVIIa, given preoperatively to liver transplant recipients with severalriskfactorsforhighintraoperativebleeding, adjusts these patients to a normal risk group without an increased risk for thrombotic complications.

Autologous blood transfusion can be performed during many surgical procedures to reduce the risks associated with heterologous transfusion. In patients with advanced cirrhosis, the RBC mass may be adequate to use for the replacement of RBCs, but platelets and clotting factor levels are usually so low that avoidance of FFP and platelet transfusion may not be possible. The use of cell salvage to collect and reinfuse shed, autologous blood is a common practice in surgery with an expected high blood loss. However, some question its applicability to cancer surgery, fearing that malignant cells will be redistributed in the salvaged blood.

Muscari and colleagues³ addressed this issue in a 1-year follow-up of 47 patients who underwent liver transplantation for hepatocellular malignancy. Sixteen patients were operated on without cell salvage; the device was used in 31 others. The percentage of recurrence observed in the 2 groups was similar: 6.4% in the cell salvage group vs 6.3% in the group without cell salvage. The authors concluded that cell salvage could be used in liver transplantation for hepatocellular malignancy because it does not modify the risk of neoplastic recurrence.

Volume expansion is one additional method used more frequently in other surgical procedures to decrease the requirement of heterologous transfusion of PRBCs. The anesthesiologist draws 1 unit of blood from the patient before transplantation and replaces the volume with crystalloid. The number of RBCs lost during the operation is thus lowered, and the unit can be reinfused when needed.

Reports have described liver transplantation in Jehovah's Witness patients who received no blood products, PRBCs, platelets, or FFP. Jabbour and colleagues^{4, 5} continue to lead the field in performing liver transplantation without the use of blood or blood products. They recently reported favorable results in 27 consecutive patients who underwent transfusion-free liver transplantation. This team used a combination of preoperative stimulation of red cell production using recombinant human erythropoietin and iron and intraoperative hemodilution, cell salvage, and tolerance of moderate anemia. They reported 100% graft and patient survivals in the 19 patients who received living donor grafts and 75% in 8 deceased-donor recipients. This group has also reported on the successful use of recombinant factor VIIa in 10 patients. Factor rFVIIa was used at a dose of 80 mcg/kg, administered intravenously just prior to the incision in all patients; a second intraoperative dose was used in 3 patients.

Drugs that Minimize Blood Loss

Increased fibrinolytic activity is observed in some patients with ESLD. The mechanisms include increased t-PA activity and reduced synthesis of fibrinolysis inhibitors. In addition, enhanced fibrinolysis is noted in the anhepatic phase of OLT. This may result from a lack of t-PA activity clearance. A subgroup of patients develops a further increase of t-PA activity after reperfusion. The resulting fibrinolysis is one of the chief causes of excessive bleeding during OLT. Various antifibrinolytic agents have been used to counter this accelerated fibrinolysis in the second and third phases of OLT. These include aprotinin, epsilon amino caproic acid (epsilon-ACA), and tranexamic acid.

Aprotinin

Aprotinin is a serine protease inhibitor that prevents the lysis of fibrinogen by inhibiting plasmin, kallikrein, and leukocyte elastase, which are 3 proteases involved in fibrinolysis. This serves to decrease platelet aggregation and increase both the aPTT and activated clotting time.

A randomized, double-blinded, placebo-controlled study of 137 liver transplantation subjects given high-dose and regular-dose aprotinin demonstrated significantly lower (60%) blood loss and PRBC transfusion volume when compared with control subjects.⁶ No increase in thrombotic complications was reported. In this study, a large dose of aprotinin, ie, 2 million kallikrein inhibitor units (KIU), was administered as the initial dose and additional smaller doses of 500,000 KIU/h were administered during surgery. Additional studies have demonstrated that lower aprotinin doses (500,000 KIU initially and 150,000-200,000 KIU/h) are not different from large doses in terms of reduced blood loss or morbidity.^{7, 8} However, other studies have not reported a benefit with aprotinin use. Therefore, the precise role of aprotinin remains undefined.

Epsilon-aminocaproic acid

Epsilon-ACA has been used intraoperatively to inhibit fibrinolysis. It was found to be effective for decreasing blood requirements in some studies but not in others. One prospective, double-blinded, placebo-controlled, randomized study evaluated the effects of prophylactic doses of tranexamic acid and epsilon-ACA on blood loss. This group found a significant difference in RBC transfusion volume for the tranexamic acid group compared with either epsilon-ACA or placebo; no other differences were found, nor was any mechanism of action explained.

Tranexamic acid

Tranexamic acid is another synthetic drug that inhibits fibrinolysis. Both high- and low-dose tranexamic acid has significantly reduced the use of intraoperative PRBCs in several studies. Tranexamic acid also decreases transfusion requirements in some but not all studies. In a double-blinded, randomized, controlled study, high-dose (20 g) tranexamic acid significantly reduced intraoperative blood loss and transfusion requirements for 45 consecutive liver transplantation subjects. Smaller doses were shown to reduce fibrinolysis without affecting transfusion requirements. Mechanisms of action are hypothesized to include decreased platelet aggregation inhibition and inhibition of plasmin-induced platelet dysfunction.

Other drugs

Anecdotal reports describe the use of other drugs to reduce transfusion requirements in persons undergoing OLT. These include clonidine and estrogen.

Clonidine, a centrally acting alpha2-adrenergic receptor agonist, significantly decreased transfusion and fluid requirements in a small prospective, randomized controlled trial. It was hypothesized that excessive sympathetic stimulation occurred in patients with cirrhosis because of a spillover of excess epinephrine and norepinephrine. Clonidine acted to decrease sympathetic activity on the splanchnic circulation and, thus, decreased flow and pressure in the portal circulation. However, this study was quite small and requires confirmation by others.

Conjugated estrogen administered just prior to surgery and just after graft reperfusion has been shown to decrease blood loss and transfusion requirements. A prospective, randomized trial of 30 OLT subjects demonstrated significant intraoperative decreases in RBC, FFP, and platelet transfusion requirements. A retrospective report from the same group described significant decreases in PRBC, platelet, and FFP use after the administration of 100 mg of estrogen. Hypothesized mechanisms of action include an increased platelet count secondary to an increase in thromboxane B2 and beta-thromboglobulin. Because actual mechanisms, half-life, optimal dosing, and morbid effects are not well understood, estrogen is not in mainstream use, nor is it the standard of care.

Transplantation Without Transfusion

The literature includes cases of OLT performed without transfusion of any blood products and OLT performed safely without additional blood products if blood loss is limited to 1600-3400 mL. Various techniques for intraoperative blood salvage and sparing are discussed in Operative techniques that minimize blood loss.

SPECIAL DIAGNOSES AND PATIENT POPULATIONS

Section 7 of 10  

• Authors and Editors
• Introduction
• History and Background
• Bleeding During Liver Transplantation
• Transfusion Requirements
• Alternatives To Transfusion
• Special Diagnoses and Patient Populations
• Outcomes, Complications, and Costs
• Conclusion
• References

Several populations of liver transplantation patients may be challenging in terms of bleeding and transfusion requirements. These include IgA-deficient patients, hemophiliac patients, alloimmunized patients, children, and obese recipients.

IgA-deficient patients

IgA-deficient patients have circulating anti-IgA antibodies that attack IgA when present in their serum. OLT recipients who require large volumes of blood during and after the procedure must be given IgA-deficient blood. This usually requires autologous plasmapheresis or manual washing of erythrocytes and platelets. Proper planning can ensure that IgA-deficient blood products are available for these patients.

Hemophiliac patients

Hemophiliac patients often become cirrhotic and ESLD patients secondary to transfusion-contracted hepatitis. Liver transplantation can result in a cure for hemophilia, and 11 such cases have been reported. Hemophiliac patients require factor VIII or IX in addition to blood products when undergoing liver transplantation, and results have been good. Unfortunately, many of these patients are also infected with HIV, so long-term life expectancy is poor. For those with HIV infection, a US National Institutes of Health study for liver transplantation, evaluating improved life expectancy, is available.

Alloimmunized patients

Hemolysis secondary to alloimmunization can present a challenge in OLT, and it can greatly increase requirements for transfusion.

Weber and coworkers preoperatively identified patients who were highly alloimmunized (from either multiple transfusions or pregnancy) and compared them with nonsensitive patients. Sensitivity was determined by panel-reactive antibody testing. Highly sensitized patients required significantly more intraoperative blood products despite venovenous bypass without heparin. Preoperative screening for lymphocytotoxicity can predict which patients will require additional blood products, both RBCs and platelets, during and after transplantation.

Pediatric patients

Children undergo OLT for biliary cirrhosis secondary to congenital or acquired neonatal biliary atresia. Pediatric liver recipients are frequently poorly matched for size with the donor liver because of a lack of availability. In this circumstance, graft reduction is necessary, although this technique often contributes to increased blood loss from the raw liver surface after reperfusion.

Obese patients

Obese patients undergoing OLT who have a body mass index greater than 30 kg/m² may experience higher intraoperative and postoperative complications, including infection. In one study, length of hospital stay and total cost were higher for obese patients. However, no increase in transfusion requirements or blood loss has been reported for liver transplantation patients who are obese.

OUTCOMES, COMPLICATIONS, AND COSTS

Section 8 of 10  

• Authors and Editors
• Introduction
• History and Background
• Bleeding During Liver Transplantation
• Transfusion Requirements
• Alternatives To Transfusion
• Special Diagnoses and Patient Populations
• Outcomes, Complications, and Costs
• Conclusion
• References

Complications and Risks of Transfusion

Many complications are associated with transfusion. This section briefly describes transfusion-related infection, transfusion reactions, and metabolic derangements.

Transfusion-related infection

Many infectious complications arise from the transfusion of blood; these complications make matters worse for the critical condition of liver transplantation patients. Well-described infectious complications include hepatitis, HIV infection, and cytomegalovirus infection. More rare transmissions, which are described herein, include endotoxin effects and malaria transmission.

Endotoxemia was studied in a clinical trial of OLT patients. Patients undergoing OLT were evaluated before, during, and after transplantation for platelet count and endotoxemia level. They were monitored clinically and divided into 2 groups based on postoperative pulmonary progress (early or late extubation). Intraoperative endotoxemia levels were correlated with additional requirements for platelet transfusion. The authors discussed the effect of endotoxemia, elaborated by enteric flora and cleared by the liver, on decreased platelet numbers.

One case report detailed the transmission of Plasmodium ovale in a platelet transfusion during OLT. The patient was diagnosed with malaria after OLT, and the infection was traced to the transfusion. Another possible route of malaria transmission is the graft itself. In addition, latently infected patients may experience a resurgence of infection because of immunosuppression.

Transfusion reactions

Transfusion reactions are well described in the literature, such as acute intravascular immune hemolytic reactions from ABO incompatibility, delayed immune hemolytic reactions, and febrile reactions. The risk of a fatal hemolytic reaction is less than 1 in 1 million. Febrile reactions, believed to be cytokine-mediated, are also similar to transfusion-related lung injury, which can manifest as adult respiratory distress syndrome.

Metabolic derangements

Metabolic complications associated with blood transfusion during OLT include benzodiazepine-associated encephalopathy, metabolic alkalosis, hypercalcemia, and hypomagnesemia.

One report described the exacerbation of hepatic encephalopathy in patients receiving OLT. Zeneroli and colleagues evaluated 14 OLT patients for preoperative benzodiazepine levels and hepatic encephalopathy. After surgery, they tested the blood products infused during OLT and they evaluated patients for benzodiazepine levels, ammonia, and encephalopathy. Five patients had increased levels of benzodiazepines after surgery despite no infusion of this class of drug. Additionally, patients exhibiting encephalopathy were treated with flumazenil and showed clinical improvement. The blood products were tested and found to contain commercially available benzodiazepines, including nordazepam, diazepam, lorazepam, and delorazepam. This finding was reiterated in a comment in the same journal by a different source.

Metabolic alkalosis was reported in 5 patients who received large-volume transfusions, including a mean of 750 mEq citrate from transfused blood from a blood bank. The protracted alkalosis was not explained by sodium bicarbonate administration during the anhepatic phase, but it correlated with a rise in serum citrate levels.

Blood is treated with citrate to bind ionized calcium (Ca²⁺) and prevent its action as a cofactor in the coagulation cascade. Massive infusion of citrated blood products may cause hypocalcemia and hypomagnesemia, particularly in patients with poor hepatic function, neonates, and patients with hypothermia. During OLT, patients are at increased risk of citrate toxicity and subsequent hypocalcemia because aconitase, a citrate-metabolizing enzyme, is not produced. Hypocalcemia is treated with intraoperative calcium as needed to prevent ventricular hypocontractility and decrease peripheral vascular resistance.

Citrate can cause important hypomagnesemia. Ionized hypomagnesemia was measured across time during OLT in 9 patients; significant decreases occurred and were inversely related with serum citrate increases. Mean total transfusion of whole blood, PRBCs, platelets, and FFP was 33 units, all of which were treated with citrate. Ionized hypomagnesemia, which may be present in the setting of normal total magnesium concentrations, can result in loss of electrolyte pump control and intracellular hypercalcemia. These complications can lead to cell death, macroscopic dysrhythmia, and decreased cardiac inotropy.

Thrombosis and anticoagulation

Vascular thrombosis following liver transplantation is a significant enough problem to warrant the use of heparin anticoagulation. Both unfractionated heparin and low molecular weight heparin can be used. The dose of the former is typically adjusted to maintain the level of activated clotting time (ACT) between 130 and 160 seconds. Bleeding has been reported in up to 15% of patients treated with heparin, so the ACT must be monitored carefully.

Cost Analysis

Liver transplantation is a very expensive undertaking, of which blood products may represent a variable portion. Cost analysis of blood salvage and autotransfusion during liver transplantation was presented for 70 procedures, and the average charge for autotransfusion was $1048 per patient compared with a mean transfusion cost of $428 per patient. When larger volumes of blood loss are encountered, cell-saver use is economical.

Plan for Transfusion Alternatives

While minimizing transfusion requirements is the goal of any good surgeon, many situations necessitate blood products. In these instances, planning for anticipated needs can minimize transfusion-associated complications. Several treatment plans that minimize or prevent heterologous transfusion are described.

Plasma

Coagulopathy remains a serious complication of liver disease and transplantation. FFP is used to correct deficiencies in plasma coagulation factors, but it carries a risk of viral transmission. When FFP is needed, it can be treated with solvent-detergent to inactivate viral particles. Treated plasma has lower factor VIII and alpha-2 antiplasmin activity, but patients who receive treated FFP demonstrate a similar correction of the international normalized ratio, aPTT, and transfusion requirements compared with patients who receive untreated FFP. Patients who receive treated FFP also have a decreased risk of viral infection. However, until further studies are performed, treated plasma should be used with caution during OLT in light of a recent report that suggested increased fibrinolysis with the use of solvent-detergent–inactivated plasma.

Erythropoietin

Erythropoietin is a safe and effective drug for acute blood-loss anemia, although it requires time to work. It can be used preoperatively in patients who are scheduled to undergo surgery, and it can be used postoperatively to stimulate bone marrow stem cells to produce erythrocytes more quickly. Used in conjunction with intravenous iron, erythropoietin can effectively enhance erythropoiesis.

Erythropoietin also was used in a Jehovah's Witness patient who underwent OLT for biliary cirrhosis. Preoperative total hemoglobin levels increased from 11.1 mg/dL to 14 mg/dL within 5 weeks of erythropoietin treatment (2000 IU/d for 5 or 7 d). In lieu of PRBC transfusion, the patient was treated with meticulous hemostasis, argon-beam coagulation, continuous autotransfusion of salvaged blood, tranexamic acid, and transfusion of both platelets and cryoprecipitate.

Autotransfusion

Use of the cell-saver device is a safe and effective method of salvaging RBCs during OLT. Autotransfusion decreases some of the complications of homologous transfusions, including citrated products, infection transmission, metabolic derangements, benzodiazepine toxicity, and coagulopathy. Additionally, autotransfusion conserves blood bank resources and reduces overall costs. First used during OLT in 1982, autotransfused PRBCs saved approximately $1000-1600 per patient. Autotransfusion for living-donor liver transplantation has also been successful in preventing heterologous transfusion. Its use also has been described in a Jehovah's Witness patient undergoing OLT; a continuous circuit was established and maintained.

CONCLUSION

Section 9 of 10  

• Authors and Editors
• Introduction
• History and Background
• Bleeding During Liver Transplantation
• Transfusion Requirements
• Alternatives To Transfusion
• Special Diagnoses and Patient Populations
• Outcomes, Complications, and Costs
• Conclusion
• References

OLT, hepatic resection, and living-donor liver transplantation are operations associated with large losses of blood volume. Historically, patient support has required large volumes of transfused PRBCs, platelets, FFP, and cryoprecipitate and the administration of albumin and crystalloid. Transfusion is associated with many risks and complications, and efforts to minimize blood loss and transfusion volume have been described. Technological advances, drug therapy, and transfusion alternatives have contributed to an overall increase in survival and a decreased in morbidity and transfusion requirements during OLT.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• History and Background
• Bleeding During Liver Transplantation
• Transfusion Requirements
• Alternatives To Transfusion
• Special Diagnoses and Patient Populations
• Outcomes, Complications, and Costs
• Conclusion
• References

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Article Last Updated: Jun 24, 2008