Transfusion Requirements in Liver Transplantation

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 allogeneic and autologous (cell saver) transfusions of packed red blood cells (PRBCs), fresh frozen plasma (FFP), platelets, and cryoprecipitate. Drugs are given along with the blood products, to help correct metabolic and coagulation abnormalities.

Transfusions, however—especially large-volume transfusions—are associated with a range of complications. ^[1] Increased blood requirements in OLT are associated with a more frequent occurrence of sepsis, longer stays in the intensive care unit, a higher rate of severe cytomegalovirus infection, and higher rates of graft failure and patient mortality. However, it remains unclear whether these differences in outcome are related to the transfusion as an independent risk factor or the transfusion is a marker for a technically more difficult surgery.

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.

Because of many transfusion-related complications, especially those from large-volume transfusions, alternative therapies and approaches to transfusion are being investigated in transplantation and other surgical fields.

For other discussions on liver transplantation, see the overview topics Liver Transplantation and Pediatric Liver Transplantation.

For patient education information, see Cirrhosis and Liver Transplant.

In 1963, Starzl and colleagues performed the first liver transplantation procedure. This patient, along with the next 4, died of bleeding complications. 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.

Contributing factors to blood loss during liver transplantation can be categorized as preoperative, intraoperative, or postoperative.

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. In advanced liver failure, this abnormality may not be correctable, even with oral or parenteral vitamin K administration.

Thrombocytopenia is another common problem in cirrhotic patients. 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 end-stage liver disease (ESLD) demonstrate increased fibrinolytic activity. This results in a low-grade disseminated intravascular coagulation–like picture.

Intraoperative factors

Liver transplantation surgery may be divided into 3 stages. Stage I (preanhepatic period) begins with dissection of the inflow and outflow vascular structures of the liver 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 collateral vessels that develop as a result of 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. Addressing these abnormalities is crucial. The anesthesiologist must aggressively attempt to correct the international normalized ratio (INR) and platelet count by transfusing plasma and platelets early in the operative procedure. 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. ^[2]

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.

Clotting function is assessed during liver transplantation with the standard coagulation tests (ie, PT, aPTT, fibrinogen level). In addition, the thromboelastogram and coagulation and platelet function analyzer (eg, Sonoclot) are used.

The thromboelastogram is used to monitor clot formation until an endpoint of clot lysis or retraction is determined. The thromboelastogram, which is performed using whole blood, analyzes the interactions of plasma coagulation proteins with platelets and fibrinogen. Specific details regarding the interpretation of the thromboelastogram are beyond the scope of this article, but its findings correlate 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.

Bleeding during the postanhepatic phase also may be related to disseminated intravascular coagulation (DIC) 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 space of Disse and the sinusoids, along with phagocytosis by Kupffer cells. Additionally, many platelets that remained were found to be degranulated or nonfunctional. DIC has been correlated with ischemic damage of the graft liver. Antithrombin III administration has not been shown to be effective for reversing reperfusion-related DIC.

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, bleeding after liver transplantation is due to thrombocytopenia. This may result from platelet consumption, platelet-associated immunoglobulin M and immunoglobulin A (IgA) antibody production, sequestration, and thrombin generation. ^[3] Other causes of thrombocytopenia include viral infection, cytomegalovirus-induced hematophagic histiocytosis, treatment with antiviral agents, and ABO-incompatible GVHD.

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 favorable 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. ^[4]

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. ^[5]

This study also reported a statistically significant difference in non-PRBC (packed red blood cells) 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. A study by Ozier et al in children undergoing OLT found that the PT was correlated with blood loss 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. ^[6]

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. ^[7]

A study to assess the risk factors associated with massive transfusion (administration of red blood cells ≥100% of the total blood volume during liver transplantation) found high white blood cell (WBC) count, low platelet count, and cadaveric donors were significant predictive factors. The graft failure rate within 6 months in the massive transfusion group tended to be higher than that in the no-massive transfusion group (6.6% vs. 1.8%, P = 0.068). However, the patient mortality rate within 6 months did not differ significantly between the two groups.{ref

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. However, laboratory analysis of coagulation factors was not helpful for predicting blood loss in retransplantation patients.

In a retrospective review of 205 transplantation patients, 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%. ^[8] The authors concluded that because of the great variability of transfusion requirements, preoperative factors were not helpful in predicting large-volume loss and large transfusion requirements; however, large transfusion requirements were predictive of outcome.

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 orthotopic liver transplantation (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. ^{[9, 10, 11]}

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, creation of a shunt could be accomplished only with surgery, but a transjugular intrahepatic portosystemic shunt (TIPS) is now available.

The TIPS procedure is designed to decompress the portal system in order to decrease the risk of variceal rebleeding and minimize ascites. In a comparison of TIPS versus surgical portosystemic shunts before OLT, Menegaux et al reported that patients who underwent TIPS had decreased blood requirements, shorter operative time, shorter intensive care unit stays, and shorter hospital stays. ^[12]

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. ^[13] Kidney failure directly attributable to low CVP was not observed. In this prospective study of 100 hepatic resections, 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. ^[13]

Massicotte and colleagues 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. ^[14] 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.

Treatment with recombinant factor VIIa (rFVIIa) may reduce blood loss during OLT. In a pilot study by Hendriks et al, transfusion requirements were significantly lower in 6 adult end-stage liver disease (ESLD) patients who received rFVIIa than in matched controls. ^[15] 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.

A trial in 20 patients by Pugliese et al found that the units of blood products transfused and total blood loss during OLT were statistically significantly lower in patients receiving a single bolus of 40 mcg/kg of rFVIIa than in controls. In this double-blind, placebo-controlled, prospective, randomized trial, inclusion criteria were hemoglobin level greater than 8 g/dL, international normalized ratio (INR) greater than 1.5, and fibrinogen level greater than 100 mg/dL. ^[16] Notably, no thromboembolic events occurred in the rFVIIa group. Similar results have been duplicated by several other small pilot trials. ^[17]

Kalicinski and colleagues at the Warsaw Children's Hospital reported that rFVIIa, given preoperatively to pediatric liver transplant recipients with several risk factors for high intraoperative bleeding, adjusts these patients to a normal risk group. ^[18] Treatment with rFVIIa, which was given in a bolus just before transplantation, produced immediate correction of coagulopathies, with no increase in thrombotic complications.

As with many other surgical procedures, autologous (cell salvage) blood transfusion can be performed in OLT to reduce the risks associated with allogeneic transfusion. In patients with advanced cirrhosis, the RBC mass may be adequate to support autologous RBC transfusion, but platelet concentrations and clotting factor levels are usually so low that avoidance of platelet and fresh frozen plasma (FFP) 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. Some question its applicability to cancer surgery, fearing that malignant cells will be redistributed in the salvaged blood.

However, Muscari and colleagues concluded that cell salvage could be used in liver transplantation for hepatocellular malignancy because it does not modify the risk of neoplastic recurrence. ^[19] On 1-year follow-up of 47 patients, 6.4% of patients operated on with cell salvage experienced recurrence, versus 6.3% of patients in whom cell salvage was not used.

Volume expansion is another method used more frequently in other surgical procedures to decrease the requirement of allogeneic 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 transfusions. ^[20]  Costanzo et al performed a retrospective review of 13 consecutive Jehovah's Witness patients who received liver transplantation at a single center in 2007 to 2016. All patients received preoperative red cell mass optimization and the intraoperative use of normovolemic hemodilution, veno-venous bypass and low central venous pressure. Three patients received fibrinogen concentrate and one tranexamic acid to correct ongoing hyperfibrinolysis. At 12-month follow-up, one death had occurred, from septic complications. ^[21]

Jabbour and colleagues continue to lead the field in performing liver transplantation without the use of blood or blood products. In 27 consecutive patients who underwent transfusion-free liver transplantation, this team reported 100% graft and patient survivals in the 19 patients who received living donor grafts and 75% in 8 deceased-donor recipients. ^[22]

Jabbour and colleagues used a combination of preoperative stimulation of red cell production with recombinant human erythropoietin and iron and intraoperative hemodilution, cell salvage, and tolerance of moderate anemia. This group has also reported on the successful use of rFVIIa at a dose of 80 mcg/kg, administered intravenously just prior to the incision in all patients, with a second intraoperative dose if necessary. ^[23]

Increased fibrinolytic activity is observed in some patients with end-stage liver disease (ESLD). The mechanisms include increased tissue plasminogen activator (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. ^[24] Recently, aprotinin has incited significant controversy.

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 activated partial thromboplastin time (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 packed red blood cell (PRBC) transfusion volume when compared with control subjects. ^[25] 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. ^{[26, 27]}

However, other studies have not reported a benefit with aprotinin use. Therefore, the precise role of aprotinin remains undefined. Currently, aprotinin is available only via a limited-access protocol.

Fergusson et al and the Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) study investigators reported an increased risk for death with the use of aprotinin compared with tranexamic acid or aminocaproic acid in high-risk cardiac surgery. ^[28] Despite modest evidence that aprotinin was actually the more effective hemostatic agent—reducing the risk of massive postoperative hemorrhage as well as the requirement for postoperative transfusion of blood products at 30 days—aprotinin increased the risk of death by greater than 50%.

This increased risk led the investigators to terminate the trial early and conclude that the strong negative mortality trend associated with the use of aprotinin compared to other antifibrinolytics precluded its use in high-risk cardiac surgery. The increase in mortality seen with aprotinin has been postulated as secondary to its superiority as an antifibrinolytic agent; perhaps it alters the delicate balance between procoagulant and anticoagulant mediators in a way that is not yet appreciated (ie, through off-target effects). ^{[28, 29]}

A small meta-analysis of the use of aprotinin in orthotopic liver transplantation (OLT) patients did not demonstrate a negative effect on postoperative outcomes. ^[30] Nevertheless, the important lessons learned leading up to and after the BART study should caution against the further use of aprotinin outside the setting of a carefully conducted prospective clinical trial.

Prior to the BART study, although several prospective observational epidemiological studies pointed toward an increased mortality risk associated with aprotinin use, other meta-analyses did not detect this association, leading to the continued usage of aprotinin, as meta-analyses are felt to be superior to observational studies. The recent experience with aprotinin in cardiac surgery suggests that pooling data from many small trials that were not designed to study mortality may not be the best way to draw meaningful conclusions.

Epsilon-aminocaproic acid

Epsilon-aminocaproic acid (epsilon-ACA) has been used intraoperatively to inhibit fibrinolysis. It has been found effective for decreasing blood requirements in some studies but not in others. In a prospective, double-blinded, placebo-controlled, randomized study by Dalmau et al, prophylactic epsilon-ACA did not reduce intraoperative total PRBC transfusion during OLT; however, tranexamic acid did significantly reduce intraoperative transfusion requirements. ^[31]

Tranexamic acid

Tranexamic acid (TXA) is another synthetic drug that inhibits fibrinolysis. ^[32] Both high- and low-dose tranexamic acid have significantly reduced the use of intraoperative PRBCs in several studies. ^{[31, 33]} Tranexamic acid also decreased postoperative transfusion requirements in some but not all studies. However, concerns of increased thrombotic risk have impededi widespread adoption of TXA in this setting. ^[34]  

A systematic review and meta-analysis confirmed that TXA reduced the need for perioperative blood transfusion in liver resection and transplantation (odds ratio [OR] 0.09; 95% CI 0.01 to 0.72) but did not increase the incidence of thromboembolic events (OR 2.22; 95% CI 0.47 to 10.43) and mortality (OR 0.60; 95% CI 0.13 to 2.76). ^[35]

In a double-blinded, randomized, controlled study, high-dose (20 g) TXA 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. ^[36] 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. ^[37] A retrospective report from the same group described significant decreases in PRBC, platelet, and FFP use after the administration of 100 mg of estrogen. ^[38]

Hypothesized mechanisms of action of estrogen in this setting 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 standard of care.

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

IgA-deficient patients

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

Hemophiliac patients

Until the introduction of viral inactivation techniques in the mid-1980s, plasma-derived clotting factor concentrates were sometimes contaminated with hepatitis C virus (HCV), and the vast majority of patients with hemophilia treated with these products were exposed to and infected with HCV. ^[39] As a result, many hemophiliac patients developed chronic hepatitis eventuating in cirrhosis and end-stage liver disease (ESLD). Liver transplantation in such cases can also result in a cure for hemophilia, ^[40] 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 is available that evaluated 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 found that, compared with nonsensitized patients, those who were highly alloimmunized (from either multiple transfusions or pregnancy) required significantly more intraoperative blood products during OLT despite venovenous bypass without heparin. ^[41] 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

Patients who have a body mass index greater than 30 kg/m² may experience higher intraoperative and postoperative complications with OLT, including infection. In one study, length of hospital stay and total cost were higher for obese patients. ^[42] However, no increase in transfusion requirements or blood loss has been reported for liver transplantation patients who are obese.

Many complications are associated with transfusion, such as 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.

In a clinical trial of orthotopic liver transplantation (OLT) patients, intraoperative endotoxemia levels correlated with the need for perioperative platelet transfusions, postoperative ventilator dependency, and 1-month case-fatality. ^{[43, 44]} Patients undergoing OLT were evaluated before, during, and after transplantation for platelet count and endotoxemia level. Endotoxemia was more severe in patients who needed ventilatory support for more than 5 days or who died within 5 days.

One case report detailed the transmission of Plasmodium ovale in a platelet transfusion during OLT. ^[45] 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. They include 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.

Platelet transfusions have been identified as an independent risk factor for survival after OLT. A retrospective analysis by Pereboom et al showed that patient survival and graft survival after OLT were significantly reduced in patients who received platelet transfusions, as compared with those who did not (74% vs 92% patient survival, and 69% vs 85% graft survival, at 1 y). ^[46] Lower survival rates in patients who received platelets were attributed to a significantly higher rate of early mortality because of acute lung injury (4.4% vs 0.4%).

Metabolic derangements

Metabolic complications associated with blood transfusion during OLT include the following:

• Benzodiazepine-associated encephalopathy
• Metabolic alkalosis
• Hypercalcemia
• Hypomagnesemia

Zeneroli and colleagues described the exacerbation of hepatic encephalopathy in patients receiving OLT, which in some cases could be traced to benzodiazepines present in transfused blood products. ^[47] These researchers evaluated 14 OLT patients and found that 5 patients had increased levels of benzodiazepines after surgery despite no infusion of this class of drug.

The blood products were tested and found to contain commercially available benzodiazepines, including nordazepam, diazepam, lorazepam, and delorazepam. Additionally, patients exhibiting encephalopathy showed clinical improvement after treatment with the benzodiazepine antagonist flumazenil.

Metabolic alkalosis was reported in 5 patients who received large-volume transfusions. ^[48] Driscoll et al reported that the protracted alkalosis was not explained by sodium bicarbonate administration during the anhepatic phase, but it correlated with a rise in serum citrate levels; the patients had received a mean of 750 mEq citrate from the transfused blood.

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 decreased peripheral vascular resistance.

Citrate can cause important hypomagnesemia. Scott et al found significant decreases in plasma concentrations of ionized magnesium across time during OLT in 9 patients; these decreases were inversely related to serum citrate increases. ^[49] Mean total transfusion of whole blood, packed red blood cells (PRBCs), platelets, and fresh frozen plaza (FFP) was 33 units, all of which had been 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 sufficiently significant 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 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.

Liver transplantation is a very expensive undertaking, of which blood products may represent a variable portion.

A cost analysis of blood salvage and autotransfusion for 70 orthotopic liver transplantation (OLT) procedures performed during the years 1993-1994 showed that the average charge for autotransfusion was $1048 per patient, compared with a mean transfusion cost of $428 per patient. ^[50]

When larger volumes of blood loss are encountered, cell-saver use is economical.

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. Fresh frozen plasma (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 (INR) and activated partial thromboplastin time (aPTT), and they have transfusion requirements similar to those of patients who receive untreated FFP. ^[51] 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. ^[52]

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. ^[53] 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 packed red blood cell (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. A systematic review by Davies et al concluded that cell salvage may be a cost-effective method to reduce exposure to allogeneic blood transfusion, but acute normovolemic hemodilution may be more cost-effective than cell salvage. ^{[54, 55]}

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.