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Perioperative Coagulation Management in Liver Transplant Recipients

Bezinover, Dmitri MD, PhD1; Dirkmann, Daniel MD2; Findlay, James MB, ChB3; Guta, Cosmin MD4; Hartmann, Matthias MD2; Nicolau-Raducu, Ramona MD5; Mukhtar, Ahmed M. MD6; Moguilevitch, Marina MD7; Pivalizza, Evan MB, ChB, FFASA8; Rosenfeld, David MD9; Saner, Fuat MD10; Wray, Christopher MD11; Wagener, Gebhard MD12; West, James MD13

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doi: 10.1097/TP.0000000000002092
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Perioperative coagulation management in liver transplantation (LT) has been very controversial. First attempts at LT were frequently associated with uncontrollable hemorrhaging related not only to surgical technique, but also to coagulopathy. With increasing transplant experience, our understanding of the physiology of liver failure have improved. As a result, there has been a dramatic reduction in intraoperative blood loss, morbidity, and mortality. It has become apparent that the underlying coagulation abnormalities of patients with end-stage liver disease (ESLD) are more complicated than initially thought.

We review here the current understanding of the coagulation system in patients with ESLD. We critically analyzed a number of publications related to coagulation management in LT and have made suggestions for clinical management. Papers used for preparation of recommendations were evaluated using the Grading of Recommendations Assessment and Evaluation approach.1 Quality of Evidence was determined to be: high (level I), moderate (level II), low (level III), and very low (level IV). Recommendations for management (A, B, C, and D) were made based on quality of evidence presented in available studies and assessment of the balance between desirable and undesirable effects associated with a particular type of management.

Current Concepts of Coagulation in ESLD

The first widely accepted enzymatic model of coagulation that included 2 waterfall-like cascades of coagulation factors (extrinsic and intrinsic pathways) was proposed in 1964.2,3 Both cascades result in a final common pathway where pro-thrombin is converted to thrombin triggering the conversion of fibrinogen to fibrin resulting in clot formation. The enzymatic model was well suited to explain the mechanism of action of anticoagulants (ACs) (mainly heparin and warfarin) and to understand the results of conventional coagulation tests (prothrombin time [PT] and activated partial thromboplastin time [aPTT]). Clot formation in vivo could not be completely explained with this model.

In 2001, a new cell-based model of coagulation was proposed by Hoffman and Monroe.4 This model provided a more convincing explanation for in vivo clot formation than the enzymatic model. The cell-based model includes 3 phases of clot formation. During the initiation phase, injury to the vascular endothelium exposes the tissue factor (TF) thromboplastin to circulating factor VII (FVII). This TF-VII complex is then activated by proteases to TF-FVIIa complex which subsequently activates factors IX (FIX) and X (FX). Activated FX (FXa) binds to and activates factor V (FV). The FXa/FVa (prothrombinase) complex produces a small amount of thrombin which is necessary to activate platelets. During the amplification phase, platelets adhere to the collagen-von Willebrand factor (vWF) complex (GP-Ib), initiating aggregation. Activated platelets then bind FIXa and FVIIIa and promote the release of FV that is again activated by thrombin and FXa. During the propagation phase, the FIXa-VIIIa complex adhering to the surface of the platelet activates FX and binds to FVa. The FVa-Xa complex then converts prothrombin into thrombin. Thrombin initiates the conversion of fibrinogen to fibrin resulting in a fibrin burst with subsequent clot formation (Figure 1).

FIGURE 1
FIGURE 1:
Cell-based model of coagulation. Adapted from Hoffman M and Monroe DM*. Three stages of the coagulation process: Initiation, Propagation, and Amplification. *Hoffman M, Monroe DM. A cell-based model of hemostasis. Thromb Haemostasis. 2001;85:958-965.

ESLD causes profound derangements in coagulation homeostasis. The concentration of almost all procoagulant factors are decreased (except for FVIII) resulting in abnormal coagulation tests, especially those dependent on the extrinsic pathway. At the same time, the concentration of AC factors produced by the liver, including protein C,5 protein S, and antithrombin III are significantly decreased. There are also compensatory increases in the concentration of liver-independent coagulation factors produced in the vascular endothelium (FVIII and vWF) and to lesser extent, an increase in the concentration of plasminogen activator inhibitor 1 (PAI-1).6-9 Increases in these coagulation factors is caused by profound endothelial dysfunction due to both endotoxemia and nitric oxide dysregulation seen in patients with ESLD10 which contribute to both coagulopathy and dramatic clotting events.

A predisposition to hypercoagulability is common and frequently underestimated characteristic of ESLD. This is related to fundamental changes in the coagulation profile seen in this population. Thrombin formation in patients with ESLD can be normal or even high when conventional coagulation tests of thrombin activity, such as International Normalized Ratio (INR), are abnormal.11-13 Cirrhosis alone is associated with significant resistance to thrombomodulin,14,15 a protein C activator and an important cofactor in the anticoagulation pathway.

Splenic sequestration of platelets, a marker of portal hypertension in ESLD, contributes to thrombocytopenia in this patient population but does not necessarily result in a clinically relevant coagulopathy. The reason for this is most likely related to a compensatory increase in levels of vWF.9,16 Levels of the circulating ADAM (a disintegrin and metalloproteinase) protein with thrombospondin motifs-13 (ADAMTS-13) are also decreased. This metalloproteinase produced in liver is necessary to cleave and deactivate vWF. Low levels of ADAMTS-13 result in decreased vWF cleavage and exaggerated increases in active vWF.16,17

Significant changes occur in the fibrinolytic and antifibrinolytic systems associated with liver failure. All liver-dependent factors (plasminogen,18 α2-antiplasmin, histidine-rich glycoprotein,19 thrombin-activatable fibrinolysis inhibitor18 and FXIII20) are significantly decreased. Liver-independent factors (including tissue plasminogen activator [tPA, due to decreased liver clearance] and PAI-1 (due to increase endothelial expression), are increased.21 The final effect of these changes likely results in a new balance between fibrinolytic and antifibrinolytic factors.9,22 In some subpopulations, the level of PAI-1 is increased more than in others (such as ESLD related to cholestatic conditions21 or nonalcoholic steatotic hepatitis with concomitant increased PAI-1 and decreased tPA levels23,24). This predisposes these subpopulations to hypercoagulability.

When a clot finally forms, it frequently has an abnormal structure. In particular, clots in patients with ESLD have significantly decreased permeability.25 This is associated with decreased clot lysis which can promote thrombotic events.26

Due to these complex alterations in the coagulation system, patients with ESLD undergoing LT are not only prone to significant bleeding but are also at increased risk for thromboembolic complications9 (Figure 2).

FIGURE 2
FIGURE 2:
Effect of ESLD on the coagulation system. TM, thrombomodulin; TAFI, thrombin-activatable fibrinolysis inhibitor. With ESLD there is a decrease in the concentration of several liver dependent coagulation and anticoagulation factors along with an increase in the concentration of several liver independent coagulation factors. This results in a new, but unstable balance of coagulation factors. Without signs of bleeding, any coagulation management intervention carries the risk of thrombosis.

Use of Blood Products and Factor Concentrates in Patients Undergoing LT

Transfusion of blood and blood products are strong predictors of overall survival after LT.27,28 In addition to significant variability in transfusion practices between transplant centers,29,30 several recipient, donor, and procedural factors affect transfusion requirements.31 Recipient factors include severity of disease, age, and baseline coagulation status27,32,33; donor-related factors include length of ICU stay, cerebrovascular accident as a cause of death, African American race, duration of cold ischemia time, and organ procurement outside of the local donor service area. Additional bleeding risks are related to graft quality, including donation after circulatory death status, and the use of partial or split grafts.34-36 Surgical factors that can increase transfusion requirements include previous abdominal surgery, center experience, severity of portal hypertension, and presence of portal vein thrombosis (PVT).37-39

Several algorithms and protocols have been used to guide blood products administration in the management of coagulopathy during LT. These are listed as non-Level 1 evidence guided suggestions.

Fresh Frozen Plasma

Fresh frozen plasma (FFP) contains procoagulant factors I, II, V, VIII, IX, X, XI, XIII AC proteins C and S, antithrombin III, immunoglobulins, albumin, and acute phase proteins.40 Goal-directed FFP administration is used to mitigate associated risks such as transfusion-associated acute lung injury,41,42 sepsis,42,43 postreperfusion syndrome44 and thrombotic complications including deep venous thrombosis (DVT), pulmonary embolus (PE),45 and hepatic artery thrombosis (HAT).46 FFP should be administered when there is evidence of coagulopathy as indicated by an increased INR, prolonged aPTT, or increased clotting times (CTs) in viscoelastic tests (VET) in the face of clinically significant bleeding. FFP is frequently used for fibrinogen replacement despite a relatively low fibrinogen content (100-150 mg/dL). Although it has been demonstrated that patients with ESLD have normal thrombin generation,9,12 delayed fibrin formation (as a consequence of factor but not fibrinogen deficiency) should be confirmed with VET before administering FFP. The volume of FFP required to replace fibrinogen can be excessive.47

Recommendations

FFP should be administered in the setting of clinically significant bleeding. Prophylactic use of FFP cannot currently be recommended.12,13 Doses as high as 10 to 15 mL/kg may be required, with up to 30 mL/kg or higher in the setting of massive transfusion.48,49 VET is helpful for perioperative management. Indications for FFP administration derived from published algorithms are summarized in Table 1. Level of evidence is II/III B/C.

TABLE 1
TABLE 1:
Recommendations for blood product and factor concentrate administration

Cryoprecipitate

Cryoprecipitate is a source of FI, FVIII, vWF, and FXIII. One unit of cryoprecipitate per 10 kg body weight raises the plasma fibrinogen concentration by approximately 50 mg/dL in the absence of continued consumption or massive bleeding.62 In many countries, cryoprecipitate is unavailable and fibrinogen concentrate (FC) is used for the management of hypofibrinogenemia.63

Recommendations

Cryoprecipitate should be administered in the setting of clinically significant bleeding. A target fibrinogen level of 150 to 200 mg/dL can be carefully recommended. VET is helpful for perioperative management. Indications for cryoprecipitate administration are summarized in Table 1. Level of evidence is II/III B/C.

FC

FC is a pasteurized, lyophilized product derived from virally inactivated, pooled human plasma supplied as a 1-g vial (0.9-1.3) (RiaSTAP, CSL Behring). It is Food and Drug Administration (FDA)-approved for the management of acute bleeding in patients with congenital fibrinogen deficiency (afibrinogenemia or hypofibrinogenemia).64 In vitro data demonstrates significant clot strengthening with FC especially after graft reperfusion.65 Even when used preemptively, FC has a favorable safety profile66 relative to thrombotic complications in the LT setting.54,59 FC administration is theoretically less prothrombotic compared to cryoprecipitate due to the absence of VWF, FVIII, and FXIII. Although there is no FDA approval for FC to correct hypofibrinogenemia in LT an evolving consensus is that the use of FC in the management of clinically significant bleeding in patients undergoing LT can be, in fact, beneficial.

Recommendations

FC should be administered in the setting of clinically significant bleeding. Doses as high as 25 to 70 mg/kg may be required. A target fibrinogen level of 150 to 200 mg/dL can be carefully recommended. The use of VET is helpful for perioperative management. In certain circumstances, the use of FC might be safer in comparison to cryoprecipitate. Suggested indications for FC administration derived from published algorithms are summarized in Table 1. Level of evidence is II/III B/C.

Prothrombin Complex Concentrate

Prothrombin complex concentrate (PCC) is a non-activated 4-factor product (Kcentra; CSL Behring) containing factors II, VII, IX, and X, protein C and S, and a small amount of heparin and AT-III. Factor half-life ranges from 5 to 6 hours (VII) to 60 hours (II). It is FDA-approved for urgent reversal of acquired coagulopathy induced by vitamin K antagonists. Current data suggests efficacy in LT54 without increased risk of thromboses.67

PCC administration has a lower risk of viral transmission and is not associated with volume overload compared to FFP.68 The incidence of significant adverse effects, including thromboembolism, between PCC and FFP, appears similar.54,69,70 Chai-Adisaksopha et al70 performed a meta-analysis of 13 studies comparing PCC and FFP for warfarin reversal. They concluded that the use of PCC was associated with reduced mortality, more rapid INR correction, and less risk of volume overload or thromboses. A double-blind, multicenter, placebo-controlled randomized study is currently underway (PROTON Trial) evaluating the effectiveness of PCC to reduce transfusion requirements in LT.71 Results are not yet available.

Recommendations

PCC should be administered in the setting of clinically significant bleeding. The initial recommended dose of PCC is 25 mg/kg or less which is typically used to reverse an INR of 2 to 4.54 VET is helpful for perioperative management. Indications for PCC administration are summarized in Table 1. Level of evidence is III C.

Platelets

Cirrhotic patients frequently have low platelet counts due to portal splenic sequestration, decreased platelet growth factor (thrombopoietin) production, and (autoimmune-mediated) platelet destruction.72 During the neohepatic phase, thrombocytopenia often worsens due to sinusoidal obstruction and entrapment of platelets in the new liver, generalized platelets aggregation, and through a consumptive disseminated intravascular coagulation-like process.73-75 Despite a low platelet count, ESLD patients frequently have increased platelet activity which contributes to hypercoagulability.16,61,76

Platelets also participate in inflammatory reactions, angiogenesis, and tissue repair. Platelet transfusion is associated with reperfusion injury and is an independent risk factor for graft and patient survival after LT due to acute lung injury.77,78

Recommendations

Platelets should be administered in the setting of clinically significant bleeding. Target platelets level of 50 000/mm3 can be carefully recommended. VET is helpful for perioperative management. Indications for platelets administration are summarized in Table 1. Level of evidence is II/III C.

Recombinant Factor VIIa

Recombinant FVIIa (rFVIIa) was developed to treat bleeding in patients with hemophilia A complicated by alloantibodies inhibiting FVIII coagulant activity.79 rFVIIa is thought to act at sites of vascular injury via 2 mechanisms, both of which enhance thrombin generation on the surface of activated platelets providing the enzymatic activity necessary for the formation of fibrin.80 Two randomized controlled trials (RCTs) have failed to demonstrate any clinical benefit for rFVIIa use during LT.81,82 Systematic reviews, meta-analyses,83,84 and a Cochrane review,85 have demonstrated no significant differences between rFVIIa and placebo in terms of mortality or blood transfusion requirements during LT.

Recommendations

Because of the concern for precipitating severe thrombotic events related to rFVIIa administration, its use during LT cannot be currently recommended.79,86 Level of evidence is II B.

Despite the lack of level 1 evidence, extensive clinical experience and many retrospective studies allow us to recommend the algorithms presented (Table 1).

Coagulation Monitoring During LT

Coagulation monitoring and management for major surgical procedures is challenging and usually based on standard laboratory tests (SLTs). Haas et al87 performed a meta-analysis evaluating the usefulness of SLTs to both diagnose and manage coagulopathy in the perioperative setting.87 Eleven guidelines and 53 studies were identified. Only 3 prospective studies (none of them RCTs), with a total of 108 patients, found that SLTs were effective in coagulopathy management.

SLTs in the setting of ESLD are even less reliable.6,13 Tripodi et al12,88 demonstrated that PT and aPTT prolongation in patients with ESLD did not reflect actual thrombin generation because of incomplete thrombin activation under in-vitro conditions. In a retrospective evaluation of 200 cirrhotic patients with hemorrhage after liver biopsy, Eve et al89 found no correlation between SLTs and duration of bleeding.

VET has been demonstrated to be more reliable than SLTs in not only monitoring and diagnosing coagulopathy, but also in guiding management in patients with ESLD.90

Thromboelastography (TEG) was invented in 1948 by Hartert.91 It produces a graphic representation of viscosity change during clot formation. VET represents the cell-based model of homeostasis and assesses the interaction between procoagulant and ACs, and platelets.4 VET provides dynamic and rapid information about the entire coagulation process. Currently, 2 types of VETs are available: rotational thromboelastometry (ROTEM) and TEG.

ROTEM use a small amount of blood placed in an immobile cuvette with a rotating pin.

The available ROTEM assays include:

  1. EXTEM: coagulation is activated by recalcification with the addition of TF and phospholipids. CT reflects thrombin generation via the extrinsic and common pathways. Clot firmness variables at 5 and 10 minutes (amplitudes A5 and A10), and maximum clot firmness (MCF) correlates well with platelet count.
  2. INTEM: coagulation is activated by recalcification with the addition of ellagic acid and phospholipids. CT reflects thrombin generation via the intrinsic and common pathways. Similar to EXTEM, MCF correlates with platelet count.
  3. FIBTEM: coagulation is activated as in EXTEM, with platelet effects blocked by the addition of cytochalasin D. It assesses fibrinogen formation and polymerization.
  4. APTEM: coagulation is activated as in EXTEM with the addition of either aprotinin or tranexamic acid (to block any ongoing fibrinolysis). This confirms hyperfibrinolysis.
  5. HEPTEM: coagulation is activated as with INTEM with the addition of heparinase. This rules out any heparin effect.

The TEG system uses a different technology with a cylindrical cuvette that moves around an immobile pin. Clot formation produces shear forces causing oscillation of the pin that is connected to a recording system via a torsion wire. This system is more sensitive to vibration than ROTEM. The latest TEG technology (TEG 6s) measures resonance frequencies in blood samples and is significantly less susceptible to external vibration. TEG 6s test uses a citrated microfluidic cartridge for bedside use. Cartridge configurations include:

  1. Citrate+ Kaolin (CK): reaction is activated by kaolin and represents intrinsic pathway activation.
  2. Citrated Rapid TEG (CRT): this “rapid TEG” reaction is activated by both TF and kaolin and represents activation of both extrinsic and intrinsic pathways. CRT allows complete testing in 15 to 20 minutes.
  3. Citrated Functional Fibrinogen (CFF): this “functional fibrinogen TEG” is activated by TF with the addition of a GPIIb/IIIa platelet receptor inhibitor. It assesses the contribution of fibrinogen and platelets in clot formation.
  4. Citrate+Kaolin + Heparinase (CKH): reaction is activated by kaolin with the addition of heparinase. It assesses coagulation in the presence of heparin.

Many investigations demonstrating the value of VET-based coagulation management have been performed during cardiovascular surgery; VET-based coagulation management during LT has been less extensively studied. In a meta-analysis of 8332 cardiac surgery patients (9 RCT and 8 observational studies), Deppe et al92 demonstrated that VET-guided therapy was associated with both a lower rate of blood product transfusion and re-exploration due to bleeding (odds ratio, 0.63; P < 0.00001 and odds ratio, 0.56; P < 0.00001). Wikkelso et al93 performed a review of RCTs from the Cochrane Central Register (1493 patients) and also found that the use of a VET-guided transfusion protocol was associated with decreased component utilization. These results, however, were based almost entirely on patients having elective cardiac surgery.

In patients undergoing LT, TEG-based algorithms have led to a reduction in blood, FFP, and platelet transfusions.58,94 Krzanicki et al95 demonstrated that the TEG’s R value and MA (maximum amplitude) were superior in predicting hypercoagulability in comparison to SLTs. Blasi et al96 found that a ROTEM EXTEM A10 greater than 35 mm was predictive of coagulopathic bleeding. Song et al97 demonstrated a very close correlation between the A5 in EXTEM and FIBTEM, with the MCF in EXTEM and FIBTEM. This enables the physician to diagnose and treat a coagulopathy in nearly real time. It has been demonstrated that ROTEM-based coagulation management in patients with ESLD may decrease the amount of coagulation factors transfused when compared to SLT.98 Mallett et al13 have reported that VET has established itself to be the basis for developing criteria for both assessment of coagulation and treatment of bleeding in patients with liver disease.

Abuelkasem et al99 compared fibrinolysis detected by TEG and ROTEM during LT and found that ROTEM had a higher sensitivity, specifically with the use of FIBTEM. The same investigators demonstrated that ROTEM was more sensitive than rapid TEG in detecting a F-X deficiency.100 In a TEG-based prospective study, Wang et al50 demonstrated no difference in either blood loss or increased plasma requirement with early treatment as compared to treatment when there was a 35% reduction below reference values.

VET has some limitations. Measurements are performed in vitro without endothelial exposure and under no-flow conditions. These conditions exclude some important interactions such as thrombomodulin/thrombin induced protein C and S AC pathway activation. Another consideration is the relatively small number of prospective investigations evaluating the role of VET in coagulation management during LT. ROTEM-based protocols were used in the majority of these studies.

All VETs have a high negative predictive value, but only a low positive predictive value for bleeding during elective surgery.96 As a consequence, therapeutic decisions should be made in the context of the clinical situation. Another limitation of conventional VET is in the assessment of bleeding in patients with von Willebrand disease or in assessing platelet function in patients taking either aspirin or any GbIIb/IIIa antagonist. Platelet function under these conditions can now be evaluated using the TEG platelet mapping assay and the ROTEM platelet-function analyzer (see “Liver transplantation in patients on antiplatelet or AC therapy”).

Recommendations

VET has been demonstrated to be superior in comparison to SLTs for diagnosis, monitoring, and management of bleeding during major surgical procedures. VET can be used for the development of transfusion guideless during LT.13 VET-based coagulation management can be recommended with a high level of confidence. Level of evidence is II B/C.

Administration of Antifibrinolytic Agents

Hyperfibrinolysis most frequently occurs during the anhepatic and neohepatic phases of LT. The 2 currently available antifibrinolytics are ε-aminocaproic acid (EACA) and tranexamic acid (TA). Both are lysine analogues101,102 used to both prevent and treat fibrinolysis. A Cochrane review of 33 trials involving 1913 patients undergoing LT found no significant differences in 60-day mortality, rate of re-transplantation or increased incidence of thromboembolic episodes between TA or control groups.85 Conclusions, however, were based on only a few clinical trials, each with a high risk of bias (systematic overestimation of benefits and a high risk of random error due to small number of patients). This analysis was not able to demonstrate a benefit of any particular method of decreasing blood loss or transfusion requirement in patients undergoing LT. No recommendation regarding antifibrinolytic use could be made because the individual studies were not powered to demonstrate a difference in thromboembolic events. A recent cohort study using propensity matching of 367 patients who received TA prophylactically during LT103 demonstrated both reduced red cell (P = 0.003) and FFP (P = 0.032) transfusion without an increase in thromboembolic events. This study was underpowered to detect a difference in serious thromboembolic events and included patients at a low risk for bleeding.

Four studies evaluating the efficacy and safety of prophylactic administration of EACA in LT demonstrated conflicting results.104-106 Dalmau et al104 observed no effect while Kong et al105 and Mangus et al106 reported reduced blood transfusion requirements for patients prophylactically treated with EACA. The authors found an increased incidence of DVT in patients receiving EACA.106 However, when EACA was used for treatment of fibrinolysis, no increased incidence of thromboses, renal failure or mortality was detected (Table 2).107 There was no significant difference in 1-year survival or incidence of DVT when comparing high versus low MELD recipients receiving EACA either prophylactically or for the treatment of medical bleeding.106,107 In patients with higher MELD scores, EACA administration for treatment of fibrinolysis was associated with a reduced incidence of bleeding-related reoperations.108

TABLE 2
TABLE 2:
EACA: prophylactic administration versus treatment

The lowest effective dose of lysine agonists in patients with ESLD remains unknown.101 TA is usually administered in either 1 to 2 g boluses109,110 or up to 30 mg/kg111 as an infusion, while EACA is administered in doses from 0.25 to 2 g99,108,112-115 up to 5 to 10 g.107 Quach et al116 reported that in patients with ESLD, blood levels were insufficient to inhibit fibrinolysis after the administration of EACA as a 5-g bolus followed by 1 g/h intravenous infusion. Additional studies are needed to clarify the optimal dose of antifibrinolytics. VET has been recommended to both differentiate between early and late fibrinolysis and to guide treatment.55,99,111

Despite the lack of clear evidence of an increased risk of hypercoagulability associated with the use of antifibrinolytics during LT, a significant number of case reports have described dramatic thrombotic events likely related to administration of this class of medications.114,115,117,118 As a result, routine prophylactic administration of antifibrinolytics for patients undergoing LT cannot currently be supported; particularly in the case of acute liver failure, live donors, or in patients with cholestatic liver disease. Antifibrinolytics should not be given to any patient exhibiting either hypercoagulability or disseminated intravascular coagulation (stage I DIC).55

Recommendation

Antifibrinolytic therapy (EACA or TA) should only be considered for LT recipients with significant bleeding when hyperfibrinolysis is either suspected or confirmed by VET.55 The benefit of prophylactic antifibrinolytic administration during LT has not been demonstrated. Level of evidence is II/III C.

Monitoring and Treatment of Intraoperative Thrombosis

LT is associated with both coagulopathy and hypercoagulability.119-124 The incidence of intracardiac thrombosis (ICT) has been reported to be between 0.7% and 6.25%, and of PE between 0.4% and 4%.119,125 The intraoperative mortality due to thrombotic events is between 30% and 70%, with an overall mortality of 45% to 80%.119,126 Both ICT and PE occur most frequently after graft reperfusion; however, thrombotic events occur during all phases of LT.126 The etiology of intraoperative thrombosis is most likely related to hypercoagulability associated with ESLD. Specific risk factors for ICT or PE formation include sepsis, disseminated intravascular coagulation, presence of a pulmonary artery catheter, administration of antifibrinolytics, platelet and blood component administration, hepatitis B, immune globulin administration, use of venovenous bypass, preexisting thromboembolic disease, intraoperative hypotension, and protein C and S deficiencies.119,126,127

Transesophageal echocardiogram (TEE) is beneficial for early clot detection. Intraoperative TEE also allows real-time imaging of cardiac structures and monitoring of both cardiac function and volume status. A focused survey of 30 high-volume LT centers demonstrated that almost 86% of them performed intraoperative TEE during LT.128 TEE in ESLD is associated with very low incidence of complications even in the presence of esophageal varices.129 The presence of ICT alone or in combination with biventricular dysfunction is predictive of poor short- and long-term postoperative outcomes.130 Xia et al131 retrospectively studied the incidence of ICT and associated risk factors in 426 patients undergoing LT. Incidental ICTs were identified in 8 patients (1.9%). In all these patients, intraoperative management was modified: antifibrinolytic administration was discontinued (5 patients), and administration of clotting factors or platelets was discontinued or reduced. Symptomatic or surgically treated portal hypertension before LT and intraoperative hemodialysis have been identified as risk factors associated with ICT. Authors recommended the use of TEE for early clot identification.

There is no consensus about the treatment for a suspected or confirmed ICT. The primary goal is to maintain hemodynamic stability with inotropic and vasopressor support. It is unclear whether asymptomatic and incidentally found ICT should be treated. Although one group recommended no treatment,131 others suggested treatment if the clot reaches a particular size (clot greater than 1 cm2 or a propagating strand).132 Intraoperative TEE monitoring is essential to establish a diagnosis and allows rapid identification of both a change in clot size and any impact on cardiac function.132,133

Heparin boluses of 2000 to 5000 U have been recommended as the first step in the treatment of ICT.132-134 Recent reports recommend the use of tPA for the treatment of an acute, symptomatic ICT.133-135 Boone et al134 reported four cases of successful use of low-dose tPA (0.5-4 mg) during LT and concluded that this low dose tPA is safe and effective.

Surgical interventions such as thrombectomy with or without cardiopulmonary bypass have been reported for the management of massive thromboemboli and are associated with mortality rates of up to 50%.126,136,137 While much of the literature offers suggestions on how to treat thrombosis, preventing intraoperative thrombotic complications remains an unsolved problem.

Recommendation

At this time, evidence-based recommendations for the treatment of intraoperative thromboses cannot be given because the majority of publications are based on expert opinion, case reports, and a small number of low powered, retrospective studies. The routine use of TEE during LT is associated with a low risk of adverse effects. The use of TEE might be helpful for both the early detection of thromboses and management of antithrombotic therapy. Basic TEE training for liver transplant anesthesiologists can be recommended. Level of evidence is III/IV C/D.

LT in Patients on Antiplatelet or AC Therapy

LT candidates with preexisting cardiovascular conditions are frequently receiving antiplatelet therapy (APT) and other AC medications including warfarin derivatives and direct-acting oral ACs (DOACs). The mainstay medication in the treatment of coronary and cerebrovascular arterial disease is APT and the most frequently used regimen is a combination of aspirin and an ADP-receptor-antagonist (dual APT [DAPT]). The number of cirrhotic patients treated with APT and ACs is growing.138,139 There are few case reports describing use of APT during LT.140,141 The administration of these medications in the LT setting can potentially shift the balance towards bleeding that is difficult to control.

APT

The American College of Cardiology-American Heart Association recently published recommendations for the management of patients receiving APT undergoing elective, non-cardiac surgery.142,143 Aspirin and P2Y12 inhibitors are the most frequently used medications after therapeutic interventions. Aspirin (acetylsalicylic acid) suppresses the production of thromboxanes (TXA) in platelets by its irreversible inhibition of cyclooxygenase, which is necessary for TXA synthesis. TXA A2 increase expression of GP IIb/IIIa receptors what leads to the platelets activation with subsequent platelets aggregation.144

Clopidogrel and prasugrel are examples of P2Y12 receptor inhibitors. The P2Y12 receptor is an important component for ADP simulated activation of GP IIb/IIIa receptors.145 Blockade of P2Y12 receptors prevents connection with ADP with subsequent irreversible inhibition of platelets activation and aggregation. Clopidogrel is a prodrug that require a 2-step activation to produce active metabolites.146 This makes the action of clopidogrel less predictable in comparison to other P2Y12 receptors inhibitors. The effect of clopidogrel seems not to be affected by ESLD.147 Prasugrel is activated in 1 step with a greater availability of active metabolites at receptors.148 Ticagrelor and cangrelor (an intravenous agent) are direct P2Y12 receptor inhibitors with reversible action. They are more effective inhibitors of platelet aggregation than clopidogrel.149

Patients with stable coronary artery disease should receive P2Y12 inhibitors for at least 6 months after placement of a drug eluting stent and for 1 month after a bare-metal stent (Class I Recommendation). Low-dose aspirin therapy should be continued indefinitely. Elective surgery should be postponed for 30 days after bare-metal stent implantation and 6 months after drug-eluting stent implantation. Despite the known prevalence of CAD in LT candidates, the literature regarding the management of dual APT in LT patients with CAD undergoing LT is limited to case reports.140,141 Srivastava et al141 described a case of a live donor LT in which clopidogrel was stopped 1 week before LT and prophylaxis was maintained with enoxaparin administration. Enoxaparin was stopped 12 hours before transplantation and clopidogrel was restarted on the first postoperative day. Spieker et al140 reported a successful LT without discontinuing DAPT. In the absence of larger trials, no recommendation can be given as to managing DAPT.

ACs

Several types of venous thromboembolism (VTE) have been reported in patients with ESLD.120,122,150-152 It is well recognized that patients with ESLD are prone to hypercoagulation at each stage of transplantation. The incidence of VTE in patients with cirrhosis is between 0.5%153 and 8%.154 A higher 30-day mortality from PE alone has been demonstrated in patients with cirrhosis when compared to patients without (35 vs 16% respectively).155 The incidence of PVT in patients listed for LT is about 2%, but up to 4% in those transplanted.151 The incidence of all types of intraoperative thromboses has been reported to be between 1%114 and 6%156 and is usually associated with poorer outcomes. Posttransplant thrombotic complications including PVT (2%157) and HAT (over 6%158) are frequently associated with increased graft failure and mortality. The incidence VTE after LT is between 5% and 10 %.159 In addition, an association between preoperative PVT and postoperative thrombotic complications has been demonstrated.121,122 This predisposition to thromboses is the result of a persistent imbalance in the coagulation profile.

There are some subpopulations at higher risk for thromboses including patients with cirrhosis related to nonalcoholic steatotic hepatitis,120 autoimmune conditions,122 hepatitis C,160 and Budd-Chiari syndrome.161,162 Although few studies have investigated the effect of antithrombotic prophylaxis or treatment in these high-risk groups, one group of investigators demonstrated the effectiveness of antithrombotic therapy as a part of stepwise algorithm for the management of Budd-Chiari syndrome.163,164

Coumadin, DOACs, various forms of heparin, and fondaparinux have also been used in this patient population.139 Warfarin remains most commonly prescribed AC for the treatment and prophylaxis of VTE in cirrhotic patients.165 No specific recommendations regarding target INR in this patient population have been made. The rate of thrombus recanalization is commonly used as a measure of treatment effectiveness.150

Low molecular weight heparin (LMWH) has also been used for both prophylaxis and treatment of thromboses.166-168 The administration of LMWH does not impact a patient’s MELD score.167 The main disadvantage is a practical one; the need for subcutaneous injections. Villa et al166 in a small prospective randomized, but not blinded, investigation found that prophylactic administration of low-molecular-weight heparin (LMWH) (4000 U/day) was associated with decreased de novo PVT development, decreased incidence of hepatic decompensation, and better survival. There was no difference in bleeding complications between groups. In a study of 28 patients treated with 200 U/kg per day of enoxaparin for 6 months, Amitrano et al167 demonstrated complete or partial recanalization of the portal vein in 33% and 50% of patients respectively. In all studies, the use of LMWH was not associated with an increased incidence of bleeding.169,170

The few reports evaluating the effect of aspirin prophylaxis on bleeding (mostly postoperative studies) generally agree there was no increase in bleeding complications.171-173

New DOACs are now available for clinical use. They include the factor IIa inhibitor dabigatran and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban. Experience with these type of medications is limited in patients with cirrhosis.174 In a retrospective study, De Gottardi et al175 demonstrated that the use of DOACs in cirrhotic patients with splanchnic vein thrombosis was safe and effective. The safety profile of their use in patients with ESLD has to be further evaluated.

Deceased donor LT is usually performed on an urgent basis which does not allow time for effective preoperative withdrawal or bridging APT and/or ACs. For this reason, compounds providing fast offset of action and rapid reversibility may be preferable. In this setting, APT and ACs should be discontinued immediately at the time of organ offer. Various strategies for reversing the effects of APTs and ACs have been proposed, but little data specifically refer to LT patients.176,177

The usefulness of conventional coagulation testing varies with each specific medication and specific assays are frequently necessary.177 New VET modalities that include platelet function are under evaluation. Impedance aggregometry measures platelet function in whole blood. The cause of decreased platelet aggregation can be determined with ROTEM by using ADPTEM (for clopidogrel inhibition), TRAPTEM (GP IIb/IIIa antagonist), and ARATEM (ASS) tests. Similar tests are available for the Multiplate (lyophilized preparation of arachidonic acid [ASPI] test, adenosine 5'-diphosphate [ADP] test, thrombin receptor activating peptide [TRAP], and ristocetin [RISTO]). The RISTO test is unique in that it provides a quantitative in vitro determination of vWF- and GP Ib-dependent platelet aggregation in whole blood. TEG also offers a similar test, the ADP platelet mapping assay.

Recommendations for coagulation testing and reversal of APTs and ACs are summarized in Table 3. Even though most publications have a level of evidence of I/II, B/C, the majority of recommendations are not from the field of LT.

TABLE 3
TABLE 3:
Recommendations for reversal of antiplatelet and AC therapy

CONCLUSIONS

Coagulation management during LT is complex and cannot be reduced to merely treating bleeding. Extensive research has caused a paradigm shift in our understanding of coagulation in cirrhotic patients which has resulted in an appreciation that hypercoagulability is associated with ESLD. Transplant centers are providing care to a wider variety of patients presenting with comorbidities that would have previously excluded them from transplantation. Many of these patients present now receive anti-AC and/or and anti-platelet therapy affecting perioperative coagulation management strategies. VET allows a more rapid and dynamic assessment of coagulation and helps guide transfusion therapy in LT. Future advances in the coagulation management of patients for LT will likely include genetic analysis and result in the introduction of strategies for perioperative anticoagulation in susceptible patients.

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