A Novel Framework for Factor Replacement in Patients Undergoing Liver Transplantation for End Stage Liver Disease

doi:10.21203/rs.3.rs-7982596/v1

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A Novel Framework for Factor Replacement in Patients Undergoing Liver Transplantation for End Stage Liver Disease

https://doi.org/10.21203/rs.3.rs-7982596/v1

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Background

The management of coagulopathy and rebalanced hemostasis in end-stage cirrhosis is challenging. Additionally, a certain subset of patients presenting for transplant may have additional acquired or inherited coagulation disorders in addition to liver disease. In patients with these coagulation disorders, there is no updated guidance for isolated factor replacement. Inspired by a case at our institution, we conducted a pilot study to propose a framework to develop a goal-directed dosing strategy for factor repletion in patients presenting for liver transplantation.

Methods

To determine the level of coagulation factors and the between and within patient variation, factors FVII, FIX, FX, Antithrombin (AT), Protein C (PC), and Protein S (PS) were measured in 41 patients with end stage liver disease and undergoing liver transplantation.

Results

Coagulation factor data was collected from forty-one patients presenting for liver transplantation. The median level of all measured coagulation factors was below 80% (range 26–76%). The median levels varied widely in studied population (2.1-fold median interquartile range). Notably, measured levels of FIX were strongly correlated with other factors in individual patients: FIX versus FVII (R = 0.81, p < 0.001), FX (R = 0.74, p < 0.001), AT (R = 0.77, p < 0.001), and Protein C (R = 0.86, p < 0.001).

Discussion

Considering that the median levels were below 80%, for all factors, that levels varied widely among patients, and that levels were highly intercorrelated in an individual patient, it seems appropriate to propose and alternative and empiric target when substituting FIX in patients with hemophilia B before undergoing liver transplantation. We propose the average level of a set of highly inter-correlated coagulation factors as an empiric target when determining goal level for factor repletion.

Hemophilia

Liver Transplant

Coagulation

Bleeding

HIV infection

Cirrhosis

Intra-cardiac thrombus

Perioperative management of coagulopathy in end stage liver disease (ESLD) is complex due to rebalanced hemostasis and can result in both severe bleeding and life-threatening thrombosis. Anesthesiologists play a crucial role in coagulation management in the perioperative period. Thromboembolic events during liver transplantation, such as intracardiac, portal venous, or hepatic arterial thrombosis, can result in graft loss, significant morbidity, and mortality. The incidence of intracardiac thrombosis in liver transplantation has been reported to be between 0.7% and 6.25%, and risk of pulmonary embolism between 0.4% and 4% [1, 2]. The intraoperative mortality due to thrombotic events is between 30 and 70%, with an overall mortality of 45% to 80% [2].

The management of rebalanced hemostasis in end-stage cirrhosis is challenging. Patients with ESLD have rebalanced hemostasis resulting in a marked decrease in procoagulant factors except Factor VIII. At the same time, anticoagulant factors produced by the liver including protein C, protein S, and antithrombin III are also decreased [2]. Additionally, there is decreased clearance of activated factors, hyperfibrinolysis, increased von Willebrand Factor, and both quantitative and qualitative platelet defects. Common strategies for assessing adequate factor repletion in liver transplantation include coagulation laboratory testing and viscoelastic testing, as well as surgical field visualization. Coagulation factors are typically replenished by transfusion of fresh frozen plasma (FFP) and cryoprecipitate; however, there may also be some utility in individual factor concentrates as well as prothrombin complex concentrates [3, 4].

Additionally, a certain subset of patients presenting for transplant may have additional acquired or inherited coagulation disorders in addition to the coagulation disorders of liver disease including Hemophilia or Von Willebrand Disease (vWD). In a study done by Yokoyoma et al., between 1994 and 2008, of the 3800 patients who underwent liver transplantation at King’s College, 18 (0.47%) also had hemophilia [5]. This included 13 patients with Factor VIII deficiency, 4 patients with Factor IX deficiency, and one patient with Factor X deficiency. In addition to alterations due to decreased liver factor synthesis, these patients will require additional isolated coagulation factor replacement.

Recommendations for hemophilia therapy typically entails determining the activity level of the deficient factor in question while assuming the other factor levels remain within normal limits, which may not be the case in the population of patients presenting for liver transplantation. Factor concentrate supplementation is controversial – guidelines from the American Association for the Study of Liver Disease (AASLD) state that efficacy and safety data are lacking for the use of prothrombin complex concentrates (PCC) targeting procoagulant deficiency in patients with liver disease [6], while the International Society on Thrombosis and Haemostasis goes further and states that PCC should be avoided entirely in the periprocedural setting [7]. Concomitant coagulation disorders such as hemophilia introduce another level of complexity – the World Federation of Hematology [8] recommends repletion of deficient factors to 80–100% of normal levels, and has no specific recommendations for dose reduction in cirrhosis, despite the fact cirrhosis is a known risk factor for thrombosis with factor administration.

To determine factor replenishment, the World Federation of Hematology recommends trough level determination of the deficient clotting factor prior to major surgery and replenishment to target serum levels of 80 to 100% of normal levels [8, 9]. No specific recommendations exist for hemophilia patients with end-stage liver cirrhosis who have decreases in both procoagulant and anticoagulant factors, leading to a crucial gap in this population when presenting for liver transplantation. Currently, only case reports exist describing individual institution management of factor repletion during transplant. In a review of several living donor liver transplant recipients by Togashi et al., the targeted clotting factor level was 120% from the start of transplantation until reperfusion⁹. Patients received a single bolus of 50 IU/kg of the deficient factor and then the infusion was titrated to clotting factor activity and activated partial thromboplastin time (aPTT). Another case report describes a 39-year-old who received 80 unit/kg bolus preoperatively for a baseline Factor IX of 12% prior to surgery, and thromboelastography was subsequently used to guide blood product transfusion [10]. Despite this replacement, the patient experienced severe hemorrhage during the case requiring massive transfusion of > 20 units as well as a takeback to the operating room for bleeding to gain hemostasis. Another transplant group who had a patient with severe hemophilia A present for transplant used an intrinsic stimulated thromboelastometry assay to create a prediction model to strategize Factor VIII repletion [11]. Kamyszek, et al. presented a case of a transplant of a patient with hemophilia A, recombinant Factor VIII was infused to target a concentration of 50% to 80% [12].

A patient presented for liver transplant with a history of nonalcoholic steatohepatitis and hemophilia B, maintained on a stable outpatient regimen of recombinant Factor IX following standard recommendations from hematology, targeting 100% serum levels of Factor IX as needed for bleeding episodes and prior to major procedures. Preoperative labs were notable for hemoglobin 8.2 g/dL, platelets 71,000/microliter, INR 2.8, and MELD-Na 34. Factor IX level was 9.6% preoperatively prior to supplementation.

After uneventful induction of anesthesia, arterial and central venous access was obtained, and transesophageal echocardiography (TEE) was performed. 9,000 units of Factor IX were administered 30 minutes prior to incision, per standard hematologic guidelines for patients with hemophilia. A subsequent thromboelastogram (TEG® 5000, Haemonetics Corporation, Boston, MA, USA) showed an R time of 6.2 minutes, an alpha angle of 51.1 degrees, and a maximal amplitude of 34.0 millimeters, suggesting adequate factor activity, slightly deficient fibrinogen activity, and moderately deficient platelet activity. One unit of platelets and ten pooled units of cryoprecipitate were administered for subjective oozing in the surgical field.

Shortly after initiation of portal-internal jugular bypass and removal of the liver, the patient became acutely hypotensive and hypoxic; a large amount of mobile clot was noted in the right atrium on TEE. Epinephrine and vasopressin were administered, and the clot migrated to the right pulmonary artery with improvement in hemodynamics, hypoxia, and right heart strain. The decision was made to proceed with the case, the remainder of which was uneventful. Factor IX level was 50.6% after liver reperfusion, with TEG® R time 8.8 min, angle 41.7 deg, MA 33.8 mm, and lysis 43.5%. This correlated with adequate clinical hemostasis in the surgical field with self-limiting fibrinolysis, so neither Factor IX nor antifibrinolytics were re-dosed.

While both the patient and graft survived the operation and are doing well over two years later without major sequelae, this event raised the question of how to best replete isolated factors in patients with liver disease and rebalanced hemostasis.

With this clinical context, we sought to obtain pilot data and propose a framework to develop a goal-directed dosing strategy for coagulation factor repletion in patients presenting for liver transplantation.

This pilot project was conducted at Stanford Medicine to better understand the coagulation factor profile of adult patients with cirrhosis presenting for liver transplantation. All data was collected by retrospective chart review. The Stanford University Institutional Review Board (Stanford, CA, USA) (IRB #61845) determined that the study met the criteria for a waiver of informed consent. The study was conducted in compliance with the Declaration of Helsinki and this manuscript adheres to the applicable Standards for Quality Improvement Reporting Excellence (SQUIRE 2.0).

Adult patients presenting for liver transplantation were eligible for inclusion. Data collection occurred between June and December 2024. Blood samples were drawn as part of standard pre-operative laboratory work. Coagulation Factors VII, IX, X, as well as Antithrombin III, Protein C, and Protein S were evaluated before surgical incision. No patients received factor or fibrinogen concentrates. These laboratory tests were selected due to their altered levels in liver disease, and all tests were run at Stanford Medicine Anatomic Pathology & Clinical Laboratories (Stanford, CA, USA). Patient data were retrospectively extracted from electronic health records. Sigma Plot version 15 (Grafiti Inc., Palo Alto, CA, USA) was used for descriptive statistics, Pearson correlation analysis, and the calculation of prediction errors.

Forty-one patients with an age range of 45 to 64 years (median 59 years) presented for transplant. Twenty-five patients were male, and twelve were diagnosed with hepatocellular carcinoma. The most common indications for LT were alcoholic cirrhosis (15), nonalcoholic steatohepatitis (11), viral hepatitis (5), and liver metastases (3).

Coagulation laboratory results are presented in Table 1. Strong positive correlations were detected between Factor IX and Factor VII (R = 0.81, p < 0.001), Factor X (R = 0.74, p < 0.001), antithrombin (R = 0.77, p < 0.001), and Protein C (R = 0.86, p < 0.001) (Fig. 1). The correlation between Factor VII and Protein S level was moderate (R = 0.41, p = 0.009). The median error for predicting Factor IX levels based on the measured levels of Factor VII, Factor X, antithrombin, and Protein C ranged from 14–20% as shown in Fig. 2. Moderate negative correlations were detected between the Model for End Stage Liver Disease (MELD-Na) scores and Factor VII (R = -0.60, p < 0.001), Factor IX (R = -0.49, p = 0.001), Factor X (R = -0.53, p < 0.001), antithrombin (R = -0.56, p < 0.001), and Protein C (R = -0.57, p < 0.001). No significant correlation was detected for Protein S. In this cohort, no major thrombotic complications occurred in the perioperative period, including intracardiac thrombus, pulmonary embolus, hepatic artery thrombosis, or deep vein thrombosis.

Table 1

Laboratory parameters¹
Factor VII (%) Factor IX (%) Factor X (%) Antithrombin 3 (%) Protein C (%) Protein S (%) Plasma INR Plasma creatinine (mg/dl) Plasma bilirubin total (mg/dl) Plasma sodium (mmol/l) TEG² R time (min) TEG angle (degree)	26 (15–54) 55 (42–81) 48 (45–63) 45 (32–72) 34 (17–61) 76 (61–94) 1.5 (1.2–1.9) 1.0 (0.7–1.3) 3.2 (1.1–8.9) 135.0 (131.0-139.0) 4.9 (3.8–5.7) 67.1 (57.6–71.0)
TEG maximum amplitude (mm)	54.6 (50.6–61.4)
1) Values represent median and interquartile range
2) Thromboelastogram

Based on our preliminary findings, we propose a novel framework for determining target coagulation factor levels in patients with ESLD before liver transplantation. There was a strong correlation between measured coagulant and anticoagulant levels (except Protein S), with median prediction errors ranging from 14–20%. This suggests that targeting measured levels of these highly correlated factors may be more appropriate than targeting levels of 100% when replenishing factors prior to the start of the case.

To our knowledge, this is the first report of a cohort of patients presenting for liver transplantation with preoperative measurements of coagulation Factors VII, IX, X, antithrombin, Protein C, and Protein S levels. Our findings are compatible with the pathophysiology of liver disease, wherein patients experience decreases in both procoagulant and anticoagulant factors, and as such, repletion of one specific coagulation factor to 100% may increase the risk for thrombotic complications. Importantly, perioperative thrombotic complications can be more difficult to address than hemorrhagic complications, resulting in reoperation for large vessel thrombosis, graft failure, intracardiac thrombosis, pulmonary embolism, re-transplantation, and/or recipient mortality.

In small case series and case reports regarding patients with ESLD and hemophilia, various management strategies have been proposed, including viscoelastic testing, factor activity levels, as well as surgical field visualization [9–12]. However, standard dosing of factor concentrates has not been agreed upon for this population. This is relevant for patients who not only have coagulopathy of liver disease but also have pre-existing bleeding disorders, such as hemophilia.

Factor replenishment is of course associated with thrombosis, being the primary warning on their usage included in some of the package inserts. At our institution, we experienced a case of patient with hemophilia B and cirrhosis who underwent liver transplantation. The case was complicated by intracardiac thrombus. Our institution has performed hundreds of liver transplantations with veno-venous bypass and portal vein to internal jugular venous bypass over the years. The incidence of inappropriate clotting during the case raised the question of the necessity of repletion of isolated factors to 100% or greater, when patients with end stage cirrhosis are known to lack factors manufactured by the liver.

We found that measured clotting factors were generally lower than 80% in the studied population, while the extent of the decrease varied widely among patients. In our cohort, 75% of patients with cirrhosis had Factor IX activity levels well below 80% of normal, with concomitant decreases in Factor VII, Factor X, Protein C, and antithrombin. Most importantly, though, was the observation that the decrease in individual factors was highly inter-correlated in individual patients, which would allow using the average level of measured clotting factors as the empiric target. Using the prediction errors as a metric of accuracy of our correlation plots, a median prediction error of 14% and a maximum error of 30% for AT3 is quite remarkable. It may be possible to utilize these lab values as surrogate markers to define a repletion target level when administering factor concentrates.

Commonly utilized laboratory measures of hemostasis have limitations in liver disease. They do not account for variables such as volume status, platelet dysfunction, renal function, or liver synthetic function [13]. The volume associated with transfusion of fresh frozen plasma and platelets can have the secondary effect of increasing portal venous pressure and contributing to bleeding and variceal bleeding.

Limitations to this quality improvement project include our sample size and distribution of severity of disease. There were a limited number of individuals who were in decompensated liver failure requiring ICU admission pre-operatively. Several individuals had MELD exception points, which meant that they had less severe disease and therefore would expect laboratory values in the normal range. We do not measure factor levels intraoperatively or postoperatively due to cost considerations, also we are not able to do any longitudinal follow up of factor levels due to the same financial constraints.

Despite our limited sample size, our data suggests the possibility of using a subset of coagulation factor levels as a guide to determine an individualized target for individual factor repletion in patients with coagulation disorders in addition to end-stage cirrhosis such as Hemophilia. Due to the rarity of patients with both hemophilia and cirrhosis, multi-centered studies would be necessary in the future to better characterize the optimal treatment strategy.

We hope that this small pilot study will provide a new framework to help guide coagulation management for the small, but important subset of patients with inherited or acquired coagulation disorders. These data are most useful in guiding pre-operative optimization of factors given the turnaround time of these labs. It can also be used in ESLD patients with high MELD scores, or in intensive care units prior to transplantation to help with coagulation management during dissection and reduce volume status changes. Liver transplantation is curative for patients with certain congenital factor deficiencies; however, due to the low incidence of liver transplantation in this population, it has been difficult to make recommendations for management beyond case reports. Larger, multi-institution studies are needed to better understand these coagulation deficiencies among patients with cirrhosis and coagulation disorders.

Clinical Trial Number

Not Applicable

Ethics approval and consent to participate:

This pilot study underwent review (#64815) by the Stanford University Institutional Review Board (Stanford, CA, USA) which determined that retrospective chart review qualifies for waiver of informed consent. Informed consent was not needed from participants. All organs were from deceased donors and allocated per the United Network for Organ Sharing in the United States. The organs were NOT procured from prisoners.

Consent for publication:

not applicable

Funding:

Not applicable

Author Contribution

- Dr. Ruan: Contributed to concept/design, data collection, data analysis/ interpretation, writing and editing of manuscript- Dr. Zhou: Contributed to data collection, data analysis/ interpretation, writing and editing of manuscript- Dr. Panigrahi: Contributed to critical revision of manuscript- Dr. Angst: Contributed to concept/design, data analysis/ interpretation, critical revision of article

Acknowledgement

The authors would like to thank Dr. David R. Drover for his assistance with editorial support of the article.

Data Availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

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No competing interests reported.

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A Novel Framework for Factor Replacement in Patients Undergoing Liver Transplantation for End Stage Liver Disease

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