The impact of low preoperative fibrinogen level on intraoperative blood products requirements during liver transplantation with surgical vena cava preservation technique: a retrospective cohort study.

doi:10.21203/rs.3.rs-1644806/v1

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The impact of low preoperative fibrinogen level on intraoperative blood products requirements during liver transplantation with surgical vena cava preservation technique: a retrospective cohort study.

https://doi.org/10.21203/rs.3.rs-1644806/v1

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Background

Hypofibrinogenemia is commonly found in patients with end stage liver disease and may increase blood transfusion during liver transplantation. In this study, we aim to identify the impact of preoperative hypofibrinogenemia on blood products transfusion requirements during liver transplantation recipients performed with surgical vena cava preservation technique.

Methods

This retrospective cohort study included 123 patients who underwent liver transplantation with surgical vena cava preservation technique between January 2016 through December 2019 in a tertiary hospital in Saudi Arabia. The study population was divided into two groups based on preoperative fibrinogen levels: normal (>1.5 g/L) vs low (<1.5 g/L). The primary endpoint was total requirements of blood products transfused intraoperatively. Secondary endpoints were total length of intensive care unit (ICU) and hospital stay. Mann-Whitney U test was used to measure differences between groups and Spearman rank test was used for correlation analysis.

Results

Forty (32.52%) patients out of 123 in the study had low (<1.5 g/L) fibrinogen level preoperatively. Preoperative hypofibrinogenemia was significantly associated with increased requirements of packed red blood cells, platelets, cryoprecipitates, fresh frozen plasma and fibrinogen concentrate. Correlation analysis showed that preoperative fibrinogen levels negatively and significantly correlated with intraoperative blood products requirements (P< 0.001). Hypofibrinogenemia was weakly associated with length of ICU stay (Median= 3 days [Q1, Q3: 2, 5.50] days compared to 2 days [2.00, 4.00] in normal group, P= 0.049. Length of hospital stay was approximately similar between both groups.

Conclusions

Low preoperative levels of fibrinogen significantly correlate with increased blood products requirements during liver transplantation with surgical vena cava preservation technique. Guided by preoperative fibrinogen levels, this study proposes that correction of fibrinogen levels before liver transplantation may reduce the need for transfusion of larger amounts of blood products.

Fibrinogen

Hypofibrinogenemia

blood transfusion

liver transplantation

Preoperative fibrinogen

Surgical vena cava preservation

Massive bleeding and massive transfusion of blood products are common in liver transplantation. Transfusion of red blood cells occurs in 20–86% of Liver transplantation [1–4]. Despite the significant advancement in both surgical technique and anaesthetic management of liver transplantation,10–20% of patients require large transfusion volume of blood and blood products. Risk factors associated with higher incidence on increased blood products requirements are surgical technique, pre-existing coagulopathy as a result of end stage liver disease (ESLD), anti-fibrinolytic therapy and preoperative haemoglobin level [5–8].

Fibrinogen, a procoagulant factor, is synthesized in the liver and circulates in the plasma at 1.5–4.5 g/L concentration [9–11]. Hypofibrinogenemia and dysfibrinogenemia are commonly found in candidates for liver transplant [12–14]. Hypofibrinogenemia stimulates blood product requirements intraoperatively. Clevenger et al, reported that 100 % of livertransplantation patients will experience hyperfibrinolysis during liver transplantation with baseline Extem maximum amplitude of < 35 mm on thromboelastometry and fibrin degradation products > 48 mg/L. Furthermore, haemodilution and massive bleeding happen during liver transplantation affect fibrinogen level which may reaches critical low levels [15, 16].

Currently, the guidelines about perioperative fibrinogen level that should be maintained to minimize bleeding remain unclear. While international guidelines recommend fibrinogen levels of 1.0 g/L or more to obtain normal values of standard laboratory tests (PT and PTT), higher fibrinogen levels of (1.5 to 2.0 g/L) are recommended by the European guidelines [17, 18]. Fibrinogen administration guided by thromboelastometry is most commonly used as a point-of-care method to treat low fibrinogen levels intraoperatively. However, there is a lack of evidence that support early administration of fibrinogen to reduce surgical bleeding [19, 20]. In the current study, we assessed the relationship between preoperative hypofibrinogenemia during liver transplants performed with surgical vena cava preservation technique with intraoperative blood products transfusion requirements and postoperative length of hospital and ICU stay.

Setting and study design

This retrospective, single-centre, cohort study was performed to investigate the relationship between preoperative fibrinogen levels and intraoperative blood products requirements in liver transplantation recipients performed with surgical vena cava preservation technique. For this purpose, we reviewed all adult patients who underwent liver transplantation at King Abdulaziz Medical City, Riyadh, Saudi Arabia, over a 4-years period (January 2016 through December 2019). The study was approved by the Institutional Review Board (IRB) at King Abdullah International Medical Research center (KAIMRC). Informed consent was waived by the IRB because of the retrospective nature of the study.

Study population

A total of 138 adult patients (>18 years) underwent liver transplant recipient with surgical vena cava preservation technique over the study period. Cases were selected according to a propensity matching analysis meeting the following inclusion criteria: liver transplantation with surgical vena cava preservation technique, preoperative haemoglobin range between 90 to 120 g/L, platelets count >50 x10⁹/L and international normalized ratio (INR) < 2.0. Patients meeting one of the following criteria were excluded from the study: traditional liver transplant using vena cava resection technique, preoperative haemoglobin level <90 g/L, preoperative haemoglobin level >120 g/L, preoperative platelets count <50 x10⁹/L, Preoperative INR >2, existence of preoperative haematological disorder, and missing of preoperative plasma fibrinogen values.

Study outcomes

The study cohort was divided based on preoperative fibrinogen level into two groups: normal fibrinogen level (>1.5 g/L) group and hypofibrinogenemia (<1.5 g/L) group. Our primary outcome was total blood products transfused intraoperatively in normal fibrinogen level group compared to hypofibrinogenemia group. Preoperative fibrinogen was measured within 24 hours before surgery. Our secondary outcome was postoperative length of stay in ICU and hospital in normal fibrinogen level group compared to hypofibrinogenemia group.

Data collection

For all patients, demographic and clinical variables were collected from the patients’ electronic medical records. These include age, gender, Model for End-stage Liver Disease (MELD) score, surgical time, anaesthesia time, postoperative length of intensive care unit (ICU) stay and total length of hospital stay. Multiple preoperative laboratory data including fibrinogen, haemoglobin, platelets and clotting tests were recorded. Total number of transfused blood products units intraoperatively was also recorded. These include packed red blood cells (PRBCs), fresh frozen plasma (FFP), platelets, cryoprecipitates and fibrinogen concentrates.

Statistical analysis

Data were assessed for normality using Shapiro-Wilk test. Continuous data were reported as median and (first and third quartiles). Categorical variables were reported as number (%). Differences in medians of continuous variables between two groups were assessed by Mann-Whitney U test. Correlations between preoperative fibrinogen levels and intraoperative blood products requirements were evaluated using Spearman rank test. Statistical analysis was performed using SPSS (version 28). A P value (two-tailed) of less than 0.05 was considered statistically significant.

Patient characteristics

One hundred and thirty-eight patients received a liver transplantation surgery during the study period. patients were excluded due to incomplete data (n = 14) and death during surgery (n = 1). A total of 123 patients were analysed (Fig. 1).

Demographic and clinical characteristics of the entire study population are summarised in Table 1. Recipients of liver transplantation had a median age of 58 years [Q1, Q3: 53.00, 63.00] and a median MELD score of 21 [15.00, 24.00]. The median preoperative fibrinogen level was 1.86 g/L [1.40, 2.46]. In 123 liver transplantation procedures, administration of blood products was as follows: PRBCs was administered in 112 (91.1%) patients with median amount of 6 units [2.00, 10.00], 75 (61%) patients received platelet concentrates with median amount of 6 units [0.00, 12.00], 86 (69.9%) patients received cryoprecipitates with median amount of 10 units [0.00, 30.00], 91 (74%) patients received FFP with median amount of 4 units [0.00, 6.00] and 90 (73.4%) patients received fibrinogen concentrate with median concentration of 4.00 g [0.00, 8.00].

Table 1

Demographic and clinical characteristics of study cohort

Characteristic	All patients (n=123)
Age (years), median [Q1, Q3]	58.00 [53.00, 63.00]
Gender (male), n (%)	80 (65)
MELD score, median [Q1, Q3]	21.00 [15.00, 24.00]
Preoperative laboratory values, median [Q1, Q3]
Fibrinogen (g/L)	1.86 [1.40, 2.46]
Haemoglobin (g/dl)	107.00 [90.00, 121.00]
Platelets (x10⁹/L)	82.00 [63.00, 128.00[
INR	1.40 [1.24, 1.69]
PT (seconds)	15.10 [13.50, 18.20]
PTT (seconds)	32.90 [30.10, 38.70]
Intraoperative blood products, median [Q1, Q3]
PRBCs (units)	6.00 [2.00, 10.00]
Platelets (units)	6.00 [0.00, 12.00]
Cryoprecipitates (units)	10.00 [0.00, 30.00]
FFP (units)	4.00 [0.00, 6.00]
Fibrinogen concentrate (g)	4.00 [0.00, 8.00]
Anaesthesia time (hours)	10.00 [8.39, 11.47]
Surgical time (hours)	8.35 [7.00, 10.07]

MELD: Model for End-stage Liver Disease; INR: international normalized ratio; PT: Prothrombin time; PTT: Partial thromboplastin time; PRBCs: packed red blood cells; FFP: fresh frozen plasma; g/L: gram per litre; g/dl: gram per decilitre; Q1, Q3: first and third quartiles. Data are expressed as medians with Q3 and Q1 or number (%).

Primary outcome

Out of 123 patients, 40 (32.5%) had preoperative hypofibrinogenemia. As shown in figure 2A, the median preoperative level of fibrinogen in normal group (>1.5g/L) was 2.14 g/L [Q1, Q3: 1.85, 2.80] compared to 1.17 g/L [0.92, 1.39] in hypofibrinogenemia group (<1.5g/L). In comparison to normal group, the amount of blood products transfusion was significantly higher in hypofibrinogenemia group (Fig.2B-F). The median requirements of respective blood products in hypofibrinogenemia group compared to normal fibrinogen group was as follow: 9 PRBCs units [6.25, 13.75] versus 5 [2, 8]; P< 0.001, 12 platelets units [6, 22] versus 6 [0, 12]; P< 0.001, 20 cryoprecipitates units [10, 40] versus 10 [0, 20]; P< 0.001, 6 FFP units [4, 10] versus 2 [0, 5]; P< 0.001) and 8g fibrinogen concentrate [4, 12] versus 4 [0, 8]; P= 0.002.

Potential correlations between preoperative fibrinogen levels and intraoperative blood products transfusion requirements were also investigated. As shown in figure 3, preoperative fibrinogen levels were inversely and significantly correlated with intraoperative transfusion of PRBCs, platelets, cryoprecipitates, FFP and fibrinogen concentrate (all P< 0.001).

Secondary outcomes

The comparison of ICU length of stay (3 [2, 5.50] vs 2 [2, 4]) showed that it was higher in the hypofibrinogenemia group than in the normal fibrinogen group (P= 0.049). However, no significant difference in length of hospital stay was observed between the two group (Table 2).

Table 2

Association between preoperative fibrinogen levels and postoperative length of ICU and hospital stay

All patient

(n= 123)

Hypofibrinogenemia group (<1.5 g/L)

(n=40)

Normal fibrinogen group (>1.5 g/L)

(n=83)

P-value

Length of ICU stay (days), median [Q1, Q3]

2.00 [2.00, 4.00]

3 [2, 5.50]

2 [2, 4]

0.049

Length of hospital stay (days), median [Q1, Q3]

13.00 [10.00, 18.00]

14 [10, 19.75]

13 [10, 18]

0.477

ICU: intensive care unit; n: number; Q1, Q3: first and third quartiles.

In this study, we evaluated the association between the preoperative fibrinogen levels and intraoperative blood products transfusion requirements in liver transplantation recipients performed with surgical vena cava preservation technique. We found that elevated intraoperative requirements of blood products were significantly associated with preoperative hypofibrinogenemia. In addition, there was a significant inverse correlation between preoperative fibrinogen levels and intraoperative requirements of blood products. The elucidation of preoperative hypofibrinogenemia as a contributing factor to increased intraoperative blood transfusion requirements could bridge important clinical utility in liver transplantation.

Despite the clinical benefits of blood products transfusion, their deleterious impact on outcomes is well-known in liver transplant recipients [21–25]. The effect of platelets transfusion during liver transplantation has been identified as a significant prognostic factor for patient survival and graft loss [26–28]. Furthermore, the transfusion of more than five units of packed PRBCs is associated with a higher morbidity and mortality rate [29]. Thus, minimizing transfusion of blood products should enhance patients’ outcome. However, several preoperative factors could influence blood products transfusion requirements during liver transplantation [30–33].

In the current study, we assessed the relationship between low preoperative fibrinogen level and the amount of intraoperative blood products transfused for patients undergoing liver transplantation. The effect of other contributing factors including preoperative haemoglobin level, platelets count, and surgical technique were considered when the study’s cohort was selected. Our findings showed that the requirements of intraoperative transfusion of PRBCs, platelets, FFP and cryoprecipitate significantly correlate with preoperative fibrinogen level below 1.5 g/L. Costa and colleagues found that preoperative fibrinogen levels is associated with blood product transfusion in liver transplantation. Although their findings are consistent with our results, their cut-off value of fibrinogen level was 2 g/L with no correlation analysis [34].

Blood transfusion is a critical determinant of prolonged hospital and ICU length of stay [35, 36]. Our findings demonstrated an increase in length of ICU stay in the group with low fibrinogen level. However, we did not observe any differences in hospital length of stay. Nevertheless, our study should be interpreted in the context of several limitations. It was conducted in a single centre retrospectively. Although the association between preoperative hypofibrinogenemia and increased blood products transfusion was observed in our study, the causal relationship should be elucidated by future prospective studies. In other words, whether interventions to correct preoperative hypofibrinogenemia can reduce the requirement for blood products during surgery needs to be elucidated.

This study demonstrates that intraoperative blood transfusion requirements increase when surgical patients had a preoperative fibrinogen level less than 1.5 g/L. Therefore, this may affect the overall patient’s outcomes. Our study has highlighted the value of normal preoperative plasmatic fibrinogen in minimizing blood transfusion requirements.

ICU: Intensive care unit

ESLD: End stage liver disease

MELD: Model for End-stage Liver Disease

INR: international normalized ratio

PT: Prothrombin time

PTT: Partial thromboplastin time

PRBCs: packed red blood cells

FFP: fresh frozen plasma

Ethical approval and consent to participate

This study was approved by the Institutional Review Board at King Abdullah International Medical Research Centre (IRBC/ RC19/057/R). All data analysed in this study was retrieved from electronic health records of the patients via the hospital’s data system. Therefore, the need for informed consent was waived by the IRB due to the retrospective design of this study. All the methods used in this study were performed in accordance with regulations and guidelines of our institution and Helsinki declaration.

Consent for publication

Not applicable

Availability of data and materials

The data that support the findings of this study are available from King Abdullah International Medical Research Centre but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the corresponding author (AS) upon reasonable request and with approval of King Abdullah International Medical Research Centre.

Competing interests

The authors declare that they have no competing interests

Funding

This study was funded by King Abdullah International Medical Research Centre’s (KAIMRC), Saudi Arabia.

Authors’ contribution

AS: Conceptualisation, proposal writing, funding acquisition. MA: data analysis, manuscript writing, manuscript editing and review. RA: proposal writing, data collection. SA: manuscript writing. LO: manuscript writing, manuscript editing and review. FA: proposal writing, data collection. MA: manuscript editing and review. All authors read and approved the final manuscript.

Acknowledgements

Not applicable

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No competing interests reported.

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The impact of low preoperative fibrinogen level on intraoperative blood products requirements during liver transplantation with surgical vena cava preservation technique: a retrospective cohort study.

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