Research ArticleFresh frozen plasma transfusion in patients with cirrhosis and coagulopathy: Effect on conventional coagulation tests and thrombomodulin-modified thrombin generation
Graphical abstract
Introduction
Over the last decade there has been considerable progress in understanding the complex mechanisms behind the coagulopathy of cirrhosis. Landmark studies have demonstrated that there is a substantial balance between pro- and anticoagulant factors in cirrhosis. Despite preserving normal thrombin generation, this balance is relatively unstable and prone to tip towards hemorrhage or thrombosis, depending on the prevailing circumstantial risk factors to which patients are exposed.[1], [2] In this process, factor VIII, an endothelial-released coagulation factor (typically increased in cirrhosis) to some extent counteracts the decline of the other procoagulant factors synthesized by the liver. As the levels of the naturally occurring anticoagulants are also decreased in cirrhosis, the anticoagulant effect of protein C, protein S and antithrombin on thrombin generation is attenuated when compared to normal individuals.3 Indeed, it has been shown in vitro that plasma of patients with cirrhosis may generate adequate thrombin amounts when exposed to tissue factor and exogenous phospholipids, provided that plasmatic protein C is activated by its main physiological activator, thrombomodulin (TM).[3], [4]
Despite abnormal results of conventional coagulation tests, patients with cirrhosis are not ‘auto-anticoagulated’, as was previously believed. Conversely, some are at risk of venous thromboembolism when compared to the general population of non-cirrhotic individuals, because the balance may shift toward the production of higher than normal amounts of thrombin and hypercoagulability.[4], [5], [6] Conventional coagulation tests such as the prothrombin time (PT) and activated partial thromboplastin time (aPTT) are based on clot formation as an endpoint, which occurs when approximately 5% of thrombin is generated.7 Therefore these tests are suitable for assessing the procoagulant arm of coagulation, but fail to fully assess its anticoagulant counterpart.4 Furthermore, TM is not added to these tests to mimic the endothelial activation of the protein C pathway. Therefore, PT and aPTT are not reliable indicators of in vivo thrombin generation, so they are not suitable for investigating coagulopathy in cirrhosis and guiding transfusion policy.
However, it is still common practice to attempt to correct the deficiency of coagulation factors, suggested by PT/international normalized ratio (INR) and aPTT, with fresh frozen plasma (FFP) transfusions before invasive procedures or to control ongoing bleeding events. This practice is illustrated by a nationwide British study that collected data from 85 hospitals over a 28-day period, which showed that 30% of the patients with cirrhosis were transfused with at least one blood component during their admission to the hospital, and that FFP was prescribed in nearly 30% of cases.8 Similar figures were observed in a survey in the United States, showing that patients with cirrhosis consumed a disproportionate 32.4% of the units of FFP in a tertiary hospital, despite accounting for less than 8% of total hospital admissions.9
FFP has been used for many years on the assumption that patients with cirrhosis are at high risk of bleeding because they have frequent episodes of digestive hemorrhage and prolonged PT and aPTT. However, scarce data are available on the effect of FFP transfusions on thrombin generation to support biological plausibility and indiscriminate use. There are few published studies, and most provide insufficient evidence to make strong recommendations in this regard. Data from an in vitro study simulating the effect of transfusion by mixing samples of pooled normal plasma with plasma from patients with cirrhosis suggested that thrombin generation does not appreciably change after the addition of normal plasma, despite PT and aPTT shortening suggesting otherwise.10 Although the prohemostatic effect was small, a different in vitro study showed a difference in response to FFP transfusion in patients with acute-on-chronic liver failure (ACLF) compared to patients with acute decompensation of cirrhosis, compensated cirrhosis and healthy controls.11 This gives grounds to hypothesize that a very limited number of patients would benefit from FFP transfusion in real life settings, because thrombin generation is already expected to be preserved before transfusion in most patients with cirrhosis.
Our aim was to prospectively assess the effect of FFP transfusion on TM-modified thrombin generation procedures (this corresponds to the total amount of generated thrombin) in patients with cirrhosis and impaired conventional coagulation tests.
Section snippets
Patients
Patients with cirrhosis who were candidates for FFP transfusion were enrolled in the study. All patients were admitted to the University of São Paulo School of Medicine Hospital between August 2014 and January 2018. Two physicians interviewed and examined all patients prior to transfusion and 6 h after the administration of FFP to assess acute transfusion reactions. Bleeding events were assessed at the end of each procedure and daily for 5 days after inclusion during hospital stay. Any bleeding
Patients
Two-hundred and seventy-six patients were enrolled in the study, as shown in Fig. 1. Two-hundred and five patients were excluded during the screening phase of the study and 18 were secondarily excluded because they did not reach stable thrombin curves. These 18 patients had ACLF syndrome (n = 15; CLIF-C ACLF score of 12.3 ± 3.2; grade I n = 3, grade II n = 4, grade III n = 8), acute decompensation of cirrhosis (n = 2), active bacterial infections (n = 15) and shock (n = 7).
After exclusions, 53
Discussion
Over the last 2 decades, guidelines have been developed to establish rational standards for transfusion of FFP. Although not specifically aimed at patients with cirrhosis, most guidelines adopt arbitrary cut-offs based on INR/PT ratios and/or aPTT prolongation greater than 1.5 times the normal value to trigger FFP transfusion before procedures deemed to increase the risk of bleeding, or in an attempt to stop overt hemorrhage. In this study, we examined the role of FFP transfusion on thrombin
Financial support
This study was supported by the São Paulo Research Foundation (FAPESP), Brazil (Grant number 2015/00883-5). Sponsor had no role in the study design, in the collection, analysis, or in the interpretation of date.
Conflict of interest
The authors declare no conflicts of interest that pertain to this work.
Please refer to the accompanying ICMJE disclosure forms for further details.
Authors’ contributions
Amanda Bruder Rassi: study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; statistical analysis; obtained funding; Elbio Antonio d’Amico: study concept and design; critical revision of the manuscript for important intellectual content; study supervision; obtained funding.
Armando Tripodi: study concept and design; critical revision of the manuscript for important intellectual content; final approval of the version to be published.
Tania
Acknowledgements
Marta Araujo for the help with illustration and to the local Institutional Blood Bank (Fundação Pró Sangue) for warning us every fresh frozen plasma prescribed.
Justin Axelberg for the English language editing service.
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