Transfusing common sense instead of blood products into coagulation testing in patients with cirrhosis: Overtreatment ≠ safety
Authors: Robert S. Rahimi, Jacqueline G. O'Leary
Journal: Hepatology (2015)

Potential conflict of interest: Dr. O'Leary received grants from Fisher Scientific. See Article on Page 566. In patients with cirrhosis the imbalance of procoagulants and anticoagulants combined with potential alterations in fibrinolysis and platelet number and function can alter standard laboratory coagulation testing. Prothrombin time and platelet count are frequently abnormal and, in our risk‐averse health care system, often result in preprocedure transfusions to achieve "safer" thresholds.1 But what are we actually achieving: a risk of portal hypertensive bleeding, transfusion reaction, transfusion‐related acute lung injury, infection transmission, human leukocyte antigen (HLA) antibody development, superior test results, or improved coagulation? According to the International Symposium on Coagulopathy and Liver Disease, rebalanced hemostasis is what we need to measure, which stems from both the prohemostatic and antihemostatic pathways working in concert.2 Disproportionately fewer nonportal hypertension‐related bleeding complications occur in patients with cirrhosis relative to their prothrombin time and platelet values. This results from relatively rebalanced hemostasis. Despite this, many health care professionals continue to transfuse blood products (i.e., fresh frozen plasma [FFP] and platelets) prophylactically to improve laboratory profiles, regardless of function and prior data demonstrating a low risk of bleeding complications in patients with cirrhosis, especially for minimally invasive procedures like paracentesis.3 Fortunately, the study by De Pietri and colleagues in this issue of hepatology offers an alternative to unnecessary preprocedural use of blood products in patients with cirrhosis with an elevated international normalized ratio (>1.8) and/or thrombocytopenia (<50 × 103/μL) using thromboelastography (TEG) to guide transfusions.4 TEG was adopted into clinical practice in 1985, more than 35 years after the procedure was first pioneered for research purposes.5 Using approximately 0.35 mL of whole blood in an oscillating cup at 37oC, this test uses mechanically transduced waves at different rates to graphically illustrate the patient's coagulation function. TEG is already used clinically in liver transplant, cardiovascular, trauma, and obstetric surgery where dynamic changes in blood volume and coagulation occur. This semiautomated bedside instrument easily yields an overall coagulation assessment in 30 minutes, with prolonged times resulting in blood product transfusions.6 A prolonged reaction time measures clot formation, indicative of coagulation factor function and results in transfusion (i.e., usually FFP), while a prolonged maximum amplitude measures clot strength, indicative of platelet function and results in transfusion. The authors of this open‐label, intention‐to‐treat trial randomized patients to TEG‐guided transfusion where patients only received transfusion if their functional coagulation was altered versus standard of care preprocedural prophylactic transfusion therapy.4 Of note, only 16.7% of TEG‐guided patients received transfusions compared to 100% of patients in the standard of care arm (P = 0.009). Although platelet levels >50,000/μL have sufficient thrombin production, the use of FFP and platelet transfusions in patients with cirrhosis rarely, if ever, achieves complete normalization of coagulation parameters by standard testing. Of note, although allogenic transfusions at times are necessary, their cost and more importantly risk must also be taken into account (Table 1). The risk of overtransfusion was highlighted in a recent randomized controlled trial comparing liberal (hemoglobin <9 g/dL) versus restrictive (hemoglobin <7 g/dL) pack red blood cell (RBC) transfusion strategies in acute upper gastrointestinal bleeding.7 This trial subsequently resulted in a lower hemoglobin threshold (<7 g/dL) for RBC transfusion in general clinical care. Furthermore, liberal blood transfusions in patients with cirrhosis, compared to restrictive strategies, had the additional risk of worsening portal hypertension (P = 0.03) and resulted in higher bleeding complication rates (P = 0.01), a longer length of stay (P = 0.01), and more adverse events (P = 0.02; especially transfusion associated overload, P = 0.001), culminating in an increased all‐cause 45‐day mortality (P = 0.02). Table 1 - The Significant Risk and Cost of Blood Product Transfusion Variable(s) FFP Platelets Cost11 Raw $52 $500 Per unit transfused (estimated adjustment) $1600‐$2400 Relative cost savings (per unit reduction) 300 cases/year $480,000‐$720,000 500 cases/year $800,000‐$1,200,000 700 cases/year $1,120,000‐$1,680,000 Outcomes Short term Transfusion reactions Cross‐match errors Prolonged ventilator time Exacerbation of portal hypertension Transfusion‐related acute lung injury Increased mortality Infection transmission Potential hypercoagulable complications, e.g., portal vein thrombosis Intermediate Increased intensive care unit stay Increased hospital length of stay Systemic inflammatory response syndrome Transfusion‐related acute lung injury Increased mortality Long term HLA antibody formation Disease transmission Increased mortality In addition, patients with cirrhosis awaiting transplantation who receive blood products (including FFP that has soluble class I HLA antigens) can develop donor‐specific HLA alloantibodies, resulting in a potential decrement in posttransplant outcomes.8 Furthermore, although the etiology of transfusion‐related acute lung injury is multifactorial, associations with HLA class I and II antibodies and granulocyte antibodies have been demonstrated.10 Therefore, clinicians must be cognizant of the potential dangers blood transfusions can cause immediately and years later, highlighting the need for transfusion minimization in all patients with cirrhosis. Although the current study should be used as a springboard for future confirmatory studies that hopefully will result in TEG‐based transfusion for all procedures in patients with cirrhosis, there are several limitations worth mentioning. First, the type of procedures performed in the two groups varied (see Di Pietri et al.'s table 24). The major treatment challenge remains in patients undergoing high‐risk procedures; therefore, more patients undergoing high‐risk procedures need to be studied in the future. Second, a range of cutoff values needs further exploration for both low‐risk and high‐risk procedures as they may be different. Third, patients with ascites undergoing paracentesis should be excluded from further studies because bleeding is so uncommon during paracentesis that prophylactic transfusions are not recommended even when the platelet count is as low as 19 × 106/L or the international normalized ratio is as high as 8.7.3 Fourth, there was no mention of the use or exclusion of cryoprecipitate or the type of FFP used, which might be something to consider in future studies. Finally, this study focused on FFP and platelet transfusions based on TEG‐guided therapy; however, in both the TEG and standard of care arms, four patients received a total of six and 10 RBC units, respectively, for anemia during hospitalization. These transfusions were supposedly not related to any procedure performed or overt bleeding episode. Although, liberal blood transfusions have demonstrated an increase in portal pressures and higher bleeding rates,7 future studies should consider a decrease in hemoglobin resulting in blood transfusion an important data point, even in the absence of overt bleeding. Because of the known risks of liberal transfusion strategies, future studies should also standardize RBC transfusion indications. It is interesting how "common sense is not so common" (Voltaire) anymore; however, in this issue of hepatology, De Pietri and colleagues4 transfused common sense into the field of coagulation in patients with cirrhosis. Although a small study that needs validation, exploration of different cutoffs, and a larger experience in patients undergoing high‐risk procedures, TEG‐directed transfusion minimization seems to be an exciting way to safely decrease the substantial risk and cost of procedure‐related transfusions.