INR-Triggered Transfusion In GI Bleeders From ER

Advances in the understanding of the coagulation imbalance in liver disease have experts
questioning the clinical efficacy of current plasma transfusion practices in patients with
liver disease17-18. Having recently discovered a large previously unrecognized risk (TRALI)
of plasma transfusion in this patient population, we now believe the current clinical
transfusion paradigm under-recognizes risk and overvalues the benefit of plasma transfusion
in bleeding patients with liver disease. Though experts have recommended more judicious use
of plasma, clinical practice remains variable18. Transfusion triggers and thresholds are
often arbitrarily set based on conventional coagulation studies and evidence to guide
clinicians on plasma dosing required to achieve these laboratory thresholds does not exist.
We hypothesize that a restrictive plasma transfusion strategy in critically ill chronic
liver disease patients with acute gastrointestinal bleeding will decrease a surrogate
measure of TRALI without increasing bleeding complications (figure 1). With the
collaborative support of the pulmonary/critical care, hepatology, and transfusion medicine
services, we will conduct a randomized controlled trial comparing a restrictive versus
liberal strategy of plasma transfusion in bleeding patients with liver disease. In addition,
we will refine and validate our plasma transfusion dosing algorithm so clinicians will have
the tools to appropriately dose plasma to reach evidence-based transfusion targets.

The development of TRALI is believed to require two pathophysiologic events. First, a
pro-inflammatory stimulus, such as sepsis, leads to exposure of endothelial surface adhesion
proteins and consequent capture of polymorphonuclear leukocytes (PMNs) within the pulmonary
microvasculature. Second, these adherent PMNs are activated by mediators within transfused
blood components, leading to neutrophilic inflammation and TRALI. Emerging evidence suggests
that the process of neutrophil adhesion in the lung involves degradation of the endothelial
glycocalyx, a thin layer of glycosaminoglycans (GAGs) lining the vascular lumen(S) 22-23. In
mice, sepsis results in pulmonary glycocalyx loss, neutrophil adhesion and subsequent
development of ALI(S). Glycocalyx degradation is also associated with organ injury in
humans, as evidenced by an increase in circulating GAG fragments (e.g. heparinoids) in
septic shock22, 24-25. Circulating heparinoids can be detected quickly and accurately by a
point of care heparinase-I modified thromboelastogram (TEG) study26-27. Detection of
heparinoids by TEG may therefore indicate pulmonary microvasculature propensity for PMN
adhesion (first event) and be utilized as a predictive biomarker for TRALI. Restrictive
plasma transfusion strategies could then be individualized to high risk patients to decrease
the probability of a second event resulting in the clinical syndrome of TRALI. In
conjunction with our clinical trial, we will perform a translational observational study to
assess whether detection of systemic heparinoids predict the subsequent development of a
TRALI surrogate, post-transfusion hypoxemia. These clinical studies will pave the way for
larger clinical trials guiding future plasma transfusion practice and decreasing the
significant TRALI burden in the critically ill.

Inclusion Criteria: Subjects will be eligible to participate in the study if they meet all
of the following criteria:

1. Admit to an ICU due to gastrointestinal bleeding AND an INR in first 12 hours >1.8;
(INR ≥ 1.6 if received ≥ 2 units plasma)

2. Patient has chronic liver disease defined as 1 or more of the three following
diagnostic criteria:

- Previous diagnosis of chronic liver disease OR Imaging or biopsy diagnosis of
cirrhosis

- Signs of portal hypertension (ascites, varices, hypersplenism)

- Laboratory evidence of synthetic dysfunction (INR>1.5, Bilirubin> 2.0, Albumin<
2.5) AND ≥2 physical exam findings on admission associated with chronic liver
disease (palmar erythema, spider angiomata, asterixis, caput medusa,
gynecomastia)

Exclusion Criteria:Subjects will be ineligible to participate in the study if they meet
any of the following criteria:

1. Patient under age 18 OR pregnant OR incarcerated

2. Patient meets criteria for acute respiratory distress syndrome (ARDS)
(PaO2/FiO2<165)41

3. Patient admitted to ICU for re-bleed on same hospital admission OR has already
received >4 units of plasma.

4. Patient already underwent therapeutic endoscopy with noted hemostasis

5. History of inheritable or acquired clotting or bleeding disorder (hemophilia A or B
or acquired clotting factor inhibitor)

6. Patient is being actively anticoagulated with vitamin K antagonists, direct thrombin
inhibitors, heparins or anti-Xa antagonists

7. Inability to obtain consent OR clinical team believes one of the transfusion
strategies will be harmful to the patient

8. Congestive heart failure (previous clinical diagnosis or Ejection Fraction (EF) <50%)

9. Patient is do-not-resuscitate (DNR) or unexpected to live > 72 hours