Stravitz 26 provides an excellent summary with examples of TEG curves during a variety of clinical scenarios thrombocytopenia, acute hepatic failure, decompensated cirrhosis, etc. As a result, TEG has been described as cost-effective overall. Specific to liver disease, TEG-guided transfusion protocols during liver transplantation decrease the amount of bleeding but have no effect on overall mortality. Overall, the majority of the TEG studies and specifically those specific to liver disease are small and not without limitations.
The potential benefit of TEG with respect to point-of-care assessment of whole blood coagulation characteristics makes it a tool worthy of further study with larger populations in randomized controlled studies.
It would appear the best management of suspected coagulopathy, as assessed by INR and whether the patient is actually hyper- or hypocoagulable, is the treatment of the underlying cause for the hepatic and synthetic dysfunction. A major risk of blood product transfusions to correct an elevated INR in the setting of hepatic dysfunction is due to the lack of efficacy and inability to accurately assess the transfusion-related risk borne by the patient.
In patients with liver disease in particular, the prophylactic transfusion of cryoprecipitate has been associated with an increased risk of thrombotic events in end-stage liver disease ESLD patients 17 and thus should be avoided if not absolutely necessary.
Administering factor VIIa may be considered if FFP and vitamin K has not corrected the coagulopathy, but care should be taken to avoid treating simply to correct an abnormal laboratory result.
The final aspect of the management of coagulopathy in cirrhotic patients with elevated INR values is prophylactic anticoagulation for venous thromboembolism VTE. Hemostasis in cirrhotic patients is a dynamic balance. The commonly accepted dogma in the ED that an elevated INR is associated with increased risk of hemorrhagic events while protected from thrombotic complications is not supported by the literature 10 , 15 or by the underlying theory of INR testing.
In patients with abnormal coagulation testing results in the setting of liver disease, INR and PT may be best used to provide the practitioner with information about the synthetic function of the liver but not to assess hemorrhagic risk. The safest assumption that a practitioner in an acute and critical setting can make about any cirrhotic patient is that, even on their healthiest day, they are at an elevated risk of adverse outcomes that may be associated with an adverse thrombotic rather than the commonly feared catastrophic hemorrhagic event.
Conflicts of Interest : By the West JEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias.
No author has professional or financial relationships with any companies that are relevant to this study. There are no conflicts of interest or sources of funding to declare. National Center for Biotechnology Information , U.
West J Emerg Med. Published online Aug 8. Michael F. Harrison , MD, PhD. Author information Article notes Copyright and License information Disclaimer. Corresponding author. Email: gro. This article has been cited by other articles in PMC. Abstract The international normalized ratio INR represents a clinical tool to assess the effectiveness of vitamin-K antagonist therapy.
The following criteria were used to search these databases: Access to full-text articles, reports, books, and book chapters in English. Open in a separate window. As a result, liver disease does not decrease plasma concentrations of von Willebrand factor vWf ; the chronic inflammation associated with chronic liver disease may actually increase plasma concentrations of vWf.
Risk of Hemorrhagic Events with Procedures, Trauma, and Critical Illness The primary concern related to the elevated INR often observed in cirrhotic patients relates to either unintended or uncontrollable bleeding despite literature suggesting this to be a rare event.
Risk of Thrombotic Events in Critically Ill Patients with Hepatic Dysfunction A paradox is commonly observed during the care of patients with liver cirrhosis: Despite elevated INR values, clinicians often evaluate for and subsequently diagnose portal vein thromboses while clotting of extra corporeal circuits e. Figure 1. Burden of liver disease in the United States: summary of a workshop. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from to Clin Gastroenterol Hepatol.
The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol. The burden of selected digestive diseases in the United States. Acute liver failure. Impact of cirrhosis on outcomes in trauma.
J Am Coll Surg. Association of preexisting medical conditions with in-hospital mortality in multiple-trauma patients. Management of cirrhotic patients with blunt abdominal trauma: analysis of risk factor of postoperative death with the Model for End-Stage Liver Disease score. However, the most commonly observed risk factor for bleeding during surgery may be the severity of portal hypertension and the presence of collateral veins. A study performed in patients undergoing laparoscopic liver biopsy failed to demonstrate any correlation between bleeding at the hepatic puncture site and coagulation tests prior to the procedure, which would indicate that the extent of liver esection may be the most important risk factor for bleeding during this procedure.
Liver biopsy is widely used diagnostically to grade the severity of liver disease or fibrosis. Moreover, it is an essential tool after liver transplantation to diagnose rejection and other causes of graft dysfunction. Bleeding complications occur in 0. Direct ultrasound guidance is often used to mark the optimal biopsy site, and may reduce the risk of complications recommended in some guidelines.
Despite the evidence that there were no threshold abnormalities of clotting tests associated with risk of bleeding during laparoscopic liver biopsy, thresholds for INR and platelet count are still often used to determine the risk of bleeding during percutaneous liver biopsy. A cut-off for platelet count is difficult to justify from the literature. Burroughs, et al. If clotting parameters are outside stipulated ranges, a transjugular liver biopsy can be performed more safely without plasma or platelet therapy , despite the recommendation for percutaneous liver biopsy in some guidelines.
A plugged liver biopsy may also be safer than standard percutaneous biopsy, except that it may cause a greater risk of bleeding in hypocoagulable patients. There are no firm guidelines for clotting test result requirements in order to perform thoracentesis, paracentesis, lumbar puncture, or dental extraction in patients with liver disease without the use of blood products.
The largest review on patients with cirrhosis who underwent paracentesis or thoracentesis with mild coagulation abnormalities reported 0. Central venous catheterization can be safely performed in patients with abnormalities of haemostatis without blood product infusion. The internal jugular route should be used.
If hyperfibrinolysis is present, its correction reduces the risk of bleeding during central venous access. A prospective multicenter study on the prognostic role of coagulation testing in predicting gastrointestinal bleeding after variceal band ligation failed to find any correlation. However, it is important to limit invasive procedures to those where the perceived benefit is clearly greater than the risk of bleeding, because the latter cannot be accurately estimated.
The recent findings that many patients with cirrhosis may not be hypocoagulable may well influence recommendations for use of plasma products and platelets in the future. During acute variceal bleeding and massive blood transfusion, in order to avoid dilutional decrease of clotting factors, for every 2 units of blood, 1 unit of fresh-frozen plasma FFP is typically given.
A report described initially effective hemostasis after infusion of recombinant activated factor VII rFVIIa in 10 patients with variceal bleeding, but six experienced early re-bleeding and all of them died. The safety of rFVIIa, especially regarding possible prothrombotic effect or triggering of DIC, remains to be assessed in large studies of patients with liver disease. Two randomized controlled trials which evaluated the role of rFVIII in patients with variceal bleeding did not show a decrease in morbidity and mortality.
Therapy for hemostatic abnormalities of liver disease is needed only during variceal bleeding, surgery, or before invasive procedures. Intravenous vitamin K injection of 10mg daily for 24 to 48 hours can reverse vitamin K deficiency. FFP contains all clotting factors and can often correct an elevated PT, depending on the volume infused and the baseline PT abnormality.
Whether or not this correction of the PT results in improved hemostasis is not known. In addition, correction is brief 24 to 48 hours , and especially dependent on the half-life of factor VII. A common indication for FFP infusion is the presence of persistent bleeding in patients with INR greater than or equal to 2 or PT prolongation greater than 4 seconds. Despite the possible improvement in standard laboratory assessment of coagulation after administration of FFP in cirrhotic patients, thrombin generation is not increased after addition of FFP in vitro to the plasma of cirrhotic patients.
Because of the high volume required, adequate replacement is difficult both in cirrhotic patients intravascular plasma volume is already expanded and ascites may be present , and in acute liver failure increasing plasma volume can lead to increases in intracerebral pressure. Transjugular biopsy should be used in patients with coagulopathy not sufficiently corrected with FFP. Platelet transfusion, 1 unit every 10kg, is typically administered. The platelet count should be checked 1 hour after the infusion; however, no correlation among amelioration of bleeding time, increase in platelet count, and enhanced hemostasis has been shown.
It can improve bleeding time and enhance primary hemostasis at the dose of 0. It may also have a promising role in the treatment of the coagulation disorders in liver disease, as recombinant factor VIIa corrects prolonged PT in a dose dependent manner in non-bleeding cirrhotic patients. However, a randomized study using rFVIIa in 71 patients undergoing laparoscopic liver biopsy found no differences in liver bleeding.
In acute liver failure, rFVIIa may be useful in normalizing PT in the setting of intracranial pressure monitoring, as only a small volume of infusion is required. A recent meta-analysis of four randomized clinical trials on the prophylactic use of rFVII in cirrhotic patients undergoing liver resection or liver transplantation showed no significant difference between rFVII and placebo in terms of mortality, red blood cell units transfused, or adverse events.
In cirrhosis, plasma levels of coagulation factors are indicators of hepatic synthesis, and thus of liver function. A prolonged PT, which is not corrected by intravenous vitamin K administration 10mg daily for 2 days helps differentiate vitamin K deficiency from parenchymal liver diseases.
PT is part of the Child-Pugh score, which is the most commonly used prognostic assessment of the severity of liver disease. Factor V has less prognostic value in acetaminophen-induced fulminant hepatic failure.
Infection is associated with early variceal re-bleeding and increased mortality. Prophylactic antibiotic therapy led to less early re-bleeding and better control of bleeding in two randomized controlled trials. Using TEG, 20 cirrhotic patients who experienced early re-bleeding were found to have worsening TEG parameters the day before the episode. Moreover, patients with a bacterial infection have worse TEG parameters, which can be corrected in vitro by heparinase cleavage of heparin-like substances.
The routine use of FFP for primary prophylaxis prior to invasive procedures is not recommended. The large volumes of FFP required to significantly increase clotting factor levels may result in volume overload and exacerbation of portal hypertension paradoxically increasing the risk of bleeding. Prophylactic infusion of FFP may also delay procedures and expose patients to unnecessary risks.
It is still unclear whether global assays of hemostasis such as TEG may be effective for guiding prophylactic therapy. The results of a recently completed study of the use of TEG to guide blood product transfusion in cirrhotic patients undergoing invasive procedures are not yet available NCT Thrombocytopenia may be an obstacle to the timely performance of invasive procedures. There is no consensus on the threshold platelet count for prophylactic transfusion in patients with liver disease.
Cirrhotic plasma with a platelet count adjusted to at least 56 showed a level of thrombin generation corresponding to the lower limit of the normal reference range. Prophylactic platelet transfusions do not ensure adequate hemostasis. In a small study of patients with cirrhosis and thrombocytopenia undergoing endoscopic variceal ligation, transfusion of a single unit of platelets resulted in only a slight increase in platelet count without normalization of thrombin generation or TEG parameters.
The demonstration of reduced TPO production and activity in chronic liver disease provides a rationale for use of thrombopoietin receptor TPO R agonists to increase platelet production. The lower incidence of portal vein thrombosis 1. Thrombotic complications may reflect a disruption of rebalanced hemostasis by a rapid and sustained increase in activated platelets. These initial studies of TPO R agonists demonstrate how small perturbations can overcome compensatory mechanisms and rapidly shift the balance toward thrombosis in an individual patient.
Additional trials are necessary before TPO R agonists can be routinely recommended for patients with liver disease undergoing elective invasive procedures or surgery. Bleeding complications in chronic liver disease are infrequently related to abnormal hemostasis.
The majority of clinically significant bleeding episodes are due to increased portal pressure rather than deranged hemostasis. Risk factors for variceal bleeding are primarily related to hemodynamic and mechanical factors portal pressure, varix size. Rebalanced hemostasis in patients with liver disease is potentially unstable and may be tipped toward hemorrhage by several triggers including progression of portal hypertension, renal failure, and infection Table 2.
Renal failure develops in a substantial number of patients with end stage liver disease and may result in a bleeding tendency due to acquired platelet dysfunction and abnormal endothelial function. Bacterial infections may act as a trigger for variceal bleeding and are associated with failure to control bleeding.
Endotoxin may also release endogenous heparinoids, the glycosaminoglycans that maintain the physiologic antithrombotic surface of the endothelium. There is evidence that bacterial infections may impair hemostasis in cirrhosis by triggering the release of these heparin-like substances. Several studies found that bacterial infections induced a heparin-like effect detected by TEG, which reversed after antibiotic treatment and resolution of the infection.
The presence of infection was associated with anti-Xa activity suggesting high levels of endogenous heparinoids may reflect a response to bacterial infection.
Standard treatment for acute variceal hemorrhage includes a combination of a vasoconstrictor and endoscopic therapy. Recent United Kingdom consensus guidelines recommend a combination of pharmacologic vasoconstrictor and endoscopic therapy for initial management of active variceal bleeding. There are no evidence-based guidelines for treatment of abnormal hemostasis during acute bleeding. Platelet transfusion is recommended for patients with thrombocytopenia and active bleeding.
There is no evidence that prophylactic plasma or platelet transfusions reduce the risk of re-bleeding in patients with varices. Several randomized studies found the use of rFVIIa in addition to standard pharmacologic and endoscopic therapy no beneficial effect on clinically relevant outcomes in patients with cirrhosis and active variceal bleeding.
This decision requires careful consideration of potential thrombotic risks, as well as likely benefit. The composition of different PCC products varies considerably. Four-factor PCC contain clinically adequate amounts of all the vitamin K-dependent factors including protein C and protein S.
PCC have several advantages over FFP including delivery of a smaller volume with a fold higher concentration of coagulation factors and more rapid correction of hemostatic parameters. However there is no evidence that administration of PCC as adjunctive or rescue therapy in cirrhotic patients with active bleeding improves outcome. PCC may increase thrombotic risk in patients with liver disease.
A multicenter randomized trial is currently investigating the efficacy of preoperative administration of PCC in patients undergoing liver transplantation. In the absence of evidence confirming benefit, the routine use of PCC for bleeding complications of chronic liver disease is not recommended. There is no evidence that desmopressin improves control of bleeding or clinical outcome in patients with variceal bleeding.
Several studies found that desmopressin did not reduce blood loss in patients with acute variceal hemorrhage or undergoing hepatectomy or liver transplant. Although antifibrinolytic agents such as tranexamic acid were shown to reduce blood loss during liver transplantation, there is inadequate evidence of benefit outside of the transplant setting. A Cochrane systematic analysis of the use of tranexamic acid for upper GI bleeding suggested reduced mortality although the poor quality of the trials included precluded confirmation of benefit Cochrane Database Systematic Review.
The ongoing randomized controlled HALT-IT hemorrhagic alleviation with tranexamic acid-intestinal system trial is investigating the effectiveness and safety of tranexamic acid in patients with GI bleeding NCT There is currently insufficient evidence to support the routine use of tranexamic acid in the setting of acute variceal hemorrhage or other bleeding.
The balance is fragile and may be perturbed by superimposed insults such as infection or renal failure. Global assays of hemostasis show promise for assessing bleeding risk and guiding therapy but high quality data validating their use is still lacking. Bleeding in chronic liver disease is more often the result of hemodynamic and mechanical factors than deranged hemostasis. Additional studies are needed to define evidence-based guidelines for the prevention and treatment of bleeding in liver disease.
Off-label drug use: I discuss the clinical trials of recombinant factor VIIa in variceal bleeding due to liver disease. Therapy with vitamin K may be a useful option in patients with increased prothrombin time due to vitamin K deficiency; in patients with malnutrition; in patients using antibiotics; and in patients with cholestatic liver disease, particularly prior to invasive procedures.
Infusion of fresh frozen plasma is more often effective and is recommended in patients with liver disease before invasive procedures or surgery, as such patients require transient correction in their prothrombin time.
Therapy with plasma exchange may be considered in patients who cannot be treated with fresh frozen plasma due to volume overload risk.
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