The interpretation and management of abnormal coagulation testing in individuals with advanced liver disease remains a common yet challenging topic, one that is especially difficult when these individuals need invasive procedures or experience bleeding or clotting. Although liver disease progression is closely linked to changes in coagulation parameters including thrombocytopenia and prolongation of the international normalized ratio (INR), it has become increasingly clear that individuals with advanced liver disease are not only at risk for bleeding but also for venous thrombosis and that risks of bleeding are not predicted by these traditional tests of coagulation [1–6].
The challenge that clinicians must consider is that synthetic dysfunction of the liver, often with coexisting portal hypertension, can affect all stages of hemostasis. In the cell-based model of hemostasis, three phases lead to clot formation and dissolution—primary hemostasis (in which activated platelets form the initial platelet plug), coagulation (in which the intrinsic and extrinsic pathways lead to the generation and cross-linking of fibrin), and fibrinolysis (in which the fibrin mesh is broken down to dissolve the clot once hemostasis is achieved) [7,8]. With liver disease, there are often lower numbers of circulating platelets, deficiencies in multiple factors in the coagulation cascade, and an altered fibrinolytic system with a proportion of individuals experiencing hyperfibrinolysis [9▪,10–12].
The purpose of this review is to provide clinicians with an improved understanding of coagulation testing in individuals with liver disease, to discuss the procoagulants available and the rationale for their use, and to provide management strategies in a variety of common clinical scenarios.
SECTION 2: TESTS OF HEMOSTASIS
Although traditional tests of hemostasis are often abnormal in individuals with cirrhosis, these tests do not reliably predict bleeding risk in this population . Prothrombin time (PT) and partial thromboplastin time (PTT) are prolonged in cirrhosis, reflecting decreased synthesis of procoagulant factors in the setting of hepatic dysfunction. These tests do not, however, capture the concomitant decrease in anticoagulant factors that leads to ‘rebalanced’ hemostasis and can thus be misleading. The platelet count is often reduced in cirrhosis because of both splenic sequestration and decreased production of thrombopoeitin by the liver [14,15]. Although clinical data correlating platelet count with bleeding risk in cirrhosis are sparse, recommendations suggest a platelet goal of 50 000/mL in the setting of active bleeding and prior to high-risk procedures [16▪▪]. This is supported by ex vivo data demonstrating that a platelet count of 56 000/mL preserves normal thrombin generation in the setting of cirrhosis . Levels of fibrinogen, the final substrate required for clot formation, are also known to be reduced in individuals with cirrhosis . Although low fibrinogen levels have been correlated with increased bleeding risk, correction of fibrinogen has not been clearly shown to reduce bleeding .
Several global measures of hemostasis have been evaluated in cirrhosis. Viscoelastic testing, that is rotational thrombelastometry (ROTEM) and thromboelastography (TEG), is available as a point-of-care test and its use is well established in the setting of liver transplantation . Both ROTEM and TEG measure the time to clot formation of whole blood in the setting of shear stress, with common parameters used to quantify results shown in Table 1. Unique to ROTEM is the use of various channels with different reagents to measure the different phases of clot formation. The ROTEM EXTEM maximum clot formation (MCF) of 45 mm has been demonstrated to reflect a platelet level of 52 000/mL and ROTEM FIBTEM MCF of 8 mm has been correlated with a fibrinogen level of 128 mg/dl . Viscoelastic testing has demonstrated changes in hemostasis in the setting of acute-on-chronic liver failure, infection, and renal failure, and its use has been shown to reduce blood product transfusion both in liver transplantation and in the setting of individuals with cirrhosis undergoing procedures [22–26]. Although these tests can provide practical information for clinicians and may eventually have a role in the routine care of individuals with liver disease, there are currently no validated target levels [16▪▪]. An additional global measure of hemostasis is thrombin generation analysis (TGA), which quantifies the amount of thrombin produced in platelet-poor plasma. Although not used clinically at this time, there is significant clinical research applying TGA in cirrhosis.
SECTION 3: PREVENTING AND TREATING BLEEDING IN THE SETTING OF ABNORMAL COAGULATION TESTING: A PRACTICAL GUIDE
Any practitioner who cares for individuals with liver disease is likely to encounter a variety of scenarios in which they must decide how to respond to abnormal coagulation tests—carefully weighing the risks of new or ongoing bleeding versus the risks and costs of using agents to correct these tests. Although management decisions should always be made on a case-by-case basis, the following scenarios provide a framework for clinicians caring for these patients and are summarized in Table 2. A key guiding principle is that the use of fresh frozen plasma (FFP) to correct the INR will require large volumes of product that have adverse effects on portal pressures, expose patients to a variety of risks including antibody formation, and transfusion related lung injury, which are not evidence-based [27,28].
Clinical scenario 1: Abnormal coagulation testing without bleeding
In individuals with advanced liver disease, abnormalities in routine tests of coagulation are common and can provide valuable information to the clinician. The INR is commonly used as a prognostic measure (including calculating the Child Pugh Score and the Model for End-Stage Liver Disease Score), and the degree of thrombocytopenia is often used as an indicator of portal hypertension. Although these tests measure the quantity of factors and platelets in the blood, they are known to be poor markers of bleeding risk in liver disease and do not accurately assess the functional coagulation potential of whole blood .
As a rule of thumb, interventions are not necessary in the setting of asymptomatic laboratory changes without bleeding. The exception to this rule would be administration of vitamin K in those who may be deficient (such as individuals with poor nutrition, cholestatic disease, diarrhea, or recent antibiotic use). In the absence of bleeding or a planned procedure, platelets do not need to be repleted unless they reach critical thresholds (usually less than 10 000–15 000) and routine use of FFP to correct a prolonged INR is associated with a variety of risks and costs without a high quality of evidence to show clinical benefit.
Clinical scenario 2: Abnormal coagulation testing in the setting of invasive procedures
Another common challenge in the care of patients with cirrhosis is reducing bleeding risk during and after invasive procedures are performed. Although the INR provides limited information regarding hemostasis in this population, it continues to have widespread use by clinicians who perform these procedures. A variety of studies have confirmed that the INR does not accurately predict procedural bleeding risk in these patients, including for procedures such as liver biopsy, paracentesis, and high-risk endoscopic therapies such as polypectomy or percutaneous endoscopic gastrostomy [5,13,29–32]. In addition, when attempts are made to normalize the INR using FFP prior to procedures, clinicians often use doses that would not achieve their original INR goals .
The task of the clinician performing the procedure is to determine the risk of any invasive procedure and to individualize care based on a variety of considerations, including the potential consequences of bleeding and the degree of vascular disruption caused by the procedure [34▪▪]. Potential examples of low-risk procedures include paracentesis, thoracentesis, central line placement, diagnostic endoscopy, variceal band ligation, uncomplicated polypectomy, and dental extraction. Potential examples of intermediate and high-risk procedures include lumbar puncture, liver biopsy, biliary sphincterotomy, locoregional therapies for hepatocellular carcinoma, large polypectomies, and major surgery.
With low-risk procedures, expert opinion recommends against routinely correcting thrombocytopenia or coagulopathy related to liver disease [16▪▪,35–37]. For intermediate and high-risk procedures, the goal should be to optimize clot formation by targeting specific goals for platelet counts and fibrinogen levels. Platelets should be given as near as possible to the start of the procedure, with a target goal of 50 000 to 100 000 as this range has been associated with normal thrombin production . In situations where individuals are scheduled to have intermediate or high-risk procedures, thrombopoietin receptor antagonists (avatrombopag or lusutrombopag) can be given to raise the platelet count provided that there is sufficient time for these drugs to take effect. Both of these medications have been effective in randomized placebo-controlled trials and are FDA approved [38,39].
In regards to plasma products for intermediate-risk and high-risk procedures, routinely administering FFP or cryoprecipitate to achieve INR goals prior to a procedure has not been shown to be beneficial in several large reviews [7,40–44]. Rather, transfusing cryoprecipitate to a goal fibrinogen level of greater than 120 mg/dl is a reasonable target.
Clinical scenario 3: Abnormal coagulation testing in setting of active bleeding
When evaluating an individual with active bleeding, management depends on multiple considerations including the location and severity of bleeding and the degree of hemostatic impairment.
Variceal bleeding is one of the more common bleeding events in cirrhosis. In the setting of high portal pressures, however, hemostatic mechanisms are less important than in other bleeding situations. There remains no evidence supporting prophylactic transfusion before esophageal variceal band ligation (EVBL) and little evidence that abnormal coagulation parameters increase the risk for post-EVBL bleeding . In this setting there are no specific recommendations by the ASGE or AASLD regarding coagulation parameters for prophylactic variceal band ligation [45–47]. In acute variceal bleeding, resuscitation should aim for a hemoglobin of around 7–8 g/dl, noting that excessive blood product transfusion can result in increased portal pressures and rebleeding [48–51]. Optimal platelet and fibrinogen levels remain uncertain, although a platelet count above 50 000/dl and a fibrinogen level above 100–150 mg/dl with cryoprecipitate transfusions may be reasonable targets.
When nonvariceal bleeding occurs, considerations should include evaluating comorbidities, treating infection or uremia (which can impair hemostasis), avoiding aggressive transfusions that can raise portal pressures (in the absence of shock or active bleeding), and determining if anticoagulant therapies should be held or reversed. It is useful to monitor platelets and fibrinogen levels and a global viscoelastic assay of hemostasis (if available) and to use these tests to decide which products to administer. Viscoelastic testing in the management of cirrhosis and bleeding has been shown in a randomized trial for nonvariceal upper gastrointestinal bleeding to result in less blood product transfusions and fewer adverse events, with similar rates of bleeding control as compared to transfusing to platelet and INR goals . Specific transfusion strategies include infusing cryoprecipitate to maintain a fibrinogen above 100–120 mg/dl, packed red blood cells to maintain a hemoglobin above 7 g/dl, and platelets to maintain a platelet count above 50 000/dl. When possible, FFP should be avoided. If delayed bleeding or persistent oozing occurs, the diagnosis of hyperfibrinolysis should be entertained, with possible considerations for antifibrinolytic agents. Table 3 highlights procoagulant agents for reversal, including dosing and goals for each agent.
Clinical scenario 4: Monitoring anticoagulation effect for individuals with cirrhosis receiving treatment
Patients with cirrhosis may benefit from therapeutic anticoagulation in multiple settings. There is a high prevalence of portal venous thrombosis (PVT) in this population and most guidelines recommend considering anticoagulation in those who are liver transplant candidates [53–55]. In addition, patients with cirrhosis are at increased risk for venous thromboembolism compared to the general population  and atrial fibrillation has a prevalence of 5% in this group . In general, patients with cirrhosis should have endoscopic variceal screening prior to initiation of therapeutic anticoagulation to minimize risk of variceal bleeding.
The use of anticoagulants in patients with cirrhosis is somewhat challenging as this population was universally excluded from safety and efficacy trials. Nonetheless, several classes of anticoagulants have been used in cirrhosis including warfarin, low molecular weight heparin (LMWH), and direct oral anticoagulants (DOACs). Warfarin has the most safety data in cirrhosis, although the ability to monitor dosing levels via INR can be difficult in patients who have abnormal baseline testing and can preclude its use in advanced liver disease. LMWH has a significant amount of data in the setting of cirrhosis, including randomized controlled data showing that prophylactic LMWH reduces PVT formation and potentially reduces progression of cirrhosis and mortality . Monitoring of both LMWH and unfractionated heparin is challenging as low levels of antithrombin in cirrhosis can result in low anti-Xa levels and prolonged PTT in these patients at baseline . DOACs have been increasingly used in patients with cirrhosis and there have been small studies that suggest that bleeding risk is comparable to warfarin and LMWH in cirrhosis [59–61]. Per FDA labeling, DOACs may need dose-adjustments in cirrhosis and should be avoided in the setting of Child Pugh Class C and decompensated patients. Although little pharmacodynamic data are available for DOAC use in patients with cirrhosis, ex-vivo data suggest their potency may be increased in patients with advanced liver disease . This, in combination with the challenges monitoring the anticoagulation effects of these drugs, warrants caution when using DOACs and highlights the importance of close collaboration with hepatology and hematology.
Clinical scenario 5: Acute liver failure
With acute liver failure, individuals with previously normal liver function experience profound hepatic synthetic dysfunction and an associated prolongation of their PT/INR. Despite this lab abnormality, however, these individuals have normal hemostasis by thromboelastography, suggesting a maintained hemostatic balance . In this setting, prophylactic transfusions of procoagulants without clinically apparent bleeding is unlikely to be beneficial. With high-risk procedures, a one-time dose of recombinant activated factor VII (given at 40 μg/kg within minutes of the procedure) can correct the INR to near normal .
SECTION 4: FUTURE DIRECTIONS AND CONCLUSION
The field of coagulation and liver disease continues to evolve as we learn more about the complex interplay of hemostatic factors in these patients. Although bleeding may be widely prevalent in liver disease, it is important to note that thrombosis can also have serious clinical consequences . Although studies show that healing from fibrin deposition can drive liver regeneration after a partial resection, coagulation continuing in an uncontrolled fashion may cause microscopic thrombi and ischemia leading to parenchymal extinction and accelerated fibrosis [65,66]. Therefore, testing for deficiencies leading to hypocoaguable states may be essential, but avoiding overcorrection and identifying hypercoaguability may be just as important.
Although traditional serologic testing by INR, fibrinogen, or platelet counts may be insufficient, whole blood viscoelastic testing remains difficult to interpret. A survey of practicing physicians and scientists in 2005 demonstrated diverse opinions on coagulation in liver disease . A follow up survey from a similar group in 2017 showed more agreement on the limitations of traditional measures to assess bleeding risk, but still demonstrated varying opinions in the areas of therapy and management [34▪▪]. As our testing capabilities become more refined, these opinions may start to coalesce. Basic science and translational research will continue to explore theories of hemostasis in this population. By using these theories, the goal is to develop dependable and accurate methods to predict bleeding and clotting risk that can guide our management of patients with liver disease.
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Conflicts of interest
There are no conflicts of interest.
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