Hemostasis in Liver Disease: Implications of New Concepts for Perioperative Management

doi:10.1016/j.tmrv.2014.03.002

Transfusion Medicine Reviews

Volume 28, Issue 3, July 2014, Pages 107-113

https://doi.org/10.1016/j.tmrv.2014.03.002 Get rights and content

Abstract

The hemostatic profile of patients with liver diseases is frequently profoundly different from that of healthy individuals. These complex alterations lead to abnormal results from routine laboratory tests, but because of the nature of these assays, they fail to accurately represent the patient’s hemostatic state. Nevertheless, based on abnormal laboratory coagulation values, it has long been assumed that patients with liver disease have a natural bleeding tendency and are protected from thrombosis. This assumption is false; the average patient with liver disease is actually in a state of “rebalanced hemostasis” that can relatively easily be tipped toward both bleeding and thrombosis. The new paradigm of rebalanced hemostasis has strong implications for the clinic, which are presented in this review. There is no evidence that prophylactic transfusion of plasma helps to prevent procedure-related bleeding. In addition, the presence of independent risk factors such as poor kidney status or infections should be carefully assessed before invasive procedures. Furthermore, central venous pressure plays an important role in the risk of bleeding in patients with liver diseases, so during procedures, a restrictive infusion policy should be applied. Finally, thrombosis prophylaxis should not be withheld from patients with cirrhosis or acute liver failure, and clinicians should be alert to the possibility of thrombosis occurring in these patients.

Section snippets

The Hemostatic Profile of Patients With Liver Disease

The liver plays a central role in hemostasis as it synthesizes nearly all circulating coagulation factors and inhibitors, as well as some of the components of the fibrinolytic system. In addition, the liver synthesizes thrombopoeitin, which is a hormone essential for stimulation of platelet production from megakaryocytes in the bone marrow. Therefore, liver diseases (whether acute or chronic) frequently are associated with complex alterations of the hemostatic system. The typical hemostatic

Rebalanced Hemostasis

The classical interpretation of the hemostatic profile in patients with liver disease was that these patients have a bleeding tendency. This was believed to be supported by the abnormal laboratory coagulation test results and the observation that spontaneous bleeding occurs frequently in this group of patients. Furthermore, the fact that liver transplant recipients frequently required massive amounts of blood products during the procedure was also considered evidence of an existing bleeding

The Limitations of PT and APTT and the Potential of Thrombin Generation Assays

The PT has been developed as a tool to diagnose defects or deficiencies in individual procoagulant proteins and to evaluate patients using vitamin K antagonist therapy [26]. However, the PT has been adopted as a general indicator of coagulation in a broad range of patients. Because of the nature of the assays, the PT and APTT cannot predict the risk of bleeding in patients with complex hemostatic alterations such as observed in liver disease [26], [29], [30], [31], [32]. The main reason for

Bleeding Does Occur Frequently But Is Mostly of Hemodynamic Origin

Bleeding from esophageal varices occurs in 25% to 35% of patients with cirrhosis and accounts for 80% to 90% of bleeding episodes in these patients [42]. It has now been widely accepted that the presence and rupture of varices is a consequence of portal hypertension and local vascular abnormalities with a (at most) minor role for hemostasis [43]. It has been shown that central venous pressure (CVP) and the splanchnic venous pressure are key factors in the hemostatic balance during liver surgery

Thrombosis Occurs Frequently and Might Be Underreported

As mentioned before, it has long been incorrectly assumed that patients with liver disease are auto-anticoagulated and therefore protected against thrombotic complications [25], [56], [57]. However, portal vein thrombosis (PVT) is a common complication in patients with cirrhosis that is encountered in 8% to 26% of patients who are candidate for liver transplantation [58], [59], [60], [61] as compared with a lifetime cumulative incidence of 1% in the general population [62]. The reduced portal

Blood Transfusion Is Potentially Harmful and May Not Help in Preventing Bleeding

Blood (product) transfusion is associated with the risk of adverse effects and may be a risk factor for increased mortality [73], [74], [75], [76], [77]. A recent randomized controlled trial showed that the use of a restrictive RBC transfusion policy in patients with acute upper gastrointestinal bleeding (a common complication of cirrhosis) improves survival and reduces rebleeding risk, by mechanisms related to decreased administration of volume as well as direct adverse effects of RBCs [78].

Treatment Guidelines

The narrative outlined to this point largely originates from the field of liver transplantation, in which it is in many centers a common practice not to administer any blood products prior to or during the procedure unless active bleeding occurs [2], [28], [39], [55], [76], [87], [88]. It is reasonable to assume that this restrictive transfusion policy is also valid for smaller invasive procedures performed on patients with liver disease. Surprisingly, prophylactic transfusions are frequently

Watchful Waiting

Given the aforementioned considerations, we believe that a policy of watchful waiting is most likely superior to preventive correction of laboratory tests, as evidenced by the experience in liver transplantation, although admittedly both strategies have not yet been compared in randomized studies with clinically relevant end points. Because the laboratory testing available at this time cannot predict the risk of bleeding, the best option is to treat only those patients with significant

Prevention and Treatment of Thrombosis

Because liver disease does not protect against thrombosis, thrombosis prevention schemes related to immobilization or invasive procedures should not be withheld from these patients [106]. Although there is accumulating experience with the use of LMWH, the use of these drugs is complicated because of serious dosing and monitoring [107] issues as a result of the abnormal hemostatic profile in patients with liver disease [108], [109]. Specifically, the anticoagulant potency of LMWH appears to be

Conclusion

It has been well established that the average patient with liver failure is in hemostatic balance and may experience both bleeding and thrombotic events. The platelet count, PT, and APTT are poor predictors of bleeding risk and the prophylactic correction of these parameters with platelet concentrates or plasma does not reduce bleeding. Furthermore, the use of blood products has severe adverse effects and may cause bleeding by increasing volume load.

These insights should be put to practice in

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Splanchnic vein thrombosis (SVT) is an uncommon manifestation of venous thromboembolism in the splanchnic venous system, with scarce evidence surrounding its management. We assessed the efficacy and safety of direct oral anticoagulant (DOAC) to low-molecular-weight heparins (LMWH), vitamin-k antagonists (VKAs), or no anticoagulation.
We conducted a systematic review and meta-analysis with the primary efficacy outcome being complete recanalization of affected vessels and primary safety outcome being major bleeding. Meta-analysis was done using a random-effects model, with dichotomous outcomes being synthesized with odds ratios (ORs) and corresponding 95 % CIs.
Seven non-randomized and one randomized study involving 883 participants were included for analysis. DOACs were more effective than VKAs (OR = 4.33; 95 % CI: 2.4, 7.83; n = 1 study) in non-cirrhotic patients and no anticoagulation in cirrhotic patients (OR = 3.86; 95 % CI: 1.49, 10.03; n = 3 studies). DOACs had a statistically significant reduction in major bleeding compared to observation [OR = 0.09; 95 % CI: 0.03, 0.29; n = 3 studies], LMWHs [OR = 0.13; 95 % CI: 0.03, 0.29; n = 1 study] and VKAs [OR = 0.12; 95 % CI: 0.02, 0.69; n = 2 studies] in non-cirrhotic patients. No difference in major bleeding was found between DOACs and observation, LMWH, or VKAs in cirrhotic patients.
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Portal hypertension has no role in perioperative bleeding during liver transplantation with systematic porto-caval shunt
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More than a half of patients undergoing liver transplantation (LT) receive intraoperative transfusion. Portal hypertension (PHT) may contribute to perioperative blood loss. We study the relationship between preoperative hepatic venous pressure gradient (HVPG) values and intraoperative transfusion requirements in adult patients undergoing LT.
160 cirrhotic patients undergoing first elective LT (2009–2019) with an HVPG measurement within the previous 6 months were included. Surgical technique was piggyback with portocaval shunt (PCS). The association of HVPG and other variables with transfusion requirements and blood loss were studied.
Blood loss (ml/kg) was positively correlated with HVPG, among other variables, but at multivariable analysis it only remained associated with MELD-Na and HCC indication. Regarding RBC transfusion, MELD-Na and hemoglobin were independently associated with the need and magnitude of RBC transfusion. Subanalysis by surgical stage (hepatectomy, anhepatic, neohepatic) and by serial HVPG cut-offs found no clear associations with either bleeding or transfusion.
The severity of PHT plays a minor role on bleeding and transfusion during LT in a contemporary cohort with systematic PCS. Main determinants of transfusion are liver function and baseline hemoglobin, which would seem the suitable goal to optimize transfusion in LT.
Cirrhosis and the surgical patient
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Cirrhosis can be challenging to recognize and manage in the perioperative setting. The Fibrosis 4 (FIB-4) score is a screening test that can help determine the likelihood of underlying advanced fibrosis or cirrhosis in patients with chronic liver disease. Liver stiffness correlates with severity of fibrosis and cirrhosis and can be measured noninvasively with transient elastography or MR elastography; a normal liver stiffness effectively rules out cirrhosis. Perioperative risk calculators include the Child-Turcotte-Pugh Score, the Mayo Risk Score, the Veterans Outcomes and Costs Associated with Liver Disease-Penn (VOCAL-Penn) score; each has its limitations. In addition to reviewing the above tools, we will briefly discuss common perioperative dilemmas in patients with cirrhosis, including selection of patients for umbilical hernia repair or bariatric surgery, and will highlight methods to optimize patients with cirrhosis prior to surgical interventions.
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Preservation of platelet function in patients with cirrhosis and thrombocytopenia undergoing esophageal variceal ligation
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Thrombocytopenia is a possible risk factor for bleeding after band ligation of esophageal varices. However, elevated von Willebrand factor (VWF) in cirrhosis improves platelet function and could decrease this risk. Our objective was to assess platelet function in patients with cirrhosis undergoing esophageal variceal ligation (EVL).
The assessment consisted of platelet count, antigen and activity of VWF and VWF-cleaving protease ADAMTS-13 activity, and a platelet adhesion and aggregation test simulating vascular flow in vivo (Impact-R^Ⓡ) prior to EVL.
Totally 111 patients were divided into three groups according to platelet count: (1) < 50 × 10⁹/L (n = 38, 34.2%); (2) 50 × 10⁹/L to 100 × 10⁹/L (n = 47, 42.3%); and (3) > 100 × 10⁹/L (n = 26, 23.4%). No statistically significant difference was found in the aggregate size of platelets [group 1: 41.0 (31.8–67.3) µm²; group 2: 47.0 (33.8–71.3) µm²; and group 3: 47.0 (34.0–66.0) µm²; P = 0.60] and no significant correlation was found between aggregate size and platelet count (Spearman r = 0.07; P = 0.47). Surface coverage was 4.1% (2.8%–6.7%), 8.5% (4.0%–10.0%), and 9.0% (7.1%–12.0%) (P < 0.001) in groups 1, 2 and 3, respectively and correlated with platelet count (Spearman r = 0.39; P < 0.0001). There was no significant difference between groups in VWF or ADAMTS-13. Post-EVL bleeding occurred in six (5.4%) patients (n = 2 in group 1, n = 1 in group 2, and n = 3 in group 3; P = 0.32). Patients with bleeding had higher MELD scores [15.0 (11.3–20.3) versus 12.0 (10.0–15.0); P = 0.025], but no difference was demonstrated for platelet function parameters.
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2020 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Solution Set Oversight Committee
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: Funding: This work was not funded.

: Conflicts: The authors report no conflicts of interest.

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Original ArticleHemostasis in Liver Disease: Implications of New Concepts for Perioperative Management

Abstract

Section snippets

The Hemostatic Profile of Patients With Liver Disease

Rebalanced Hemostasis

The Limitations of PT and APTT and the Potential of Thrombin Generation Assays

Bleeding Does Occur Frequently But Is Mostly of Hemodynamic Origin

Thrombosis Occurs Frequently and Might Be Underreported

Blood Transfusion Is Potentially Harmful and May Not Help in Preventing Bleeding

Treatment Guidelines

Watchful Waiting

Prevention and Treatment of Thrombosis

Conclusion

J Hepatol

Am J Gastroenterol

J Thromb Haemost

Pharmacol Ther

J Hepatol

Gastroenterology

J Thromb Haemost

J Thromb Haemost

J Hepatol

J Hepatol

J Hepatol

Clin Liver Dis

Blood

Transplant Proc

J Hepatol

J Hepatol

Am J Surg

Blood Rev

Dig Liver Dis

J Thromb Haemost

J Thromb Haemost

Blood

Blood

Blood

Transfus Clin Biol

Transf Apheres Sci

J Vasc Interv Radiol

J Cardiothorac Vasc Anesth

Blood

J Hepatol

Chest

Thromb Res

Transfusion rate for 500 consecutive liver transplantations: experience of one liver transplantation center

Transplantation

Predicting hemorrhage using preoperative coagulation screening assays

Curr Hematol Rep

Why do physicians request fresh frozen plasma?

Transfusion

Hemostatic alterations in liver disease: a review on pathophysiology, clinical consequences, and treatment

Dig Surg

Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management

Hepatology

Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity

Hepatology

Factor VIII expression in liver disease

J Thromb Haemost

Pooling of platelets in the spleen: role in the pathogenesis of “hypersplenic” thrombocytopenia

J Clin Invest

Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults

Aliment Pharmacol Ther

Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008

Clin Gastroenterol Hepatol

Hemostatic alterations in fatty liver disease

Blood Coagul Fibrinolysis

The coagulopathy of acute liver failure and implications for intracranial pressure monitoring

Neurocrit Care

Coagulopathy does not fully protect hospitalized cirrhosis patients from peripheral venous thromboembolism

Am J Gastroenterol

The prothrombin time-derived international normalized ratio: great for warfarin, fair for prognosis and bad for liver-bleeding risk

Liver Int

Paucity of studies to support that abnormal coagulation test results predict bleeding in the setting of invasive procedures: an evidence-based review

Transfusion

MELD score and blood product requirements during liver transplantation: no link

Transplantation

Coagulation defects do not predict blood product requirements during liver transplantation

Transplantation

Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests

Original Article
Hemostasis in Liver Disease: Implications of New Concepts for Perioperative Management