Liver disease, coagulopathies and transfusion therapy

Introduction

In advanced liver disease bleeding from esophageal varices develops in up to 25% of patients, with a mortality rate as high as 15–20%. Moreover, major blood losses occur during and after surgical operations such as transplantation and hepatectomy. Because in end-stage liver disease haemorrhagic symptoms are associated with multiple abnormalities of laboratory tests that explore blood coagulation^1,2, a cause-effect relationship was inferred to be plausible. Hence, it is common clinical practice in these patients to treat or prevent bleeding with transfusional and non-transfusional agents (fresh-frozen plasma, platelet concentrates, antifibrinolytic drugs, prothrombin complex concentrates and recombinant activated factor VII) with the goal to potentiate haemostasis. In general, the capacity of these drugs to prevent or stop bleeding is not validated by randomised clinical trials, but based upon their capacity to improve or correct the abnormalities of the coagulation tests. With this background, we review the pattern of haemostasis abnormalities in patients with end-stage liver disease; the changes of these abnormalities induced by haemostatic agents; the recent evidence that questions the long standing belief that the bleeding tendency of these patients is causally related to the abnormalities of their haemostasis tests, and that transfusional and non-transfusional agents are clinically useful to prevent or stop bleeding.

Haemostasis defects in liver disease

Patients with end-stage liver disease (approximately 400,000 are on the waiting list for transplantation in the USA) have complex alterations that involve all the components of haemostasis (Table I). Thrombocytopenia is frequent, with platelet counts ranging between 30 and 100×10⁹/L. Defective platelet aggregation explains why the skin bleeding time is often prolonged³. The screening tests commonly used to explore coagulation (prothrombin time, partial thromboplastin time) are usually prolonged, because multiple coagulation factors are low in plasma in rough proportion to the degree of compromised protein synthetic capacity of the liver (Figure 1). Hyperfibrinolysis is reported on the basis of the increase of tissue plasminogen activator in plasma and decrease of the naturally-occurring inhibitors of plasmin⁴ (Figure 2), but not clearly substantiated by means of global tests.

Table I.

Haemostasis rebalance in liver cirrhosis.

Haemostasis component	Anti-haemostatic abnormalities	Pro-haemostatic abnormalities
Primary haemostasis	Thrombocytopenia, defective platelet aggregation on light transmission aggregometry	High von Willebrand factor, low ADAMTS-13 (the VWF-cleaving protease)
Blood coagulation	Low procoagulant factors (fibrinogen, prothrombin, factors V, VII, IX, X, XI, XIII)	High factor VIII Low anticoagulants (antithrombin, protein C, protein S, tissue factor pathway inhibitor)
Fibrinolysis	High plasminogen activator, low plasmin inhibitors	Low plasminogen, high plasminogen activator inhibitor

Figure 1.

Schematic representation of the steps of coagulation factor activation (indicated by solid arrows) leading to thrombin formation and the corresponding steps of inhibition (indicated by broken arrows).

Coagulation factors are represented by roman numbers. TF, tissue factor. AT, antithrombin. TM-APC-PS, thrombomodulin-activated protein C-protein S. TFPI, tissue factor pathway inhibitor.

Figure 2.

Schematic representation of fibrinolysis steps leading to plasmin formation.

Solid and broken arrows represent activators and anti-activators. HRGP, histidin-rich glycoprotein. TAFI, thrombin activatable fibrinolysis inhibitor. PAI, tissue plasminogen activator inhibitor. PI, plasmin inhibitor. FXIIa, activated factor XII. tPA, tissue-type plasminogen activator. uPA, urokinase-type plasminogen activator.

The important mechanistic role of a deranged haemostasis as the main cause of the bleeding tendency in patients with advanced liver disease was first challenged by the demonstration that routine haemostasis tests fail to reflect the bleeding tendency in cirrhosis, because of their poor capacity to predict the onset and severity of bleeding from esophageal varices, after liver biopsy and at the time of major operations such as transplantation^5–7. In addition, these laboratory alterations that indicate an impaired haemostasis are indeed accompanied by opposing prothrombotic alterations (Table I)^5–7. Pertaining to primary haemostasis, thrombocytopenia and thrombocytopathy are paralleled by a marked increase of plasma von Willebrand factor (VWF), the main platelet-vessel wall adhesive protein⁸. With regards to blood coagulation, low procoagulant factors are rebalanced by the concomitant plasma decrease of naturally occurring anticoagulants such protein C, protein S, tissue factor pathway inhibitors, and others¹⁰. An additional important contribution to coagulation rebalance is provided by the marked increase of plasma factor VIII (Figure 1)⁹. Laboratory changes consistent with hyperfibrinolysis tend to be compensated by antifibrinolytic abnormalities (Figure 2)¹⁰. That the concomitant alterations of both prohemostatic and antihemostatic components in cirrhosis ultimately result in a restored balance^5–7 (Table I) is unequivocally demonstrated by global tests such as thrombin generation assays^9–11, that explore both the pro- and anti-coagulant components. However, these global tests are not yet standardised, nor validated and employed widely enough in the clinical setting, so that it is premature to propose them as routine alternatives to the clearly inadequate traditional coagulation screening tests^12–14.

Transfusional and non transfusional haemostatic drugs in liver disease

Fresh-frozen plasma is often employed in an attempt to prevent bleeding during liver biopsy or other invasive procedures when patients with liver disease present a prolonged prothrombin and/or partial thromboplastin time². Plasma is also commonly employed when these patients bleed acutely from esophageal varices, in spite of contradictory guidelines of the American Association for the Study of Liver Disease¹⁵ and in vitro studies showing that plasma shortens the prolonged prothrombin time but does not affect the amount of thrombin formed¹⁶. Against the use of plasma infusions stands also knowledge that the resulting volume expansion contributes to increase portal vein hypertension, aggravates decompensation and increases the risk of bleeding and rebleeding from esophageal varices.

Platelet concentrates are employed to increase the low count of cirrhosis patients, even though it is unclear which count threshold triggers the need for transfusion. Most clinicians set this threshold at at least 50×10⁹/L and optimally at 100×10⁹/L, but there are limited laboratory¹⁶ and clinical data¹⁷ that these are the critical values. Neither is it known which dose of platelet should be transfused, the most commonly used regimen being one standard adult concentrate (corresponding to approximately 300±33×10⁹ platelets). This regimen increases platelet count to a very small degree and fails to assure the normalisation of such global haemostasis tests as thrombin generation and thromboelastography. The thrombopoietin receptor agonist eltrombopag increases platelet counts in cirrhosis more markedly than transfusion, but the evaluation of this drug in cirrhosis was interrupted due the occurrence of thrombotic complications¹⁸.

Recombinant activated factor VII (rFVIIa), originally licensed for the treatment of bleeding in haemophilia A complicated by anti-factor VIII alloantibodies, was also used off-label for variceal bleeding and major surgical operations such as hepatectomy and liver transplantation. The majority of these studies were negative with regards to clinically relevant outcomes (arrest of bleeding, reduction of rebleeding, mortality)^19,20. Hence, rFVIIa is not recommended as an adjunctive haemostatic treatment for variceal bleeding, nor for bleeding prophylaxis in patients undergoing liver biopsy, transplantation or resection^21,22. Plasma concentrates of vitamin-K dependent factors (also called prothrombin complex concentrates) were used in advanced liver disease at a time when our knowledge on the poor clinical relationship between bleeding and coagulation factor deficiencies was not available². These plasma-derived products shorten or fully correct the prolonged coagulation tests and low factor plasma levels², but their clinical effect on bleeding is not substantiated, and the risk of thrombosis is looming large.

Among antifibrinolytic drugs a potential candidate is tranexamic acid that, given orally or intravenously, blocks the binding to fibrin of plasminogen and hence its conversion to plasmin. According to a Cochrane meta-analysis²³ this drug is not effective as an adjuvant in the management of acute variceal bleeding. In patients undergoing orthotopic transplantation tranexamic acid reduces to some degree blood loss and transfusion requirements^24,25, but the overall clinical benefit is generally modest because the marked improvement of surgical and anesthesiological techniques has dramatically reduced the need for transfusion during and after this operation.

All in all, transfusional and non-transfusional haemostatic drugs have an uncertain role in the prevention and treatment of bleeding in clinical settings associated with end-stage liver disease, consistently with current knowledge that bleeding does not find its main cause in the defects of haemostasis but rather in the haemodynamic alterations of portal hypertension, endothelial dysfunction, bacterial infections and renal failure. These views are supported by a review article on the treatment of variceal bleeding, which does not mention at all any haemostatic drug²⁶, whereas detailed recommendations are given on the main therapeutic approaches based upon vasoconstrictors, antibiotics and endoscopy²⁶.

Thrombotic complications in liver disease

While it is appreciated that liver disease is associated with a bleeding diathesis, it is less understood that there is a thrombotic tendency that with the aging of the patient population is likely to become more and more clinically relevant. Clinicians tend to think that owing to the prolongation of standard coagulation tests patients with chronic liver disease are naturally anticoagulated and protected from thrombosis. The risk of venous thromboembolism is indeed two-fold higher in patients with liver disease than in controls²⁷, the corresponding clinical manifestations being not only portal-vein thrombosis (that has a frequency as high as 8 to 25% in patients with advanced disease candidates for liver transplantation²⁸), but also deep vein thrombosis and pulmonary embolism²⁷. Accordingly, anticoagulant drugs should be employed in patients with liver disease who develop venous thromboembolism, notwithstanding the widespread belief that these drugs are contraindicated in patients with severe liver disease. By the same token, patients with cirrhosis are not protected from clinical manifestations of atherothrombosis (coronary artery disease and ischaemic stroke)²⁹, even though it is unknown whether or not they are at higher risk than people with no liver disease. When atherothrombotic complications occur, antiplatelet agents should be considered for secondary prophylaxis, even though in patients with severe thrombocytopenia (less than 50×10⁹/L) the risk of bleeding is not trivial.

Conclusions

The pathogenesis of bleeding in chronic liver disease is complex and multifactorial, and the haemorrhagic tendency is not explained by the multiple abnormalities of haemostasis tests. Portal hypertension with related haemodynamic alterations is much more critical than haemostasis defects in causing the bleeding tendency. Accordingly, drugs that potentiate haemostasis have a limited role in the prevention and treatment of bleeding. Antithrombotic prophylaxis and treatment should be implemented as needed in these patients, but the risk of increasing the haemorrhagic diathesis demands careful evaluation of the balance between benefits and risks in each patient.