Advances in Medical SciencesMedical University ofBialystok, DOI: 10.2478/v10039-010-0018-3 Vol.

55(1) 2010 pp 16-21 Poland

Coagulopathy in liver diseases

Pluta A1, Gutkowski K2*, Hartleb M2
1 Basildon and Thurrock University Hospital, Basildon, Essex, United Kingdom 2 Department of Gastroenterology and Hepatology, Medical University of Silesia, Katowice,Poland

* CORRESPONDING AUTHOR: Department of Gastroenterology and Hepatology, Medical University of Silesia, ul. Medykw 14; 40-752 Katowice, Poland telephone: 0048327894401 e-mail: kgutski@intertele.pl (Krzysztof Gutkowski)

Received 03.11.2009 Accepted 08.04.2010 Advances in Medical Sciences Vol. 55(1) 2010 pp 16-21 DOI: 10.2478/v10039-010-0018-3 Medical University of Bialystok, Poland

ABSTRACT
Liver cirrhosis is associated with number of hematological complications and coagulation disturbances. In view of various haemostatic abnormalities it is surprising that many patients do not bleed spontaneously. Severe coagulopathy of liver disease is more frequently seen in acute liver failure, but still remains important complication of liver cirrhosis and chronic liver failure. Decreased production of blood coagulation factors by the liver plays a key role in altered haemostasis in liver diseases. Altered fragile balance of blood coagulation proteins and infection are associated with both worsening coagulopathy and bleeding risk. Additional haemostatic abnormalities in patients with severe liver diseases are thrombocytopenia, chronic disseminated intravascular coagulation, accelerated fibrinolysis, hypofibrinogenemia and dysfibrinogenemia. In this review we discuss a complicated issue of multiple coagulopathies in patients with advanced liver dysfunction. Key words: coagulopathy, liver disease, haemostasis, fibrinolysis

INTRODUCTION
Gastrointestinal haemorrhage is common complication in patients with advanced liver disease. In majority of cases it originates from specific sites such like esophageal or gastric varices, peptic ulcer and gastric mucosa. Coagulopathy in liver disease is directly linked to liver function, since hepatic parenchymal cells produce most factors of clotting and of fibrinolytic systems[1]. Haemostasis can be disrupted by a variety of liver diseases, however in majority of patients laboratory abnormalities reflecting impaired haemostasis are not apparent clinically. Cirrhosis, which is a final stage of many liver diseases, is known to be associated with number of hematological complications, especially thrombocytopenia and coagulation disorders. In patients with severe liver disease altered blood coagulation, accelerated intravascular coagulation and fibrinolysis (pseudo-DIC), dysfibrinogenemia and thrombocytopenia are common findings (Tab. 1). In this review we discussed a sequence of events, which may lead to coagulopathy in patients with advanced liver dysfunction.

REVIEW
Altered fragile balance of blood coagulation proteins

Liver is the site of synthesis of fibrinogen, factors II, V, VII, IX, XI, XII, and XIII [1]. Factor VIII is synthesized mainly by the sinusoidal endothelial cells and in small amounts is also released by endothelial cells of kidney, spleen, lungs and brain [2,3,4]. In chronic inflammatory liver diseases, the serum level of Von Willebrand factor (vWF) and factor VIII may be normal or increased [4-6]. Liver is contributing in vitamin K dependent post ribosomal conversion of glutamic acid residues in the protein precursors to gamma carboxyglutamic acid, which is active in blood coagulation process [7]. A failure of carboxylation of coagulation factors result in production of abnormal protein molecules (proteins induced by vitamin K absence, PIVKA), than cannot be bound by calcium bridges to form structural phospholipids surfaces. Among vitamin K dependent factors, factor VII is the most sensitive marker of liver injury due to shortest half-life time [8], however factor VII considerably reduced levels are still sufficient for effective hemostasis needs due to its only induction role in secondary hemostasis.

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Pluta A, Gutkowski K, Hartleb M

In chronic liver diseases the levels of anticoagulative proteins like antithrombin III, proteins S, protein C and alpha-2 macroglobulin are reduced. At the same time, levels of plasminogen and heparin cofactor II are elevated [8,9]. The haemostatic state in patients with severe liver disease should not be considered as intrinsically pro or anticoagulant condition, but rather as a state of reduced capability to maintain the fragile haemostatic balance. In hepatic failure a reduction in the levels of the pro- and anticoagulant proteins synthesized by the liver does not impair thrombin generation until its concentration is quite low. Indeed, there is no significant change in the ability of the system to generate haemostatic levels of thrombin, when thrombomodulin, the activator of the anticoagulant protein C, is added to the test mixture [10]. However, the ability of the fragile coagulation system to tolerate or recover from an insult is markedly impaired in liver disease, easily tipped into a state favoring either haemorrhage or less frequent thrombosis [11]. Vast majority of patients are not presenting with bleeding tendency, but coagulation tests show often prolonged prothrombin time, (PT), raised D-dimers and prolonged activated partial thromboplastin time (aPTT). Each stressing factor e.g. infection, limits buffering capacity and makes the system fragile and prone to escape from this balance. Liver function reserve is poor, and the delicate haemostatic balance may also be perturbated by other conditions, such as infection, variceal bleeding or renal failure [12,13].

Blood coagulation in patients with bacterial infections and chronic liver disease (heparin-like effect)

Recently the role of heparin-like substances has been studied in patients who have liver cirrhosis and bacterial infection. Bacterial infections has been associated with an increased risk of early recurrent bleeding in many patients. Twenty cirrhotic patients who experienced early rebleeding after variceal haemorrhage were studied prospectively and found to have worsening thromboelastography (TEG) parameters the day before rebleeding compared to cirrhotics who did not rebleed [18]. This finding was not accompanied by different values of standard coagulation parameters, and the only difference between the two groups was the incidence of bacterial infection. Similar results were obtained by Papatherodoridis et al. [19]. In study by Montalto et al. the blood of 28 among 30 infected cirrhotics showed a heparin-like effect and abnormal TEG trace [20]. It therefore seems that endogenous heparinoids contribute to coagulopathy in patients with liver disease, most likely due to increased release of heparinoids from endothelium in response to bacterial endotoxins. Antibiotics therapy has an established place in prevention of infection during variceal bleeding, and this approach reduces rebleeding rate and mortality.

Levels of natural anticoagulants as protein C and AT-III are reduced paralelly with levels of the procoagulants [14]. PT and aPTT are reflecting thrombin generation and are less sensitive to reflect the inhibition of thrombin-mediated anticoagulants. They are suitable tests to investigate congenital or warfarininduced deficiencies of coagulation factors, but not to explore the acquired deficiencies of procoagulants and anticoagulants [14,15]. For this reason, PT and aPTT are poor predictors of bleeding in patients with cirrhosis [15]. Since platelets contribute to the generation of thrombin, the occurrence of thrombocytopenia or platelets dysfunction could affect the generation of thrombin in liver cirrhosis [16]. Patients with liver disease present more complex blood coagulation abnormalities in comparison to patients on warfarin or with inherited deficiencies of clotting factors. Even results of thrombin generation tests performed in cirrhotics (platelet-rich plasma in the presence of thrombomodulin), were indistinguishable from that of healthy individuals under the same experimental conditions, provided that the platelet levels were higher than 60 x 109/l. [17]. History of bleeding, presence and size of oesophageal varices, degree of portal hypertension, presence of co-morbid conditions such as renal failure or anemia represents better predictive value of bleeding in cirrhotic patients than routine coagulation tests.

PT and APTT in cirrhotic liver disease

It is well known that hyperfibrinolysis may complicate the clinical course of decompensated cirrhosis or acute liver failure. There are several reasons for increased rate of fibrinolysis and clot breakdown. First, the patients with severe liver disease have an increased concentration of tissue plasminogen activator because of its decreased hepatic clearance. Second, hepatic production of the fibrinolysis inhibitor and the thrombin activatable fibrinolysis inhibitor is decreased. Pro and antifibrinolytic proteins are synthesized by the liver with the exception of tpa (tissue plasminogen activator) which is produced also by endothelial cells. Finally, in patients with liver cirrhosis a decreased concentration of alpha2-antiplasmin, an inhibitor of plasmin activity was found [21,22] Bacterial infection may be involved in hyperfibrinolysis through increased release of tpa [23]. In patients with peritoneovenous shunt the ascitic fluid re-entering the systemic circulation may start or accelerate fibrinolysis [24]. The most important endoscopic predictors of oesophageal bleeding are the size of varices and red wale marks seen on their surface [25]. It was also shown, that increased blood level of D-dimers predicted gastrointestinal bleeding and was associated with degree of ascites and liver failure [26]. Increased fibrinolysis worsens variceal bleeding by delaying blood clotting, causing platelets dysfunction and inhibiting fibrin polymerization.

Hyperfibrinolysis

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Although DIC-like laboratory abnormalities (so called pseudoDIC) are frequently observed in chronic liver diseases, clinically evident DIC is rare and autopsy studies in cirrhotics have shown little evidence for fibrin deposition [27]. Fibrinpeptide A is sensitive marker, quantifying dynamics of proteolytic cleavage reaction. Occurrence of increased concentrations of D-dimers, high molecular weight fibrin/ fibrinogen complexes or soluble fibrin reflects an abnormal profile called accelerated intravascular coagulation and fibrinolysis [AICF]. AICF probably results from the formation of fibrin clot that is more susceptible to plasmin degradation because of elevated levels of tissue plasminogen activator (tPa) or presence of abnormal fibrinogen [28]. AICF is present in about 30% of cirrhotics and seems to occur predominantly in patients who have moderate-to-severe liver failure, being not detected in patients with preserved liver function [29]. This disorder may be more important in the portal venous than in systemic circulation being related to more significant endotoxemia [8,30].

Accelerated fibrinolysis

intravascular

coagulation

and

Dysfibrinogenemia

Serum fibrinogen level is usually slightly reduced or remains normal despite severe hepatic failure. However, the fibrinogen produced in such patients has increased amount of sialic acid (similar to fetal fibrinogen) that renders the fibrinogen molecule abnormal and prolongs thrombin time. Despite this alteration, it is unlikely that the dysfibrinogenemia associated liver disease significantly contributes to systemic bleeding in vast majority of patients [38].

Platelets abnormalities in liver diseases

Hypercoagulation in liver disease; DIC syndrome

Despite clinical evidence of increasing bleeding tendency in cirrhotic patients many facts indicate to local and systemic hypercoagulability leading to portal vein thrombosis, deep vein thrombosis and pulmonary embolism [31]. Northup et al. [31], classified hyperocoagulable conditions in cirrhotics into macrovascular (portal and hepatic veins thrombosis, deep nonsplanchnic venous thrombosis and pulmonary embolism) and microvascular thrombotic disease. The prevalence of extrahepatic portal vein thrombosis in cirrhotic patients ranges from 3% to 13,8% [32,33]. The cause of increased incidence of portal vein thrombosis in cirrhotic patients seems to be combination of sluggish blood flow in the hypertensive portal venous system with overlapping heterozygotic mutations in genes controlling coagulation/fibrynolysis balance, especially prothrombin gene 20210 mutation [34]. Diagnostic screen of thrombophlia is recommended in such patients. Microvascular thrombotic disease may contribute to portopulmonary hypertension, hepatorenal syndrome and spontaneous bacterial peritonitis. DIC syndrome is common complication of peritoneovenous shunts [35-37]. Ragni et al. [36] detected DIC syndrome in 10 of 11 patients with peritoneovenous shunts and Rubinstein et al. [37] reported this syndrome in 14 of 27 patients who underwent shunt procedures. It has been evidenced that thrombin activity is retained in ascitic fluid and tissue factors, bearing monocytes and macrophages may be infused along with the ascitic fluid into the blood. The only effective treatment of symptomatic DIC is to discontinue the shunt. The laboratory abnormalities that accompany peritoneovenous shunts, fatty liver of pregnancy or massive hepatic necrosis of different etiologies are compatible with clinical and laboratory presentations of acute DIC [37].

Many patients with acute viral hepatitis, drug-induced hepatitis, acute liver failure of any cause and chronic liver disease with portal hypertension may present with thrombocytopenia. The pathogenesis of thrombocytopenia includes splenic sequestration in portal hypertension, impaired platelet production and thrombin mediated platelet consumption [39]. Rarely thrombocytopenia is caused by presence of antiplatelet antibodies. Thrombocytopenia may also be a consequence of myelosupression resulting from HCV infection, folic acid deficiency or ethanol chronic consumption, which has a negative effect on megacaryocytopoiesis [40-43]. Bleeding as a result of isolated thrombocytopenia is uncommon in chronic liver diseases unless it is severe or associated with coagulation abnormalities or renal impairment. Von Willebrand factor is markedly elevated in blood of patients with liver disease what may compensate for any defect in platelet function and to some extent for the decrease in platelet counts [44]. Testing of platelet functions from cirrhotic patients in models using flowing blood does not show their apparent impairments [45]. In particular, the capacity of platelets to provide a surface for thrombin generation is not altered, what confirms that there is no intrinsic platelet defect in patients with liver cirrhosis [46].

Clinically oriented differential diagnosis based on coagulation tests

Tab. 1 summarise coagulation screening tests results used in diagnostic steps of investigation bleeding tendency in liver diseases. Some physicians [38], beliefs that haemostatic screening tests may help differentiate certain types of liver diseases: acute hepatitis, obstruction of the biliary system and liver cirrhosis (Tab.2). Normal level of factor VIII (produced by endothelial cells) with decreased levels of factors II, V and VII suggest liver failure. Factor VIII is an acute phase reactant, which can be elevated to supraphysiological levels and then drop to normal levels during a consumptive coagulopathy. Thus, a ,,normal factor VIII activity cannot rule out DIC syndrome. Importantly, coagulopathy of liver failure and DIC are not mutually exclusive, and they can occur simultaneously in some patients.

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Pluta A, Gutkowski K, Hartleb M

Table 1. Results of some coagulation tests in advanced liver diseases. LABORATORY ALTERATIONS FACTOR VII DEFICIENCY EXCESSIVE FIBRINOLYSIS* FACTORS II,V,VII DEFICIENCES DIC SYNDROME HYPOFIBRINOGENEMIA DYSFIBRINOGENEMIA THROMBOCYTOPENIA HEPARIN CONTAMINATION PT Sec N N or N or N APTT Sec N N Nor N or N or Nor N N or TT N N or N N or N Fibrinogen N N N N N N Platelets N N N N N N D-DIMER N N or N or N N N N FIBRINOLYSIS* N N N or N or N or N N F VII N or N N N N

Excessive fibrinolysis may be associated with a raised Ddimer, low fibrinogen concentration and prolongation of PT, PTT, TT. Fibrinolysis can be assessed by clot lysis time, euglobulin lysis time, D-dimer assay, fibrinogen degradation product assays, test of tissue plasminogen activity or thromboelastogram clot lysis index. Table 2. Coagulative abnormalities in different types of liver pathology. PT DIC SEVERE ACUTE HEPATITIS LIVER FAILURE BILIARY OBSTRUCTION END STAGE LIVER DISEASE BILIARY ATRESIA PTT FVIII or N N N N FVII FV Fibrinogen N or

Severe acute hepatitis is associated with marked abnormalities in screening tests, including markedly elevated PT/PTT and very low fibrinogen level. Factors V and VII are moderately decreased with significant elevation of factor VIII. Biliary obstruction is accompanied by: disproportionably elevated PT compared to moderate early rise in PTT, normal to slightly increased fibrinogen level and markedly low factor VII, but normal to only slightly suppressed factor V. Biliary cirrhosis, such as occurs due to congenital biliary atresia or primary biliary cirrhosis, is hematologically similar to end stage liver disease, presenting a slightly elevated fibrinogen level and slightly decreased both the factor V and the platelet count. End stage liver disease is similar to biliary obstruction in terms of the markedly elevated PT, normal to slightly increased PTT and decreased factor VII. On the other side, end-stage liver disease may be differentiated from biliary obstruction by a slightly decreased fibrinogen and platelet count, and moderately decreased factor V. Factor VIII tends to be more elevated in end-stage liver disease. End-stage cirrhosis differs from acute hepatitis by manifesting only a slightly increased PTT and decreased fibrinogen level, compared to the marked discrepancies in both of these screening tests in acute hepatitis [38].

CONCLUSSIONS
1. Coagulation defects in severe liver disease are multifactorial and depends from altered fragile balance between reduced concentration of pro- and anticoagulation proteins. 2. Reduced levels of pro and anticoagulant factors is much harder to maintain effective haemostasis in stressful situations as infections . 3. Heparin like effect is a newly recognized abnormality reported in patients with advanced liver diseases and bacterial infections. It can be diagnosed by TEG studies. 4. Accelerated intravascular coagulation with fibrinolysis and chronic DIC are commonly seen in these patients groups. 5. Prolonged global coagulation tests are poor predictors of bleeding complications.

1. Kelly DA, Summerfield JA. Hemostasis in liver disease. Semin Liver Dis. 1987 Aug;7(3):182-91. 2. Wion KI, Kelly D, Summerfield JA, Tuddenham

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