Coagulation Disorders in Liver Disease

• ABSTRACT
• HEMOSTATIC ABNORMALITIES IN LIVER DISEASE
• Platelet Disorders
• Decreased Synthesis of Coagulation Factors
• Vitamin K Deficiency
• Dysfibrinogenemia
• Fibrinolysis
• Disseminated Intravascular Coagulation
• COAGULATION DISORDERS IN SPECIFIC CLINICAL SITUATIONS
• Invasive Procedures
• Liver Transplantation
• Pregnancy
• Sepsis
• Thrombosis
• THERAPY
• ABBREVIATIONS
• REFERENCES

ABSTRACT

The liver plays a central role in the clotting process, and acute and chronic liver diseases are invariably associated with coagulation disorders due to multiple causes: decreased synthesis of clotting and inhibitor factors, decreased clearance of activated factors, quantitative and qualitative platelet defects, hyperfibrinolysis, and accelerated intravascular coagulation. The bleeding tendency accounts for increased risk of morbidity and mortality in patients with liver disease undergoing diagnostic or therapeutic invasive procedures. Peculiar coagulation disorders are prevalent in patients with acute fatty liver of pregnancy or undergoing liver transplantation. Emerging evidence shows that sepsis further impairs hemostasis in patients with liver cirrhosis bleeding from esophageal varices. Thrombotic events, even if rare in cirrhotic patients, occur mainly in the portal and mesenteric veins. The therapeutic approach to coagulative disorders is also discussed.

The liver plays a key role in the blood coagulation process because it is the site of synthesis of all clotting factors and their inhibitors (Table [1]). Liver damage is commonly associated with variable impairment of hemostasis. Hemostasis is the process of blood clot formation to prevent excessive blood loss due to vessel injury. Subsequent to endothelial injury, the platelets adhere to subendothelial matrix through two platelet-collagen receptors (glycoproteins [GP] Ia, IIa, and VI).[1] The activated platelets express the receptor GPIb-IX-V complex that further strengthens the adhesion by linking to von Willebrand factor (vWF) expressed on the subendothelial matrix.[2] A platelet monolayer covers all the injured area, and additional activated platelets are recruited and aggregated to form a platelet plug by the linking to fibrinogen molecules via another receptor, GPIIb/IIIa.[3] Formation and deposition of fibrin occurs by activation of the clotting cascade concomitantly with platelet plug formation. A sequential activation of a series of inactive precursors leads ultimately to the formation of thrombin that cleaves fibrinogen to fibrin (Fig. [1]). As the hemostatic process starts, a series of inhibitory mechanisms is activated to localize and limit clotting formation to the damaged area (Fig. [2]): antithrombin III, protein C, protein S synthesised from the liver, the tissue factor pathway inhibitors 1 and 2 (TFPI-1 and TFPI-2), and platelet inhibitors (prostaglandin I2, nitric oxide). Once a clot is formed, fibrinolytic mechanisms assure its remodeling and elimination to restore vessel patency. Plasmin is the key enzyme of fibrinolysis, which cleaves the polymerized fibrin to fibrin degradation products (FDPs). The fibrinolytic process is regulated by a series of activators and inhibitors (Fig. [2]).

HEMOSTATIC ABNORMALITIES IN LIVER DISEASE

Considering the key role of the liver in the coagulation process, liver disease results in variable impairment of hemostasis by multiple causes: quantitative and qualitative platelet defects; decreased production of coagulation and inhibitor factors; vitamin K deficiency; synthesis of abnormal clotting factors, decreased clearance of activated factors by the reticuloendothelial system, hyperfibrinolysis, and disseminated intravascular coagulation.

Platelet Disorders

A mild thrombocytopenia is seen in 52% and 16% of cases of acute hepatitis with and without liver failure, respectively[4]; rarely a severe thrombocytopenia due to aplastic anemia complicates the course of acute hepatitis.[5] Thrombocytopenia is a common feature in chronic advanced liver disease. It is found in about 30 to 64% of cirrhotic patients,[6] [7] but the platelet count is rarely below 30,000 to 40,000/mm³, and spontaneous bleeding is not common. Splenomegaly due to portal hypertension is considered the main cause of the low platelet count in cirrhosis. The relationship between portal hypertension and thrombocytopenia is documented by the association between a low platelet count and the presence of gastroesophageal varices.[8] [9] Even if the platelet mass is normal, up to 90% of platelets are pooled in the spleen. However, these are still able to participate in the hemostatic process. Direct correlation between spleen size and platelet count has not been demonstrated, and decompression of the portal system by surgical or radiologic shunts does not completely correct the platelet count.[10] A recent flow cytometric study showed a reduced number of reticulated platelets, indicating impaired platelet production[11] in cirrhotic patients. Thrombopoietin (TPO) is a cytokine produced by the liver responsible for the maturation of megakaryocytes and the formation of platelets. Serum levels of TPO are reduced in cirrhotic patients with thrombocytopenia.[12] After liver transplantation TPO concentration promptly increases and reaches a peak on the fifth day, and a subsequent increase in the number of platelets is observed within 4 to 6 days after the peak of TPO.[13] These data suggest that low levels of TPO due to decreased hepatic synthesis play a role in the thrombocytopenia of cirrhotic patients. Increased destruction of platelets by immune mechanisms has been described: high levels of immunoglobulin G (IgG), IgM, C3-C4, and platelet-associated immune complexes have been found in acute and chronic liver diseases.[14] Furthermore, reduction of the platelet count can be ascribed to the coexistence of disseminated intravascular coagulation (DIC) during sepsis, acute hepatic failure, hemolysis elevated liver enzyme and low platelet (HELLP) syndrome. Ethanol,[15] folate deficiency,[16] and drugs may contribute to thrombocytopenia by direct suppression of bone marrow thrombopoiesis.[17] [18] Stored blood or red blood cells do not provide viable platelets or Factor V; therefore, the platelet count decreases when large quantities of blood are transfused.[19] In the absence of any coagulation factor deficiencies, a prolonged bleeding time with a normal platelet count is attributed to abnormalities of platelet functions. Defective interaction among platelets, endothelial surface, and coagulation factors, demonstrated by impaired aggregation to adenosine diphosphate, epinephrine, collagen, thrombin, and ristocetin have been described in patients with liver disease.[20] [21] As a whole, their clinical implications remain to be elucidated.

Decreased Synthesis of Coagulation Factors

The liver is the site of the synthesis of all coagulation factors except for vWF. The degree of impairment of procoagulants as an expression of decreased liver synthesis is related to the severity of liver damage, bleeding tendency, and prognosis of liver disease. The clotting factors measured by the common screening tests are in the normal range until plasma levels of procoagulants are reduced below 30 to 40% (Table [2]). The measurement of plasma levels of single clotting factors, even if available for most of them, provides little adjunctive information. The determination of Factor V, VII, and VIII activity is useful in specific clinical settings such as fulminant hepatic failure and DIC. Coagulation disorders are not common features of uncomplicated acute hepatitis. Impairment of hemostasis implies severe liver functional derangement and it is related to the severity of liver damage. Decreased hepatic synthesis and impaired clearance of clotting factors and their inhibitors coexist in patients with acute liver failure (ALF).[22] In these patients prothrombin time (PT) is commonly used as a prognostic indicator of outcome and the need for liver transplantation. In the King's College experience, PT greater than 100 seconds was predictive of mortality in 72% and 100% of cases in acetaminophen-induced and non-acetaminophen-induced ALF.[23] Factors V and VII have the shortest half-lives (12 hours and 4-6 hours, respectively), and have been evaluated as prognostic indicators in ALF. In the French-language literature, a Factor V level below 20% in patients under 30 years of age or a Factor V level below 30% in patients over 30 years of age were criteria for liver transplantation in the presence of encephalopathy grade 3 to 4.[24] Factor VIII and fibrinogen as well as the other acute phase reactants are increased, and their progressive reduction may indicate the presence of a DIC.

Depressed levels of procoagulant factors and their inhibitors are present in liver cirrhosis. In compensated liver cirrhosis, PT is usually in the normal range or only moderately prolonged. Depressed synthesis of extrinsic pathway factors, particularly Factor VII, accounts for these abnormalities.[25] Levels of fibrinogen and Factor V are normal. As liver damage worsens, Factors XII and XI, high-molecular-weight kininogens, and prekallikrein (i.e., the intrinsic pathway) are involved in the deficit of protein synthesis, and activated partial thromboplastin time is prolonged.[26] [27] PT prolongation is related to the severity of liver failure and is one of the parameters of common prognostic indices (Child-Pugh, Mayo end-stage liver disease).[28] [29] The international normalized ratio (INR) for evaluation of prothrombin time is commonly used but has not been validated in patients with liver cirrhosis.[30] Factor VIII levels may remain normal or elevated even in the presence of severe liver failure, either because of its extrahepatic synthesis or because of a decreased liver clearance of the vWF-Factor VIII complex. Plasma fibrinogen, being an acute-phase reactant, remains normal or even increases in chronic liver disease. Its decreased levels in severe liver insufficiency are attributed to decreased liver synthesis as well as extravascular loss (i.e., ascites) or concomitant DIC. Only fibrinogen levels below 100 mg/dL have clinical and prognostic significance.[31] In obstructive jaundice and primary biliary cirrhosis, normal or elevated levels of clotting factors are detectable in the absence of vitamin K deficiency,[32] due to a nonspecific activation of protein synthesis. A hypercoagulative state, evaluated by thromboelastography, may be present in patients with primary biliary cirrhosis and primary sclerosing cholangitis.[33] Natural inhibitors of coagulation, antithrombin III, protein C, and protein S are synthesized by the liver as well. Their levels are reduced in advanced liver disease.[34] Nevertheless, plasma activity below 50 to 70% is not associated with increased thrombotic events, possibly because of the proportional impairment of clotting activators.[35]

Vitamin K Deficiency

A further reduction of plasma levels of Factors II ,VII, IX, and X, and proteins C and S may be due to a concomitant vitamin K deficiency. These factors require vitamin K as a cofactor for γ-carboxylation of glutamic acid residues in their amino-terminal region. Gamma-carboxylated residues allow the binding to calcium ions essential for functional activity of these vitamin K- dependent clotting factors. Vitamin K deficiency is not caused by liver injury per se but is frequently associated with liver disease.Vitamin K is a fat-soluble vitamin requiring biliary salts for its intestinal absorption. The intestinal bacteria flora is involved as well, either participating in the biliary salt metabolism or producing a small amount of vitamin K. Thus, reduced intestinal absorption of vitamin K occurs during intra- or extrahepatic cholestasis,[36] presence of biliary fistulae, and use of cholestyramine[37] and oral antibiotics, especially cephalosporins.[38] Moreover, vitamin K deficiency may be part of the malnutrition state often associated with alcoholism.[39] High levels of decarboxylated precursors of vitamin K-dependent clotting factors are dosable in plasma in the presence of vitamin K deficiency. These precursors (named PIVKA, for precursors induced by vitamin K absence) are found in small amounts in acute and chronic liver disease possibly caused by a deficit of hepatic decarboxylase.[40] However, their clinical significance does not seem to be relevant. Conversely, high titers of decarboxylated prothrombin (DCP), antigenically identical to that induced by warfarin therapy, are found in patients with hepatocellular carcinoma.[41] An acquired posttranslational defect of γ-carboxylation induced by the tumoral cells is postulated,[42] and a DCP level greater than 100 ng/mL is considered more specific than α-fetoprotein in the diagnosis of hepatocellular carcinoma.[43]

Dysfibrinogenemia

Dysfibrinogenemia is the most common qualitative abnormality of clotting factors, found in about 60 to 70% of acute and chronic liver disease and hepatoma.[44] It is characterized by abnormal polymerization of fibrin monomers leading to a disproportionate prolonged thrombin time despite mild prolonged PT, partial thromboplastin time (PTT), and normal amount of fibrinogen. An excessive number of syalic acid residues on the molecule of fibrinogen interferes with the enzymatic activity of thrombin. Dysfibrinogenemia induced by liver damage is a reversible abnormality due to an increased activity of the enzyme syalil-transferase because of a reexpression of the fetal gene in hepatic cells.[45]

Fibrinolysis

Increased fibrinolysis is a common finding in patients with advanced liver disease. It is revealed by shortened whole blood euglobin clot lysis time and elevated levels of plasma D-dimer, fibrin and fibrinogen degradation products. High levels of plasminogen activators, especially tissue plasminogen activator (tPA), due to decreased hepatic clearance, account for hyperfibrinolysis. Levels of the tPA inhibitor plasminogen activator inhibitor-1 are normal or slightly elevated but are insufficient to counteract the increase of tPA.[46] Moreover, low levels of α₂-antiplasmin and thrombin activatable fibrinolysis inhibitor, caused by progressive liver damage, may be an adjunctive cause of accelerated fibrinolysis.[47] Controversy still exists over whether fibrinolysis is a primary phenomenon or induced by clotting activation.[46] [48] [49] Hyperfibrinolysis is seen in patients with advanced chronic liver disease but not in patients with acute liver disease. It is present in 31% of patients with compensated liver cirrhosis[50] and in 93% of patients with ascites[51] and it is related to the severity of the disease. Elevated levels of D-dimer and FDPs together with low fibrinogen and plasminogen have been found in ascitic fluid of cirrhotic patients, suggesting ascitic hyperfibrinolytic activity. Thus, it is thought that ascites reabsorption into systemic circulation contributes to the hyperfibrinolytic state found in cirrhotic patients.[51] These data are in accordance with previous observations of hyperfibrinolysis-like changes in plasma of cirrhotic patients undergoing ascites reinfusion.[52] The clinical relevance of hyperfibrinolysis in the bleeding tendency of cirrhotic patients has not been clearly established. Accelerated fibrinolysis may enhance bleeding from mucous membranes and increase the incidence of fatal bleeding.[53] [54] In a large prospective study, hyperfibrinolysis was found as a main predictive marker of the first episode of upper gastrointestinal bleeding in cirrhotics with portal hypertension.[55]

Disseminated Intravascular Coagulation

Disseminated intravascular coagulation is a widespread intravascular fibrin deposition due to massive activation of the clotting cascade. Intravascular fibrin deposition is the result of uncontrolled thrombin generation overwhelming natural anticoagulant pathways. Thrombin activation is mediated exclusively by high levels of tissue factor with consequent activation of the extrinsic pathway.[56] Deposition of fibrin in small and medium-sized vessels leads to arterial or venous thrombosis and progressive multiorgan failure. The consumption of clotting factors, platelets, and secondary fibrinolysis activation are responsible for bleeding manifestations. Moreover, microangiopathic hemolytic anemia may be due to enhanced erythrocyte destruction by fibrin strands. The clinical course of DIC may be extremely variable from asymptomatic to chronic and acute forms, depending mostly on the underlying cause, rapidity of clotting activation, and efficacy of compensatory mechanisms.[57] The fact that DIC and decompensated cirrhosis share similar coagulation abnormalities poses the question whether a low-grade DIC is present in decompensated liver disease or hepatic coagulopathy mimics a DIC-like pattern.[48] [58] [59] The issue is still a matter of debate. More recently, the availability of new sensitive and specific assays, prothrombin fragment F1+2, fibrinopeptide A, soluble fibrin, D-dimer, thrombin- antithrombin (TAT) complexes, and plasmin-α₂-antiplasmin (PAP) complexes, have allowed the recognition of accelerated intravascular coagulation and fibrinolysis (AICF) in liver cirrhosis.[60] AICF, previously defined as low-grade DIC, is not a part of stable liver cirrhosis but is found in about 30% of patients with advanced liver disease and is related to its severity.[61] AICF may be reduced by heparin administration, as already suggested by previous studies.[62] Patients with liver cirrhosis and AICF are prone to develop overt DIC in the presence of complications such as sepsis, shock, surgery, trauma, and ascites recirculation. The diagnosis of DIC in cirrhotic patients remains difficult and is based on the presence of a known triggering clinical event; the progressive worsening of coagulation test results and platelet counts; a disproportionate reduction of Factor V; and concomitant decreased level of a previously normal Factor VIII.

COAGULATION DISORDERS IN SPECIFIC CLINICAL SITUATIONS

Clinical manifestations of coagulative disorders in patients with liver disease depend on the degree of hemostatic impairment. Minor signs of the bleeding tendency are skin hemorrhages such as bruising, petechiae, purpura, and ecchymosis, or mucosal bleeding such as epistaxis, gingival bleeding, or metrorrhagia. The bleeding diathesis may have more severe and life-threatening consequences in cirrhotic patients bleeding from the gastrointestinal tract or undergoing invasive procedures or surgery.

Invasive Procedures

Patients with advanced liver disease run an increased risk of bleeding complications because of underlying coagulopathy during invasive diagnostic and therapeutic procedures. Patients with liver cirrhosis undergoing abdominal surgery have increased risks for morbidity and mortality.[63] [64] Bleeding accounts for 60% of all causes of death.[65] PT is related both to bleeding risk and mortality; patients with a PT prolongation of more than 1.5 seconds and more than 2.5 seconds have mortality rates of 47% and 87% , respectively versus 7% for patients with normal PT.[66] Hence, an accurate preoperative evaluation of cirrhotic patients undergoing surgery is mandatory. A PT prolonged for more than 3 seconds and a platelet count of less than 50,000/mm³ are considered contraindications to elective surgery.[64] Moreover, the concomitant presence of portal hypertension contributes to excessive intra- or postoperative blood loss during liver surgery for trauma, neoplasm, or portocaval shunts. Hyperfibrinolysis and clotting activation occur during resective liver surgery,[67] and they are related to the extension of liver resection and plasma levels of tPA.[68]

Liver biopsy is a widespread tool used to diagnose diffuse or focal hepatic diseases. Intraperitoneal hemorrhage is the main complication of liver biopsy. Significant bleeding, defined as a decrease in hemoglobin level of greater than 20 g/L, occurs in 0.35 to 0.5% of cases.[69] [70] A fatal hemorrhage is reported from 0.01 to 0.1%[71] and is often associated with advanced cirrhosis or malignancy. PT and platelet count are widely accepted tests used to evaluate the bleeding risk in patients undergoing liver biopsy. However, no peripheral coagulative parameters have been found related to liver bleeding time observed at laparoscopy.[72] Several studies demonstrated no increased bleeding risk associated with a prolongation of PT until 4 to 7 seconds.[69] [71] [73] On the other hand, a doubled bleeding risk is reported in patients with INR greater than 1.5 compared with patients with INR of 1.3 to 1.5.[74] Platelet count values above which liver biopsy is safely performed range from 56,000 to 80,000 mm³ in different specialized centers.[71] [74] The routine use of the bleeding time as a better indicator of hemorrhagic risk is still debated.[75] [76] It is currently used in no more than 30% of liver units before liver biopsy. Liver biopsy can be safely performed[77] if the platelet count is greater than 60,000 mm³ and PT is prolonged for less than 4 seconds. If the platelet count is between 40,000 and 60,000 mm³ and PT is prolonged for 4 to 6 seconds, platelet and fresh frozen plasma transfusions have to be given. If the platelet count is under 40,000 mm³ and PT is prolonged for over 6 seconds, a plugged, transjugular, or laparoscopic biopsy should be considered.[78] Minor invasive procedures such as paracentesis, thoracentesis, and lumbar puncture do not usually necessitate platelet or plasma transfusion.

Liver Transplantation

Coagulopathy is one of the main problems in patients undergoing orthotopic liver transplantation (OLT). Intra- and postoperative bleeding is frequent and strictly related to the mortality rate of OLT.[79] Different mechanisms are implicated in the bleeding tendency during the various phases of OLT. In the pre-anhepatic phase the duration and complexity of the surgical procedure and the presence of portal hypertension together with preexisting impaired hemostasis are the main causes of the blood loss.[80] [81] The preoperative hemostatic impairment is related to transfusion requirements and patient survival.[82] Coagulation tests are less compromised in patients with primary biliary cirrhosis,[83] and a hypercoagulative state may be present.[33] In the anhepatic phase, bleeding is due both to the absence of hepatic clotting factor production and to hyperfibrinolysis caused by increased levels of tPA not cleared by the liver.[84] A brisk increase in tPA, PAP complexes, and D-dimer levels after liver graft reperfusion indicate hyperfibrinolysis.[85] The release of tPA by graft endothelial cells contributes to hyperfibrinolysis in this phase.[86] Prophylactic administration of aprotinin, a broad-spectrum serine protease inhibitor, markedly reduces fibrinolysis and both intra- and postoperative blood product requirements by at least 30%.[87] [88] Moreover, tranexamic acid, another antifibrinolytic agent, can reduce total packed blood red cell use during OLT.[89] Other mechanisms account for bleeding tendency during OLT: a nonspecific activation of phagocytic proteases during the reperfusion phase[90]; an increased intrinsic heparin-like activity[91]; a transient platelet count decrease because of sequestration and activation of platelets in the graft sinusoids[92]; and a reduced platelet aggregation due to adenosine contained in University of Wisconsin fluid.[79] Continuous clotting monitoring during the different phases of OLT is obtained by thromboelastography (TEG), which provides rapid information (within 30 minutes) on coagulation, fibrinolysis, and platelet activity. It has proven to be a valuable guide for blood product replacement.[93]

Pregnancy

Two peculiar syndromes, HELLP syndrome and acute fatty liver of pregnancy, occurring in the third trimester of pregnancy, are associated with coagulative disorders. HELLP syndrome, first described in 1982 by Weinstein,[94] is characterized by elevation of liver enzymes, hemolysis, and low platelet count. It occurs in 10% of preeclampsia and eclampsia, and it is caused by diffuse platelet and fibrin deposition on the damaged sinusoidal endothelium. The systemic endothelial dysfunction is determined by an increased vascular sensitivity to endogenous pressor agents.[95] Fibrin deposition leads to periportal and portal tract hemorrhages and to ischemic necrosis that may progress to intrahepatic hematoma and liver rupture.[96] Moreover, hemolysis due to microangiopathic hemolytic anemia as well as thrombocytopenia[97] is generally mild. PT and PTT are normal, but FDPs, D-dimer, soluble fibrin, and PAP and TAT complexes increase as markers of secondary fibrinolysis and clotting activation.[98] An overt DIC may be diagnosed in only 20% of cases.[99] Plasma levels of coagulation and fibrinolysis parameters have prognostic value in HELLP syndrome. An antithrombin III level of less than 79%, D-dimer of more than 4 μg/mL, and TAT of more than 26 ng/mL have been proposed as indices for termination of pregnancy in patients with HELLP syndrome.[98] Acute fatty liver of pregnancy is an acute disorder during pregnancy evolving into fulminant hepatic failure.[100] It is characterized by acute hepatic fatty microvesicular degeneration, in some cases due to inherited mitochondrial fatty acid oxidation enzyme defects.[101] It is associated with elevated maternal and infant mortality. Thrombocytopenia and a decrease in clotting factors and their inhibitors are due both to impaired hepatic synthesis and accelerated consumption. DIC is present in almost all patients,[102] although bleeding complications ensue in about 25% of cases.[103]

Sepsis

High rates of bacterial infection have been demonstrated in cirrhotic patients with gastrointestinal hemorrhage.[104] It is closely related to mortality and the failure to control bleeding.[105] [106] Sepsis is generally thought to be a complication of bleeding; however, it can cause bleeding and rebleeding from esophageal varices. This is because of an increase in portal hypertension and a further impairment of hemostasis.[107] A hypocoagulable state has been demonstrated in cirrhotic patients with sepsis[108] and in those with early rebleeding from esophageal varices.[109] Hyperfibrinolysis is associated with the risk of gastrointestinal bleeding,[55] [110] [111] [112] and bleeding from esophageal varices overlaps the circadian rhythm of fibrinolysis in patients with liver cirrhosis.[113] Infection enhances the production of the cytokines interleukin-1 (IL-1), IL-6, and tumor necrosis factor that are able to activate clotting and fibrinolysis[114] via stimulation of the extrinsic pathway. Endotoxins, produced by bacteria, stimulate tissue factor expression on macrophages and clotting activation via an oxidative process.[115] [116] A relationship has been demonstrated between tissue factor levels and markers of lipid peroxidation, clotting activation, and fibrinolysis in cirrhotic patients.[117] Hyperfibrinolysis delays clotting activation through clotting factor consumption and inhibition of fibrin polymerization and reduces platelet adhesion and aggregation as well.[58] Platelet functions are further impaired by increased prostacyclin levels, which are induced by endotoxin and endothelin via nitric oxide formation.[107] How these phenomena induced by sepsis can trigger gastroesophageal bleeding remains speculative and requires further study.

Thrombosis

Coagulation disorders during liver disease mostly results in an increased bleeding tendency. However, the balance between the reduced levels of clotting activators and inhibitors may sometimes lead to hypercoagulation and thrombosis. A hypercoagulable state has been found in patients with primary biliary cirrhosis, primary sclerosing cholangitis,[83] and advanced cirrhosis, in which an accelerated intravascular coagulation may be present. Thrombosis can develop if these patients are suffering from sepsis or trauma. Spontaneous thrombosis occurs mainly in the portal and mesenteric veins in patients with liver cirrhosis. The prevalence of non-neoplastic portal vein thrombosis (PVT) ranges from 8 to 16%,[118] [119] and it is associated with increased morbidity and mortality during liver transplantation.[120] Portal vein thrombosis, like other venous thrombotic events, is due to the concomitant presence of congenital or acquired, or local or systemic risk factors.[121] The slowing of the blood flow in the splanchnic venous bed due to portal hypertension represents the local acquired risk factor. A prothrombotic state due to inherited disorders of clotting factors, Factor V Leiden, and prothrombin G20210A mutation has been found in PVTs of cirrhotic patients.[122] [123] Anticardiolipin antibodies, usually associated with antiphospholipid syndrome, an acquired thrombophilic condition, have been advocated in the pathogenesis of PVT.[124] However, the association between anticardiolipin antibodies and clinical thrombotic events in patients with chronic hepatitis,[125] [126] liver cirrhosis,[127] or patients receiving a liver transplant has not been demonstrated.[128] Further studies addressing this issue are needed.

THERAPY

Spontaneous bleeding is infrequent in patients with advanced liver disease, and treatment of hemostatic abnormalities is not generally required. On the other hand, correction of coagulation disorders in patients with liver disease has to be pursued in cases of active persistent bleeding, before diagnostic or therapeutic invasive procedures, before major surgery, and in patients with ALF. Different blood and nonblood products are available as supportive or repletive treatments.

Fresh frozen plasma (FFP) contains all clotting and inhibitor factors. Administration of 10 to 20 mL/kg body weight of FFP may curtail PT prolongation to less than 3 seconds.[27] The correction of coagulation parameters is prompt but lasts no more than 12 to 24 hours. The lack of correction of clotting parameters after adequate FFP transfusion suggests the presence if inhibitors such as FDP or dysfibrinogenemia. Administration of FFP is indicated in cases of persistent bleeding in order to gather an INR of under 2[129] and to correct a PT prolongation of more than 4 seconds in patients undergoing liver biopsy.[77] However, the large amounts of FFP (>1,500 mL) required to achieve the hemostatic effect could be contraindicated in some patients.[130] The risk of transmission of infectious agents by FFP transfusion, as for other blood products should not be underestimated.[131]

The solvent detergent-treated plasma is effective to lessen the risk of transmission of viral infections, but it is deficient in Factor VIII, protein C, protein S, and α₂-antiplasmin.[132]

Cryoprecipitate, obtained when FFP is thawed at 4°C, contains Factor VIII, fibrinogen, vWF, fibronectin, and Factor XIII. One unit of cryoprecipitate (20-30 mL) for every 10 kg body weight increases plasma fibrinogen by 50 mg/dL.[133] Administration of cryoprecipitate is indicated in bleeding patients when fibrinogen levels are less than 80 to 100 mg/dL because of DIC or massive blood transfusion.

Prothrombin complex is a concentrate of Factors II, VII, IX, and X, obtained from the plasma of several thousand donors. The use of prothrombin complex is limited by the risk of infectious disease transmission,[134] anaphylaxis, and the risk of DIC because of the presence of activated clotting factors.[135] [136]

Recombinant Factor VIIa is a promising agent to correct hemostatic impairment in patients with liver failure.[137] In preliminary reports, 80 μg/kg dose of recombinant Factor VIIa (Novoseven, Novo Nordisk Pharmaceuticals) normalized PT for more than 12 hours in patients with Child-Pugh class B and C cirrhosis.[138] It has been successfully used to restore coagulative parameters in a small number of patients with acute liver failure.[139] Lastly, a single dose of Novoseven seems to reduce blood product requirements during liver transplantation.[140] The overall potential benefits and risks of recombinant Factor VIIa need to be confirmed in large controlled studies.

Platelet transfusion is required in patients with active persistent bleeding when the platelet count is less than 50,000/mm³.[133] [141] A platelet count of around 100,000/mm³ needs to be attained.[27] Prophylactic use of platelet concentrates is only indicated in patients undergoing invasive diagnostic procedures or elective surgery when the platelet count is less than 60,000/mm³.[77] [133] One unit of platelet concentrate increases the peripheral blood count by about 10,000/mm³, and the therapeutic dose is 1 U/10 kg body weight.[133] Platelets derived from a single donor by apheresis correspond to six random platelet concentrates. Repeated platelet transfusion induces alloimmunization and refractiveness to new transfusion.[141] This is an important issue in patients on the waiting list for liver transplantation in which HLA-matched and cross-matched platelets may be required.[142] The use of recombinant TPO for the correction of thrombocytopenia of cirrhotic patients is still under investigation.[143]

Vitamin K deficiency is not usually present in patients with liver cirrhosis, whereas it is likely in patients with cholestatic disease. A trial of 10 mg vitamin K for 3 days has to be attempted to correct PT prolongation.[95] Vitamin K can be administered intravenously with the advantage of a therapeutic effect within 6 to 8 hours,[144] but anaphylaxis can occur. Subcutaneous administration has an inconstant rate of absorption, whereas intramuscular injection has to be avoided because of the risk of hematoma formation. Menadiol, the water-soluble formulation of vitamin K, has proved effective when given orally to correct the INR in patients with cholestasis.[145]

Desmopressin, 1-deamino-8-D-arginine vasopressin (DDAVP), a derivative of antidiuretic hormone, can increase plasma levels of Factor VIII and vWF,[146] [147] releasing them from storage sites.[148] Bleeding time, PT, and PTT are shortened by DDAVP in patients with liver cirrhosis despite normal or elevated Factor VIII and vWF.[146] [147] However, no clinical benefits have been demonstrated in cirrhotic patients bleeding from esophageal varices.[149] Its use is proposed in patients with liver disease and prolonged bleeding time undergoing invasive procedures.[148]

Antifibrinolytic agents such as aprotinin, epsilon-aminocaproic acid, and tranexamic acid are the most commonly used antifibrinolytic agents. They induce inhibition of plasminogen activation and plasmin activity. These drugs have proved useful in the reduction of blood loss and transfusion requirements during major liver surgery and OLT.[85] [87] [88] [89]

Administration of antifibrinolytic agents in patients with liver cirrhosis is limited by the risk of thrombosis when DIC is present.

ABBREVIATIONS

AICF accelerated intravascular coagulation and fibrinolysis

ALF acute liver failure

DCP decarboxylated prothrombin

DDAVP 1-deamino-8-D-arginine vasopressin

DIC disseminated intravascular coagulation

FDPs fibrin degradation products

FFP fresh frozen plasma

INR international normalized ratio

OLT orthotopic liver transplantation

PAP plasmin-α₂-antiplasmin complexes

PT prothrombin time

PTT partial thromboplastin time

PVT portal vein thrombosis

TAT thrombin-antithrombin complexes

TFPI tissue factor pathway inhibitor

tPA tissue plasminogen activator

TPO thrombopoietin

vWF von Willebrand factor

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