Patients with severe liver disease are at increased risk for bleeding either spontaneous or induced by drugs or invasive procedures (i.e., liver biopsy, paracenthesis). The bleeding in chronic liver diseases usually comes from esophageal or gastric varices, and less commonly from congested gastric mucosa or gastro-duodenal ulcers. Systemic bleedings are rare and usually manifest from skin, mouth, nose as well as from sites of intravenous catheterization or endotracheal tubes. In many patients with portal hypertension bleeding is aggravated by coexisting clotting alterations commonly present in advanced liver diseases. Platelet count <50.000/μl and PT prolongation of>3 seconds are relative contraindications to elective surgery (1, 2).

Treatment of coagulative abnormalities in liver disease is complex and challenging, since it is influenced on one hand by the type of coagulopathy and on the other, by relative unreliability of routine coagulation tests like prothrombin time (PT), international normalization ratio (INR) or partial thromboplastin time (PTT) (3).

Vitamin K should be given by parenteral way if there is cholestasis related to biliary obstruction or an evidence of bacterial overgrowth, malnutrition or prolonged use of antibiotics. Generally, vitamin K has poor efficacy in treatment of coagulopathies caused by parenchymal liver injury without cholestasis. Anyway, the dose of 10 mg of vitamin K may be given intravenously for 3 days to ensure that vitamin K deficiency is not contributing to haemostatic disorders.

Plasma frozen within 8 hours of collection (fresh frozen plasma; FFP) is the main product used in patients with hepatic-related coagulopathies. Common indication for FFP infusion is persistent bleeding in patients with INR>2 or PT prolongation over 4 sec of normal value (4). The recommended starting dose is 15 ml/kg body weight, however, in practice often larger amounts of FFP are needed to effectively correct haemostatic defect (up to 25 ml/kg).

In majority of cirrhotic patients normally used doses of FFP are inadequate to restore deficient clotting factors. For example, 4 units of FFP increase levels of most clotting factors by only 10%, leaving bleeding patients with increased INR (5). The efficacy of FFP in bleeding patients with severe liver disease should be assessed clinically, because PT or PTT may be not credible indicators of haemostasis in these circumstances (6, 7).

FFP administration is associated with many complications, of which most important are transfusion-related lung injury (TRALI), allergic reactions and transfusion-associated circulatory overload (TACO). Table 1 shows diagnostic criteria and treatment approaches in TRALI and TACO. Biologically active molecules being present in FFP, such like cytokines and antibodies, activate leukocytes, which damage endothelial cells in pulmonary microvessels, leading to development of vascular-related pulmonary edema (8). The treatment of TRALI includes oxygenation and ventilatory support. Diuretics should not be used in this setting. Cautious use of larg amounts of FFP is the most important measure to prevent TRALI. Interestingly, plasma from male donors, who have not been transfused with blood products before donation, contains fewer leucocytes activating molecules than female donated plasma. TRALI remains the most serious complication of FFP transfusion, occurring 12-folds more commonly than it happens with other blood products and carrying a 5-10% mortality (9, 10).

Allergic reactions related to FFP infusion are reported in 1-3% of cases and can be life-threatening in multitransfused patients. Transmission of prions still raises concern regarding FFP therapy (8).

TACO is mainly seen in patients with cardiac failure. Treatment measures are compatible with management of pulmonary edema, but patients may poorly and slowly respond to diuretics. Isovolemic exchange transfusion is the best preventive measure (9). Generally, the volume of transfused FFP should not exceed 2000 ml, and in patients requiring fluid restriction no more than 600-800 ml of FFP may be infused (tab. 2).

Cryoprecipitate (CRYO) is not expensive concentrated source of fibrinogen. Apart from fibrinogen CRYO contains factor VIII, von-Willebrand factor (VWF), fibronectin and factor XIII. It should be remembered that CRYO is depleted of some coagulation factors.

CRYO is recommended in patients with disseminated intravascular coagulation (DIC) or active fibrinolysis with severe hypofibrinogenemia (<50-100 mg/dl). Haemostatic level of fibrinogen is believed to be higher than 100 mg/dl, however, many patients with plasma fibrinogen levels below 50 mg/dl may not present bleeding. An advantage of CRYO in patients with late-stage liver cirrhosis or acute liver failure is small volume of infusion (1 unit has a volume of 10-15 ml). The clinical experience with CRYO in hepatic coagulopathies is limited.

CRYO is transfused within 10-15 minutes after thawing. A single unit of CRYO given per 10 kg body weight is expected to increase fibrinogen concentration by 50 mg/dl in the absence of significant endogenous consumption of fibrinogen or bleeding (11). CRYO replacement therapy does not correct the underlying hyperfibrinolytic defect, but temporary improves fibrinogen concentration. In the randomized comparative clinical trial performed in haemorrhagic patients with acute liver failure, 5 units of CRYO were less effective in improving PT than 4 units of FFP, but one patient in the FFP group developed pulmonary edema (12).

Volume expansion is sometimes required in patients with cirrhosis who are bleeding, have bacterial infection or developed renal failure. Albumin is the most effective volume expander with long half-life. Albumin has shown benefit in maintaining renovascular homeostasis while having minimal effect on portal haemodynamics and haemostasis (13). Volume expansion should be performed with caution, since fluid overload may augment portal pressure, increasing the likelihood of variceal bleeding.

Recombinant factor VIIa (rVIIa) is currently a second-line haemostatic drug characterized by short biological half-life (2-3 hours). A single dose of 4.8 mg should be administered within 10-15 minutes as intravenous transfusion (14) (tab. 2). In study by Bosch et al. (15) 242 cirrhotic patients with gastrointestinal bleeding were randomized to two treatment arms i.e., eight doses of rVIIa 100 μg/kg and placebo. All patients were receiving standard therapy to achieve haemostasis. Benefit in control of bleeding with rVIIa treatment was observed only in patients with advanced cirrhosis (Child Pugh class C). In another study from the same center low and high doses of rVIIa were compared with respect to control esophageal varices bleeding in patients with advanced liver cirrhosis (16). The study showed no difference in controlling bleeding within first 24 hours and no difference in rebleeding and mortality rates at day 5. Shami et al. (17) retrospectively compared eight patients with acute hepatic failure who had been treated with FFP alone with seven patients with the same disease who had been given FFP and low dose rVIIa (40 ?g/kg). The target of this study was correction of INR before placement of intracranial pressure sensor. Only patients treated with FFP plus rVIIa achieved normal INR values, while in those who received FFP alone no correction of the INR has been noticed. Again no differences were seen between both groups regarding bleeding complications, survival time or need for liver transplantation.