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© Borgis - Postępy Nauk Medycznych 1/2010, s. 63-68
Andrzej Pluta1, *Krzysztof Gutkowski2, Marek Hartleb2
Leczenie koagulopatii w ciężkich uszkodzeniach wątroby
Treatment of coagulopathies in severe liver disease
1Department of Haematology, Basildon & Thurrock University Hospital, United Kingdom
Head of the Department: dr. Paul Cervi MRCPath
2Department of Gastroenterology and Hepatology, Medical University of Silesia, Poland
Head of the Department: prof. Marek Hartleb
Koagulopatie u pacjentów z zaawansowaną chorobą wątroby są konsekwencją wielu zaburzeń w zakresie układu hemostazy. Do najistotniejszych należy obniżenie stężeń osoczowych czynników krzepnięcia i fibrynolizy, których synteza odbywa się głównie w hepatocytach i komórkach śródbłonka naczyń zatokowych wątroby. Niewydolna wątroba odpowiada także za obniżony klirens aktywatorów i inhibitorów procesu krzepnięcia. Zaawansowane hepatopatie powodują niedobór witaminy K i zaburzenia gamma-karboksylacji skutkujące produkcją wadliwych czynników krzepnięcia, a nadciśnienie wrotne stanowi przyczynę małopłytkowości. Nieprawidłowości te zwiększają ryzyko krwawień lub rzadziej powikłań zakrzepowych. W większości przypadków leczenie zaburzeń hemostazy u pacjentów z ciężkim uszkodzeniem wątroby jest konieczne wyłącznie w przypadku krwawienia lub przed planowanymi inwazyjnymi procedurami diagnostycznymi i terapeutycznymi.
W niniejszej pracy przedstawiamy problematykę zastosowania różnych opcji terapeutycznych u chorych z zaburzeniami hemostazy w przebiegu ciężkich uszkodzeń wątroby ze szczególnym uwzględnieniem aktualnie obowiązujących zaleceń.
Coagulopathy in patients with severe liver disease results from multiple abnormalities in the haemostatic system. The most important is reduced plasma levels of both procoagulative and anticoagulative factors synthesized by hepatocytes and endothelial sinusoidal cells. Failing liver is responsible for impaired clearance capacity of proteins playing a role of both the activators and inhibitors of coagulation factors. Patients with severe liver disease suffer from vitamin K deficiency leading to production of abnormal clotting factors because of impaired gamma-carboxylation. Additionally, portal hypertension is responsible for reducing the number of circulating platelets. These all factors put the patients with advanced liver diseases at increased risk of bleeding or less frequently thrombotic complications. In most cases specific therapy for coagulation disturbances is needed only during bleeding or before scheduled invasive diagnostic procedures or surgeries. In this paper the role of various treatment approaches in patients with severe liver diseases and haemostatic abnormalities have been discussed with special attention paid to current recommendations.

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
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.
Fresh frozen plasma
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).
Table 1. Diagnostic criteria of transfusion related lung injury (TRALI) and transfusion associated circulatory overload (TACO).
Risk factors
Female donor FFP, blood products containing anti-leucocytic antibodies.Elderly of small stature, small children, patients with compromised cardiac fuction.
Immune mediated (anti-HLA or anti-neutrophilic antibodies, typically against recipients antigens).Volume overload.
Clinical characteristics
Onset of symptoms within 6 hours of transfusion.Onset of symptoms within 6 hours of transfusion.
Hypoxemia (alveolar-arterial gradient >300 mmHg or room air Sp02 <90%).Hypoxemia (alveolar-arterial gradient >300 mmHg or room air Sp02 <90%).
Bilateral infiltrates in interstitial and alveolar spaces, o cardiomegaly.Alveolar and interstitial edema, Kerley B lines, pleural effusions or cardiomegaly.
Normal or low central venous pressure or pulmonary artery occlusion pressure. Normal brain natriuretic peptide, BNP.Presence of any of the following: pulmonary artery occlusion pressure >18 mmHg, BNP>250 pg/ml or pre/post transfusion BNP ratio >1.5; absence of rapid improvement with diuretic therapy.
No underlying lung injury.Systolic ejection fraction <45% or systolic blood pressure >160 mmHg.
Stop transfusion, oxygenation, ventilatory supportive care, mechanical ventilation, vasopressor medication. Medication are not effective.Cessation or reduction rate of FFP infusion, placement of patient in sitting, position, oxygenation. Medication are not very effective. Phlebotomy in severe cases.
Only male donor FFP. Prudent use, mainly in active haemorrhage with low fibrinogen. Avoid further transfusion from implicated donor.Isovolemic exchange transfusion. Transfuse future blood products more slowly. Consider pre-emptive diuretic therapy.
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).
Table 2. Treatment approach to coagulopathies in severe liver disease.
ProductDoseIndications, side effects, remarks
Fresh frozen plasma 15 ml/kg body weight within 60-90 minutesBleeding in patients with INR>2 or PT>4 sec of normal, concerns regarding TRALI and TACO.
Cryoprecipitate1 unit/5-10 kg body weight or 10 units as starting doseBleeding with: hypofibrinogenemia, low fibrinogen level in DIC, hyperfibrinolysis. Fever, chills, allergic reactions.
Epsilon aminocaproic acidAverage dose 10-30 g/24 hoursHyperfibrinolysis, dysfibrinogenemia May cause renal dysfunction and skeletal muscle weakness. Contraindicated in DIC.
Tranexamic acid 25-40 mg/kg/24 h by slow infusion Hyperfibrinolysis, dysfibrinogenemia Increased risk of thrombosis, nausea. Contraindicated in DIC.
Recombinant factor VII For adults 4.8 mg i.v. within 10-15 minutes, higher dose may required if body weight > 70 kg.Severe bleeding in liver coagulopathy, not very efficient in patients with low fibrinogen. Due to short half-life next dose may be needed after 3-4 hours.
Prothrombin complex concentrate25 IU/kg body weight i.v. within 15-20 minutes Licensed in UK for Warfarin induced coagulopathy. Use in chronic liver disease is still investigational. May cause thrombotic complication.
Exchange transfusionBased on assessment of fluid overloadUsed when FFP fail to correct coagulopathy or in patients with coexistent severe fluid overload.
Red packed cells Adequate to keep haematocrit >25%Indicated before invasive procedures for improving blood rheology.
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
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
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.

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otrzymano: 2009-10-30
zaakceptowano do druku: 2009-12-04

Adres do korespondencji:
*Krzysztof Gutkowski
Department of Gastroenterology and Hepatology
Medical University of Silesia
14 Medyków Str., 40-752 Katowice
tel.: +48 (32) 789-44-01
e-mail: kgutski@intertele.pl

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