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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
Streszczenie
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.
Summary
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.
Introduction
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).
TRALITACO
Risk factors
Female donor FFP, blood products containing anti-leucocytic antibodies.Elderly of small stature, small children, patients with compromised cardiac fuction.
Mechanism
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.
Treatment
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.
Prophylaxis
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).

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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

Postępy Nauk Medycznych 1/2010
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