© 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).
TRALI | TACO |
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).
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.
Product | Dose | Indications, side effects, remarks |
Fresh frozen plasma | 15 ml/kg body weight within 60-90 minutes | Bleeding in patients with INR>2 or PT>4 sec of normal, concerns regarding TRALI and TACO. |
Cryoprecipitate | 1 unit/5-10 kg body weight or 10 units as starting dose | Bleeding with: hypofibrinogenemia, low fibrinogen level in DIC, hyperfibrinolysis. Fever, chills, allergic reactions. |
Epsilon aminocaproic acid | Average dose 10-30 g/24 hours | Hyperfibrinolysis, 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 concentrate | 25 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 transfusion | Based on assessment of fluid overload | Used 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
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.
Powyżej zamieściliśmy fragment artykułu, do którego możesz uzyskać pełny dostęp.
Mam kod dostępu
- Aby uzyskać płatny dostęp do pełnej treści powyższego artykułu albo wszystkich artykułów (w zależności od wybranej opcji), należy wprowadzić kod.
- Wprowadzając kod, akceptują Państwo treść Regulaminu oraz potwierdzają zapoznanie się z nim.
- Aby kupić kod proszę skorzystać z jednej z poniższych opcji.
Opcja #1
24 zł
Wybieram
- dostęp do tego artykułu
- dostęp na 7 dni
uzyskany kod musi być wprowadzony na stronie artykułu, do którego został wykupiony
Opcja #2
59 zł
Wybieram
- dostęp do tego i pozostałych ponad 7000 artykułów
- dostęp na 30 dni
- najpopularniejsza opcja
Opcja #3
119 zł
Wybieram
- dostęp do tego i pozostałych ponad 7000 artykułów
- dostęp na 90 dni
- oszczędzasz 28 zł
Piśmiennictwo
1. Friedman LS: The risk of surgery in patients with liver diseases. Hepatology 1999; 29: 167-1623.
2. Senzolo M, Burroughs AK: Hemostatic alterations in liver disease and liver transplantation in: Kitchens CS, Alving BA, Kessler CM editors. Consultative Hemostasis and Thrombosis 2nd ed. Philadelphia, Saunders Elsevier 2007; p. 647-659.
3. Argo CK, Balogun RA: Blood products, volume control and renal support in the coagulopathy of liver disease: Clin Liver Dis 2009; 13: 73-85.
4. Everson GT: A hepatologist perspective on the management of coagulative disorders before liver transplantation. Liver Transpl Surg 1997; 3: 646-652.
5. Holland LL, Brooks JP: Toward rational fresh frozen plasma transfusion: the effect of plasma transfusion on coagulation test results. Am J Clin Pathol 2006; 126: 1-7.
6. Spector I, Corn M, Ticktin HE: Effect of plasma transfusion on the prothrombin time and clotting factors in liver disease. N Engl J Med 1966; 275: 1032-1037.
7. Clayton DG, Miro AM, Kramer DJ et al.: Quantification of thromboelastographic changes after blood component transfusion in patients with liver disease in the intensive care unit. Anest Analg 1995; 81: 272-278.
8. Webert KE, Kleinman SH, Blajchman MA: Transfussion-related acute lung injury. [In:] Hillyer CD, Silberstein LE, Ness PA, Anderson K, Roback J (editiors): Blood Banking and Transfussion Medicine, Basic Principle&Practice. Philadelphia Churchill Livingstone Elsevier: Philadelphia, 2007; p. 677-690.
9. Heddle N, Webert KE: Febrile, Allergic and other noninfectious transfusion reactions. [In:] Hillyer CD, Silberstein LE, Ness PA, Anderson K, Roback JD, Hillyer CD, Silberstein LE, Ness PA, Anderson K, Roback J. 2nd ed. Blood Banking and Transfusion Medicine, Basic Principle&Practice. Philadelphia Churchill Livingstone Elsevier: Philadelphia, 2007; p. 691-700.
10. Khan H, Belsher J, Yimaz M et al.: Fresh-frozen plasma and platelet transfusions are associated with development of acute lung injury in critically ill medical patients. Chest 2007; 131: 1308-14.
11. Eder F, Herron R, Strupp A et al.: Transfusion-related acute lung injury surveillance (2003-2005) and the potential impact of the selective use of plasma from male donors in the American Red Cross. Transfusion 2007; 47: 599-607.
12. French CJ, Belomo R, Angus P: Cryoprecypitate for the correction of coagulopathy associated with liver disease. Anesth Intensive Care 2003; 31: 357-361.
13. Stanford SJ: Americal Society of Hematology Education Program Book, 2007. The evidence-based use of FFP and cryoprecypitate for abnormalities of coagulopathy. Hematology 2007; 1: 1-14.
14. Shah NL, Calwell SH, Berg CL: The role of anti-fibrinolytics rVII and other pro-coagulants: prophylactic versus rescue? Clin Liver Dis 2009; 13: 87-93.
15. Bosch J, Thabut D, Bendsten F: Recombinant factor VIIa for upper gastrointestinal bleeding in patients with cirrhosis: a randomized,double-blind trial. Gastroenterology 2004; 2: 78-84.
16. Bosch J, Thabud D, Albillos A et al.: Recombinant factor VIIa for variceal bleeding in patients with advanced cirrhosis: a randomized, controlled trial. Hepatology 2008; 47: 1604-14.
17. Shami VM, Caldwell SH, Hespenheide EE et al.: Recombinant factor VIIa for variceal bleeding in ptients with advanced cirrhosis: a randomized, controlled trial. Liver Transpl 2003; 9: 138-43.
18. Markiewicz M, Kalicinski P, Kaminski A et al.: Acute coagulopathy after reperfussion of the liver graft in children correction with recombinant activated factor VII. Transplant Proc 2003; 35: 2318-2319.
19. Northup Pg HA, Caldwell SH: Factor VII versus FFP for bleeding associated with percutaneous liver biopsy: a cost effectiveness evaluation (poster). American Asocation for the Study of Liver Diseases, 57-th Annual Meting. Boston MA. Hepatology 2006; 44: 466A.
20. Boylan JF, Klinck JR, Sandler AN et al.: Tranexamic acid reduces blood loss, transfusion requirements, and coagulation factor use in primary orthopedic liver transplantation. Anesthesiology 1996; 85: 1043-8.
21. Dalmau A, Sabate A, Koo M et al.: The prophylactic use of tranexamic acid and aprotinin in orthotopic liver transplantation: a comparative study. Liver Transpl 2004; 10: 279-84.
22. Gunawan B, Runyon B: The efficacy and safety of epsilon-aminocaproic acid treatment in patients with cirrhosis and hyperfibrinolysis. Aliment Pharmacol Ther 2006; 23: 115-20.
23. Manucci PM, Levi M: Prevention and treatment of major blood loss. N Engl J Med 2007; 356: 2301-11.
24. Lorenz R, Kienast J, Otto U: Efficacy and safety of a prothrombin complex concentrate with two virus inactivation steps in patients with severe liver damage. Eur J Gastroenterol Hepatol 2003; 15: 15-20.
25. White GC, Roberts HR, Kingdon HS et al.: Prothrombin complex concentrates: potentially thrombogenic materials and clues to the mechanism of thrombosis in vivo. Blood 1977; 49:159-170.
26. Braunstein AH, Oberman HA: Transfusion of plasma components. Transfusion 1984; 24: 281-6.
27. Silberstein LE, Kruskall MS, Stehling LC et al.: Strategies for the review of transfusion practices. JAMA 1989; 262:1993-7.
28. Manucci PM, Franchi F, Dioguardi N: Correction of abnormal coagulopathy. Thromb Hemost 1997; 77: 477-480.
29. Kaul V, Munoz AJ: Coagulopathy of liver disease. Curr Treat Options Gastroenterol 2000; 3: 433-438.
30. Bergqvist D, Arfors KE: The effect of normovolemic hemodilution on microvascular hemostasis in the rabbit. Res Exp Med 1979; 175: 61-6.
31. Turitton VT, Weiss HJ: Red blood cells: their dual role in thrombus formation. Science 1980; 207: 541-3.
32. Grant A, Nueberger J: Guidelines on the use of liver biopsy in clinical practice. British Society of Gastroenterology. Gut 1999; 45: Suppl. 4, IV1-IV11.
33. Pache, Bilodeau M: Severe haemorrhage following abdominal paracentesis for ascites in patients with liver disease. Aliment Pharmacol Ther 2005; 21: 525-529.