DigDis 1992;10:162-172
Universitá degli Studi di Roma ‘La Sapienza'. Istituto di I Clínica Medica Generale, Istituto di Terapia Medica, Roma, Italia
KeyW ords
Chronic liver disease Decreased clotting factor synthesis Platelet dysfunction Hyperfibrinolytic syndrome Gastrointestinal bleeding
Clotting Abnormalities in Chronic Liver Disease
Abstract
In patients with chronic liver disease (CLD), several clotting changes can be observed. The most frequent abnormality is the reduced synthesis of many clotting factors, including vitamin-K-dependent and vitamin-K-independent ones. A low platelet count is another frequent feature of patients with CLD, which, however, is not always associated with the pro longation of bleeding time. Hyperfibrinolytic syndrome is usually seen in patients with decompensated state, and may further deteriorate the clotting abnormalities and favor bleed ing complications. The assessment of the clotting system may be a useful approach to evaluate liver function and predict prognosis of patients with CLD.
Introduction
The clinical history of chronic liver disease is often complicated by hemorrhagic episodes occurring prevalently in the gastrointestinal tube. This bleeding complication is partly de pendent on the important functional relation ship between liver cells and the clotting sys tem. In fact all the procoagulant factors, ex cept for von Willebrand, are synthesized by liver cells [1-4] (fig. 1). Furthermore, the he patic cell is an important regulator of the clot ting system since it also synthesizes clotting
Supported in part by The Andrea Cesalpino Foundation.
inhibitors, i.e. antithrombin (AT) III, protein C and S and heparin cofactor II [5-9] and important components of the fibrinolytic sys tem. i.e. plasminogen and plasmin inhibitors such as Cb-antiplasmin and a 2 -macroglobulin [10, 11]; in addition, cultured human hepatocytes were demonstrated to synthesize the inhibitor of tissue plasminogen activator (PAI) [ 12, 13]. Finally, the reticuloendothelial liver cells play an important role in the clear ance of activated clotting factors and plasmin ogen activators [14-18]. One of the most common abnormalities found in patients with liver cirrhosis (LC) is the reduced activity of
Francesco Violi, MD Universitá degli Studi di Roma ‘La Sapienza’ Istituto di I Clínica Medica Generale e Terapia Medica, Policlinico Umberto 1 I— 00181 Rcmc(Italy)
© 1992 S. Kargcr AG. Bascl 0257-2753/92/ 0103— 0162S2.75
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Francesco ViolF Domenico Ferroa Claudio Quintarelli3 Mirella Saliolaa Corrado Cordovab Francesco Balsano3
XII
Xlla
HMW-K
XI ---» xia
++ I
ca 1 IX
--- »
THROMBIN
TISSUE FACTOR
VIII
VII
Ca
Ca PL
l
1
X
Xa
THROMBIN
->
V
PROTHROMBIN
++
Ca PL
THROMBIN
L XIII
♦♦
Ca
FIBRIN
Fig. 1. Schematic coagulation and fibrinolytic system. PK = Prckallikrein; K = kallikrein; HMW-K = high molecular weight kininogen: PL = phospholipids.
Table 1. Clotting and platelet abnormalities in liver cirrhosis
Decreased synthesis of clotting factors Dysfibrinogenemia Hyperfibrinoivtic syndrome
Thrombocytopenia Thrombocytopathia
-FIBRINOGEN
* 1 FIBRIN
PLASMINOGEN
S I
T PLASMIN , . ALPHA-2-ANTIPLASMIN
•PAI
1
This overview deals with the types of clot ting disorders occurring in patients with liver cirrhosis, their relationship to hemorrhage, and their clinical usefulness as prognostic in dexes.
Diminished Hepatic Protein Synthesis
The close relationship between liver insuf ficiency and diminished synthesis of the clot ting factor is sufficiently demonstrated by the decrease of clotting factor activity during acute hepatitis and chronic liver disease [3. 24-26], Vitamin K-dependent factors, such as factors II, IX, X, and especially factor VII,
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almost all the components of the clotting and fibrinolytic system, due to the diminished he patocellular protein synthesis [19]. Other al terations can also be detected including changes in primary hemostasis and in the acti vation of the fibrinolytic system [20-23] (ta ble 1).
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assessing hepatic cell damage [42,43]. Among the vitamin-K-dependent factors, the study of factor VII. considering its short half-life, might turn out to be very useful, as it proved to be the most sensitive index of cell damage [44], As the method to assess prothrombin and factor VII activities is easy and cheap, these laboratory tests should be recommended to evaluate liver failure. Other laboratory tests such as AT III. protein C. etc., should not be performed as routine tests unless particular clotting changes, for instance disseminated intravascular coagulation (DIG), are sus pected. Due to the diminished activity of most clotting factors, other global clotting tests, such as activated partial thromboplastin time (aPTT), may be altered, especially in cases of decompensated LC. It must be recognized, however, that in some LC patients, aPTT pro longation may depend not only on the re duced activity of the coagulation factors but also on the presence of anticardiolipin anti bodies or lupus-like antiphospholipid anti bodies, known to prolong the phospholipiddependent coagulation tests in vitro [45-47],
Thrombocytopenia and Thrombocytopathia
Platelet count and function have been studied largely in patients with liver cirrhosis. A platelet count below 100 X 109/1 is quite common in LC patients, particularly in de compensated LC patients [21. 48], Kinetic studies with radiolabeled platelets showed a substantially reduced platelet survival with an increased splenic sequestration of platelets [49], The increased turnover of platelets seems to be the mechanism accounting for the low platelet count observed in liver cirrhosis [50. 51],
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seem to be the most sensitive indexes [27,28], It is not clear whether this depends on their short half-life (factor VII, e.g„ has a 100- to 300-min half-life) or on a particular sensitiv ity to hepatocellular damage. Fujii et al. [29], while measuring the hepatic flow in cirrhotic patients, reported a close relationship be tween hepatic blood flow and the activity of vitamin-K dependent factors, suggesting that the activity of these factors reflected the resid ual functional liver mass. A following study confirmed this finding and also demonstrated that other components of the fibrinogenic and fibrinolytic system are sensitive to liver dam age [30], This suggestion was corroborated by a study of the clotting system in patients with different degrees of liver failure [31 -33], In patients with chronic active hepatitis, compensated and decompensated LC, reduc tion of vitamin-K-dependent factors and of other clotting factors such as prekallikrcin and AT III, plasminogen, etc., appeared to be closely dependent on the degree of liver fail ure, with proteins having the lowest values in patients with decompensated LC [25. 34], Similar findings were obtained when clotting factors of the contact phase were studied. In 30 patients. 10 with chronic active hepatitis and 20 with LC, the Hageman factor and high molecular weight kininogen activities were found to be reduced in relation to the degree of liver failure [35]. Among the clotting inhibitors, AT III, pro tein C (an inhibitor of factor V and VIII). pro tein S (a cofactor of activated protein C) and heparin cofactor II (which inactivates throm bin in the presence of heparin or dermatan sulfate) were found to be decreased in patients with LC [36-41]. These findings indicate that evaluation of the clotting system is a useful approach to assess the entity of liver failure. Prothrombin activity, which explores the vitamin-K-dependent factors, is. in fact, one of the most common and simple methods for
relation to the severity of liver damage, fur ther suggesting that LC patients with more advanced LC have more pronounced abnor mal platelet function [57. 60], Additionally reduced ATP and serotonin platelet release gave further support to the suggestion that platelet function is decreased in LC [61, 62], The low volume of platelets observed in LC patients could explain this dysfunction since a direct correlation has been found between platelet size and platelet aggregation [63, 64], Small platelets showed a reduced function, which could account for a diminished production of thromboxane A2 , a potent aggregating and vasoconstrictor agent [65], Actually, platelets of LC patients have low arachidonic acid content and produce less thromboxane A2 than controls, suggesting that abnormalities of arachidonic acid metab olism could explain this platelet dysfunction [58, 66]. However, the evaluation of platelet thromboxane A2 production in vivo is lacking and further study should be addressed to eval uating the relationship between bleeding time and thromboxane A2 production in vivo. Other mechanisms which might inhibit platelet aggregation include an inhibitory ef fect mediated by HDL cholesterol, whose Apo E content is increased in LC [67, 68] or by high Fibrin(ogen) degradation product (FDP) levels, which inhibit fibrinogen binding to platelet membrane [59, 60. 69], However, the changes in platelet function are more frequent when liver failure is severe and it is likely that more than one mechanism is responsible for abnormal platelet activa tion. Whether the changes in primary hemo stasis should be considered a risk of hemor rhagic complications is still being debated. A retrospective study showed that the prolonga tion of primary hemostasis may play a role in bleeding gastrointestinal varices [55]. This suggestion needs to be investigated in pro spective longitudinal research.
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The presence of low-grade intravascular co agulation (see below) together with intravascu lar platelet destruction might explain the low platelet count but this cannot be assumed to be the mechanism since low platelet count can be observed independently of the occurrence of low-grade intravascular clotting activation [21, 52]. It is not yet clear whether increased platelet turnover depends on primary hypersplenism or whether structural changes of platelet membrane lead to their increased de struction. This last hypothesis had prompted the assessment of antiplatelet antibodies on platelet membrane. Although some authors found immunoglobulins on platelet surface, this did not seem to account completely for thrombocytopenia [53, 54], From a clinical point of view it is impor tant to know whether thrombocytopenia in duces changes in primary hemostasis and whether it may increase the risk of hemor rhage in cirrhotic patients. In a large study recently published. Blake et al. [48] found an abnormal change in primary hemostasis, doc umented by the prolongation of bleeding time in 42% of LC patients. The prolongation of bleeding time was only minimally explained by low platelet count: interestingly, bleeding time was longer in patients with more severe liver failure, but the reason for this associa tion is to be elucidated. Thus, previous conllicting results reporting normal or prolonged bleeding time could depend on the clinical selection of LC patients [49, 55], If low plate let count does not fully explain the prolonga tion of bleeding time, it is obvious that some platelet dysfunction must account for the ab normality of primary hemostasis. As for bleeding time, data on platelet function are apparently equivocal, reporting, in fact, both normal and reduced platelet aggregation in LC [49. 56-59], In most reports, however, it would seem evident that platelet aggregation is reduced in
The shortening of euglobulin lysis time and the serum increase of FDP are laboratory features which suggest the occurrence of ac celerated fibrinolysis in patients with LC [22, 23, 70,71], Regarding the alterations of primary he mostasis, these changes seem to be more com mon in patients with severe liver failure. Boks et al. [72] found higher values of FDP in patients of the C class, than in patients of the B class, according to the Child classification. Hersch et al. [71] studied three different groups of cirrhotic patients and found that those with a more marked increase in fibrino lytic activity displayed a poorer liver func tion. The development of new techniques to measure tissue plasminogen activator (t-PA) and its inhibitor, PAI. has prompted the eval uation of whether eventual changes in these indexes could account for the above reported findings. There is general agreement that pa tients with liver cirrhosis had increased val ues of t-PA antigen [71-74] probably depen dent on reduced hepatic clearance [75, 76] while the measure of PAI gave conflicting results. Tran-Thanget al. [77] found high val ues of PAI in LC but they did not distinguish between the patients according to the severity of liver failure. Boks et al. [72] found a con siderable variability of fast-acting PA inhibi tor, which was higher in cirrhotic patients than in normal subjects; however, in patients with more severe liver insufficiency very low values of PAI were observed. This finding is in accordance with the investigation of Hersch et al. [71] showing lower values of PAI antigen in patients with more severe liver failure, as compared to LC patients in a compensated state. Therefore the increased fibrinolytic activity present in LC patients with severe insufficiency could be explained
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with the increased activity of t-PA which escapes the binding and the neutralization of its inhibitor PAI. The reduced activity of ci2-antiplasmin has also been suggested to promote a hyperfibri nolytic state but the findings cannot be con sidered conclusive [71, 78]. Finally, Leebeek et al. [79] studied histi dine-rich glycoprotein, a protein which forms a complex with plasminogen, thus reducing its activity, but no particular changes were found. A different approach to the interpreta tion of accelerated fibrinolysis has been sug gested by the hypothesis that patients with LC may have low-grade intravascular clotting ac tivation with secondary hyperfibrinolysis. In creased turnover of prothrombin, plasmino gen and fibrinogen and the prolongation of their survival after heparin administration suggested that intravascular clotting activa tion may occur in LC [49. 80, 81]; however, the validity of this observation has been ques tioned due to the inability to measure the peritoneal loss of these proteins, which could account for increased catabolism of the clot ting factors [82, 83]. There was further doubt about the pres ence of DIC in LC because of the possibility that the laboratory findings of intravascular clotting activation merely reflected (as a phe nomenon of back diffusion) clotting activa tion occurring in ascitic fluid. This hypothesis has been partly corroborated by many au thors. who found both FDP and D-dimer in the ascites of LC patients [84, 85] but a clear demonstration of FDP in the ascites with sec ondary backdiffusion into the circulatory sys tem has not yet been documented. An approach to documenting intravascular clotting activation has been based on the study of thrombin generation in vivo. Intra vascular clotting activation can be detected bymeasuring a number of parameters, including fibrinopeptide A (FpA), AT III, prothrombin
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Hyperfibrinolytic Syndrome
vated. A recent study showed that a positive D-dimer test can confirm truly positive FDP measurements [98]. The study of D-dimer in LC demonstrated that 20% of decompensated patients had high values of D-dimer and clot ting factor consumption, suggesting that a low-grade intravascular activator may be ob served in patients with severe liver failure [99]. Further laboratory tests for the diagnosis of primary or secondary hyperfibrinolysis could be taken into account, such as the simultaneous evaluation of FpA and FDP or B-[3-15-42 peptide [100] but the cost and the time required for these tests do not recom mend their use for clinical purposes. In the case of diagnosis of hyperfibrinoly sis, it is not yet clear if and how it should be treated. Some studies indicated that LC pa tients with hyperfibrinolysis have a higher risk of bleeding (see below); however, these studies are retrospective or the follow-up pe riod in LC patients is short. Thus they need to be supported by large prospective trials. At the moment, therefore, no treatment of hyperfibrinolytic syndrome in LC could be recommended, even if some authors reported that low-dose heparin or the antifibrinolytic drug may improve clotting changes or reduce the risk of hemorrhage [22, 101, 102], Future studies should attempt to clearly define which laboratory approach is to be fol lowed in order to differentiate primary or sec ondary hyperfibrinolysis and to recognize the mechanism leading to this syndrome (ta ble 2).
Clotting Changes as Predictors of Hemorrhage and Survival
The study of the clotting and fibrinolytic system in LC could represent a useful ap proach to evaluate the risk of hemorrhage and
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activation fragments F |+? and thrombin-antithrombin complex. The evaluation of FpA, a split-off product of thrombin activity, demonstrated that in some patients with chronic active hepatitis an LC, an increased thrombin generation may occur [86, 87], Further support to this sugges tion was given by the partial reduction of FpA values after heparin administration [87, 88], However, this finding was not considered to indicate DIC since in most cases a clotting consumption could not be demonstrated [89], AT III is an indirect measure of thrombin generation, but in cirrhotic patients it can be low, due to an impaired synthesis [36] which causes the results to be difficult to interpret. Concerning the prothrombin activation fragments F 1+2 and thrombin-antithrombin complex, some authors have demonstrated the presence of DIC in patients with acute leu kemia [90], but a study of cirrhotic patients has not yet been carried out. The diagnosis of hyperfibrinolysis in LC might be supported by several laboratory tests. The evaluation of FDP by latex aggluti nation assay should be the first diagnostic approach [91]; however, this test may be falsely positive in case of poorly clottable fibrinogen, not fully removed from the serum [23, 92]. Acquired dysfibrinogenemia has been demonstrated in liver diseases, includ ing cirrhosis [93. 94], This abnormality seems to be due to an impairment of fibrin polymer ization, probably due to an increased sialic acid content of the (5- and y-chains of fibrino gen [95]. In addition, cirrhotic patients have a greater proportion of low-molecular-weight fibrinogen with a decrease in high-molecularweight fibrinogen [96]. The evaluation of D-dimer, a cross-linked fibrin degradation fragment, may confirm the diagnosis of hyperfibrinolysis, secondary to DIC [97]. In fact, D-dimer can only be gener ated if both thrombin and plasmin are acti
Increased t-PA antigen and activity Decreased co-antiplasmin activity Decreased PAI-1 activity Reduced synthesis of coagulation inhibitors Reduced hepatic clearance of activated clotting factors Release of thromboplastin like substance ?
Extravascular clotting activation
Primary hyperfibri nolvsis
Screening Tests step Platelet function
1st
Platelet count Bleeding time
Coagulation system
1st
Prothrombin time aPTT Fibrinogen Prekallikrein activity Factor Vll activity FpA
Intravascular clotting activation
2nd
Fibrinolytic system Secondary hyperfibrinolysis
to. assess the life expectancy of individual patients. As regards the risk of hemorrhage, several factors are considered to have predictive val ues. in particular variceal size, intrahepatic gradient pressure, or the degree of liver failure 1103-105], Many attempts have been made to relate clotting abnormalities to bleeding but the results are not unequivocal. In fact a strik ing association between low clotting factor activity and bleeding has never been found despite the fact that bleeding complications occur more frequently in patients with severe liver failure where both impaired synthesis of clotting factors and hyperfibrinolysis may coexist [22, 72, 106, 107], The occurrence of hyperfibrinolysis could be regarded as an im portant warning sign of bleeding since it may further reduce clotting activity and impair platelet function [69, 99, 108]. The blood activity of clotting factors has also been investigated to evaluate the clinical
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Table 3. Laboratory tests suggested to assess clot ting abnormalities in liver function
1st 2nd
D-dimer FDP Plasminogen activity ai-Antiplasmin activity t-PA activity PAI activity
course of LC. The prothrombin activity is largely also used in score models, to define the degree of liver damage and to assess prognosis and, in fact, its abrupt reduction is associated with a lower life expectancy [42, 109-111], However, this test is unsatisfactory when used to assess individual life expectancy as it does not permit a differentiation of survivors from nonsurvivors [112], Among vitamin-K-dependent factors the evaluation of factor VII provided interesting results; in patients with acute hepatitis values of factor VII < 10% identified all patients who died of liver failure [27,44], Similar findings were obtained studying patients with liver failure followed up for approximately 2 months; factor VII values < 38% differentiated patients who died from survivors [113]. The evaluation of prekallikrein activity could also represent another interesting future laboratory approach to as sess prognosis of individual patients. Cordova
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Table 2. Hypothetical mechanism leading to hypcrfibrinolyis
et al. [113] and Agnholt et al. [114] showed that the prekallikrein activity may be a useful index of imminent death in patients followed up for 2 months. However, most of these data should be considered as preliminary to be fur ther assessed in a large population study for a longer period of time.
Conclusions There is a growing body of evidence supporting the hypothesis that primary hemostasis and clotting sys tem are abnormal in LC. The reported changes are closely related to liver function since they are more seriously altered in case of severe liver failure. Screen ing for laboratory tests to assess these changes is rec ommended in order to evaluate liver function (ta ble 3). Two steps of laboratory tests may be suggested: the first step includes simple and cheap tests to be per formed basically, the second step includes more so phisticated and expensive tests, the real clinical useful ness of which needs to be verified in future studies. This laboratory approach may be useful not only to assess liver function but also to study in future the rela tionship between clotting abnormalities, life expec tancy and the risk of bleeding.
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64 Thompson CB. Jakubosky JA, Quinn PG. Deykin D. Valeri R: Platelet size as a determinant of platelet function. J Lab Clin Med 1983:101:285-292. 65 Thompson CB. Eaton KA. Princiotta SM. Rushin CA. Valeri CR: Size dependent platelet subpopula tions: Relationship of platelet vol ume to ultrastructure enzymatic ac tivity. and function. Br J Haematol 1982;50:509-519. 66 Laffi G, Cominelli F, La Villa G. Fedi S. Pinzani M, Meacci E, Gentilini P: Reduced platelet thrombox ane A2 production as a possible cause of defective platelet aggrega tion in cirrhosis: in Samuelsson B. Paoletti R. Ramwell PW (eds): Ad vances in Prostaglandins, Throm boxane and Leukotriene Research. New York, Raven Press 1987. vol 17. pp 366-369. 67 Owen JS. Goodall H, Mistry P. Harry DS. Day RC. Mc Intyre N: Abnormal high density lipoprotein from patients with liver disease reg ulate cholesterol metabolism in cul tured human skin fibroblast. J Lipid Res 1984;25:919-931. 68 Desai K. Bagget C, Bellamy MF. Mistry P, Burroughs AK, Owen JS: Inhibition of platelet aggregation by abnormal high density lipoprotein particles in plasma from patients with hepatic cirrhosis. Lance: 1989: i:683—685. 69 Pecrschcke EL: The platelet fibrino gen receptor. Semin Hematol 1985: 22:241-259. 70 Fletcher AP. Biederman O. Moore D: Abnormal plasminogen plasmin system activity (fibrinolysis) in pa tients with hepatic cirrhosis: Its cause and consequences. J Clin In vest 1964:43:681-695. 71 Hersch SL, Kunelis T. Francis RB: The pathogenesis of accelerated fi brinolysis in liver cirrhosis: A criti cal role for plasminogen activator inhibitor. Blood 1987:69:13151319. 72 Boks AL. Brommer EJP. Schalm SW. Van Vliet HHDM: Hemostasis and fibrinolysis in severe liver fail ure and their relation to hemor rhage. Hepatology 1986:6/1:79-86.
73 Booth NA. Andersen JA. Bennet B: Plasminogen activators alcoholic cirrhosis: Demonstration of in creased tissue type and urokinase type activator. J Clin Pathol 1984: 37:772-777. 74 Lasierra J. Aza MJ, Vilades E. Poblct S, Barrao F, Bayon E. Gonzales J: Tissue plasminogen activator and plasminogen activator inhibitor in patients with liver cirrhosis. Fibri nolysis 1991;5:117-120. 75 Rijkcn DC. Enteis JJ: Clearance of the heavy and light polypeptide chains of human tissue-type plas minogen activator in rats. Biochcm J 1986:238:643-646. 76 Einarsson M, Smedsrod B, Pertoft H: Uptake and degradation of tissue plasminogen activator in rats liver. Thromb Haemost 1988:59:474479. 77 Tran-Thang C. Fasel-Felley J. PralongG. Hofstetter JR, Bachmann F, KruithofT EKO: Plasminogen acti vators and plasminogen activator inhibitors in liver deficiencies caused by chronic alcoholism or in fectious hepatitis. Thromb Haemost 1989;62:651-653. 78 Aoki N. Yamanaka T: The alpha-2 plasmin inhibitor levels in liver dis ease. Clin Chim Acta 1978:84:99105. 79 Leebeek FW, Kluft C, Knot EAR. De Maat MP: Histidine-rich glyco protein is elevated in mild liver cir rhosis and decreased in moderate and severe liver cirrhosis. J Lab Clin Med 1989;113:493-497. 80 Collen D. Rouvier J, Chamone DAF. Verstraete M: Turnover of radiolabelled plasminogen and pro thrombin in cirrhosis of the liver. EurJ Clin Invest 1978:8:185-188. 8! Coleman M. Finlayson N. Bettigole RE. Sadula D. Cohn M. Pasmantier M: Fibrinogen survival in cirrhosis improvement by 'low dose' heparin. Ann Intern Med 1975;83:79-81. 82 Straub PW: Diffuse intravascular coagulation in liver disease? Semin Thromb Hemosl 1977;4:29-39. 83 Rucgg R. Straub PW: Exchange be tween intravascularly and extravascularly injected radioiodinated fi brinogen and its in vivo derivatives. J Lab Clin Med 1980:95:842-856.
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53 Barrison IG. Knight ID. Viola L. Boots MA. Murray-Lyon IM. Mit chell TR: Platelet associated immu noglobulins in chronic liver disease. BrJ Haematol 1981;48:347-350. 54 LuzzalO G. Fabris F. Gerunda GE. MafTci Faccioli A, Naccaralo R. Girolami A: Thrombocytopenia in liver cirrhosis complicated by variceal hemorrhage: Lack of increase in platelet count after splenorenal dis tal shunt. Folia Haematol (Leipz) 1987: Is: 145—152. 55 Audhuy B, Doffoel M, Wiessel ML, Hemmendinger S. Cazenave JP. Bockcl R: Importance des troubles de l'hémostase primaire dans la sur venue des hémorragies digestives hautes du cirrhotique. Ann Gas troenterol Hepatol 1984:20/4:177182. 56 Thomas DP. Ream J, Stuart RK: Platelet aggregation in patients with Laennec's cirrhosis of the liver. N Engl J Med 1967:276:1344-1348. 57 Rubin MH, Weston MJ. Langley PG. White Y, Williams R: Platelet function in chronic liver disease. Relationship to disease severity. Dig DisSci 1979:24/3:197-202. 58 Owen JS. Hutton RA, Day RC. Bruckdorfer R. Me Intyre N: Plate let lipid composition and platelet ag gregation in human liver disease. J Lipid Res 1981:22:423-430. 59 Thomas DP: Abnormalities of plate let aggregation in patients with alco holic cirrhosis. Ann Acad Sci 1972: 201:243-250. 60 Ballard HS. Marcus AJ: Platelet ag gregation in portal cirrhosis. Arch Intern Med 1976:136:316-319. 61 Zaima M. Noguchi M, Wada Y. Mori K, Ozawa K: Adenine nucleo tide metabolism of blood platelet in human liver cirrhosis. Thromb Res 1988:51:127-134. 62 Marasini B, Biondi ML. Agostoni A: Platelet and plasma serotonin in pa tients with liver cirrhosis. J Chem Clin Biochem 1989:27:419-421. 63 Jorgensen B. Fisher E. Ingebcrg S. Hollander N. Ring-Larsen H. Henriksen JH: Decreased blood platelet volume and count in patients with liver disease. Scand J Gastroenterol 1984:19:492-496.
222. 86 Violi F. Alessandri C. Ferro D. Gallina G. Iuliano L, Balsano F: Fibrinopeptide A behaviour in chronic active hepatitis patients. Haematologica 1984;69:665-670. 87 Coechcri S. Mannucci PM. Palareti G. Gcrvasoni W. Poggi M. Vigano S: Significance of plasma fibrinopeptide A and high molecular weight fibrinogen in patients with liver cirrhosis. Br J Haematol 1982: 52:503-509. 88 Cordova C, Violi F. Alessandri C, Musca A, Balsano F: Low doses of calcium heparin in liver cirrhosis. Thromb Haemosl I985;54:55l. 89 Monbclli G, Monotti R. Haebcrli A. Straub PW: Relationship between fibrinopeptide A and fibrinogen/fibrin fragment E in thromboembo lism, DIC. and various non-thromboembolic diseases. Thromb Haemost 1987;58:758-763. 90 Bauer KA. Rosenberg RD: Throm bin generation in acute promyelocytic leukemia. Blood 1984:64:791 — 7%. 91 Marder VJ, Martin SE, Francis CW: Consumptive thrombohemorrhagic disorders; in Colman RW. Hirsh J. Marder VJ, ct al (eds): Hemostasis and Thrombosis: Basic Principles and Clinical Practice, cd 2. Philadel phia, Lippincott. 1987, pp 9751015. 92 Tanaka M. Ohkita T: Analysis of fibrinogen degradation product in severe liver disorders by immunoblotting. Tohoku J Exp Med 1987: 153:179-187. 93 Green G. Poller L. Thompson JM. Dymock IW: Association disease of abnormal fibrin polymerization with severe liver disease. Gut 1977: 18:909-912. 94 Francis J. Armstrong DJ: Acquired dysfibrinogenemia in liver disease. J Clin Pathol 1982:35:667-672.
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95 Martinez J. Keane PM. Gilman PB: The abnormal carbohydrate composition of the dysfibrinogen emia associated with liver disease. Ann NY Acad Sci 1983:408:388396. 96 Lipinski B. Lipinska 1. Nowak A. Gurewich V: Abnormal fibrinogen heterogeneity and fibrinolytic ac tivity in advanced liver disease. J Lab Clin Med 1977:90:187-193. 97 Elms MJ. Bunce IH. Bundesen PG. Rylatt DB. Webber AJ, Masci PP. Whitaken AM: Rapid detec tion of cross-linked fibrin degrada tion products in plasma using monoclonal antibody-coated latex particles. Am J Clin Pathol 1986; 85:360-364. 98 Carr JM, Kinney M. Me DonaghJ: Diagnosis of DIC: Role of D-dimer. Am J Clin Pathol 1989:91: 280-287. 99 Violi F. Ferro D. Saliola M, Quintarelli C, Alessandri C: Evaluation of D-Dimer in patients with liver cirrhosis. Thromb Haemost 1989; 62:1149-1150. 100 Marongiu F, Mameli G, Acca MR. Mamusa AM. Mulas G. Balestrieri A: Low garde DIC in liver cirrho sis: Fact or fiction? Thromb Hae most 1988:59:344. 101 Johansson S: Studies on blood co agulation factors in a case of liver cirrhosis. Remission of the hemor rhagic tendency on treatment with heparin. Acta Med Scanc 1964: 175:177-183. 102 Cordova C, Musca A, Violi F, Alessandri C. Vezza E: Improve ment of some blood coagulation factors in cirrhotic patients treated with low doses of heparin. Scand J Haematol 1982;29:235-240. 103 Lebrec D, De Fleury P, RuefT B. Nahum H. Benhamou JP: Portal hypertension, size of oesophageal varices, and risk of gastrointestinal bleeding in alcoholic cirrhosis. Gas troenterology 1980:79:1139-1144. 104 Groszmann RJ. Bosh J, Grace ND. Conn HO. Garcia-Tsao G. Navasa M.AlbertsJ.RodesJ.FisherR. Bcrmann M, Role J. Patrick M. Lemer E: Hemodynamic events in a pro spective randomized trial of pro pranolol versus placebo in the pre vention of a first variceal hemor rhage. Gastroenterology I990;99: 1401-1407.
105 The North Italian Endoscopic Club for the Study and Trealment of Oe sophageal Varices: Prediction of the first variceal hemorrhage in pa tients w ith cirrhosis of the liver and oesophageal varices. N Engl J Med 1988:319:983-989. 106 Bertaglia M, Belmonte P. Vertolli V, Azzurro M. Marlines D: Bleed ing in cirrhotic patients: A precipi tating factor due to intravascular coagulation or to hepatic failure. Haemostasis 1983:13:328-334. 107 Kelly DA. Summerfield JA: Hemo stasis in liver disease. Semin Liver Dis 1987;7:182-191. 108 Violi F. Alessandri C, Ferro D. Sal iola M, Cordova C, Musca A. Balsano F: Interrelation between factor VII. prekallikrein and hyperfibri nolysis in advanced cirrhosis. J Clin Pathol 1989:42:1246-1249. 109 Gines P, Quintero E. Arroyo V, Teres J. Bruguera M. Rimola A. Caballeria J. Rodes J. Rozman C: Compensated cirrhosis: Natural history and prognostic factors. He patology 1987:7/1:122-128. 110 Schlichting P, Christensen E, An dersen PK. Fauerholdt L, luhl E, Tygstrup N: Prognostic factors in cirrhosis identified by Cox's regres sion model. Hepatology I983;3: 889-895. 111 Orrego H. Israel Y, Blake JE. Med line A: Assessment of prognostic factors in alcoholic liver disease: Toward a global quantitative ex pression of severity. Hepatology 1983;3:896-905. 112 Infante-Rivard C, Esnaola S. Vil leneuve JP: Clinical and statistical validity of conventional prognostic factors in predicting short-term sur vival among cirrhosis. Hepatology 1987;7:660-664. 113 Cordova C. Violi F. Alessandri C. Ferro D, Saliola M. Musca A. BalsanoF: Prekallikrein and factor VII as prognostic indexes of liver fail ure. Am J Clin Pathol 1986:85:579582. 114 Agnholl J. Mikkelsen JH. Bud M. Moller-Petersen J. Rasmussen SN, Dyeberg J: Plasma prekallikrein as a prognostic indicator in chronic liver insufficiency. Scand J Gas troenterol 1990:25:40-44.
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84 Bâcle G. Rasquin K. Barbier F: Coa gulant. fibrinolytic and aggregating activity in ascitic fluid. Am J Gas troenterol 1986;81:440-443. 85 Wilde JT, Cooper P. Kennedy IIJ. Trigcr DR. Preston FE: Coagulation disturbances following ascites recir culation. J Hepatol 1990; 10:217—
Universitá degli Studi di Roma ‘La Sapienza'. Istituto di I Clínica Medica Generale, Istituto di Terapia Medica, Roma, Italia
KeyW ords
Chronic liver disease Decreased clotting factor synthesis Platelet dysfunction Hyperfibrinolytic syndrome Gastrointestinal bleeding
Clotting Abnormalities in Chronic Liver Disease
Abstract
In patients with chronic liver disease (CLD), several clotting changes can be observed. The most frequent abnormality is the reduced synthesis of many clotting factors, including vitamin-K-dependent and vitamin-K-independent ones. A low platelet count is another frequent feature of patients with CLD, which, however, is not always associated with the pro longation of bleeding time. Hyperfibrinolytic syndrome is usually seen in patients with decompensated state, and may further deteriorate the clotting abnormalities and favor bleed ing complications. The assessment of the clotting system may be a useful approach to evaluate liver function and predict prognosis of patients with CLD.
Introduction
The clinical history of chronic liver disease is often complicated by hemorrhagic episodes occurring prevalently in the gastrointestinal tube. This bleeding complication is partly de pendent on the important functional relation ship between liver cells and the clotting sys tem. In fact all the procoagulant factors, ex cept for von Willebrand, are synthesized by liver cells [1-4] (fig. 1). Furthermore, the he patic cell is an important regulator of the clot ting system since it also synthesizes clotting
Supported in part by The Andrea Cesalpino Foundation.
inhibitors, i.e. antithrombin (AT) III, protein C and S and heparin cofactor II [5-9] and important components of the fibrinolytic sys tem. i.e. plasminogen and plasmin inhibitors such as Cb-antiplasmin and a 2 -macroglobulin [10, 11]; in addition, cultured human hepatocytes were demonstrated to synthesize the inhibitor of tissue plasminogen activator (PAI) [ 12, 13]. Finally, the reticuloendothelial liver cells play an important role in the clear ance of activated clotting factors and plasmin ogen activators [14-18]. One of the most common abnormalities found in patients with liver cirrhosis (LC) is the reduced activity of
Francesco Violi, MD Universitá degli Studi di Roma ‘La Sapienza’ Istituto di I Clínica Medica Generale e Terapia Medica, Policlinico Umberto 1 I— 00181 Rcmc(Italy)
© 1992 S. Kargcr AG. Bascl 0257-2753/92/ 0103— 0162S2.75
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Francesco ViolF Domenico Ferroa Claudio Quintarelli3 Mirella Saliolaa Corrado Cordovab Francesco Balsano3
XII
Xlla
HMW-K
XI ---» xia
++ I
ca 1 IX
--- »
THROMBIN
TISSUE FACTOR
VIII
VII
Ca
Ca PL
l
1
X
Xa
THROMBIN
->
V
PROTHROMBIN
++
Ca PL
THROMBIN
L XIII
♦♦
Ca
FIBRIN
Fig. 1. Schematic coagulation and fibrinolytic system. PK = Prckallikrein; K = kallikrein; HMW-K = high molecular weight kininogen: PL = phospholipids.
Table 1. Clotting and platelet abnormalities in liver cirrhosis
Decreased synthesis of clotting factors Dysfibrinogenemia Hyperfibrinoivtic syndrome
Thrombocytopenia Thrombocytopathia
-FIBRINOGEN
* 1 FIBRIN
PLASMINOGEN
S I
T PLASMIN , . ALPHA-2-ANTIPLASMIN
•PAI
1
This overview deals with the types of clot ting disorders occurring in patients with liver cirrhosis, their relationship to hemorrhage, and their clinical usefulness as prognostic in dexes.
Diminished Hepatic Protein Synthesis
The close relationship between liver insuf ficiency and diminished synthesis of the clot ting factor is sufficiently demonstrated by the decrease of clotting factor activity during acute hepatitis and chronic liver disease [3. 24-26], Vitamin K-dependent factors, such as factors II, IX, X, and especially factor VII,
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almost all the components of the clotting and fibrinolytic system, due to the diminished he patocellular protein synthesis [19]. Other al terations can also be detected including changes in primary hemostasis and in the acti vation of the fibrinolytic system [20-23] (ta ble 1).
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assessing hepatic cell damage [42,43]. Among the vitamin-K-dependent factors, the study of factor VII. considering its short half-life, might turn out to be very useful, as it proved to be the most sensitive index of cell damage [44], As the method to assess prothrombin and factor VII activities is easy and cheap, these laboratory tests should be recommended to evaluate liver failure. Other laboratory tests such as AT III. protein C. etc., should not be performed as routine tests unless particular clotting changes, for instance disseminated intravascular coagulation (DIG), are sus pected. Due to the diminished activity of most clotting factors, other global clotting tests, such as activated partial thromboplastin time (aPTT), may be altered, especially in cases of decompensated LC. It must be recognized, however, that in some LC patients, aPTT pro longation may depend not only on the re duced activity of the coagulation factors but also on the presence of anticardiolipin anti bodies or lupus-like antiphospholipid anti bodies, known to prolong the phospholipiddependent coagulation tests in vitro [45-47],
Thrombocytopenia and Thrombocytopathia
Platelet count and function have been studied largely in patients with liver cirrhosis. A platelet count below 100 X 109/1 is quite common in LC patients, particularly in de compensated LC patients [21. 48], Kinetic studies with radiolabeled platelets showed a substantially reduced platelet survival with an increased splenic sequestration of platelets [49], The increased turnover of platelets seems to be the mechanism accounting for the low platelet count observed in liver cirrhosis [50. 51],
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seem to be the most sensitive indexes [27,28], It is not clear whether this depends on their short half-life (factor VII, e.g„ has a 100- to 300-min half-life) or on a particular sensitiv ity to hepatocellular damage. Fujii et al. [29], while measuring the hepatic flow in cirrhotic patients, reported a close relationship be tween hepatic blood flow and the activity of vitamin-K dependent factors, suggesting that the activity of these factors reflected the resid ual functional liver mass. A following study confirmed this finding and also demonstrated that other components of the fibrinogenic and fibrinolytic system are sensitive to liver dam age [30], This suggestion was corroborated by a study of the clotting system in patients with different degrees of liver failure [31 -33], In patients with chronic active hepatitis, compensated and decompensated LC, reduc tion of vitamin-K-dependent factors and of other clotting factors such as prekallikrcin and AT III, plasminogen, etc., appeared to be closely dependent on the degree of liver fail ure, with proteins having the lowest values in patients with decompensated LC [25. 34], Similar findings were obtained when clotting factors of the contact phase were studied. In 30 patients. 10 with chronic active hepatitis and 20 with LC, the Hageman factor and high molecular weight kininogen activities were found to be reduced in relation to the degree of liver failure [35]. Among the clotting inhibitors, AT III, pro tein C (an inhibitor of factor V and VIII). pro tein S (a cofactor of activated protein C) and heparin cofactor II (which inactivates throm bin in the presence of heparin or dermatan sulfate) were found to be decreased in patients with LC [36-41]. These findings indicate that evaluation of the clotting system is a useful approach to assess the entity of liver failure. Prothrombin activity, which explores the vitamin-K-dependent factors, is. in fact, one of the most common and simple methods for
relation to the severity of liver damage, fur ther suggesting that LC patients with more advanced LC have more pronounced abnor mal platelet function [57. 60], Additionally reduced ATP and serotonin platelet release gave further support to the suggestion that platelet function is decreased in LC [61, 62], The low volume of platelets observed in LC patients could explain this dysfunction since a direct correlation has been found between platelet size and platelet aggregation [63, 64], Small platelets showed a reduced function, which could account for a diminished production of thromboxane A2 , a potent aggregating and vasoconstrictor agent [65], Actually, platelets of LC patients have low arachidonic acid content and produce less thromboxane A2 than controls, suggesting that abnormalities of arachidonic acid metab olism could explain this platelet dysfunction [58, 66]. However, the evaluation of platelet thromboxane A2 production in vivo is lacking and further study should be addressed to eval uating the relationship between bleeding time and thromboxane A2 production in vivo. Other mechanisms which might inhibit platelet aggregation include an inhibitory ef fect mediated by HDL cholesterol, whose Apo E content is increased in LC [67, 68] or by high Fibrin(ogen) degradation product (FDP) levels, which inhibit fibrinogen binding to platelet membrane [59, 60. 69], However, the changes in platelet function are more frequent when liver failure is severe and it is likely that more than one mechanism is responsible for abnormal platelet activa tion. Whether the changes in primary hemo stasis should be considered a risk of hemor rhagic complications is still being debated. A retrospective study showed that the prolonga tion of primary hemostasis may play a role in bleeding gastrointestinal varices [55]. This suggestion needs to be investigated in pro spective longitudinal research.
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The presence of low-grade intravascular co agulation (see below) together with intravascu lar platelet destruction might explain the low platelet count but this cannot be assumed to be the mechanism since low platelet count can be observed independently of the occurrence of low-grade intravascular clotting activation [21, 52]. It is not yet clear whether increased platelet turnover depends on primary hypersplenism or whether structural changes of platelet membrane lead to their increased de struction. This last hypothesis had prompted the assessment of antiplatelet antibodies on platelet membrane. Although some authors found immunoglobulins on platelet surface, this did not seem to account completely for thrombocytopenia [53, 54], From a clinical point of view it is impor tant to know whether thrombocytopenia in duces changes in primary hemostasis and whether it may increase the risk of hemor rhage in cirrhotic patients. In a large study recently published. Blake et al. [48] found an abnormal change in primary hemostasis, doc umented by the prolongation of bleeding time in 42% of LC patients. The prolongation of bleeding time was only minimally explained by low platelet count: interestingly, bleeding time was longer in patients with more severe liver failure, but the reason for this associa tion is to be elucidated. Thus, previous conllicting results reporting normal or prolonged bleeding time could depend on the clinical selection of LC patients [49, 55], If low plate let count does not fully explain the prolonga tion of bleeding time, it is obvious that some platelet dysfunction must account for the ab normality of primary hemostasis. As for bleeding time, data on platelet function are apparently equivocal, reporting, in fact, both normal and reduced platelet aggregation in LC [49. 56-59], In most reports, however, it would seem evident that platelet aggregation is reduced in
The shortening of euglobulin lysis time and the serum increase of FDP are laboratory features which suggest the occurrence of ac celerated fibrinolysis in patients with LC [22, 23, 70,71], Regarding the alterations of primary he mostasis, these changes seem to be more com mon in patients with severe liver failure. Boks et al. [72] found higher values of FDP in patients of the C class, than in patients of the B class, according to the Child classification. Hersch et al. [71] studied three different groups of cirrhotic patients and found that those with a more marked increase in fibrino lytic activity displayed a poorer liver func tion. The development of new techniques to measure tissue plasminogen activator (t-PA) and its inhibitor, PAI. has prompted the eval uation of whether eventual changes in these indexes could account for the above reported findings. There is general agreement that pa tients with liver cirrhosis had increased val ues of t-PA antigen [71-74] probably depen dent on reduced hepatic clearance [75, 76] while the measure of PAI gave conflicting results. Tran-Thanget al. [77] found high val ues of PAI in LC but they did not distinguish between the patients according to the severity of liver failure. Boks et al. [72] found a con siderable variability of fast-acting PA inhibi tor, which was higher in cirrhotic patients than in normal subjects; however, in patients with more severe liver insufficiency very low values of PAI were observed. This finding is in accordance with the investigation of Hersch et al. [71] showing lower values of PAI antigen in patients with more severe liver failure, as compared to LC patients in a compensated state. Therefore the increased fibrinolytic activity present in LC patients with severe insufficiency could be explained
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with the increased activity of t-PA which escapes the binding and the neutralization of its inhibitor PAI. The reduced activity of ci2-antiplasmin has also been suggested to promote a hyperfibri nolytic state but the findings cannot be con sidered conclusive [71, 78]. Finally, Leebeek et al. [79] studied histi dine-rich glycoprotein, a protein which forms a complex with plasminogen, thus reducing its activity, but no particular changes were found. A different approach to the interpreta tion of accelerated fibrinolysis has been sug gested by the hypothesis that patients with LC may have low-grade intravascular clotting ac tivation with secondary hyperfibrinolysis. In creased turnover of prothrombin, plasmino gen and fibrinogen and the prolongation of their survival after heparin administration suggested that intravascular clotting activa tion may occur in LC [49. 80, 81]; however, the validity of this observation has been ques tioned due to the inability to measure the peritoneal loss of these proteins, which could account for increased catabolism of the clot ting factors [82, 83]. There was further doubt about the pres ence of DIC in LC because of the possibility that the laboratory findings of intravascular clotting activation merely reflected (as a phe nomenon of back diffusion) clotting activa tion occurring in ascitic fluid. This hypothesis has been partly corroborated by many au thors. who found both FDP and D-dimer in the ascites of LC patients [84, 85] but a clear demonstration of FDP in the ascites with sec ondary backdiffusion into the circulatory sys tem has not yet been documented. An approach to documenting intravascular clotting activation has been based on the study of thrombin generation in vivo. Intra vascular clotting activation can be detected bymeasuring a number of parameters, including fibrinopeptide A (FpA), AT III, prothrombin
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Hyperfibrinolytic Syndrome
vated. A recent study showed that a positive D-dimer test can confirm truly positive FDP measurements [98]. The study of D-dimer in LC demonstrated that 20% of decompensated patients had high values of D-dimer and clot ting factor consumption, suggesting that a low-grade intravascular activator may be ob served in patients with severe liver failure [99]. Further laboratory tests for the diagnosis of primary or secondary hyperfibrinolysis could be taken into account, such as the simultaneous evaluation of FpA and FDP or B-[3-15-42 peptide [100] but the cost and the time required for these tests do not recom mend their use for clinical purposes. In the case of diagnosis of hyperfibrinoly sis, it is not yet clear if and how it should be treated. Some studies indicated that LC pa tients with hyperfibrinolysis have a higher risk of bleeding (see below); however, these studies are retrospective or the follow-up pe riod in LC patients is short. Thus they need to be supported by large prospective trials. At the moment, therefore, no treatment of hyperfibrinolytic syndrome in LC could be recommended, even if some authors reported that low-dose heparin or the antifibrinolytic drug may improve clotting changes or reduce the risk of hemorrhage [22, 101, 102], Future studies should attempt to clearly define which laboratory approach is to be fol lowed in order to differentiate primary or sec ondary hyperfibrinolysis and to recognize the mechanism leading to this syndrome (ta ble 2).
Clotting Changes as Predictors of Hemorrhage and Survival
The study of the clotting and fibrinolytic system in LC could represent a useful ap proach to evaluate the risk of hemorrhage and
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activation fragments F |+? and thrombin-antithrombin complex. The evaluation of FpA, a split-off product of thrombin activity, demonstrated that in some patients with chronic active hepatitis an LC, an increased thrombin generation may occur [86, 87], Further support to this sugges tion was given by the partial reduction of FpA values after heparin administration [87, 88], However, this finding was not considered to indicate DIC since in most cases a clotting consumption could not be demonstrated [89], AT III is an indirect measure of thrombin generation, but in cirrhotic patients it can be low, due to an impaired synthesis [36] which causes the results to be difficult to interpret. Concerning the prothrombin activation fragments F 1+2 and thrombin-antithrombin complex, some authors have demonstrated the presence of DIC in patients with acute leu kemia [90], but a study of cirrhotic patients has not yet been carried out. The diagnosis of hyperfibrinolysis in LC might be supported by several laboratory tests. The evaluation of FDP by latex aggluti nation assay should be the first diagnostic approach [91]; however, this test may be falsely positive in case of poorly clottable fibrinogen, not fully removed from the serum [23, 92]. Acquired dysfibrinogenemia has been demonstrated in liver diseases, includ ing cirrhosis [93. 94], This abnormality seems to be due to an impairment of fibrin polymer ization, probably due to an increased sialic acid content of the (5- and y-chains of fibrino gen [95]. In addition, cirrhotic patients have a greater proportion of low-molecular-weight fibrinogen with a decrease in high-molecularweight fibrinogen [96]. The evaluation of D-dimer, a cross-linked fibrin degradation fragment, may confirm the diagnosis of hyperfibrinolysis, secondary to DIC [97]. In fact, D-dimer can only be gener ated if both thrombin and plasmin are acti
Increased t-PA antigen and activity Decreased co-antiplasmin activity Decreased PAI-1 activity Reduced synthesis of coagulation inhibitors Reduced hepatic clearance of activated clotting factors Release of thromboplastin like substance ?
Extravascular clotting activation
Primary hyperfibri nolvsis
Screening Tests step Platelet function
1st
Platelet count Bleeding time
Coagulation system
1st
Prothrombin time aPTT Fibrinogen Prekallikrein activity Factor Vll activity FpA
Intravascular clotting activation
2nd
Fibrinolytic system Secondary hyperfibrinolysis
to. assess the life expectancy of individual patients. As regards the risk of hemorrhage, several factors are considered to have predictive val ues. in particular variceal size, intrahepatic gradient pressure, or the degree of liver failure 1103-105], Many attempts have been made to relate clotting abnormalities to bleeding but the results are not unequivocal. In fact a strik ing association between low clotting factor activity and bleeding has never been found despite the fact that bleeding complications occur more frequently in patients with severe liver failure where both impaired synthesis of clotting factors and hyperfibrinolysis may coexist [22, 72, 106, 107], The occurrence of hyperfibrinolysis could be regarded as an im portant warning sign of bleeding since it may further reduce clotting activity and impair platelet function [69, 99, 108]. The blood activity of clotting factors has also been investigated to evaluate the clinical
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Table 3. Laboratory tests suggested to assess clot ting abnormalities in liver function
1st 2nd
D-dimer FDP Plasminogen activity ai-Antiplasmin activity t-PA activity PAI activity
course of LC. The prothrombin activity is largely also used in score models, to define the degree of liver damage and to assess prognosis and, in fact, its abrupt reduction is associated with a lower life expectancy [42, 109-111], However, this test is unsatisfactory when used to assess individual life expectancy as it does not permit a differentiation of survivors from nonsurvivors [112], Among vitamin-K-dependent factors the evaluation of factor VII provided interesting results; in patients with acute hepatitis values of factor VII < 10% identified all patients who died of liver failure [27,44], Similar findings were obtained studying patients with liver failure followed up for approximately 2 months; factor VII values < 38% differentiated patients who died from survivors [113]. The evaluation of prekallikrein activity could also represent another interesting future laboratory approach to as sess prognosis of individual patients. Cordova
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Table 2. Hypothetical mechanism leading to hypcrfibrinolyis
et al. [113] and Agnholt et al. [114] showed that the prekallikrein activity may be a useful index of imminent death in patients followed up for 2 months. However, most of these data should be considered as preliminary to be fur ther assessed in a large population study for a longer period of time.
Conclusions There is a growing body of evidence supporting the hypothesis that primary hemostasis and clotting sys tem are abnormal in LC. The reported changes are closely related to liver function since they are more seriously altered in case of severe liver failure. Screen ing for laboratory tests to assess these changes is rec ommended in order to evaluate liver function (ta ble 3). Two steps of laboratory tests may be suggested: the first step includes simple and cheap tests to be per formed basically, the second step includes more so phisticated and expensive tests, the real clinical useful ness of which needs to be verified in future studies. This laboratory approach may be useful not only to assess liver function but also to study in future the rela tionship between clotting abnormalities, life expec tancy and the risk of bleeding.
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