Hyperfibrinolysis but not hypercoagulability after a new ascites-apheresis procedure in liver cirrhosis patients with refractory ascites

Fibrinotysis(1996) 10(1), 15-20 © PearsonProfessionalLtd 1996

Hyperfibrinolysis but not hypercoagulability after a new asc,tes-- "apheres,s p r o c e d u r e in liver cirrhosis p a t i e n t s w i t h refractory ascites C. Legnani ~, G. Palareti ~, S. Ludovici ~, A. Gasbarrini 2, M. Bernardi 2, S. Coccheri ~ 1Department of Angiology and Blood Coagulation, University Hospital S. Orsola, Via Massarenti, 9, 40138 Bologna, Itaty. 2Institute of PatoIogia Medica, University Hospital S. Orsola, Bologna, Italy.

Summary Given the frequent occurrence of disseminated intravascular coagulation after reinfusion of ascitic fluid in cirrhotic patients, a study involving a new ascites-apheresis apparatus was undertaken in 11 patients with decompensated liver cirrhosis and massive refractory ascites, with the aim of investigating activation of coagulation and fibrinolysis after the procedure. A large series of assays were performed in ascitic fluid and plasma before and after the apheresis sessions, and the measured values were compared with those expected and calculated on the basis of fluid and protein changes bound to the filtration and reinfusion procedures. In ascitic fluid, the measured values reflecting activation of blood clotting as prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin complexes (TAT) although increased after filtration were much lower than expected. In plasma after reinfusion, F1+2 and TAT were also significantly less increased than calculated, presumably also because of their short half-life, while values reflecting activation of fibrinolysis as total, fibrin and fibrinogen degradation products were significantly increased above those calculated. Thus, the filtration-reinfusion system employed in this study appeared to efficiently remove most of the procoagulant materials from the ascitic fluid and did not significantly activate blood clotting in plasma. The observed activation of fibrinolysis was of limited extent as no relevant changes were observed in the basic clotting tests (PT and aPTT) and fibrinogen.

Management of refractory ascites in patients with liver cirrhosis is still problematic.~ The benefits of some treatments such as repeated paracentesis and intravenous reinfusion of dialyzed ascitic fluid are usually temporary. 2-4 In 1974, the peritoneovenous LeVeen shunt was introduced for continuous reinfusion of ascitic fluid. 5 This procedure is reportedly effective since it offers the advantage of reducing ascites while maintaining renal function and preserving protein, salt and fluid balance. 5-9 However, the use of this procedure has been

Received: 8 July 1995 Accepted after revision: 7 November 1995 Corresponding author:. Dr Cristina Legnani, Tel. +51-6363420; Fax. +51-341642.

reported to be frequently associated with disseminated intravascular coagulation (DIC) with both generalized bleeding and thrombosis of the shunt, s'7'1o-i 5 A clinically significant coagulopathy occurs in 20-50% of these patients and often needs ligation of the shunt)1.13 The mechanism responsible for the ascites reinfusion-related coagulopathy is unclear and has not yet been fully elucidated. The presence in the ascitic fluid of endotoxin, 16-17 thromboplastin-like material or activated clotting factors, 18 cell derived procoagulants, 19 and collageninduced platelet aggregation 2° have been postulated as possible causes of this coagulopathy. Previous experiences in cirrhotic patients with intractable ascites with a new ascites-apheresis apparatus, based on a cascade filtration through two hollow fiber systems, have given good clinical results with no adverse 15

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effects. 2]-23 The aim of the present study was to investigate the effects of this new technique in cirrhotic patients with intractable ascites on the clotting and fibrinolytic variables measured both in the ascitic fluid (before and after filtration) and in the patients (before and after the ascites-apheresis procedure). PATIENTS

AND METHODS

Patients

Eleven patients (4 males, 31-63 years) with decompensated liver cirrhosis and massive ascites resistant to the conventional diuretic therapy were studied. Cirrhosis was due to viral infection (hepatitis B or C) in all patients; excessive alcohol abuse in the past was also recorded in one patient. Table 1 shows the duration of aseitesapheresis sessions, the total volume of ascitic fluid evacuated and reinfused, and the concentration factor of the ascitic fluid calculated as the ratio between the ascitic fluid volume evacuated and reinfused. The ascites-apheresis sessions were complicated by few and mild side-effects. Shivering of short duration (few minutes) was recorded in three cases and a low grade fever (_<37.5°C) lasting 3 h in one case. This study was designed and performed according to the principles laid down in the Declaration of Helsinki. Informed consent was obtained from all patients before inclusion in the study. The DIDECO ascites-apheresis apparatus: principle and technique

The DIDECO ascites-apheresis apparatus, a detailed description of which has been reported elsewhere, 22 consists of a double filtration system. In brief, the ascitic fluid Table I Duration of ascites-apheresis sessions, ascitic fluid volumes evacuated and reinfused, and concentration factors (CF, ratio between the volume of the evacuated and reinfused ascitic fluid)

Case

Duration min

Ascitic fluid Evacuated Reinfused ml rnl

CF

1 2 3 4 5 6 7 8 9 10 11

405 260 420 480 375 540 240 360 395 440 510

7600 6000 10000 10000 4300 9500 4000 5700 6900 8800 9100

648 250 770 720 350 920 360 468 460 730 758

11.7 24.0 13.0 13.9 12.3 10.3 11.1 12.2 15.0 12.1 12.0

Median (range)

405 (240--540)

7600 (4000--10000)

648 (250-920)

12.2 (10.3-24)

Fibrinolysis (1996) 10(1), 15-20

is first handled by a 'primary f'dter' of cellulose diacetate (Albusave BT 902, Dideco S.p.A., Mirandola, Italy) with wide pores, which separates and discards cells, cellular debris, aggregates and macromolecules with molecular weight exceeding 300 000 from plasma components with lower molecular weight such as albumin. This albuminenriched solution is then uhrafihrated by a polyacrylonitrite filter (Hemoconcentrator PAN 15, Ashai Medical Co., Tokyo, Japan) in order to remove water, salts and micromolecular components and to retain components with a molecular weight similar to albumin. The volume reduction is usually up to 20-fold compared to the ascitic fluid removed by paracentesis; the collected concentrated ascitic fluid is slowly (=100mL/h) reinfused into the patient. Methods

Blood sampling was performed before frO) and at the end (T1) of the ascites-apheresis session. Venous blood samples were taken from a forearm vein, anticoagulated and immediately cooled in melting ice. As anticoagulants, we used: (1) trisodium citrate (0.129M, 1/10 vol/vol) for the routine clotting tests, prothrombin fragments (Fl+2) and thrombin-antithrombin complexes fIAT) measurements; (2) trisodium citrate (0.129 M, 1/10 vol/vol) with addition of 1000U/rnl of aprotinin for measuring fibrin/fibrinogen/total degradation products (FbDP, FgDP, TDP respectively); and (3) a special mixture anticoagulant (containing heparin and aprotinin, 1/10 vol/vol) supplied by the manufacturer of the assay-kit for fibrinopeptide A (FPA) measurement. Platelet-poor plasma was obtained after 20min centrifugation at 2000xg and at 4°C. Samples were tested immediately or stored in small aliquots at -70°C until further processing. The ascitic fluid was also examined before its treatment by the ascites-apheresis apparatus (TO) and before its reinfusion in patients (T 1). The following tests were carried out in patient plasma samples and/or in ascitic fluid samples: prothrombin time (PT, Thromborel S, Behring Institute, Scoppito, Italy; normal range 70-120%); activated partial thromboplastin time (aFYI', Automated agIT, Organon Teknika, Belgium; normal range 28-38s); fibrinogen according to Clauss (Fgn:Act, 24) (normal range 150-350mg/dl) and also as antigen (Fgn:Ag, Nor-Partigen, Behring Institute; normal range 150-350 mg/dl); antithrombin III both as activity (ATITI:ACt, Antithrombin, Instrumentation Laboratory, Milan, Italy; normal range 80--140%) and antigen (ATIII:Ag, NorPartigen, Behring Institute; normal range 22-39mg/dl); plasminogen (Plg; normal range 7-15 rag/all), ctl antitrypsin (tzl AT; normal range 200--350mg/dl) and a2 macroglobulin (~t2 MG; normal range 150--420mg/dl) as antigen (MPartigen and Nor-Partigen, Behring Institute). El lgA methods © Pearson Professional Ltd 1996

Hyperfibrinolysis but not hypercoagulability after a new ascites-apheresis procedure in liver cirrhosis patients

were used for measuring the levels off FbDP (normal range 0.09-0.45 lag/ml), FgDP (normal range 0.14-0.92 lag/ml) and total (normal range 0.25-1.681ag/ml) degradation products (Fibrinostika, Organon Teknika); thrombinantithrombin III complexes (Behring Institute; normal range 1.0-4.1 lag/L); prothrombin fragment FI +2 (Behring Institute; normal range 0.44-1.41 nmol/L); Von Willebrand factor (VWF:Ag, Asserachrom, Biochemia Boeringer Mannheim, Mannheim, Germany; normal range 70-150%). FPA was also assayed by ELISA (Asserachrom FPA, Biochemia Boeringer Mannheim; normal range <3.4 ng/ml) in plasma extracted twice with bentonite to remove fibrinogen and its large degradation products. The normal ranges in our laboratory were obtained from a wide group (n>50) of heahh subjects. In order to evaluate the direct effects of proteins reinfused with ascitic fluid on results obtained in the patients at the end of the procedure (as if this had constituted the only source of variation), we calculated (for the quantitative assays only) the values theoretically expected after reinfusion. These values were calculated on the basis of: (1) baseline concentration of the considered variable in patient plasma, (2) measured concentration of the variable in ascitic fluid after filtration, (3) volume of ascitic fluid reinfused, and (4) patient plasma volume at end of procedure [plasma volume (ml)=body weight (Kg)x41.1 (mFKg);25]. It should be pointed out that the indirect evaluation of plasma volume based on body weight of patients with decompensated cirrhosis is not entirely reliable due to compartmentalization of extracellular fluid and muscle mass wasting. Moreover, a plasma volume of 41.1 ml/Kg b.w. represents the mean value in a healthy population, and should generally be greater in patients with cirrhosis and ascites. 26 Despite such biases, we think that such a method of calculating the expected clotting and fibrinolytic factor concentrations in the patient plasma could be useful for the purposes of this study. First, since we did not compare different groups of subjects the same kind of error could be present in all patients. Second, we weighed our patients at the end of a total paracentesis, so that the over-evaluation of the body weight was minimized. Statistical methods

The SOLO statistical software package (Version 4.0, BMDP, Los Angeles, CA, USA) was used for data processing. The results were expressed as median and range. The Wilcoxon rank sum test (paired data) was used to compare the values obtained in ascitic fluid before and after fihration and in patient plasma before and after ascitesapheresis. A P-value of <0.05 (two-tailed) was considered statistically significant. © Pearson Professional Ltd 1996

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RESULTS

The results of clotting and fibrinolytic tests obtained in the ascitic fluid samples before (TO) and after (T1) filtration by the ascites-apheresis apparatus are reported in Table 2. After filtration, the levels of all the variables assessed (except TDP, FbDP and FPA) were significantly higher than at TO. For each variable, the values that would have been expected on the basis of the concentration factor only (as if no protein material at all had been discarded) were also calculated (concentration of the variable at T0xconcentration factor). Most of the investigated variables (the exceptions were ATIII, Pig and etlAT~ had levels much lower than those theoretically expected (data not shown). To consider the effects of reinfusion of ascitic fluid in the patients, Table 3 shows the results (median and range) of the clotting and fibrinolytic tests performed on patient plasma samples before (TO) and at the end of ascites-apheresis sessions (T1). Among the routine tests, clotting Fgn levels were slightly but significantly (P<0.01) reduced after reinfusion; in contrast, PT, aPTT and ATIII values were substantially unchanged. A marked increase in the levels of Fibrin/ogen degradation products (TDP=P<0.05; FgDP=P<0.01; FbDP=P<0.01), TAT (/<0.01) and F1 +2 (P<0.01) levels was observed; FPA levels were only slightly increased (n.s.) and von Willebrand Factor levels were significantly reduced (P
Table 2 Results of clotting and fibdnolytic tests (median and range) in ascitic fluid samples before (TO) and after (T1) filtration by the ascites-apheresis apparatus TO Fgn:Ag mg/dl ATIIhAg mg/dl TDPI~g/ml FgDP pg/ml FbDPl~g/ml FPAng/ml F1+2 nmol/L TAT p.g/L vWF:Ag % Pig mg/dl a l AT mg/dl ~2 MG mg/dl

30 3 21.4 0.2 10.8 79.6 4.7 91 16 0.3 78 29

Ascitic fluid T1 (30-62) (3-9) (18.6-25.3) (0.1-2.3) (6.2-34.6) (52.1-93.2) (1.6-9.5) (19-274) (9-30) (0.3-5.2) (26-156) (29-107)

** ** ** ** ** ** ** ** **

156 41 23.4 0.5 10.6 47.4 35 247 34 6.7 950 162

(69-227) (11-69) (19.7-24.6) (0.2-5.7) (4.1-34.7) (16.7-95.9) (9.4-66) (50-427) (7-97) (2.7-13.5) (425-1083) (58-304)

**=P<0.01.

Fibrinolysis (1996) 10(1), 15-20

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Legnani et al

Table 3 Results of clotting and fibrinolytic tests (median and range) obtained in patient plasma samples before (TO) and after (T1) ascites-apheresis sessions

Plasma samples TO PT % aP]-I- sec Fgn:Act mg/dl Fgn'Ag mg/dl ATIlhAct % ATIlhAgmg/dl TDPF.g/ml FgDPi.tg/ml FbDPlag/ml Pig mg/dl FPAng/ml Fl+2nmoVL TATp.g/L vWF:Ag % c~1 AT mg/dl ct2 MG mg/dl

T1

47 43 149 205 43 14.4 4.8 0.3 2.5 6.1 13.9 0.8 3.8 192 248 249

(22-67) (10-52) (62-461) (66-375) (21-73) (3-21.8) (1.2-16.8) (0.1-3.0) (0.4-8.8) (1.2-8.8) (5.4-33.9) (0.4-1.7) (2.1-14.7) (160-368) (125-338) (162-348)

** ** * ** ** * *" ** ** **

41 40 123 180 44 11.1 23.4 4.1 9.4 5.8 35.4 2.8 24.1 174 272 211

(26-63) (10-81) (45-276) (40-281) (4-116) (3-20.5) (20-25.3) (1.7-5.3) (2.9-36.5) (0.6-7.8) (8.4-97.6) (1.2-7.4) (3.6-135) (142-348) (156-366) (151-304)

*=P<0.05: **=P<0.01.

differences were found for fibrinogen, plasminogen and et2 macroglobulin. DISCUSSION AND CONCLUSIONS

Several proteins (with molecular weight similar to albu-

FgDP

FbDP

TDP 40 35 30 -- 25

30 25 20

:t

) 2o

15

10 5 0

min, such as ATIII, plasminogen, e¢l antitrypsin) and peptides (derived from coagulation and fibrinolysis activation) were still present in the ascitic fluid after filtration by the ascites-apheresis apparatus. For many of the proteins measured, however, the actual values recorded after filtration were lower than those expected. These results are likely accounted for by removal of the proteins through the filters due to their molecular weight being either higher (fibrinogen, fibrin/ogen degradation products, ¢z2 macroglobulin, Von Willebrand factor) or lower (FPA, Fl+2) than the cut-off values of the filters used in the apparatus. Reinfusion of the filtered and concentrated ascitic fluid in the patients led to an increase in the levels of clotting activation markers (FPA, TAT, Fl+2) and fibrin/ogen degradation products (TDP, FgDP, FbDP). Nevertheless, the global clotting tests (PT, aPTT) were virtually unaffected, no substantial signs of clotting factor consumption were recorded (fibrinogen and ATIII) and the clinical condition of the patients improved. The products of clotting and fibrinolytic activation present in the ascitic fluid before reinfusion might be the source of the increased levels recorded in the patients after the ascites-apheresis session. To verify this hypothesis, the actual values of the quantitative variables measured in patient plasmas at the end of the procedure were compared with those expected. Calculation was made on

I" TO

' t T1

15 10 5 0

~ ** TO

TCV-TI

§§ T!

FpA

i

15[ toj 51

6o

20 0

0' TO

TI

TO

TCV-TI

i TO

**

I

140 120 100 80 60 40 20 ;

§§

"~ TI

TI

TCV-TI

TAT

2o i

8O

[

0l

TCV-TI

F 1+2

100

§§

§

0 TCV-T|

TO

T1

TCV-T1

Figure Results of the tests (median and range) in patient plasmas before (TO) and after (3"1)ascites-apheresis session. The theoretically calculated values at T1 (TCV-T1, see Method section) are also reported. ('=P<0.05, "*=P<0.01, TO vs T1; §=P<0.05, §§=P<0.01, T1 vs TCV-T1).

Fibrinolysis (1996) 10(1), 15-20

© Pearson Professional Ltd 1996

Hyperfibrinolysis but not hypercoagulability after a new ascites-apheresis procedure in liver cirrhosis patients

the basis of the dilution of the variables measured in filtered ascitic fluid after reinfusion in the patient's plasma volume. As expected, since the ascitic fluid was slowly reinfused (100 ml/h) and blood at T1 was sampled after the end of reinfusion, the concentration of the components with short half-life (Fl+2, TAT, ATIII and ctl antitrypsin) was found to be lower than theoretically calculated. In contrast, the measured values of fibrin/ogen degradation products (longer half-life) were higher than theoretically calculated while no significant differences were found for fibrinogen, plasminogen and t~2 macroglobulin. The marked increase in fibrin/ogen degradation products--result of fibrinolysis activation--seems to be the most significant effect of ascitic fluid reinfusion in our conditions. It is well known that cirrhotic patients have a complex hemostatic dysfunction characterized by impaired clotting factor synthesis and accelerated fibrinolysis. 27-33 Ascites has been identified as a possible mechanism accounting for hyperfibrinolysis in cirrhotic patients, its remission b y diuretics being clearly associated with reduced hypercoagulability markers and increased fibrinogen levels, a4 It might be speculated that in the unstable clotting/fibrinolytic balance of cirrhotic patients, the reinfusion of filtered and concentrated ascitic fluid containing not negligible amounts of plasminogen activators 22 elicits a further transient imbalance that m a y enhance the hyperfibrinolytic condition. As expected, m a n y of the investigated patients already presented at baseline signs of clotting activation which further underwent a 'passive' increase after ascitic fluid reinfusion because of their high concentration in the ascitic fluid itself. The increase in the fibrin/ogen degradation product levels recorded in our patients at the end of the ascites-apheresis sessions can, therefore, be interpreted as the result of primary hyperfibrinolysis rather t h a n of clotting activation. To date, the different procedures of reinfusion of ascitic fluid in the systemic circulation have invariably been associated with laboratory findings of clotting activation, sometimes also complicated b y clinically evident thrombotic events, s'7']°-~s Endotoxins 16'w and/or procoagulant materials at high clotting activation risk, TM derived from ascitic fluid, might play an important role in the pathogenesis of these alterations. It has also been suggested that some of the procoagulant activity in the ascitic fluid m a y derive from the cellular fraction, especially from peritoneal leucocytes.J9 Moreover, collagen a platelet-aggregating factor - has been reported to be present in ascites. 2° Thus, m a n y factors present in the ascitic fluid are potentially able to interact with the haemostatic system and contribute to the development of coagulopathy after peritoneovenous shunt. The apparatus and procedure investigated in this © Pearson ProfessionalLtd 1996

19

study, involving a cascade filtration of ascitic fluid through two hollow fiber filters, proved effective in removing most of the procoagulant materials, the increase in the levels of hypercoagulability markers after reinfusion being merely a passive result of the materials reinfused. On the other hand, the filtration system preserved fibrinolytic activators, whose reinfusion elicited a fibrinolysis activation. Though the most relevant effect recorded after ascitic fluid reinfusion, this p h e n o m e n o n did not, however, induce major changes in the clotting and fibrinolytic patterns of the patients. In fact, the ascites-apheresis procedure did not further worsen the altered clotting conditions. Finally, it should be pointed out that the ascites-apheresis procedure reported by us in the present and our previous study 22 using the same apparatus, gave good clinical results in all cases with no side-effects whatsoever.

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