The Veterinary Journal 193 (2012) 103–108

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The Veterinary Journal

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Haemostatic abnormalities in cats with naturally occurring liver diseases

Brigitte Dircks, Ingo Nolte, Reinhard Mischke ⇑Small Animal Clinic, University of Veterinary Medicine Hanover, Bünteweg 9, 30559 Hannover, Germany

a r t i c l e i n f o

Article history:Accepted 28 September 2011

Keywords:CatHaemostasisLiver diseaseD-dimersFactor XIII

1090-0233/$ - see front matter � 2011 Elsevier Ltd. Adoi:10.1016/j.tvjl.2011.09.026

⇑ Corresponding author. Tel.: +49 511 953 6202.E-mail address: Reinhard.Mischke@tiho-hannover.

a b s t r a c t

Alterations in the haemostatic system were characterized in cats with different naturally occurring liverdiseases. The study looked at 44 healthy cats and 45 cats with different liver diseases confirmed histolog-ically or cytologically (neoplasia, n = 9; inflammation, n = 12; hepatic lipidosis, n = 13; other degenerativeliver diseases, n = 11). The following parameters were evaluated: platelet count; prothrombin time; acti-vated partial thromboplastin time; thrombin time; factor (F) II, FV, FVII, FX, and FXIII activities; fibrinogenconcentration; activities of antithrombin, protein C, plasminogen, and a2-plasmin inhibitor, and D-dimerconcentration.

In cats with liver diseases, 44/45 (98%) had one or more abnormalities of the coagulation parametersmeasured. In cats with inflammatory liver diseases, increased D-dimer concentrations and decreasedFXIII activity were the most consistent abnormalities and were found in 83% and 75% of cats, respectively.The most common abnormality in cats with neoplastic liver disease was FXIII deficiency (78%). The mostconsistent abnormalities in cats with hepatic lipidosis were increased FV activity and D-dimer concentra-tion with 54% of cats having values above the reference range for both parameters. Cats with miscella-neous degenerative liver disease most frequently showed FXIII deficiency (64%). The results of thisstudy show that alterations of single haemostatic components are a frequent finding in cats with liverdisease. Activation of haemostasis with subsequent consumptive coagulopathy (rather than decreasedsynthesis) seems to be responsible for these alterations. Increased blood levels of different haemostaticcomponents in cats with inflammatory lesions may be related to an acute phase reaction.

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Introduction

Liver disease is associated with coagulation abnormalities andcan result in an increased risk of bleeding. The liver is not onlythe major site of production of clotting factors, inhibitors and pro-teins of the fibrinolytic system, but is also responsible for theirclearance and for the vitamin K-dependent carboxylation of clot-ting factors. Therefore, liver disease is associated with synthesisdeficits and increased consumption of coagulation factors due todisseminated intravascular coagulation (DIC) (Amitrano et al.,2002; Lisman and Leebeek, 2007).

Coagulation abnormalities are reported to be a common findingin cats with different liver diseases. Of 22 cats with various natu-rally occurring liver diseases, prolongation of prothrombin time(PT) was the most common abnormality found in 77% of cats,whereas factor (F) VII activity was reduced in 68% and activatedpartial thromboplastin time (APTT) was prolonged in 55% (Liscian-dro et al., 1998). Furthermore, liver diseases have been reported tobe associated with alterations in antithrombin activity and in con-centration of fibrin degradation products (Thomas and Green,

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de (R. Mischke).

1998). In a study by Center et al. (2000), only 4% of cats with hepa-tic lipidosis had a prolonged PT, 25% had a prolonged APTT, and75% had increased proteins invoked by vitamin K absence (PIVKA)clotting times. This indicates that the coagulation screening testsPT and APTT do not adequately mimic the whole clotting processas it occurs in vivo. These tests do not detect alterations of primaryhaemostasis or of the inhibitory and fibrinolytic system (Thachil,2008) so may not reflect the entire degree of impairment of hae-mostasis in liver disease.

Haemostatic abnormalities associated with different liver dis-eases have been investigated more extensively in dogs. As in hu-mans, activities of all coagulation factors and inhibitors exceptFVIII, as well as of plasminogen and a2-plasmin inhibitor were re-duced in eight dogs suffering from liver cirrhosis. Reduction wasmost severe in vitamin K-dependent FVII, FX, and protein C (Mis-chke et al., 1998). In a recent study Prins et al. (2010) measuredactivities of individual coagulation factors, D-dimers, and anti-thrombin and protein C activities in dogs with liver disease and57% had at least one coagulation abnormality, while APTT was pro-longed in chronic hepatitis with and without cirrhosis. Further-more, dogs with liver cirrhosis had decreased platelet counts andreduced activities of antithrombin and FIX. Whereas coagulationabnormalities and the fibrinolytic system have been studied in

104 B. Dircks et al. / The Veterinary Journal 193 (2012) 103–108

detail for dogs with liver disease, previous studies in cats havemainly addressed the global haemostatic tests.

In the present study, various individual components of differentparts of the entire haemostatic system were measured in cats withhistologically or cytologically confirmed liver disease. The hypoth-esis was that, as in dogs and humans (Mammen, 1994), cats withliver disease have frequently detectable abnormalities of singlefactors and inhibitors of the coagulation system and of proteinsof the fibrinolytic system.

Materials and methods

Animals

Forty-five cats, presented to the Small Animal Clinic, University of VeterinaryMedicine Hanover with different liver diseases, were prospectively entered intothe study. Cats were classified as having neoplastic (n = 9) or inflammatory disease(n = 12), hepatic lipidosis (n = 13), or other degenerative liver disease (n = 11). Breedand sex distribution was heterogeneous among different liver disease groups. Therewas no significant difference in age between disease groups.

Neoplastic liver diseases included hepatic lymphoma (n = 5), cholangiocarci-noma (n = 3), and pancreatic carcinoma with liver metastasis (n = 1). Inflammatoryliver diseases included neutrophilic cholangiohepatitis (n = 4), lymphatic portalhepatitis (n = 3), purulent portal hepatitis (n = 2), pyogranulomatous inflammation(n = 2), and lymphatic cholangiohepatitis (n = 1). Other degenerative liver diseasesincluded non-fatty degeneration (n = 5), Ito cell hyperplasia (n = 3), and non-specificdegenerative changes (n = 3). Liver disease was diagnosed by histology in 31 cats. Inthe remaining 14 cats, diagnosis was exclusively based on liver cytology and con-sisted of 9 cats with hepatic lipidosis, 4 with neoplasia (hepatic lymphoma), and1 cat with inflammation (pyogranulomatous inflammation).

A control group (for statistical comparison of each parameter and calculation ofreference ranges) consisted of 44 healthy cats of different ages (median, 9 years;range, 1–14 years), sex, and breeds. Cats of the control group were significantlyyounger compared to cats with liver diseases (P = 0.045). These cats had no evi-dence of disease on clinical examination, complete blood count, and biochemistryprofile. Healthy control cats were either client-, student- or staff-owned.

In accordance with the German animal welfare law, the experimental designwas announced to and approved by the official Animal Health Care Officer of theuniversity and the responsible national agency (Lower Saxony State Office for Con-sumer Protection and Food Safety; reference number 10A 035).

Sample collection

Blood was obtained from a jugular, cephalic or saphenous vein using sterile dis-posable needles (21 G) and only slight pressure was used to raise the vein. For mea-suring platelet counts, 1 mL of blood was collected into a tube containing EDTA.Samples were mixed by gentle inversion of tubes. Blood samples for measurementof platelets were stored at room temperature and measurements were performedwithin 30 min of collection. For coagulation testing, 2 mL of blood were collectedinto plastic tubes containing one part 0.11 mol/L sodium citrate solution for nineparts of blood, and immediately mixed by careful rocking. The samples were imme-diately centrifuged for 5 min at 10,000 g and then plasma was removed and frozenin aliquots at �70 �C.

Laboratory methods

Measurement of platelet counts were performed by use of a laser-based auto-mated blood cell counter (Advia 120, Bayer Diagnostics). The group tests of thecoagulation system and the individual FII, FV, FVII, and FX activities were measuredwith a coagulation analyser (Amax Destiny plus, Trinity Biotech GmbH) using theclotting (ball coagulometer) technique. PT was measured using a commercial re-agent (Thromborel S, Siemens Healthcare Diagnostics) according to (1) the standardtest procedure (i.e. manufacturer’s instructions; standard test, PTST) and (2) a mod-ified test procedure (PTMT): 25 lL of diluted platelet poor plasma (1:20-dilutionwith imidazole buffer [Siemens Healthcare Diagnostics]) was incubated with25 lL fibrinogen solution (2 g/L human fibrinogen [Haemochrom Diagnostica] inisotonic sodium chloride solution) for 2 min at 37 �C and coagulation was inducedby addition of 25 lL reagent. PTMT was converted into percentage coagulation activ-ity of a normal feline pool plasma (n = 50; activity = 100 %) using a calibration curvebased on different dilutions of the feline pool plasma.

PTMT was carried out because of a higher sensitivity for the detection of individ-ual coagulation factor deficiencies in feline plasma compared to the PTST (Mischkeet al., 1996). Furthermore, supplementation of fibrinogen in the PTMT ensures ade-quate fibrin formation despite sample dilution and makes the test independent offibrinogen concentration in the sample.

APTT was measured using a commercial reagent (PTT reagent, Roche Diagnos-tics) following the manufacturer’s instructions. Thrombin time (TT) was measuredusing bovine thrombin (Test thrombin reagent, Siemens Healthcare Diagnostics)following the recommendations of the manufacturer. Activities of individual coag-ulation factors (FII, FV, FVII, and FX) were measured with commercial human defi-cient plasmas (Siemens Healthcare Diagnostics) and Thromborel using a highersample dilution (1:40 with imidazole buffer) than is recommended for the mea-surement of human samples so as to guarantee an adequate specificity (Mischkeet al., 1994). The assay was calibrated with a standard curve based on different dilu-tions of feline pooled plasma.

Fibrinogen concentration was measured according to Jacobsson (1955) by dis-solving the fibrin clot received after thrombin addition in alkaline urea solution,measuring the extinction at 280 nm and using an extinction coefficient of E280nm/

1cm = 1.480. Each test was performed in duplicate.Antithrombin, protein C (Antithrombin III BM/ Hitachi, Protein C chromogen,

Roche Diagnostics), plasminogen, and a2-plasmin inhibitor activities (CoamaticPlasminogen, Coatest Antiplasmin, Haemochrom Diagnostica) as well as FXIII (fi-brin stabilizing factor) activity (Berichrom Factor XIII; Siemens Healthcare Diagnos-tics) were determined with commercial test kits based on chromogenic substratesusing an autoanalyser and based on instrument settings provided by the reagentmanufacturers (which had partly to be adapted to feline plasma). Different dilutionsof pooled feline plasma served as the standard.

D-dimers were measured with a latex turbidimetric assay (Tinaquant D-dimer,Roche Diagnostics) based on cross-reacting antibodies against human D-dimers.The test was calibrated with a set of human standards (D-dimer Calibrator, RocheDiagnostics). All tests conducted in the present study were validated in preliminaryinternal laboratory test series for the use in cats (data not shown).

Statistical analysis

All statistical analyses were performed using commercial software (SPSS forWindows 17.0.1). Due to the non-normally distributed data, Kruskal–Wallis testwas used to test equality between groups. If significant differences were found,pair-wise comparison of groups was performed with the Mann–Whitney U testwithout further alpha adjustment. Reference values were defined on the basis ofthe 2.5% and 97.5% quantiles from the values of the healthy control cats. Data ofeach group are presented as median, minimum, and maximum. P < 0.05 was consid-ered significant.

Results

Overall, 44/45 (98%) cats had one or more abnormalities of thecoagulation parameters measured. Among the global coagulationtests (APTT, PT, TT), prolonged APTT was the most consistentabnormality (Table 1). In 40% of all cats with liver disease the APTTwas above the reference range. Cats of all disease groups exceptthose with neoplastic liver disease had a significantly prolongedAPTT compared to the healthy control group (P < 0.01; Mann–Whitney U test) (Fig. 1).

The PTST was prolonged in 18%, and shortened in 9% of all catswith liver diseases, while PTMT values were above and below thereference range in each 18% of these cats. There was a significantdifference in PTST between cats with inflammatory liver diseasesand healthy control cats, whereas no significant difference was ob-served in PTMT between any of the liver disease groups and the con-trol group. The TT was prolonged in one-third of cats with liverdiseases. Cats with neoplastic and inflammatory liver disease andwith hepatic lipidosis had significantly longer TT than control cats.

With regard to single clotting factors, decreased FXIII activitywas the most common alteration: 78% of cats with neoplastic liverdisease, 75% of cats with inflammatory liver disease, 31% of catswith hepatic lipidosis, and 64% of cats with other degenerative li-ver disease had a FXIII activity below the reference range. Com-pared to the control group, all disease groups had significantlyreduced FXIII activities (P < 0.001).

Thirty-six per cent of all cats with liver disease had fibrinogenconcentrations exceeding the normal range and this abnormalitywas observed in 67% of cats with hepatic inflammation. Fibrinogenconcentration was significantly increased in cats with hepatic neo-plasia, inflammation, and lipidosis compared to healthy controls.Increased FV activity was seen in 40% of all diseased cats and in54% of cats with hepatic lipidosis. Cats with hepatic lipidosis and

Table 1Percentage of abnormal values for various coagulation parameters in different liver disease groups.

Parameter Neoplasia Inflammation Lipidosis Degenerationn = 9 n = 12 n = 13 n = 11

< > < > < > < >

Platelet count 22 11 25 0 15 8 27 18PTST 0 22 25 17 8 23 0 9PTMT 22 22 25 17 15 23 9 9APTT 0 33 0 42 8 46 0 36Thrombin time 11 44 0 42 0 31 27 18Fibrinogen concentration 0 22 0 67 8 31 0 18Factor II activity 22 22 25 17 23 15 9 0Factor V activity 0 33 17 50 0 54 9 18Factor VII activity 11 22 17 33 8 23 9 0Factor X activity 22 11 25 17 38 15 9 0Factor XIII activity 78 0 75 0 31 0 64 0Antithrombin activity 0 44 25 17 15 31 27 9Protein C activity 33 0 58 8 46 8 36 0Plaminogen activity 33 22 0 33 15 8 27 0a2-plasmin inhibitor activity 11 44 17 67 0 23 18 27D-dimers 0 44 0 83 0 54 0 27

Values lying below (<) or above (>) the reference range of haemostatic tests in cats with liver diseases. Reference range is based on 2.5–97.5% quantile of the results of 44 adulthealthy cats.PTST, prothrombin time (standard test); PTMT, prothrombin time (modified test); APTT, activated partial thromboplastin time.

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inflammation had significantly increased FV activities compared tothe control group. Among the vitamin K dependent clotting factors(FII, FVII, FX), there was no significant difference between diseasegroups and the control group.

Protein C activity was the most consistent abnormality for theinhibitors measured in this study: 44% of cats with various liverdiseases had protein C activities below the reference range and58% of cats with inflammatory liver disease had decreased values.All disease groups had significant lower protein C activities in com-parison to the control group (P < 0.005).

In cats with various liver diseases, 40% had increased a2-plas-min inhibitor activity. This was observed in about two-thirds ofcats with inflammatory disease. The a2-plasmin inhibitor activitywas significantly increased in all disease groups except in cats withvarious degenerative liver diseases.

Increased D-dimer concentration was present in about half ofthe patients and was the second most common alteration of all catswith liver diseases. Within the inflammatory liver disease group,an increased D-dimer concentration was observed in 83% of cats.Cats with neoplastic, and inflammatory liver diseases, and hepaticlipidosis had significantly increased D-dimer concentration com-pared to the control group (P < 0.05).

Discussion

In the present study, almost all cats with liver disease had atleast one abnormal coagulation parameter. These data supportour initial hypothesis that cats with liver disease, as in other spe-cies, have alterations in haemostasis with respect to single coagu-lation factors, inhibitors, and proteins of the fibrinolytic system.Haemostatic abnormalities are considered to be a consequence ofdecreased hepatic synthesis and increased consumption of coagu-lation factors, hyperfibrinolysis, thrombocytopenia, platelet func-tional disorders, and portal hypertension (Mammen, 1994;Amitrano et al., 2002).

The percentage of cats with abnormal parameters in the presentstudy was higher when compared to a previous study in whichcoagulation abnormalities were reported in 82% of cats with liverdisease (Lisciandro et al., 1998). However, comparability of per-centages of cats with abnormal values is limited between studiesdue to a much wider range of parameters measured in the presentstudy and the consequently increased sensitivity for detection ofhaemostastic abnormalities.

Reduced FXIII activity was the most consistent alteration amongall cats with liver disease. This should be kept in mind whencoagulation tests are performed in cats with liver disease, sincethe standard coagulation tests PT and APTT do not screen for FXIIIdeficiency. Severe FXIII deficiency is associated with bleedingdiathesis and potential life-threatening bleeding complications inhumans (Burchhardt et al., 1978; Gödje et al., 1998; Gerlachet al., 2000). FXIII plays an important role in the final stages ofthe clotting process by converting the loose fibrin polymer into afirm, highly organized, cross-linked structure (Francis and Marder,1987, 1988). Furthermore, FXIII also regulates fibrinolysis. It medi-ates binding of a2-plasmin inhibitor to fibrin, which protects fibrinagainst early lysis by plasmin (Sakata and Aoki, 1980). Extremelylow FXIII levels have been observed in seriously ill patients (Nuss-baum and Morse, 1964; Egbring et al., 1996). Furthermore, FXIIIhas been suggested as a prognostic indicator in patients with liverdisease and DIC (Song et al., 2006; Tacke et al., 2006).

Acquired FXIII deficiency is either caused by impaired synthesisor increased turnover and consumption, and has been reported invarious diseases (Egbring et al., 1996). Milder alteration of othercoagulation factors measured in the present study as well as signif-icantly increased D-dimer values in most disease groups suggestthat not only impaired synthesis but also increased consumptionis responsible for decreased FXIII activity in cats. There is an equi-molar consumption of FXIII with fibrinogen (Greenberg et al.,1985), but in contrast to equally sized fibrinogen it is only presentin low concentrations in plasma (Hedner et al., 1975). Therefore,FXIII is more affected by consumption than fibrinogen. Addition-ally, fibrinogen is an acute phase protein in cats (Ceron et al., 2005).

Elevated D-dimer concentrations in cats with hepatic diseasesin our study are well in agreement with findings in humans. In-creased D-dimer concentrations have been reported in patientswith hepatic cirrhosis (Gürsoy et al., 2005), acute viral hepatitis,and hepatocellular carcinoma (Kruskal et al., 1992). In the latterstudy patients with hepatocellular carcinoma had markedly higherD-dimer values than those with hepatitis, whereas in the presentstudy cats with inflammatory diseases had most consistentchanges. D-dimers result from the degradation of cross-linked fi-brin and their presence indicates generation of thrombin and plas-min (Carr et al., 1986).

In addition to increased intravascular formation of insoluble fi-brin with subsequent fibrinolysis (Brazzell and Borjesson, 2007),D-dimers might have been elevated in the present study due to

Fig. 1. Coagulation parameters in control cats (C), cats with neoplastic (N) and inflammatory (I) liver diseases, hepatic lipidosis (L), and other degenerative liver diseases (D).Data for each group are presented as box-and-whisker plots; boxes represent the 25th–75th percentiles, the horizontal line within each box represents the median value, andthe whiskers represent the 5th–95th percentiles. Dotted lines indicate the reference range, results of Kruskal–Wallis test are shown as P values in right top angles, and thesame small letters above the boxes indicate significant difference between groups e.g. there is a significant difference in PTST between the control group and cats withinflammatory liver disease and between cats with inflammatory liver disease and cats with hepatic lipidosis.

106 B. Dircks et al. / The Veterinary Journal 193 (2012) 103–108

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decreased hepatic clearance. Systemic inflammatory diseases cantrigger DIC (Estrin et al., 2006; Ogura et al., 2007) and are reportedto cause elevated D-dimers in cats (Tholen et al., 2009). Inflamma-tory liver diseases may not only cause local activation of haemosta-sis, but also result in systemic inflammation with subsequent DIC(Miyake et al., 2007).

The coagulation factors FII, FVII, FIX, and FX and the inhibi-tors protein C and S are vitamin K dependent (Dunn, 2009). Inthe present study, FII, FVII, FX, and protein C were measured,and only the latter was significantly decreased in liver diseasegroups compared to healthy controls. This suggests that vitaminK deficiency only played a minor role in the liver diseases in-cluded in the present study. The finding is somewhat surprisingsince at least some of the cats suffered from cholestatic diseasesand is in contrast to the conclusions of Center et al. (2000), whoindicated that vitamin K deficiency is a frequent finding in felinehepatopathies. The conclusions were based on the findings of anabnormal PIVKA test, which is, however, a modified PT test andnot specific for the presence of PIVKA. Lisciandro et al. (1998)also concluded that vitamin K deficiency is a common findingin cats with liver disease but FVII was the only factor measuredin that study, and therefore interpretation regarding the mecha-nism can be only speculative.

It is noteworthy that cat populations were not uniform in thedifferent studies and that differences in the incidence and severityof cholestatic liver disease may be partly responsible for the ob-served discrepancies. Furthermore, in all studies, the values repre-sent only one point of dynamic haemostatic changes duringdisease progression.

Our results confirm the higher sensitivity of the PTMT to detectindividual factor abnormalities, as already reported (Mischkeet al., 1996). This was achieved by the higher predilution of theplasma sample.

Protein C deficiency was seen consistently in cats with inflam-matory liver diseases. In humans, the protein C pathway isdown-regulated during states of systemic inflammation and sepsis,which can promote microvascular thrombosis, increased leukocyteadhesion, and increased cytokine formation (Esmon, 2003; Liawet al., 2004; Danese et al., 2010).

Despite suspected consumption due to activated coagulationand fibrinolysis, elevated fibrinogen concentrations as well as FVand a2-plasmin inhibitor activities were found in cats with differ-ent liver diseases. These findings may be explained by the possiblerole of these parameters as acute phase reactants in cats. Elevatedfibrinogen levels in response to inflammation and infection hasbeen shown in cats (Weiss et al., 1980; Boudreaux et al., 1989; Cer-on et al., 2005). Although the function as an acute phase protein isto our knowledge not yet reported for FV, the simultaneous eleva-tions of fibrinogen and FV in cats with inflammatory disease andhepatic lipidosis in the present study support this assumption.The function of a2-plasmin inhibitor as an acute phase protein iswell described in humans (Risberg et al., 1986; Ueyama et al.,1992) and has been suggested in dogs (Mischke, 2005). The highpercentage of cats with inflammatory liver diseases having in-creased levels of a2-plasmin inhibitor in the present study is con-sistent with a role as an acute phase reactant in the feline species.

The observed increase in FV activity could also be a conse-quence of reduced protein C activity, which may have led to re-duced inactivation of activated FV in cats with inflammatoryliver disease and hepatic lipidosis. The importance of activatedprotein C (APC) for the ‘‘down-regulation’’ of FV activity has beenwell described in humans (Nicolaes et al., 1995).

An important limitation of our study is that for some cats (al-most exclusively cats with hepatic lipidosis and lymphoma), thediagnosis of liver disease was solely based on cytology, whichhas limited specificity and sensitivity for the evaluation of liver dis-

ease, and an additional underlying liver disease might have beenoverlooked. However, hepatic lipidosis as well as lymphoma areboth conditions for which cytology is thought to be adequate fordiagnosis (Weiss and Moritz, 2002). Furthermore, this was a clini-cal study and liver biopsy sampling was only performed when nec-essary as part of the diagnostic work-up.

Another limitation is that the haemostatic abnormalities we ob-served may not have been caused by liver disease alone. The exis-tence of a concurrent disease or systemic involvement was not anexclusion criterion and post-mortem examinations were not eval-uated for the study as they were carried out only on a limited num-ber of cats. Therefore, part of the observed changes may have beeninduced by concurrent inflammatory or neoplastic diseases.

Conclusions

Alterations of single haemostatic components are a commonfinding in cats with different liver diseases, and cats with inflam-matory lesions seem to have most consistent alterations. Acutephase reactions might lead to the often elevated blood levels of dif-ferent haemostatic components in these animals. Increased D-di-mer concentrations suggest that activation of haemostasis withsubsequent consumptive coagulopathy (rather than decreasedsynthesis of coagulation proteins) is the main cause of most hae-mostatic abnormalities in cats with liver disease. Vitamin K defi-ciency did not seem to play a major role in cats with hepaticdisease in our study, since even the factor with the shortest half-life time (i.e. FVII) was not significantly decreased in any of the li-ver disease groups. Since FXIII deficiency is frequently found in catswith liver disease and has been shown to be of prognostic value inhumans with liver cirrhosis, further studies are warranted to inves-tigate its prognostic utility in cats.

Conflict of interest statement

None of the authors of this paper has a financial or personalrelationship with other people or organisations that could inappro-priately influence or bias the content of this paper.

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