coagulopathy in cirrhotic patient

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713Coagulation abnormalities in the cirrhotic patient. ,2013; 12 (5): 713-724

Coagulation abnormalities in the cirrhotic patient

Jimena Mucio-Bermejo,* Ral Carrillo-Esper,* Misael Uribe,** Nahum Mndez-Snchez**

* Intensive Care Unit, ** Liver Research Unit.Medica Sur Clinic & Foundation, Mexico City, Mexico.

ABSTRACT

The clotting process is a dynamic array of multiple processes which can be described in four phases: pla-telet plug initiation and formation, clotting process propagation by the coagulation cascade, clotting ter-mination by antithrombotic mechanisms and clot removal by fibrinolysis. The liver plays a central role ineach of these phases of clotting process, as it synthesizes the majority of coagulation factors and proteinsinvolved in fibrinolysis as well as thrombopoeitin, which is responsible for platelet production from me-gakaryocytes. Many pathological processes associated with cirrhosis, such as portal hypertension andendothelial dysfunction, as well as co-morbid conditions, may also alter the coagulation process. Conse-

quently, patients with liver disease have a disturbed balance of procoagulant and anti-coagulant factorswhich deviates from the normal coagulation cascade. This situation poses an additional problem in thediagnostic and therapeutic approach to this group of patients, since traditional coagulation test may notbe reliable for assessing bleeding or thrombotic risk and traditional transfusional strategies may not beapplicable in cirrhotic patients. In this article, we review the pathophysiological bases of coagulationabnormalities, in cirrhotic patients, the diagnostic therapeutic strategies to be followed and its impacton the clinical outcome in the cirrhotic patient.

Key words.Coagulopathy. Bleeding risk. Thrombotic risk. Liver disease.

Correspondence and reprint request: Ral Carrillo-Esper, M.D.Puente de Piedra, Nm. 150, Col. Toriello Guerra, C.P. 14050, Mxico,D.F., Mxico.Tel.: (52) 55 5424-7200, Ext. 4139E -mail: [email protected]

Manuscript received: January 24, 2013.

Manuscript accepted: April 27, 2013.

September-October, Vol. 12 No.5, 2013: 713-724

CONCISE REVIEW

INTRODUCTION

The clotting process is a dynamic array which canbe explained as occurring in four phases:

Platelet plug initiation and formation. Clotting process propagation by coagulation cas-

cade. Clotting termination by antithrombotic mecha-

nisms. Clot removal by fibrinolysis.

The liver plays a central role in each o f thesephases. As expected, cirrhotic patients have adisturbed balance between pro-coagulant and

anti-coagulant factors, and a very poor reserve

of these factors leads to increased bleeding riskas well as increased thrombotic risk. This coa-

gulation imbalance is not reflected by conven-tional coagulation test.

Although variceal bleeding remains being themost prevalent coagulopathy-associated exacer-bation, thrombotic complications are not un-common in the cirrhotic patient1-4 (Figure 1,Table 1).

PLATELET PLUG INITIATION

AND FORMATION

Cirrhotic patients commonly present quantitativeand qualitative platelet defects. Thrombocytopenia

may results from decreased Thrombopoietin (TPO)production and/or increased TPO breakdown,myelosuppression (resulting from acute hepatitis Cinfection, folic acid deficiency, or ethanol toxicity), splenicplatelet sequestration, increased plateletconsumption resulted from sustained low-gradedisseminated intravascular coagulation or auto-anti-body mediated destruction of platelets.5-8

The existence of a functional platelet defect(hypoaggregability) was described by Thomas in


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1967.9Bleeding time prolongation correlates weaklywith platelet count. Qualitative platelet defects des-cribed in cirrhotic patients includes:5-10

Acquired storage pool defects, such as decreasedAdenosin triphosphate (ATP) and serotonine indense granules.

Decreased thromboxane A2 (TXA2) synthesis. Altered transmembrane signal transduction:

quantitatively decreased glycoprotein Ib andaIIb3 receptors (as a consequence of proteolysisby the overactive fibrinolytic system), decreasedresponse to collagen, thrombin, arachidonic acid,adenosin diphosphate (ADP), epinephrine, risto-cetin.

Extrinsic factors such as abnormal high-densitylipoprotein and apolipoprotein E levels, reduced

hematocrit and increased levels of platelet inhibi-tors (such as endothelium-derived nitric oxideand prostacyclin). Defective platelet-endotheliuminteraction may exist, and additive effect of con-comitant uremia-related, sepsis related or drugrelated platelet dysfunction might also be pre-sent.

There are also factors that promote platelet acti-vation e.g. von Willebrand factor (vWF) that isreported to be upregulated in cirrhotic patients.Unconjugated bilirubin is a strong inducer ofplatelet aggregation similar to adenosine diphos-

phate (ADP) in isolated platelets.11,12 Tenfoldconcentrated ascitic fluid causes irreversible plateletaggregation and serotonin release of normalp late let -r ich p lasma s imi lar to co l lagen. 13

In cholestatic liver disease, platelets demonstratea hyperaggregability; thrombosis of portal veins hasalso been detected in 40% of primary biliary cirrho-sis (PBC) liver at the time of transplantation. 10

The bleeding time is prolonged in up to 40% of pa-tients who have liver disease and it can be explainedonly in part by a concomitant thrombocytopenia, infact, there is a weak correlation between bleedingtime, platelet count and bleeding risk.14

Desmopressin, an analogue of vasopressin, shor-tens the bleeding time in these patients, by enhan-cing endothelial-derived vWF level, but it has shownno efficacy in controlling variceal bleeding or redu-cing blood loss in patients undergoing liver trans-plantation or liver resection. This indicates thatnormalization of bleeding time does not necessarilydiminish bleeding risk, and bleeding time is not areliable prognostic factor of significant bleeding.The platelet function analyser-100 (PFA-100) is a

rapid new in vitro test that provides a quantitativemeasure of primary hemostasis at high shear stressusing citrated whole blood. This automated devicefunctions with blood flowing under a constant

vacuum through a capillary and a microscopic aper-ture in a membrane coated with collagen and ago-nists. As a result, the closure time of the aperture isa measurement of platelet adhesion/aggregation.Prolonged closure time can be corrected by elevatingthe hematocrit in the blood of patients with liverdisease, suggesting that the influence of hematocrit(and other physiologic factors) on platelet functionis probably more relevant than the intrinsic plateletdefects commonly found in patients who have liverdisease.8

The clinical relevance of thrombocytopenia andhypoagregability in cirrhosis remains unclear:

Thrombocytopenia is mostly mild to moderate, andit is not associated with severe bleeding in patientswith stable liver disease, and the clinical relevanceof thrombocytopenia in most patients who have liverdisease has a questionable significance. Plateletfunctionality, as measured by its capacity to supportthrombin generation, is not diminished in patientswho have stable cirrhosis: under physiologic condi-tions of flow, platelets from patients who have livercirrhosis are able to interact normally with collagenand fibrinogen as long as the platelet count and he-matocrit are adjusted to the levels found in healthysubjects.10,14,15

CLOTTING PROCESS PROPAGATION BY

THE COAGULATION CASCADE

The majority of procoagulant factors, of the coa-gulation cascade, such as fibrinogen and factors II,V, X, VII, VIII, IX, XI, XII are synthesized in the li-ver, therefore, when synthetic liver function fails,procoagulant factors fail in parallel to the degree ofliver failure. FV and FVII have the shortest in vivohalf-lives (12 and 4-6 h, respectively) and are themost decreased procoagulants in patients with liverdisease.16

Patients with liver disease may have vitamin K defi-ciency due to poor nutrition, or malabsorption causedby decreased bile production or biliary obstruction.The prevalence of vitamin K deficiency (defined as lowplasma vitamin-K1 levels measured by reverse-phasehigh performance liquid chromatography) in patientswith histologically proven PBC is 23.3% . These resultsdo not correlate with the vitamin- K deficiency preva-lence when prothrombin time (PT) prolongation isused as a surrogate marker, and therefore PT should


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Mucio-Bermejo J, et al. ,2013; 12 (5): 713-724716

not be assumed to be a reliable marker of vitamin Kdeficiency in patients with PBC.17,18

FVIII (synthesized in the liver and endothelial cells)and vWF (present in endothelial cells, platelets and

megakaryocytes),

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are also acute phase reactantsthus normal or elevated factor VII and vWF levels maybe found in cirrhotic patients caused by continuedendothelial cell FVIII production despite decreasedhepatic FVIII production, and increased synthesiscaused by acute disease or inflammation. Changes inthe latter result from compensatory increased produc-tion, decreased levels of a vWF cleaving protein in cir-rhotics, and an increased presence of vWF on endothelialwalls due to a chronic inflammatory state.16,19-23

Because PT is dependent on FVII levels and FVII hasthe shortest in vivohalf-life, an isolated prolonged PTis common for patients with liver disease. Although it is

important to know the expected procoagulant syntheticand coagulation test profile in cirrhotic patients, themost important question is whether or not clinical blee-ding can be predicted based on the concentration of pro-coagulant factors (i.e. prolongation of procoagulantlaboratory tests) the prolongation of procoagulant labo-ratory tests. Some insight into this problem is providedby the study from hemophilias A and B, in which pa-tients with more than 6% of the normal activity level ofa given coagulation factor is enough to prevent sponta-neous bleeding, but this single factor coagulation defi-ciency model may not be applicable to cirrhosis, inwhich almost every coagulation factor is deficient. Un-

til now, no significant correlation has been found bet-ween fibrinogen concentration, PT prolongation, factorV activity and bleeding tendency clinical markers suchas melena, hematemesis, variceal bleeding, gastric ulcerbleeding , persistent skin bleeding after liver biopsy ,menorrhagia, positive fecal occult blood test and bloodtransfusion requirements.16

CLOTTING TERMINATION BY

ANTITHROMBOTIC MECHANISMS

Patients with liver disease commonly have decrea-sed levels of proteins C, S, and antithrombin. Pro-teins C and S are vitamin-K-dependent proteinssynthesized by hepatocytes. Protein C, protein S,and antithrombin deficiencies observed in patientswith liver disease have been attributed to decreasedhepatocyte function, increased consumption due todisseminated Intravascular coagulation (DIC) or hy-perfibrinolysis, and vitamin K deficiency.16

Infection has been associated with increased de-tection of endogenous heparinoids, probably as a re-flection of endothelial dysfunction and associated

changes in the endothelial glycocalyx, possibly me-diated by infection-related changes in nitric oxidemetabolism. Glycosaminoglycans (heparinoids)found in the vessel wall are bound by the endothe-

lium and help to maintain hemostatic balance bypreventing clot formation and facilitating blood flowwithin a vessel. Two specific glycosaminoglycans(GAGs), heparan sulphate and dermatan sulphate,have anticoagulant properties similar to heparin.Increased levels of these proteins, measured bythromboelastography (TEG), have been found in pa-tients with cirrhosis, and even higher concentrationswere found in subjects with cirrhosis and activebleeding or infection.24,25

CLOT REMOVAL BY FIBRINOLYSIS

Clot and fibrin degradation is determined by theendothelial release of tissue plasminogen activator(t-PA) and its subsequent inhibition by plasmino-gen activator inhibitor type-1 (PAI-1). To maintaina normal fibrinolytic balance, increases in plasmat-PA concentrations are associated with compensa-tory increases in plasma PAI-1 concentrations.PAI-1 forms a complex with t-PA to cause an overallreduction in free tPA activity. In patients withcirrhosis, plasma t-PA activity is up to seven timeshigher, and it is proportional to the severity ofcirrhosis and may contribute to the risk of vari-ceal hemorrhage by the removal of fibrin clot at the

site of vascular injury. Patients with alcoholiccirrhosis have a higher basal plasma t-PA anti-gen concentration but a normal stimulated releaseof t-PA. However, because of a failure to increaseplasma concentrations of its inhibitor PAI-1, plasmat-PA activity is elevated during both basal andstimulated t-PA release.26,27

According to the degree of liver dysfunction, evi-dence of fibrinolysis may be found in 30 to 60% ofpatients with chronic liver disease, and clinicallyevident hyperfibrinolysis has been estimated to oc-cur in 5 to 10% of those with decompensated cirrho-sis. Hyperfibrinolysis promotes clot dissolution anddecrease platelet aggregation due to degradation ofvWF and fibrinogen platelet receptors.28,29

TAFI (thrombin activatable fibrinolysis inhibitor)is a plasmatic proenzyme synthesized in the liverthat, upon activation by thrombin or other enzymes(plasmin, trypsin, neutrophil elastase), inhibits fi-brinolysis by removing carboxy-terminal lysine resi-dues from partially degraded fibrin. Therebyreducing plasmin formation TAFI is an importantregulator of physiological fibrinolysis and alterations


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in TAFI-activating mechanisms or in TAFI levelscontribute to bleeding or thrombotic manifes-tations.27

Decreased plasma levels of TAFI have been repor-

ted in patients with acute or chronic hepatocellulardiseases of different aetiology, and the degree ofTAFI levels is proportional to the severity of the disease.TAFI deficiency is probably, related with increasedfibrynolysis and impaired thrombin generation. In aprospective follow up study including 65 patientswith liver cirrhosis with a mean follow up of 816days, lower TAFI levels, were strongly correlatedwith fibrinolysis time, and TAFI levels were lower innon-survivors, but fibrinolysis time was not signifi-cantly related to survival. TAFI levels were an inde-pendent predictor of mortality after correction forage, sex, aetiology of cirrhosis, and Child-Pugh

class.27

BLEEDING AND THROMBOTIC

EVENTS IN THE CIRRHOTIC PATIENT

Cirrhosis accounts an increased risk for bothbleeding and thrombotic episodes. Bleeding episodesin cirrhotic patients may be classified as sponta-neous (variceal, non-variceal gastrointestinal blee-ding and cerebral hemorrhage) or procedure-related(including biopsy, central vein cannulation and pa-racentesis). Thrombotic episodes are categorized ac-cording to the affected anatomic region (e.g. deep

vein thrombosis, pulmonary embolism).30-31

Spontaneous bleeding episodes:

a) Variceal bleeding.Variceal bleeding occurs in20-30% of cirrhosis patients and accounts for80-90% of bleeding episodes in these patients,30% of initial bleeding episodes are fatal andas many as 70% of survivors have recurrentbleeding after two weeks from the first epi-sode. Gastrointestinal bleeding is mainly hae-modynamic in its mechanisms and is relatedto portal hypertension. Risk factors for deve-loping variceal bleeding include advancedChild-Pugh class, large varices and the pre-sence of red wale markings. Constipation,vomiting, severe coughing, excessive con-sumption of alcohol and bacterial infectionsmay also contribute to variceal bleeding. Highlevels of D-dimer and t- PA have beendescribed as significant laboratory markersof risk of variceal bleeding, independently ofother laboratory markers and severity of liver

disease. In decompensated cirrhotic patients,variceal bleeding is also the main coagulopa-thy-related problem, representing 50% of allhemorrhagic events.4,31

b) Intracerebral haemorrhage.The prevalence ofspontaneous intracerebral hemorrhage in hospi-talized cirrhotic patients, is low (0.8% for all ae-tiologies, 80.3% in virus-related and 1.8% inalcohol-related groups), and it is reported not tobe related to Child-Pugh score or prolonged PT.31

While a retrospective population-based case-control study found an increased risk of intra-cerebral hemorrhage for both alcoholic liverand non-alcoholic liver cirrhosis patients (ad-justed OR of 4.8 and 7.7 respectively), a fiveyear cohort study found no increased risk ofhemorrhagic stroke in patients with non alco-

hol-related cirrhosis after adjusting for thepatients geographical location, hypertension,diabetes, coronary heart disease, heart failure,atrial fibrillation and hyperlipidaemia.32,33

Alcohol-related cirrhotic patients have theshortest time interval between diagnosis ofliver disease and hospitalization due to brainhemorrhage (2.3 years vs.6.2 years in non-al-coholic cirrhosis) and heavy drinkers had asignificantly higher risk of hemorrhagicstroke than non-heavy drinkers. In somecases, cerebral metastasis bleeding may be theinitial manifestation of hepatocellular carcino-

ma in cirrhotic patients.31

Procedure-related bleeding episodes:

a) Biopsy-associated bleeding.The incidence ofbiopsy-associated bleeding in patients withhistological diagnosis of cirrhosis is 0.7%; nei-ther PT nor prolonged Activated partialthromboplastin time (aPTT) and thrombo-cytopenia are reliable predictors of biopsy rela-ted bleeding.31 In a multicenter study of liverbiopsy-related complications in patients withadvanced hepatitis C that involved 2,740 per-cutaneous biopsies performed over 7 years(80% performed with ultrasound guidance,40% performed by aspiration needle, and 60%used a cutting needle) the bleeding risk was0.4% for patients with an international nor-malized ratio (INR) of 1.1 or less, 1.1% for pa-tients with an INR of 1.2, and 2.4% forpatients with an INR of 1.3 or greater; howe-ver, 37.5% of the patients who had bleedinghad INR < 1 and none of the patients under-


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going a biopsy with INR values greater than1.5 experienced bleeding. Other factors thatwere statistically different between those withbleeding and those without were lower albu-

min, presence of varices, platelets less than60,000.34

b) Central venous canulation.Bleeding complica-tions during central venous canulation in cirr-hotic patients are rare and can be safelyperformed in patients with liver disease andabnormal coagulation tests, even if the INR is1.5 or more. Although the occurrence of seve-re bleeding complications is very low for bothfor subclavian and internal jugular routes ofaccess, in order to prevent minor bleedingsand vascular complications, cannulationsshould to be performed by experienced practi-

tioners with ultrasound guidance.31

c) Paracentesis.Paracentesis has a 0.2% inciden-ce of severe haemorrhage, with a death rate of0.016%. Paracentesis-related bleeding risk hasnot been found to be associated with a PT pro-longed up to twice the midpoint of normal orwith a platelet count of < 50,000.31

As mentioned above, not only bleeding but alsothrombosis complicates the clinical course of cirrho-sis, mostly venous thromboembolism (VT), and por-tal vein thrombosis (PVT).

Venous thromboembolism.Patients with cirr-hosis have been found to have a 1.65-1.74 relati-ve risk of VT when compared with controls. Theprevalence of VT in hospitalized cirrhotic pa-tients is 0.8%, and 0.5% of hospitalized cirrhoticpatients present their first venous thrombosisduring hospitalization. Reduced aPTT, and lowserum albumin levels have been found to be anindependent predictor of developing VT, whileprolonged INR did not appear to protect againstthe development of hospital-acquired VT.30,35

Shah, in a prospective study on decompensatedcirrhotic patients admitted to a inpatient Hepato-logy Service described that, over a 6 month pe-riod, 7% of the patients presented DVT.4

Portal vein thrombosis and pulmonary em-bolism. PVT is the most common thromboticevent in cirrhotic patients, with a reported inci-dence of 7.4 to 11%. Reported risk factors inclu-de prothrombotic states arising from protein C,protein S and antithrombin III deficiencies, mye-loproliferative disorders, sclerotherapy of esopha-geal varices, abdominal surgery, hepatocellular

carcinoma, antiphospholipid syndrome, mutationsof prothrombin (PTHR G20210A), factor VLeiden (FVL G1691A) and methylenetetrahydro-folate reductasa, a key enzyme in the folate cycle

and homocysteine metabolism (MTHFRC677T).35,36

Northup, in a case control study that included113 cirrhotic patients reported a 0.5% incidenceof deep vein thrombosis (DVT) /Pulmonary embo-lism (PE). From all thrombotic events registered,65.5% corresponded to DVT 19.5% correspondedto PE, 15% to patients with both DVT and PE,and only 7% of the patients who presentedthrombosis were receiving medical thrombopro-phylaxis at the time the thrombotic eventoccur.37Garcia-Fuster, in a retrospective studythat included 2074 cirrhotic patients the DVT/PE

incidence were 0.8%; 59% of the events corres-ponded to DVT, 35% toPE and 6% correspondedto patients with both DVT and PE.38

SPECIAL LABORATORY

EVALUATION OF COAGULATION IN

CIRRHOTIC PATIENTS

The PT and aPTT are used ostensibly to investigatepatients who have cirrhosis even though these tests areknown to be poor predictors of bleeding in this categoryof patients because cirrhosis is a condition in which le-vels of such naturally occurring anticoagulants as pro-

tein C and antithrombin are reduced in parallel with theprocoagulants, and PT and aPTT are responsive onlyto the thrombin generated as a function of procoagu-lants but are much less responsive to the inhibition ofthrombin mediated by the anticoagulants. The PT alsohas been used over the years in combination with otherclinical and laboratory parameters to calculate suchprognostic indexes as the Child-Pugh or the model ofend-stage liver disease (MELD).39,40

TEG allows continuous registration of the blood vis-coelastic changes upon activation by cephaline or tis-sue-factor plus calcium-chloride: the variables analyzedby this test includes:41

The R value (reaction time, clotting time), repre-sents the time until the first evidence of a clot isdetected.

The K value (clot formation time), is the timefrom the end of R until the clot reaches 20 mm,representing the speed of clot formation.

The angle is the tangent of the curve made asthe K is reached and offers similar information toK value.


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The maximum amplitude, maximum clot firm-ness is a reflection of clot strength.

A mathematical formula determined by the manu-

facturer can be used to determine a CoagulationIndex, an overall assessment of coagulability.41

In a study where citrated blood samples from 51adult cirrhotic patients were submitted to thrombo-elastographic study, 27% had abnormal clot time,80% presented abnormal clot formation time and76% had abnormal maximum clot firmness. Clot for-mation time and maximal clot firmness were corre-lated with the platele t-count, antithrombin andfibrinogen, PT was correlated with K value and maximalamplitude, and none of the coagulation parameterswere correlated with R value. The correlation of theChild-Pugh-score versus maximal clot firmness or

PT was -0.457 (p < 0.001) or 0.484 (p < 0.001), sug-gesting that maximal clot firmness may be a suita-ble prognostic index.42

TEG has also been used to provide evidence forthe generation of endogenous heparinoids as possi-ble contributors to the coagulopathy in patients whohave liver disease. In this application, TEG usingnative blood could be useful in clinical practice todetect the anticoagulant effect of endogenous hepari-noids and the associated hemorrhagic events.41In astudy of the prognostic value of TEG as a rebleedingpredictor in cirrhotic patients with variceal hemor-rhage, those who present rebleeding were more

hypocoagulable before the day of rebleeding asshown by longer R (42 v 24 mm, p < 0.001) and K(48 v 13 mm, p < 0.001) and smaller angle (12 v 38degrees, p < 0.001) compared with the mean of dailyresults of the non-rebleeding group. Routine coagu-lation test, however, showed no significant differen-ces between the two groups.43

THERAPEUTIC APPROACHES

TO THROMBOTIC COMPLICATIONS

Since the recognition that cirrhosis does not representa self-autoanticoagulation state (but rather a mixure ofboth prothrombotic and antithrombotic anomalies),it has been evident that, even in the presence of ab-normal coagulation tests, cirrhotic patients mayneed thromboprophylaxis or anticoagulation in cer-tain clinical scenarios, especially those involving anadditional thrombotic risk (e.g. venous stasis, infec-tion, congestive heart failure, acute respiratorydisease, and surgery).44

Bechmann evaluated the pharmacokinetics ofLMWH in 84 consecutive patients with cirrhosis

and a clinical indication for prophylactic or thera-peutic anticoagulation. Antifactor Xa activity wasnegatively correlated with the severity of the liverdisease, and a positive correlation was observed bet-

ween antithrombin-III levels and antifactor-Xavalue. Antithrombin-III itself was negatively corre-lated with the severity of liver disease. Seven pa-tients had an episode of variceal bleeding. Nopatient died during the observation interval and nothromboembolic events occurred. These results sug-gest that prophylactic use of low molecular weightheparin (LMWH) in cirrhotic patients is safe. A de-creased anti-Xa value in cirrhotic patients and a ne-gative correlation with liver function challenge theunconditional use of anti-Xa assays in LMWH moni-toring in cirrhotic patients and reveals a potentiallimitation of anti-Xa analysis in these patients. Low

levels of antithrombin, because of reduced hepaticsynthesis, are the most likely cause of this pheno-menon. Cirrhotic patients have also been found tohave an increased response to LMWH, which corre-lates with the severity of liver disease, despite redu-ced antithrombin and anti-Xa activity levels.45,46

The factor Xa inhibitors rivaroxaban and apixa-ban are metabolized in the liver and they are contra-indicated in severe hepatic diseases because theirmetabolic inactivation is impaired. Metabolic con-version of the prodrug dabigatran etexilate to dabi-gatran, a thrombin inhibitor, is completed in theliver and followed by partial biliary excretion of a

conjugated derivate. Idraparinux, an antithrombindependent FXa inhibitor, has no hepatic clearance,but its long half-life (approximately 80 h) and thelack of antidote do represent major problems if blee-ding occurs. These drugs must be use with cautionor are contraindicated in the presence of renalfailure.47

In respect to the safety and efficacy of anticoa-gulation for the treatment of thrombotic compli-cations of cirrhosis, Senzolo48found that, among33 patients with PVT treated with LMWH (95anti-Xa U/Kg body weight tid), 12 (36.36%)reached complete repermeation and 9 (27.27%) reachedpartial repermeation only, and only 2 patients(6%) experienced complications (1 patient develo-ped heparin-induced thrombocytopenia and ano-ther experienced non variceal bleeding).

In a study of 55 cirrhotic patients with PVT,Delgado49described the clinical outcomes after anti-coagulation treatment in 47 patients with PVT andhad received anticoagulation treatment. LMWH wasthe initial treatment in 47 patients: of them, 21were shifted to vitamin K antagonist (VKA) after 17


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days; 8 patients received VKA to reach a target INRof 2.5 as the initial treatment: 25 patients reachedtotal repermeation, 8 reached partial repermeation,5 patients presented non variceal bleeding and 6

presented variceal bleeding.In cirrhotic patients with acute variceal bleedingand PVT, anticoagulation with LMWH administeredafter hemostasis is achieved (by band ligation, re-peated band ligation or injection sclerotherapy com-bined with argon plasma coagulation) has reportedto achieve complete recanalization of the portal veinwithin 2-11 days, with no significant increase in re-bleeding incidence. Even after resection of hepato-carcinoma, thromboembolism has been reported tobe higher between cirrhotic patients who do not re-ceive thromboprophylaxis, and thromboprofilaxiswith LMWH has not shown any increase the rela

tive risk of postoperative bleeding.50,51

Villa52in a randomized non-blinded single-centercontrolled trial, evaluated the safety and efficacy ofenoxaparin versus no treatment, in preventing PVTin patients with advanced cirrhosis. Patency of por-tal vein was evaluated by ultrasound every threemonths and by computed tomography every six mon-ths. After 48 weeks of follow up, none of the patientsreceiving enoxaparin had developed PVT, comparedwith 6 of 36 (16.6%) of controls (P = 0.025). At 96weeks, no patient developed PVT in the enoxaparingroup, compared with 10 of 36 (27.s7%) controls (P< 0.001). The incidence of new onset descompensa-

tion was not statistically different between theenoxaparin and control group. Enoxaparin treatedgroup. showed a trend toward amelioriation in renalfunction biomarkers, liver function test and highersurvival rates. The incidence of thrombocytopeniaand esophageal variceal bleeding shown no signifi-cant difference between enoxaparin-treated and con-trol groups.

Amitrano53evaluated the safety and efficacy ofLMWH to treat non-neoplastic PVT in cirrhotic pa-tients who were suitable for liver transplantation,and did not had any active source of bleeding (en-doscopic examination of varices and betablockadewas started prior to the administration of LMWH).Once PVT was documented with ultrasound andcomputed tomography, LMWH al 200 U/kg/day wasstarted and continued for at least six months. Pa-tients were submitted to Doppler ultrasound exami-nation monthly. Ultrasonographic follow-upwas performed monthly and computed tomography wasperformed at sixth month. At six months completerecanalization occurred in 33.3%, partial recanalizationin 50% and 16.7% of patient had no response.

Among patients who had achived partial recanaliza-tion, 65% reached complete recanalization aftercontinuing anticoagulation for 7 to 17 months.Overall, complete recanalization was achived in

75% of patients in a median time of 11 months. Nopatient presented severe side effects which requiresinterruption of therapy. Until now, the results ob-tained from published series on anticoagulation the-rapy for PVT thrombosis in cirrhotic patients haveshown that anticoagulation is effective in achievingportal vein repermeation and does not increase therisk of mayor complications (Table 2).

THERAPEUTIC APPROACHES

ON BLEEDING COMPLICATIONS

The use of plasma-based blood products has been

a dogmatic treatment for the coagulopathy of liverdisease. It may also represent a public health issuesince blood product administered to decompensatedcirrhotic patients accounts for 7.7% of the totaltransfused red blood cell packages, 32.4% of thefresh frozen plasma units and 13.2% of platelet unitsconsumed in a tertiary care hospital.4

Randomized clinical trials provide little support,however, using plasma before invasive procedures,except for bleeding diathesis is clearly indicated. Al-though plasma is commonly used in patients whohave cirrhosis with prolonged INR, injudicious useshould be regarded as a risk and liability in light of

the limitations of the INR and the risks associatedwith plasma use. Moreover, the amount of fresh fro-zen plasma requested is typically inadequate toreach the desired INR in the great majority of cirr-hotic patients. Morover, transfusion-related compli-cations rate has been reported to be 15% at 48 hafter transfusion. Described transfusion-relatedcomplication in cirrhotic patients include transfu-sion related acute lung injury and acute kidnay in-jury related to tubular necrosis.4,54,55

Adequate thrombin production seems to be pre-sent in cirrhosis when platelet counts are approxi-mately 50,000 to 60,000/cc3, whereas optimal levelsare seen with levels of 100,000/cc3or more. Thus re-commended platelet levels of at least 50,000/cc3formoderate-risk procedures (ie, liver biopsy) and clo-ser to 100,000/cc3in veryhigh-risk procedures (ie,intracranial pressure monitor placement).15,54-55

Rheologic studies have indicated that normal pla-telet flow (at the periphery of the circulating bloodstream where they are closer to potential binding si-tes in the event of vascular breach) is adverselyaffected with hematocrit levels less than 25%, sup


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porting the recommendation to maintain this levelin cirrhotic patients experiencing bleeding or aboutto undergo a high-risk procedure. While portal hy-pertension plays a central role on the bleeding risk,

infused volume should be considered when usingblood products. The risk of transfusion related toacute lung injury, transfusion-related volume over-load and other transfusion related adverse events,should be taken into account before using blood pro-ducts in cirrhotic patients.54

Initial studies of desmopressin in compensated cirr-hotics showed that it shortened the bleeding timeand partial thromboplastin time with increases infactor VIII and vWF, but it has shown no efficacyin controlling variceal bleeding or reducing bloodloss in patients undergoing liver transplantation orliver resection, indicating that normalization of blee-

ding time not necessarily diminishes bleeding risk,and bleeding time does is not a reliable prognosticfactor of significant bleeding. The combination ofdesmopressin and terlipressin increased the reblee-ding rate compared with terlipressin alone.56,57

Stanca,58in a prospective, randomized controlledtrial, evaluated the efficacy of intranasal desmopres-sin as an alternative to transfusion to correct thecoagulopathy of cirrhotic patients undergoing den-tal extraction. The etiology of liver cirrhosis in thestudied population was hepatitis C in 22 patients(61%), multifactorial in 6 (16%) alcohol in 3 (8%),and criptogenic in 2 (6.1%), hemochromatosis, pri-

mary sclerosing cholangitis and hepatitis B repre-sented 3.1% each. No patient receiving desmopressinhad significant bleeding post procedure; in compari-son, 1 patient in the transfusion group bled and re-quired further transfusion, and another patientexperienced an allergic reaction. In addition, treat-ment associated average costs were lower for desmo-pressin ($700/patient) compared with transfusion($1,173/patient) group.

Several formal studies have evaluated the role offactor VII in the control of bleeding during varicealhemorrhage, liver transplantation, and partial hepa-tectomy. None of these reports demonstrated effica-cy of factor VII on the composite endpoint of failureto control bleeding within 24 h, failure to preventclinically significant rebleeding or death within 5days of first dosing. However, subanalyses demons-trated significant changes in the composite endpointwithin upper gastrointestinal hemorrhage in pa-tients with Child-Turcotte-Pugh class B and C cirr-hosis, higher survival, and reduced transfusionrequirements at the time of transplant. Further stu-dies are warranted with Factor VII in light of recent

advances in understanding of coagulation disordersin order to assess its efficacy in more specific situa-tions (i.e. avoid its use in conditions of hypercoagu-lability).59-62

CONCLUSIONS

The liver is a key element of the coagulation sys-tem. Patients with cirrhotic liver disease fail to syn-thesize both prothrombotic and antithromboticfactors. In addition, endothelial damage, endothelialdysfunction, portal hypertension, infections and re-nal failure may disrupt the coagulation system he-mostasis in cirrhotic patients. The clinicalpresentation, whenever bleeding or thrombosis, de-pends upon the stage of cirrhosis, added triggeringfactors and individual factors such as pre existing

prothrombotic or antithrombotic conditions. Regu-lar coagulation test, such as INR, PT or aPTT arepoor predictors of bleeding or thrombotic complica-tions, since they not evaluate the entire coagulationsystem. TEG may be a useful tool for evaluatingcoagulation abnormalities in cirrhotic patients,since it takes into account primary hemostasis, coa-gulation, and fibrinolysis. Therapeutic approachshould include both thrombotic and bleeding events,and should not be directed in achieving normal labo-ratory coagulation test results.

ABBREVIATIONS

ADP:adenosin diphosphate. aPTT: activated partial thromboplastin time. ATP: adenosin triphosphate. DIC: disseminated intravascular coagulation. DVT:deep vein thrombosis. GAGs:glycosaminoglycans. HIT:heparin-Induced thrombocytopenia. ICU:Intensive Care Unit. INR:international normalized ratio. LWMH:low molecular weight heparin. MELD:model of end-stage liver disease. PAI-1:Plasminogen activator inhibitor type-1. PBC:primary biliary cirrhosis. PE:pulmonary embolism. PFA-100:the platelet function analyser-100. PT:prothrombin time. PVT:portal vein thrombosis. TAFI:thrombin-activatable fibrinolysis in-

hibitor. TEG:thromboelestography. t-PA:tissue plasminogen activator. TPO:thrombopoietin.


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TXA2:thromboxane A2. VKA:vitamin K antagonist. VT:venous thromboembolism. vWF:von Willebrand factor.

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