Introduction
Patients with acute and chronic liver disease frequently acquire unique changes in
haemodynamic and haemostatic pathways that may result in life-threatening bleeding
and thrombosis. Additionally, activation of haemostatic pathways may play a role in
disease progression through parenchymal extinction, organ atrophy, recruitment of
inflammatory cells and activation of stellate cells. In the setting of a previously
entrenched set of clinical perceptions, the slowly evolving evidence-based paradigms
of haemostasis in cirrhosis are now more carefully scrutinized.
The 7th International Conference on Coagulation in Liver Disease (held biennially
since 2005) met in October of 2017 in Rome, Italy, to discuss and debate important
topics in this field. This document provides a statement-based thematic summary of
the meeting presented here amid a framework of the most current evidence. The review
of the literature, preparation of the document and presentation of each summary statement
below are based on systematic approaches used in published guidance documents.[1]
In particular, recognition of the potential disconnect between existing evidence and
actual practice, we utilized a questionnaire and real-time poll of the conference
attendees to compare actual clinical practice to the evidence-based support for each
statement. The final section summarizes the results of the most salient results of
the poll.
Laboratory Testing of the Coagulation System in Patients with Cirrhosis
1. Traditional coagulation measures, including pro-thrombin time (PT), activated partial
thromboplastin time (aPTT), international normalized ratio (INR) and bleeding time
(BT) do not measure bleeding risk in cirrhosis.
Conventional in vitro tests of the coagulation system are of limited value in estimating
haemostatic competency in cirrhosis and current literature emphasizes these limitations
when compared with global assays of coagulation.[2]
[3]
[4]
[5] PT/INR, aPTT and BT are generally prolonged in patients with cirrhosis in direct
relationship to the degree of hepatic decompensation. While useful for predicting
prognosis in chronic liver disease, these tests do not predict bleeding or thrombosis
in patients with chronic liver disease.
For the PT/INR and aPTT, a trigger reagent (tissue factor for extrinsic pathway or
kaolin for the intrinsic pathway), phospholipids and calcium are added to patient
plasma in a test tube and the time to the formation of fibrin is recorded. The PT/INR
test performs poorly in assessing coagulation capacity in patients with liver disease[6] and suffers from high inter-laboratory variability.[7]
[8] The PT/INR measures only pro-thrombotic pathways without measuring counter-balancing
anticoagulation (AC) pathways including protein C. Numerous studies and clinical experience
now clearly demonstrate that these tests do not measure in vivo activity of the coagulation
system in cirrhosis.[9]
[10]
[11]
[12]
[13]
2. Platelet count alone provides an incomplete guide to bleeding risk in cirrhosis. However,
values below 50,000/μL may be associated with higher risk of bleeding.
Thrombocytopenia is common in patients with advanced cirrhosis and indirectly correlates
with the degree of portal hypertension and hepatic decompensation.[14] In vitro evidence indicates that platelet-dependent thrombin generation is preserved
in patients with cirrhosis with platelet levels 56,000/μL or greater.[15] Notably, however, other important aspects of platelet function are not assessed
by thrombin generation assay (TGA). Severe thrombocytopenia is associated with procedural-related
bleeding events in some, but not all studies.[16]
[17] While there is no evidence that prophylactic platelet transfusion improves haemostatic
potential,[18] current guidelines and expert opinion recommend consideration of platelet transfusion
prior to high-risk procedures or when active bleeding is encountered in patients with
platelet counts below 50,000/μL.[4]
[19] A notable exception is liver transplant surgery, in which platelet counts below
50,000/μl are accepted by many centres.
3. Global viscoelastic tests (VETs) provide a more physiologic assessment of coagulation,
VETs are not standardized in patients with liver disease and do not appear to predict
bleeding or thrombosis. Application of VETs in patients with liver disease remains
controversial.
VETs measure clot strength and integrity in whole blood under low shear conditions,
attempting to more closely recreate the environment in vivo during clot formation.[20] VETs are considered point-of-care tests and provide the clinician with information
regarding the kinetics of clot formation and strength of the clot with the ability
to distinguish contributions from fibrinogen, platelets and the fibrinolytic system.
VETs are most extensively studied in patients with cirrhosis undergoing liver transplantation.[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
More recently VETs have been employed to examine the haemostatic system in a wide
variety of patients with liver disease, including well-compensated patients,[40]
[41]
[42] patients with acute liver failure[43] and in acutely ill patients with liver disease.[44]
[45]
[46] A recent randomized control trial compared transfusion-directed prophylactic therapy
in patients with cirrhosis undergoing procedures using VETs as a guide versus standard coagulation tests.[47] While significantly less blood product was used in the group undergoing VETs screening,
the low rate of bleeding events, lack of control arm and inclusion of relatively low
risk procedures significantly limits conclusions from these data.[48] Specific nuances of VETs such as test performance without stimulators (‘native’
VETs) and optimal duration of test remain uncertain in cirrhosis.
4. TGA provides a more comprehensive assessment of the haemostatic system in cirrhosis.
However, the clinical utility of TGA in patients with cirrhosis is unexplored with
current use confined mainly to research.
TGA is a valuable research tool that has led to important insights in liver disease
and coagulation.[9]
[10]
[11]
[12]
[13]
[15]
[18]
[49]
[50]
[51]
[52]
[53]
[54] It measures the rate of production and decay of thrombin after introduction of a
triggering agent (tissue factor and phospholipid).[55]
[56]
[57]
[58] With the addition of thrombomodulin (required for thrombin-mediated activation of
protein C), the integrity of the protein C anticoagulant system is measured. Tripodi
et al demonstrated that thrombin generation is preserved in cirrhosis despite prolonged
conventional coagulation assays due to decreased protein C.[10]
[13] Automation and standardization of TGA is incomplete and clinical use is not currently
available. Efforts at standardization and development of a point-of-care whole blood
thrombin generation test are in progress with the hope for future clinical utility.[52]
[59]
[60]
5. Available laboratory tests of hyperfibrinolysis are of limited value in cirrhosis
and clinical diagnosis is often necessary (see also anti-fibrinolytic therapy below).
Identifying the presence of hyperfibrinolysis in cirrhosis is challenging with limited
clinically available and laboratory testing.[61]
[62]
[63]
[64]
[65] Reliance on clinical assessment and empiric therapy are currently recommend (see
the “Pre-Procedure Prophylaxis and Treatment of Non-Portal Hypertension-Related Bleeding
in Patients with Cirrhosis” section).
The fibrinolytic system regulates clot remodelling and breakdown and is likely rebalanced
in cirrhosis. With exogenous disruption (e.g. infection), hyperfibrinolysis, a state
of abnormal fibrin degradation mediated by plasmin, can lead to delayed bleeding and
has been a recognized clinical feature of cirrhosis for over a century.[66]
[67]
[68]
[69]
[70]
[71]
[72]
[73]
[74] Joist, who coined the term ‘AICF’ or ‘accelerated intravascular coagulation and
fibrinolysis’, recognized the entity of bleeding in cirrhosis similar to, but distinct,
from disseminated intravascular coagulation (DIC).[75] This condition was seen in a clinical series where laboratory evidence of hyperfibrinolysis
was detectable in a third of hospitalized cirrhosis patients, but clinically evident
in only 6% of patients.[76] However, the divergent results of two key studies which examined the mechanistic
role of liver synthesized thrombin activatable fibrinolysis inhibitor has resulted
in on-going controversy regarding the clinical significance of AICF.[61]
[62] These studies have failed to resolve the long known and clinically evident occurrence
of diffuse mucosal bleeding or delayed post-procedure bleeding and efficacy of anti-fibrinolytic
therapy.[71]
[77] On the other hand, further laboratory-based studies have shown increased fibrinolytic
capacity in cirrhosis patients[64] suggesting a precariously balanced system more prone to clot lysis. Both endotoxemia[78] and ascites fluid egress into the systemic circulation[79] have been postulated as mechanisms of increased clot lysis.
Pre-Procedure Prophylaxis and Treatment of Non-Portal Hypertension-Related Bleeding
in Patients with Cirrhosis
Procedure-related bleeding is common in cirrhosis patients, but estimates of incidence
vary widely.[16] For many years, the PT/INR served as a surrogate marker for estimating bleeding
risk in cirrhosis. However, use of the INR and arbitrary ‘cut-offs’ as a clinical
target is not recommended or supported by scientific evidence. Nonetheless, medical-legal
concerns have dominated this field over scientific considerations for many years.
This situation is exacerbated by the limited connection between the detached clinician
performing the procedure and the ordering provider. This issue likely contributed
to early termination of the well-conceived S.H.I.P. trial (Study of Hemostasis and
Invasive Procedures NCT00233246) which did not enroll any patients. However, the field
has substantially evolved since 2005.[80] This now allows for more refined recommendations based on recent data.
Assessment of individual patient characteristics is also essential as clinical factors,
such as acute kidney injury[81] or infection[82] may alter bleeding risk in certain clinical scenarios. Global tests, such as VETs,
have offered particular insight into potential pathophysiologic mechanism in patients
with cirrhosis and active bacterial infection where release of endogenous heparinoids
may contribute to an anticoagulant effect placing patients at higher risk to bleed.[83]
[84] Large clinical studies examining bleeding outcomes are needed to provide clinicians
with better data to assess risk.
6. Pre-procedure testing of plasma fibrinogen and platelet level is recommended for high-risk
procedures (see [Table 1]) and pre-procedure correction is recommended for high risk procedures. Clinicians
performing the procedure should define the level of risk.
Table 1
Examples of procedure risk[a]
|
Higher risk procedures
|
Intermediate risk procedures
|
Lower risk procedures
|
|
Brain or spinal surgery
|
Lumbar puncture
|
Paracentesis
|
|
All major surgery (cardiac, intra-abdominal and orthopaedic)
|
Percutaneous or transjugular liver biopsy
|
Thoracentesis
|
|
Intra-cranial pressure catheter insertion
|
Transjugular intrahepatic portosystemic shunt
|
Dental extraction
|
|
Endoscopy (large polypectomy with endoscopic mucosal or sub-mucosal resection, NOTES)
|
Endoscopy (e.g. percutaneous gastrostomy placement, cystgastrostomy, biliary sphincterotomy)
|
Endoscopy (e.g. diagnostic, variceal band ligation, uncomplicated polypectomy)
|
|
Percutaneous biopsy of extra-hepatic organ or lesions
|
Cardiac catheterization
|
|
Trans-arterial or percutaneous HCC therapies
|
Central line placement
|
Abbreviations: HCC, hepatocellular cancer; NOTES, natural orifice transluminal endoscopy.
a Risk is estimated here based on relative vascularity, degree of expected vascular
breech and potential clinical consequences, but risk should always be defined by clinician
preforming the procedure.
Single test assessments and even multi-parameter measures are unlikely to capture
the nuances of a complicated physiology. Nonetheless, there are data suggesting that
platelet level and the level of fibrinogen correlates to effective haemostasis, although
it has not been established whether correction of low levels actually reduces bleeding
risk.[85] Evidence is very limited regarding any measure as a guide to prophylactic measures
and is mainly inferred from bleeding risk associative studies. Again, many centres
do not correct low fibrinogen or platelets prior to liver transplantation, and a clinical
trial has failed to demonstrate a beneficial effect of pre-emptive fibrinogen supplementation.[60] Despite the limitations and lack of firm data, with our current knowledge in the
field, these parameters are currently considered to be useful in predicting bleeding
in cirrhosis patients.
7. Routine prophylaxis for low or moderate risk procedures (see [Table 1]) is generally not recommended. However, individualized approaches are often necessary.
The most consistent finding with whole blood VETs (such as thromboelastography or
rotational thromboelastometry) has been the demonstration of intact haemostatic mechanisms
in cirrhosis with evidence that haemostatic support with blood products is not required
despite abnormal PT or platelet count.[86]
[87] Unfortunately, the majority of studies in this field have lacked a placebo control
arm which limits our understanding of the overall baseline risk in patients without
prophylaxis. To this end, we conducted a poll to assess actual current practice in
potential contradistinction to rational-based therapy—see below. The most important
point to remember is that prophylactic measures PT/INR can paradoxically increase
bleeding risk by engorging the collateral bed without any haemostatic benefit. Greater
recognition of the baseline bleeding risk and the limitations of prediction, by both clinicians that perform procedures and other
clinicians, will improve patient outcomes.
Specific Therapeutic Agents
8. Platelet transfusion prior to high-risk procedures or with active bleeding has a rational
in vitro basis, but lacks high level supportive data. Within the same limitations,
thrombopoetin agonists may have a role in pre-planned procedural prophylaxis.
Conflicting data exists regarding bleeding risk and cirrhosis-related thrombocytopenia.
The divergence in the literature likely reflects the complexity of haemostasis in
cirrhosis and marked study design variation. Among patients undergoing liver transplant
evaluation, procedure-related bleeding in one study was closely correlated to platelet
levels < 75,000/µL.[16] Similarly, bleeding risk was higher in a retrospective study of cirrhosis patients
undergoing dental extractions when platelets were < 40,000/µL.[88] Platelet levels < 30,000/µL were also an independent predictor of major bleeding
among critically ill cirrhosis patients in the intensive care unit setting.[89] On the other hand, post-procedure bleeding in cirrhosis was not predicted by baseline
platelet levels in another prospective study[90] and the platelet-related risk of post-banding ulcer bleeding has been variably reported.[91]
[92] Compensatory mechanisms which may alter overall platelet performance, such as elevated
von Willebrand factor (VWF),[93] increased circulating activated platelets[94] and platelet-derived microvesicles,[95] may also be significant factors which balance the bleeding risk related to thrombocytopenia.
Additional factors may also contribute to platelet physiology.[96]
[97]
[98] Limited yield of platelet infusion in cirrhosis is well known and raises the question
of whether platelet transfusion prior to high-risk procedures is more ‘cosmetic’ to
cover procedure-related liability or an actual effective strategy—this is an understandable
conundrum that remains unresolved. More definitive studies require placebo-controlled
trials which present clinical investigators with almost insurmountable ethical hurdles
at the current state of the art.
In elective and planned settings, such as planned dental extractions or other invasive
procedures with moderate or high risk, oral thrombopoetin agonists are an alternative
means to increase platelets prior to invasive procedures. Concern for a transient
hypercoagulable state due to thrombocytosis with eltrombopag, with early reports of
increased risk of portal vein thrombosis (PVT), have tempered enthusiasm for these
agents.[99]
[100]
[101] However, new agents are in development, such as avatrombopag and lusutrombopag,
which appear to predictably raise platelets to a range associated with improved thrombin
production without apparent increased thrombosis risk.[102]
[103]
9. The use of desmopressin in patients with cirrhosis lacks a sound physiological basis
and does not appear to significantly alter risk of bleeding.
Desmopressin (1-deamino-8-arginine vasopressin or DDAVP) has been shown to be as effective
as human blood products in cirrhosis patients undergoing dental extractions.[104] Notably, bleeding was very infrequent in both groups raising the question of actual
efficacy and no control arm without prophylaxis was studied. Other studies show no
benefit in variceal bleeding, liver biopsy in dialysis patients with chronic hepatitis
C and with partial hepatectomy.[105]
[106]
[107] A recent report further demonstrated lack of significant pro-haemostatic effects
in cirrhosis patients receiving a conventional dose of intravenous DDAVP compared
with a control group of patients with haemophilia A.[108] These concerns raise the question again of the need for placebo controls to more
definitively define the utility of various prophylactic strategies.
10. Fibrinogen replacement, pro-thrombin complex concentrates (PCC), and recombinant factor
VIIa (rVIIa) may have a role in treatment of significant bleeding in patients with
cirrhosis in specific clinical scenarios, but the utility of these agents is undefined.
Fibrinogen replacement: The clearest data regarding fibrinogen replacement in clinical bleeding is associated
with non-cirrhosis conditions of severe trauma where fibrinogen levels > 200 mg/dL
are associated with more effective haemostasis.[109] Although based on very limited data, levels below 120 mg/dL in active bleeding patients
with cirrhosis have historically required correction. However, much remains to be
learned about fibrinogen replacement in cirrhosis.[110] Replacement has conventionally involved cryoprecipitate, a plasma-derived product
rich in VWF, fibrinogen and fibronectin, made by freezing and slow thawing human plasma
and reconstituting the precipitate in 10 to 20 mL plasma. In contrast, fibrinogen
concentrates are derived from a similar cryoprecipitation process of pooled plasma
which then undergo isolation, viral exclusion and lyophilization.[111] The very low volume, standardization of fibrinogen content and lack of need for
cross matching favour its use in cirrhosis. Recent in vitro data also suggests a clear
improvement in haemostasis in cirrhosis.[112] However, further clinical studies are needed to justify the expense which currently
limits wider application.
PCC: PCC have been studied in cirrhosis sporadically for over 40 years.[113]
[114] However, recommended dosing is linked to AC therapy as the dose is based on factor
IX content of the agent, INR (while on vitamin K antagonist [VKA]) and body weight.
Data are emerging that lower doses may be effective in cirrhosis, but needs further
study.[112] A typical dose is 25 to 30 units of factor IX per kilogram of body weight. The low
volume needed for VKA-treated patients is attractive to avoid volume overload and
collateral bed engorgement in cirrhosis, however concerns over increasing the risk
of thrombosis remain.
rFVIIa: rFVIIa has mainly been studied in cirrhosis and variceal bleeding. No definitive
survival benefit was evident in patients treated with rFVIIa as an adjunct in variceal
bleeding.[115]
[116] However, the use of this agent as a rescue agent in uncontrolled haemorrhage in
cirrhosis remains unsettled by randomized trials.[117]
11. In delayed and diffuse mucosal bleeding in decompensated cirrhosis (hyperfibrinolysis
physiology), consider use of anti-fibrinolytic therapy.
Optimal treatment of patients with suspected hyperfibrinolysis lacks well-controlled
prospective trials to delineate risks and points of effective intervention. There
are two available anti-fibrinolytics that block the lysine binding site on plasminogen
preventing its attachment to fibrin and subsequent activation: trans-p-aminomethyl-cyclohexane
carboxylic acid or tranexamic acid and epsilon-aminocaproic acid (EACA).[118]
[119] Both agents can be given orally or intravenously. Neither are felt to be significantly
pro-thrombotic based on studies in cardiac surgery of EACA versus placebo.[120] Several points of caution include the possibility of thrombotic issues if there
is superimposed DIC, possible increased risk of central line related thrombosis[121] and the high concentration of the agent excreted in urine. A third agent, aprotinin,
is a serine protease inhibitor that binds to plasmin to block its activity and also
blocks thrombin-induced platelet aggregation. The agent decreased the need for blood
transfusion in liver transplantation,[122] but remained controversial in that application[123] and was associated with increased mortality in cardiac surgery ultimately leading
to marked restrictions in its clinical availability.[124]
Diagnosis and Screening for Non-Tumoural Portal Vein Thrombosis in Patients with Cirrhosis
12. Patients with advanced cirrhosis and low portal blood flow (< 15 cm/s) are at the
highest risk to develop portal or splanchnic vein thrombosis.
The risk for PVT in cirrhosis parallels the severity of liver disease and hepatic
decompensation. The prevalence of PVT is approximately 1% in compensated cirrhosis
patients as opposed to 8 to 25% in decompensated, liver transplant candidates,[125]
[126] and up to 40% in patients with hepatocellular carcinoma (HCC).[124] Of the three pathophysiologic factors predisposing to thromboembolism—slow blood
flow, endothelial damage and hypercoagulability, portal flow is the most influential.[128]
[129] Portal vein (PV) blood flow is inversely related to severity of liver disease as
measured by the Child-Turcotte-Pugh (CTP) score,[130] and rates < 10 cm/s are associated with increased mortality.[131] Patients with underlying thrombophilia are likely at increased risk for PVT, but
inherited deficiencies in natural anticoagulants can be difficult to detect in decompensated
cirrhosis.[132] Emerging data suggest that cirrhosis aetiology may also have predictive power in
determining which patients will develop future PVT. In particular, non-alcoholic steatohepatitis
may be an independent risk factor for clinically significant thrombotic events, including
PVT, in patients with decompensated cirrhosis.[133]
[134]
[135] The presence of a spontaneous portosystemic shunt is an under-appreciated risk for
PVT as a result of a ‘steal’ syndrome and resulting PV stasis.[136]
13. Patients with cirrhosis and portal hypertension should be screened for development
of PVT every 6 months with Doppler ultrasound (US).
In 2015, a systematic review concluded that PVT was associated with poorer survival
in patients with cirrhosis.[137] Although hampered by heterogeneity, a recent meta-analysis similarly showed that
PVT was associated with more frequent portal hypertension decompensation and higher
mortality rates.[138] Furthermore, several studies indicate that PVT is associated with poorer outcomes
related to variceal bleeding.[139]
[140]
[141] However, a large, multi-centre trial of over 1,200 subjects utilizing screening
US in CTP class A and B cirrhosis demonstrated that PVT was not an independent predictor
of mortality or hepatic decompensation.[142] Larger prospective studies are needed to better delineate the effect of PVT on patients
with cirrhosis. As patients with cirrhosis should undergo screening US for HCC every
6 months, assessment of the PV can be performed simultaneously with Doppler US without
significant additional cost and is recommended.
14. Patients with cirrhosis listed for liver transplantation should be screened at least
every 6 months with Doppler US for PVT.
In general, the pre-operative presence of higher grade PVT leads to worse outcomes
after liver transplantation.[126]
[135]
[143]
[144]
[145]
[146]
[147] However, some studies suggest that the presence of PVT may not necessarily alter
the outcome for patient survival.[148]
[149] These studies are challenging to compare due to the frequency of PVT in this population,
selection bias and multiple confounding factors. The ability of a surgeon to establish
a physiologic anastomosis for portal flow to the graft is the most important factor
in predicting outcome and often related to the degree of thrombus burden.[126]
[150]
[151]
Detection of PVT prior to liver transplantation aids in surgical planning and allows
for potential pre-operative therapy to re-canalize the PV. Detection of higher grade
PVT may identify patients that are not appropriate candidates for transplantation.
Re-canalization of the main PV is a high priority in transplant eligible patients.[143]
[151] As treatment for PVT has a proportionally higher rate success early after diagnosis,
timely recognition and prompt treatment is highly desirable (discussed below).
15. Patients with cirrhosis diagnosed with PVT by abdominal Doppler US should be assessed
with cross-sectional imaging to confirm and stage the extent of thrombus.
While Doppler US is generally the initial screening modality to assess cirrhosis patients
for PVT, it is limited by variation in sensitivity and specificity due in part to
operator technique and experience.[152]
[153] Despite this imprecision, Doppler US has a high negative predictive value (98%).[154] Contrast-enhanced computed tomography and magnetic resonance imaging have comparable
sensitivity in verifying the presence of PVT seen on Doppler US, and both are equally
effective in characterizing the extent of splanchnic involvement, evaluating for underlying
malignancy and other sequelae.[154]
[155]
[156] There are several systems of grading PVT severity, yet none are widely adopted in
clinical practice.[150]
[157]
[158] To date, the Yerdel system remains the most frequently utilized PVT classification
system in clinical research.[150]
16. Testing for acquired and inherited thrombophilia in cirrhosis can be considered in
patients with PVT on an individual basis, but universal screening is not currently
recommended.
Inherited thrombophilia is reported in as many as 5.6% of patients with cirrhosis
and PVT.[132] Several study cohorts have demonstrated more frequent occurrence of the pro-thrombin
G20210A gene mutation in cirrhosis patients with PVT.[159]
[160] Additional hypercoagulable risk factors may occur in patients with cirrhosis. The
JAK2 V617F mutation is found in increased prevalence in patients with cirrhosis and
PVT.[161] When a myeloproliferative neoplasm is suspected, consultation with a haematologist
is recommended for further testing. Inherited protein C, protein S or anti-thrombin
deficiencies may also predispose to PVT; however, these are difficult to detect due
to co-existent liver synthetic dysfunction.[5]
[11]
[162]
Treatment of Portal Vein Thrombosis in Patients with Cirrhosis
17. Prior to AC, patients should be assessed for portal or systemic bleeding risk.
Assessment of bleeding risk and benefit of therapy is imperative when considering
AC, but not yet well-defined in this population. Contraindications to AC include recent
unexplained gastrointestinal (GI) bleeding, active alcohol abuse and poor functional
status due to fall risk. Severe thrombocytopenia (< 50 × 109/L) may be predictive of bleeding events in cirrhosis patients treated with AC for
PVT and thus special consideration should be given to this particular group.[163] Prior to AC, patients should ideally undergo upper endoscopy to assess for the presence
of gastroesophageal varices.[164] If high-risk stigmata are found, endoscopic or pharmacologic therapy with non-selective
β blockade should be utilized as per guideline recommendations.[165]
[166]
18. AC appears to be a safe and effective treatment strategy in selected patients with
compensated cirrhosis and splanchnic vein thrombosis.
Safety: AC in patients with cirrhosis and splanchnic vein thrombosis is an area of increasing
interest in research.[165]
[166]
[167] Several series examining AC in PVT are currently published, the majority of which
have been retrospective evaluating low molecular weight heparin (LMWH), VKA and direct-acting
oral anti-coagulants (DOACs).[126]
[163]
[168]
[169]
[170]
[171]
[172]
[173]
[174]
[175]
[176]
[177]
[178]
[179] Bleeding rates among treated and non-treated patients are similar in these highly
selected patient populations.[180]
[181] Rates of major bleeding range from 5 to 20% and minor bleeding rates range from
1 to 13%, but definitions of bleeding are not uniform. A recent meta-analysis examined
AC for patients with cirrhosis and PVT and demonstrated a pooled bleeding rate of
all bleeding events (both major and minor) of 3.3% for LMWH or VKA.[182] Remarkably, the administration of AC did not affect outcomes of upper GI bleeding
events in patients with cirrhosis.[183] While overall bleeding rates appear acceptable, it is important to note the high
rate of variability, the disparate outcome definitions and lack of prospective randomized
studies. Caution must be maintained when considering patients with cirrhosis for treatment
with AC, particularly in patients with more advanced cirrhosis (CTP B and C). Multi-disciplinary
approaches on a case-by-case basis are needed.
Efficacy: Comparing studies examining the efficacy or safety of AC is challenging secondary
to the heterogeneity of study design, patient population and variety of types of AC
used. In general, response rates are variable and range from 42 to 82% in terms of
either a partial or a complete re-canalization of the splanchnic veins.[126]
[163]
[168]
[169]
[170]
[172]
[173]
[174]
[176] Factors associated with successful therapy (re-canalization of the PV) include recent
time of onset, early initiation of AC (< 6 months) and the degree of thrombus burden
(partial vs. complete).[163]
[184]
[185] Recurrence after discontinuing therapy for PVT following clot resolution ranges
from 27 to 38%.[163]
[174]
19. VKAs, LMWH or direct oral anticoagulants can be considered for therapy in patients
with compensated cirrhosis (CTP class A and B).
Patients with cirrhosis are no longer considered auto-anticoagulated and evidence
clearly indicates risk of splanchnic and non-splanchnic thrombosis in this population.
As patients with known liver disease have been excluded from clinical trials of these
agents, current treatment paradigms are based on data and experience in smaller studies
in cirrhosis populations.
Vitamin K antagonists: VKAs have been a cornerstone to AC therapy over many years. VKAs act through inhibition
of vitamin K epoxide reductase which inhibits post-translational modification required
for the function of factors II, VII, IX, X, protein C and protein S. Patients with
liver dysfunction represent a particular challenge when using VKA as the INR is often
elevated secondary to hepatic dysfunction. Therefore, determining the appropriate
therapeutic target is problematic. Moreover, use of VKA in patients listed for transplant
artificially inflates the MELD score and adversely affects organ allocation. Reversal
agents for VKA include administration of vitamin K, FFP and PCC. Major advantages
to VKA include familiarity through extensive clinical use over many years, low cost
and oral formulation. Disadvantages include unclear therapeutic goal in liver disease
patients, the requirement of routine monitoring with uncertain target levels and an
apparent increase in bleeding risk.[186]
Low molecular weight heparin: LMWH is a short chain polysaccharide heparin which acts through anti-thrombin to
inhibit factor Xa and thus the production of thrombin. LMWH is the most widely studied
AC in patients with cirrhosis and appears safe and effective for treatment of PVT.
However, studies in cirrhosis are generally small and retrospective with variation
in dose and inclusion/exclusion characteristics. Expense and subcutaneous injections
remain a significant disadvantage to long-term use. Monitoring therapy of LMWH to
determine dosing efficacy is also controversial. Anti-Xa assays are routinely used
for hospitalized patients on heparin-based AC; however, these assays can be misleading
in liver disease.[181]
[187]
[188] TGA may offer a more reliable tool in cirrhosis to determine efficacy; however,
these are not widely available.[50] In vitro studies using TGA suggest that the anticoagulant effect of LMWH may be
altered in patients with cirrhosis.[50]
[189] While no proven method for complete neutralization of the anticoagulant effect of
LMWH is known, partial reversal of LMWH can be accomplished with protamine sulfate
administration in severe hemorrhage.[190]
Direct oral anticoagulants: DOACs act to directly inhibit coagulation factors, factor IIa (dabigatran) and factor
Xa (apixaban, edoxaban, rivaroxaban). DOACs are now routinely used in patients without
liver function impairment with favourable safety and efficacy profiles. However, DOACs
remain largely investigational in patients with cirrhosis with experience limited
to in vitro studies and small case series.[177]
[189]
[191]
[192]
[193]
[194] The largest series comparing DOAC to traditional AC shows similar bleeding risks.[195] In vitro data suggest that DOAC may have variable effects in patients with cirrhosis
depending on the degree of hepatic decompensation present.[188]
[189]
[192] Notably, cirrhosis patients have been consistently excluded from DOAC clinical trials
and data on pharmacodynamics is limited to in vitro studies with caution in CTP B
and C cirrhosis advised. Currently, in the United States only dabigatran has an available
direct reversal agent (idarucizumab).[196]
[197] A recent report demonstrated successful reversal of dabigatran prior to liver transplantation
without major bleeding or new thrombosis highlighting the practical use of this newly
available reversal agent.[198] Clinical trials investigating andexanet α and ciraparantag as reversal agents of
factor Xa inhibitors are awaiting potential approval.[196]
[199] PCC may be considered for emergent reversal in the setting of DOAC therapy; however,
the approach retains the possibility of inducing hypercoagulability compared with
direct reversal agents.[200]
[201] Use of DOAC in patients with cirrhosis should be restricted to well-compensated
patients (CTP A or B) with platelet count > 50,000, and consultation with haematology
is advised.
20. Liver transplant candidates with PVT should be considered for AC therapy. Non-transplant
candidates may also benefit.
The indication for treatment of acute and chronic PVT in patients with cirrhosis remains
controversial. The vast majority of literature focuses on the natural history, outcome
and therapy of PVT in the context of liver transplantation.[143]
[202] Studies outside of liver transplantation are limited and the risks and benefits
of AC therapy are more difficult to estimate.
Transplant population: Significant PVT (Yerdel Grade 2 and higher) is associated with higher morbidity and
mortality in patients undergoing liver transplantation.[126]
[135]
[144]
[145]
[146]
[150]
[203] Maintaining physiologic blood flow through the PV preferably via end-to-end anastomosis
is imperative.[151] The ability to achieve physiologic inflow to the graft is generally dependent on
the extent of the PVT prior to surgery. Patients with low grade PVT (Yerdel Grade
1) and non-occlusive branch PVT have similar outcomes to patients without PVT. With
more advanced thrombus (Yerdel Grade 2 or higher) promoting re-canalization of the
main PVT or superior mesenteric vein (SMV) thrombosis prior to transplantation is
desirable. Liver transplant candidates with occlusive main PVT with or without proximal
extension into the SMV should be prioritized for treatment with AC.
Non-transplant population: While prevention of PVT with AC may delay hepatic decompensation,[204] a recent study suggests PVT is not related to liver disease progression.[142] Patients with acute PVT can develop significant portal hypertension complications
and progression of thrombosis may be a risk for intestinal ischemia or eventual cavernous
transformation. Prospective trials are currently lacking; however, certain patients
may benefit from AC therapy for acute PVT, particularly those with Yerdel Grade 2
PVT or higher where AC therapy should be considered on an individual basis after careful
deliberation and multi-disciplinary review.
21. Trans-jugular intrahepatic portosystemic shunt (TIPS) is a potentially effective treatment
of acute and chronic PVT in patients with cirrhosis requiring treatment for significant
portal hypertension.
Historically, the presence of PVT in patients with cirrhosis was a contraindication
for TIPS. However, more recent experience suggests that TIPS is safe and effective
for the treatment of PVT when performed in the presence of significant portal hypertension
or symptomatic complete occlusion of the main PV.[205]
[206]
[207] Rates of re-canalization are similar to reports from AC trials and range from 60
to 92% depending on the vascular access technique.[208]
[209]
[210] Recent reports suggest that TIPS alone may be adequate for re-canalization and no
immediate chronic AC is required to maintain stent patency.[209]
[210]
[211] Patients with chronic PVT considered potential transplant candidates may also benefit
from TIPS as reports are now emerging of the successful use of TIPS in this population
to re-vascularize the portal venous system as a bridge to liver transplantation.[209]
[210]
[212]
Venous Thromboembolic Disease in Patients with Cirrhosis
22. Hospitalized medical patients with cirrhosis are at increased risk for VTE.
Acutely ill medical patients are at risk of developing venous thromboembolism (VTE)
with an estimated rate of 4 to 15%.[213] However, large cohort studies examining the incidence of VTE and prophylactic/treatment
trials with AC have generally excluded patients with cirrhosis. Recent studies indicate
that patients with cirrhosis are at risk to develop VTE.[214]
[215]
[216]
[217]
[218]
[219]
[220]
[221]
[222] Hospitalized patients with cirrhosis are likely at an increased risk to develop
VTE and studies indicate that thromboprophylaxis is under-utilized in this group.[223]
[224]
[225]
The Padua Prediction Score (PPS) was developed as a risk assessment model to predict
the likelihood of developing VTE in hospitalized medical patients.[226] Current guidelines for prevention of VTE in non-surgical patients rely on the use
of the PPS to distinguish between low risk of VTE (score < 4) and high risk of VTE
(score > 4).[227] The PPS has been studied in a small retrospective cohort in patients with cirrhosis
and was shown to be predictive of development of VTE.[223] The IMPROVE risk assessment model was developed in a large cohort of patients, which
included patients with liver disease and can accurately risk stratify patients in
terms of thrombosis and bleeding risk.[228]
23. In high-risk hospitalized cirrhosis patients without contraindication, medical thromboprophylaxis
with LMWH or unfractionated heparin (UFH) should be considered, although efficacy
remains uncertain.
Accurate risk assessment and use of VTE medical prophylaxis is sub-optimal in hospitalized
medical patients.[229] Patients with cirrhosis are often perceived to be at higher risk of bleeding and
likely do not receive appropriate medical VTE thromboprophylaxis.[230] One study examined 75 patients hospitalized with cirrhosis receiving LMWH for VTE
prophylaxis and found relatively low rates of bleeding (five patients with reported
bleeding events).[231] Two large retrospective studies show that use of UFH and LMWH appears safe with
low in-hospital rates of bleeding.[224]
[225] Bleeding rates were not different between patients with cirrhosis treated with prophylaxis
(UFH or LMWH) (8.1%) compared with patients with cirrhosis not treated with prophylaxis
(5.5%).[225] Furthermore, LMWH was safer than UFH, with decreased incidence of procedural-related
bleeding.
While no current studies adequately assess efficacy for VTE prophylaxis in the hospitalized
cirrhosis population, prophylactic LMWH was safe and prevented development of PVT
in a small prospective cohort of cirrhosis patients.[204] Due to the relative infrequency of VTE, properly powered studies in hospitalized
patients with cirrhosis will require large cohorts. Consequently, current recommendations
are limited to extrapolation from studies in other populations without cirrhosis,
small retrospective cohorts and expert opinion.
24. Cirrhosis patients with peripheral VTE should be treated with medical therapy with
AC. LMWH, VKAs or direct oral anticoagulants can be considered.
The majority of studies examining safety and efficacy in therapeutic AC in patients
with cirrhosis have been conducted in patients with PVT (see the “Treatment of Portal
Vein Thrombosis in Patients with Cirrhosis” section). Very few retrospective studies
have evaluated safety of therapeutic AC in patients with cirrhosis with peripheral
VTE. One early, small study examined 17 patients with cirrhosis and VTE treated with
LMWH and noted high bleeding rates on AC.[232] Six of the 17 patients had a major haemorrhage (defined as bleeding requiring blood
transfusion) on AC. However, from this study the type of bleeding, the particular
agent employed or the outcome of each patient was unclear. Numerous studies since
have shown the relative safety of AC (LMWH, VKA and DOAC) at therapeutic dosing in
patients with cirrhosis treated for PVT, VTE and atrial fibrillation.[126]
[141]
[193]
[195]
[231]
[233]
[234]
[235]
[236] In a recent study examining patients with cirrhosis treated with DOAC versus traditional
AC (LMWH or VKA), 16 of the 39 patients were treated for VTE.[170] There was no difference between cohorts in bleeding events (4/20, 20% in the DOAC
group vs. 3/19, 16% in the traditional AC group). A subsequent similar study compared
DOAC and traditional AC for VTE in a total of 20 patients (8 in the traditional group
and 12 in the DOAC group).[236] Bleeding rates were similar between groups (56% traditional vs. 30% DOAC). Efficacy
was not assessed in either study.
The safety of AC and dosing strategy in peripheral VTE can likely be extrapolated
from studies in PVT. However, the efficacy of AC therapy in VTE in cirrhosis is not
well studied and the indications, timing of therapy and choice of agent are inferred
from general guidelines for treatment of VTE.[237]
25. Prior to starting AC, the bleeding risk should be re-assessed with medical history
and ideally an upper endoscopy. If high-risk varices are present, consideration of
medical or endoscopic therapy is recommended prior to long-term AC.
See comments in the “Treatment of Portal Vein Thrombosis in Patients with Cirrhosis”
section.
Survey of Concepts and Clinical Practice: Results of Polling of the 2017 7th International
Coagulation in Liver Disease Conference Faculty and Participants
In recognition of the limitations of existing data and the variation between evidence-based
and actual practice, we conducted both an interactive poll during the conference and
a more deliberative on-line poll of specific scenarios related to the above statements.
The polls were designed to address actual clinical practices as they related to evidenced-based
concepts in this field. Among 150 attendees the overall poll response rate was 80
(53%): among responders, 65% were haepatologists, 10% were anesthesiologists and 7.5%
were haematologists.
Table 2
Research goals: priorities and practicalities
|
Prophylaxis prior to procedures
|
Pre-procedural fibrinogen level and platelets have emerged as important markers of
bleeding risk. However, prospective trials are now needed to confirm these markers
and to establish other potential predictors of bleeding
|
|
Global coagulation tests
|
Future research is needed to better understand how to interpret and use global assays
of haemostasis, such as thrombin generation tests (TGA) and VETs (ROTEM and TEG) in
compensated and decompensated cirrhosis with a goal to establish standard references
within this population
|
|
PVT in cirrhosis
|
In cirrhosis, PVT most clearly affects outcomes after liver transplantation. Studies
are now needed to examine the efficacy and risk of anticoagulation for the various
grades of PVT in all patients with cirrhosis (not just transplant eligible) with a
focus on clinical outcomes. Key aspects to study include incidence, risk factors,
natural history, relationships to symptoms and risks of therapy
|
|
PVT and disease progression
|
Intra-hepatic activation of clotting and small vessel thrombosis in parenchymal extinction
may contribute to fibrosis and hepatic decompensation, but more robust studies (translational
and clinical studies in humans) are necessary
|
|
VTE prophylaxis in cirrhosis
|
Prospective studies are needed to examine the utility of current risk models in cirrhosis
patients with a goal of improving knowledge of the incidence and natural history of
VTE in cirrhosis
|
|
Anticoagulants in cirrhosis
|
The pharmacokinetics and dosing of all anti-coagulants (low molecular weight heparin,
vitamin K antagonists and direct oral anticoagulants) in patients with compensated
and decompensated cirrhosis is poorly understood. Prospective studies are now needed
to better guide therapy with these medications
|
Abbreviations: PVT, portal vein thrombosis; ROTEM, rotational thromboelasometry; TEG,
thromboelastography; TGA, thrombin generation assay; VETs, viscoelastic tests; VTE,
venous thromboembolism.
Regarding all laboratory testing of coagulation indices, agreement was modest for
most statements. However, agreement was strongest when surveying perception surrounding
the usefulness of traditional parameters of coagulation (PT/aPTT/INR) in poorly predicting
haemostasis (77%), the hazard involved in rVIIa use (73%) and the lack of utility
of DDAVP in preventing or treating bleeding (69%). One of the most interesting observations
involved the necessity of pre-procedure plasma fibrinogen and platelet count assessment
and correction: 68% of respondents agreed that these tests are useful in high-risk
procedures, but 69% felt that these were not needed in low- or moderate-risk procedures.
VTE is a dynamic topic with numerous new developments. Most respondents agreed that
hospitalized cirrhosis patients are at increased risk of VTE (84%), but less agreed
regarding the use of medical prophylaxis with heparin agents (63%). There was strong
agreement (91%) that a peripheral VTE diagnosis warrants therapeutic AC. There was
strong agreement that endoscopic control of varices was recommended prior to initiating
therapeutic AC (84%).
Regarding the diagnosis and treatment of splanchnic vein thrombosis, agreement was
generally very high (greater than 75% for most statements). Most attendees felt that
cirrhosis patients should be screened with US every 6 months for PVT (75%), and that
patients listed for liver transplant should be assessed every 3 months (79%). Agreement
with pursuing confirmation of US results with a cross-sectional imaging method prior
to consideration of treatment was nearly unanimous (91%). Results were mixed, however,
with regards to the utility of undertaking a hypercoagulability workup (56% agreement),
as many felt it would not appreciably alter treatment decision-making in terms of
both choice of AC and also duration of therapy. Attendees only had slightly more hesitation
about treatment of PVT (76%) with AC compared with peripheral DVT (83%). Use of TIPS
as a first-line modality to attempt to achieve re-canalization of PVT was less popular
with only 63% agreement.
Compared with the prior 2005 survey of actual practice and opinion,[5] this 2017 survey demonstrated greater agreement on the limitations of conventional
measures of bleeding risk assessment using PT/aPTT/INR, but fell well short of a consensus
despite existing data. Health care providers are embracing the concept of hypercoagulability
in cirrhosis and more willing to utilize therapeutic AC in the setting of peripheral
VTE and PVT. Furthermore, there is emerging consensus as to the utility of fibrinogen
and platelet measures as indicators of bleeding risk prior to high-risk procedures.
However, the utility of more elaborate testing of hypercoagulable states, such as
genetic testing remain uncertain in the setting of thrombotic complications in cirrhosis.
Notably, in the general population, a hypercoagulable work-up is currently discouraged
in the majority of patients with VTE and avoiding these tests in patients with VTE
is on the ‘Choosing Wisely’ list endorsed by multiple specialty societies.[238]
While significant gains in our understanding of the complexities of the coagulation
system in liver disease have been made over the last several years, future focused
research will be essential to advance the field ([Table 2]).
