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While advanced liver disease was previously considered to be an acquired bleeding disorder, there is increasing recognition of an associated prothrombotic state with patients being at higher risk of atrial fibrillation (AF) and stroke and venous thromboembolism (VTE) including portal vein thrombosis (PVT). We review the available literature on epidemiology, pathophysiology, and risk factors and provide guidance on anticoagulant management of these conditions in adults with cirrhosis. In patients with Child–Pugh A or B cirrhosis and AF, we recommend anticoagulation with standard-dose direct oral anticoagulants (DOACs) in accordance with cardiology guideline recommendations for patients without liver disease. In those with Child–Pugh C cirrhosis, there is inadequate evidence with respect to the benefit and risk of anticoagulation for stroke prevention in AF. In patients with cirrhosis and acute deep vein thrombosis or pulmonary embolism, we recommend anticoagulation and suggest use of either a DOAC or low-molecular-weight heparin (LMWH)/vitamin K antagonist (VKA) in Child-Pugh A or B cirrhosis and LMWH alone (or as a bridge to VKA in patients with a normal baseline international normalized ratio) in Child-Pugh C cirrhosis. We recommend anticoagulation for patients with cirrhosis and symptomatic PVT. We suggest anticoagulation for those with asymptomatic, progressing PVT and recommend continuing extended anticoagulation for liver transplant candidates with PVT.

No relevant conflicts of interest to declare.

Abstract 1099

No relevant conflicts of interest to declare.

Abstract 3160

Introduction: Advanced liver disease is associated with prolongation of the prothrombin time (PT). In order to decrease the inter-laboratory variability of PT measurement, the international normalised ratio (INR) calculated as the ratio of patient’s PT to a normal (control) sample, raised to the power of the international sensitivity index (ISI) of the particular thromboplastin used was developed. However, the ISI is derived from PT results of patients on warfarin and results cannot be extrapolated to liver patients. Despite this, the INR is still commonly performed to assess bleeding risk in patients with liver disease worldwide. Furthermore the INR is only affected by factors I, II, V, VII, and X and is not influenced by other factors such as factor VIII which is usually raised in hepatic cirrhosis. Recently it has been reportd that thrombomodulin addition (to take into account the protein C pathway) normalises thrombin generation (TG)1 despite these patients having a low TG if thrombomodulin is not used. Aim: We speculated that TG, which is a global assay of coagulation and sensitive to all coagulation factors, when triggered by a low tissue factor (TF) concentration might not correlate with the INR in patients with liver disease and that contact inhibition with corn trypsin inhibitor (CTI) might better reflect the coagulation potential in this patient group. Results: 73 unselected patients with liver cirrhosis due to various diseases and 25 normal subjects were studied. INR and TG using the calibrated automated thrombogram (CAT) at 1pM tissue factor (TF) with CTI, 5pM without CTI and with and without Protac (a Protein C activator) were performed using platelet poor plasma (PPP). The INR range was 0.8–4.0 (mean 1.6). At 5pM TF without Protac, the patient group had a significantly lower endogenous thrombin potential (ETP) than the controls (mean ETP difference 752nM/min; P <0.0001). With Protac, no significant differences could be detected between the 2 groups. However, if the ETP without Protac was divided by the ETP with Protac x 100, the liver group showed more resistance to PC activation (mean % difference 25.4; P 0.0002). At 1pM TF, the mean ETP in the cirrhosis cohort was slightly lower than the normal group (difference between means 216nM/min; P 0.03). However, only 7 (9.6%) patients had ETP values less than the normal range (mean±2SD). No correlation was found between the ETP at 1pM and the INR. The mean FVIII:C was raised at 185.6 (78–420U/dl). Conclusion: TG measured at low TF with CTI is normal in the majority of patients with cirrhosis. These patients are also more resistant to PC activation and have supranormal FVIII:C. Thus most patients have a normal or high thrombin potential despite an abnormal INR. These findings have important implications as in the absence of bleeding, “prophylactic” plasma and clotting factors are unnecessary.

Introduction: 1% of patients of warfarin experience life-threatening bleeding per year and require emergency reversal of their anticoagulation. This is usually done by using a combination of vitamin K and prothrombin complex concentrate (PCC), FVIIa or FFP. Algorithms for warfarin reversal commonly use INR thresholds to guide the PCC dose. However, the INR system has only been validated for values up to 4.5. Aim: To compare the ability of PCC, FVIIa and FFP to reverse the warfarin effects on the INR and thrombin generation (TG) as measured by the calibrated automated thrombography (CAT). We hypothesised that INRs greater than 4.5 would not correlate with TG and in which case one concentration of reversal agents would be suitable to reverse warfarin in all these patients. Methods and Results: A pool of plasma from patients on warfarin (final INR 4.8) was spiked with Beriplex P/N (25Units/kg), FVIIa (~140μg/kg) and FFP (~20ml/kg). The INR normalised with Beriplex and FVIIa and was reduced to 1.4 with FFP. However, only Beriplex completely normalised TG parameters. In view of this Beriplex was used for subsequent reversal experiments. We analysed 48 plasma samples with INR >4.5 (median 5.5; range 4.6–8.0) and measured TG at 5pM tissue factor. We found a significant moderate correlation between the INR and the endogenous thrombin potential (ETP) which is the maximum amount of thrombin generated (r=−0.59; P= <0.0001). The mean ETP was 279.4nM.min (95%CI 240 – 318.9; SD 135.9). 2 plasma samples with INR >8.0 were spiked with 5 concentrations of Beriplex P/N (7.5, 15, 25, 35 & 50Units/kg) in order to decide which is the ideal concentration of this PCC to reverse warfarin effects on the CAT. Both samples showed that a concentration between 25 and 35Units/kg could normalise TG without producing hypercoagulability. Hence we chose 30Units/kg to spike another 10 samples with INR >4.5 (mean 6.4; range 4.7–8.0). The INR, TG and FII, VII, IX and X were tested after the addition of Beriplex P/N. The INR normalised in all samples (median 1.2; range 1.08–1.3) as did the ETP (median 1942nM.min; range 1546–2753nM.min), FII (mean 114U/dl; range 76–126U/dl), FIX (mean 127U/dl; range 106–154U/dl) and FX (mean 131U/dl; range 120–140U/dl). FVII increased to a mean 52U/dl (range 20–68U/dl). A lower concentration of Beriplex (25U/ kg) did not satisfactorily normalise the INR and TG in all samples tested. Conclusion: PCCs fully reverse the effects of warfarin when compared to standard doses of FFP and FVIIa. INRs >4.5 still correlate with TG but the amount of thrombin generated was comparatively low making the use of one dose of PCC (30U/kg) suitable for reversing the effect of all INRs >4.5. This not only simplifies the reversal algorithms but reduces cost since doses up to 50U/kg are sometimes advocated for INRs >6.0.

Introduction: Advanced liver disease is associated with prolongation of the prothrombin time (PT). In order to decrease the inter-laboratory variability of PT measurement, the international normalised ratio (INR) calculated as the ratio of patient's PT to a normal (control) sample, raised to the power of the international sensitivity index (ISI) of the particular thromboplastin used was developed. However, the ISI is derived from PT results of patients on warfarin and results cannot be extrapolated to liver patients. Despite this, the INR is still commonly performed to assess bleeding risk in patients with liver disease worldwide. Furthermore the INR is only affected by factors I, II, V, VII, and X and is not influenced by other factors such as factor VIII which is usually raised in hepatic cirrhosis. Recently it has been reportd that thrombomodulin addition (to take into account the protein C pathway) normalises thrombin generation (TG)1despite these patients having a low TG if thrombomodulin is not used.

Introduction: 1% of patients of warfarin experience life-threatening bleeding per year and require emergency reversal of their anticoagulation. This is usually done by using a combination of vitamin K and prothrombin complex concentrate (PCC), FVIIa or FFP. Algorithms for warfarin reversal commonly use INR thresholds to guide the PCC dose. However, the INR system has only been validated for values up to 4.5.