Reappraisal of the conventional hemostasis tests as predictors of perioperative bleeding in the era of rebalanced hemostasis in cirrhosis.

New global laboratory procedures mimicking the in vivo hemostasis process led to the changing paradigm of cirrhosis from the prototype of hemorrhagic diseases to a condition in which hemostasis is normal but fragile, thus justifying the hemorrhagic/thrombotic tendencies that affect these patients. The new paradigm was instrumental to change the management of cirrhosis. For example, international guidelines warn against the entrenched practice of testing patients with conventional hemostasis tests and infusing those with abnormalities with fresh-frozen plasma, coagulation factor concentrates, or platelets, prior to surgery/invasive procedures. These recommendations are, however, largely disattended. The practice of testing patients with the prothrombin time or viscoelastometry and using arbitrary cutoffs to make decisions on perioperative prophylaxis is still common and probably driven by medicolegal issues. There is no doubt that prothrombin time and congeners tests are unable to predict bleeding in cirrhosis. However, it cannot be excluded that some tests may be useful in patients who are severely decompensated. Large prospective collaborative studies are warranted. Enrolled patients should be randomized to receive perioperative prophylaxis based on laboratory testing (eg, viscoelastometry, thrombomodulin-modified thrombin generation) or to usual care. However, for these trials to be useful, a third group of patients who do not receive prophylaxis should be included. In conclusion, until results from these studies are available, physicians attending cirrhosis should refrain from using laboratory tests with arbitrary cutoffs to make decision on perioperative prophylaxis. Decision should be made by considering the clinical history of individual patients and the risk of hemorrhage of specific procedures.

Laboratory investigation and diagnosis of thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a rare and potentially fatal disease for which rapid diagnosis is crucial for patient outcomes. Deficient activity (< 10%) of the liver enzyme, ADAMTS13, is the pathophysiological hallmark of TTP, and measurement of the enzyme activity can establish the diagnosis of TTP with high accuracy. Thus, along with the clinical history, appropriate laboratory assessment of a suspected case of TTP is essential for diagnosis and treatment. Here, we present a review of the available laboratory tests that can assist clinicians in establishing the diagnosis of TTP, with special focus on ADAMTS13 assays, including the measurement of the antigen and activity, and detection of autoantibodies to ADAMTS13.

Hemostasis from Bench to Bedside: The History of Three Successful Stories of Translational Medicine.

Looking at the history of hemostasis, one can easily conclude that most of the achievements we see today have been done through the ingenuity and dedication of scientists, who devoted their efforts to translate the basic concepts behind their hypotheses from the laboratory to the patient bedside. I am personally excited by three of these stories. This article aims to review the history on the development of D-dimer, heparin, and coagulometers, which have been chosen as paradigmatic examples of diagnostic testing, drugs, and measuring devices, respectively. They should be considered among the most successful histories of translational medicine.

Laying the foundations for gene therapy in Italy for patients with haemophilia A: A Delphi consensus study.

INTRODUCTION: Current treatment for haemophilia A involves factor VIII replacement or non-replacement (emicizumab) therapies, neither of which permanently normalise factor VIII levels. Gene therapy using adeno-associated viral (AAV) vectors is an emerging long-term treatment strategy for people with severe haemophilia A (PwSHA) that is likely to be available for clinical use in the near future. AIM: This article proposes practical guidelines for the assessment, treatment, and follow-up of potential PwSHA candidates for AAV-based gene therapy. METHOD: Using the Delphi method, a working group of Italian stakeholders with expertise in and knowledge of the care of adults with haemophilia A analysed literature for AAV-based gene therapy and drafted a list of statements that were circulated to a panel of Italian peers. During two rounds of voting, panel members voted on their agreement with each statement to reach a consensus. RESULTS: The Delphi process yielded 40 statements regarding haemophilia A gene therapy, across five topics: (1) organisational model; (2) multidisciplinary team; (3) patient engagement; (4) laboratory surveillance; and (5) patient follow-up and gene therapy outcomes. The consensus was reached for all 40 statements, with the second round of voting needed for five statements. CONCLUSION: Use of the hub-and-spoke organisational model and multidisciplinary teams are expected to optimise patient selection for gene therapy, as well as the management of dosing and patient follow-up, patient engagement, laboratory surveillance, and patient expectations regarding outcomes. This approach should allow the benefits of AAV-based gene therapy for haemophilia A to be maximised.

Interactions of adenoviruses with platelets and coagulation and the vaccine-induced immune thrombotic thrombocytopenia syndrome.

The COVID-19 pandemic has had a heavy impact on global health and economy and vaccination remains the primary way of controlling the infection. During the ongoing vaccination campaign some unexpected thrombotic events have emerged in subjects who had recently received the AstraZeneca (Vaxzevria) vaccine or the Johnson and Johnson (Janssen) vaccine, two adenovirus vector-based vaccines. Epidemiological studies confirm that the observed/expected ratio of these unusual thromboses is abnormally increased, especially in women in fertile age. The characteristics of this complication, with venous thromboses at unusual sites, most frequently in the cerebral vein sinuses but also in splanchnic vessels, often with multiple associated thromboses, thrombocytopenia, and sometimes disseminated intravascular coagulation, are unique and the time course and tumultuous evolution are suggestive of an acute immunological reaction. Indeed, plateletactivating anti-PF4 antibodies have been detected in a large proportion of the affected patients. Several data suggest that adenoviruses may interact with platelets, the endothelium and the blood coagulation system. Here we review interactions between adenoviral vectors and the hemostatic system that are of possible relevance in vaccine-associated thrombotic thrombocytopenia syndrome. We systematically analyze the clinical data on the reported thrombotic complications of adenovirus-based therapeutics and discuss all the current hypotheses on the mechanisms triggering this novel syndrome. Although, considering current evidence, the benefit of vaccination clearly outweighs the potential risks, it is of paramount importance to fully unravel the mechanisms leading to vaccineassociated thrombotic thrombocytopenia syndrome and to identify prognostic factors through further research.

Pro-coagulant imbalance in patients with community acquired pneumonia assessed on admission and one month after hospital discharge.

OBJECTIVES: Patients hospitalized because of community-acquired-pneumonia (CAP) are at risk of cardiovascular diseases. Although plasma procoagulant imbalance play a role, mechanisms are not completely understood. We aimed to investigate whether there is a measurable state of procoagulant imbalance following inflammation determined by CAP. METHODS: We analyzed blood from 51 CAP patients at admission and 51 healthy subjects (HS) for (i) pro and anticoagulants, (ii) thrombin generation (TG) with or without thrombomodulin (TM), which is the physiologic activator of the protein C anticoagulant pathway and(iii) by assessing the ratio between von Willebrand-factor (VWF) and its protease ADAMTS13. Thirty patients were re-analyzed one month after discharge when CAP was resolved. RESULTS: Median levels of TG parameters, including the endogenous thrombin potential (ETP), the ETP-TM-ratio (with/without TM), peak-thrombin and velocity index were higher in patients at baseline than HS. In particular, the median (IQR) ETP-TM-ratio in patients vs. HS was 0.88 (0.83-0.91) vs. 0.63 (0.48-0.71), p<0.001. Factor (F)VIII, a potent procoagulant involved in TG was higher in patients at baseline than HS [195 U/dL (100-388) vs. 127(108-145)], p<0.001]. The ratio of VWF/ADAMTS13 was higher at baseline than HS. Cumulatively, the findings indicate a state of pro-coagulant imbalance, which (although reduced), remained high [i.e., ETP-TM-ratio, 0.80 (0.74-0.84); FVIII, 152 U/dL (122-190)] one month after discharge when the infection was resolved. CONCLUSIONS: Patients with CAP possess a state of pro-coagulant imbalance, which remains substantially high, even when the infection is resolved. The findings suggest CAP patients as candidates for antithrombotic prophylaxis even after the resolution of infection. Clinical trials are warranted to assess the benefit/risk ratio of prophylaxis extension.

Fresh frozen plasma transfusion in patients with cirrhosis and coagulopathy: Effect on conventional coagulation tests and thrombomodulin-modified thrombin generation.

BACKGROUND & AIMS: The efficacy of fresh frozen plasma (FFP) transfusion in enhancing thrombin generation in patients with cirrhosis and impaired conventional coagulation tests has not been sufficiently explored. Thus, we aimed to assess the effect of FFP transfusion on thrombin generation in these patients. METHODS: Fifty-three consecutive patients receiving a standard dose of FFP to treat bleeding and/or before invasive procedures - if international normalized ratio (INR)/prothrombin time (PT) ratio were ≥1.5 - were prospectively enrolled. The primary endpoint was the amelioration of endogenous thrombin potential (ETP) with thrombomodulin (ETP-TM) after transfusion, which corresponds to the total amount of generated thrombin. INR/PT ratio and activated partial thromboplastin time (aPTT) were also assessed before and after transfusion. RESULTS: FFP enhanced ETP-TM by 5.7%, from 973 (731-1,258) to 1,028 (885-1,343 nM × min; p = 0.019). Before transfusion, evidence of normal or high ETP-TM was found in 94% of patients, even in those with bacterial infections. Only 1 (1.9%) patient had ETP-TM values reverting to the normal range after transfusion. Notably, no patients with low ETP-TM had bleeding. The median decrease in ETP-TM was 8.3% and the mean was 12.8% in 18 (34%) patients after transfusion (from 1,225 [1,071-1,537] to 1,124 [812-1,370] nM × min; p ≤0.0001). Similar responses to FFP transfusion were observed in patients with compensated and acute decompensated cirrhosis, acute-on-chronic liver failure, infection or shock. FFP significantly ameliorated INR and aPTT values (p <0.0001), but in a minority of patients the values were reduced to less than the cut-off point of 1.5. CONCLUSIONS: FFP transfusion enhanced thrombin generation and ameliorated conventional coagulation tests to normal values in a limited number of patients, and slightly decreased thrombin generation in 34% of cases. LAY SUMMARY: Transfusion of fresh frozen plasma in patients with cirrhosis only slightly improves coagulation test values in a limited number of patients and even appears to worsen them in a third of cases. Transfusion for the purpose of preventing or treating bleeding events could cause inherent risks and costs without clear benefits.

Diagnosis, Development, and Treatment of Portal Vein Thrombosis in Patients With and Without Cirrhosis.

Portal vein thrombosis unrelated to solid malignancy is common in patients with cirrhosis, but less frequently observed in patients without cirrhosis. Prompt diagnosis and management of acute symptomatic portal vein thrombosis are essential. Failure to detect and treat thromboses can result in mesenteric ischemia, chronic cavernous transformation, and complications of portal hypertension. In patients with cirrhosis, development of portal vein thrombosis is often insidious and remains undetected until its incidental detection. Management of portal vein thrombosis in patients with cirrhosis is more controversial. However, there are data to support treatment of specific patients with anticoagulation agents. We review the common and distinct features of portal vein thromboses in patients without liver tumors, with and without cirrhosis.

Is placental blood a reliable source for the evaluation of neonatal hemostasis at birth?

BACKGROUND: Phlebotomy is among the main determinants of anemia of prematurity. Blood sparing policies endorsed umbilical cord blood (here called placental) as an alternative source for laboratory testing. Little is known on the suitability of placental blood to evaluate neonatal hemostasis of newborn infants. We aimed to compare the hemostatic profile of paired placental and infant venous blood, by means of prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, antithrombin, protein C, thromboelastography (TEG) and thrombin generation assay (TGA). STUDY DESIGN: This was an observational single-center study. METHODS: We collected at birth venous citrated blood from both placental and infant venous source and performed PT, APTT, fibrinogen, antithrombin, protein C, TEG (reaction time-R; kinetics-K alpha angle-α, maximum amplitude-MA and lysis at 30 minutes-LY30), and TGA (endogenous thrombin potential-ETP). RESULTS: We enrolled 60 neonates with a median gestational age (range) of 37 weeks (28+1 -41) and birth-weight 2417 g (950-4170). Based on TEG and TGA, placental blood showed a procoagulant imbalance as indicated by lower median R (4.0 vs. 6.1 min; p < 0.001) and K (1.3 vs. 2.2 min; p < 0.001); higher α-angle (69.7 vs. 57.4°; p < 0.001) and ETP (1260 vs. 1078; p = 0.002) than those observed for infant venous blood. PT and APTT did not differ significantly between the two groups. CONCLUSIONS: While placental and neonatal blood samples are equally suitable to measure the standard coagulation tests PT and APTT, placental blood leads to a procoagulant imbalance when testing is performed with TEG or TGA. These effects should be considered when interpreting results stemming from investigation of neonatal hemostasis.

Management of patients with severe haemophilia a without inhibitors on prophylaxis with emicizumab: AICE recommendations with focus on emergency in collaboration with SIBioC, SIMEU, SIMEUP, SIPMeL and SISET.

INTRODUCTION: The factor VIII (FVIII)-mimetic bispecific monoclonal antibody, emicizumab, previously approved for prophylaxis in haemophilia A with inhibitors, has been recently licensed in several countries also in patients with severe haemophilia A (PWSHA) without inhibitors. The introduction of this innovative agent requires the development of specific pathways at Haemophilia Treatment Centres (HTC), particularly regarding laboratory testing and treatment of breakthrough bleeds and invasive procedures/surgeries, even more critical when patients are managed by non-specialist professionals. Limited literature data and clinical experience in PWSHA without inhibitors on emicizumab are currently available. AIM: To promote awareness and overcome these challenges, the Italian Association of Haemophilia Centres (AICE) issued a guidance on the management of PWSHA without inhibitors on emicizumab prophylaxis, focused on emergency and shared with other National Scientific Societies in the field. METHODS: The document, drafted by an AICE expert panel and approved through online consultation, was further revised by a multidisciplinary working group, including members of 5 haemostasis, laboratory and emergency scientific societies. The final version was approved by the Council of each society. RESULTS: General recommendations about use of FVIII concentrates for the treatment of bleeding or haemostatic coverage of invasive procedures/surgeries and laboratory monitoring in PWSHA without inhibitors on emicizumab are provided. Specific issues of the management in the emergency room are focused, highlighting the need for direct involvement or formalized supervision by specialist HTC physicians. CONCLUSIONS: This guidance provides a reference pathway to be implemented in the different healthcare organizations, especially for the challenging emergency management in this setting.

Unexpected, isolated activated partial thromboplastin time prolongation: A practical mini-review.

A common inquiry in coagulation laboratories is how to interpret an unexpected, isolated prolonged activated partial thromboplastin time (APTT). In this context, isolated means together with a normal prothrombin time (PT) and/or normal international normalized ratio (INR). This finding may lead to contact with laboratory doctors for further advice on a diagnostic strategy. Occasionally, the need for a diagnostic algorithm can be subacute, where surgery has to be postponed until an explanation for the isolated, prolonged APTT has been established. Activated partial thromboplastin time as a coagulation test was developed to monitor patients with hemophilia. Different APTT reagents display considerable differences in their sensitivity to deficiencies of coagulation factors. An isolated, prolonged APTT is seen in (a) individuals/patients with lupus anticoagulants, (b) patients in treatment with anticoagulants, mainly heparin, and (c) patients with deficiencies of specific coagulation factors. In this tutorial review, we summarize what may cause an isolated prolonged APTT and we present a simple diagnostic algorithm to differentiate between lupus anticoagulants (common) and factor deficiencies (rare). The identification of an isolated prolonged APTT as well as the underlying cause can be of the utmost importance in ensuring the correct therapeutic follow-up.

Emicizumab, the factor VIII mimetic bi-specific monoclonal antibody and its measurement in plasma.

Objectives: Emicizumab, a monoclonal antibody mimicking the function of factor (F) VIII in the activation of FX by FIXa, is widely used for prophylaxis in hemophilia patients with or without inhibitors to FVIII. Although it is administered at fixed dose, its measurement could be occasionally required. In principle, the emicizumab procoagulant effect could be assessed by the one-stage assay (OSA) currently used to measure FVIII. However, the OSA for FVIII presents with limitations. Furthermore, owing to its potent FVIII-like activity, emicizumab interferes with the measurement of the inhibitor to FVIII, which is often needed in patients on emicizumab. Methods: We prepared test samples by spiking a FVIII-deficient plasma with graded amounts of emicizumab. We modified the OSA for FVIII and tested plasma samples for emicizumab concentrations. Furthermore the chromogenic assay (CA) for FVIII with bovine reagents was used to assess for the FVIII inhibitor in patients on emicizumab. Results: Slight modification of the OSA for FVIII (i.e., higher test plasma dilution and longer coagulometer acquisition time) made the regular OSA as a reliable laboratory tool to measure emicizumab concentration as shown by the identity of the regression (observed vs. expected) lines. Furthermore, the inhibitors to FVIII in patients on emicizumab, which were negative when measured by the regular Bethesda assay, were reliably measured by the CA assay employing bovine reagents. Conclusions: The methods currently used to measure FVIII can be easily modified to make the general clinical laboratory able to assist clinicians when dealing with patients on emicizumab.

Effect of emicizumab on global coagulation assays for plasma supplemented with apixaban or argatroban.

Emicizumab is a bi-specific humanized monoclonal antibody mimicking the factor (F) VIII cofactor activity in mediating the activation of FX by FIXa. Recent observations showed that emicizumab when added to pooled normal plasma (PNP), hemophilic plasma or PNP added with unfractionated heparin is able to interfere with coagulation assays. To further explore the mechanisms of assay interference we investigated the effect of emicizumab on global coagulation assays for the PNP added with two direct oral anticoagulants, apixaban or argatroban. Aliquots of PNP were added with purified apixaban or argatroban at a concentration of 500 ng/mL and emicizumab at concentrations ranging from 0 to 100 µg/mL. Plasma samples were then tested for the activated partial thromboplastin time (APTT) and for thrombin generation (the latter for the apixaban plasma only). Emicizumab at a 25-50 µg/mL shortened the APTT of the PNP with or without apixaban or argatroban. The extent of correction was greater for the apixaban or argatroban plasma and amounted to 35% or 42%, respectively. The parameters of thrombin generation (lag-time and time-to-peak) for the PNP supplemented with apixaban were shortened by 30% or 25%, respectively and the endogenous thrombin potential and the peak-thrombin were marginally affected. Emicizumab attenuates in vitro the anticoagulant activity of the PNP induced by apixaban or argatroban as documented by the correction of prolonged APTT and velocity of thrombin generation (i.e., lag-time and time-to-peak). Whether the above effects have any relevance in vivo is unknown.

Advances in the Treatment of Hemophilia: Implications for Laboratory Testing.

BACKGROUND: Until recently, clinical laboratories have monitored hemophilia treatment by measuring coagulation factors before/after infusion of human-derived or recombinant factors. Substantial changes are expected in the near future based on new therapeutic approaches that have been or are being developed. CONTENT: Hemophilia treatment includes replacement therapy with human-derived/recombinant factors or treatment with bypassing agents for patients without or with inhibitors, respectively. Accordingly, laboratory methods for monitoring include one-stage clotting or chromogenic assays meant to measure either factor VIII/IX or global coagulation tests to measure the effect of bypassing agents. Recently, modified long-acting coagulation factors have been introduced for which discrepant results may be expected when measurement is performed with one-stage clotting or chromogenic assays. Currently, novel drugs not based on coagulation factors are under development and are being tested in clinical studies. These drugs do require new methods and therefore laboratory evaluation of hemophilia will undergo dramatic changes in the near future. SUMMARY: From the analysis of the current practice and literature, we draw the following conclusions: (a) Thrombin generation or thromboelastometry are the logical candidate assays to monitor bypassing agents. (b) Considerable differences are expected when measuring modified long-acting coagulation factors, depending on whether one-stage or chromogenic assays are used. Although no definitive conclusions can presently be drawn, chromogenic assays are probably more suitable than one-stage clotting. (c) Novel drugs not based on coagulation factors such as emicizumab, fitusiran, or concizumab that are entering the market do require alternative methods that are not yet well established.

Procoagulant imbalance influences cardiovascular and liver damage in chronic hepatitis C independently of steatosis.

BACKGROUND & AIMS: Patients with chronic HCV infection besides hepatitis often present cardiovascular damage, the pathogenesis of which is not defined. In chronic liver diseases, including NAFLD and cirrhosis, a procoagulant imbalance, potentially responsible for atherosclerosis has been reported. We aimed at evaluating whether a procoagulant imbalance is present also in non-cirrhotic patients with HCV infection and whether the procoagulant imbalance correlates with cardiovascular damage. The correlation between the procoagulant imbalance, coexisting steatosis, and liver fibrosis was analysed. METHODS: From 2014 to 2018, 393 subjects (205 patients with chronic HCV infection from two liver units and 188 controls) were enrolled. Metabolic, cardiovascular, liver assessment and coagulation parameters-procoagulants (FII and FVIII) and anticoagulants (antithrombin and protein C [PC]), endogenous thrombin potential (ETP), peak-thrombin and their ratios (with/without thrombomodulin)-were determined. RESULTS: The procoagulant imbalance (defined as high FVIII, FVIII/PC ratio, ETP-ratio and peak-thrombin-ratio (with/without thrombomodulin)) was significantly higher in patients with chronic HCV than controls. Steatosis was detected in 87 patients (42%). No difference in coagulation imbalance, carotid and cardiac parameters and severity of liver fibrosis was observed in patients with or without steatosis, despite the latter had less severe metabolic alterations. The FVIII/PC ratio was independently associated with carotid intima-media thickness (coefficient 0.04, 95% CI 0.002-0.07, P = .04) and liver fibrosis (coefficient 0.64, 95% CI 0.37-0.92, P < .0001). CONCLUSION: Patients with HCV infection, even in the absence of cirrhosis have a procoagulant-imbalance that possibly plays a role in increasing the risk of cardiovascular disease and progression of fibrosis.

Body mass index reduction improves the baseline procoagulant imbalance of obese subjects.

Obesity is a risk factor for cardiovascular diseases. The latter being dependent (at least in part) on plasma procoagulant imbalance (i.e., hypercoagulability). Information on hypercoagulability associated with obesity is scanty and mainly based on global traditional coagulation tests or on the measurement of individual components of coagulation (i.e., pro- and anticoagulants). Plasma from 33 obese subjects was investigated soon before endoscopic balloon placement and after removal (6 months later) by thrombin-generation procedures that are thought to represent much better than any other in vitro test the coagulation process occurring in vivo. We found that obese subjects possess a state of hypercoagulability as demonstrated by the modification of the main parameters of thrombin-generation. In particular, the median value (min-max) of the endogenous thrombin potential (ETP) of obese subjects at baseline was higher than that of controls [1968 (1335-2533) vs. 1710 (1010-2119), p < 0.001]. Endoscopic balloon placement achieved a BMI reduction from 38.9 (31.7-62.3) to 31.6 (21.9-53.3), p < 0.001 and a parallel reduction of thrombin-generation as demonstrated by the following findings. The ETP measured soon after balloon removal was significantly smaller than that measured at baseline [1783 (1224-2642) vs. 1968 (1335-2533), p < 0.01]. The other parameters of thrombin-generation, including lag-time, peak-thrombin, time-to-reach the peak and velocity index showed a pattern consistent with the ETP, both at baseline and soon after balloon removal. Endoscopic balloon placement achieves concomitant reduction of BMI and thrombin-generation in subjects with obesity.

Harmful and Beneficial Effects of Anticoagulants in Patients With Cirrhosis and Portal Vein Thrombosis.

BACKGROUND & AIMS: Vitamin K antagonists (VKAs) promote recanalization of portal vein thrombosis (PVT) in patients with cirrhosis. However, the benefit of PVT recanalization might be offset by major and minor bleeding associated with use of anticoagulants. We evaluated harmful and beneficial effects of VKA in patients with PVT and cirrhosis. METHODS: We performed a retrospective study of 63 consecutive patients with cirrhosis given anticoagulants for the first detection of non-neoplastic PVT from 2003 to 2015 in Italy. We collected data on bleeding events in these patients and compared them with those from patients without cirrhosis with venous thromboembolism (VTE) (n = 160) for up to 4 years. Time in the therapeutic range, based on the international normalized ratio, was used to determine the quality of anticoagulation. We also collected data from 139 patients with cirrhosis who did not receive VKAs (controls), to analyze portal hypertension-related events. We performed survival analyses to determine the effects of VKA in patients with PVT vs controls. RESULTS: The group with VTE and the group with PVT were comparable in age, sex, and time in the therapeutic range, but patients with VTE received VKAs for a longer time period (31.1 ± 16.9 mo vs 23.3 ± 16.2 mo; P = .002). The incidence of major or minor bleeding was higher in patients with PVT than patients with VTE (major, 24% vs 7%; P = .012; minor, 29% vs 19%; P = .024). Patients with PVT had a higher rate of major bleeding from the upper-gastrointestinal tract than patients with VTE (P = .019), but there were no significant differences in other types of major bleeding (P = .376). Patients with PVT and controls had the same rate of upper-gastrointestinal bleeding. Complete recanalization in patients with PVT receiving VKA (n = 31) was independently associated with increased portal hypertension-related event-free and transplantation-free survival times. CONCLUSIONS: In a retrospective analysis of 63 patients with cirrhosis given anticoagulants for PVT, we found VKA use to increase risk of minor bleeding, compared with patients without cirrhosis given VKA. However, this risk is offset by the ability of VKA to increase portal hypertension-related, event-free, and transplantation-free survival of patients with PVT recanalization. Portal hypertension, rather than anticoagulants, could account for the difference in risk of major bleeding between patients with PVT vs patients with VTE.