Marco Marietta

Enoxaparin Prevents Portal Vein Thrombosis and Liver Decompensation in Patients With Advanced Cirrhosis

BACKGROUND & AIMS We performed a randomized controlled trial to evaluate the safety and efficacy of enoxaparin, a low-molecular-weight heparin, in preventing portal vein thrombosis (PVT) in patients with advanced cirrhosis. METHODS In a nonblinded, single-center study, 70 outpatients with cirrhosis (Child-Pugh classes B7-C10) with demonstrated patent portal veins and without hepatocellular carcinoma were assigned randomly to groups that were given enoxaparin (4000 IU/day, subcutaneously for 48 weeks; n = 34) or no treatment (controls, n = 36). Ultrasonography (every 3 months) and computed tomography (every 6 months) were performed to check the portal vein axis. The primary outcome was prevention of PVT. Radiologists and hepatologists that assessed outcomes were blinded to group assignments. Analysis was by intention to treat. RESULTS At 48 weeks, none of the patients in the enoxaparin group had developed PVT, compared with 6 of 36 (16.6%) controls (P = .025). At 96 weeks, no patient developed PVT in the enoxaparin group, compared with 10 of 36 (27.7%) controls (P = .001). At the end of the follow-up period, 8.8% of patients in the enoxaparin group and 27.7% of controls developed PVT (P = .048). The actuarial probability of PVT was lower in the enoxaparin group (P = .006). Liver decompensation was less frequent among patients given enoxaparin (11.7%) than controls (59.4%) (P < .0001); overall values were 38.2% vs 83.0%, respectively (P < .0001). The actuarial probability of liver decompensation was lower in the enoxaparin group (P < .0001). Eight patients in the enoxaparin group and 13 controls died. The actuarial probability of survival was higher in the enoxaparin group (P = .020). No relevant side effects or hemorrhagic events were reported. CONCLUSIONS In a small randomized controlled trial, a 12-month course of enoxaparin was safe and effective in preventing PVT in patients with cirrhosis and a Child-Pugh score of 7-10. Enoxaparin appeared to delay the occurrence of hepatic decompensation and to improve survival.

Prevention and treatment of bleeding complications in patients receiving vitamin K antagonists, Part 1: Prevention

Oral anticoagulant therapy with coumarins is widelyused for the prevention and treatment of venous andarterial thrombosis. The most common complication ofvitamin K antagonist therapy is bleeding, with majorbleeding events occurring in 1–3% of patients annually.Although a number of potential predictors for bleedinghave been described, little research is available to pro-vide evidence-based guidelines for the prevention ofbleeding. To address this knowledge gap, we assembleda panel of international experts and posed a series offocused clinical questions. The experts were asked toperform a systematic literature review and summarize theresults of that review within the context of their clinicalquestion. In many cases, data were lacking and theexperts were asked to supplement their answer with clin-ical expertise. To minimize bias the reviews were vettedby three internationally recognized scholarly bodies. Ourgoal in this project is to provide ‘‘best evidence’’ forclinicians faced with the problem of minimizing the riskof bleeding in patients on vitamin K antagonist therapy.The number of patients receiving vitamin K antagonisttherapy increases annually and probably exceeds three mil-lion in the United States. Despite monitoring and carefuldose adjustment, the time spent in the therapeutic Interna-tional Normalized Ratio (INR) range varies from below 47%to a maximum of 81% of the time [1]. Major bleedingevents occur in up to 3% of ‘‘standard risk’’ patients treatedwith an oral vitamin K antagonist in one year. Despite thehigh frequency of use of vitamin K antagonists, very littleresearch has been performed examining techniques toreduce the risk of bleeding. In particular, the role of clinicalbleeding prediction rules is uncertain and further study ofthe role of drug and food interactions, the impact of patienteducation, the risk to benefit ratio of combining differentantithrombotic drugs, the role of pharmacogenomic testing,and on the optimal management of patients presentingwith elevated INR values is required. However, despitethese needs clinicians are still required to initiate andmonitor vitamin K antagonists while mitigating the risks ofbleeding and thrombosis. This article provides recommen-dations designed to assist clinicians in estimating andmanaging bleeding risk in patients receiving oral vitamin Kantagonists.Clinical questions were formulated by three of theauthors (WA, MC, DG) and authors were selected basedon their published experience. In each case, a North Ameri-can and Italian expert were asked to co-author theresponse to the question. The authors were asked to per-form a comprehensive literature review and make specificrecommendations on the basis of this review in concertwith their clinical experience. Given the anticipated lack ofevidence, the recommendations are largely opinion-based.To increase the rigor of the recommendations, each sectionwas carefully reviewed by members of the Italian Societyfor Studies on Haemostasis and Thrombosis, the Federa-tion of Centers for the Diagnosis of Thrombosis and Sur-veillance of Antithrombotic Therapies, and the Anticoagula-tion Forum.To provide readers with information on the strength of therecommendations, we have asked the authors to use theAmerican College of Chest Physicians GRADE system toevaluate the quality of the recommendations [2]. In thissystem, grades of 1A, 1B, 1C, 2A, 2B, and 2C are possible.A 1A recommendation is a strong recommendation basedon evidence from randomized trials or exceptional qualityobservational data which is thought to apply to mostpatients, in most circumstances. A 2C recommendation is avery weak recommendation, based on poor quality evi-dence, and for which there is doubt as to which patientsthe recommendation applies. Our goal with this project is toboth provide guidance to clinicians and to stimulate addi-tional research designed to improve the quality of evidenceon which treatments for vitamin K antagonist associatedbleeding are based.Clinical Scenario 1A 79-year-old woman with atrial fibrillation and well-con-trolled hypertension is assessed for anticoagulant therapy.She has no history of diabetes, congestive heart failure,stroke, or transient ischemic attack (TIA). Two years agoshe had an upper gastrointestinal bleed treated with a pro-

Hyperhomocysteinemia and Other Newly Recognized Inherited Coagulation Disorders (Factor V Leiden and Prothrombin Gene Mutation) in Patients with Idiopathic Cerebral Vein Thrombosis

Background: Idiopathic cerebral vein thrombosis (iCVT) represents approximately 30% of the cases of cerebral vein thrombosis (CVT). New, inherited – factor V Leiden (FVL) and prothrombin gene mutation (PTHRA20210) – and inherited/acquired – hyperhomocysteinemia (HHcy) – prothrombotic conditions have been detected recently. Methods: We assessed fasting plasma homocysteine (Hcy) levels and main Hcy determinants, FVL and PTHRA20210 in 30 patients with documented iCVT and 40 age- and sex-matched healthy subjects. Results: A strong and significant association of PTHRA20210 [30% (9/30) vs. 2.5% (1/40) iCVT vs. controls, respectively, p = 0.001; OR = 16.174, p = 0.002] and HHcy [13/30 (43.3%) vs. 4/40 (10%) iCVT vs. controls, respectively; p = 0.002, OR = 6.88, p = 0.002] with iCVT was found. Conclusions: PTHRA20210 and HHcy should be considered when screening for thrombophilia and should be assessed in patients with a family or personal history of CVT.

L-ARGININE INFUSION DECREASES PLATELET AGGREGATION THROUGH AN INTRAPLATELET NITRIC OXIDE RELEASE

Nitric Oxide (NO) inhibits platelet aggregation via activation of an intraplatelet soluble guanylate cyclase which induces an increase in cyclic GMP (1). It has been also demonstrated that platelets contain a constitutive, calcium-dependent, NO synthase which is activated by collagen-induced platelet aggregation. This leads to a NO synthesis from L-Arginine (L-Arg), which in turn increases cyclic GMP and down-regulates platelet aggregation (2). In vitro administration of supraphysiological concentrations of L-Arg enhances platelet cyclic GMP levels by increasing NO production and reduces platelet aggregation. This effect is reversed by pre-incubation with NO-synthase inhibitors (3). These results indicate that the L-Arg: NO pathway plays an important role in the modulation of human platelet aggregation (4). In vivo L-Arg, when administered i.v., induces hypotension (5) and vasodilatation (6,7) in humans, and when orally supplemented reduces platelet aggregability both in hypercholesterolemic rabbits and healthy men (8,9).

Acquired haemophilia in HIV negative, HHV-8 positive multicentric Castleman's disease: a case report

Abstract: Multicentric Castlemans Disease (MCD) is an atypical lymphoproliferative disorder, related to human herpesvirus 8 (HHV‐8) infection and often associated with autoimmune diseases such as haemolytic anaemia and thrombocytopenia. Acquired haemophilia (AH) is a rare, life‐threatening disease, which can occur in association with lymphoproliferative disorders, although only one case of AH in MCD has been described so far. We report the case of a human immuno deficiency virus negative 71‐yr‐old woman referred to our hospital for prolonged bleeding on surgical site following a lymph node biopsy. Lymph node histology revealed MCD, while the screening for the bleeding disorder showed prolonged activated partial thromboplastin time (APTT) (ratio: 1.89, normal value <1.24), low factor VIII (FVIII:C) levels (6%) with anti‐factor VIII antibodies (2.3 Bethesda units), leading to a diagnosis of AH. Virological studies on plasma, lymphocyte and bronchoalveolar wash showed positivity for HHV‐8 infection. Treatment with steroids (metilprednisolone 1–1.5 mg/kg/d) and cyclophosphamide (100 mg/d orally) was unsuccessful, and then antiviral therapy with cidofovir (5 mg/kg/wk) was started. A transient normalisation of APTT was seen after two administrations of cidofovir, but then coagulation parameters worsened and a large haematoma of the arm appeared. Bleeding was successfully stopped with two boluses of recombinant activated factor VII (Novoseven® 90 μg/kg). Therapy with anti‐CD 20 monoclonal antibody rituximab (Mabthera® 375 mg/m2 once a week for 4 wk) was started, and following two administrations APTT normalised once again. Cardiological and neurological complications arised before the third dose of rituximab and the patient died shortly afterwards.

Elevated plasma levels of factor VIII in women with early recurrent miscarriage

Summary.  Aims: Inherited and acquired thrombophilia have been found to be associated with recurrent pregnancy loss. This paper examines whether or not elevated factor (F)VIII:C plasma levels, which have been demonstrated to be an independent risk factor for venous thromboembolism, are a risk factor for early recurrent miscarriages also. Patients and methods: Consecutive women referred to our clinic with a history of early recurrent abortion (at least three pregnancy losses before week 13 of gestation) were eligible for the study. Exclusion criteria were endocrine, immunological, anatomical and genetic causes of embryo demise, as well as any thrombophilic abnormality, either congenital or acquired, or a personal or familial history of venous thromboembolism. FVIII:C plasma levels were determined in 51 cases and in 51 controls matched for age, ethnicity and blood group. Results: The mean FVIII:C level in the control subjects was 106.8 IU dL−1, compared with 128.2 IU dL−1 in the patients group (P = 0.0002). Thirteen (25.5%) of the 51 patients had FVIII:C values exceeding the 90th centile of the control population (145 IU dL−1), compared with four subjects in the control group (χ2 = 4.52; P = 0.033; odds ratio = 4.02, 95% confidence interval 1.09, 16.05). No cases with increase in FVIII:C levels attributable to an acute‐phase reaction, as assessed by C‐reactive protein plasma concentration, were found. Conclusions: We found FVIII:C levels significantly higher in women with early recurrent miscarriage compared with controls. This finding suggests a possible association between this thrombophilic condition and early reproductive failures.

Hemostatic balance in patients with liver cirrhosis: Report of a consensus conference

Patients with cirrhosis present with hemostatic alterations secondary to reduced availability of pro-coagulant and anti-coagulant factors. The net effect of these changes is a rebalanced hemostatic system. The Italian Association of the Study of the Liver (AISF) and the Italian Society of Internal Medicine (SIMI) promoted a consensus conference on the hemostatic balance in patients with cirrhosis. The consensus process started with the review of the literature by a scientific board of experts and ended with a formal consensus meeting in Rome in December 2014. The statements were graded according to quality of evidence and strength of recommendations, and approved by an independent jury. The statements presented here highlight strengths and weaknesses of current laboratory tests to assess bleeding and thrombotic risk in cirrhotic patients, the pathophysiology of hemostatic perturbations in this condition, and outline the optimal management of bleeding and thrombosis in patients with liver cirrhosis.

Intracerebral haemorrhage: an often neglected medical emergency.

Intracerebral haemorrhage (ICH) is the deadliest form of stroke, carrying a mortality rate between 30% and 55%, increasing to 67% in patients on oral anticoagulant therapy (OAT). Despite its relevant incidence, the treatment of ICH has been until recently a largely neglected item, addressed by only a few trials. Early treatment of ICH in non-anticoagulated patients with recombinant activated factor VII (rFVII) has been demonstrated to be able to limit the growth of the haematoma, but such a promising result requires further confirmations. In ICH patients receiving OAT a prompt reversal of the anticoagulant effect should be warranted in order to reduce the consequences of this dreadful adverse event. In clinical practice, however, just a small proportion of anticoagulated patients receive this treatment, probably because of the fear of thromboembolic complications. It is now time to check our way of thinking about ICH, regarding and treating it as a compelling medical emergency.

1186 ANTICOAGULANT THERAPY IS SAFE AND EFFECTIVE IN PREVENTING PORTAL VEIN THROMBOSIS (PVT) IN ADVANCED CIRRHOTIC PATIENTS: A PROSPECTIVE RANDOMIZED CONTROLLED STUDY

1185 ELTROMBOPAG IN CHRONIC LIVER DISEASE PATIENTS WITH THROMBOCYTOPENIA UNDERGOING AN ELECTIVE INVASIVE PROCEDURE: RESULTS FROM ELEVATE, A RANDOMISED CLINICAL TRIAL N. Afdhal, E. Giannini, G.N. Tayyab, A. Mohsin, J.W. Lee, A. Andriulli, L. Jeffers, J. McHutchison, F. Campbell, N. Blackman, D. Hyde, A. Brainsky, D. Theodore. Division of Gastroenterology/Liver Center, Beth Israel Deaconess Medical Center, Boston, MA, USA; Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy; Department of Medicine/Gastroenterology & Hepatology, Post Graduate Medical Institute & Lahore General Hospital, Department of Gastroenterology, Services Hospital Lahore, Services Institute of Medical Sciences, Lahore, Pakistan; Department of Internal Medicine, Inha University Hospital and School of Medicine, Incheon, Republic of Korea; Department of Internal Medicine Division of Gastroenterology, Casa Sollievo Sofferenza Hospital, San Giovanni Rotondo, Italy; Center for Liver Diseases, University of Miami, Miller School of Medicine, Miami, FL, Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA; Clinical Development, GlaxoSmithKline, Stockley Park, Uxbridge, UK; Biometrics and Epidemiology, Clinical Development, GlaxoSmithKline, Collegeville, PA, Clinical Development, GlaxoSmithKline, Research Triangle Park, NC, USA E-mail: nafdhal@bidmc.harvard.edu

PLATELET RESPONSIVENESS TO L-ARGININE IN HYPERTENSIVE DISORDERS OF PREGNANCY

Objective: In chronically hypertensive (CH), preeclamptic (PE), and normotensive pregnant women (N), we investigated ex vivo platelet aggregation in response to L-arginine (L-Arg) and sodium nitroprusside (SN), which are respectively the substrate and donor of nitric oxide (NO). Methods: Platelet aggregation was determined with a dual-channel aggregometer by measuring transmittance of light through the sample in comparison to platelet poor plasma, as a reference. Aggregation induced by adenosine diphosphate was continuously recorded for 3 min and measured before and after preincubation with L-Arg and SN. Results: Preincubation with L-Arg significantly reduced platelet aggregation in N and CH patients (p < 0.05) but not in PE women. Preincubation with SN affected aggregation in PE women also (p < 0.001). No correlation was found between platelet response to L-Arg or SN stimuli and the severity of hypertensive disorders expressed as week of gestation at delivery or birth weight. Conclusions: The present study demonstrates that a decreased platelet sensitivity to L-Arg characterizes PE women, whereas SN maintains its antithrombotic power. This impairment seems to be specific for PE, because platelets of CH patients utilize L-Arg normally. This finding supports the involvement of the L-Arg-NO pathway in the pathogenesis of the procoagulative features of PE and probably in the onset of the disease. The maintained response to SN in PE patients suggests a possible therapeutical use of NO donors in the disease.