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Enoxaparin is safe and effective for restoring and preserving forward portal venous flow in children with End Stage Liver Disease

  • Author Footnotes
    # These authors have contributed equally as first author
    Shreya B. Kishore
    Correspondence
    Corresponding author. Shreya Bhushan Kishore, Department of Gastroenterology, Hepatology and Liver Transplantation, Queensland Children's Hospital, 501 Stanley Street, South Brisbane, QLD 4101, Australia. Tel: 61 7 3068 4502, Fax: 61 7 3068 3799,
    Footnotes
    # These authors have contributed equally as first author
    Affiliations
    Department of Gastroenterology, Hepatology and Liver Transplantation, Queensland Children's Hospital, Brisbane, Queensland, Australia
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  • Author Footnotes
    # These authors have contributed equally as first author
    Peter Lewindon
    Footnotes
    # These authors have contributed equally as first author
    Affiliations
    Department of Gastroenterology, Hepatology and Liver Transplantation, Queensland Children's Hospital, Brisbane, Queensland, Australia
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  • Charlton Noble
    Affiliations
    Department of Gastroenterology, Hepatology and Liver Transplantation, Queensland Children's Hospital, Brisbane, Queensland, Australia
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  • Fariha Balouch
    Affiliations
    Department of Gastroenterology, Hepatology and Liver Transplantation, Queensland Children's Hospital, Brisbane, Queensland, Australia
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  • Author Footnotes
    # These authors have contributed equally as first author
Published:November 08, 2022DOI:https://doi.org/10.1016/j.jhep.2022.11.001

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      • Haemostatic alterations and management of haemostasis in patients with cirrhosis
        Journal of HepatologyVol. 76Issue 6
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          Patients with cirrhosis frequently acquire complex changes in their haemostatic system including a decreased platelet count and decreased levels of various haemostatic proteins. Although historically patients with cirrhosis were thought to have a haemostasis-related bleeding tendency, it is now widely accepted that the haemostatic system of patients with cirrhosis remains in balance as a result of simultaneous changes in pro- and anti-haemostatic systems. The concept of rebalanced haemostasis has led to changes in clinical management, although firm evidence from well-designed clinical studies is largely lacking.
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      Dear Editor,
      We refer to the excellent, timely review by Lisman et al
      • Lisman T.
      • Caldwell S.H.
      • Intagliata N.M.
      Haemostatic alterations and management of haemostasis in patients with cirrhosis.
      on “Hemostatic alterations and management of haemostasis in patients with cirrhosis”. Children with advanced liver disease awaiting liver transplantation or close to listing are at high risk of losing portal venous flow and portal thrombosis because of high hepatic resistance and a fragile, rebalanced hemostatic state. Loss of portal flow is reported to herald irreversible portal thrombosis, hepatocyte extinction with worsening hepatocyte function and risk of portal vein clot extension
      • Iranpour P.
      • Lall C.
      • Houshyar R.
      • Helmy M.
      • Yang A.
      • Choi J.I.
      • Ward G.
      • Goodwin S.C.
      Altered Doppler flow patterns in cirrhosis patients: an overview.
      . Treatment with anti-coagulation has been proposed for this complication but there is little published experience, especially in children. We report our experience from a statewide, paediatric liver transplant service after commencing a policy of frequent doppler ultrasound to monitor for and treat reversal of portal flow in children with end stage liver disease (Table 1).
      Table 1Summary of patients included in study with liver, renal function and coagulation pre and post enoxaparin (at treatment initiation and pre transplantation), and transplant outcomes.
      PatientAge at treatment initiation (months)DiagnosisMELD/PELD score at treatment initiationINR pre and postFibrinogen pre and post (g/L)Platelet count pre and post (x109/L)Total bilirubin pre and post (umol/L)ALT/AST pretreatment (U/L)Creatinine (umol/L) /urea (mmol/L) pretreatmentDose of enoxaparinDiagnostic and therapeutic procedures after commencing treatmentAge at LTx (months)Outcome of PV flow reversal post treatment
      13EBHA14.21.3/1.21.4/2.4330/53230/33121/21720/41.5mg/kg BDAbdominal paracentesis, CVAD, Ladd, Gastrostomy, LTx3Antegrade
      24EHBA9.61.1/1.61.5/0.6282/247211/293107/14225/4.71.5mg/kg BDLTx, liver biopsy, incisional hernia repair5Antegrade
      34EBHA28.4 (passed away before LTx)1.2/1.81.9/1.9206/61216/31078/122<30/3.81.5mg/kg BDnil LTx, thoracotomy and chest drain for haemopneumothoraxPassed away before LTxAntegrade
      44.5EBHA3.31.1/2.23/1176/59116/500418/326<30/3.11mg/kg BDLTx, ECMO8Antegrade
      55.5EBHA24.81.9/1.61.1/2218/151100/85326/423<30/2.51.5mg/kg BDCVAD, ascitic tap, gastroscopy, LTx7Antegrade
      624CFRLD11.81.9/1.91.1/1.1164/187152/2343/135<30.2.41mg/kg BDCVAD, LTx, bronchoscopy30.5Antegrade
      7141EBHA131.3/21.6/0.944/3536/4286/98<30/4.31mg/kg maneEndoscopy and biopsy of upper GIT, LTx147.5Antegrade then oscillating
      83.5EBHA16.61.4/1.33.2/3.4389/122138/36272/21612/1.60.5mg/kg BDliver biopsy, cholangiography, exploratory laparotomy, LTx5Antegrade then retrograde
      96EBHA26.31.6/3.21.2/1.4103/25320/16155/106<30/3.50.5mg/kg BDLTx9Antegrade then retrograde
      107EBHA3.31.1/1.12.9/4.4213/42339/4578/186<30/1.11mg/kg BDCVAD, LTx9Antegrade then retrograde
      115.5EBHA15.11.8/1.51.2/2.2255/58490/148196/324<30/2.90.5mg/kg BDLTx6Nil further USS pre LTx
      124.5EBHA9.91.1/1.71.8/1.2297/37121/2468/11712/3.71mg/kg BDLTx7.5No change
      134.5EBHA19.51.8/1.42.1/2.5718/60320/7738/6434/3.51mg/kg BDCVAD, bronchoscopy, LTx, liver biopsy6No change
      14182CFRLD141.3/1.72.4/1.755/4329/3985/12838/2.11mg/kg BDLTx183No change
      Abbreviations: EHBA – extrahepatic biliary atresia; CFRLD – cystic fibrosis related liver disease; MELD score – model for end stage liver disease; PELD score – pediatric end state liver disease; LTx – liver transplant; PV – portal vein; INR – international normalised ratio; APTT – activated partial thromboplastin time; ALT – alanine transaminase; AST – aspartate transaminase; CVAD – central venous access device; GIT – gastrointestinal tract; BD - twice daily.
      From July 2016 to June 2022, our service performed 51 paediatric transplants and, while being considered/waiting for transplant, 14 children aged 3 months to 15 years, median 5 months, 5 females and 9 males with advanced liver disease (12 biliary atresia, 2 cystic fibrosis related liver disease) were found to have reversal of portal flow on doppler ultrasound and started on Enoxaparin. 13 had ultrasounds during admission for clinical deterioration, 1 during elective outpatient review. A prior ultrasound showing antegrade portal flow was noted a mean 7 weeks (1-14 weeks) prior.
      Of the remaining 37 paediatric liver transplants performed during the study period, the mean age of transplant was 5.1 years (range 0.1-15.3), with none developing portal venous thrombosis. Most common indications for transplant were extra hepatic biliary atresia (16), metabolic disease including citrullinemia, tyrosinemia, Niemann Pick (7), cystic fibrosis related liver disease (3) and various other conditions (11 patients).
      After commencing Enoxaparin (prophylaxis 0.5mg/kg twice daily to therapeutic 1.5mg/kg twice daily), antegrade portal flow was restored, on 1-2 weekly Doppler ultrasound, in 10 of 14 children after a median 3.5 weeks therapy (4 days to 2 months).. Antegrade portal flow with continued Enoxaparin treatment was sustained safely until subsequent liver transplant a median 3.5 weeks later (range 4 days to 6 weeks) in 5 children and in a sixth child until they passed away without transplant due to complex congenital cardiac disease. The remaining 4 of the 10 children achieved temporary antegrade portal flow after starting Enoxaparin (after a mean 14.5 days) but returned to oscillating or retrograde flow a median 4 (1-24) weeks later. A further child was only on Enoxaparin for 4 days prior to transplantation and did not have a repeat ultrasound. Her explant did not show any clotting in portal or hepatic vessels.
      There were no unexpected adverse events during Enoxaparin therapy - in particular no bleeding concerns during the 44 procedures (5 CVADs, 39 other), nor concern over oozing from cannulation sites or any thrombotic events. It was difficult to demonstrate significant improvements in functional parameters (INR, albumin, bilirubin) as many of the children were infants with rapidly progressive end stage liver disease. As albumin support was given to support all 14 patients, this confounded albumin as an outcome.
      We can confirm that in no patient receiving Enoxaparin did the loss of portal flow lead to a portal vein clot. We were unable to demonstrate that Enoxaparin achieved successful reversal of retrograde flow back to antegrade in 4 children but were unable to demonstrate a reversal of functional deterioration in this cohort with deteriorating liver disease. The key question of whether maintenance of portal flow extended the life of the deteriorating liver was beyond the scope of this small report.
      A limitation of our series was that Enoxaparin treatment was not standardised. Choice of treatment dosing was provided by our Haematology service and 4 earlier patients received the lower, prophylactic dose of 0.5mg/kg twice daily. This is no longer our practice, and we now use a standardised dose of 1mg/kg twice daily in line with the International Society of Thrombosis and Haemostasis guidelines.
      • Tullius B.P.
      • Athale U.
      • Van Ommen C.H.
      • Chan A.K.
      • Palumbo J.S.
      • Balagtas J.M.
      The identification of at-risk patients and prevention of venous thromboembolism in pediatric cancer: guidance from the SSC of the ISTH.
      All patients were included in our study for completeness.
      Preservation of portal blood flow is crucial for the stability of liver function and transplant anatomy. While reversal of portal flow can be temporary with intercurrent illness increasing hepatic resistance, in the setting of rapidly advancing liver disease in children awaiting transplant it is our experience that spontaneous return to antegrade flow is not common. This is the first report of Enoxaparin being used systematically in children with advanced liver disease with reversal or absent portal blood flow. We have demonstrated that Enoxaparin is safe and effective to assist recovery of antegrade portal blood flow and maintain portal blood flow in this setting.

      Conflict of Interest Statement

      The authors have no conflicts of interest to declare.

      Financial Support Statement

      The authors received no financial support for this paper.

      Authors Contributions

      SK acquired and analysed the data and wrote the first version of the manuscript. CN was involved in data acquisition and manuscript revision. PL and FB provided the conceptual framework, critically analysed and interpreted the data, edited and revised the final manuscript.

      References

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