Advertisement

Factor VIII as a potential predictor of recurrent thrombosis in patients with non-cirrhotic portal vein thrombosis

  • Tingting Li
    Affiliations
    National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College
    Search for articles by this author
  • Zhenhua Lu
    Correspondence
    Corresponding author. Department of General Surgery, Beijing Hospital, NO. 1 DaHua Road, Dong Dan, Beijing 100730, P.R. China, .
    Affiliations
    Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
    Search for articles by this author
Published:October 11, 2022DOI:https://doi.org/10.1016/j.jhep.2022.09.024

      Keywords

      Linked Article

      To the Editor:
      We read the recent article "Incidence and factors predictive of recurrent thrombosis in patients with non-cirrhotic portal vein thrombosis" by Baiges et al. with great interest
      • Baiges A.
      • Procopet B.
      • Silva-Junior G.
      • Llop E.
      • Tellez L.
      • Darnell A.
      • et al.
      Incidence and factors predictive of recurrent thrombosis in patients with non-cirrhotic portal vein thrombosis.
      . This study retrospectively assessed the thrombosis recurrence rate in patients with idiopathic/isolated local factor non-cirrhotic splanchnic vein thrombosis (NC-SVT), and identified risk factors associated with recurrent thrombosis in a subgroup of patients not receiving long-term anticoagulation therapy. The authors found that patients with NC-SVT were at high risk of recurrent thrombosis, with factor VIII (FVIII) >150% identified as a risk factor, providing new insights to guide the clinical management and prognostic analysis of patients with NC-SVT. However, there are some issues in this study that deserve further discussion.
      First, the authors concluded that FVIII was the only risk predictor of recurrent thrombosis using univariate and multifactorial Cox analyses, without considering confounding factors including age, sex, body mass index, and thrombotic extension range. Since these confounding factors can lead to thrombosis in different ways
      • Cannegieter S.C.
      • van Hylckama Vlieg A.
      Venous thrombosis: understanding the paradoxes of recurrence.
      , it would be more accurate to include these confounding factors in univariate and multifactorial Cox to identify risk factors. While related studies have shown that FVIII can predict recurrent thrombosis in a dose-dependent manner and have a high predictive value
      • Timp J.F.
      • Lijfering W.M.
      • Flinterman L.E.
      • van Hylckama Vlieg A.
      • le Cessie S.
      • Rosendaal F.R.
      • et al.
      Predictive value of factor VIII levels for recurrent venous thrombosis: results from the MEGA follow-up study.
      , the cutoff value deserves further discussion. The cutoff value was set at 150% by Baiges et al
      • Baiges A.
      • Procopet B.
      • Silva-Junior G.
      • Llop E.
      • Tellez L.
      • Darnell A.
      • et al.
      Incidence and factors predictive of recurrent thrombosis in patients with non-cirrhotic portal vein thrombosis.
      . Although some studies
      • Saleem T.
      • Burr B.
      • Robinson J.
      • Degelman K.
      • Stokes J.
      • Noel C.
      • et al.
      Elevated plasma factor VIII levels in a mixed patient population on anticoagulation and past venous thrombosis.
      agree with this cutoff value, other studies have used 213% as their cutoff value
      • Nagler M.
      • Van Kuijk S.M.J.
      • Ten Cate H.
      • Prins M.H.
      • Ten Cate-Hoek A.J.
      Predicting Recurrent Venous Thromboembolism in Patients With Deep-Vein Thrombosis: Development and Internal Validation of a Potential New Prediction Model (Continu-8).
      . We suggest that the optimal cutoff value in the study can be determined by the maximum Youden index, and the accuracy of FVIII as a predictive factor for recurrent thrombosis can be evaluated by calculating the area under the receiver operating characteristic curve in both the training and validation cohorts.
      Second, the accuracy of FVIII detection results remains to be confirmed. As the patients included in this study were seen at different centers over a span of multiple years, high requirements are set for sample preservation and measurement standards. The samples were obtained from the local biospecimen bank, and the preservation time and temperature of the samples, as well as the testing time after reincorporation by each laboratory, were not clearly articulated. Moreover, the comparability study of FVIII included data obtained by different measurement systems, with R2 values ranging from 0.798 to 0.925
      • Lee M.Y.
      • Lee W.I.
      • Kang S.Y.
      • Kim M.H.
      • Park Y.S.
      Verification and Comparison of Chromogenic Factor VIII Activity Assays in Patients With Hemophilia Treated With and Without Emicizumab.
      . Therefore, a detailed description of the measurement systems and quality control used for coagulation indicators is necessary for this study, rendering its results referenceable to other researchers.
      Admittedly, long-term follow-up in multiple centers is a difficult and demanding task, and the authors have down an excellent job of it. Patients in the training cohort were observed from 2003 to 2015, with an average follow-up time of 88 months (range 5-156 months), whereas those in the validation cohort were observed after 2015, with an average follow-up time of 66 months (range 2-80 months). This means that patients in the validation cohort had a shorter follow-up time than those in the training cohort. The rate of patients experiencing recurrent thrombosis might have been higher with an equivalent follow-up time. According to the findings of Baiges et al., the thrombosis recurrence rate in patients with NC-SVT who were not receiving long-term anticoagulation therapy was 25% in the training cohort and 27% in the validation cohort
      • Baiges A.
      • Procopet B.
      • Silva-Junior G.
      • Llop E.
      • Tellez L.
      • Darnell A.
      • et al.
      Incidence and factors predictive of recurrent thrombosis in patients with non-cirrhotic portal vein thrombosis.
      . Otero et al. followed patients who had experienced cancer-related thrombosis, and found that the recurrence rate of venous thromboembolism within 6 months after discontinuation of low-molecular-weight heparin was 9.87%
      • Otero R.
      • Solier-López A.
      • Sánchez-López V.
      • Oto J.
      • Arellano E.
      • Marín S.
      • et al.
      Biomarkers of Venous Thromboembolism Recurrence after Discontinuation of Low Molecular Weight Heparin Treatment for Cancer-Associated Thrombosis (HISPALIS-Study).
      . We thus recommend using cumulative recurrence rates spanning different times (6 months, 1 year, and 3+ years), which may be more accurate.
      In conclusion, patients with NC-SVT without thrombophilia are at risk of rethrombosis, and identifying patients at high-risk of rethrombosis is a critical step in precision medicine. FVIII is a predictor of clinical recurrent thrombosis; however, more multicenter, prospective studies are needed to validate its predictive value and determine the optimal cutoff value.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors' contributions

      All authors participated in drafting the manuscript and approved its final form.

      Conflict of interest

      The authors declare no conflicts of interest pertaining to this work. Please refer to the accompanying ICMJE disclosure forms for further details.

      References

        • Baiges A.
        • Procopet B.
        • Silva-Junior G.
        • Llop E.
        • Tellez L.
        • Darnell A.
        • et al.
        Incidence and factors predictive of recurrent thrombosis in patients with non-cirrhotic portal vein thrombosis.
        J Hepatol. 2022;
        • Cannegieter S.C.
        • van Hylckama Vlieg A.
        Venous thrombosis: understanding the paradoxes of recurrence.
        J Thromb Haemost. 2013; 11: 161-169
        • Timp J.F.
        • Lijfering W.M.
        • Flinterman L.E.
        • van Hylckama Vlieg A.
        • le Cessie S.
        • Rosendaal F.R.
        • et al.
        Predictive value of factor VIII levels for recurrent venous thrombosis: results from the MEGA follow-up study.
        J Thromb Haemost. 2015; 13: 1823-1832
        • Saleem T.
        • Burr B.
        • Robinson J.
        • Degelman K.
        • Stokes J.
        • Noel C.
        • et al.
        Elevated plasma factor VIII levels in a mixed patient population on anticoagulation and past venous thrombosis.
        J Vasc Surg Venous Lymphat Disord. 2021; 9: 1119-1127
        • Nagler M.
        • Van Kuijk S.M.J.
        • Ten Cate H.
        • Prins M.H.
        • Ten Cate-Hoek A.J.
        Predicting Recurrent Venous Thromboembolism in Patients With Deep-Vein Thrombosis: Development and Internal Validation of a Potential New Prediction Model (Continu-8).
        Front Cardiovasc Med. 2021; 8655226
        • Lee M.Y.
        • Lee W.I.
        • Kang S.Y.
        • Kim M.H.
        • Park Y.S.
        Verification and Comparison of Chromogenic Factor VIII Activity Assays in Patients With Hemophilia Treated With and Without Emicizumab.
        Ann Lab Med. 2023; 43: 96-99
        • Otero R.
        • Solier-López A.
        • Sánchez-López V.
        • Oto J.
        • Arellano E.
        • Marín S.
        • et al.
        Biomarkers of Venous Thromboembolism Recurrence after Discontinuation of Low Molecular Weight Heparin Treatment for Cancer-Associated Thrombosis (HISPALIS-Study).
        Cancers (Basel). 2022; 14