Advertisement
Clinical Research Study| Volume 131, ISSUE 8, P972.e1-972.e7, August 2018

Association of Anemia with Venous Thromboembolism in Acutely Ill Hospitalized Patients: An APEX Trial Substudy

      Abstract

      Background

      Anemia is a common finding and independent predictor for adverse outcomes in hospitalized patients with medical illness. It remains unclear whether anemia is a risk factor for venous thromboembolism and whether the presence of anemia can refine risk assessment for prediction of venous thromboembolism, thereby adding incremental utility to a validated model.

      Methods

      In the Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban trial (APEX), 7513 hospitalized medical patients were randomized to receive either betrixaban or standard-of-care enoxaparin for thromboprophylaxis. Baseline hemoglobin concentrations were obtained in 6861 patients, with a follow-up of 77 days. Symptomatic venous thromboembolism events, including symptomatic deep vein thrombosis, pulmonary embolism, and venous thromboembolism–related mortality, were compared between low-hemoglobin and normal-hemoglobin groups (normal range: 12.5-17.0 g/dL for males and 11.0-15.5 g/dL for females). The relationship between anemia and venous thromboembolism events was assessed by fitting a univariable and multivariable logistic regression model composed of thromboprophylaxis and risk factors. Venous thromboembolism risk refinement by hemoglobin measurement was evaluated in the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) risk assessment model.

      Results

      Low hemoglobin at baseline was associated with a greater risk of symptomatic venous thromboembolism (relative risk [RR] 1.94 [95% confidence interval, 1.27-2.98]; P = .002), symptomatic deep vein thrombosis (RR 2.29 [1.12-4.68]; P = .019), and nonfatal pulmonary embolism (RR 2.63 [1.22-5.65]; P = .010) but not venous thromboembolism–related mortality (RR 1.47 [0.71-3.04]; P = .30). After adjusting for thromboprophylaxis, history of previous venous thromboembolism, intensive or coronary unit admission, and D-dimer, low hemoglobin (as a categorical or continuous variable) remained associated with an increased likelihood of venous thromboembolism (adjusted odds ratio 1.71 [95% confidence interval, 1.09-2.69]; P = .020). Low hemoglobin also improved risk discrimination and reclassification after inclusion in the IMPROVE model.

      Conclusions

      Anemia was independently associated with a greater risk of symptomatic venous thromboembolism among acutely ill medical patients despite the provision of thromboprophylaxis. Hemoglobin measurement also improved risk stratification by the IMPROVE venous thromboembolism risk score.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The American Journal of Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Guralnik J.M.
        • Ershler W.B.
        • Schrier S.L.
        • Picozzi V.J.
        Anemia in the elderly: a public health crisis in hematology.
        Hematology Am Soc Hematol Educ Program. 2005; : 528-532
        • Woodman R.
        • Ferrucci L.
        • Guralnik J.
        Anemia in older adults.
        Curr Opin Hematol. 2005; 12: 123-128
        • Kikuchi M.
        • Inagaki T.
        • Shinagawa N.
        Five-year survival of older people with anemia: variation with hemoglobin concentration.
        J Am Geriatr Soc. 2001; 49: 1226-1228
        • Penninx B.W.
        • Pahor M.
        • Woodman R.C.
        • Guralnik J.M.
        Anemia in old age is associated with increased mortality and hospitalization.
        J Gerontol A Biol Sci Med Sci. 2006; 61: 474-479
        • Cohen A.T.
        • Harrington R.
        • Goldhaber S.Z.
        • et al.
        The design and rationale for the Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban (APEX) study.
        Am Heart J. 2014; 167: 335-341
        • Spyropoulos A.C.
        • Anderson Jr, F.A.
        • FitzGerald G.
        • et al.
        Predictive and associative models to identify hospitalized medical patients at risk for VTE.
        Chest. 2011; 140: 706-714
        • Tapson V.F.
        • Decousus H.
        • Pini M.
        • et al.
        Venous thromboembolism prophylaxis in acutely ill hospitalized medical patients: findings from the International Medical Prevention Registry on Venous Thromboembolism.
        Chest. 2007; 132: 936-945
        • Gibson C.M.
        • Spyropoulos A.C.
        • Cohen A.T.
        • et al.
        The IMPROVEDD VTE risk score: incorporation of D-dimer into the IMPROVE score to improve venous thromboembolism risk stratification.
        TH Open. 2017; 1: e56-e65
        • Cleveland W.S.
        • Devlin S.J.
        Locally weighted regression: an approach to regression analysis by local fitting.
        J Am Stat Assoc. 1988; 83: 596-610
        • Pencina M.J.
        • D'Agostino Sr, R.B.
        • D'Agostino Jr, R.B.
        • Vasan R.S.
        Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond.
        Stat Med. 2008; 27 (discussion 207-212): 157-172
        • Spyropoulos A.C.
        • Raskob G.E.
        New paradigms in venous thromboprophylaxis of medically ill patients.
        Thromb Haemost. 2017; 117: 1662-1670
        • Coutinho J.M.
        • Zuurbier S.M.
        • Gaartman A.E.
        • et al.
        Association between anemia and cerebral venous thrombosis: case-control study.
        Stroke. 2015; 46: 2735-2740
        • Stolz E.
        • Valdueza J.M.
        • Grebe M.
        • et al.
        Anemia as a risk factor for cerebral venous thrombosis? An old hypothesis revisited. Results of a prospective study.
        J Neurol. 2007; 254: 729-734
        • Kunadian V.
        • Mehran R.
        • Lincoff A.M.
        • et al.
        Effect of anemia on frequency of short- and long-term clinical events in acute coronary syndromes (from the Acute Catheterization and Urgent Intervention Triage Strategy Trial).
        Am J Cardiol. 2014; 114: 1823-1829
        • Westenbrink B.D.
        • Alings M.
        • Connolly S.J.
        • et al.
        Anemia predicts thromboembolic events, bleeding complications and mortality in patients with atrial fibrillation: insights from the RE-LY trial.
        J Thromb Haemost. 2015; 13: 699-707
        • Sabatine M.S.
        • Morrow D.A.
        • Giugliano R.P.
        • et al.
        Association of hemoglobin levels with clinical outcomes in acute coronary syndromes.
        Circulation. 2005; 111: 2042-2049
        • Brener S.J.
        • Mehran R.
        • Dangas G.D.
        • et al.
        Relation of baseline hemoglobin levels and adverse events in patients with acute coronary syndromes (from the acute catheterization and urgent intervention triage strategy and harmonizing outcomes with revascularization and stents in acute myocardial infarction trials).
        Am J Cardiol. 2017; 119: 1710-1716
        • Cantu C.
        • Alonso E.
        • Jara A.
        • et al.
        Hyperhomocysteinemia, low folate and vitamin B12 concentrations, and methylene tetrahydrofolate reductase mutation in cerebral venous thrombosis.
        Stroke. 2004; 35: 1790-1794
        • Hung S.H.
        • Lin H.C.
        • Chung S.D.
        Association between venous thromboembolism and iron-deficiency anemia: a population-based study.
        Blood Coagul Fibrinolysis. 2015; 26: 368-372
        • Franceschi C.
        • Campisi J.
        Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases.
        J Gerontol A Biol Sci Med Sci. 2014; 69: S4-S9
        • Kulnigg-Dabsch S.
        • Evstatiev R.
        • Dejaco C.
        • Gasche C.
        Effect of iron therapy on platelet counts in patients with inflammatory bowel disease-associated anemia.
        PLoS ONE. 2012; 7 (e34520)
        • Wallaert J.B.
        • De Martino R.R.
        • Marsicovetere P.S.
        • et al.
        Venous thromboembolism after surgery for inflammatory bowel disease: are there modifiable risk factors? Data from ACS NSQIP.
        Dis Colon Rectum. 2012; 55: 1138-1144
        • Khorana A.A.
        • Kuderer N.M.
        • Culakova E.
        • Lyman G.H.
        • Francis C.W.
        Development and validation of a predictive model for chemotherapy-associated thrombosis.
        Blood. 2008; 111: 4902-4907
        • Henry D.H.
        • Dahl N.V.
        • Auerbach M.A.
        Thrombocytosis and venous thromboembolism in cancer patients with chemotherapy induced anemia may be related to ESA induced iron restricted erythropoiesis and reversed by administration of IV iron.
        Am J Hematol. 2012; 87: 308-310
        • Solovey A.
        • Lin Y.
        • Browne P.
        • Choong S.
        • Wayner E.
        • Hebbel R.P.
        Circulating activated endothelial cells in sickle cell anemia.
        N Engl J Med. 1997; 337: 1584-1590
        • Hebbel R.P.
        Ischemia-reperfusion injury in sickle cell anemia: relationship to acute chest syndrome, endothelial dysfunction, arterial vasculopathy, and inflammatory pain.
        Hematol Oncol Clin North Am. 2014; 28: 181-198
        • Yildiz A.
        • Oflaz H.
        • Pusuroglu H.
        • et al.
        Left ventricular hypertrophy and endothelial dysfunction in chronic hemodialysis patients.
        Am J Kidney Dis. 2003; 41: 616-623
        • Vannucchi A.M.
        • Barbui T.
        Thrombocytosis and thrombosis.
        Hematology Am Soc Hematol Educ Program. 2007; : 363-370