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Semin Thromb Hemost 2024; 50(01): 096-103
DOI: 10.1055/s-0043-1769013
Review Article

Prevention of Venous Thromboembolism in Medical Patients with Thrombocytopenia or with Platelet Dysfunction: The Last 10 Years

Antonella Tufano
1   Department of Clinical Medicine and Surgery, “Federico II” University of Naples, Via Sergio Pansini, Naples, Italy
,
Benjamin Brenner
2   Department of Hematology and Bone Marrow Transplantation, Haifa, Israel
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Abstract

Current guideline recommendations for primary prophylaxis of venous thromboembolism (VTE) are based on randomized clinical trials that usually exclude subjects at a potentially high risk of bleeding complications. For this reason, no specific guideline is available for thromboprophylaxis in hospitalized patients with thrombocytopenia and/or platelet dysfunction. However, except in patients with absolute contraindications to anticoagulant drugs, antithrombotic prophylaxis should always be considered, for example, in hospitalized cancer patients with thrombocytopenia, especially in those with multiple VTE risk factors. Low platelet number, platelet dysfunction, and clotting abnormalities are also very common in patients with liver cirrhosis, but these patients have a high incidence of portal venous thrombosis, implying that cirrhotic coagulopathy does not fully protect against thrombosis. These patients may benefit from antithrombotic prophylaxis during hospitalization. Patients hospitalized for COVID-19 need prophylaxis, but frequently experience thrombocytopenia or coagulopathy. In patients with antiphospholipid antibodies, a high thrombotic risk is usually present, even in the presence of thrombocytopenia. VTE prophylaxis in high-risk conditions is thus suggested in these patients. At variance with severe thrombocytopenia (< 50,000/mm3), mild/moderate thrombocytopenia (≥ 50,000/mm3) should not interfere with VTE prevention decisions. In patients with severe thrombocytopenia, pharmacological prophylaxis should be considered on an individual basis. Aspirin is not as effective as heparins in lowering the risk of VTE. Studies in patients with ischemic stroke demonstrated that thromboprophylaxis with heparins is safe in these patients also during antiplatelet treatment. The use of direct oral anticoagulants in the prophylaxis of VTE in internal medicine patients has been recently evaluated, but no specific recommendation exists for patients with thrombocytopenia. The need for VTE prophylaxis in patients on chronic treatment with antiplatelet agents should be evaluated after assessing the individual risk of bleeding complications. Finally, the selection of patients who require post-discharge pharmacological prophylaxis remains debated. New molecules currently under development (such as the inhibitors of factor XI) may contribute to improve the risk/benefit ratio of VTE primary prevention in this setting of patients.

Keywords

venous thromboembolism - prophylaxis - thrombocytopenia - low-molecular-weight heparin


Publication History

Article published online:
18 May 2023

© 2023. Thieme. All rights reserved.

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  • References

  • 1 Anderson Jr FA, Wheeler HB, Goldberg RJ. et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151 (05) 933-938
    CrossrefPubMedSearch in Google Scholar
  • 2 Rubinstein I, Murray D, Hoffstein V. Fatal pulmonary emboli in hospitalized patients. An autopsy study. Arch Intern Med 1988; 148 (06) 1425-1426
    CrossrefPubMedSearch in Google Scholar
  • 3 Di Minno G, Mannucci PM, Tufano A. et al; First Ambulatory Screening on Thromboembolism (FAST) Study Group. The first ambulatory screening on thromboembolism: a multicentre, cross-sectional, observational study on risk factors for venous thromboembolism. J Thromb Haemost 2005; 3 (07) 1459-1466
    CrossrefPubMedSearch in Google Scholar
  • 4 Samama MM, Cohen AT, Darmon J-Y. et al. A comparison of enoxaparin with placebo for the prevention of VTE in acutely ill medical patients. Prophylaxis in Medical Patients Study Group. N Engl J Med 1999; 341 (11) 793-800
    CrossrefPubMedSearch in Google Scholar
  • 5 Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Vaitkus PT, Goldhaber SZ. PREVENT Medical Thromboprophylaxis Study Group. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 2004; 110 (07) 874-879
    CrossrefPubMedSearch in Google Scholar
  • 6 Cohen AT, Davidson BL, Gallus AS. et al; ARTEMIS Investigators. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006; 332 (7537): 325-329
    CrossrefPubMedSearch in Google Scholar
  • 7 Geerts WH, Bergkvist D, Pineo GF. et al. Prevention of venous thromboembolism: ACCP evidence-based clinical practice guidelines (8th edition). Chest 2008; 133 (06) 381S-453S
    CrossrefPubMedSearch in Google Scholar
  • 8 Tapson VF, Decousus H, Pini M. et al; IMPROVE Investigators. Venous thromboembolism prophylaxis in acutely ill hospitalized medical patients: findings from the International Medical Prevention Registry on Venous Thromboembolism. Chest 2007; 132 (03) 936-945
    CrossrefPubMedSearch in Google Scholar
  • 9 Monreal M, Kakkar AK, Caprini JA. et al; RIETE Investigators. The outcome after treatment of venous thromboembolism is different in surgical and acutely ill medical patients: findings from the RIETE Registry. J Thromb Haemost 2004; 2 (11) 1892-1898
    CrossrefPubMedSearch in Google Scholar
  • 10 Cohen AT, Tapson VF, Bergmann JF. et al; ENDORSE Investigators. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet 2008; 371 (9610): 387-394
    CrossrefPubMedSearch in Google Scholar
  • 11 Forgo G, Micieli E, Ageno W. et al. An update on the global use of risk assessment models and thromboprophylaxis in hospitalized patients with medical illnesses from the World Thrombosis Day Steering Committee: systematic review and meta-analysis. J Thromb Haemost 2022; 20 (02) 409-421
    CrossrefPubMedSearch in Google Scholar
  • 12 Lippi G, Favaloro EJ, Cervellin G. Prevention of venous thromboembolism: focus on mechanical prophylaxis. Semin Thromb Hemost 2011; 37 (03) 237-251
    Thieme ConnectPubMedSearch in Google Scholar
  • 13 Santagata D, Cammà G, Donadini MP, Squizzato A, Ageno W. Current and emerging drug strategies for the prevention of venous thromboembolism in acutely ill medical inpatients. Expert Opin Pharmacother 2022; 23 (14) 1651-1665
    CrossrefPubMedSearch in Google Scholar
  • 14 Barbar S, Noventa F, Rossetto V. et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. J Thromb Haemost 2010; 8 (11) 2450-2457
    CrossrefPubMedSearch in Google Scholar
  • 15 Prandoni P, Samama MM. Risk stratification and venous thromboprophylaxis in hospitalized medical and cancer patients. Br J Haematol 2008; 141 (05) 587-597
    CrossrefPubMedSearch in Google Scholar
  • 16 Maynard GA, Morris TA, Jenkins IH. et al. Optimizing prevention of hospital-acquired venous thromboembolism (VTE): prospective validation of a VTE risk assessment model. J Hosp Med 2010; 5 (01) 10-18
    CrossrefPubMedSearch in Google Scholar
  • 17 Tufano A, Di Minno G. Prophylaxis of venous thromboembolism in internal medicine units: the RAMs issue. Intern Emerg Med 2018; 13 (04) 463-465
    CrossrefPubMedSearch in Google Scholar
  • 18 Tufano A, Guida A, Di Minno MN, Prisco D, Cerbone AM, Di Minno G. Prevention of venous thromboembolism in medical patients with thrombocytopenia or with platelet dysfunction: a review of the literature. Semin Thromb Hemost 2011; 37 (03) 267-274
    Thieme ConnectPubMedSearch in Google Scholar
  • 19 Prisco D, Tufano A, Cenci C. et al. Position paper of the Italian Society of Internal Medicine (SIMI) on prophylaxis and treatment of venous thromboembolism in patients with cancer. Intern Emerg Med 2019; 14 (01) 21-38
    CrossrefPubMedSearch in Google Scholar
  • 20 Farge D, Frere C, Connors JM. et al; International Initiative on Thrombosis and Cancer (ITAC) Advisory Panel. 2022 International Clinical Practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer, including patients with COVID-19. Lancet Oncol 2022; 23 (07) e334-e347
    CrossrefPubMedSearch in Google Scholar
  • 21 Farge D, Frere C, Connors JM. et al; International Initiative on Thrombosis and Cancer (ITAC) Advisory Panel. 2019 International Clinical Practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol 2019; 20 (10) e566-e581
    CrossrefPubMedSearch in Google Scholar
  • 22 Falanga A, Ay C, Di Nisio M. et al; ESMO Guidelines Committee. Electronic Address: clinicalguidelines@esmo.org. Venous thromboembolism in cancer patients: ESMO Clinical Practice Guideline. Ann Oncol 2023; S0923-7534 (22)04786-X
    PubMedSearch in Google Scholar
  • 23 Zwicker JI, Roopkumar J, Puligandla M. et al. Dose-adjusted enoxaparin thromboprophylaxis in hospitalized cancer patients: a randomized, double-blinded multicenter phase 2 trial. Blood Adv 2020; 4 (10) 2254-2260
    CrossrefPubMedSearch in Google Scholar
  • 24 Patell R, Rybicki L, McCrae KR, Khorana AA. Predicting risk of venous thromboembolism in hospitalized cancer patients: utility of a risk assessment tool. Am J Hematol 2017; 92 (06) 501-507
    CrossrefPubMedSearch in Google Scholar
  • 25 Hull RD, Schellong SM, Tapson VF. et al; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients with Prolonged Immobilization) Study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med 2010; 153 (01) 8-18
    CrossrefPubMedSearch in Google Scholar
  • 26 Goldhaber SZ, Leizorovicz A, Kakkar AK. et al; ADOPT Trial Investigators. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med 2011; 365 (23) 2167-2177
    CrossrefPubMedSearch in Google Scholar
  • 27 Cohen AT, Spiro TE, Büller HR. et al; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013; 368 (06) 513-523
    CrossrefPubMedSearch in Google Scholar
  • 28 Di Nisio M, Carrier M, Lyman GH, Khorana AA. Subcommittee on Haemostasis and Malignancy. Prevention of venous thromboembolism in hospitalized medical cancer patients: guidance from the SSC of the ISTH. J Thromb Haemost 2014; 12 (10) 1746-1749
    CrossrefPubMedSearch in Google Scholar
  • 29 Roberts LN, Hernandez-Gea V, Magnusson M. et al. Thromboprophylaxis for venous thromboembolism prevention in hospitalized patients with cirrhosis: guidance from the SSC of the ISTH. J Thromb Haemost 2022; 20 (10) 2237-2245
    CrossrefPubMedSearch in Google Scholar
  • 30 Afdhal N, McHutchison J, Brown R. et al. Thrombocytopenia associated with chronic liver disease. J Hepatol 2008; 48 (06) 1000-1007
    CrossrefPubMedSearch in Google Scholar
  • 31 Lisman T, Hernandez-Gea V, Magnusson M. et al. The concept of rebalanced hemostasis in patients with liver disease: communication from the ISTH SSC working group on hemostatic management of patients with liver disease. J Thromb Haemost 2021; 19 (04) 1116-1122
    CrossrefPubMedSearch in Google Scholar
  • 32 Northup PG, Caldwell SH. New concepts of coagulation and bleeding in liver disease. Intern Emerg Med 2010; 5 (01) 3-6
    CrossrefPubMedSearch in Google Scholar
  • 33 Tripodi A, Primignani M, Mannucci PM. Abnormalities of hemostasis and bleeding in chronic liver disease: the paradigm is challenged. Intern Emerg Med 2010; 5 (01) 7-12
    CrossrefPubMedSearch in Google Scholar
  • 34 Northup PG, McMahon MM, Ruhl AP. et al. Coagulopathy does not fully protect hospitalized cirrhosis patients from peripheral venous thromboembolism. Am J Gastroenterol 2006; 101 (07) 1524-1528 , quiz 1680
    CrossrefPubMedSearch in Google Scholar
  • 35 La Mura V, Bitto N, Tripodi A. Rational hemostatic management in cirrhosis: from old paradigms to new clinical challenges. Expert Rev Hematol 2022; 15 (12) 1031-1044
    CrossrefPubMedSearch in Google Scholar
  • 36 Tripodi A, Primignani M, Mannucci PM, Caldwell SH. Changing concepts of cirrhotic coagulopathy. Am J Gastroenterol 2017; 112 (02) 274-281
    CrossrefPubMedSearch in Google Scholar
  • 37 Ambrosino P, Tarantino L, Di Minno G. et al. The risk of venous thromboembolism in patients with cirrhosis. A systematic review and meta-analysis. Thromb Haemost 2017; 117 (01) 139-148
    Thieme ConnectPubMedSearch in Google Scholar
  • 38 Roberts LN, Lisman T, Stanworth S. et al. Periprocedural management of abnormal coagulation parameters and thrombocytopenia in patients with cirrhosis: guidance from the SSC of the ISTH. J Thromb Haemost 2022; 20 (01) 39-47
    CrossrefPubMedSearch in Google Scholar
  • 39 Campello E, Zanetto A, Bulato C. et al. Coagulopathy is not predictive of bleeding in patients with acute decompensation of cirrhosis and acute-on-chronic liver failure. Liver Int 2021; 41 (10) 2455-2466
    CrossrefPubMedSearch in Google Scholar
  • 40 Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020; 18 (04) 844-847
    CrossrefPubMedSearch in Google Scholar
  • 41 Wu C, Chen X, Cai Y. et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020; 180 (07) 934-943
    CrossrefPubMedSearch in Google Scholar
  • 42 Marietta M, Coluccio V, Luppi M. COVID-19, coagulopathy and venous thromboembolism: more questions than answers. Intern Emerg Med 2020; 15 (08) 1375-1387
    CrossrefPubMedSearch in Google Scholar
  • 43 Rahi MS, Jindal V, Reyes SP, Gunasekaran K, Gupta R, Jaiyesimi I. Hematologic disorders associated with COVID-19: a review. Ann Hematol 2021; 100 (02) 309-320
    CrossrefPubMedSearch in Google Scholar
  • 44 Kyriakoulis KG, Dimakakos E, Kyriakoulis IG. et al; COVID-19 Thrombosis Collaborative Group, Endorsed by VAS-European Independent Foundation in Angiology/Vascular Medicine, UEMS Division of Angiology/Vascular Medicine/and ESVM-European Society of Vascular Medicine and Supported by the Balkan Working Group. Practical recommendations for optimal thromboprophylaxis in patients with COVID-19: a consensus statement based on available clinical trials. J Clin Med 2022; 11 (20) 5997
    CrossrefPubMedSearch in Google Scholar
  • 45 Schulman S, Sholzberg M, Spyropoulos AC. et al; International Society on Thrombosis and Haemostasis. ISTH guidelines for antithrombotic treatment in COVID-19. J Thromb Haemost 2022; 20 (10) 2214-2225
    CrossrefPubMedSearch in Google Scholar
  • 46 Coccheri S. A re-appraisal of thrombogenesis in COVID-19, seen as a multiple complex system. Bleeding. Thrombosis and Vascular Biology 2022; 1: 48
    PubMedSearch in Google Scholar
  • 47 Thomas MR, Scully M. Clinical features of thrombosis and bleeding in COVID-19. Blood 2022; 140 (03) 184-195
    CrossrefPubMedSearch in Google Scholar
  • 48 Iba T, Levy JH. Thrombosis and thrombocytopenia in COVID-19 and after COVID-19 vaccination. Trends Cardiovasc Med 2022; 32 (05) 249-256
    CrossrefPubMedSearch in Google Scholar
  • 49 Yang X, Yang Q, Wang Y. et al. Thrombocytopenia and its association with mortality in patients with COVID-19. J Thromb Haemost 2020; 18 (06) 1469-1472
    CrossrefPubMedSearch in Google Scholar
  • 50 Spyropoulos AC. To prophylax or not, and how much and how long? Controversies in VTE prevention for medical inpatients, including COVID-19 inpatients. Hematology (Am Soc Hematol Educ Program) 2022; 2022 (01) 506-514
    CrossrefPubMedSearch in Google Scholar
  • 51 Spyropoulos AC, Cohen SL, Gianos E. et al; COVID-19 Consortium Group. Validation of the IMPROVE-DD risk assessment model for venous thromboembolism among hospitalized patients with COVID-19. Res Pract Thromb Haemost 2021; 5 (02) 296-300
    CrossrefPubMedSearch in Google Scholar
  • 52 Goldin M, Lin SK, Kohn N. et al. External validation of the IMPROVE-DD risk assessment model for venous thromboembolism among inpatients with COVID-19. J Thromb Thrombolysis 2021; 52 (04) 1032-1035
    CrossrefPubMedSearch in Google Scholar
  • 53 Ramacciotti E, Barile Agati L, Calderaro D. et al; MICHELLE Investigators. Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre, randomised, controlled trial. Lancet 2022; 399 (10319): 50-59
    CrossrefPubMedSearch in Google Scholar
  • 54 Lim W. Antiphospholipid syndrome. Hematology (Am Soc Hematol Educ Program) 2013; 2013: 675-680
    CrossrefPubMedSearch in Google Scholar
  • 55 Miyakis S, Lockshin MD, Atsumi T. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4 (02) 295-306
    CrossrefPubMedSearch in Google Scholar
  • 56 El Hasbani G, Saliba AN, Uthman I, Taher AT. Hematological manifestations of antiphospholipid syndrome: going beyond thrombosis. Blood Rev 2023; 58: 101015
    CrossrefPubMedSearch in Google Scholar
  • 57 Breen KA, Sanchez K, Kirkman N. et al. Endothelial and platelet microparticles in patients with antiphospholipid antibodies. Thromb Res 2015; 135 (02) 368-374
    CrossrefPubMedSearch in Google Scholar
  • 58 Proulle V, Furie RA, Merrill-Skoloff G, Furie BC, Furie B. Platelets are required for enhanced activation of the endothelium and fibrinogen in a mouse thrombosis model of APS. Blood 2014; 124 (04) 611-622
    CrossrefPubMedSearch in Google Scholar
  • 59 Cikrikcioglu MA, Hursitoglu M, Erkal H. et al. Splenomegaly in primary antiphospholipid syndrome without accompanying portal hypertension or comorbidity. Pathophysiol Haemost Thromb 2010; 37 (2-4): 104-109
    CrossrefPubMedSearch in Google Scholar
  • 60 Avcin T, Jazbec J, Kuhar M, Zupancic M, Rozman B. Evans syndrome associated with antiphospholipid antibodies. J Pediatr Hematol Oncol 2003; 25 (09) 755-756
    CrossrefPubMedSearch in Google Scholar
  • 61 Tektonidou MG, Andreoli L, Limper M. et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis 2019; 78 (10) 1296-1304
    CrossrefPubMedSearch in Google Scholar
  • 62 Cohen H, Cuadrado MJ, Erkan D. et al. 16th International Congress on Antiphospholipid Antibodies Task Force Report on antiphospholipid syndrome treatment trends. Lupus 2020; 29 (12) 1571-1593
    CrossrefPubMedSearch in Google Scholar
  • 63 Xourgia E, Tektonidou MG. An update on antiphospholipid syndrome. Curr Rheumatol Rep 2022; 23 (12) 84
    CrossrefPubMedSearch in Google Scholar
  • 64 Collet JP, Thiele H, Barbato E. et al; ESC Scientific Document Group. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Rev Esp Cardiol (Engl Ed) 2021; 74 (06) 544
    PubMedSearch in Google Scholar
  • 65 Kebede S, Prakasa KR, Shermock K. et al. A systematic review of venous thromboembolism prophylaxis strategies in patients with renal insufficiency, obesity, or on antiplatelet agents. J Hosp Med 2013; 8 (07) 394-401
    CrossrefPubMedSearch in Google Scholar
  • 66 Field TS, Hill MD. Prevention of deep vein thrombosis and pulmonary embolism in patients with stroke. Clin Appl Thromb Hemost 2012; 18 (01) 5-19
    CrossrefPubMedSearch in Google Scholar
  • 67 Landi G, D'Angelo A, Boccardi E. et al. Venous thromboembolism in acute stroke. Prognostic importance of hypercoagulability. Arch Neurol 1992; 49 (03) 279-283
    CrossrefPubMedSearch in Google Scholar
  • 68 Sherman DG, Albers GW, Bladin C. et al; PREVAIL Investigators. The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): an open-label randomised comparison. Lancet 2007; 369 (9570): 1347-1355
    CrossrefPubMedSearch in Google Scholar
  • 69 Sandercock PAG, Counsell C, Kamal AK. Anticoagulants for acute ischaemic stroke. Cochrane Database Syst Rev 2008; 4 (04) CD000024
    PubMedSearch in Google Scholar
  • 70 De Caterina R, Prisco D, Eikelboom JW. Factor XI inhibitors: cardiovascular perspectives. Eur Heart J 2023; 44 (04) 280-292
    CrossrefPubMedSearch in Google Scholar
  • 71 Poenou G, Dumitru Dumitru T, Lafaie L, Mismetti V, Heestermans M, Bertoletti L. Factor XI inhibition for the prevention of venous thromboembolism: an update on current evidence and future perspectives. Vasc Health Risk Manag 2022; 18: 359-373
    CrossrefPubMedSearch in Google Scholar
  • 72 Nopp S, Kraemmer D, Ay C, Factor XI. Factor XI inhibitors for prevention and treatment of venous thromboembolism: a review on the rationale and update on current evidence. Front Cardiovasc Med 2022; 9: 903029
    CrossrefPubMedSearch in Google Scholar