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Venous Thromboembolism in Patients with Primary Bone or Soft-Tissue Sarcomas
Sheryl Y. Mitchell, BSc1; Elizabeth A. Lingard, MPH1; Patrick Kesteven, MB, FRACP1; Andrew W. McCaskie, MB, FRCS(Tr&Orth)2; Craig H. Gerrand, MB ChB, FRCSEd(Tr&Orth)2
1 Departments of Orthopaedics (S.Y.M. and C.H.G.) and Haematology (P.K.), Freeman Hospital, Newcastle Upon Tyne, NE7 7DN, England. E-mail address for S.Y. Mitchell: sheryl.Mitchell@nuth.northy.nhs.uk
2 School of Surgery and Reproductive Sciences, The Medical School, University of Newcastle, Framlington Place, Newcastle Upon Tyne, NE2 4HH, England
View Disclosures and Other Information
Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from an unrestricted educational grant from Sanofi-Synthélabo for a research nurse salary. In addition, one or more of the authors or a member of his or her immediate family received, in any one year, payments or other benefits of less than $10,000 or a commitment or agreement to provide such benefits from a commercial entity (Leo Pharma). No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.
Investigation performed at the Department of Orthopaedics, Freeman Hospital, Newcastle Upon Tyne, England

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2007 Nov 01;89(11):2433-2439. doi: 10.2106/JBJS.F.01308
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Abstract

Background: Venous thromboembolism has been independently associated with both malignant disease and orthopaedic surgery. Patients with bone or soft-tissue tumors who undergo orthopaedic surgery may therefore be at high risk for thromboembolic events. The purpose of the present retrospective study was to determine the rate of clinically detected deep venous thrombosis and pulmonary embolism in patients with trunk or extremity bone or soft-tissue sarcomas.

Methods: The medical records of patients with a confirmed diagnosis of primary bone or soft-tissue sarcoma who had presented to our unit between 1998 and 2003 were reviewed with use of a standardized chart abstraction tool. The data that were retrieved included patient-related data (demographic characteristics, diagnoses, and surgical interventions), the use of adjuvant chemotherapy or radiation therapy, additional risk factors for thromboembolism, the use of thromboembolic prophylaxis, and confirmed thromboembolic events.

Results: Of the 252 patients who were identified, ninety-four had a diagnosis of primary bone sarcoma and 158 had a diagnosis of primary soft-tissue sarcoma. Approximately 70% of the cohort received thromboprophylaxis, with 57% receiving low-molecular-weight heparin. Thirty-seven patients were clinically suspected of having a deep venous thrombosis. Nine patients had a deep venous thrombosis that was confirmed radiographically, and in one case the diagnosis was made at another center, resulting in a rate of clinically evident deep venous thrombosis of 4%. Nine patients had a clinically suspected pulmonary embolism. One patient had confirmation of the pulmonary embolism with use of a ventilation-perfusion scan, one patient died of pulmonary embolism, and one patient had diagnosis of the pulmonary embolism at another center, resulting in an overall rate of pulmonary embolism of 1.2% and a rate of fatal pulmonary embolism of 0.4%. All patients with thromboembolic events had a tumor involving the hip or thigh, with the majority of the events occurring prior to definitive surgery.

Conclusions: The risk of a clinically apparent thromboembolic event in patients with bone or soft-tissue sarcomas is comparable with that in other orthopaedic patients. However, tumors in the hip or thigh may be associated with a particularly high risk of thromboembolism. A prospective study is needed to investigate factors that are predictive of thromboembolism and the role of chemical thromboprophylaxis.

Level of Evidence: Prognostic Level IV. See Instructions to Authors for a complete description of levels of evidence.

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    Accreditation Statement
    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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    Benedict A Rogers, MA, MSc. MRCGP, MRCS
    Posted on November 16, 2007
    Venous Thromboembolism in Patients with Primary Bone or Soft –Tissue Sarcomas
    St Peter's Hospital, Chertsey, UK

    To The Editor:

    I read with interest the Nov 2007 paper by Mitchell et al.(1) and would like to make the following points:

    The second paragraph of the introduction quotes numerous published guidelines relating to thromboprophylaxis. A recent audit we have carried out (Rogers et al. unpublished data) has shown poor awareness and application of all guidelines in the UK. To date, no concensus has been achieved for the most appropriate method of thromboprophylaxis in joint arthroplasty surgery, let alone sarcoma surgery. One of the reasons we believe this is the case is the plethora of current guidelines including those of the the British Orthopaedic Association, the National Institute of Clinical Excellence(2) and the British Haematological Society(3).

    The study rightly highlights the significant mortality and morbidity that is associated with venous thromboembolism. However, there are also significant risks associated with chemoprophylaxis using low molecular weight heparin particularly bleeding(2,4-7) (intrahepatic, intracranial and intraabdominal) and heparin induced thrombocytopenia (8-9). This is in addition to bleeding associated with soft tissue tumours and any possible related surgery.

    The results show that the thirteen patients who developed venous thromboembolism had taken low-molecular weight heparin for a variable period of time (0 – 21 days), a shorter period of time than suggested for abdominal and pelvis cancer patients receiving enoxaparin (10). Future studies will need to evaluate the optimal duration of chemoprophlaxis in relation to the venous thromboembolism risk highest.

    Since low molecular weight can be safely administered in a primary care setting(11), do the authors feel this would be suitable for the sarcoma patient cohort and, if so, who should monitor its use?

    We agree with the final conclusion of this study that a further evaluation of the risk factors for thromboembolism in this patient group would be beneficial. However, there are numerous confounding factors inherent in these patients that can all influence the coagulation:

    1. Patient factors: age, weight, co-morbidity

    2. Tumour factors: location, histological type, grade, size

    3. Treatment factors: adjuvant chemo- and radio –therapy

    Any future study would need to include a large patient cohort in order to adjust for these confounding factors.

    The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

    References:

    1. Mitchell,S.Y., Lingard,E.A., Kesteven,P., McCaskie,A.W., and Gerrand,C.H.: Venous thromboembolism in patients with primary bone or soft -tissue sarcomas. J Bone Joint Surg Am, 89:2433-2439, 2007.

    2. Venous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery. National Institute of Clinical Excellence . 2007. 14-11-2007. Ref Type: Internet Communication

    3. Baglin,T., Barrowcliffe,T.W., Cohen,A., and Greaves,M.: Guidelines on the use and monitoring of heparin. Br J Haematol, 133:19-34, 2006.

    4. Dickinson,L.D., Miller,L.D., Patel,C.P., and Gupta,S.K.: Enoxaparin increases the incidence of postoperative intracranial hemorrhage when initiated preoperatively for deep venous thrombosis prophylaxis in patients with brain tumors. Neurosurgery, 43:1074-1081, 1998.

    5. Houde,J.P. and Steinberg,G.: Intrahepatic hemorrhage after use of low-molecular-weight heparin for total hip arthroplasty. J Arthroplasty, 14:372-374, 1999.

    6. Shaieb,M.D., Watson,B.N., and Atkinson,R.E.: Bleeding complications with enoxaparin for deep venous thrombosis prophylaxis. J Arthroplasty, 14:432-438, 1999.

    7. Lilikakis,A.K., Papapolychroniou,T., Macheras,G., and Michelinakis,E.: Thrombocytopenia and intra-cerebral complications associated with low-molecular-weight heparin treatment in patients undergoing total hip replacement. A report of two cases. J Bone Joint Surg Am, 88:634-638, 2006.

    8. Chong,B.H.: Heparin-induced thrombocytopenia. Br J Haematol, 89:431-439, 1995.

    9. King,D.J. and Kelton,J.G.: Heparin-associated thrombocytopenia. Ann Intern Med, 100:535-540, 1984.

    10. Bergqvist,D., Agnelli,G., Cohen,A.T., Eldor,A., Nilsson,P.E., Le Moigne-Amrani,A., and etrich-Neto,F.: Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med, 346:975-980, 2002.

    11. Imberti,D., Ageno,W., Dentali,F., Giorgi,P.M., Croci,E., and Garcia,D.: Management of primary care patients with suspected deep vein thrombosis: use of a therapeutic dose of low-molecular-weight heparin to avoid urgent ultrasonographic evaluation. J Thromb Haemost, 4:1037-1041, 2006.

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