A. Markel

Prevention and Treatment of Venous Thromboembolism International Consensus Statement (Guidelines according to scientific evidence)

All patients at moderate to high risk for the development of venous thrombo- embolism should receive prophylaxis. The approaches of proven value include low-dose heparin, low molecular weight heparin, oral anticoagulants and intermittent pneumatic compression.

Diagnosis and Anticoagulant Treatment

2012;97(1):95-100. 64. Brill-Edwards P, Ginsberg JS, Gent M, et al. Safety of withholding heparin in pregnant women with a history of venous thromboembolism. Recurrence of clot in this pregnancy study group. N Engl J Med. 2000;343(20):1439-1444. 65. De Stefano V, Martinelli I, Rossi E, et al. The risk of recurrent venous thromboembolism in pregnancy and puerperium without antithrombotic prophylaxis. Br J Haematol. 2006;135(3):386-391. 66. White RH, Chan WS, Zhou H, Ginsberg JS. Recurrent venous thromboembolism after pregnancy-associated versus unprovoked thromboembolism. Thromb Haemost. 2008;100(2):246-252. 67. Pabinger I, Schneider B. Thrombotic risk in hereditary antithrombin III, protein C, or protein S deficiency. A cooperative, retrospective study. Gesellschaft fur Thromboseund Hamostaseforschung (GTH) Study Group on Natural Inhibitors. Arterioscler Thromb Vasc Biol. 1996;16(6):742-748. 68. Conard J, Horellou MH, Van Dreden P, Lecompte T, Samama M. Thrombosis and pregnancy in congenital deficiencies in AT III, protein C or protein S: study of 78 women. Thromb Haemost. 1990;63(2):319-320. 69. McColl MD, Ramsay JE, Tait RC, et al. Risk factors for pregnancy associated venous thromboembolism. Thromb Haemost. 1997;78(4):1183-1188. 70. Robertson L, Wu O, Langhorne P, et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol. 2006;132(2):171-196. 71. Serour GI, Aboulghar M, Mansour R, Sattar MA, Amin Y, Aboulghar H. Complications of medically assisted conception in 3,500 cycles. Fertil Steril. 1998;70(4):638-642. 72. Mara M, Koryntova D, Rezabek K, et al. Thromboembolic complications in patients undergoing in vitro fertilization: retrospective clinical study. Ceska Gynekol. 2004;69(4):312-316. 73. Chan WS, Dixon ME. The ‘‘ART’’ of thromboembolism: a review of assisted reproductive technology and thromboembolic complications. Thromb Res. 2008;121(6):713-726. 74. Di Nisio M, Rutjes AW, Ferrante N, Tiboni GM, Cuccurullo F, Porreca E. Thrombophilia and outcomes of assisted reproduction technologies: a systematic review and meta-analysis. Blood. 2011;118(10):2670-2678. 75. Nelson-Piercy C, Powrie R, Borg JY, et al. Tinzaparin use in pregnancy: an international, retrospective study of the safety and efficacy profile. Eur J Obstet Gynecol Reprod Biol. 2011;159(2): 293-299. 76. Byrd LM, Shiach CR, Hay CR, Johnston TA. Osteopenic fractures in pregnancy: is low molecular weight heparin (LMWH) implicated? J Obstet Gynaecol. 2008;28(5):539-542. 77. Hellgren M, Tengborn L, Abildgaard U. Pregnancy in women with congenital antithrombin III deficiency: experience of treatment with heparin and antithrombin. Gynecol Obstet Invest. 1982;14(2):127-141. 78. Tiede A, Tait RC, Shaffer DW, et al. Antithrombin alfa in hereditary antithrombin deficient patients: a phase 3 study of prophylactic intravenous administration in high risk situations. Thromb Haemost. 2008;99(3):616-622. 79. Pernod G, Biron-Andreani C, Morange PE, et al. Recommendations on testing for thrombophilia in venous thromboembolic disease: a French consensus guideline. J Mal Vasc. 2009;34(3): 156-203. 80. Baglin T, Gray E, Greaves M, et al. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol. 2010;149(2): 209-220. 81. Kearon C. Influence of hereditary or acquired thrombophilias on the treatment of venous thromboembolism. Curr Opin Hematol. 2012;19(5):363-370. 82. Jenkins PV, Rawley O, Smith OP, O’Donnell JS. Elevated factor VIII levels and risk of venous thrombosis. Br J Haematol. 2008; 157(6):653-663.

Prevention of postthrombotic syndrome.

bosis: a clinical outcome study. Thromb Haemost. 2001; 86(5):1170-1175. 101. Lindhoff-Last E, Kreutzenbeck HJ, Magnani HN. Treatment of 51 pregnancies with danaparoid because of heparin intolerance. Thromb Haemost. 2005;93(1):63-69. 102. Tardy B, Tardy-Poncet B, Viallon A, Piot M, Mazet E. Fatal danaparoid-sodium induced thrombocytopenia and arterial thrombosis. Thromb Haemost. 1998;80(3):530. 103. Farner B, Eichler P, Kroll H, Greinacher A. A comparison of danaparoid and lepirudin in heparin-induced thrombocytopenia. Thromb Haemost. 2001;85(6):950-957. 104. Kodityal S, Manhas AH, Udden M, Rice L. Danaparoid for heparin-induced thrombocytopenia: an analysis of treatment failures. Eur J Haematol. 2001;71:109-113. 105. Haas S, Walenga JM, Jeske WP, Fareed J. Heparin-induced thrombocytopenia: clinical considerations of alternative anticoagulation with various glycosaminoglycans and thrombin inhibitors. Clin Appl Thromb Hemost. 1999;5(1):52-59. 106. Lobo B, Finch C, Howard A, Minhas S. Fondaparinux for the treatment of patients with acute heparin-induced thrombocytopenia. Thromb Haemost. 2008;99(1):208-214. 107. Grouzi E, Kyriakou E, Panagou I, Spiliotopoulou I. Fondaparinux for the treatment of acute heparin-induced thrombocytopenia: a single-center experience. Clin Appl Thromb Hemost. 2010;16(6):663-667. 108. Warkentin TE, Pai M, Sheppard JI, Schulman S, Spyropoulos AC, Eikelboom JW. Fondaparinux treatment of acute heparininduced thrombocytopenia confirmed by the serotonin-release assay: a 30-month, 16-patient case series. J Thromb Haemost. 2011;9(12):2389-2396. 109. Hook K, Abrams CS. Treatment options in heparin-induced thrombocytopenia. Curr Opin Hematol. 2010;17(5):424-431. 110. Greinacher A, Alban S, Drummel V, Franz G, Mueller-Eckhardt C. Characterization of the structural requirements for a carbohydrate-based anticoagulant with a reduced risk of inducing the immunological type of heparin-associated thrombocytopenia. Thromb Haemost. 1995;74(4):886-892. 111. Walenga JM, Koza MJ, Lewis BE, Pifarre R. Relative heparininduced thrombocytopenic potential of low molecular weight heparins and new antithrombotic agents. Clin Appl Thromb Hemost. 1996;2(suppl 1):S21-S27. 112. Warkentin TE, Elavathil LJ, Hayward CP, Johnston MA, Russett JI, Kelton JG. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med. 1997;127(9):804-812. 113. Srinivasan AF, Rice L, Bartholomew JR, et al. Warfarininduced skin necrosis and venous limb gangrene in the setting of heparin-induced thrombocytopenia. Arch Intern Med. 2004; 164(1):66-70. 114. Hursting MJ, Lewis BE, MacFarlane DE. Transitioning from argatroban to warfarin therapy in patients with heparininduced thrombocytopenia. Clin Appl Thromb Hemost. 2005; 11(3):279-287. 115. Bartholomew JR, Hursting MJ. Transitioning from argatroban to warfarin in heparin-induced thrombocytopenia: an analysis of outcomes in patients with elevated international normalized ratio (INR). J Thromb Thrombolysis. 2005;19(3):183-188. 116. Walenga JM, Drenth AF, Mayuga M. Transition from argatroban to oral anticoagulation with phenprocoumon or acenocoumarol: effect on coagulation factor testing. Clin Appl Thromb Hemost. 2008;14(3):325-331.

Cost-Effectiveness of Prevention and Treatment of VTE

factors associated with retrobulbar/peribulbar block: a prospective study in 1383 patients. Br J Anaesth. 2000;85(5):708-711. 19. Hirschman DR, Morby LJ, Hirschman DR, Morby LJ. A study of the safety of continued anticoagulation for cataract surgery patients. Nursing Forum. 2006;41(1):30-37. 20. Hylek EM, Regan S, Go AS, Hughes RA, Singer DE, Skates SJ. Clinical predictors of prolonged delay in return of the international normalized ratio to within the therapeutic range after excessive anticoagulation with warfarin. Ann Intern Med. 2001;135(6):393-400. 21. O’Donnell MJ, Kearon C, Johnson J, et al. Preoperative anticoagulant activity after bridging low-molecular-weight heparin for temporary interruption of warfarin. Ann Intern Med. 2007; 146(3):184-187. 22. Woods KDJ, Kathirgamanathan K, Yi Q, Crowther MA. Lowdose oral vitamin K to normalize the international normalized ratio prior to surgery in patients who require temporary interruption of warfarin. J Thromb Thrombolys. 2007;24(2):93-97. 23. Gerotziafas GT, Dupont C, Spyropoulos AC, et al. Differential inhibition of thrombin generation by vitamin K antagonists alone and associated with low-molecular-weight heparin. Thromb Haemost. 2009;102(1):42-48. 24. Dunn AS, Spyropoulos AC, Turpie AG, Turpie AGG. Bridging therapy in patients on long-term oral anticoagulants who require surgery: the prospective peri-operative enoxaparin cohort trial (PROSPECT). J Thromb Haemost. 2007;5(11):2211-2218. 25. Bath PM, Lindenstrom E, Boysen G, et al. Tinzaparin in acute ischaemic stroke (TAIST): a randomised aspirin-controlled trial. Lancet. 2001;358(9283):702-710. 26. Spyropoulos AC. Bridging of oral anticoagulation therapy for invasive procedures. Curr Hematol Rep. 2005;4(5):405-413. 27. Spyropoulos AC, Frost FJ, Hurley JS, Roberts M. Costs and clinical outcomes associated with low-molecular-weight heparin vs unfractionated heparin for perioperative bridging in patients receiving long-term oral anticoagulant therapy. Chest. 2004; 125(5):1642-1650. 28. Spyropoulos AC, Turpie AG, Dunn AS, et al. Perioperative bridging therapy with unfractionated heparin or low-molecularweight heparin in patients with mechanical prosthetic heart valves on long-term oral anticoagulants (from the REGIMEN Registry). Am J Cardiol. 2008;102(7):883-889. 29. Douketis JD, Johnson JA, Turpie AG. Low-molecular-weight heparin as bridging anticoagulation during interruption of warfarin: assessment of a standardized periprocedural anticoagulation regimen. Arch Intern Med. 2004;164(12):1319-1326. 30. Jaffer AK, Brotman DJ, Bash LD, Mahmood SK, Lott B, White RH. Variations in perioperative warfarin management: outcomes and practice patterns at nine hospitals. Am J Med. 123(2):141-150. 31. Hammerstingl C, Tripp C, Schmidt H, et al. Periprocedural bridging therapy with low-molecular-weight heparin in chronically anticoagulated patients with prosthetic mechanical heart valves: experience in 116 patients from the prospective BRAVE registry. J Heart Valve Disease. 2007;16(3):285-292. 32. Pengo V, Cucchini U, Denas G, et al. Standardized lowmolecular-weight heparin bridging regimen in outpatients on oral anticoagulants undergoing invasive procedure or surgery: an inception cohort management study. Circulation. 2009; 119(22):2920-2927. 33. Katholi RE, Nolan SP, McGuire LB. The management of anticoagulation during noncardiac operations in patients with prosthetic heart valves. A prospective study. Am Heart J. 1978;96(2):163-165. 34. Spyropoulos AC, Turpie AG, Dunn AS, et al. Clinical outcomes with unfractionated heparin or low-molecular-weight heparin as bridging therapy in patients on long-term oral anticoagulants: the REGIMEN registry. J Thromb Haemost. 2006; 4(6):1246-1252. 35. Garcia DA, Regan S, Henault LE, et al. Risk of thromboembolism with short-term interruption of warfarin therapy [see comment]. Arch Intern Med. 2008;168(1):63-69. 36. Malato AAR, Cigna V, Sciacca M, Abbene I, Saccullo G, Lo Cocco L, Siragusa S. Perioperative bridging therapy with low molecular weight heparin in patients requiring interruption of long-term oral anticoagulant therapy. Haematologica. 2006;91:10. 37. Hammerstingl C, Omran H. Bridging of oral anticoagulation with low-molecular-weight heparin: experience in 373 patients with renal insufficiency undergoing invasive procedures. Thromb Haemost. 2009;101(6):1085-1090. 38. Jaffer AK, Ahmed M, Brotman DJ, et al. Low-molecular-weightheparins as periprocedural anticoagulation for patients on longterm warfarin therapy: a standardized bridging therapy protocol. J Thromb Thrombolysis. 2005;20(1):11-16. 39. Spyropoulos AC. Bridging therapy and oral anticoagulation: current and future prospects. Curr Opin Hematol. 2010;17(5):444-449. 40. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate–a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103(6):1116-1127. 41. Douketis JD. Pharmacologic properties of the new oral anticoagulants: a clinician-oriented review with a focus on perioperative management. Curr Pharm Des. 2010;16(31):3436-3441.

General, vascular, bariatric, and plastic surgical patients.

International consensus statement. Guidelines according to scientific evidence. Int Angiol. 2005;24:1-26. 24. Scurr JH, Coleridge-Smith PD, Hasty JH. Deep venous thrombosis: a continuing problem. BMJ. 1988;297(6640):28. 25. White RH, Gettner S, Newman JM, Trauner KB, Romano PS. Predictors of rehospitalization for symptomatic venous thromboembolism after total hip arthroplasty. N Engl J Med. 2000; 343:1758-1764. 26. Eikelboom JW, Quinlan DJ, Douketis JD. Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials. Lancet. 2001;358(9275):9-15. 27. Vaitkus PT, Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Goldhaber SZ. Mortality rates and risk factors for asymptomatic deep vein thrombosis in medical patients. Thromb Haemost. 2005;93(1):76-79. 28. Kucher N, Koo S, Quiroz R, et al. Electronic alerts to prevent venous thromboembolism among hospitalized patients. N Engl J Med. 2005;352(10):969-977. 29. Cohen AT, Agnelli G, Anderson FA, et al. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost. 2007;98(4):756-764. 30. Kucher N, Spirk D, Kalka C, et al. Clinical predictors of prophylaxis use prior to the onset of acute venous thromboembolism in hospitalized patients swiss venous thromboembolism registry (SWIVTER). J Thromb Haemost. 2008;6(12):2082-2087. 31. Cohen AT, Tapson VF, Bergmann JF, et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet. 2008;371(9610):387-394. 32. Kucher N, Spirk D, Baumgartner I, et al. Lack of prophylaxis before the onset of acute venous thromboembolism among hospitalized cancer patients: the swiss venous thromboembolism registry (SWIVTER). Ann Oncol. 2010;21(5):931-935. 33. Anderson FA, Jr, Goldhaber SZ, Tapson VF, et al. Improving practices in US hospitals to prevent Venous Thromboembolism: lessons from ENDORSE. Am J Med. 2010;123(12):1099-1106 e8. 34. Vaughan-Shaw PG, Cannon C. Venous thromboembolism prevention in medical patients: a framework for improving practice. Phlebology. 2011;26(2):62-68. 35. Kucher N, Puck M, Blaser J, Bucklar G, Eschmann E, Luscher TF. Physician compliance with advanced electronic alerts for preventing venous thromboembolism among hospitalized medical patients. J Thromb Haemost. 2009;7:1291-1296.

Combined modalities in surgical patients.

Despite contemporary developments in pharmacology and biomedical engineering, venous thromboembolism (VTE) is not fully preventable and thus still remains a serious complication of trauma, surgery, and medical conditions. Current and previous guidelines recommend risk stratification to tailor implementation of prophylactic methods so that combined modalities are recommended based on supportive evidence in high-risk patients, although cost and potential adverse events make them less effective for low-risk groups. The reason for the increased efficacy of combined modalities is based on the multifactorial etiology of VTE as first described by Rudolph Virchow in the 19th century. Physical methods reduce venous stasis while pharmacological methods affect hypercoagulopathy. The fact that combined modalities are more effective than single modalities was first shown by Borow in 1983 followed by several studies supporting this concept. Although elastic stockings are effective in reducing further VTE rates achieved by perioperative antithrombotic prophylactic pharmacotherapy, as indicated in several places in this document, most modern studies have evaluated the role of the combination of intermittent pneumatic compression (IPC) with pharmacological methods, and this will be the focus of this section. A recent Cochrane review evaluated the efficacy of combined modalities (IPC) and pharmacological prophylaxis: treatment group) against single modalities alone (control group) to prevent pulmonary embolism (PE) and deep vein thrombosis (DVT) in patients at high risk of VTE. A total of 11 studies that included 7431 patients were identified, of which 6 were randomized-controlled trials (RCTs). The studies evaluated orthopedic patients (n 1⁄4 6), urology patients (n 1⁄4 2), and general surgery, cardiothoracic, and gynecology patients (n 1⁄4 3). Compared to compression alone, combined modalities significantly reduced the incidence of both symptomatic PE (from about 3% to 1%; odds ratio [OR] 0.39; 95% confidence interval [CI] 0.25-0.63) and DVT (from about 4% to 1%; OR 0.43; 95% CI 0.24-0.76). Compared to pharmacological prophylaxis alone, combined modalities significantly reduced the incidence of DVT (from 4.21% to 0.65%; OR 0.16; 95% CI 0.07-0.34). The studies were underpowered with regard to PE. The comparison of compression plus pharmacological prophylaxis versus compression plus aspirin showed a nonsignificant reduction in PE and DVT in favor of the former group. Repeat analysis restricted to the RCT confirmed the above findings. The additive role of mechanical and pharmacological modalities suggests that venous stasis and hypercoagulopathy are independent pathogenetic risk factors. The IPC reduces venous stasis by producing active flow enhancement and also increases tissue factor pathway inhibitor plasma levels. The results of the above meta-analyses endorse a recommendation that high-risk patients should receive multimodal prophylaxis. Although most patients who used combined modalities in the studies reviewed were considered to be at high risk of developing VTE, future studies on this topic should use the most recent and validated criteria to define the high-risk patient.

Orthopedic surgery and trauma.

ing heparin in pregnant women with a history of venous thromboembolism. Recurrence of clot in this pregnancy study group. N Engl J Med. 2000;343(20):1439-1444. 55. Pabinger I, Grafenhofer H, Kyrle PA, et al. Temporary increase in the risk for recurrence during pregnancy in women with a history of venous thromboembolism. Blood. 2002;100(3):1060-1062. 56. Smith MP, Norris LA, Steer PJ, Savidge GF, Bonnar J. Tinzaparin sodium for thrombosis treatment and prevention during pregnancy. Am J Obstet Gynecol. 2004;190(2):495-501. 57. Norris LA, Bonnar J, Smith MP, Steer PJ, Savidge G. Low molecular weight heparin (tinzaparin) therapy for moderate risk thromboprophylaxis during pregnancy. A pharmacokinetic study. Thromb Haemost. 2004;92(4):791-796. 58. Nelson-Piercy C, Powrie R, Borg JY, et al. Tinzaparin use in pregnancy: an international, retrospective study of the safety and efficacy profile. Eur J Obstet Gynecol Reprod Biol. 2011;159(2): 293-299. 59. Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ. 1997;314(7076):253-257. 60. Empson M, Lassere M, Craig J, Scott J. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev. 2005;(2):CD002859. 61. Nelson-Piercy C, MacCallum P, Mackillop L, et al. Reducing the risk of thrombosis and embolism during pregnancy and the puerperium. Royal College of Obstetricians and Gynaecologists; 2009. 62. Checketts MR, Wildsmith JA. Epidural haematoma following anticoagulant treatment in a patient with an indwelling epidural catheter. Anaesthesia. 1999;54(1):87-88. 63. Horlocker TT, Wedel DJ. Neuraxial block and low-molecularweight heparin: balancing perioperative analgesia and thromboprophylaxis. Reg Anesth Pain Med. 1998;23(6 suppl 2):164-177. 64. McKenna R, Cole ER, Vasan U. Is warfarin sodium contraindicated in the lactating mother? J Pediatr. 1983;103(2):325-327. 65. O’Reilly R. Anticoagulant, antithrombotic and thrombolytic drugs. In: Gillman AG, et al, eds. The Pharmacologic Basis of Therapeutics. New York, NY: Macmillan; 1980:1347. 66. Bonnar J, Walsh J. Prevention of thrombosis after pelvic surgery by British dextran 70. Lancet. 1972;1(7751):614-616. 67. Walsh JJ, Bonnar J, Wright FW. A study of pulmonary embolism and deep leg vein thrombosis after major gynaecological surgery using labelled fibrinogen-phlebography and lung scanning. J Obstet Gynaecol Br Commonw. 1974;81(4):311-316.

Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia is a threatening complication of heparin treatment. The physio-pathological mechanism is the production of antibodies, the most frequent target of which is the complex heparin-platelet factor 4. These antibodies may activate the coagulation and lead to venous or arterial thromboembolic manifestations. Clinical features as well as functional and immunological tests are used for the diagnosis. The treatment consists in discontinuing heparin administration and in setting up an alternative treatment for which two drugs are indicated in France: Orgaran and Refludan.

The problem and the need for prevention.

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are major health problems with potential serious outcomes. Acute PE may be fatal. Pulmonary hypertension can develop in the long term from recurrent PE. Often overlooked is postthrombotic chronic venous disease occurring as a result of DVT causing deep venous reflux or obstruction, with skin changes and ulceration causing an adverse impact on quality of life and escalation of health care costs. In North America and Europe, the annual incidence is approximately 160 per 1 00 000 for DVT, 20 per 1 00 000 for symptomatic nonfatal PE, and 5 per 1 00 000 for fatal autopsy-detected PE. The prevalence of venous ulceration is at least 300 per 1 00 000 and approximately 25% are due to DVT. Estimates of the overall annual costs of cumulative volume index vary from 600 to 900 million € (US

Critical Care Medical Patients

720 million-1 billion) in Western European countries, representing 1% to 2% of the total health care budget, to 2.5 billion € (US