K. Myers

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.

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.

Critical Care Medical Patients

intermittent pneumatic compression for venous thromboembolism prophylaxis in general surgery. Int Angiol. 2008;27(6):500-506. 79. Czechanowski B, Heinrich F. [Prevention of venous thrombosis in recent ischaemic cerebrovascular accident: double-blind study with heparin-dihydroergotamine (author’s transl)]. Dtsch Med Wochenschr. 1981;106(39):1254-1260. 80. McCarthy ST, Turner JJ, Robertson D, Hawkey CJ, Macey DJ. Low-dose heparin as a prophylaxis against deep-vein thrombosis after acute stroke. Lancet. 1977;2(8042):800-801. 81. Warlow C, Ogston D, Douglas AS. Venous thrombosis following strokes. Lancet. 1972;1(7764):1305-1306. 82. Moser KM, LeMoine JR, Nachtwey FJ, Spragg RG. Deep venous thrombosis and pulmonary embolism. Frequency in a respiratory intensive care unit. JAMA. 1981;246(13):1422-1424. 83. Emerson PA, Marks P. Preventing thromboembolism after myocardial infarction: effect of low-dose heparin or smoking. Br Med J. 1977;1(6052):18-20. 84. Handley AJ. Low-dose heparin after myocardial infarction. Lancet. 1972;2(7778):623-624. 85. Nicolaides AN, Kakkar VV, Renney JT, Kidner PH, Hutchison DC, Clarke MB. Myocardial infarction and deep-vein thrombosis. Br Med J. 1971;1(746):432-434. 86. Warlow C, Terry G, Kenmure AC, Beattie AG, Ogston D, Douglas AS. A double-blind trial of low doses of subcutaneous heparin in the prevention of deep-vein thrombosis after myocardial infarction. Lancet. 1973;2(7835):934-936. 87. Prescott SM, Richards KL, Tikoff G, Armstrong JD, Jr, Shigeoka JW. Venous thromboembolism in decompensated chronic obstructive pulmonary disease. A prospective study. Am Rev Respir Dis. 1981;123(1):32-36. 88. Schonhofer B, Kohler D. Prevalence of deep-vein thrombosis of the leg in patients with acute exacerbation of chronic obstructive pulmonary disease. Respiration. 1998;65(3):173-177. 89. Oger E, Bressollette L, Nonent M, et al. High prevalence of asymptomatic deep vein thrombosis on admission in a medical unit among elderly patients. Thromb Haemost. 2002;88(4):592-597.

Gynecology and obstetrics.

The Risk. Thromboembolic complications after gynecologic surgery occur with approximately the same frequency as for general surgery (Table 5.1). Pulmonary embolism (PE) is a leading cause of death following gynecologic cancer surgery and accounts for approximately 20% of the perioperative hysterectomy deaths. Patients undergoing major gynecologic surgery (eg, over 30 minutes duration) aged 40 years or above have a significant risk of postoperative venous thromboembolism (VTE). The risk is increased by age, obesity, malignancy, history of VTE, immobility, and hereditary or acquired thrombophilia. 4 This risk is also affected by the nature and duration of the operation, type of anesthesia, dehydration, sepsis, varicose veins, and hormone therapy. Known clinical risk factors allow for classification of patients into high, moderate, and low risk of developing VTE (Table 5.2). The incidence of symptomatic VTE appears to be minimal for benign laparoscopic gynecologic surgery and as high as 16% in surgery for ovarian cancer. As indicated above, a common additional risk factor for VTE is estrogen contained in combined oral contraceptives (COCs), which had been used by 18% of women in a UK study. The COCs increase the risk of VTE. However, the absolute risk is small and represents an increase from 5 to 15 to 30 per 1 00 000 women years. The latter is lower than the risk of pregnancy, which is estimated at 100 cases per 1 00 000 maternities. The risk of postoperative VTE showed an increase from 0.5% to 1% for pill users versus nonusers in early studies. The absolute excess risk in COC users has to be balanced against the risk of stopping the pill 4 to 6 weeks before surgery which includes unwanted pregnancy, the effects of surgery and anesthesia on a pregnancy, and the risks of subsequent termination. Each case should be assessed in relation to additional risk factors. Before major surgery, COCs should be discontinued for at least 4 weeks and alternative contraception should be advised. If it is elected not to discontinue COCs, then the patient should receive prophylaxis as if for at least a moderate-risk patient. Other estrogen-containing preparations should be considered to carry the same risk as COCs at least until studies become available. In emergency surgery or when COCs have not been discontinued, VTE prophylaxis should be given at least as moderate-risk category. The COCs do not need to be discontinued before minor surgery without immobilization. Progestogen-only oral contraceptives need not be discontinued even when immobilization is expected. For other contraceptive preparations, consult the manufacturers’ data sheets. Hormone replacement therapy (HRT) should be included as a risk factor for VTE when assessing patients for elective or emergency surgery. The HRT does not need to be stopped routinely prior to surgery provided that appropriate thromboprophylaxis is used such as low-molecular-weight heparin (LMWH). An individual assessment is required in each woman to balance the risks of postoperative VTE against the changes in the quality of life which may result from cessation of the therapy. Transdermal HRT has less effect on blood coagulation and appears to have a substantially lower VTE risk than oral HRT. In assisted reproduction, ovarian stimulation is used which results in a hyperestrogen state and activation of coagulation. The risk of venous thrombosis is increased and even upper extremity deep vein thrombosis (DVT) extending to subclavian and internal jugular veins can occur. In women with ovarian hyperstimulation syndrome, thromboprophylaxis with pregnancy dosage of LMWH is advised.