Pediatric Cardiology

, Volume 31, Issue 6, pp 834–842 | Cite as

Long-Term Anticoagulation in Kawasaki Disease: Initial Use of Low Molecular Weight Heparin is a Viable Option for Patients with Severe Coronary Artery Abnormalities

  • Cedric Manlhiot
  • Leonardo R. Brandão
  • Zeeshanefatema Somji
  • Amy L. Chesney
  • Catherine MacDonald
  • Rebecca C. Gurofsky
  • Tarun Sabharwal
  • Nita Chahal
  • Brian W. McCrindle
Original Article


Patients with severe coronary artery involvement after Kawasaki disease (KD) require long-term systemic anticoagulation. We sought to compare our experience with thrombotic coronary artery occlusions, safety profile, and degree of coronary artery aneurysm regression in KD patients treated with low molecular weight heparin (LMWH) versus warfarin. Medical records of all KD patients diagnosed between January 1990 and April 2007 were reviewed. Of 1374 KD patients, 38 (3%) received systemic anticoagulation, 25 patients received LMWH from diagnosis onward, 12 of whom were subsequently switched to warfarin, and 13 received warfarin from onset. The frequency of thrombotic coronary artery occlusions was similar between drugs. Severe bleeding was more frequent in patients on warfarin, but minor bleeding was more frequent for patients on LMWH. Patients on warfarin were at greater risk of underanticoagulation or overanticoagulation (defined as achieving an anti-activated factor X level or an international normalized ratio below or above target level) than patients on LMWH (P < 0.05). Maximum coronary artery aneurysm z-scores diminished with time for patients on LMWH (P = 0.03) but not for those on warfarin (P = 0.55). This study suggests that LMWH is a potentially viable alternative for patients, especially young ones, with severe coronary artery involvement after KD.


Anticoagulants Coronary disease Kawasaki disease Pediatric Thrombosis 



This study was supported by the CIBC World Markets Children’s Miracle Foundation Chair in Child Health Research (BWM).


  1. 1.
    Albisetti M, Chan AK, McCrindle BW, Wong D, Vegh P, Adams M et al (2003) Fibrinolytic response to venous occlusion is decreased in patients after Kawasaki disease. Blood Coagul Fibrinolysis 14:181–186CrossRefPubMedGoogle Scholar
  2. 2.
    Andrew M, Marzinotto V, Brooker LA, Adams M, Ginsberg J, Freedom R et al (1994) Oral anticoagulation therapy in pediatric patients: a prospective study. Thromb Haemost 71:265–269PubMedGoogle Scholar
  3. 3.
    Barnes C, Newall F, Ignjatovic V, Wong P, Cameron F, Jones G et al (2005) Reduced bone density in children on long-term warfarin. Pediatr Res 57:578–581CrossRefPubMedGoogle Scholar
  4. 4.
    Bonduel MM (2006) Oral anticoagulation therapy in children. Thromb Res 118:85–94CrossRefPubMedGoogle Scholar
  5. 5.
    Boyle JP, Smart RH, Shirey JK (1964) Heparin in the treatment of chronic obstructive bronchopulmonary disease. Am J Cardiol 14:25–28CrossRefPubMedGoogle Scholar
  6. 6.
    Burns JC, Glode MP, Clarke SH, Wiggins J Jr, Hathaway WE (1984) Coagulopathy and platelet activation in Kawasaki syndrome: identification of patients at high risk for development of coronary artery aneurysms. J Pediatr 105:206–211CrossRefPubMedGoogle Scholar
  7. 7.
    de Zorzi A, Colan SD, Gauvreau K, Baker AL, Sundel RP, Newburger JW (1998) Coronary artery dimensions may be misclassified as normal in Kawasaki disease. J Pediatr 133:254–258CrossRefPubMedGoogle Scholar
  8. 8.
    Delaney JA, Opatrny L, Brophy JM, Suissa S (2007) Drug–drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding. CMAJ 177:347–351PubMedGoogle Scholar
  9. 9.
    Dix D, Andrew M, Marzinotto V, Charpentier K, Bridge S, Monagle P et al (2000) The use of low molecular weight heparin in pediatric patients: a prospective cohort study. J Pediatr 136:439–445CrossRefPubMedGoogle Scholar
  10. 10.
    Elsayed E, Becker RC (2003) The impact of heparin compounds on cellular inflammatory responses: a construct for future investigation and pharmaceutical development. J Thromb Thrombolysis 15:11–18CrossRefPubMedGoogle Scholar
  11. 11.
    Hidaka T, Nakano M, Ueta T, Komatsu Y, Yamamoto M (1983) Increased synthesis of thromboxane A2 by platelets from patients with Kawasaki disease. J Pediatr 102:94–96CrossRefPubMedGoogle Scholar
  12. 12.
    Hirsh J, Dalen J, Anderson DR, Poller L, Bussey H, Ansell J et al (2001) Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 119(Suppl):8S–21SCrossRefPubMedGoogle Scholar
  13. 13.
    Kato H, Sugimura T, Akagi T, Sato N, Hashino K, Maeno Y et al (1996) Long-term consequences of Kawasaki disease: a 10- to 21-year follow-up study of 594 patients. Circulation 94:1379–1385PubMedGoogle Scholar
  14. 14.
    Khorana AA, Sahni A, Altland OD, Francis CW (2003) Heparin inhibition of endothelial cell proliferation and organization is dependent on molecular weight. Arterioscler Thromb Vasc Biol 23:2110–2115CrossRefPubMedGoogle Scholar
  15. 15.
    Kuramochi Y, Ohkubo T, Takechi N, Fukumi D, Uchikoba Y, Ogawa S (2000) Hemodynamic factors of thrombus formation in coronary aneurysms associated with Kawasaki disease. Pediatr Int 42:470–475CrossRefPubMedGoogle Scholar
  16. 16.
    Kurotobi S, Nagai T, Kawakami N, Sano T (2002) Coronary diameter in normal infants, children and patients with Kawasaki disease. Pediatr Int 44:1–4CrossRefPubMedGoogle Scholar
  17. 17.
    Lever R, Hoult JR, Page CP (2000) The effects of heparin and related molecules upon the adhesion of human polymorphonuclear leucocytes to vascular endothelium in vitro. Br J Pharmacol 129:533–540CrossRefPubMedGoogle Scholar
  18. 18.
    Levy DM, Silverman ED, Massicotte MP, McCrindle BW, Yeung RS (2005) Long-term outcomes in patients with giant aneurysms secondary to Kawasaki disease. J Rheumatol 32:928–934PubMedGoogle Scholar
  19. 19.
    Manlhiot C, Millar K, Golding F, McCrindle BW (2010) Improved classification of coronary artery abnormalities based only on coronary artery z-scores after Kawasaki disease. Pediatr Cardiol 31:242–249CrossRefPubMedGoogle Scholar
  20. 20.
    McCrindle BW (2004) Cardiovascular complications—Coronary artery structure and function. Prog Pediatr Cardiol 19:147–152CrossRefGoogle Scholar
  21. 21.
    Monagle P, Michelson AD, Bovill E, Andrew M (2001) Antithrombotic therapy in children. Chest 119(Suppl):344S–370SCrossRefPubMedGoogle Scholar
  22. 22.
    Monagle P, Chan AKC, Massicotte P, deVeber G (2005) Andrew’s handbook of pediatric thromboembolism and stroke. Decker, Hamilton, Ontario, CanadaGoogle Scholar
  23. 23.
    Monagle P, Chalmers E, Chan A, DeVeber G, Kirkham F, Massicotte P et al (2008) Antithrombotic therapy in neonates and children: American college of chest physicians evidence-based clinical practice guidelines, 8th edn. Chest 133(Suppl):887S–968SCrossRefPubMedGoogle Scholar
  24. 24.
    Nakamura Y, Yanagawa H, Harada K, Kato H, Kawasaki T (2000) Mortality among persons with a history of Kawasaki disease in Japan: existence of cardiac sequelae elevated the mortality. J Epidemiol 10:372–375PubMedGoogle Scholar
  25. 25.
    Nakamura Y, Aso E, Yashiro M, Uehara R, Watanabe M, Tajimi M et al (2005) Mortality among persons with a history of Kawasaki disease in Japan: can paediatricians safely discontinue follow-up of children with a history of the disease but without cardiac sequelae? Acta Paediatr 94:429–434PubMedGoogle Scholar
  26. 26.
    Nash MC, Shah V, Dillon MJ (1995) Soluble cell adhesion molecules and von Willebrand factor in children with Kawasaki disease. Clin Exp Immunol 101:13–17PubMedCrossRefGoogle Scholar
  27. 27.
    Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC et al (2004) Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the committee on rheumatic fever, endocarditis, and Kawasaki disease, council on cardiovascular disease in the young, American Heart Association. Pediatrics 114:1708–1733CrossRefPubMedGoogle Scholar
  28. 28.
    Niboshi A, Hamaoka K, Sakata K, Yamaguchi N (2008) Endothelial dysfunction in adult patients with a history of Kawasaki disease. Eur J Pediatr 167:189–196CrossRefPubMedGoogle Scholar
  29. 29.
    Onouchi Z, Hamaoka K, Sakata K, Ozawa S, Shiraishi I, Itoi T et al (2005) Long-term changes in coronary artery aneurysms in patients with Kawasaki disease: comparison of therapeutic regimens. Circ J 69:265–272CrossRefPubMedGoogle Scholar
  30. 30.
    Sabharwal T, Manlhiot C, Benseler SM, Tyrrell PN, Chahal N, Yeung RS et al (2009) Comparison of factors associated with coronary artery dilation only versus coronary artery aneurysms in patients with Kawasaki disease. Am J Cardiol 104:1743–1747CrossRefPubMedGoogle Scholar
  31. 31.
    Schwarz UI, Ritchie MD, Bradford Y, Li C, Dudek SM, Frye-Anderson A et al (2008) Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med 358:999–1008CrossRefPubMedGoogle Scholar
  32. 32.
    Streif W, Andrew M, Marzinotto V, Massicotte P, Chan AK, Julian JA et al (1999) Analysis of warfarin therapy in pediatric patients: a prospective cohort study of 319 patients. Blood 94:3007–3014PubMedGoogle Scholar
  33. 33.
    Sugahara Y, Ishii M, Muta H, Iemura M, Matsuishi T, Kato H (2008) Warfarin therapy for giant aneurysm prevents myocardial infarction in Kawasaki disease. Pediatr Cardiol 29:398–401CrossRefPubMedGoogle Scholar
  34. 34.
    Suzuki A, Kamiya T, Arakaki Y, Kinoshita Y, Kimura K (1994) Fate of coronary arterial aneurysms in Kawasaki disease. Am J Cardiol 74:822–824CrossRefPubMedGoogle Scholar
  35. 35.
    Suzuki A, Miyagawa-Tomita S, Nakazawa M, Yutani C (2000) Remodeling of coronary artery lesions due to Kawasaki disease: comparison of arteriographic and immunohistochemical findings. Jpn Heart J 41:245–256CrossRefPubMedGoogle Scholar
  36. 36.
    Takahashi M, Mason W, Lewis AB (1987) Regression of coronary aneurysms in patients with Kawasaki syndrome. Circulation 75:387–394PubMedGoogle Scholar
  37. 37.
    Takahashi M (1996) Management of giant coronary aneurysms due to Kawasaki syndrome. ACC Curr J Rev 5:74–76CrossRefGoogle Scholar
  38. 38.
    Tsuda E, Kamiya T, Kimura K, Ono Y, Echigo S (2002) Coronary artery dilatation exceeding 4.0 mm during acute Kawasaki disease predicts a high probability of subsequent late intima-medial thickening. Pediatr Cardiol 23:9–14CrossRefPubMedGoogle Scholar
  39. 39.
    Vrij AA, Jansen JM, Schoon EJ, de Bruine A, Hemker HC, Stockbrugger RW (2001) Low molecular weight heparin treatment in steroid refractory ulcerative colitis: Clinical outcome and influence on mucosal capillary thrombi. Scand J Gastroenterol 234(Suppl):41–47CrossRefGoogle Scholar
  40. 40.
    Widlak P, Garrard WT (2006) The apoptotic endonuclease DFF40/CAD is inhibited by RNA, heparin and other polyanions. Apoptosis 11:1331–1337CrossRefPubMedGoogle Scholar
  41. 41.
    Williams RV, Minich LL, Tani LY (2001) Pharmacological therapy for patients with Kawasaki disease. Paediatr Drugs 3:649–660CrossRefPubMedGoogle Scholar
  42. 42.
    Williams RV, Wilke VM, Tani LY, Minich LL (2002) Does Abciximab enhance regression of coronary aneurysms resulting from Kawasaki disease? Pediatrics 109:E4CrossRefPubMedGoogle Scholar
  43. 43.
    Williams RV, Tcheng WY, Minich L (2004) Anticoagulation in the acute and long-term management of Kawasaki disease. Prog Pediatr Cardiol 19:179–188CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Cedric Manlhiot
    • 1
  • Leonardo R. Brandão
    • 2
  • Zeeshanefatema Somji
    • 1
  • Amy L. Chesney
    • 1
  • Catherine MacDonald
    • 1
  • Rebecca C. Gurofsky
    • 1
  • Tarun Sabharwal
    • 1
  • Nita Chahal
    • 1
  • Brian W. McCrindle
    • 1
  1. 1.Division of Cardiology, Department of PediatricsUniversity of Toronto, Labatt Family Heart Centre, The Hospital for Sick ChildrenTorontoCanada
  2. 2.Division of Hematology, Department of PediatricsUniversity of Toronto, Labatt Family Heart Centre, The Hospital for Sick ChildrenTorontoCanada

Personalised recommendations