990 T Asano et al. might have been due to the fact that infused plasma contains a certain amount of vitamin B12.2 For these reasons, vitamin B12 deficiency could cause decreased ADAMTS13 activity and also improvement in hematological condition on plasma exchange. Vitamin B12 deficiency in children produces neurological sequelae that precede hematological findings and devastate the nervous system. Children with vitamin B12 deficiency often have neurodevelopmental delay or regression, irritability, hypotonia, ataxia, and seizures, and such sequelae could be permanent.7 When we encounter cases of TTP in children, vitamin B12 deficiency should be included in the differential diagnose of TTP.
2 3 4
5
Acknowledgment The authors declare no conflicts of interest.
6
References
7
1 Scully M, Hunt BJ, Benjamin S et al. on behalf of British Committee for Standards in Haematology. Guidelines on the diagnosis and
management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br. J. Haematol. 2012; 158: 323–335. Green R. Anemias beyond B12 and iron deficiency: The buzz about other B’s, elementary, and nonelementary problems. Hematology Am. Soc. Hematol. Educ. Program 2012; 2012: 492–8. Nappo F, De Rosa N, Marfella R et al. Impairment of endothelial functions by acute hyperhomocysteinemia and reversal by antioxidant vitamins. JAMA 1999; 281: 2113–18. Johnson CF. Nonorganic failure to thrive. Abuse and neglect of children. In: Behrman RE, Kliegman RM, Jenson HB (eds). Nelson textbook of Pediatrics, 17th edn. Saunders, Tokyo, 2004; 129–30. Dimond A, George JN, Hastings C. Severe Vitamin B-12 deficiency in a child mimicking thrombotic thrombocytopenic purpura. Pediatr. Blood Cancer 2009; 52: 420–22. Motto D. Endothelial cells and thrombotic microangiopathy. Semin. Nephrol. 2012; 32: 208–14. Simsek OP, Gonc N, Gumruk F, Cetin M. A child with vitamin B12 deficiency presenting with pancytopenia and hyperpigmentation. J. Pediatr. Hematol. Oncol. 2004; 26: 834–6.
Strict management of a pregnant patient with giant coronary artery aneurysm due to Kawasaki disease Kosuke Taniguchi,1 Hiroshi Ono,2 Anna Sato,1 Satoko Kinomoto,1 Naomi Tagawa,1 Nagayoshi Umehara,1 Hitoshi Kato2 and Haruhiko Sago1 1 Center of Maternal-Fetal, Neonatal and Reproductive Medicine and 2Division of Cardiology, National Center for Child Health and Development, Setagaya, Tokyo Japan Abstract
Coronary artery aneurysms (CAA) may occur in Kawasaki disease (KD). Patients with giant CAA (diameter >8 mm), in particular, have higher risk of myocardial infarction. Previous reports have demonstrated the necessity of anticoagulation therapy in such cases. The management of patients with KD complicated by giant CAA later in life, however, remains controversial. Here, we describe the strict management in the case of a 28-year-old pregnant Japanese woman with KD with giant CAA (diameter, 11 mm). Instead of warfarin, the patient was given low-dose aspirin and i.v. unfractionated heparin during pregnancy to prevent thrombosis in the giant CAA. At 38 weeks of gestation, she had spontaneous delivery of a healthy baby. No thrombotic or bleeding complications were observed. The strict anticoagulation therapy resulted in successful pregnancy and delivery without any adverse events.
Key words coronary aneurysm, Kawasaki disease, low-dose aspirin, pregnancy, unfractionated heparin. Kawasaki disease (KD) is an acute febrile illness of unknown etiology that primarily affects children younger than 5 years of age. It is thought to be an autoimmune disease with inflammation of medium-sized blood vessels throughout the body. For the management of the disease, early diagnosis and high-dose i.v. Correspondence: Haruhiko Sago, MD, PhD, Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan. Email: [email protected] Received 30 October 2014; revised 3 February 2015; accepted 13 February 2015. doi: 10.1111/ped.12679 © 2015 Japan Pediatric Society
gammaglobulin (IVIG) are essential. Despite proper management, complications such as coronary artery aneurysm (CAA) can arise later in life. In the case of giant CAA (diameter >8 mm), there is a high risk of myocardial infarction due to thrombosis in the aneurysm, which can lead to sudden death.1 Warfarin in combination with aspirin has been reported to be effective in reducing the incidence of cardiac events in patients with CAA secondary to KD,2,3 but the proper management of pregnant patients with similar condition is not yet established. At present, many such patients receive only aspirin or no medication at all.4 Furthermore, reports on the long-term prognosis are scarce due to the low
Kawasaki disease in a pregnant woman 991 Case report
Fig. 1 On contrast computed tomography the internal diameter of the giant coronary artery aneurysm, located on the main trunk of the left coronary artery, was 11 mm (arrow). (Volume-rendered image).
incidence of such cases. Notably, pregnancy can cause hypercoagulation in some cases, whereby appropriate antiplatelet and anticoagulation therapy is required. In this article, we describe the detailed management (low-dose aspirin and i.v. unfractionated heparin [UFH]) of a pregnant Japanese woman with CAA due to KD.
A 28-year-old gravida 0 para 0 Japanese woman was referred for prenatal and delivery care at 7 weeks of gestation. She developed KD at 2 years of age but IVIG was not administered. She had been prescribed aspirin and had been taking it since that time. At 18 years of age, giant CAA (8 mm diameter) was detected on coronary angiography at the main trunk of the left coronary artery (section 5). Echocardiography showed the CAA in the same region but no other abnormalities were detected. Electrocardiogram (ECG) was normal. She had no angina sign and New York Heart Association grade was class I. In spite of the giant CAA, warfarin was not used as per her request. She was prescribed only aspirin (330 mg/day). Two months before conception, contrast computed tomography showed giant CAA (diameter, 11 mm; Fig. 1) in the main trunk of the left coronary artery (section 5) and stenosis at the left anterior descending coronary artery (section 10) just after branching from the giant CAA. Although no thrombosis was detected, we found mild progression of the stenosis (section 10) compared with 2 years prior. The cardiologist recommended anticoagulant therapy in view of the progression of the stenosis, but, in spite of the recommendation, the patient again refused warfarin due to concern about teratogenicity in future pregnancies. Keeping in mind the potential of pregnancy being an additional risk for thrombosis in aneurysm, we added continuous UFH injection to oral low-dose aspirin at 7 + 4/7 weeks of gestation. UFH dose was maintained at either 1.5–2.5-fold activated partial thromboplastin time (aPTT) compared with normal pregnancy, or at a plasma heparin level around 0.20 U/mL (Fig. 2). The target aPTT or heparin level was determined based on previous reports.5–7 Fibrin degradation products were monitored to detect any early signs of thrombosis. Echocardiography conducted at
Fig. 2 Clinical course of anticoagulation therapy. aPTT, activated partial thromboplastin time. © 2015 Japan Pediatric Society
992 K Taniguchi et al. 20, 30 and 36 weeks of gestation, and monthly ECG during pregnancy, showed no thrombosis in the giant CAA. Low-dose aspirin was discontinued at 36 weeks of gestation. Heparin injection was withdrawn after labor pain onset at 38 + 1/7 weeks of gestation to avoid massive bleeding at delivery. The patient had spontaneous delivery of a healthy 3456 g male infant. Apgar score was 7/9 (1 min/5 min). Blood loss at delivery was 605 g. Upon confirmation of postpartum bleeding being controlled, heparin injection was recommenced. From the day after delivery, heparin injection was replaced with warfarin. Twenty days after delivery, together with her infant, the patient was discharged without any chest symptoms or thrombotic complications. At the time of writing, 6 months after delivery, the patient had no angina or signs of heart failure. In addition, no signs of thrombosis were noted on blood test, echocardiography or ECG with aspirin and warfarin.
heparin dose to maintain aPTT between 1.5 and 2.5-fold the control level5 in view of the normal range in pregnancy.7 As a reference, we introduced plasma heparin level monitoring with the aim to maintain plasma heparin at between 0.1 and 0.4 U/mL.6 With regard to heparin treatment route, we did consider switching from i.v. to subcutaneous, but we could not control aPTT even with an increase in the subcutaneous UFH injection volume, therefore we continued with the former. Although we believed this was the best approach for the patient, we could not confirm if such a strict management was absolutely necessary. Therefore, additional reports are needed to determine the proper approach for anticoagulation therapy in pregnant patients with giant CAA due to KD. In conclusion, anticoagulation therapy using low-dose aspirin and i.v. UFH resulted in successful pregnancy and delivery without any adverse events in a patient with giant CAA caused by KD.
Discussion We describe herein the successful pregnancy in a woman with giant CAA secondary to KD treated with full anti-coagulation therapy consisting of low-dose aspirin and continuous UFH injection. Suda et al. described 83 KD patients with giant CAA treated with aspirin and warfarin.2 Among them, 8/83 patients (9.6%) had cardiac events while 75/83 (90.4%) did not. In the cardiac event-free group, warfarin was discontinued in 30 patients (40%) due to various reasons. Three patients (10%) had acute myocardial infarction and one patient died. Onouchi et al. showed that the rate of freedom from occlusion or recanalization as a result of aspirin and warfarin; aspirin; warfarin; or no medication was 100%, 72%, 33% and 24%, respectively.3 Taking into account that pregnancy can induce hypercoagulation and that, notably, the present left anterior descending artery stenosis had progressed slightly, we considered treatment of only aspirin to be insufficient for pregnant patients with giant CAA due to KD. Tsuda et al. reported on a Japanese nationwide survey of pregnant patients with coronary arterial lesions caused by KD.4 Among the 30 patients found to have such a condition, 16 had giant CAA. Of these, six were not on any medication while 10 took low-dose aspirin only. Additional anticoagulation therapy was not required and no adverse outcomes were reported, but we could not rely too heavily on those results because the sample size was very small and no long-term prognosis was reported. In the interest of the present patient, we deemed anticoagulation therapy necessary. Regarding anti-coagulation during pregnancy, the American Heart Association guideline recommends warfarin use in the mid-period of gestation, but not the early or late periods.8 Therefore, we preferred to use warfarin, which is also easy to monitor using international normalized ratio of prothrombin time. We were, however, unable to obtain patient consent despite the sufficient information provided to her. As an alternative, we introduced continuous UFH injection. We adjusted the
© 2015 Japan Pediatric Society
Acknowledgments We thank Julian Tang from the Department of Education for Clinical Research, National Center for Child Health and Development, for assistance with this manuscript. The authors declare no conflicts of interest.
References 1 Newburger JW, Takahashi M, Gerber MA et al. 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. Circulation 2004; 110: 2747–71. 2 Suda K, Kudo Y, Higaki T et al. Multicenter and retrospective case study of warfarin and aspirin combination therapy in patients with giant coronary aneurysms caused by Kawasaki disease. Circ. J. 2009; 73: 1319–23. 3 Onouchi Z, Hamaoka K, Sakata K et al. Long-term changes in coronary artery aneurysms in patients with Kawasaki disease: Comparison of therapeutic regimens. Circ. J. 2005; 69: 265–72. 4 Tsuda E, Kawamata K, Neki R, Echigo S, Chiba Y. Nationwide survey of pregnancy and delivery in patients with coronary arterial lesions caused by Kawasaki disease in Japan. Cardiol. Young 2006; 16: 173–8. 5 JCS Joint Working Group. Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease (JCS 2008): Digest version. Circ. J. 2010; 74: 1989–2020. 6 Hirsh J, Anand SS, Halperin JL, Fuster V, American Heart Association. Guide to anticoagulant therapy: Heparin: a statement for healthcare professionals from the American Heart Association. Circulation 2001; 103: 2994–3018. 7 Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: A reference table for clinicians. Obstet. Gynecol. 2009; 114: 1326–31. 8 Nishimura RA, Otto CM, Bonow RO et al. 2014 AHA/ACC Guideline for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129: e521–643.
2 3 4
5
Acknowledgment The authors declare no conflicts of interest.
6
References
7
1 Scully M, Hunt BJ, Benjamin S et al. on behalf of British Committee for Standards in Haematology. Guidelines on the diagnosis and
management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br. J. Haematol. 2012; 158: 323–335. Green R. Anemias beyond B12 and iron deficiency: The buzz about other B’s, elementary, and nonelementary problems. Hematology Am. Soc. Hematol. Educ. Program 2012; 2012: 492–8. Nappo F, De Rosa N, Marfella R et al. Impairment of endothelial functions by acute hyperhomocysteinemia and reversal by antioxidant vitamins. JAMA 1999; 281: 2113–18. Johnson CF. Nonorganic failure to thrive. Abuse and neglect of children. In: Behrman RE, Kliegman RM, Jenson HB (eds). Nelson textbook of Pediatrics, 17th edn. Saunders, Tokyo, 2004; 129–30. Dimond A, George JN, Hastings C. Severe Vitamin B-12 deficiency in a child mimicking thrombotic thrombocytopenic purpura. Pediatr. Blood Cancer 2009; 52: 420–22. Motto D. Endothelial cells and thrombotic microangiopathy. Semin. Nephrol. 2012; 32: 208–14. Simsek OP, Gonc N, Gumruk F, Cetin M. A child with vitamin B12 deficiency presenting with pancytopenia and hyperpigmentation. J. Pediatr. Hematol. Oncol. 2004; 26: 834–6.
Strict management of a pregnant patient with giant coronary artery aneurysm due to Kawasaki disease Kosuke Taniguchi,1 Hiroshi Ono,2 Anna Sato,1 Satoko Kinomoto,1 Naomi Tagawa,1 Nagayoshi Umehara,1 Hitoshi Kato2 and Haruhiko Sago1 1 Center of Maternal-Fetal, Neonatal and Reproductive Medicine and 2Division of Cardiology, National Center for Child Health and Development, Setagaya, Tokyo Japan Abstract
Coronary artery aneurysms (CAA) may occur in Kawasaki disease (KD). Patients with giant CAA (diameter >8 mm), in particular, have higher risk of myocardial infarction. Previous reports have demonstrated the necessity of anticoagulation therapy in such cases. The management of patients with KD complicated by giant CAA later in life, however, remains controversial. Here, we describe the strict management in the case of a 28-year-old pregnant Japanese woman with KD with giant CAA (diameter, 11 mm). Instead of warfarin, the patient was given low-dose aspirin and i.v. unfractionated heparin during pregnancy to prevent thrombosis in the giant CAA. At 38 weeks of gestation, she had spontaneous delivery of a healthy baby. No thrombotic or bleeding complications were observed. The strict anticoagulation therapy resulted in successful pregnancy and delivery without any adverse events.
Key words coronary aneurysm, Kawasaki disease, low-dose aspirin, pregnancy, unfractionated heparin. Kawasaki disease (KD) is an acute febrile illness of unknown etiology that primarily affects children younger than 5 years of age. It is thought to be an autoimmune disease with inflammation of medium-sized blood vessels throughout the body. For the management of the disease, early diagnosis and high-dose i.v. Correspondence: Haruhiko Sago, MD, PhD, Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan. Email: [email protected] Received 30 October 2014; revised 3 February 2015; accepted 13 February 2015. doi: 10.1111/ped.12679 © 2015 Japan Pediatric Society
gammaglobulin (IVIG) are essential. Despite proper management, complications such as coronary artery aneurysm (CAA) can arise later in life. In the case of giant CAA (diameter >8 mm), there is a high risk of myocardial infarction due to thrombosis in the aneurysm, which can lead to sudden death.1 Warfarin in combination with aspirin has been reported to be effective in reducing the incidence of cardiac events in patients with CAA secondary to KD,2,3 but the proper management of pregnant patients with similar condition is not yet established. At present, many such patients receive only aspirin or no medication at all.4 Furthermore, reports on the long-term prognosis are scarce due to the low
Kawasaki disease in a pregnant woman 991 Case report
Fig. 1 On contrast computed tomography the internal diameter of the giant coronary artery aneurysm, located on the main trunk of the left coronary artery, was 11 mm (arrow). (Volume-rendered image).
incidence of such cases. Notably, pregnancy can cause hypercoagulation in some cases, whereby appropriate antiplatelet and anticoagulation therapy is required. In this article, we describe the detailed management (low-dose aspirin and i.v. unfractionated heparin [UFH]) of a pregnant Japanese woman with CAA due to KD.
A 28-year-old gravida 0 para 0 Japanese woman was referred for prenatal and delivery care at 7 weeks of gestation. She developed KD at 2 years of age but IVIG was not administered. She had been prescribed aspirin and had been taking it since that time. At 18 years of age, giant CAA (8 mm diameter) was detected on coronary angiography at the main trunk of the left coronary artery (section 5). Echocardiography showed the CAA in the same region but no other abnormalities were detected. Electrocardiogram (ECG) was normal. She had no angina sign and New York Heart Association grade was class I. In spite of the giant CAA, warfarin was not used as per her request. She was prescribed only aspirin (330 mg/day). Two months before conception, contrast computed tomography showed giant CAA (diameter, 11 mm; Fig. 1) in the main trunk of the left coronary artery (section 5) and stenosis at the left anterior descending coronary artery (section 10) just after branching from the giant CAA. Although no thrombosis was detected, we found mild progression of the stenosis (section 10) compared with 2 years prior. The cardiologist recommended anticoagulant therapy in view of the progression of the stenosis, but, in spite of the recommendation, the patient again refused warfarin due to concern about teratogenicity in future pregnancies. Keeping in mind the potential of pregnancy being an additional risk for thrombosis in aneurysm, we added continuous UFH injection to oral low-dose aspirin at 7 + 4/7 weeks of gestation. UFH dose was maintained at either 1.5–2.5-fold activated partial thromboplastin time (aPTT) compared with normal pregnancy, or at a plasma heparin level around 0.20 U/mL (Fig. 2). The target aPTT or heparin level was determined based on previous reports.5–7 Fibrin degradation products were monitored to detect any early signs of thrombosis. Echocardiography conducted at
Fig. 2 Clinical course of anticoagulation therapy. aPTT, activated partial thromboplastin time. © 2015 Japan Pediatric Society
992 K Taniguchi et al. 20, 30 and 36 weeks of gestation, and monthly ECG during pregnancy, showed no thrombosis in the giant CAA. Low-dose aspirin was discontinued at 36 weeks of gestation. Heparin injection was withdrawn after labor pain onset at 38 + 1/7 weeks of gestation to avoid massive bleeding at delivery. The patient had spontaneous delivery of a healthy 3456 g male infant. Apgar score was 7/9 (1 min/5 min). Blood loss at delivery was 605 g. Upon confirmation of postpartum bleeding being controlled, heparin injection was recommenced. From the day after delivery, heparin injection was replaced with warfarin. Twenty days after delivery, together with her infant, the patient was discharged without any chest symptoms or thrombotic complications. At the time of writing, 6 months after delivery, the patient had no angina or signs of heart failure. In addition, no signs of thrombosis were noted on blood test, echocardiography or ECG with aspirin and warfarin.
heparin dose to maintain aPTT between 1.5 and 2.5-fold the control level5 in view of the normal range in pregnancy.7 As a reference, we introduced plasma heparin level monitoring with the aim to maintain plasma heparin at between 0.1 and 0.4 U/mL.6 With regard to heparin treatment route, we did consider switching from i.v. to subcutaneous, but we could not control aPTT even with an increase in the subcutaneous UFH injection volume, therefore we continued with the former. Although we believed this was the best approach for the patient, we could not confirm if such a strict management was absolutely necessary. Therefore, additional reports are needed to determine the proper approach for anticoagulation therapy in pregnant patients with giant CAA due to KD. In conclusion, anticoagulation therapy using low-dose aspirin and i.v. UFH resulted in successful pregnancy and delivery without any adverse events in a patient with giant CAA caused by KD.
Discussion We describe herein the successful pregnancy in a woman with giant CAA secondary to KD treated with full anti-coagulation therapy consisting of low-dose aspirin and continuous UFH injection. Suda et al. described 83 KD patients with giant CAA treated with aspirin and warfarin.2 Among them, 8/83 patients (9.6%) had cardiac events while 75/83 (90.4%) did not. In the cardiac event-free group, warfarin was discontinued in 30 patients (40%) due to various reasons. Three patients (10%) had acute myocardial infarction and one patient died. Onouchi et al. showed that the rate of freedom from occlusion or recanalization as a result of aspirin and warfarin; aspirin; warfarin; or no medication was 100%, 72%, 33% and 24%, respectively.3 Taking into account that pregnancy can induce hypercoagulation and that, notably, the present left anterior descending artery stenosis had progressed slightly, we considered treatment of only aspirin to be insufficient for pregnant patients with giant CAA due to KD. Tsuda et al. reported on a Japanese nationwide survey of pregnant patients with coronary arterial lesions caused by KD.4 Among the 30 patients found to have such a condition, 16 had giant CAA. Of these, six were not on any medication while 10 took low-dose aspirin only. Additional anticoagulation therapy was not required and no adverse outcomes were reported, but we could not rely too heavily on those results because the sample size was very small and no long-term prognosis was reported. In the interest of the present patient, we deemed anticoagulation therapy necessary. Regarding anti-coagulation during pregnancy, the American Heart Association guideline recommends warfarin use in the mid-period of gestation, but not the early or late periods.8 Therefore, we preferred to use warfarin, which is also easy to monitor using international normalized ratio of prothrombin time. We were, however, unable to obtain patient consent despite the sufficient information provided to her. As an alternative, we introduced continuous UFH injection. We adjusted the
© 2015 Japan Pediatric Society
Acknowledgments We thank Julian Tang from the Department of Education for Clinical Research, National Center for Child Health and Development, for assistance with this manuscript. The authors declare no conflicts of interest.
References 1 Newburger JW, Takahashi M, Gerber MA et al. 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. Circulation 2004; 110: 2747–71. 2 Suda K, Kudo Y, Higaki T et al. Multicenter and retrospective case study of warfarin and aspirin combination therapy in patients with giant coronary aneurysms caused by Kawasaki disease. Circ. J. 2009; 73: 1319–23. 3 Onouchi Z, Hamaoka K, Sakata K et al. Long-term changes in coronary artery aneurysms in patients with Kawasaki disease: Comparison of therapeutic regimens. Circ. J. 2005; 69: 265–72. 4 Tsuda E, Kawamata K, Neki R, Echigo S, Chiba Y. Nationwide survey of pregnancy and delivery in patients with coronary arterial lesions caused by Kawasaki disease in Japan. Cardiol. Young 2006; 16: 173–8. 5 JCS Joint Working Group. Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease (JCS 2008): Digest version. Circ. J. 2010; 74: 1989–2020. 6 Hirsh J, Anand SS, Halperin JL, Fuster V, American Heart Association. Guide to anticoagulant therapy: Heparin: a statement for healthcare professionals from the American Heart Association. Circulation 2001; 103: 2994–3018. 7 Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: A reference table for clinicians. Obstet. Gynecol. 2009; 114: 1326–31. 8 Nishimura RA, Otto CM, Bonow RO et al. 2014 AHA/ACC Guideline for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129: e521–643.
