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Pediatrics International (2013) 55, e111–e115
doi: 10.1111/ped.12130
Patient Report
Thrombolytic therapy in Kawasaki disease: A report of four cases Mana Harada, Katsumi Akimoto, Masao Otaka, Keiko Sato, Hisayuki Oda, Masahiro Otsuki, Ken Takahashi, Masahiko Kishiro and Toshiaki Shimizu Pediatrics and Adolescent Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan Abstract
Four patients with a thrombus in a coronary artery aneurysm due to Kawasaki disease (KD) were treated at our hospital between 1994 and 2009. All the cases were treated with intravenous coronary thrombolysis (IVCT) therapy and the cases with acute myocardial infarction were treated with additional intracoronary thrombolysis therapy. Although both thrombolytic therapies were effective, IVCT required more time than intracoronary thrombolysis to resolve the thrombus. We concluded that IVCT can be used as the first-line thrombolytic therapy for KD, except in cases with acute myocardial infarction.
Key words acute myocardial infarction, intracoronary thrombolysis, intravenous coronary thrombolysis, Kawasaki disease, tissue polypeptide antigen.
There are established guidelines for the treatment of a thrombus in an aneurysm caused by Kawasaki disease (KD),1 but specific criteria for drug selection and doses have not yet been determined. The development of this condition in patients is rare, and in our own hospital, only four patients with a thrombus in a coronary artery aneurysm were treated from 1994 to 2009. In the present study, we examined the drugs administered, the associated doses, and the effectiveness of the treatment in these patients.
Case report The drugs administered, the associated doses, and the prothrombin time-international normalized ratio of the patients receiving the antithrombotic therapy and the thrombolytic therapies are presented in Tables 1 and 2. Case 1
A 3-month-old boy was diagnosed with KD on the 5th day of illness. He was administered intravenous immunoglobulin (IVIG) and aspirin, but continued to exhibit a fever. On the 16th day of illness, IVIG caused the fever to subside. On the 18th day of illness, an aneurysm – 7 mm in diameter – was noted in segments 1–4 of the right coronary artery (RCA) and an aneurysm – 9 mm in diameter – was noted in segment 6 of the left coronary artery (LCA). Antithrombotic therapy was then initiated. On the 33rd day of illness, we noted that the levels of cardiac enzymes were elevated, and electrocardiogram indicated ST-T changes on the II, III, and aVf leads. Cardiac ultrasonography indicated a thrombus in the aneurysm, now 10 mm in Correspondence: Mana Harada, MD, Department of Pediatrics, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Email: [email protected] Received 8 May 2011; revised 12 February 2012; accepted 10 April 2013.
© 2013 The Authors Pediatrics International © 2013 Japan Pediatric Society
diameter, in segment 6 of the LCA, and the patient was therefore diagnosed with acute myocardial infarction (AMI). Intravenous coronary thrombolysis (IVCT) was administered with tissue plasminogen activator (tPA), but no changes in the thrombus were noted. Intravenous heparin was subsequently discontinued and intracoronary thrombolysis (ICT) was performed. The thrombus dissolved and normal blood flow was noted. Thereafter, heparin treatment was promptly resumed. On the 42nd and the 65th day of illness, AMI developed, with findings similar to those noted previously in segment 6 of the LCA. After IVCT and ICT, IVCT was again performed for 3 days; however, no changes in the thrombus were noted. However, ischemic changes gradually disappeared. At 1 year of age, AMI developed at the same site in the same manner as before. The patient received similar treatment and IVCT was performed for 3 days as an additional therapy, due to which the thrombus was dissolved. The patient underwent a coronary arterial bypass graft at 2 years of age at another hospital. His clinical condition is currently satisfactory. Case 2
A 3-month-old boy was diagnosed with KD on the 4th day of illness. He was administered IVIG and aspirin. On the 7th day of illness, methylprednisolone (mPSL) was administered and the patient’s fever subsided. However, on the 17th day of illness, two aneurysms – both measuring 5 mm in diameter – were detected in segment 1 of the RCA and segment 6 of the LCA. Antithrombotic therapy was then initiated. On the 32nd day of illness, the aneurysm in segment 1 measured 14 mm in diameter and the aneurysm in segment 6 measured 7 mm in diameter. On the 36th day of illness, ventricular fibrillation (Vf) developed and was alleviated using a defibrillator. Ultrasonography examination revealed complete thrombotic occlusion in segment 1 of the RCA.
© 2013 The Authors Pediatrics International © 2013 Japan Pediatric Society
Aspirin: 30 mg/kg/day IVIG: 2 g/kg/day
IVIG: 2 g/kg/day
mPSL: 30 mg/kg/day for 3 days
Day 7
Day 9
Aspirin: 30 mg/kg/day IVIG: 1 g/kg for 2 days mPSL: 10 mg/kg/day for 3 days
Day 5
Day 9
Day 6
Day 7
Aspirin: 30 mg/kg/day Dipyrydamole: 5 mg/kg/day IVIG: 2 g/kg/day mPSL: 30 mg/kg/day for 3 days
–
1 year of age
Day 4
Aspirin: 30 mg/kg/day IVIG: 200 mg/kg/day for 5 days
Day 5
Initial treatment for KD
Aspirin: 5 mg/kg/day Warfarin: 0.1–0.15 mg/kg/day Ticlopidine hydrochloride: 5 mg/kg/day Dipyridamole: 5 mg/kg/day
Day 18
Day 18
Day 17
Aspirin: 5 mg/kg/day Warfarin: 0.15–0.2 mg/kg/day Ticlopidine hydrochloride: 5 mg/kg/day Dipyridamole: 5 mg/kg/day
Aspirin: 5 mg/kg/day Warfarin: 0.15 mg/kg/day Dipyridamole: 5 mg/kg/day
Aspirin: 5 mg/kg/day Warfarin: 0.15 mg/kg/day
1.5–3.0
2.0–2.6
1.8
2.0–2.5
1.8–2.5
PT-INR
Antithrombotic therapy
Aspirin: 5 mg/kg/day Warfarin: 0.15 mg/kg/day Ticlopidine hydrochloride: 5 mg/kg/day Dipyridamole: 5 mg/kg/day
Day 18
Oral administration Heparin: 200 U/kg/day
Day 18
Day 18
Day 17
Heparin: 300 U/kg/day
Heparin: 300 U/kg/day
Heparin: 200 U/kg/day
Heparin: 200 U/kg/day
Day 18
Intravenous infusion; via a peripheral vein Pre-ICT: tPA(t): 25,000 U/kg
Day 60
Day 53
Day 22
Day 36
Pre-ICT: tPA(a): 300,000 U/kg Post-ICT: tPA(m): 27,500 units/kg for 3 days Pre-ICT: tPA(a): 300,000 U/kg Post-ICT: tPA(m): 27,500 units/kg for 3 days
Pre-ICT: tPA(a): 300,000 U/kg Post-ICT: tPA(m): 27,500 units/kg for 3 days
Pre-ICT: tPA(t): 36,000 U/kg/day
tPA(t): 50,000 U/kg for 2 times
tPA(t): 25,000 units/kg for 3 times tPA(t): 50,000 U/kg for 2 times
ICT
Day 60
Day 53
Day 22
Day 36
tPA(a): 250,000 U/kg for 3 times tPA(a): 250,000 U/kg for 3 times
Urokinase: 10,000 U/kg for 2 times
tPA(m): 50,000 U/kg/day for 3 times
tPA(t): 25,000 U/kg for 3 times
Day 65
Day 42
Day 33
Thrombolytic therapy
Pre-ICT: tPA(t): 35,000 U/kg Post-ICT: tPA(t): 35,000 U/kg for 3 days Day 65 Pre-ICT: tPA(t): 35,000 U/kg Post-ICT: tPA(t): 35,000 U/kg for 3 days Pre-ICT: tPA(t): 35,000 U/kg Post-ICT: t-PA(t): 35,000 U/kg for 3 days
Day 42
Day 33
IVCT
a, alteplase; ICT, intracoronary thrombolysis; IVCT, intravenous coronary thrombolysis; IVIG, intravenous immunoglobulin; KD, Kawasaki disease; m, monteplase; mPSL, methylprednisolone; PT-INR, prothrombin time-international normalized ratio; S, successful; t, tisokinase; tPA, tissue polypeptide antigen; U, unsuccessful.
4
3
2
1
Case
Table 1 Drugs administered, associated doses, and PT-INR of the patients receiving antithrombotic therapies and thrombolytic therapies
e112 M Harada et al.
Thrombolysis in Kawasaki disease
e113
Table 2 Results of thrombolytic therapy Case
1
Age at onset
3 months
1 year
Day of ICT
Day 33 Day 42 Day 65
2
3 months
*LCA (#6): 11 mm RCA (#1-4): 7 mm Day 36
3
10 months
Day 22
4
12 months
Day 53 Day 60
Size of aneurysm (Segment) *Thrombus (+)
AMI
*LCA (#6): 9 mm RCA (#1-4): 7 mm *LCA (#6): 11 mm RCA (#1-4): 10 mm +
+ + +
LCA (#6): 7 mm *RCA (#1): 14 mm *LCA (#5): 11 mm RCA (#1-2): 6 mm *LCA (#5): 11 mm *RCA (#1-4): 11 mm
+
tPA(t)
-
Thrombolytic therapy
Effect of ICT
Effect of IVCT
IVCT (pre-ICT)
ICT
IVCT (post-ICT) – tPA(t)
tPA(t)
tPA(t)
Complication
S U U
U
S
tPA(m)
–
S
tPA(a)
Urokinase
tPA(m)
U
tPA(a)
tPA(a)
tPA(m)
U U
a, alteplase; AMI, acute myocardial infarction; ICT, intracoronary thrombolysis; IVCT, intravenous coronary thrombolysis; LCA, left coronary artery; m, monteplase; RCA, right coronary artery; S, successful; t, tisokinase; tPA, tissue polypeptide antigen; U, unsuccessful.
Following a diagnosis of AMI, IVCT was performed, but no changes were noted in the thrombus. Therefore, ICT was performed, during which heparin administration was discontinued. ICT led to dissolution of the thrombus and resumption of blood flow (Fig. 1a,b). However, Vf developed again after 8 h and the patient died. An autopsy revealed complete thrombotic occlusion in segment 1 and segment 6. Case 3
A 10-month-old boy was diagnosed with KD on the 6th day of illness. He was administered IVIG and aspirin. On the 9th day of illness, mPSL was administered. On the 18th day of illness, an aneurysm – 6 mm in diameter – was noted in segments 1–2 of the RCA and an aneurysm – 8 mm in diameter – was noted in segment 5 of the LCA. Antithrombotic therapy was therefore initiated. On the 22nd day of illness, a thrombus was noted in segment 5; therefore, IVCT was performed, but no thrombotic changes were noted. The patient was asymptomatic, but a massive thrombus was detected within the aneurysm in the LCA; therefore, ICT was performed, during which heparin administration was discontinued. After ICT, no thrombotic changes were noted. Subsequently, an additional course of IVCT was administered. Following this therapy, the thrombus gradually dissolved. The diameter of the left anterior descending artery aneurysm had increased to 30 mm, and accordingly the size of the thrombus decreased. The thrombus had dissolved by the 40th day of illness (Fig. 1c,d). The patient is currently 5 years of age and is still receiving strict antithrombotic therapy. Thus far, in this patient, AMI has not developed. Case 4
A 12-month-old boy was diagnosed with KD on the 5th day of illness and was administered IVIG and aspirin. On the 7th day
of illness, an additional course of IVIG was administered. On the 9th day of illness, mPSL was administered and the fever subsided. On the 18th day of illness, two aneurysms – 8 mm in diameter – were noted in segments 1–4 of the RCA and segment 5 of the LCA; therefore, antithrombotic therapy was initiated. On the 53rd day of illness, a giant coronary artery aneurysm (measuring 11 mm in diameter) was noted in segments 1–4 of the RCA and segment 5 of the LCA. Ultrasonography examination revealed a thrombus within the aneurysm in segment 5 of the LCA. IVCT was performed, but no changes in the thrombus were noted and the patient remained asymptomatic. ICT was performed, during which heparin administration was discontinued. After ICT, no changes were noted in the thrombus. IVCT was again performed for 3 days, following which the thrombus gradually dissolved. On the 60th day of illness, a thrombus was detected in the aneurysm of the RCA (segments 1–4). The same therapy was performed and the patient’s course was similar; the thrombus had dissolved by the 67th day of illness. At present, the 4-year-old patient does not exhibit stenosis and is being monitored closely.
Discussion Cases Case 1
When this patient was diagnosed, there were no established guidelines for the treatment of thrombi associated with KD. Treatment was in accordance with the guidelines for thrombolytic therapy in cardiovascular medicine. Intensive therapy was required to avoid serious events, such as occlusion of small coronary arteries in the infant during the subsequent AMI and recurrent AMI because segment 6, and thus cardiac function, was affected. IVCT as an additional therapy was also performed. © 2013 The Authors Pediatrics International © 2013 Japan Pediatric Society
e114
M Harada et al.
Fig. 1 (a) Case 2: Coronary angiography indicated complete occlusion of segment 6 of the left coronary artery (LCA) on the 32nd day of illness. (b) Case 2: Coronary angiography. After intracoronary thrombolysis of the LCA, segment 6 was reperfused. (c) Case 3: Cardiac ultrasonography on the 22nd day of illness showed a thrombus in an aneurysm, 14 mm in diameter, in segment 5 of the LCA. (d) Case 3: Cardiac ultrasonography. On the 40th day of illness after intravenous coronary thrombolysis, the thrombus gradually dissolved.
Case 2
A thrombus formed again after ICT. IVCT with tPA may have been required as an additional therapy. Cases 3 and 4
These two cases did not have AMI. Although the thrombi showed no change immediately after the ICT, they gradually dissolved 3 days after IVCT was initiated. It is possible that the combination of ICT and IVCT resulted in the dissolution of the thrombi. Therefore, this treatment may be worthwhile when the thrombus is in the dilated coronary artery. © 2013 The Authors Pediatrics International © 2013 Japan Pediatric Society
Therapeutic strategies for managing thrombi: Practices at this hospital
The guidelines provide details of the doses of tPA and urokinase to be administered via the peripheral vein and the doses of tPA to be administered via the coronary artery.1 However, they do not differentiate between cases with and without AMI. Furthermore, they lack information on drug selection, duration of administration, and the need for additional therapy. Catheter intervention, including thrombectomy, is a promising therapeutic strategy for the management of thrombus. However, when considering catheter intervention, we suggest that the size of the patient should be
Thrombolysis in Kawasaki disease close to that of an adult. The main reason of AMI in patients with giant aneurysm is the thrombus. Therefore, the tPA will be more effective in patients with KD compared to those with atherosclerosis. Although only urokinase is currently approved for ICT, tPA with a high fibrin affinity is recommended for both ICT and IVCT.2 Of the tPA, alteplase has a half-life of approximately 4 min, while monteplase has a half-life of 20 min or longer.3 The tPA used should be selected according to its half-life. Several reports have described continuous administration of tPA to treat thrombi in newborn infants.4,5 This method of treatment needs to be studied further. In the present cases, IVCT was initially performed. If a thrombus then failed to dissolve, ICT was performed. With either approach, IVCT is then performed for 3 days as an additional therapy to prevent recurrent thrombi. Administration of heparin was discontinued only during ICT to avoid bleeding. Heparin treatment was resumed during IVCT. The repeated doses set by the guidelines were administered and serious bleeding complications were not found in these cases. Based on the cases seen in this hospital, IVCT requires a longer duration to demonstrate its efficacy, but eventually proves
e115
efficacious. In an emergency, such as AMI, ICT should also be performed, whereas, in other situations, only IVCT should prove sufficient.
References 1 Ogawa S, Akagi T, Baba K et al. Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease (JCS2008). Circ. J. 2010; 74: 1989–2020. 2 Bergmann SR, Fox KA, Ter-Pogossian MM, Sobel BE, Collen D. Clot-selective coronary thrombolysis with tissue-type plasminogen activator. Science 1983; 220: 1181–3. 3 Kawai C, Yui Y, Hosoda S et al. A prospective, randomized, doubleblind multicenter trial of a single bolus injection of the novel modified tPA E6010 in the treatment of acute myocardial infarction: comparison with native tPA. E6010 Study Group. J. Am. Coll. Cardiol. 1997; 29: 1447–53. 4 Grieg A. Thrombolysis of a neonatal brachial artery thrombosis with tissue plasminogen activator. J. Perinatol. 1998; 18: 460–2. 5 Watkins S, Yunge M, Jones D, Kiely E, Petros AJ. Prolonged use of tissue plasminogen activator for bilateral lower limb arterial occlusion in a neonate. J. Pediatr. Surg. 2001; 36: 654–6.
© 2013 The Authors Pediatrics International © 2013 Japan Pediatric Society
Pediatrics International (2013) 55, e111–e115
doi: 10.1111/ped.12130
Patient Report
Thrombolytic therapy in Kawasaki disease: A report of four cases Mana Harada, Katsumi Akimoto, Masao Otaka, Keiko Sato, Hisayuki Oda, Masahiro Otsuki, Ken Takahashi, Masahiko Kishiro and Toshiaki Shimizu Pediatrics and Adolescent Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan Abstract
Four patients with a thrombus in a coronary artery aneurysm due to Kawasaki disease (KD) were treated at our hospital between 1994 and 2009. All the cases were treated with intravenous coronary thrombolysis (IVCT) therapy and the cases with acute myocardial infarction were treated with additional intracoronary thrombolysis therapy. Although both thrombolytic therapies were effective, IVCT required more time than intracoronary thrombolysis to resolve the thrombus. We concluded that IVCT can be used as the first-line thrombolytic therapy for KD, except in cases with acute myocardial infarction.
Key words acute myocardial infarction, intracoronary thrombolysis, intravenous coronary thrombolysis, Kawasaki disease, tissue polypeptide antigen.
There are established guidelines for the treatment of a thrombus in an aneurysm caused by Kawasaki disease (KD),1 but specific criteria for drug selection and doses have not yet been determined. The development of this condition in patients is rare, and in our own hospital, only four patients with a thrombus in a coronary artery aneurysm were treated from 1994 to 2009. In the present study, we examined the drugs administered, the associated doses, and the effectiveness of the treatment in these patients.
Case report The drugs administered, the associated doses, and the prothrombin time-international normalized ratio of the patients receiving the antithrombotic therapy and the thrombolytic therapies are presented in Tables 1 and 2. Case 1
A 3-month-old boy was diagnosed with KD on the 5th day of illness. He was administered intravenous immunoglobulin (IVIG) and aspirin, but continued to exhibit a fever. On the 16th day of illness, IVIG caused the fever to subside. On the 18th day of illness, an aneurysm – 7 mm in diameter – was noted in segments 1–4 of the right coronary artery (RCA) and an aneurysm – 9 mm in diameter – was noted in segment 6 of the left coronary artery (LCA). Antithrombotic therapy was then initiated. On the 33rd day of illness, we noted that the levels of cardiac enzymes were elevated, and electrocardiogram indicated ST-T changes on the II, III, and aVf leads. Cardiac ultrasonography indicated a thrombus in the aneurysm, now 10 mm in Correspondence: Mana Harada, MD, Department of Pediatrics, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Email: [email protected] Received 8 May 2011; revised 12 February 2012; accepted 10 April 2013.
© 2013 The Authors Pediatrics International © 2013 Japan Pediatric Society
diameter, in segment 6 of the LCA, and the patient was therefore diagnosed with acute myocardial infarction (AMI). Intravenous coronary thrombolysis (IVCT) was administered with tissue plasminogen activator (tPA), but no changes in the thrombus were noted. Intravenous heparin was subsequently discontinued and intracoronary thrombolysis (ICT) was performed. The thrombus dissolved and normal blood flow was noted. Thereafter, heparin treatment was promptly resumed. On the 42nd and the 65th day of illness, AMI developed, with findings similar to those noted previously in segment 6 of the LCA. After IVCT and ICT, IVCT was again performed for 3 days; however, no changes in the thrombus were noted. However, ischemic changes gradually disappeared. At 1 year of age, AMI developed at the same site in the same manner as before. The patient received similar treatment and IVCT was performed for 3 days as an additional therapy, due to which the thrombus was dissolved. The patient underwent a coronary arterial bypass graft at 2 years of age at another hospital. His clinical condition is currently satisfactory. Case 2
A 3-month-old boy was diagnosed with KD on the 4th day of illness. He was administered IVIG and aspirin. On the 7th day of illness, methylprednisolone (mPSL) was administered and the patient’s fever subsided. However, on the 17th day of illness, two aneurysms – both measuring 5 mm in diameter – were detected in segment 1 of the RCA and segment 6 of the LCA. Antithrombotic therapy was then initiated. On the 32nd day of illness, the aneurysm in segment 1 measured 14 mm in diameter and the aneurysm in segment 6 measured 7 mm in diameter. On the 36th day of illness, ventricular fibrillation (Vf) developed and was alleviated using a defibrillator. Ultrasonography examination revealed complete thrombotic occlusion in segment 1 of the RCA.
© 2013 The Authors Pediatrics International © 2013 Japan Pediatric Society
Aspirin: 30 mg/kg/day IVIG: 2 g/kg/day
IVIG: 2 g/kg/day
mPSL: 30 mg/kg/day for 3 days
Day 7
Day 9
Aspirin: 30 mg/kg/day IVIG: 1 g/kg for 2 days mPSL: 10 mg/kg/day for 3 days
Day 5
Day 9
Day 6
Day 7
Aspirin: 30 mg/kg/day Dipyrydamole: 5 mg/kg/day IVIG: 2 g/kg/day mPSL: 30 mg/kg/day for 3 days
–
1 year of age
Day 4
Aspirin: 30 mg/kg/day IVIG: 200 mg/kg/day for 5 days
Day 5
Initial treatment for KD
Aspirin: 5 mg/kg/day Warfarin: 0.1–0.15 mg/kg/day Ticlopidine hydrochloride: 5 mg/kg/day Dipyridamole: 5 mg/kg/day
Day 18
Day 18
Day 17
Aspirin: 5 mg/kg/day Warfarin: 0.15–0.2 mg/kg/day Ticlopidine hydrochloride: 5 mg/kg/day Dipyridamole: 5 mg/kg/day
Aspirin: 5 mg/kg/day Warfarin: 0.15 mg/kg/day Dipyridamole: 5 mg/kg/day
Aspirin: 5 mg/kg/day Warfarin: 0.15 mg/kg/day
1.5–3.0
2.0–2.6
1.8
2.0–2.5
1.8–2.5
PT-INR
Antithrombotic therapy
Aspirin: 5 mg/kg/day Warfarin: 0.15 mg/kg/day Ticlopidine hydrochloride: 5 mg/kg/day Dipyridamole: 5 mg/kg/day
Day 18
Oral administration Heparin: 200 U/kg/day
Day 18
Day 18
Day 17
Heparin: 300 U/kg/day
Heparin: 300 U/kg/day
Heparin: 200 U/kg/day
Heparin: 200 U/kg/day
Day 18
Intravenous infusion; via a peripheral vein Pre-ICT: tPA(t): 25,000 U/kg
Day 60
Day 53
Day 22
Day 36
Pre-ICT: tPA(a): 300,000 U/kg Post-ICT: tPA(m): 27,500 units/kg for 3 days Pre-ICT: tPA(a): 300,000 U/kg Post-ICT: tPA(m): 27,500 units/kg for 3 days
Pre-ICT: tPA(a): 300,000 U/kg Post-ICT: tPA(m): 27,500 units/kg for 3 days
Pre-ICT: tPA(t): 36,000 U/kg/day
tPA(t): 50,000 U/kg for 2 times
tPA(t): 25,000 units/kg for 3 times tPA(t): 50,000 U/kg for 2 times
ICT
Day 60
Day 53
Day 22
Day 36
tPA(a): 250,000 U/kg for 3 times tPA(a): 250,000 U/kg for 3 times
Urokinase: 10,000 U/kg for 2 times
tPA(m): 50,000 U/kg/day for 3 times
tPA(t): 25,000 U/kg for 3 times
Day 65
Day 42
Day 33
Thrombolytic therapy
Pre-ICT: tPA(t): 35,000 U/kg Post-ICT: tPA(t): 35,000 U/kg for 3 days Day 65 Pre-ICT: tPA(t): 35,000 U/kg Post-ICT: tPA(t): 35,000 U/kg for 3 days Pre-ICT: tPA(t): 35,000 U/kg Post-ICT: t-PA(t): 35,000 U/kg for 3 days
Day 42
Day 33
IVCT
a, alteplase; ICT, intracoronary thrombolysis; IVCT, intravenous coronary thrombolysis; IVIG, intravenous immunoglobulin; KD, Kawasaki disease; m, monteplase; mPSL, methylprednisolone; PT-INR, prothrombin time-international normalized ratio; S, successful; t, tisokinase; tPA, tissue polypeptide antigen; U, unsuccessful.
4
3
2
1
Case
Table 1 Drugs administered, associated doses, and PT-INR of the patients receiving antithrombotic therapies and thrombolytic therapies
e112 M Harada et al.
Thrombolysis in Kawasaki disease
e113
Table 2 Results of thrombolytic therapy Case
1
Age at onset
3 months
1 year
Day of ICT
Day 33 Day 42 Day 65
2
3 months
*LCA (#6): 11 mm RCA (#1-4): 7 mm Day 36
3
10 months
Day 22
4
12 months
Day 53 Day 60
Size of aneurysm (Segment) *Thrombus (+)
AMI
*LCA (#6): 9 mm RCA (#1-4): 7 mm *LCA (#6): 11 mm RCA (#1-4): 10 mm +
+ + +
LCA (#6): 7 mm *RCA (#1): 14 mm *LCA (#5): 11 mm RCA (#1-2): 6 mm *LCA (#5): 11 mm *RCA (#1-4): 11 mm
+
tPA(t)
-
Thrombolytic therapy
Effect of ICT
Effect of IVCT
IVCT (pre-ICT)
ICT
IVCT (post-ICT) – tPA(t)
tPA(t)
tPA(t)
Complication
S U U
U
S
tPA(m)
–
S
tPA(a)
Urokinase
tPA(m)
U
tPA(a)
tPA(a)
tPA(m)
U U
a, alteplase; AMI, acute myocardial infarction; ICT, intracoronary thrombolysis; IVCT, intravenous coronary thrombolysis; LCA, left coronary artery; m, monteplase; RCA, right coronary artery; S, successful; t, tisokinase; tPA, tissue polypeptide antigen; U, unsuccessful.
Following a diagnosis of AMI, IVCT was performed, but no changes were noted in the thrombus. Therefore, ICT was performed, during which heparin administration was discontinued. ICT led to dissolution of the thrombus and resumption of blood flow (Fig. 1a,b). However, Vf developed again after 8 h and the patient died. An autopsy revealed complete thrombotic occlusion in segment 1 and segment 6. Case 3
A 10-month-old boy was diagnosed with KD on the 6th day of illness. He was administered IVIG and aspirin. On the 9th day of illness, mPSL was administered. On the 18th day of illness, an aneurysm – 6 mm in diameter – was noted in segments 1–2 of the RCA and an aneurysm – 8 mm in diameter – was noted in segment 5 of the LCA. Antithrombotic therapy was therefore initiated. On the 22nd day of illness, a thrombus was noted in segment 5; therefore, IVCT was performed, but no thrombotic changes were noted. The patient was asymptomatic, but a massive thrombus was detected within the aneurysm in the LCA; therefore, ICT was performed, during which heparin administration was discontinued. After ICT, no thrombotic changes were noted. Subsequently, an additional course of IVCT was administered. Following this therapy, the thrombus gradually dissolved. The diameter of the left anterior descending artery aneurysm had increased to 30 mm, and accordingly the size of the thrombus decreased. The thrombus had dissolved by the 40th day of illness (Fig. 1c,d). The patient is currently 5 years of age and is still receiving strict antithrombotic therapy. Thus far, in this patient, AMI has not developed. Case 4
A 12-month-old boy was diagnosed with KD on the 5th day of illness and was administered IVIG and aspirin. On the 7th day
of illness, an additional course of IVIG was administered. On the 9th day of illness, mPSL was administered and the fever subsided. On the 18th day of illness, two aneurysms – 8 mm in diameter – were noted in segments 1–4 of the RCA and segment 5 of the LCA; therefore, antithrombotic therapy was initiated. On the 53rd day of illness, a giant coronary artery aneurysm (measuring 11 mm in diameter) was noted in segments 1–4 of the RCA and segment 5 of the LCA. Ultrasonography examination revealed a thrombus within the aneurysm in segment 5 of the LCA. IVCT was performed, but no changes in the thrombus were noted and the patient remained asymptomatic. ICT was performed, during which heparin administration was discontinued. After ICT, no changes were noted in the thrombus. IVCT was again performed for 3 days, following which the thrombus gradually dissolved. On the 60th day of illness, a thrombus was detected in the aneurysm of the RCA (segments 1–4). The same therapy was performed and the patient’s course was similar; the thrombus had dissolved by the 67th day of illness. At present, the 4-year-old patient does not exhibit stenosis and is being monitored closely.
Discussion Cases Case 1
When this patient was diagnosed, there were no established guidelines for the treatment of thrombi associated with KD. Treatment was in accordance with the guidelines for thrombolytic therapy in cardiovascular medicine. Intensive therapy was required to avoid serious events, such as occlusion of small coronary arteries in the infant during the subsequent AMI and recurrent AMI because segment 6, and thus cardiac function, was affected. IVCT as an additional therapy was also performed. © 2013 The Authors Pediatrics International © 2013 Japan Pediatric Society
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M Harada et al.
Fig. 1 (a) Case 2: Coronary angiography indicated complete occlusion of segment 6 of the left coronary artery (LCA) on the 32nd day of illness. (b) Case 2: Coronary angiography. After intracoronary thrombolysis of the LCA, segment 6 was reperfused. (c) Case 3: Cardiac ultrasonography on the 22nd day of illness showed a thrombus in an aneurysm, 14 mm in diameter, in segment 5 of the LCA. (d) Case 3: Cardiac ultrasonography. On the 40th day of illness after intravenous coronary thrombolysis, the thrombus gradually dissolved.
Case 2
A thrombus formed again after ICT. IVCT with tPA may have been required as an additional therapy. Cases 3 and 4
These two cases did not have AMI. Although the thrombi showed no change immediately after the ICT, they gradually dissolved 3 days after IVCT was initiated. It is possible that the combination of ICT and IVCT resulted in the dissolution of the thrombi. Therefore, this treatment may be worthwhile when the thrombus is in the dilated coronary artery. © 2013 The Authors Pediatrics International © 2013 Japan Pediatric Society
Therapeutic strategies for managing thrombi: Practices at this hospital
The guidelines provide details of the doses of tPA and urokinase to be administered via the peripheral vein and the doses of tPA to be administered via the coronary artery.1 However, they do not differentiate between cases with and without AMI. Furthermore, they lack information on drug selection, duration of administration, and the need for additional therapy. Catheter intervention, including thrombectomy, is a promising therapeutic strategy for the management of thrombus. However, when considering catheter intervention, we suggest that the size of the patient should be
Thrombolysis in Kawasaki disease close to that of an adult. The main reason of AMI in patients with giant aneurysm is the thrombus. Therefore, the tPA will be more effective in patients with KD compared to those with atherosclerosis. Although only urokinase is currently approved for ICT, tPA with a high fibrin affinity is recommended for both ICT and IVCT.2 Of the tPA, alteplase has a half-life of approximately 4 min, while monteplase has a half-life of 20 min or longer.3 The tPA used should be selected according to its half-life. Several reports have described continuous administration of tPA to treat thrombi in newborn infants.4,5 This method of treatment needs to be studied further. In the present cases, IVCT was initially performed. If a thrombus then failed to dissolve, ICT was performed. With either approach, IVCT is then performed for 3 days as an additional therapy to prevent recurrent thrombi. Administration of heparin was discontinued only during ICT to avoid bleeding. Heparin treatment was resumed during IVCT. The repeated doses set by the guidelines were administered and serious bleeding complications were not found in these cases. Based on the cases seen in this hospital, IVCT requires a longer duration to demonstrate its efficacy, but eventually proves
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efficacious. In an emergency, such as AMI, ICT should also be performed, whereas, in other situations, only IVCT should prove sufficient.
References 1 Ogawa S, Akagi T, Baba K et al. Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease (JCS2008). Circ. J. 2010; 74: 1989–2020. 2 Bergmann SR, Fox KA, Ter-Pogossian MM, Sobel BE, Collen D. Clot-selective coronary thrombolysis with tissue-type plasminogen activator. Science 1983; 220: 1181–3. 3 Kawai C, Yui Y, Hosoda S et al. A prospective, randomized, doubleblind multicenter trial of a single bolus injection of the novel modified tPA E6010 in the treatment of acute myocardial infarction: comparison with native tPA. E6010 Study Group. J. Am. Coll. Cardiol. 1997; 29: 1447–53. 4 Grieg A. Thrombolysis of a neonatal brachial artery thrombosis with tissue plasminogen activator. J. Perinatol. 1998; 18: 460–2. 5 Watkins S, Yunge M, Jones D, Kiely E, Petros AJ. Prolonged use of tissue plasminogen activator for bilateral lower limb arterial occlusion in a neonate. J. Pediatr. Surg. 2001; 36: 654–6.
© 2013 The Authors Pediatrics International © 2013 Japan Pediatric Society
