Christoph Male, Division of Paediatric Cardiology, Department of Paediatrics and Adolescent Medicine, Medical University of Vienna, Waehringer Gürtel 18-20, 1090 Vienna, Austria. Tel.: +43 1 40400 3154; fax: +43 1 40400 3154. E-mail: email@example.com
Summary. Background: During cardiac catheterization (CC) in children, unfractionated heparin (UFH) is used for primary prophylaxis of thrombotic events (TE). However, the optimal UFH dose to minimize TE and bleeding in children has yet to be established. Objectives: To (i) objectively assess the incidence of TE and bleeding during pediatric CC using clinical assessment and ultrasound; and (ii) compare a high-dose vs. low-dose UFH protocol for thromboprophylaxis. Methods: A randomized controlled trial (RCT) comparing high-dose UFH (100 units kg−1 bolus, followed by 20 units kg h−1 continuous infusion) vs. low-dose UFH (50 units kg−1 bolus) during CC. Outcome assessment was by clinical examination and vascular ultrasound, performed by blinded examiners before and within 48 h after CC. Children with no consent for randomization were followed in a cohort receiving standard-of-care UFH (parallel-cohort RCT). Results: A total of 227 children were included; 137 were randomized and 90 followed in the cohort study. The overall incidence of TE was 4.6% and bleeding 6.6%. The RCT was stopped early for futility as there were no differences between the high-dose and the low-dose UFH in TE (5% vs. 3%; risk ratios [RR] 1.5, 95% confidence interval [CI] 0.3; 9) and bleeding (7% vs. 12%, RR 0.6, 95% CI 0.2; 2). There were also no differences when RCT and cohort study populations were combined. Conclusions: The incidences of TE and bleeding during CC in children were low. There were no differences between the high-dose and the low-dose UFH protocols studied. Although Heparin Anticoagulation Randomized Trial in Cardiac Catheterization (HEARTCAT) was not designed as non-inferiority trial, low-dose UFH (50 units kg−1 bolus) appears sufficient for thromboprophylaxis during CC.
Thrombotic events (TE) at the site of vascular access are the most common complication of cardiac catheterization (CC) in children [1–6]. Incidences reported in the literature range from 0.8% to 40% for arterial thrombosis and 0% to 20% for venous thrombosis of the femoral vessels [7–15]. Long-term vascular complications include chronic ischemia with impaired leg growth or claudication, post-thrombotic syndrome and a loss of future vascular access[16–26]. To date, most studies have only used clinical assessment for the detection of CC-related TE and the true incidence of thrombosis is unknown. Therefore, studies using objective screening by ultrasound are needed.
Unfractionated heparin (UFH) is used for primary prevention of TE during pediatric CC. However, the optimal UFH dose has yet to be established. Only a few studies have compared different UFH protocols with doses ranging from 50 to 150 units per kg body weight and their results were inconclusive [7–11,27]. Current recommendations are to use a bolus of 100–150 units per kg body weight UFH and an additional bolus during the procedure [28,29]. Lower UFH doses could potentially be sufficient, as some previous studies reported incidences of TE to be low and largely not different between various dose levels [8,9]. Moreover, the risk of TE may have changed over time. Improved access devices and catheter surface material may cause less vascular trauma and TE. Conversely, recent interventional techniques using larger-sized catheters and sheaths may cause an increased risk of TE, requiring a higher UFH dose than previously reported. Finally, UFH carries a risk of bleeding, which would be expected to increase with higher UFH doses [30,31]. The optimal UFH protocol minimizing the risk of TE and of bleeding during pediatric CC remains to be established.
The objectives of the Heparin Anticoagulation Randomized Trial in Cardiac Catheterization (HEARTCAT) study were to (i) objectively determine the incidences of TE and bleeding during CC in children; and (ii) compare the efficacy and safety of a high-dose UFH protocol vs. a low-dose UFH protocol. UFH protocols were chosen with the aim to represent two clearly distinct doses at the upper and lower end of dose ranges reported in the literature.
The study design was a single-center, double-blinded, randomized controlled trial (RCT) of consecutive children undergoing CC comparing a high-dose vs. a low-dose UFH protocol. Patients with no consent for randomization received UFH as per standard-of-care and were followed in a parallel cohort study. RCT and cohort study patients received the same outcome assessment (‘parallel-cohort RCT’ design) . The study protocol was approved by the ethics committee of the Medical University of Vienna. The present study was registered as a clinical trial in EudraCT, registration number 2005-004150-27 (https://www.clinicaltrialsregister.eu).
The study population consisted of patients, 0–20 years of age, requiring diagnostic or interventional CC at the Division of Paediatric Cardiology, Department of Paediatric and Adolescent Medicine, Medical University of Vienna, Vienna, Austria. Written informed consent was obtained from parents and patients of an appropriate age. Exclusion criteria for the RCT were pre-existing anticoagulation or antiplatelet therapy. During the first study year, interventional CC was defined as exclusion criterion for the RCT but the protocol was later amended to allow these patients into the RCT. Patients excluded from the RCT or patients for whom consent for randomization was not given received UFH as per standard-of-care (see below) and were followed in a parallel cohort study.
Demographic variables and risk factors
Baseline demographic variables recorded were age, gender, body weight and length, body surface area, underlying cardiac disease, cyanotic heart defect, other co-morbidities, number and sites of previous CC, previous TE, anticoagulant therapy or prophylaxis and antiplatelet therapy. Congenital and acquired risk factors for thrombosis assessed included laboratory prothrombotic markers and procedural factors. Data on these risk factors and their association with outcome will be reported in a separate study.
All patients received UFH (UFH ‘Immuno’ 1000 IU mL−1; EBEWE Pharma Ges.m.b.h., Unterach, Austria) during CC. Patients included in the RCT were randomly assigned in a 1:1 ratio to one of two anticoagulation protocols. The high-dose UFH arm received a bolus of 100 units per kg body weight UFH at the time of vascular access, followed by a continuous infusion of 20 units kg h−1 standard UFH for children older than 1 year (or 28 units kg h−1 UFH for infants) during the procedure. The low-dose UFH arm received a bolus of 50 units per kg body weight UFH at the time of vascular access, and an additional bolus of 50 units kg−1 every 2 h during the procedure. Randomization was stratified by the patient’s age (children < 1 year vs. children 1 year and older). Randomization sequences were computer generated by an independent statistician. Randomization codes were allocated using sequentially numbered, opaque sealed envelopes. Envelopes were opened by an assistant in the CC laboratory, and the allocated UFH protocol presented to the anesthesist who was responsible for UFH administration via a peripheral vein. Patients, physicians performing the CC, those performing the clinical outcome assessment or vascular ultrasound and the study coordinators were blinded to treatment allocation.
Children in the cohort study received UFH as per standard-of-care at our center (bolus of 50 units kg−1 for venous access, bolus of 100 units kg−1 for arterial access).
Laboratory monitoring of UFH levels
To determine heparin levels during CC, blood samples were taken to assess activated partial thromboplastin time (APTT), activated clotting time (ACT), anti-factor (X)a, anti-IIa, UFH concentrations by protamine titration, antithrombin levels at baseline, 30 and 60 min after UFH administration, and then hourly until the end of the procedure. These data will be reported in a separate study.
The primary efficacy outcome was a TE at the puncture site diagnosed by vascular ultrasonography, performed before CC and within 48 h after CC. Peripheral vascular real time B-mode and a color-coded Doppler imaging ultrasound was performed using a linear-array transducer, 7.5 MHz (Vivid 7 cardiovascular ultrasound system, GE Healthcare, Wauwatosa, WI, USA). A bilateral investigation of the femoral and iliac arteries and veins was performed in longitudinal and transverse views.
The primary safety outcome was bleeding at the puncture site or other locations. Severity of bleeding was documented by the need for prolonged compression of punctured vessels or the need for medical therapy (protamin infusion, red cell transfusion).
Secondary study outcomes were clinical symptoms and signs of TE at the access site (palpation of femoral and distal leg pulses, skin temperature and skin color and swelling of the legs). Patients with clinical signs of a pulmonary or systemic embolism had confirmatory investigations performed but asymptomatic patients were not systematically screened for systemic TE.
Dual blinding was maintained because treatment allocation was only known to staff in the catheter laboratory (assistant and anesthesist) not otherwise involved in study procedures and outcome assessment. Ultrasound and clinical outcome assessment was performed by investigators blinded to patients’ treatment allocation and independent of the results of the respective other examination.
The study design assumed superiority of the high-dose UFH protocol compared with the low-dose UFH protocol. The sample size calculation was based on the expected incidence of TE diagnosed by ultrasound. In previous studies, 10–20% of children undergoing CC developed TE as detected clinically. Using ultrasound screening, the baseline incidence of TE was estimated to be at least 25% (low-dose UFH). To detect a relative risk reduction of 60% or an absolute risk reduction of 15%, for example an absolute incidence of 10% of TE (high-dose UFH), with a significance level of alpha < 0.05 (two-tailed) and a power of 1-beta = 0.80, 100 patients per group (total 200) were estimated to be required.
The primary comparison between UFH dose arms was done in the RCT population using intention-to-treat analysis. A second analysis compared UFH dose arms, separately for RCT and cohort study populations, in a per-protocol analysis. In a third analysis, the RCT and cohort study populations were combined to compare UFH dose arms (parallel-cohort RCT). The analysis compared proportions of primary efficacy and safety outcome events between UFH dose arms in univariate analysis and multivariate analysis adjusting for age group (< 1 year of age vs. older), type of catheterization (interventional vs. diagnostic CC), gender and testing for interactions with dose group.
Statistical analysis was performed using SPSS version 15.0 for Windows (SPSS, Chicago, IL, USA). Continuous variables are presented as the median, minimum and maximum values, categorical variables as absolute frequencies and percentages. Comparisons between groups were analyzed using t-test or Wilcoxon’s test for continuous variables and chi-square or Fisher’s exact test for categorical variables. The significance level was < 0.05 (two-tailed). Multivariate analyzes used logistic regression. Risk ratios (RR) and 95% confidence intervals (CI) were calculated.
Flow of participants
Figure 1 shows the flow of study participants. Between January 2006 and November 2009, 479 patients underwent diagnostic or interventional CC (668 procedures). In all, 252 patients were not enrolled of whom 167 patients could not be approached for the study, mainly for logistic reasons, for example an emergency CC with no sufficient time to obtain informed consent. In the present study, 227 patients were enrolled, of whom 137 were randomized and 90 followed in the cohort study.
An interim blinded analysis at about two-thirds of the planned sample size for the RCT revealed a much lower than expected overall incidence of TE. Recalculating the sample size resulted in a required number of approximately 1200 patients. Consequently, the randomization code was opened and a group comparison performed. The lack of differences between dose arms confirmed the futility of continuing with the study.
Of the 137 patients included in the RCT, 68 patients were allocated to the high-dose UFH protocol (Fig. 1). One patient received a continuous UFH infusion only without a prior bolus, and one patient received a higher dose of 200 units kg−1 UFH instead of 100 units kg−1. Both patients were analyzed in the RCT for intention-to-treat analysis but in the cohort study for per protocol analysis. Of the remaining 66 patients, four were lost to follow-up owing to the lack of ultrasound evaluation. Therefore, the RCT high-dose group consisted of 64 patients for intention-to-treat analysis and 62 patients for per protocol analysis.
In all, 69 patients were allocated to the low-dose UFH protocol. In two patients, a higher UFH dose was given by the anesthetist and in two patients the UFH bolus was repeated too early. Those four patients were therefore followed in the prospective cohort study for per protocol analysis. Seven patients were lost to follow-up owing to the lack of ultrasound assessment. Therefore, the RCT low-dose group consisted of 62 patients for intention-to-treat analysis and of 58 patients for per protocol analysis.
Baseline demographic data were compared between study participants and children with concurrent CC not enrolled in the study to judge the representativeness of the study population. In the RCT study, patients were older (median 5.6 years vs. 4.6 years, P = 0.03), had a lower proportion of infants (23% vs. 40%; P < 0.001), higher body weights (median 17.0 kg vs. 14.8 kg; P = 0.009) and a lower proportion of emergency CC (3% vs. 27%; P < 0.001). There were no differences in gender (39% vs. 39%, P = 0.98) and the proportion of interventional CC (47% vs. 46%, P = 0.81). Of the 227 study patients, 205 (90%) had congenital heart disease and 22 (10%) underwent CC for other reasons (e.g. pulmonary hypertension, Kawasaki syndrome and cardiomyopathy). All study patients were catheterized via the femoral vessels.
Baseline demographic data were compared between RCT and cohort study populations (Table 1). Except for lower proportions of patients with pre-existing anticoagulation (0% vs 17%, P < 0.001) and of interventional CC (40% vs 58%, P = 0.009) in the RCT owing to the exclusion criteria, there were no significant differences between RCT and cohort study patients. The same demographic baseline data were also compared between the high-dose and low-dose arms within the RCT and cohort study, respectively (Table 1). None of the baseline variables differed significantly, except for a trend towards a higher proportion of infants in the low-dose arm of the cohort study (29% vs. 13%, P = 0.09).
Table 1. Baseline characteristics comparing randomized control trial (RCT) (n = 137) and cohort study (n = 90) patients, and high-dose vs. low-dose UFH arms
High-dose n = 68
Low-dose n = 69
High-dose n = 31
Low dose n = 59
CHD, congenital heart disease; DVT, deep venous thrombosis; AT, arterial thrombosis; CC, cardiac catheterization. Numbers represent n (%) or * median (minium; maximum). Differences between the RCT and cohort study: +0% vs 17%, P < 0.001, ++40% vs 58%, P = 0.009; no other significant differences between the RCT and cohort study and within dose arms.
3.5 (0; 19)
5.8 (0; 17)
6.6 (0; 19)
6.9 (0; 20)
15.0 (3; 91)
19.4 (3; 76)
20.2 (5; 74)
20.1 (3; 77)
Presence of CHD
Presence of cyanotic CHD
Patients with previous DVT
Patients with previous AT
Patients with previous CC
Number of previous CC
2 (1; 6)
2 (1; 6)
2 (1; 6)
2 (1; 8)
CC duration (min)*
86 (11; 300)
95 (23; 250)
91 (24; 270)
90 (20; 250)
UFH infusion after CC
Overall incidence of thrombosis and bleeding
Baseline ultrasound screening Out of 227 study patients, 99 patients had previously undergone CC with puncture of the femoral vessels. Baseline ultrasound screening before CC identified pre-existing vessel occlusions in 11 (11%) patients, eight with a venous occlusion and three with an arterial occlusion. For the current CC, these patients were punctured at the contralateral, unaffected side.
Primary outcomes In the total study population, 202 patients had outcome assessment by ultrasound performed by investigators blinded to patients’ treatment allocation. Nine (4.6%) patients had TE at the puncture site. Six patients (3%) had an arterial thrombosis, five of whom were infants. Three patients (1.6%) with a deep venous thrombosis (DVT) were all older than 1 year. Of the 227 patients assessed for safety outcome, 15 (6.6%) had bleeding at the puncture site, which was mostly minor (n = 14 patients). One patient on high-dose UFH had major bleeding per definition as he received a red cell transfusion. However, this infant had had frequent diagnostic blood sampling during CC which predominantly contributed to the need for a transfusion.
Other vascular complications Arterio-venous fistulae were detected in three (2%) patients and pseudoaneurysms of the femoral artery in two (1%) patients.
Clinical signs of thrombsosis Clinical signs of an arterial thrombosis (absent pulse) were found in two out of six patients with an arterial thrombosis as per ultrasound, while the remaining four patients with an arterial thrombosis only had weak pulses. Out of 196 patients with regular arterial ultrasound findings, five patients had absent pulses who were considered to have transient vasospasms. Of the patients with a femoral DVT (only partial occlusions), none showed clinical signs.
Systemic TE No patient developed clinical signs of a pulmonary embolism. One patient with significant supravalvular aortic stenosis, randomized to high-dose UFH, developed a myocardial infarction after CC and died. An autopsy showed a massive myocardial infarction but no signs of thrombosis in the coronary arteries, which was explained by a low systemic blood pressure after CC with critical perfusion of coronary arteries. Two patients in the cohort study receiving low-dose UFH developed a cerebral infarction within 24 h of CC: one patient after catheterization of a systemic-to-pulmonary shunt and one after stent re-dilatation in the aortic isthmus. Combining TE at the puncture site and these three cases of possible systemic TE, the total incidence of TE was 12/202 (5.9%).
Comparison between high-dose and low-dose UFH
Table 2 shows the primary efficacy outcome and safety outcome in the RCT population comparing the high-dose vs. the low-dose UFH arm by intention-to-treat analysis. There were no significant differences in TE and bleeding complications.
Table 2. Primary efficacy and safety outcome in the randomized control trial (RCT) population comparing the high-dose vs. the low-dose arm
RR (95% CI)
High dose n = 64*
Low dose n = 62*
Intention-to-treat analysis. RR, risk ratio. Numbers represent n (%). *Efficacy population (n = 126); †Safety population (n = 137).
Thrombosis at puncture site
1.5 (0.3; 9)
P = 0.51
1.0 (0.1; 7)
P = 0.68
Deep venous thrombosis
P = 0.50
High dose n = 68†
Low dose n = 69†
0.6 (0.2; 2)
P = 0.56
0.7 (0.2; 2)
P = 0.76
P = 0.50
Table 3 shows primary efficacy and safety outcomes, in the RCT and cohort study populations, comparing high-dose vs. low-dose UFH arms in per-protocol analyzes. There were no significant differences in either population. In the cohort study, there was a trend towards a decreased frequency of bleeding in the low-dose UFH arm, however, there was no such difference in the RCT.
Table 3. Primary efficacy outcome and safety outcome, in the randomized control trial (RCT) and cohort study populations, comparing high-dose vs. low-dose arms
RR (95% CI)
RR (95% CI)
High dose n = 62*
Low dose n = 58*
High dose n = 33*
Low dose n = 49*
RR, risk ratio. Per protocol analysis. Numbers represent n (%). *Efficacy population (n = 202); †Safety population (n = 227).
Thrombosis at puncture site
0.9 (0.1; 6)
P = 0.95
2.4 (0.4; 13)
P = 0.39
0.9 (0.1; 7)
P = 0.99
1.5 (0.1; 23)
P = 0.66
Deep venous thrombosis
3.0 (0.3; 31)
P = 0.29
High dose n = 66†
Low dose n = 65†
High dose n = 34†
Low dose n = 62†
0.8 (0.3; 3)
P = 0.73
5.5 (0.6; 51)
P = 0.13
0.8 (0.2; 3)
P = 0.76
3.6 (0.3; 39)
P = 0.29
P = 0.35
As baseline characteristics between the RCT and cohort study populations were reasonably similar, a final analysis combined both populations to increase the power for a comparison of the high-dose vs. the low-dose UFH arms. This analysis similarly did not reveal any significant differences in efficacy and safety outcomes between the UFH dose arms. A thrombosis at the puncture site occurred in five out of 95 (5%) patients on high-dose UFH vs. four out of 107 (4%) patients on low-dose UFH (RR 1.4, 95% CI 0.4, 5; P = 0.74). Bleeding occurred in eight out of 100 (8%) patients on high-dose UFH vs. seven out of 127 (6%) patients on low-dose UFH (RR 1.5, 95% CI 0.5, 4; P = 0.59). Including all TE (local and systemic), there was also no difference between the UFH dose arms.
Infants had an increased incidence of TE compared with children aged 1 year and older (P = 0.027). There was no interaction between the UFH dose group and the age group, for example there was no significant difference between high-dose and low-dose UFH in infants (10% vs. 11.5%) and older children (4.0% vs. 1.2%), respectively (test for interaction, P = 0.37). When considering all (local and systemic) TE, these relationships did not change. Infants also had a significantly increased incidence of bleeding compared with older children (P = 0.034). There was no interaction between the UFH dose group and the age group in relation to bleeding (P = 0.64).
Catheterization type (diagnostic vs. interventional) was not associated with the incidence of TE at the puncture site or bleeding and there was no interaction with dose. Again, these relationships did not change when considering all (local and systemic) TE.
The HEARTCAT Study was a parallel cohort RCT comparing two UFH protocols for primary prevention of CC-associated TE in children. In the overall study population, the incidence of TE based on objective testing was 4.6% and of bleeding complications 6.6%, which were mostly minor. As a consequence of the parallel-cohort RCT design, the overall study population is well representative of children who received CC at this institution with minor variations to the background population. With the limitation that this was a single center study, HEARTCAT provides a valid estimate of the current risk of TE and bleeding during CC in children.
HEARTCAT was the first RCT comparing UFH doses in children that used objective outcome assessment by ultrasound screening. Previous trials in children comparing different UFH dose regimens used clinical outcome assessment only and probably underestimated the true incidence of TE after CC [7–11]. Other studies that used ultrasound screening did not compare different UFH doses . As catheter material and techniques have changed in recent years, a current estimate of the risk of TE and bleeding is important. Moreover, the optimal UFH dose balancing prevention of TE and bleeding under current conditions needed to be established.
The frequency of TE determined by the present study was much lower than expected from previous literature reports which resulted in insufficient power to detect potential differences between UFH doses. However, there were not even trends to differences that might have been substantiated with higher patient numbers. Therefore, the study was stopped early for futility. It is important to emphasize that the results do not statistically prove equivalence between dose arms. A methodological limitation of the present study was that screening for systemic thrombosis was not part of the protocol. Therefore, the study may have overlooked some asymptomatic systemic TE, for example small pulmonary emboli. However, intracardiac clots would probably have been identified by echocardiography (routinely performed in all patients after CC) and arterial emboli by clinical manifestations. Finally, local ultrasound examination was performed within 48 h of CC to allow timely diagnosis and management of TE. A second ultrasound screening after several days may have improved the reliability of outcome assessment. However, the authors consider that children without radiographical evidence of TE within 48 h after CC are unlikely to develop TE later. Long-term outcome ultrasound follow-up of study patients is underway and will be reported separately.
The incidence of arterial TE in HEARTCAT was 3%. In spite of ultrasound screening, the incidence was similar to previous studies assessing clinical signs only [1,2,4,6–9,16,18,33–36]. Consistent with the literature, the majority of patients with an arterial thrombosis were infants [7,34]. Only one-third of patients with an arterial TE had absent pulses, thus the diagnosis of an arterial TE would have been missed or been uncertain without ultrasound screening in two-thirds. Moreover, five patients with absent pulses had no signs of an arterial TE on ultrasound. These findings underline the importance of objective radiographic screening for TE in children.
The incidence of venous TE was 2% which is lower than reported in most previous studies [12,13,15] but in accordance with two recent studies that used ultrasound screening for DVT in children after CC [14,34]. None of the three patients developed clinical signs of venous TE, probably because they only had partial venous occlusion.
The incidence of bleeding events in HEARTCAT was 6.6%, which, in all but one case, were considered minor and subsided after applying local pressure. Previous studies in CC have reported similarly low frequencies [7,8,37]. This is in contrast to critically ill children requiring UFH who are at a significant risk of bleeding . Apparently, the elective setting of CC and the possibility to control bleeding at a puncture site implies a lower risk.
In HEARTCAT, an UFH dose of 100 units kg−1 was not superior to 50 units kg−1 in the prevention of TE. These results corroborate the report of Saxena et al.  who compared the same dose levels and found no differences in clinical signs of TE (9.3 vs. 9.8%). The data are complemented by the results of Bulbul et al.  who found no differences in arterial thrombosis comparing 150 and 100 units kg−1. Although HEARTCAT was not designed as non-inferiority study, one may cautiously conclude that a bolus of 50 units kg−1 (with repetition every 2 h) is sufficient for prevention of TE at a puncture site under usual conditions. A small proportion of TE resulting from trauma to the vessel wall at catheterization may not be completely avoidable and, probably, cannot be influenced by UFH, irrespective of the dose.
Whether certain patient subgroups may require increased UFH doses may not have been fully established by HEARTCAT for its sample size. HEARTCAT did demonstrate that infants are at an increased risk of TE, probably because of an increased risk of trauma in smaller vessels. However, the higher UFH dose was not more efficacious in the subgroup of infants. Moreover, infants generally had an increased risk of bleeding. In summary, the data do not support a higher UFH dose in infants.
Diagnostic and interventional CC were associated with a similar risk of TE and bleeding. Again there was no differential effect of UFH dose in these subgroups. Including systemic TE in the analysis did not change the results of the dose comparison. However, because of the clinical relevance of systemic TE, a higher UFH for interventional CC dose may be considered given the low incidence of relevant bleeding. Whether a higher UFH dose in interventional CC would provide an improved benefit risk balance would need to be substantiated in future RCT.
In conclusion, HEARTCAT demonstrated a relatively low incidence of TE and bleeding related to CC in children. Although the study was not designed as non-inferiority study and lacks power as a result of low events rates, the results suggest that a low UFH dose of 50 units kg−1 is usually sufficient for the prevention of TE at puncture sited in pediatric CC. Increased attention needs to be paid to infants who are at an increased risk both of thrombotic and bleeding complications.
Disclosure of Conflict of Interest
The authors state that they have no conflict of interest.