Venous and Arterial Thromboembolism in Children

Paul Monagle

M. Patricia Massicotte

Anthony K. Chan

INTRODUCTION

Thromboembolic disease in infancy and childhood has been described as a new epidemic of tertiary pediatric care. Evidence supports the concept that the frequency of thromboembolism (TE), in all forms including venous, arterial, and intracardiac thromboembolic phenomenon, is increasing in neonates and children. The reasons for this are likely related to the increased survival of children with severe underlying medical and surgical conditions; the increased intensity and invasiveness of supportive care, in particular the increased use of vascular access devices; heightened awareness of this condition amongst pediatricians leading to more regular and appropriate investigations; and potentially the ever lowering age at which traditionally “adult” therapies such as, for example, the oral contraceptive pill are being used en masse. Similarly, the increased prevalence of previously “adult” risk factors such as obesity may also contribute to increased thrombotic risk in children.

The diagnosis of thrombosis in children is often difficult for practical and theoretical reasons. Invasive and even noninvasive imaging of children often requires general anesthesia which not only increases the risks involved, especially in sick children, but pragmatically often makes timely diagnosis difficult to organize. Further the algorithms for interpretation of diagnostic vascular imaging have not been validated in children.¹ There are multiple reasons including reduced vessel size, lower pulse pressures, and blood flow rates, and potential other causes of bias that raise questions about whether the same algorithms and strategies used in adults are valid in children.

The natural history of TE in neonates and children remains largely unknown. This is problematic when clinicians are trying to balance the risks of antithrombotic therapy versus the risks of untreated disease. This dilemma is most evident when considering asymptomatic TE, which is often diagnosed on routine imaging or postprocedural examination. The aim of pediatrics in general is not only to ensure long-term survival of children, but to do so in a manner that enables the child to lead a productive and full adult life. Therefore, any impact of antithrombotic therapy on normal development needs to be considered, especially in situations that long-term anticoagulation therapy is being considered. Currently, the ability of clinicians to give parents and children good information about their longer term health and support requirements subsequent to a thromboembolic episode is very limited.

The use of antithrombotic drugs in pediatric patients is different from adults for a variety of reasons.² First, the epidemiology of TE in pediatric patients is vastly different from that seen in adults.³, ⁴, ⁵, ⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹, ¹², ¹³, ¹⁴, ¹⁵ Second, the hemostatic system is a dynamic evolving entity that not only likely affects the frequency and natural history of TEs in children, but also the response to therapeutic agents.¹⁶, ¹⁷, ¹⁸ Third, the distribution, binding, and clearance of antithrombotic drugs are age dependent.¹⁹, ²⁰, ²¹ Fourth, the frequency and type of intercurrent illnesses and concurrent medications varies with age. Fifth, limited vascular access reduces the ability to effectively deliver some antithrombotic therapies and can influence the choice of antithrombotic agent. Often, the only vascular access available is used for drug delivery; consequently accurate monitoring of blood anticoagulant levels is difficult. Sixth, specific pediatric formulations of antithrombotic drugs are not available, making accurate, reproducible dosing difficult. This is especially the case for vitamin K antagonists (VKAs) (no suspension/liquid preparation) and low molecular weight heparin (LMWH) (available most readily in predosed syringes based on adult weights). Seventh, dietary differences make the use of oral VKAs particularly difficult. This is especially true in neonates, as breast milk and infant formulas have very different vitamin K levels. Finally, compliance issues are vastly different in, for example, small infants who cannot understand the need for therapy, in adolescents who intellectually comprehend but emotionally are unable to cooperate, and in children who suffer the effects of inadequate parenting. The social, ethical, and legal implications of these issues frequently interfere with the ability to provide the “best” treatment for individual neonates and children.

This chapter discusses the epidemiology of TE in neonates and children, and then focuses on issues of clinical presentation, diagnosis, and management that are specific for children compared to adults. There remain many unanswered questions, and much research is required to improve the current standards of care for children with thromboembolic disease.

EPIDEMIOLOGY OF THROMBOEMBOLISM IN NEONATES AND CHILDREN

Venous Thromboembolism and Pulmonary Embolism

There are a number of published national or international registries that have collected data on venous thromboembolism (VTE) and other thrombotic events in neonates and children (Table 121.1).⁴, ¹¹, ¹², ¹³, ²² Two neonatal registries from Canada and Germany have prospectively collected data on neonatal thrombosis, while a third from the Netherlands includes data from both neonates and older children.¹¹, ¹², ¹³ Two registries (from Canada and the United Kingdom) have collected data on older children.⁴, ²² Inclusion criteria have varied between registries, particularly with regard to the registration of arterial and central nervous system (CNS) events, and the inclusion or not of asymptomatic events.

Table 121.1 National and international large pediatric thrombosis registries

Registry	Dates of Case Collection	Age Criteria for Inclusion	Number of Children Reported	Types of Thrombosis Included	Inclusion of CNS Thrombosis	Incidence of Venous Thrombosis
Canadian & International-Neonatal¹²	1990-1993	1st mo	N = 97	VTE Arterial	No	2.4/1,000 NICU^b admissions
German-Neonatal¹¹	1992-1994	1st mo	N = 79	VTE Arterial	Yes	0.51/10,000 births
Canadian-Children²²	1990-1992	1 mo to 16 y	N = 137	DVT/PE	No	0.07/10,000 children
DPSU¹³	1997-1999	Birth to 18 y	N ;= 115	VTE^a	Yes	0.14/10,000 children
BPSU⁴	2001-2003	1 mo to 16 y	N = 200	VTE Arterial	No	0.07/10,000 children
United States¹⁵	2001-2007	Birth to 18 y	N = 11 337	VTE	No	34-58/10,000 pediatric hospital admissions
^aIncludes asymptomatic neonatal events.
^bNeonatal intensive care unit.

The incidence of VTE is dramatically influenced by age in adults such that the estimated incidence of first time deep vein thrombosis (DVT) in those aged 25 to 30 years is around 30 cases per 100,000 persons, which increases exponentially to 300 to 500 cases per 100,000 persons in those aged 70 to 79 years.¹⁴ The incidence of DVT and pulmonary embolism (PE) in children in Canada, using data collected from 15 tertiary care centers, was estimated to be 0.07 per 10,000 children and 5.3 per 10,000 hospital admissions.²² However, more recently, Raffini et al.¹⁵ reported that the annual incidence of VTE in children discharged from pediatric hospitals in the United States increased from 34 per 10,000 admissions in 2001 to 58 per 10,000 admissions in 2007, representing an increase of 70% in 7 years. The Dutch registry collected data via the Dutch Paediatric Surveillance Unit (DPSU) using a monthly mailing system sent to all pediatricians in primary and secondary care and to specific contact persons in tertiary centres.¹³ The overall incidence of venous thrombosis was 0.14 per 10,000 children aged 0 to 18 years and 0.05 per 10,000 children after excluding neonates and nonextremity VTE.¹³ The British Paediatric Surveillance unit (BPSU) used a similar methodology,⁴ and the estimated incidence of all events was 0.07 per 10,000 children. The first registry of neonatal thrombosis was an international registry involving 64 centers in Canada, the United States, and Europe. Based on data reported from Canada, which was considered to be complete, the incidence of clinically apparent thrombosis was 2.4 per 1,000 admissions to the neonatal intensive care unit (ICU).¹² In contrast, the German neonatal registry reported the incidence of symptomatic events was 0.51 per 10,000 births.¹¹ The Dutch study reported the incidence of neonatal venous thrombosis as 0.07 per 10,000 children.¹³

Many other studies have examined the rates of VTE in specific high-risk groups such as children and neonates with central venous access.²³, ²⁴, ²⁵ Children with malignancy, with or without central venous access, are often highlighted as a particular high-risk group, with rates as high as 30% to 50%, although there are many causative factors involved, including insertion technique, site of central line placement type of cancer involved, treatment protocol, and the diagnostic techniques applied.⁷, ¹⁰, ²⁶, ²⁷, ²⁸ Children with short-term central venous access whilst in pediatric intensive care units have thrombosis in 18.3% to 26% of cases.²⁹, ³⁰ Children undergoing solid organ transplant have frequent thromboembolic complications,³¹, ³², ³³, ³⁴, ³⁵ but perhaps the highest risk group in children is in those receiving long-term home parenteral nutrition, with cross-sectional studies reporting thrombosis in up to 66%.³⁶, ³⁷, ³⁸ With respect to PE, there is limited data on epidemiology. General population retrospective autopsy studies report PE in children at 0.05% to

4%³⁹, ⁴⁰, ⁴¹, ⁴² (Table 121.2).

Arterial Thrombosis

There are few studies that report the incidence of arterial thrombosis in children. The majority of arterial thrombosis in children are iatrogenic, related to invasive vascular access,⁴³, ⁴⁴, ⁴⁵, ⁴⁶, ⁴⁷, ⁴⁸, ⁴⁹, ⁵⁰, ⁵¹, ⁵², ⁵³, ⁵⁴, ⁵⁵, ⁵⁶, ⁵⁷, ⁵⁸, ⁵⁹, ⁶⁰, ⁶¹, ⁶², ⁶³ less commonly associated with solid organ transplantation and Kawasaki disease. Spontaneous arterial thrombosis is rare in children.⁶⁴, ⁶⁵, ⁶⁶, ⁶⁷, ⁶⁸, ⁶⁹, ⁷⁰, ⁷¹, ⁷², ⁷³, ⁷⁴, ⁷⁵, ⁷⁶ One prospective registry conducted between 1999 and 2002 reported arterial thrombosis at 8.5 per 10,000 hospital admissions (102 thromboses in 119,487 admissions),⁷⁷ suggesting that arterial thrombosis is as common as venous thrombosis in tertiary institutions.

Intracardiac Thrombosis

Right atrial and intracardiac thrombosis are most commonly diagnosed in children who have central venous access devices extending into the right atrium.⁷⁸, ⁷⁹ Children also may develop intracardiac thrombosis following cardiac surgery, including
after Glenn,⁸⁰, ⁸¹, ⁸², ⁸³, ⁸⁴, ⁸⁵ Fontan,⁸⁶, ⁸⁷ Norwood procedures,⁸⁸, ⁸⁹ and prosthetic valve replacement.⁹⁰, ⁹¹, ⁹², ⁹³, ⁹⁴, ⁹⁵, ⁹⁶, ⁹⁷, ⁹⁸, ⁹⁹, ¹⁰⁰, ¹⁰¹, ¹⁰², ¹⁰³, ¹⁰⁴, ¹⁰⁵, ¹⁰⁶

Table 121.2 Incidence of pulmonary embolus in children with selected underlying clinical conditions

Author	Year	Study Design	N	Clinical Condition	Diagnostic Method	Incidence (%)
Hoyer³⁴³	1986	Retrospective	26	Asymptomatic NS	V/Q	27
Desai³⁴⁴	1989	Retrospective	178	Fatal burns	Autopsy	1.7
Hsu³⁴⁵	1991	Cross-sectional	62	Preheart transplantation	V/Q, PA	9.7
Marraro³⁴⁶	1991	Prospective	205	Leukemia	Perfusion scan, PA	3.4
Uderzo³⁴⁷	1993	Retrospective	67	BMT for leukemia	V/Q, PA	4.5
Uderzo³⁴⁸	1993	Prospective	452	Leukemia and respiratory failure	Perfusion scan, PA	2.7
McBride³²³	1994	Retrospective	28,692	Trauma	Clinical	0.0069
Dollery³⁷	1994	Cross-sectional	34	Long-term total parenteral nutrition (TPN)	V/Q, CRX	32
Andrew²²	1994	Prospective	137	Venous thrombotic event	V/Q	16
Nuss³⁴⁹	1995	Retrospective	61	Thrombotic event	V/Q	20
Derish³⁵⁰	1995	Retrospective	21	Intensive care unit deaths	Autopsy	24
Massicotte³⁵¹	1998	Prospective	244	Catheter-related thrombosis	V/Q	16
Huang³⁵²	2000	Prospective	20	NS and elevated D-dimer	V/Q,CRX	40
Monagle⁸	2000	Prospective	405	Venous thrombosis	V/Q	17
Van Ommen¹³	2001	Prospective	100	Venous thrombosis	V/Q	10
Levy³⁵³	2003	Retrospective	24	SLE with positive LAC	V/Q	8.3
Adapted from Van Ommen CH, Peters M. Acute pulmonary embolism in childhood. Thromb Res 2006;118(1):13-25.

These complex surgical procedures are common in children with congenital heart disease, and the underlying surgical procedures may have specific implications for the potential consequences of intracardiac thrombosis.¹⁰⁷ A few specific examples are described below.

Blalock-Taussig (B-T) shunts are commonly performed in the neonatal period to increase pulmonary blood flow. B-T shunts may be performed as a single palliative procedure with more definitive surgery planned later or as part of a more complex surgical intervention (e.g., Norwood procedure). B-T shunts are performed as either classic or modified B-T shunts. In classic B-T shunts, the subclavian artery is anastomosed directly to the ipsilateral pulmonary artery. The shunt is usually performed on the right side unless there is a right-sided aortic arch, in which case, the shunt is performed on the left. In contrast, modified B-T shunts involve a Gore-Tex tube graft being placed between the subclavian artery and the ipsilateral pulmonary artery. The Gore-Tex tube may be as small as 3 mm in diameter, depending on the size of the infant, but is usually 3.5 or 4 mm in diameter. Blockage of the B-T shunt will compromise pulmonary blood flow and is often a major clinical event requiring immediate surgery. Patients with B-T shunts may have reduced peripheral pulses in the ipsilateral arm and may have measurably reduced growth of the arm. This can be of significance when assessing for postthrombotic syndrome, which may occur in the upper limbs secondary to central venous thrombosis.

The Norwood procedure is the initial surgery performed in infants with hypoplastic left heart syndrome (HLHS). The surgery is performed early in the neonatal period. HLHS usually includes severe hypoplasia of the left ventricle, hypoplasia of the ascending aorta and aortic arch, and critical stenosis of aortic or mitral valves.

The first stage involves the following:

Division of the main pulmonary artery and closure of the distal stump with a patch.
Ligation and division of the patent ductus arteriosus.
Using an aortic or pulmonary artery allograft, the proximal pulmonary artery is anastomosed to the hypoplastic aortic arch, which itself is enlarged to create a large arterial trunk.
The atrial septum is excised to allow adequate interatrial mixing.
A modified B-T shunt (right-sided, Gore-Tex tube, usually 3.5 to 4 mm) from the right innominate to the right pulmonary artery. This will be the only source of pulmonary blood flow.

This procedure results in systemic venous and pulmonary venous return entering into a common atrium. Blood then enters a common ventricle and leaves the heart via a common outflow tract, providing systemic blood flow via the aortic arch and pulmonary blood flow via the B-T shunt.

The implications of this procedure with respect to thrombosis are as follows:

Venous flow has direct access to systemic arterial flow, so deep venous thrombosis, whether central venous line (CVL) related or otherwise, readily causes systemic emboli and potentially arterial ischemic stroke.
A clotted B-T shunt causes loss of entire pulmonary blood flow.
There are substantial intravascular suture lines as potential sources of thrombosis.
The patients will need a subsequent Glenn procedure and eventually completion to a full Fontan procedure. The development of central thrombosis with associated collateral branches can significantly hinder these subsequent surgical interventions. Therefore, increased aggressiveness of any antithrombotic therapy may be appropriate. Even in the absence of symptoms, thrombolysis or surgical thrombectomy may be considered if a central venous thrombosis was thought to be impairing the hemodynamics required for future surgery.

The bidirectional cavopulmonary shunt (BCPS) or bidirectional Glenn procedure is an end (superior vena cava [SVC]) to side (right pulmonary artery) venous shunt. This is a palliative procedure that increases oxygen saturation, but without increasing left ventricular work, and is usually performed in children with univentricular cardiac physiology as the first stage of the two-stage Fontan procedure. The inferior vena cava (IVC) is unchanged after a Glenn procedure.

The implications with respect to thrombosis are that, following a Glenn procedure, the SVC blood flows directly to the lungs without any assistance from the heart. Hence, any reduction in SVC flow, owing to thrombus occlusion, will dramatically reduce pulmonary blood flow. Pulmonary emboli are of specific concern in that if the pulmonary vascular resistance is increased, the patient may become unsuitable for a Fontan completion, which limits long-term survival significantly in the absence of cardiac transplantation. Blood flow from the IVC still bypasses the lungs, meaning that any thrombus in the lower venous system can give rise to paradoxical emboli. Collateral branches around central venous thrombosis may interfere with the ability to complete the Fontan surgery. The threat of being unable to complete the Fontan may be justification for more aggressive antithrombotic therapy (thrombolysis or surgery) than might otherwise be indicated.

There are numerous modifications of the final Fontan procedure, but the basic principles remain the same. Both the SVC (usually done in a first-stage BCPS) and the IVC are anastomosed to the pulmonary arteries. Hence, the pulmonary blood flow is totally passive, depending on venous flow mechanisms without any cardiac pump assistance. The univentricle is then able to function as a left ventricle, providing systemic blood flow. Postoperatively, many patients have deliberate, limited, right to left interatrial shunting via a “fenestration.” The blood flow in such cases increases the risk of paradoxical emboli.

The implications with respect to thrombosis following Fontan surgery are significant. First, the presence of right to left communication continues the potential for paradoxical emboli. Second, any pulmonary emboli that increase pulmonary vascular resistance have an accentuated impact on pulmonary blood flow because the pulmonary pressure cannot be increased to overcome a pressure gradient. The Fontan circuit makes the diagnosis of pulmonary emboli particularly difficult. Depending on the attachment of the SVC and IVC to the pulmonary arteries, isotope may need to be injected into both an arm and a leg to achieve full lung perfusion scanning. As for patients with severe pulmonary hypertension having ventilation-perfusion scans, the transient obstruction of pulmonary capillaries by the macroaggregated isotope-labeled albumin may rarely precipitate a hypoxic episode. Finally, depending on the exact type of Fontan surgery, the risk of late (many years later) thrombosis associated with dysrhythmias may be increased.

CLINICAL PRESENTATION OF THROMBOSIS IN NEONATES AND CHILDREN

Venous Thrombosis

The clinical symptoms/complications of VTE can be classified as acute or long term and vary depending on site and severity. A high proportion of venous thrombosis in children occur in the upper venous system (defined as subclavian, brachiocephalic, internal jugular veins, and SVC), as distinct from the lower venous system (defined as the popliteal, femoral, iliac veins, and the IVC), which is more commonly affected in adults with VTE. These upper system VTEs are commonly associated with CVL placement. The acute clinical symptoms, besides loss of CVL patency, include swelling, pain, and limb discolouration,²² swelling of the face and head with SVC syndrome,¹⁰⁸ and respiratory compromise with PE.⁸ Renal vein thrombosis (RVT) classically presents with a flank mass, hematuria, proteinuria, thrombocytopenia, and nonfunction of the involved kidney. Any venous thrombosis may present with a paradoxical embolus causing a stroke, notably in neonates with a patent foramen ovale.

Children often do not present with acute symptoms (FIGURES 121.1 and 121.2). Long-term clinical symptoms and/or complications include prominent cutaneous collateral circulation, loss of CVL patency requiring local thrombolytic treatment, CVL replacement, loss of venous access, CVL-related sepsis, chylothorax,¹⁰⁹, ¹¹⁰ chylopericardium,¹¹¹ recurrent VTE necessitating long-term anticoagulation, and postthrombotic syndrome (PTS).¹¹² Specific long-term sequelae of umbilical vein catheter (UVC)-related VTE include portal hypertension,¹¹³ splenomegaly,¹¹⁴ gastric and esophageal varices, variceal bleeding, and hypertension.¹¹⁵

Arterial Thrombosis

Arterial thrombosis is most frequently iatrogenic, and loss of vascular access is a common presenting symptom.⁷⁷ Acute symptoms will depend on the site of arterial thrombosis and whether there is adequate collateral flow to prevent tissue ischemia. Peripheral limb ischemia is characterized by diminished
or absent pulses, a prolonged capillary refill time, and a cool, pale limb. Thrombotic occlusion of the radial artery produces more severe symptoms with accompanying ulnar artery occlusion. Chronic symptoms may develop even in the absence of acute symptoms and include limb hypoplasia and claudication (FIGURE 121.3). The clinical presentation of umbilical artery catheter (UAC)-related thromboembolic events varies, the majority of newborns being asymptomatic or only minimally affected, but a small proportion having major symptoms of severe leg ischemia and organ dysfunction, including necrotizing enterocolitis secondary to mesenteric artery occlusion, hypertension with or without renal failure secondary to renal artery thrombosis, and limb compromise secondary to embolic events.

FIGURE 121.1 This boy presented at 10 years of age with prominent abdominal collaterals. He had gastroschisis repaired during the neonatal period and had a lower system venous access device placed during this period. There were no acute symptoms of thrombosis documented; however on current scans he has chronic thrombosis with no flow to the IVC below the renal veins.

DIAGNOSIS OF THROMBOEMBOLISM IN NEONATES AND CHILDREN

Venous Thromboembolism

There are no studies comparing the validity of the commonly used diagnostic tests for DVT in neonates, and little is known about the precision and accuracy of noninvasive imaging techniques. The low pulse pressure in premature newborns likely makes ultrasound (US) difficult to interpret, and the presence of a CVL makes compressibility difficult to assess, reducing sensitivity of the test. In neonates with UVCs, Doppler US is inferior to contrast venography for detecting asymptomatic thrombi.¹¹⁶

By contrast, US is the gold standard for diagnosing RVT, because of its sensitivity to an enlarged kidney, which is echogenic with prominent echo-poor medullary pyramids. Renal swelling subsequently decreases, with loss of corticomedullary differentiation, and ultimately, depending on the degree of recovery, US may demonstrate focal scarring or atrophy. Magnetic resonance imaging (MRI) and computed tomography (CT) have also been used to diagnose RVT, but have no apparent advantages over color Doppler, which may show absent renal venous flow in the early stages of RVT. In neonates with suspected VTE, venography is the gold standard, but clinicians must use clinical assessment and suboptimal imaging to make decisions, because the gold standard is practically unachievable.

In older children, US is poorly sensitive (20%) for upper system CVL-related thrombosis, compared to venography. In a comparison of venography versus US for the diagnosis of asymptomatic upper venous system CVL-related VTE, US had a sensitivity of only 20% for intrathoracic thrombosis, but detected jugular vein thrombi that were missed by venography.²⁴ Shankar et al studied 25 children with multiple CVL insertions, who were suspected of having major central venous thrombosis. The authors found: catheter contrast studies consistently underestimated the extend of thrombosis; US identified jugular thrombosis, but failed to identify more central thrombosis, in fact detecting only 7 of 18 thrombosis noted by magnetic resonance venography (MRV), and underestimated the extent of the thrombosis in 4 of the 7. (ref 116) Further, MRV identified a patent vein for reinsertion of CVL in 22 of 25 children, subsequently confirmed in 20 of 22 patients (91%).¹¹⁶ Further, MRV identified a patent vein for reinsertion of CVL in 22 of 25 children, as confirmed in 20 of 22 patients (91%). There are no reported studies that determine the sensitivity and specificity of diagnostic testing for lower venous system CVL-related thrombosis in children.

In summary, for children with suspected upper system thrombosis, a combination of US (jugular veins) and bilateral upper limb venography (subclavians and central veins) is recommended, although MRV may be a viable alternative to formal venography depending upon local expertise. US is a reasonable alternative for DVT distal to the groin, based on adult experience, but for more proximal veins, venography or MRV should be considered.

Pulmonary Embolus

There are no published studies determining the sensitivity and specificity of diagnostic testing for PE in children. However, literature would support that PE is significantly underdiagnosed in children, especially in the ICU setting. There are difficulties with interpreting ventilation/perfusion (V/Q) scans in children in at-risk children, particularly following Fontan cardiac surgery, during which total pulmonary blood flow cannot be assessed by upper limb isotope injection. There are concerns as well regarding the safety of perfusion scanning in children with significant right to left cardiac shunts, as likely significant amounts of macroaggregated albumin may lodge in the cerebral circulation.¹¹⁷ Ventilation perfusion scanning remains the recommended
investigation for PE in neonates and children, although pulmonary angiography is the gold standard, and clinicians may need to make a presumptive diagnosis based on clinical findings and the presence or absence of source thrombosis. CT pulmonary angiography may miss small peripheral pulmonary emboli, and repeat studies involve significant radiation exposure, notably to breast tissue in young female patients.¹¹⁸ Clinical prediction rules, such as the Well clinical probability score, have been validated in adults presenting with symptoms of PE and provide a useful measure of pretest probability.¹¹⁹

FIGURE 121.2 This girl presented during her teenage years with a rash on her legs that was demonstrated to be severe postthrombotic syndrome (A). She developed venous ulceration 6 months later (B). Imaging confirmed femoral vein occlusion with chronic collateral circulation. She had had a right femoral vein cardiac catheter when 3 years of age and had no immediate symptoms of her thrombosis.

FIGURE 121.3 This girl presented with right leg length shortening and atrophy. The femoral artery was occluded as a result of thrombosis following catheterization 10 years previously. There were no acute symptoms at the time of the catheter procedure.

The combination of a negative D-dimer and low clinical probability score can safely rule out PE, negating the need for diagnostic imaging.¹²⁰ However, no such clinical probability score has been validated in a pediatric cohort, and evidence suggests that the algorithms are not valid.¹²¹ Further, a negative D-dimer test did not rule out PE in 4 of 30 children tested and was negative in 36% and 40% of children with PE in two other studies,¹²² demonstrating a poor negative predictive value of this assay. Use of highly sensitive D-dimer tests would probably lead to more false-positive results. As symptoms and signs of DVT may be masked by the underlying diagnosis, the roles of clinical probability scores and D-dimer assays are currently unknown in children and should not be utilized.¹²¹, ¹²³

Arterial Thrombosis

There is little specific information related to diagnostic strategies in neonates or children,⁷⁷ although contrast angiography remains the “gold standard.” Peripheral arterial thrombosis is usually diagnosed clinically, and US is the most commonly used diagnostic test.⁷², ¹²⁴, ¹²⁵, ¹²⁶ Aortic thrombosis, either secondary to
UAC, or spontaneous, requires radiologic diagnosis. US cardiac echocardiography is of value if the obstruction is in the aortic arch.⁶⁸

Contrast angiography is rarely feasible in critically ill newborns. In one comparative study, US failed to visualize aortic thrombosis in four patients, three of whom had complete aortic obstruction by contrast angiography. Thus, clinicians often use clinical findings and suboptimal imaging to make clinical decisions. In older children, arterial thrombosis is usually diagnosed on clinical grounds alone. False-negative US is reported in spontaneous femoral artery thrombosis in children, and false-positive MRA has been reported for chronic femoral artery obstruction, in comparison with angiography.¹²⁷ In suspected peripheral artery thrombosis, clinicians should consider the possibility of intramural or external hematoma causing arterial compression in the differential diagnosis, and for peripheral arteries, US may be sufficiently sensitive to exclude this phenomenon.¹²⁸ For hepatic artery thrombosis after liver transplant, serial testing with pulsed Doppler combined with real-time US of the liver parenchyma has a sensitivity of approximately 70%. As false-positive and -negative results occur, angiography is usually required to confirm the diagnosis, but CT may be useful in equivocal cases.¹²⁹ Spiral CT is sensitive and specific in adults, but the value of MRI is yet to be fully determined.

Intracardiac Thrombosis

Three studies have compared transthoracic echocardiography (TTE) to transesophageal echocardiography (TEE) in the diagnosis of intracardiac thrombosis following Fontan surgery.¹³⁰, ¹³¹, ¹³² Stumper et al. found three intracardiac thromboses in 18 patients using TEE, of which only one was detected by TTE, Fyfe et al. found six thrombi in four pediatric patients using TEE, of which only one was detected by TTE, and Balling et al. found 17 of 52 patients (33%) with intracardiac thrombosis after Fontan surgery by TEE, of which only one was identified on TTE. Thus, TTE is likely insufficient to exclude intracardiac thrombosis in children after Fontan surgery. Right atrial thrombosis, especially CVL-related thrombosis, is commonly diagnosed using TTE.⁷⁹

ANTITHROMBOTIC THERAPY IN PEDIATRIC PATIENTS

The evidence supporting most recommendations for antithrombotic therapy in neonates and children remains weak.¹³³ Studies addressing appropriate drug target ranges and monitoring requirements are urgently required in addition to site- and clinical situation-specific thrombosis management strategies.¹³³ While there is some data to guide treatment decisions in neonates, almost none of the data reported separates premature from term infants, despite the obvious differences in risk/benefit considerations. Similarly adolescents are often managed according to data based on adults, but at what point an adolescent should transition from recommendations based on data in children to that in adults and whether age alone should be the determining factor for that transition is unknown.¹³³ The remainder of this chapter discusses the principles of antithrombotic therapy applicable to neonates and children. For specific treatment recommendations, the reader is referred to the most recent guidelines published by the American College of Chest Physicians.¹³³

Heparin in Neonates and Children

Unfractionated heparin (UFH) remains a commonly used anticoagulant in pediatric patients. In tertiary pediatric hospitals, approximately 15% of inpatients are exposed to UFH each day.¹³⁴ There are a number of specific factors that may alter the effect of UFH in children. For example, UFH acts via antithrombin (AT)-mediated inhibition of thrombin and factor Xa, but children have reduced levels of AT and prothrombin,¹⁷, ¹³⁵, ¹³⁶, ¹³⁷ reduced capacity to generate thrombin,³, ¹³⁶, ¹³⁸ an age-related different ratio of anti-Xa: anti-IIa activity,¹³⁹, ¹⁴⁰, ¹⁴¹ alterations in plasma binding of UFH,¹⁹, ²⁰, ²¹, ¹³⁹ and age-related differences in tissue factor pathway inhibitor release.¹³⁹ The clinical implications of these changes on dosing, monitoring, and the effectiveness/safety profile of UFH in children remain to be fully elucidated.

There have been no reported clinical outcome studies to determine the therapeutic range for UFH in neonates or children, so the therapeutic range for all indications is extrapolated from those used in adults. This equates to an activated partial thromboplastin time (APTT) that reflects a heparin level by protamine titration of 0.2 to 0.4 U/mL or an antifactor Xa level of 0.35 to 0.7 U/mL.¹⁴² Extrapolating the APTT range from adults to pediatric patients may well be invalid. For example, baseline APTTs in pediatric patients, especially neonates, are often increased compared to adults, so a therapeutic range represents a reduced increment in APTT values in pediatric patients receiving adult-equivalent heparin therapy.¹⁷, ¹⁸ Schmidt reported that routine assays underestimate UFH concentration especially in neonates.¹⁴³ Recent in vitro and in vivo data also indicate that the APTT range that correlates to an antifactor Xa level of 0.35 to 0.7 U/mL varies significantly with age and heparin dose.¹⁹, ¹³⁸, ¹³⁹, ¹⁴⁰, ¹⁴¹, ¹⁴⁴ Further, protamine titration results vary with age¹⁴⁰ and different commercial anti-Xa kits produce substantial variations in results on the same samples.¹³⁸ These differences are magnified in infants whose endogenous AT levels are reduced.¹⁴⁵

Only gold members can continue reading. Log In or Register to continue