T h ro m b o s i s i n t h e N e o n a t a l In t e n s i v e Care Unit Matthew A. Saxonhouse,
KEYWORDS Neonatal thrombosis Anticoagulation Prothrombotic disorder Thrombolysis Perinatal arterial ischemic stroke Cerebral sinovenous thrombosis KEY POINTS Thrombosis is a significant problem affecting both term and preterm neonates. Most neonates that develop thrombosis have acquired risk factors or prothrombotic disorders. Proper imaging is essential for accurately identifying thromboses. The use of central venous/arterial catheters significantly increases a neonate’s risk for thrombosis. Recommendations for neonatal treatment are based on expert opinion and data from case studies/series.
Neonates have the highest risk for thrombosis among Pediatric patients (Box 1).1,2 The placement of central venous and arterial catheters significantly increases this risk. Many prothrombotic disorders have been implicated in the pathogenesis of neonatal thrombosis, yet their exact role remains unclear. Despite treatment recommendations, there is a significant lack of randomized controlled trials demonstrating the efficacy of these treatments. Management of neonatal thromboses should occur at an experienced tertiary center that has proper support in place. This review focuses on a brief discussion of the neonatal hemostatic system highlighting why neonates are at risk for thrombosis, discusses the most common locations of neonatal thromboses and how to accurately image for them, reviews prothrombotic disorders’ role in neonatal thrombosis, and discusses possible treatment modalities.
Division of Neonatology, Levine Children’s Hospital at Carolinas Medical Center, 1000 Blythe Boulevard, 7th Floor, Charlotte, NC 28203, USA E-mail address: [email protected]
Clin Perinatol 42 (2015) 651–673 http://dx.doi.org/10.1016/j.clp.2015.04.010 perinatology.theclinics.com 0095-5108/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
Box 1 Incidence of neonatal thrombosis Incidence of symptomatic neonatal thrombosis is 5.1 per 100,000 live births1 and 2.4–6.8 per 1000 neonatal intensive care admissions2,7 Term and preterm and male and female neonates are affected equally.1,2,25
The neonatal coagulation system (anticoagulation and fibrinolytic systems) differs from those of children and adults (Table 1).7,8 These differences shift the neonate into a somewhat prothrombotic state, which is balanced by other factors preventing spontaneous thromboses in well neonates.9 However, numerous acquired and prothrombotic disorders may disrupt this balance, placing a neonate at risk for developing a clinically significant thrombosis (Table 2).3–6,9 Age-appropriate reference ranges of coagulation and anticoagulation proteins are published.3,5,6 TYPES AND LOCATIONS OF NEONATAL THROMBOSES
Common locations, presenting signs and symptoms, and imaging modalities recommended for different types of thromboses are presented in Table 3. Arterial Thromboses Perinatal arterial ischemic stroke
Perinatal arterial ischemic stroke (PAIS), which affects both preterm and term infants, mainly occurs in the left hemisphere within the distribution of the middle cerebral artery, with multifocal cerebral infarctions usually being of embolic origin.12 The exact pathophysiologic mechanisms responsible for PAIS are unknown. A patent foramen ovale allowing thrombi from the placental circulation to pass into the cerebral arterial vasculature resulting in vessel occlusion has been one suggested theory.32 Pathologic examination of the placenta from any high-risk delivery may
Table 1 Anticoagulant and procoagulant protein levels in neonates compared with adults Protein
Neonatal Level Compared with Adult Level
Neonatal Procoagulant proteins
Factor VIII von Willebrand factor activity
Neonatal anticoagulant proteins
Factor II Factor VII Factor IX Factor X Factor XI Factor XII Protein C Protein S Antithrombin Heparin cofactor II
Adapted from Manco-Johnson M. Controversies in neonatal thrombotic disorders. In: Ohls RY, editor. Hematology, immunology and infections disease: neonatology questions and controversies. Philadelphia: Saunders Elsevier; 2008. p. 59; with permission.
Thrombosis in the NICU
Table 2 Risk factors implicated in the development of neonatal thromboses Maternal Risk Factors
Delivery Risk Factors
Neonatal Risk Factors
Infertility Oligohydramnios Prothrombotic disorder Preeclampsia Diabetes Intrauterine growth restriction Chorioamnionitis Prolonged rupture of membranes Autoimmune disorders
Emergent cesarean section Fetal heart rate abnormalities Instrumentation Meconium-stained fluid
CVCsa Arterial catheters CHD Sepsis Meningitis Birth asphyxia Respiratory distress syndrome Dehydration Congenital nephritic/nephrotic syndrome Necrotizing enterocolitis Polycythemia Pulmonary hypertension Prothrombotic disorders (see Box 3) Surgery Extracorporeal membrane oxygenation Medications (steroids)
Greatest risk factor for thrombosis. From Saxonhouse MA, Manco-Johnson MJ. The evaluation and management of neonatal coagulation disorders. Semin Perinatol 2009;33:56; with permission; and Data from Refs.2,10–24
assist with supporting this theory. Other risk factors implicated in the cause of PAIS are listed in Table 2, with prothrombotic disorders being reported in more than half of the population studied with PAIS.32 Current guidelines recommend anticoagulation treatment only for neonates with proven cardioembolic stroke or recurrent PAIS.27 Iatrogenic arterial thrombosis
The use of indwelling arterial catheters is frequent in the neonatal intensive care unit (NICU) and has significant clinical benefits for managing critically ill neonates. Unfortunately, the presence of these catheters coupled with other risk factors in the ill neonate (see Table 2) may increase the risk for a symptomatic arterial thrombosis. Iatrogenic arterial thromboses have been associated with umbilical arterial catheters (UACs), peripheral arterial catheters (PALs), and femoral arterial catheters (Box 2).33 High UAC positioning may have fewer complications,27,34 whereas continuous heparin infusion at 1 unit/mL may prolong catheter patency without reducing the risk for thrombosis.34,35 The longer a UAC remains in place, the higher the probability for thrombus formation (80% incidence if used for 21 days).36 Spontaneous arterial thrombosis
Spontaneous arterial thromboses are rare (see Table 3) and warrant an evaluation for a prothrombotic disorder (Box 3).38 Treatment depends on the clinical symptoms and location of the thrombus. Venous Thromboses Central venous catheter–related thrombosis (excluding intracardiac)
Umbilical venous catheters (UVCs) and percutaneous intravenous central catheters (PICCs) are routinely used in the NICU; however, occlusion and infection remain the 2 most commonly reported long-term problems (Box 4).48 An analysis of 3332 neonates with central venous catheters (CVCs; including UVCs, PICCs, and surgically
Table 3 Types of neonatal thromboses, presenting signs/symptoms, and best imaging modalities to diagnose them Type of Thromboses (Vessels Potentially Involved) Arterial
PAIS (left middle cerebral artery,a anterior cerebral artery, posterior cerebral artery) Iatrogenicc (abdominal aorta, radial artery, renal artery, mesenteric artery, popliteal artery) Spontaneous (iliac artery, left pulmonary artery, aortic arch, descending aorta)
Iatrogenicc/spontaneous vessel occlusion (superior vena cava, inferior vena cava, hepatic vein, subclavian vein, abdominal veins, peripheral veins) Renal vein
Portal venous Cerebral sinovenous (superior sagittal sinus,a transverse sinuses of the superficial venous system, straight sinus of the deep system) CHD-related (right/left atria, right/left ventricle, superior vena cava, inferior vena cava) a b c
Seizures,b lethargy, hypotonia, apnea, feeding difficulties Line dysfunction,b extremity blanching or cyanosis,b persistent thrombocytopenia, sepsis, other symptoms depending on location Symptoms depend on location
Diffusion-weighted MRI/magnetic resonance angiography
Line dysfunction, persistent thrombocytopenia, persistent infection, pericardial tamponade, symptoms of right heart failure, superior vena cava syndrome Triad of (1) macroscopic hematuria, (2) palpable abdominal mass, and (3) thrombocytopenia; acute hypertension Thrombocytopenia, elevations of liver enzymes Seizures,b respiratory distress, poor feeding, irritability, fever, apnea, lethargy, jitteriness Pericardial tamponade, symptoms of right heart failure, superior vena cava syndrome
Doppler ultrasound (limited in low-birthweight infants; 27-g catheters are not consistently visualized during ultrasound examinationsc,26)
Diffusion-weighted MRI with venography
Most common vessel involved. Most common symptom. Catheter related. Data from Refs.12,20,23,27–31; and Adapted from Saxonhouse MA. Management of neonatal thrombosis. Clin Perinatol 2012;39:192–3; with permission.
Thrombosis in the NICU
Box 2 Key points: iatrogenic arterial thrombosis Complications from UAC-associated thromboses include mesenteric ischemia, renal failure, tissue necrosis, hypertension, septicemia, and even death.36,37 Suspicion or confirmation of an arterial thrombosis due to catheter placement should warrant prompt removal of the catheter. Imaging should be performed before catheter removal, and careful consideration should be given to whether local thrombolysis via the catheter may be indicated.27
placed CVCs) demonstrated an incidence rate of thrombosis of 9.2% (1.1%– 66.7%).48 Other studies have reported the thrombosis rate for PICC lines to range from 2.2% to 33.6%.49 Autopsies have estimated that 20% to 65% of infants who die with a UVC in situ have microscopic evidence of thromboses.50–52 Small-for-gestational-age, polycythemic neonates requiring central venous access may represent a significantly high-risk population for thrombosis.48 The site of insertion does not seem to affect the incidence and morbidity of CVC-related thrombosis.48 Removal of a CVC should follow the diagnosis of a thrombosis; however, because of the risk for emboli, current recommendations are to delay CVC removal until 3 to 5 days after anticoagulant therapy has been started, although no clinical studies exist to support this practice.27 The treatment of CVC-related thrombosis depends on the Box 3 Prothrombotic disorders implicated in the development of neonatal thrombosis Factor V Leiden mutationa,b,c Factor II G20210A gene mutationa,c Increased apolipoprotein (a) Methylenetetrahydrofolate reductase gene mutation (MTHFR C677T) genotypeb,c Hyperhomocysteinemia Protein C deficiencya,c Protein S deficiencya,c Antithrombin deficiencya,b Heparin cofactor II deficiency Dysfibrinogenemia PAI-1 4G/5G gene mutationc Increased levels of factor VIIIC, IX, XI, or fibrinogen Antiphospholipid antibodies (including anticardiolipin antibodies, lupus anticoagulant) Chromosome 2q Chromosome 2q13 deletion Either a single disorder, or more commonly, the combination of multiple disorders may result in a prothrombotic phenotype. a May follow autosomal-dominant inheritance model. b Increased risk for spontaneous arterial thrombosis. c Implicated with development of RVT.39,40 Data from Refs.13,15–17,25,41–47
Box 4 Key points: central venous catheter–related thrombosis Long-term complications of CVC-related thromboses include venous chronic venous obstruction with cutaneous collateral circulation, chylothorax, portal hypertension (see discussion in text), and postthrombotic syndrome.53–56 The Centers for Disease Control and Prevention currently recommend that UVCs be limited to 14 days.57
presence of clinical symptoms, the location of the thrombus, and whether the thrombus is stagnant or propagating following detection.48 Further specific management guidelines are presented later. Intracardiac thromboses not associated with congenital heart disease
The placement of CVCs in the right atrium remains controversial because of the risks for pericardial tamponade or intracardiac thrombi.41,58 Intracardiac (mainly right atrial thrombi) thrombi is a life-threatening condition due to the risk for dissemination of emboli into the lungs or obstruction of the right pulmonary artery.59,60 Please refer to the treatment section for specific details. Renal vein thrombosis
Symptoms of renal vein thrombosis (RVT), not always present in triad, are presented in Table 3. Most neonatal RVTs are unilateral (70%) and tend to involve the left kidney, with a male predominance (Box 5).10 Current treatment recommendations for RVT are presented in Table 4. Portal vein thrombosis
Spontaneous regression of neonatal PVT may occur,64,65 and recanalization occurs more frequently in cases with partial thrombi (70%–77%) than in cases with occlusive thrombi (31%–48%)26,66 with a mean time of resolution of 63 days (2–626 days; median 25 days).66 The major concern with neonatal PVT is the development of portal hypertension, although this long-term complication is uncommon, especially if the thrombus remains in the left portal vein and does not propagate into the main or right portal vein (Box 6).26,67–71 One study demonstrated portal hypertension occurring at a mean of 5.7 years after the acute event; therefore, routine follow-up is recommended for any neonate diagnosed with PVT.72 Another complication of neonatal PVT is liver lobe atrophy. Although no evidence for anticoagulation or thrombolysis exists for cases of neonatal PVT, there are circumstances wherein treatment may be warranted (Table 5).67 Box 5 Key points: renal vein thrombosis Complications of RVT include adrenal hemorrhage, extension into the inferior vena cava, hypertension, renal failure, and death.10 Most infants with RVT will suffer either complete, cortical, or segmental infarction of the affected kidneys.63 Prothrombotic disorders have been found in 43% to 67% of patients with RVT (see Box 3).10,11,61,62
Thrombosis in the NICU
Table 4 Management options for neonates with renal vein thrombosis Unilateral RVT
Absence of renal impairment or extension into the inferior vena cava
Supportive care with monitoring of the RVT for extension If extension occurs, anticoagulation for 6 wk to 3 moa
Supportive care with monitoring of the RVT for extension If extension occurs, anticoagulation for 6 wk to 3 moa
Extension into the inferior vena cava
Initial thrombolyticb therapy with rTPA, followed by anticoagulationa
See Tables 9 and 10 for dosing options. See Tables 10 and 11 for dosing options and appropriate monitoring. Data from Refs.10,11,27,61,62 and Adapted from Saxonhouse MA. Management of neonatal thrombosis. Clin Perinatol 2012;39:195; with permission.
Cerebral sinovenous thrombosis
Most neonates with cerebral sinovenous thrombosis (CSVT) will present on the day of birth or within the first week of life (Box 7).76–78 Impaired or absent venous drainage in one of the cerebral sinuses leads to increased venous pressure, vasogenic edema, and secondary infarction.32 Hemorrhagic infarction may be present in 50% to 60% of newborns on first imaging.79 A spontaneous intraventricular or thalamic hemorrhage in a late-preterm or full-term neonate warrants evaluation for CSVT. The primary goal in the management of CSVT is to treat the underlying cause that may have predisposed the infant to develop CSVT (see Table 2).79 Studies in infants with CSVT demonstrate that in the supine position, compression of the occipital bone occurs, which may reduce cerebral blood flow. Adjusting the infant’s positioning to decompress the occipital bone has been shown to increase flow in the sigmoid and superior sagittal sinuses, offering a noninvasive therapy.80 Thrombosis in Infants with Congenital Heart Disease
Neonates with congenital heart disease (CHD), especially those undergoing cardiac surgery, represent a high-risk group for thrombosis (Box 8). Blood flow disturbances Box 6 Key points: portal vein thrombosis Sepsis, omphalitis, and UVCs have been specifically implicated in the development of neonatal PVT.67 Other than placement in the portal vein, UVC position does not seem to be significantly associated with PVT.67 Most neonates with PVT remain asymptomatic during the neonatal period (see Table 3).67 Acute complications include liver necrosis, cerebral infarction from paradoxic emboli, hepatic hematoma, hemorrhagic ascites, intrapulmonary bleeding, and death.73–75 Neonatologists must continue to understand the risks associated with UVC placement and the potential complications of PVT. Proper placement must be confirmed and should only occur if the placement of a UVC outweighs its risks.
Table 5 Management options for neonates with portal venous thrombosis Recommended Ultrasound (US) Follow-Up
Description of PVT
No extension observed and infant clinically stable
Extension into the IVC, RA, or RV but no end-organ compromise
10 d If thrombus resolved, may stop therapy. If still present, treat for 6 wk to 3 mo depending on US follow-up
End-organ compromise with extension of the thrombosis into the IVC, RA, or RV
Daily May stop thrombolysis when symptoms improve but would transition to anticoagulation
Abbreviations: IVC, inferior vena cava; RA, right atrium; RV, right ventricle. Adapted from Williams S, Chan AK. Neonatal portal vein thrombosis: diagnosis and management. Semin Fetal Neonatal Med 2011;16:337; with permission.
due to hypoplastic ventricles with limited inflow/outflow, dilated atria, arterial or femoral venous catheters, and surgically placed shunts all create an environment conducive to thrombus formation.81 Cardiac surgery is associated with platelet dysfunction/activation, inflammation, and blood hypercoagulability.81,82 RISK FACTORS FOR NEONATAL THROMBOSES INCLUDING APPROPRIATE LABORATORY EVALUATION
The combination of acquired risk factors (see Table 2) and prothrombotic disorders (see Box 3) may represent the perfect storm for the development of clinically significant neonatal thromboses. Registry data and case series have demonstrated that most symptomatic neonatal thromboses either are associated with multiple prothrombotic disorders or are a combination of prothrombotic disorders and acquired risk factors.1,2,10,11,13–17,42–45,61,88–90 Therefore, it is recommended that neonates with clinically significant thromboses (regardless of acquired risk factors) be tested for prothrombotic disorders.18 Homozygous or compound heterozygous disorders, such as severe protein C, protein S, or antithrombin III deficiency, usually present in newborns with severe clinical manifestations (purpura fulminans).27 Laboratory Evaluation
Important points to remember when performing the laboratory evaluation for a prothrombotic disorder in a neonate are presented in Box 9. The timing of the evaluation
Box 7 Key points: cerebral sinovenous thrombosis Management algorithm for neonatal CSVT is presented in Fig. 1. Mortality from CSVT ranges from 2% to 24% with disabilities such as epilepsy, cerebral palsy, and cognitive impairments ranging from 10% to 80% of patients.79
Thrombosis in the NICU
Confirmed diagnosis of CSVT by MRI/MRV
If no evidence of hemorrhage, start UFH or LMWH
If hemorrhage present, no treatment
Repeat MRI/MRV in 5-7 days and if imaging demonstrates propagation of thrombus, start UFH or LMWH
Repeat MRI/MRV in 6 weeks for vessel recanalization. If complete, stop therapy. If not, consider additional 6 weeks of treatment
Fig. 1. Management of neonatal CSVT. The figure displayed represents the current recommendations for appropriate evaluation, management, and follow-up of neonates diagnosed with CSVT. If either UFH or LMWH is provided, dosing guidelines are provided in Tables 9 and 10, respectively. MRV, magnetic resonance venography. (Data from Yang JY, Chan AK, Callen DJ, et al. Neonatal cerebral sinovenous thrombosis: sifting the evidence for a diagnostic plan and treatment strategy. Pediatrics 2010;126:e693–700.)
should be based on the severity of the thrombosis, presence of other acquired risk factors, and treatment plan.13 Further details are outlined in Tables 6 and 7. MANAGEMENT OF THROMBOSIS
Management of neonates with clinically significant thromboses should take place at a tertiary referral center that has an experienced Neonatologist or Pediatric Hematologist. The center should also have adequate laboratory, radiology, pharmacy, transfusion medicine, and pediatric surgical support.9,27 Treatment options include observation, nitroglycerin ointment (vasospasm), anticoagulant or thrombolytic therapy, or surgery. Withholding therapy and monitoring sequentially for alterations in the size of the thrombus in infants with asymptomatic thrombi associated with CVCs is a reasonable plan.27 Recommendations and dosing regimens for anticoagulant/thrombolytic therapy in neonates are based on uncontrolled studies, extrapolation from adult and pediatric data, small case series, cohort studies, and expert opinion.27 There are situations
Box 8 Key points: thrombosis in infants with congenital heart disease Lower levels of antithrombin in neonates with CHD may predispose aortopulmonary shunt thrombosis.83 Complications of thrombosis in neonates with CHD include pulmonary embolism, stroke, hemorrhage, and cardiac failure.84,85 Occurrence of thrombosis after pediatric cardiac surgery has been linked to a 3.4-fold increase in mortality.86,87
Box 9 Key points to remember in the laboratory evaluation for a suspected prothrombotic disorder Due to many of the pro-/anticoagulation protein levels being lower than adult values, the diagnosis of a coagulation disorder may be difficult in the immediate neonatal period. Certain protein-based assays may aid in treatment during the neonatal period (antithrombin and plasminogen assays) and may be performed during the neonatal period. DNA-based assays are accurate and may be obtained at any time. The different evaluations listed in the text are based on the presence of acquired risk factors, type of thrombosis, severity of thrombosis, and treatment regimen (if indicated). The initiation of long-term anticoagulation will usually not occur during the neonatal period and, therefore, the complete evaluation for a prothrombotic disorder may take place at 3 to 6 months of age. Laboratory testing should be unique for each patient and in concordance between Neonatology and Pediatric Hematology at an experienced tertiary referral center that has either a reference laboratory or a reliable referral center limiting blood loss in neonates. Baseline complete blood count, prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen levels should be performed before any evaluation.
when neonatal thromboses are life-, organ-, or limb-threatening. Efficacy has been demonstrated from case studies/series on the use of recombinant tissue plasminogen activator (rTPA) or anticoagulation with limited side effects.27 Therefore, it is reasonable to assume that a randomized trial demonstrating the effectiveness of rTPA or anticoagulation for limb-/life-threatening neonatal thromboses may never be done because the risk to withhold such treatment may far outweigh the benefit of a controlled trial.63 Still, serious complications (intracranial hemorrhage, ICH) must be considered in any
Table 6 Evaluation for prothrombotic disorder: presence of acquired risk factors Laboratory Testing
Antiphospholipid antibody panel, anticardiolipin, and lupus anticoagulanta (immunoglobulin G, immunoglobulin M)
Protein C activityb Protein S activityb Plasminogen levelb (if considering thrombolytic therapy) Antithrombin (activity assay)b
Factor V Leiden Prothrombin Gc
EDTA (Ethylenediaminetetraacetic acid)
The evaluation presented may be performed in its entirety during the neonatal period or may be performed at 3–6 months of age. The entire evaluation listed may be done in 1–2 mL of blood. a May be performed from maternal serum during first few months of life. b Protein-based assays are affected by the acute thrombosis and must be repeated at 3–6 months of life, before a definitive diagnosis may be made.13,91 If anticoagulation is being administered, then these assays should be obtained 14–30 days after discontinuing the anticoagulant. c DNA-based assays. Adapted from Saxonhouse MA, Manco-Johnson MJ. The evaluation and management of neonatal coagulation disorders. Seminars in Perinatology 2009;33:59; with permission.
Thrombosis in the NICU
Table 7 Evaluation for prothrombotic disorder: no acquired risk factors present Laboratory Testing
Antiphospholipid antibody panel, anticardiolipin, and lupus anticoagulant (immunoglobulin G, immunoglobulin M)a
Protein C activityb Protein S activityb Antithrombin (activity assay)b
Factor V Leidenc Prothrombin Gc Methylenetetrahydrofolate reductasec PAI-1 4G/5G mutationc
Homocysteineb Lipoprotein ab
FVIII activityb FXII activityb Plasminogen activityb Heparin cofactor IIb
The evaluation presented may be performed in its entirety during the neonatal period or may be performed at 3–6 months of age. The entire evaluation listed may be done in 5–6 mL of blood. A possible limitation to this approach is the amount of blood required for adequate testing, especially when evaluating a premature or anemic infant. a May be performed from maternal serum during the first few months of life. b Protein based-assays are affected by the acute thrombosis event and must be repeated at 3– 6 months of life, before a definitive diagnosis may be made.13,91 If anticoagulation is being administered, then these assays should be obtained 14–30 days after discontinuing the anticoagulant. c DNA-based assays. Adapted from Saxonhouse MA, Manco-Johnson MJ. The evaluation and management of neonatal coagulation disorders. Seminars in Perinatology 2009;33:59; with permission.
neonate before initiating antithrombotic therapy. Absolute and relative contraindications for thrombolytic and anticoagulant therapy in neonates are displayed in Table 8. Clinicians may use 1-800-NO CLOTS to receive up-to-date management guidance from expert consultants over the phone.27
Table 8 Absolute and relative contraindications for initiating thrombolytic/anticoagulant therapy in neonates
1. Central nervous system surgery or ischemia (including birth asphyxia) within 10 d 2. Active bleeding 3. Invasive procedures within 3 d 4. Seizures within 48–h
1. Platelet count <50 104/mL (100 104/mL for ill neonates) 2. Fibrinogen concentration <100 mg/dL 3. INR (international normalized ratio) >2 4. Severe coagulation deficiency 5. Hypertension
Adapted from Manco-Johnson M. Controversies in neonatal thrombotic disorders. In: Ohls RY, editor. Hematology, immunology and infections disease: neonatology questions and controversies. Philadelphia: Saunders Elsevier; 2008. p. 68; with permission; and Data from Refs.21,27,33,53,91
Management of peripheral vasospasm following UAC or PAL placement is presented in Fig. 2. Nitroglycerine is a nitric oxide donor that may have a direct effect on vascular smooth muscle producing local vasodilatation of veins and arteries.93–95 Resultant increased blood flow, due to this acute dilatation, may overcome the vasospasm, allowing flow around microthrombi or improving collateral circulation to the affected areas.96,97 Anticoagulation
Low-molecular-weight heparins (LMWHs) are the most commonly used anticoagulants in infants and children, with enoxaparin being the most frequently used.100–103 Enoxaparin has the best factor Xa/factor IIa inhibition ratio and has demonstrated fewer bleeding complications in clinical trials, the longest half-life, and the most consistent pharmacokinetic and pharmacodynamic pediatric data.104–106 (Dusky fingersoforperipheral toes, blanching, swelling) Symptoms vasospasm (Duskiness of fingers, toes, hands, or feet; blanching of extremity, edema)
Warming of contralateral extremity for 15 minutes
Resolution of symptoms
Continue to follow closely
If symptoms still present, local application of 2% nitroglycerin ointment at 4 mm/kg Follow BP closely during use
Fig. 2. Management of peripheral vasospasm. The figure displayed represents the current recommendations for the evaluation and management for neonates with peripheral vasospasm most likely due from complications from PALs or UACs. Nitroglycerin dosing is provided. BP, blood pressure. (Data from Refs.27,96–99)
Thrombosis in the NICU
Antithrombin levels are lower in neonates compared with adults.3,5,6 Because of these lower levels and an increased rate of heparin clearance, neonates tend to require higher doses of anticoagulation to achieve therapeutic levels.77 Antithrombin concentrate has been used to optimize heparin therapy and provide a more consistent state of anticoagulation during extracorporeal membrane oxygenation, cardiopulmonary bypass, and aortopulmonary shunt placement, without increasing the risk for excessive bleeding.83,107–111 Anticoagulation dosing in neonates is based on lower levels of antithrombin; therefore, if antithrombin concentrate is administered to achieve anticoagulation and the anticoagulant dose is not adjusted, significant bleeding complications may occur. Unfractionated Heparin
Dosing and monitoring guidelines are displayed in Table 9. Unfractionated heparin (UFH) therapy is usually continued for 2 to 30 days,27 but data to support this Table 9 Clinical indications and recommended dosing guidelines for unfractionated heparin therapy in neonates Clinical Indication
Other Recommended Dosinga,112
<28-wk GA Asymptomatic or Any GA Bolus dose: 25 units/kg Bolus dose: symptomatic IV over 10 min 75 units/kg thrombus but Maintenance dose: IV over 10 min non-limb15 units/kg/h Maintenance threatening 28–37-wk GA dose: Bolus dose: 50 units/kg 28 units/kg/h over 10 min Maintenance dose: 15 units/kg/h >37-wk GA Bolus dose: 100 units/kg over 10 min Maintenance dose: 28 units/kg/h
Appropriate Monitoring (Applied to All Dosing Regimens) Maintain anti-factor Xa level of 0.03–0.7 units/mL (aPTT of 60– 85 s) Check anti-factor Xa level 4 h after loading dose and 4 h after each change in infusion rate Dosing adjustments based on anti-factor Xa levels are published elsewhere27,113 Complete blood count, platelet count, and coagulation screening (including aPTT, PT, and fibrinogen) should be performed before starting UFH therapy Recommendations are that platelet count and fibrinogen levels should be repeated daily for 2–3 d once therapeutic levels are achieved and at least twice weekly thereafter27
Abbreviation: GA, gestational age. a Safety and efficacy of this dosing have not been confirmed by clinical studies; use with caution.112 Data from Refs.27,91,112 and Adapted from Armstrong-Wells JL, Manco-Johnson MJ. Neonatal thrombosis. In: de Alarcon P, Werner EJ, Christensen RD, editors. Neonatal Hematology. New York: Cambridge University Press; 2013. p. 282; with permission.
recommendation are lacking. The major complication of UFH in neonates is bleeding, with one registry reporting a 2% major hemorrhage rate.2 UFH has a short half-life and cessation of the infusion usually resolves any excessive bleeding. If cessation of the infusion does not control bleeding, then a full coagulation assessment should be performed and hemostatic deficiencies replaced. Protamine may be considered in the setting of an anti-Xa activity level greater than 0.8 U/mL with active bleeding. One unit of protamine will neutralize 100 units of UFH. The plasma heparin burden can be estimated by multiplying estimated plasma volume by anti-Xa concentration.9 Protamine dosing should be conservative, and one-half the calculated dose is generally given initially (excess protamine is an anticoagulant). Heparin-induced thrombocytopenia (HIT) is rare in neonates114,115; however, a drop in the platelet count by 50% or persistent platelet counts less than 70 to 100,000/mm3 occurring 5 to 10 days after the first exposure to heparin should alert the clinician to the possibility of HIT.
Dosing and management guidelines are displayed in Table 10. Although adverse effects from LMWH are rare, several major complications have been described.93–95,116
Table 10 Clinical indications and recommended dosing guidelines for low-molecular weight heparin (enoxaparin) therapy in neonates Traditional Clinical Situation Dosing
Other Recommended Prophylactic Appropriate Dosinga,112 Dose Monitoring
<28 wk gestation Any GA Asymptomatic 1.25 mg/kg SQ 1.5 mg/kg or symptomatic every 12 h SQ every thrombus but 28–37 wk gestation 12 h non-limb1.5 mg/kg SQ threatening every 12 h >37 wk gestation 1.625 mg/kg SQ every 12 h
0.75 mg/kg SQ every 12 h
Goal of anti-FXa levels of 0.5 to 1.0 U/mL Check level 4 h after second dose and then every few days or weekly104 Dosing adjustments based on anti-FXA levels are published elsewhere27,113 If infant with high hemorrhagic profile, use dosing regimen of 1 mg/kg SQ every 12-h27
Enoxaparin must be withheld for 24-h before any invasive procedure. LMWH may be administered either by subcutaneous injection or through an indwelling subcutaneous catheter (Insuflon;Unomedical, Birkerod, Denmark). Studies have demonstrated up to 56% in incidence of local adverse effects with Insuflon usage and caution should be used in very low birth weight infants.27,91,93,94,116–118 Abbreviations: GA, gestational age; SQ, subcutaneous. a Safety and efficacy of this dosing has not been confirmed by clinical studies; use with caution.112 Adapted from Armstrong-Wells JL, Manco-Johnson MJ. Neonatal thrombosis. In: de Alarcon P, Werner EJ, Christensen RD, editors. Neonatal Hematology. New York: Cambridge University Press; 2013. p. 282; with permission.
Thrombosis in the NICU
Overall, LMWH therapy has been effective in the NICU and centers have reported partial or complete resolution of thromboses in 59% to 100% of cases.93,117 Thrombolysis
Thrombolytic therapy, mainly rTPA, for use in neonates, should be reserved for limb-, organ-, or life-threatening thromboses, including catheter-related right atrial thromboses.27,33,63,119–121 The safety and efficacy of rTPA treatment in neonates have been demonstrated in limited reports, but these have demonstrated either complete or partial clot lysis.91,119–121 rTPA has also been used in the management of premature infants with infective endocarditis122; however, one must use caution when administering thrombolytics to premature infants because of the high incidence of intracranial hemorrhage (ICH). Extensive discussion with an infant’s family should occur before the use of rTPA in neonates because of its serious risks. Dosing recommendations are displayed in Table 11, and appropriate careful monitoring for thrombolytic therapy is presented in Table 12. Surgery
The use of microsurgical techniques with thrombolysis has been reported in patients with peripheral arterial occlusion.124 One center has reported their experience with 11 patients with arterial vascular access-associated thrombosis secondary to peripheral arterial line complications. Five patients required arteriotomy, embolectomy, and subsequent microvascular reconstruction.124 When faced with limb-/life-threatening arterial or venous thrombosis and antithrombotic therapy is absolutely contraindicated, surgery may be a viable option.
Table 11 Clinical indications and recommended dosing guidelines for recombinant tissue plasminogen activator therapy in neonates Clinical Situation
<28 wk >28 wk
0.03 mg/kg/h or 0.06 mg/kg/h Infuse UFHa at 10 units/kg/h May use same as for <28-wk or 0.1–0.5 mg/kg/h for 6–12 h and repeat daily for up to 3 d112 Infuse UFHa at 10 units/kg/h
Dose escalation up to 0.24 mg/kg/h can be considered, but has to be done slowly with continuing monitoring of the patientb (see Table 12) Supplementation with plasminogen (FFP) before commencing therapy is recommended to ensure adequate thrombolysis27
a rTPA does not inhibit clot propagation or directly affect hypercoagulability; therefore, simultaneous infusion of UFH is recommended.27,119 b See Table 12. Abbreviation: FFP, fresh frozen plasma. Data from Refs.91,119. Adapted from Armstrong-Wells JL, Manco-Johnson MJ. Neonatal thrombosis. In: de Alarcon P, Werner EJ, Christensen RD, editors. Neonatal Hematology. New York: Cambridge University Press; 2013. p. 282; with permission.
Table 12 Monitoring recommendations for thrombolytic therapy in neonates Testing
Levels Desired (If Applicable)a
Imaging of thrombosis
Before initiation of treatment Every 12–24 h during treatment
Before initiation of treatment 4–6 h after starting treatment Every 12–24 h
Minimum of 100 mg/dL123 Supplement with cryoprecipitate
Before initiation of treatment 4–6 h after starting treatment Every 12–24 h
Minimum of 50–100 104/mL,92 dependent on bleeding risk
Before initiation of treatment Daily
Before initiation of treatment 4–6 h after starting treatment Every 12–24 h
Before initiation of treatment 4–6 h after starting treatment Every 12–24 h
Adequate to achieve thrombolysis Supplementation with plasminogen (FFP) before commencing therapy is recommended to ensure adequate thrombolysis27,119
Line associated or mucosal oozing
All clinical assessments
Topical thrombin as needed
a Levels should be obtained before the initiation of treatment, 4–6 hours after starting treatment, and every 12–24 hours during treatment. Adapted from Saxonhouse MA. Management of neonatal thrombosis. Clin Perinatol 2012;39:191–208; with permission; and Data from Refs.33,119,120
Neonatal thrombosis represents an increasing problem affecting some of our most fragile patients. The lack of randomized clinical trials addressing the management of neonatal thrombosis forces neonatologists to base their medical decisions on limited evidence. As more data are obtained from centers specializing in neonatal thrombosis, more knowledge will be gained on how to optimize therapy. Current guidelines have been presented to assist Neonatologists and Pediatric Hematologists to make the most educated medical decisions. Despite numerous acquired risk factors implicated in the development for neonatal thrombosis, prothrombotic disorders continue to be reported in neonates. Neonatologists and others caring for high-risk infants with thromboses should continuously refer to the literature because new guidelines are recommended and others are updated. For now, the ultimate goal is to treat effectively without causing additional harm.
Best Practices What is the current practice for thrombosis in the NICU? Evaluation and treatment of any neonate with a clinically symptomatic thrombosis should occur at a tertiary referral center that has proper neonatology, pediatric hematology, pharmacy, radiology, and laboratory support. The use of central catheters is a major risk factor for the development of a clinically significant thrombosis. Most recommendations for treatment are based on expert opinion, case series, and data registries.
Thrombosis in the NICU
What changes in current practice are likely to improve outcomes? Further clinical studies and data collection will enhance what the best treatment strategies should be for neonates with clinically significant thromboses. Proper imaging modalities should be performed based on the type of thrombosis that one is concerned about. Laboratory evaluations for prothrombotic disorders should be performed at specific time periods, allowing for proper diagnosis, and should be sent to specific referral laboratories, limiting blood volumes needed for these evaluations. Is there a clinical algorithm? Treatment algorithms are presented for peripheral vasospasm, renal vein thromboses, portal vein thromboses, and cerebral sinovenous thromboses. However, most recommendations for treatment and management are grade 2C. The use of rTPA and anticoagulation in neonates is based on limited evidence. 1. Monagle P, Chan AK, Goldenberg NA, et al. Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-based Clinical Practice Guidelines. Chest 2012;141:e737S–801S. 2. Manco-Johnson MJ. How I treat venous thrombosis in children. Blood 2006;107:21–9. Summary Neonatal thrombosis represents an increasing problem affecting some of our most fragile patients. As more data are obtained from centers specializing in neonatal thrombosis, more knowledge will be gained on how to optimize therapy and minimize complications. Neonatologists and others caring for high-risk infants with thromboses should continuously refer to the literature because new guidelines are recommended and others are updated. For now, the ultimate goal is to treat effectively without causing additional harm.
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