The neonatal hemostatic system can be tipped toward thrombosis by a variety of acquired risk factors, and greater than 95% of neonatal VTE is associated with at least one clinical risk factor (5, 9) (Table 1). The most common clinical risk factor is the presence of a CVC (5, 9–13). A prospective study of neonates who underwent CVC placement indicated a 13% incidence of CVC-associated VTE (14), while another evaluating only umbilical catheter revealed a higher incidence of 22% (15). A recent systematic review of the literature noted that risk factors for CVC thrombosis development are not reliably documented across studies, however; birth weight, gestational age, prolonged catheter duration (>6 days), umbilical venous catheter (UVC) mal-placement, and the addition of blood products to UVC infusions were all highlighted as risk factors for CVC-related thromboses (5, 16).

In addition to CVCs, sepsis, mechanical ventilation, perinatal asphyxia, congenital heart disease, and dehydration are recognized risk factors for neonatal VTE (11, 13, 17). The contribution of maternal risk factors to neonatal VTE development is not as well studied, however; infection, placental disease, diabetes mellitus, hypertension, pre-eclampsia, dyslipidemia, metabolic syndrome, antiphospholipid antibody syndrome, inherited thrombophilia, emergent Cesarean section, and premature rupture of membranes have been associated with increased risk of neonatal VTE (18). At least one or more maternal risk factor for neonatal VTE has been found in up to 56% of neonates with venous thrombosis (18). Risk factors for renal vein thrombosis (RVT) are similar to other neonatal VTE risk factors and include prematurity, maternal diabetes, dehydration, infection, perinatal asphyxia, and umbilical vein catheter (13, 19). The pathophysiology is suggested to result from impaired renal perfusion under the listed clinical circumstances, which leads to vasoconstriction and subsequent impaired venous blood flow which puts the postglomerular circulation at increased risk for thrombosis (20).

The role of inherited thrombophilic risk factors in neonatal VTE development is poorly defined (21). A recent systematic review analyzed 13 publications from 2008 to 2014 evaluating the role of inherited thrombophilia in neonatal VTE development and treatment. The authors concluded that neonatal VTE is multifactorial and clinical risk factors weigh more heavily on the prothrombotic scale than inherited thrombophilia, particularly in CVC-associated VTE (9). In an earlier study, the overall prevalence of inherited thrombophilia in neonates with VTE was not different than that of the healthy population, concluding that screening neonates with VTE for inherited thrombophilia was not necessary (12). In contrast, in another study of catheter-related VTE, 15 of 18 infants with VTE had at least one inherited thrombophilia (10). Further, in an Italian registry of neonatal VTE, an inherited thrombophilia was found in 33% of infants with an “early-onset” VTE (VTE in the first day of life) (18). While inherited thrombophilia appears to be present in some neonates with VTE, both CVC related and not, the role of inherited thrombophilia testing in neonates with VTE remains up for debate as it does not appear, at this time, to influence type or duration of treatment (9).

Imaging modalities employed to diagnose VTE in neonates include ultrasound, venography, computed tomography (CT), and magnetic resonance imaging (MRI). Ultrasound is the most common imaging modality employed to diagnose neonatal VTE, although venography is considered the reference standard for diagnosis of VTE (23). In the Canadian VTE registry study, Doppler ultrasound was used to diagnose 67% of the venous thromboses (11). Similarly, Doppler ultrasound was the most common imaging modality in the German VTE registry study (17). The availability of Doppler ultrasound as well as its non-invasive nature makes it an attractive diagnostic modality. However, it is operator dependent and its sensitivity and specificity decline when evaluating intrathoracic vessels as well as the iliac vessels or if the patient is edematous or has interfering skin abnormalities (23). A prospective study aimed at determining the incidence of asymptomatic venous thromboses associated with UVCs found that Doppler echocardiography was less sensitive than contrast venography (24). Further, the Prophylactic Antithrombin Replacement in Kids with ALL treated with Asparaginase study recommended a combination of ultrasound and venography to investigate upper extremity, line associated VTE (25). Venography is not often employed, though, given its invasive nature, technical demands, and radiation exposure (23). CT or MRI can be employed to evaluate the intrathoracic venous system for thromboses (26). A reasonable approach may be to start with ultrasound, and if negative and clinical suspicion remains high, then pursue evaluation with MRI or CT depending on diagnostic modality availability and contributing clinical factors.

Therapeutic monitoring of UFH is recommended with a goal anti-Xa level of 0.35–0.7 units/mL (28). It is suggested that UFH boluses should not be greater than 75–100 units/kg and should be avoided in those children where a significant bleeding risk exists (28). CHEST guidelines recommend starting the initial infusion at 28 units/kg per hour for infants but individual risk factors should be considered when choosing initial dosing (28). Neonatal dosing of LMWH is higher than older children and adults, and frequently doses of 1.5–2 mg/kg twice daily are needed to get into the therapeutic anti-Xa range of 0.5–1 units/mL (28, 34–36).

Thrombolytic therapy employs different agents [tissue plasminogen activator (tPA), streptokinase, urokinase] to convert plasminogen to plasmin, which ultimately cleaves fibrinogen and fibrin to fibrinogen/fibrin-degradation products (27). The decreased plasminogen concentration in neonates may decrease the efficacy of these agents, though (27). On the other side, the delicate neonatal cerebral vasculature and immaturity of the hemostatic system may predispose the infant to bleeding complications. A retrospective review of thrombolysis from 1964 to 1995 identified that intracranial hemorrhage occurred in 1/83 term infants and 11/86 preterm infants receiving tPA (37). In another review of 16 neonates treated with tPA, 7 had complete resolution of their thrombosis while 7 had partial resolution. One neonate died while receiving tPA from massive intracranial hemorrhage, but tPA was given despite severe thrombocytopenia in this patient, which was thought to be a confounding factor in the patient’s bleeding (38). Current consensus guidelines recommend against thrombolysis therapy unless the thrombosis is life-, limb-, or organ-threatening (28). If thrombolysis is used, tPA is the recommended agent, and plasminogen administration (through transfusion of fresh frozen plasma) is recommend prior to beginning thrombolysis (28).

Data regarding morbidity and mortality of VTE in neonates are lacking as follow-up in the majority of registry studies is short. In the Canadian registry, mortality in neonates with RVT was 5%, with other venous thrombosis was 18%, and with arterial thrombosis was 21%. However, all deaths were not directly attributable to the thromboses (11). The mortality rates for both aortic and right atrial/superior vena cava thromboses were 33% (11). In further analysis of the outcomes in the Canadian registry, for children 1 month to 18 years, the all-cause mortality was 16% with a thrombosis-related mortality of 2.2% (39). In the German registry study, 9% (7/79) of neonates with thromboses died, with three of the deaths related to thrombosis (17).

Recurrence rates are also difficult to determine accurately due to short follow-up times in most studies. The recurrence rate in the Canadian registry for children >1 month was 8.1% (39). The role of inherited thrombophilia on recurrent VTE is variable. Some studies suggest that the most important risk factor of recurrent thromboses is the presence of a clinical risk factor or the recurrence of the original clinical risk factor (12). However, other authors suggest that the presence of inherited thrombophilias, especially in combination, are risk factors for recurrent thrombosis and thus advocate their screening (40–42). Guidelines regarding the implementation of pharmacologic prophylaxis are lacking, and thus as no treatment change is currently recommended due to the presence of an inherited thrombophilia, testing for an inherited thrombophilia should be performed on an individual basis or, ideally, in the context of a clinical study.

Postthrombotic syndrome is a chronic complication of deep vein thrombosis and is characterized by chronic venous insufficiency. PTS results from a combination of residual thrombus causing obstruction and secondary valvular reflux (43). The data on neonates are lacking owing to variability in duration of follow-up in most of the studies and registries. In a retrospective study of children with upper extremity VTE, 16% of neonates developed mild PTS with collateral vein formation and increased extremity circumference. Lack of clot resolution and extension of the clot were identified as risk factors for PTS development (44). In the Canadian registry, PTS was diagnosed in 12.4% of the children with VTE (39). Data support the use of thrombolytic regimens in treatment of acute lower extremity DVT to reduce the risk of PTS in older children, but data are lacking in neonates (45).

Heparin-induced thrombocytopenia is a drug-induced, immune-mediated thrombocytopenia that is associated with the potential for serious thrombotic complications (46). The thrombocytopenia is typically moderate and the bleeding risk is low, however; the thrombosis risk is high (47). There is little literature on the development of HIT in the pediatric population, but the incidence is likely lower in children than in adults (46). The lower incidence is thought to be secondary to age-dependent differences in both the coagulation and immune systems (46). A recent review of the pediatric HIT literature reported an incidence between 0 and 1.7% in the neonatal subpopulation of anti-PF4/heparin antibodies but no cases of neonatal HIT (47). Further studies are needed to better understand HIT in the neonatal population. Given its significant deleterious outcomes, if suspected, all heparin should be stopped and a non-heparin alternative, such as a direct thrombin inhibitor (DTI), should be started until HIT is ruled out (48). Argatroban is the only DTI that has been prospectively studied in pediatric patients with HIT, and dosing guidelines are now included in the prescribing information (49, 50).