Neonatal thrombosis: Management and outcome

INTRODUCTION — Thrombotic events are uncommon in newborns; however, they are increasingly recognized as complications of contemporary neonatal care and they contribute to neonatal morbidity and mortality.

The management of neonatal thrombosis is reviewed here. The clinical features and diagnosis of neonatal thrombosis are discussed separately. (See "Neonatal thrombosis: Clinical features and diagnosis".)

This topic focuses on thrombotic events occurring outside of the central nervous system. Thrombosis involving the central nervous system (ie, neonatal stroke) is reviewed in detail separately. (See "Neonatal thrombosis: Clinical features and diagnosis" and "Stroke in the newborn: Classification, manifestations, and diagnosis" and "Stroke in the newborn: Management and prognosis".)

GENERAL APPROACH — Newborns are at risk for thrombosis because of the unique characteristics of their coagulation and fibrinolytic system as compared with older age groups, as well as because of triggers such as indwelling catheters. Because these risk factors usually are transient, the recurrence risk is low. Therefore, the primary goal of treatment in this age group is to prevent or minimize end-organ damage [1,2]. Rarely, a neonate has a chronic condition that predisposes to thrombosis, such as neonatal purpura fulminans or congenital nephrotic syndrome; in such cases, longer-term treatment is warranted. (See 'Special circumstances' below.)

Data on different management strategies and the efficacy and safety of specific therapeutic agents in the neonatal population are limited. The approach to an individual infant must balance the risks and benefits.

In most cases of neonatal thrombosis, consultation with a pediatric hematologist is advised. If such expertise is not available at the institution caring for the neonate, a free service is provided by a group of clinicians with extensive experience in neonatal thrombosis (call 1-800-NOCLOTS) [3].

TREATMENT BASED ON THROMBUS LOCATION — When choosing between conservative management (ie, supportive care and close monitoring) versus initiating anticoagulation, the approach depends upon the location of the thrombus and whether there are associated symptoms.

Catheter-associated thrombosis — For neonates with catheter-associated venous thrombosis (excluding renal vein thrombosis [RVT], portal vein thrombosis [PVT], and right atrial [RA] thrombosis, which are discussed below), our suggested approach is as follows:

●For neonates with asymptomatic catheter-associated thrombosis, we suggest supportive care and close monitoring of the size of the thrombus [1,4]. If the thrombus is associated with a central venous catheter (CVC) or umbilical venous catheter (UVC), the catheter should be removed if possible. Follow-up imaging is obtained initially within three to five days and if stable, it is repeated one to two weeks later. If the thrombus is stable or decreasing, subsequent ultrasound monitoring can be spaced out to every one to two months until resolved.

The rationale for this approach is that most asymptomatic thrombi resolve without treatment (particularly if the catheter is removed) and conservative management avoids bleeding complications that can be associated with anticoagulation therapy. However, initial treatment with an anticoagulant is a reasonable option when it is not feasible to remove the catheter, due to the patient's clinical condition.

If serial monitoring demonstrates extension of the thrombus or if the patient becomes symptomatic from the thrombus, we suggest anticoagulation as described in the next section [1].

●For symptomatic catheter-associated thrombosis, we suggest therapeutic anticoagulation (typically with low molecular weight heparin LMWH). (See 'Choice of agent' below.)

The optimal duration of therapy is uncertain. Our approach is to monitor the thrombus with serial ultrasounds. If the thrombus resolves and the patient is asymptomatic by six weeks, we discontinue anticoagulation. Otherwise, we continue anticoagulation for three months or until the thrombus has resolved and the patient is asymptomatic, whichever is shorter. Clinical trial data suggest that six weeks of anticoagulant therapy is sufficient for most patients with CVC-associated venous thrombosis [5].

CVCs and UVCs associated with thrombosis should be removed, if possible, immediately or after three to five days of anticoagulation [1]. When the decision is made to remove the CVC or UVC, we typically remove it after three to five days of initial anticoagulation; however, there are scant data to support this approach and it is reasonable to remove the CVC or UVC sooner. If the CVC or UVC remains in place at the time of completion of therapeutic anticoagulation, we suggest treatment with a prophylactic dose of LMWH until the device is removed.

●Management of arterial catheter-associated thrombosis is discussed below. (See 'Arterial thrombosis' below.)

Renal vein thrombosis — The optimal management approach for neonates with RVT is uncertain, and practice varies. The available data are limited to small retrospective case series [6,7]. The need for and choice of anticoagulant is based on whether the infant has unilateral or bilateral involvement, whether there is associated renal insufficiency, and whether the thrombus extends into the inferior vena cava (IVC) [1]. For all neonates with RVT, if there is a CVC or UVC in place in the IVC, it should be removed if possible.

●Unilateral RVT with normal renal function AND without extension into the IVC – In our practice, neonates with unilateral RVT with normal renal function and without extension into the IVC are treated with anticoagulation unless the patient has a high bleeding risk. The rationale for treating such infants is to minimize potential complications of RVT (eg, chronic kidney disease and hypertension) [8,9]. However, since the risk of these complications is relatively low in patients with unilateral RVT (as compared with bilateral RVT), an alternative approach is to manage initially with supportive care and close monitoring. If the thrombosis progresses or there is extension into the IVC, anticoagulation should be started.

When the decision is made to treat with anticoagulant therapy, the typical treatment duration is three months. A shorter duration is reasonable if the thrombus resolves on follow-up imaging and the patient is asymptomatic.

●Bilateral RVT, associated renal insufficiency, OR extension into the IVC – For neonates with bilateral RVT, compromised renal function, or extension into the IVC, we suggest therapeutic anticoagulation for three months unless there are contraindications to its use.

The choice of agent and dosing for anticoagulant therapy depend on the neonate's renal function, as discussed below. (See 'Choice of agent' below and 'Dose' below.)

In patients with extensive thrombus that compromises renal function, concomitant use of thrombolytic therapy can be considered to potentially reduce the risk of developing chronic renal failure [1,7]. (See 'Thrombolytic therapy' below.)

In a systematic review of 13 case series published from 1992 to 2006 involving 271 neonates with RVT (70 percent unilateral, 30 percent bilateral), therapeutic anticoagulation was used in 60 percent of cases and 40 percent were managed conservatively [6]. Thrombolytic therapy was used in a small minority of patients (approximately 10 percent). In the seven studies (143 infants) that reported long-term outcomes, 74 percent of patients had evidence of kidney atrophy on imaging at last follow-up, with similar rates in heparin-treated and -untreated patients.

Portal vein thrombosis — PVT is almost always associated with the use of a UVC, and, thus, the UVC should be removed if possible. The benefit of anticoagulation in neonatal PVT is uncertain since many resolve without intervention [10]. Thus, for most neonates with PVT that is limited to the left portal vein, we suggest conservative management with supportive care and serial monitoring. If the thrombus extends into the main portal vein and/or IVC, anticoagulation should be initiated (typically with LMWH) [10]. The usual treatment duration is three months, though a shorter duration is reasonable if the thrombus resolves on follow-up imaging and the patient is asymptomatic.

Right atrial thrombosis — RA thrombi are usually associated with CVCs. They can compromise cardiac function or lead to pulmonary embolism. If possible, the catheter should be removed. We usually treat RA thrombosis with anticoagulation (typically with LMWH) unless there is a contraindication to its use. The usual treatment duration is three months, though a shorter duration is reasonable if the thrombus resolves on follow-up imaging and the patient is asymptomatic. If cardiac function is compromised, we begin thrombolytic therapy. (See 'Thrombolytic therapy' below.)

A systematic review that included data from neonates and children (mean age 3.6 years) with RA thrombus suggested that thrombi with low-risk features (ie, small size [<2 cm] and not pedunculated, mobile, or snake-shaped) can be treated conservatively without anticoagulation [11]. However, it should be noted that the critical clot size depends on the age of the child [12]. In neonates, smaller thrombi may be considered high risk. If conservative management is chosen, the thrombus should be monitored closely and anticoagulation should be started if the thrombus increases in size [11].

Arterial thrombosis — Treatment should be initiated for arterial thrombosis that causes significant impairment of blood flow to an extremity or vital organ. If the thrombus is associated with an arterial catheter, it should be removed. We usually begin anticoagulation therapy with LMWH or unfractionated heparin (UFH) [1]. If the thrombus is thought to be limb-threatening, a surgical consultation should be obtained for a multidisciplinary approach to management.

Thrombolytic therapy may be warranted in cases of arterial thrombosis that are life-threatening or that jeopardize the viability of a limb or if a vital organ is jeopardized [1]. Concomitant anticoagulant therapy (typically using UFH without a bolus) is typically provided during thrombolytic therapy. The thrombus should be monitored by clinical examination and ultrasonography (see 'Thrombolytic therapy' below). Surgical thrombectomy is an appropriate alternative in cases in which thrombolysis is contraindicated.

Central nervous system — Management of neonatal stroke is discussed separately. (See "Stroke in the newborn: Management and prognosis".)

PRETREATMENT EVALUATION — Before starting therapeutic anticoagulation, the following tests should be obtained:

●Laboratory tests, including:

•Activated partial thromboplastin time (aPTT)

•Prothrombin time (PT) and international normalized ratio (INR)

•Plasma fibrinogen concentration

•Complete blood count, including platelet count

•Kidney function tests (blood urea nitrogen and creatinine)

•Liver transaminases (if treatment with a direct oral anticoagulant [DOAC] is planned, which is uncommon)

●Cranial ultrasound – This is especially important for preterm infants, who are at increased risk of developing an intracranial hemorrhage (see "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis")

Patients with significant thrombocytopenia or evidence of coagulopathy prior to treatment (eg, prolonged PT or aPTT, low fibrinogen level) should undergo evaluation for the cause. Anticoagulant therapy may need to be deferred until the abnormality is treated or resolved. Prior to starting anticoagulant treatment, the platelet count should be >50,000/microL and the fibrinogen concentration should be >100 mg/dL (>1 g/L). (See "Neonatal thrombocytopenia: Etiology" and "Neonatal thrombocytopenia: Clinical manifestations, evaluation, and management".)

ANTICOAGULANT AGENTS

Choice of agent — For most neonates requiring treatment for thrombosis, we suggest low molecular weight heparin (LMWH) rather than other agents.

●Preference for LMWH – LMWHs have many advantages over unfractionated heparin (UFH) [13,14]. These include greater bioavailability when given by subcutaneous injection, longer duration of anticoagulant effect, and clearance that is independent of dose (which results in a more predictable response). LMWHs do not require intravenous access and require less laboratory monitoring and dose adjustment compared with UFH; these are important for newborns with poor venous access. (See 'Low molecular weight heparin' below.)

●Limited role for UFH – UFH may be preferred for initial therapy in some circumstances, such as in patients with kidney failure or those with bleeding risks who require finely tuned titration and the ability to quickly turn on or off the infusion (eg, patients requiring multiple surgeries or other invasive procedures, patients receiving concomitant thrombolytic therapy). (See 'Unfractionated heparin' below.)

●Oral agents

•Direct oral anticoagulants (DOACs) – DOACs include oral factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) and the direct thrombin inhibitor dabigatran). These agents do not play a role in the treatment of thrombosis in preterm neonates since data on their safety and efficacy in this population are extremely limited. While rivaroxaban is approved for use in term neonates (≥37 weeks gestation), it is generally not a first-line agent for young infants. None of the other DOAC agents are approved for use in infants <3 months of age. (See 'Direct oral anticoagulants' below.)

•Vitamin K antagonist (warfarin) – Warfarin generally should not be used in neonates because it has an unacceptably high risk of bleeding. (See 'Warfarin' below.)

Low molecular weight heparin

Dose — Commercially available LMWH agents differ from one another both chemically and pharmacokinetically; dosing is not interchangeable between agents [15]. LMWH agents that are approved by the US Food and Drug Administration for different clinical indications include enoxaparin, dalteparin, ardeparin, and tinzaparin. Additional agents approved by other regulatory agencies include nadroparin and reviparin. We suggest not using dalteparin or tinzaparin in neonates, because data on their use are very limited. Pediatric dosing guidance for enoxaparin and other LMWH agents is provided in the table (table 1).

In the United States, the agent used most commonly for treatment of neonatal thrombosis is enoxaparin, for which dosing is as follows [16]:

●Therapeutic anticoagulation – For treatment of thrombosis in term neonates, we initiate enoxaparin at a dose of 1.5 to 1.7 mg/kg per dose given subcutaneously twice daily; the initial dose for preterm neonates is 2 mg/kg per dose given subcutaneously twice daily [16-19]. For ease of administration, we typically round the dose to whole milligrams [20,21].

The dose of enoxaparin required to achieve therapeutic anti-Xa levels is higher in neonates compared with older children. In particular, preterm neonates generally require higher doses and take longer to reach therapeutic levels compared with other populations [19,22]. In a systematic review of 19 studies (1112 pediatric patients), the mean therapeutic enoxaparin dose (using twice-daily dosing) was 2.1 mg/kg per dose for preterm neonates and 1.7 mg/kg per dose for term neonates, as compared with 1.2 mg/kg per dose in children aged one to six years old [19].

●Prophylaxis – For prophylaxis, enoxaparin is initiated at 0.75 mg/kg per dose given subcutaneously twice daily.

●Patients with mild to moderate renal insufficiency – The dose of enoxaparin (or other LMWH agent) should be adjusted in patients with renal insufficiency. There are no available data to guide practice in this setting. The authors' approach is to decrease the dose in proportion to the degree of renal insufficiency (eg, for infants estimated to have a 50 percent reduction in renal function, the daily enoxaparin dose is reduced by 50 percent, either by reducing each dose or changing the frequency to once per day). Subsequent dosing adjustments should be made according to the anti-factor Xa level. To ensure that the drug does not accumulate, both the peak and trough levels of anti-factor Xa should be monitored. (See 'Monitoring and dose adjustment' below.)

●Patients with severe renal failure – Enoxaparin and other LMWHs should not be used in patients with severe renal failure. Patients with severe renal failure who require ongoing anticoagulation should be managed with UFH. (See 'Unfractionated heparin' below.)

Monitoring and dose adjustment — The LMWH dose is adjusted according to the anti-factor Xa level measured four to six hours after the dose [1,17,23]:

●For patients receiving therapeutic anticoagulation with LMWH, the target range for anti-factor Xa levels is 0.5 to 1 units/mL

●For patients receiving LMWH for prophylaxis, the target range for anti-factor Xa levels is 0.1 to 0.3 units/mL

It should be noted that the reference ranges for anti-factor Xa levels in monitoring LMWH were established in older age groups. The therapeutic range for neonates has not been well established [24].

A nomogram for LMWH dose titration in pediatric patients is available on Lexicomp's enoxaparin drug information topic. (See "Enoxaparin (including biosimilars available in Canada): Pediatric drug information".)

In addition to monitoring anti-Xa levels, the complete blood count including platelet count should be monitored periodically. The frequency depends upon comorbidities and bleeding risk (ranging from daily in critically ill patients to once every other week or monthly in a stable outpatient). The platelet count should be maintained at >50,000/microL during treatment.

Efficacy — Based on limited information, LMWH appears to be safe and effective in newborns. A prospective cohort study including 173 children (one-third of whom were <3 months old) described the experience using enoxaparin both for treatment of documented thrombosis and for prevention in patients at high risk for thromboembolism [17]. Of patients who received therapeutic enoxaparin, 94 percent demonstrated resolution of the thrombus. In patients receiving prophylaxis, 96 percent had no symptoms of new or recurrent thromboembolic events. In a pooled analysis of six studies including a total of 138 neonates treated with LMWH, 97.1 percent had treatment success without experiencing recurrent thrombosis [25].

Data supporting the efficacy of LMWH in older infants and children are discussed separately. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Low molecular weight heparin'.)

Adverse effects — The main adverse effect of LMWH is bleeding [19,25]. In a systematic review of 30 pediatric studies including 1329 patients, many of whom were <3 months old, rates of major bleeding associated with LMWH were 1.8 percent for patients receiving therapeutic dosing and 0.6 percent for patients receiving prophylactic dosing [19]. Minor bleeding complications occurred in 16 and 1 percent, respectively. In a separate pooled analysis of 21 studies that were limited to neonates <28 days old treated with LMWH (n = 458), 3.9 percent experienced clinically apparent bleeding [25].

Other potential adverse effects include heparin-induced thrombocytopenia (HIT) and osteoporosis. However, these are rare and the risk appears to be lower with LMWH compared with UFH, as discussed below. (See 'Adverse effects' below.)

Reversal — If serious bleeding occurs, LMWH should be discontinued and protamine sulfate administered to reverse the heparin effect. However, it should be noted that protamine only partially reverses the effects of LMWH [26].

The dose of protamine sulfate depends upon the dose of enoxaparin and the time since the dose was administered:

●If enoxaparin was given within eight hours, the maximum dose of protamine is 1 mg per 1 mg enoxaparin, given by slow intravenous (IV) push

●If >8 hours have passed since the last enoxaparin dose, the dose of protamine is 0.5 mg per 1 mg enoxaparin, given by slow IV push

Unfractionated heparin — The advantages of UFH are its rapid reversibility and low cost. Disadvantages include its unpredictable pharmacokinetic response and resultant requirement for frequent monitoring.

Infusion of UFH in newborns requires a dedicated IV catheter. This avoids interruption of anticoagulation therapy by infusion of other medications and minimizes the risk of inadvertent flushing of the catheter that may lead to excessive anticoagulation.

Dose — Dosing of UFH in neonates is as follows:

●Loading dose – In our practice, we usually do not administer a loading dose to neonates unless the thrombus is severe. When a loading dose is used, it is given as 75 to 100 units/kg IV. The loading dose should be withheld or reduced if there are significant bleeding risks (eg, extremely low birth weight, septicemia, disseminated intravascular coagulation). We omit the loading dose in most cases; based on our experience, it is not necessary and limited data suggest that the activated partial thromboplastin time (aPTT) can be markedly elevated after the bolus [27].

●Maintenance dose – The initial maintenance dose is 28 units/kg per hour IV.

The above dosing is supported by a prospective study of UFH treatment in 65 children with thrombosis, of whom 29 were <1 year old, including 13 newborns [28].

Monitoring and titration — UFH dosing in the neonate should be titrated using both the anti-factor Xa level and aPTT (algorithm 1) [1]:

●The target anti-factor Xa level is 0.35 to 0.7 units/mL

●The target aPTT range is 1.5 to 2 times the upper limit of normal

Monitoring both of these is necessary for neonates because they have an increased clearance rate of UFH compared with older children or adults [28]. aPTT values can be used alone to facilitate dose adjustments but only after establishing the aPTT range that corresponds to the target anti-factor Xa activity range in an individual patient.

In addition to monitoring anti-Xa levels and aPTT, the complete blood count with platelet count should be monitored daily. The platelet count should be maintained at >50,000/microL during UFH treatment.

The efficacy of UFH may be reduced in newborns relative to older children because the physiologic plasma concentration of antithrombin (AT) is low in early infancy [29,30]. Thus, in infants requiring high doses of UFH and/or with difficulty achieving target anti-factor Xa activity, it may be reasonable to check the patient's AT level and administer AT concentrate if AT levels are low (based on age-appropriate reference ranges). Data to support this practice are limited [2,31]. However, AT administration is generally avoided in preterm infants due to concerns of potential antiangiogenic effects and evidence of increased morbidity and mortality associated with its use in this population [32,33].

It should be noted that the reference ranges for aPTT and anti-factor Xa levels in monitoring UFH were established in older age groups. The therapeutic range for neonates has not been well established [24].

Other factors to consider when adjusting the UFH dose include the clinical significance of the thrombus and the potential risk of bleeding [1,34].

The challenges of UFH therapy in young infants were demonstrated in a series of 100 infants <6 months old who were treated with UFH according to the titration protocol outlined above [35]. Approximately two-thirds of infants had successful treatment (ie, decreased or stable thrombus size) and achieved therapeutic anti-factor Xa levels on a median UFH dose of 33 units/kg per hour. However, 17 percent of patients never achieved therapeutic anti-factor Xa levels despite prolonged UFH therapy at relatively high doses. Moreover, 11 percent of patients had a major bleeding episode.

Duration of therapy — The optimal duration of therapy is uncertain. The usual duration is six weeks to three months. Serial ultrasound monitoring can be used to guide decision-making. Therapy is generally continued until the thrombus has resolved or for a maximum duration of three months [1]. In our practice, we generally switch to LMWH if treatment is needed for longer than two weeks.

Adverse effects — The major side effects of heparin are bleeding, HIT, and osteoporosis [13]. These can occur with either UFH or LMWH, though the risk is greater with UFH.

●Bleeding – The risk of bleeding in newborns is uncertain, but it likely relates to the dose of heparin and underlying disorders that predispose to bleeding. Few studies have evaluated the risk of UFH-related bleeding in the neonatal population. In a study of 100 neonates and infants <6 months old who were treated with UFH, 11 percent experienced a serious bleeding event [35]. In other studies, the incidence of bleeding ranged from 1 to 33 percent [24,28].

●HIT – HIT is a rare complication of heparin therapy in neonates. Most of the reported cases have occurred in neonates undergoing cardiac surgery or requiring extracorporeal membrane oxygenation [36-38]. However, the precise incidence of HIT in neonates is unknown because critically ill neonates commonly have thrombocytopenia and/or thrombosis due to other mechanisms.

HIT should be considered in a newborn with acute onset of severe thrombocytopenia (ie, >50 percent fall in platelet count) that is temporally associated with exposure to heparin (either UFH or LMWH) and for which no other cause is apparent. Most neonates who develop thrombocytopenia while receiving heparin have other causes identified, and, thus, many can be continued on heparin therapy while maintaining the platelet count with transfusion, if necessary. If there is strong clinical suspicion for HIT, heparin should be discontinued and, if the patient requires ongoing anticoagulation, a non-heparinoid agent should be used (eg, argatroban). (See 'Other agents' below.)

HIT is discussed in greater detail separately. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia" and "Management of heparin-induced thrombocytopenia".)

●Osteoporosis – While osteoporosis has been reported in adult patients receiving UFH for prolonged duration, there are few reports of this occurring in children and there is no information on this complication in newborns [34,39]. (See "Drugs that affect bone metabolism", section on 'Heparin'.)

Reversal — If bleeding occurs, the UFH infusion should be discontinued. For mild bleeding, stopping the infusion is generally sufficient. If the bleeding is more severe, the effects of heparin can be reversed using protamine sulfate. Since heparin disappears rapidly from the circulation, only heparin given in the preceding two to four hours should be considered when calculating the protamine dose. Assuming the half-life of heparin to be one hour, one approach is to calculate the protamine dose as follows:

●Give 1 mg of protamine per 100 units of heparin received in the past hour (ie, the full neutralizing dose), plus

●Give 0.5 mg of protamine per 100 units of heparin received in the hour preceding that (ie, one-half the neutralizing dose)

Direct oral anticoagulants — DOACs include the direct thrombin inhibitor dabigatran and factor Xa inhibitors rivaroxaban, apixaban, and edoxaban. Rivaroxaban and dabigatran are the agents that are best studied in pediatric patients, but there are very few data on either agent in neonates. Rivaroxaban is approved by the US Food and Drug Administration for treatment of venous thromboembolism (VTE) in pediatric patients, including term neonates (≥37 weeks gestation) [40,41]. Dabigatran is approved for treatment of VTE in pediatric patients ≥3 months old [42].

●Preterm neonates – DOACs do not play a role in the management of VTE in preterm neonates since data on their safety and efficacy in this population are extremely limited. None of the available DOAC agents are approved for use in preterm neonates.

●Term neonates – DOACs play a very limited role in management of VTE in term neonates. Treatment with a DOAC is a reasonable alternative option for patients with VTE who are stable after receiving initial treatment with LMWH when there is a need to transition to an oral agent. However, for most neonates with VTE, we suggest treating with LMWH for the entire treatment course. LMWH is preferred over DOACs in most instances because there is greater experience with LMWH and its efficacy and safety are well established in this age group. By contrast, the efficacy and safety of DOACs remain uncertain in this population since young infants were underrepresented in the pediatric DOAC trials. However, cautious use of a DOAC is a reasonable alternative to LMWH in select circumstances (eg, if the infant requires long-term anticoagulation).

When treatment with a DOAC is selected, we suggest rivaroxaban since it is the only agent approved for use in infants <3 months old. The neonate should be transitioned to rivaroxaban only if they meet all of the following criteria [43]:

•Gestational age ≥37 weeks

•Weight ≥2.6 kg

•Clinically stable

•No hepatic disease or severe kidney impairment

•Tolerating oral/enteral feeding for at least 10 days

•Received ≥5 days of parenteral anticoagulant therapy (typically with LMWH) before transitioning

Pediatric dosing of rivaroxaban is summarized in the table (table 2). Additional details, including guidance on pretreatment testing, monitoring, management of DOAC-associated bleeding, and a discussion of the supporting evidence, are presented separately. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Direct oral anticoagulants'.)

Warfarin — Warfarin should not be used in newborns, because of the unacceptably high risk of bleeding [39]. Warfarin's anticoagulant effect is mediated by reduction of the functional plasma concentration of the vitamin K-dependent coagulation factors (factors II, VII, IX, and X). However, the concentration of these factors is already physiologically low in newborns (often at a level similar to that seen in adults receiving warfarin therapy).

In addition, newborns may have borderline low levels of vitamin K, increasing the risk of warfarin-induced bleeding. Because human milk has low concentrations of vitamin K, breastfed newborns are especially sensitive to the effect of warfarin. On the other hand, infant formulas are supplemented with vitamin K, rendering formula-fed newborns relatively resistant to treatment.

Another problem with warfarin administration in newborns is its availability only in tablet form. Splitting or crushing the tablet into powder form may cause variability in the dose. In addition, treatment with warfarin requires frequent monitoring of the international normalized ratio (INR).

Other agents — Other anticoagulants include fondaparinux, argatroban, and bivalirudin. Use of these agents in neonates is generally limited to patients with HIT who require cessation of heparin and ongoing anticoagulation with non-heparin agents (argatroban and fondaparinux are the agents most commonly used in this setting) [38,44]. These agents are discussed in greater detail separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Parenteral direct thrombin inhibitors' and "Fondaparinux: Dosing and adverse effects" and "Management of heparin-induced thrombocytopenia".)

THROMBOLYTIC THERAPY — Thrombolytic drugs are intravenously (IV) infused plasminogen activators that facilitate clot breakdown by converting plasminogen to plasmin, with subsequent cleavage of fibrin, fibrinogen, and factors V and VIII (figure 1) [39,45].

●Indications – Thrombolytic therapy is rarely used in the management of neonatal thrombosis. Use of this treatment modality is limited to situations wherein thrombus occludes a major vessel causing critical compromise of organs or limbs [1].

Because of the high risk of major bleeding, decisions about thrombolytic therapy in newborns should ideally be made by a multidisciplinary team with input from surgical and hematology specialists. Parents/caregivers should be involved in the decision-making process and should be fully informed about the therapeutic options and risks.

The alternative to thrombolytic therapy is surgical thrombectomy. However, this is rarely performed in neonates since the success of the procedure is limited by the small size of blood vessels and the clinical instability of newborns with thrombosis [46,47].

●Contraindications – Contraindications to thrombolytic therapy are related to increased risk of bleeding and include [48]:

•Major surgery or hemorrhage within the previous 10 days

•Neurosurgery within three weeks

•Severe asphyxial event within seven days

•Any invasive procedure within three days

•Seizures within 48 hours

•Prematurity <32 weeks gestation

•Septicemia

•Active bleeding

•Inability to maintain platelets >100,000/microL or fibrinogen >100 mg/dL (>1 g/L)

●Pretreatment evaluation and management – Pretreatment testing is the same as describe above (see 'Pretreatment evaluation' above). In addition, we obtain D-dimer level before starting therapy. Thrombocytopenia (platelet count <100,000/microL), low fibrinogen concentration (<100 mg/dL [<1g/L]), and severe coagulopathy should be corrected before initiating treatment.

Fresh frozen plasma (FFP; 10 mL/kg) is given to all neonates prior to initiating thrombolytic therapy. This is because newborns have lower levels of plasminogen compared with older children and adults, which results in less plasmin generation and less clot lysis during thrombolytic therapy [49,50]. Thus, administering FFP (which contains plasminogen) supplies this physiologic deficiency and helps promote fibrinolysis [45].

●Choice of agent – Recombinant tissue-type plasminogen activator (tPA) is the thrombolytic agent of choice. Streptokinase and urokinase have been used in newborns. However, compared with the other agents, tPA has better clot lysis in vitro [49] and a lower risk of hypersensitivity [51]. Urokinase is not labeled for this indication in the United States, nor is it approved for use in children.

●Dosing and administration – The dose of tPA in newborns is extrapolated from studies involving older children and adults. tPA is administered as a continuous IV infusion (without a loading dose) via central or peripheral venous catheter. Reported dosing regimens of tPA for systemic therapy range from <0.1 to 0.6 mg/kg per hour [1]. In our practice, we typically start with a dose of 0.1 to 0.2 mg/kg per hour (without a loading dose) given over six hours (algorithm 2). An infusion of unfractionated heparin (UFH) is concurrently administered at 10 units/kg per hour.

If the response to the initial infusion is inadequate, it can be repeated with an increased dose. An alternative regimen consists of a 24-hour infusion at an initial dose of 0.03 mg/kg per hour, with subsequent dose adjustment according to response.

●Monitoring – Fibrinogen levels should be measured before and two hours after initiating therapy. The fibrinogen level should be maintained at >100 mg/dL (>1 g/L) by administering FFP and/or cryoprecipitate [1]. The platelet count should be maintained at >50,000/microL. (See "Clinical use of plasma components", section on 'Plasma products' and "Cryoprecipitate and fibrinogen concentrate".)

We assess the response to therapy by monitoring for resolution of the thrombus on serial imaging. Other laboratory-based tests are generally not helpful in monitoring the therapeutic effect of the drug. Measuring the activated partial thromboplastin time (aPTT) is not informative, particularly if fibrinogen levels are low, fibrin degradation products are present, or the patient is concurrently receiving heparin therapy. The presence of D-dimers or fibrin degradation products indicates a fibrinolytic state; however, these tests do not provide a quantitative assessment of the drug's therapeutic effect. Nevertheless, monitoring the trend in the D-dimer level helps to qualitatively assess fibrinolytic effect.

●Efficacy – Use of tPA for thrombolytic therapy in neonates is described in case reports and case series using a variety of doses and treatment regimens [52-59]. In a review of 30 case reports and case series (94 patients), complete dissolution of the clot was reported in 70 percent of cases and partial lysis occurred in 23 percent [52].

●Adverse events – In the available reports, the frequencies of adverse events associated with tPA were as follows [52,59]:

•No reported complications (40 percent of case reports)

•Local nonsevere bleeding (25 to 35 percent)

•Severe bleeding, including intraventricular hemorrhage (20 to 30 percent)

•Death due to hemorrhage (one case report)

•Rethrombosis (7 percent)

It is difficult to know to what extent the bleeding complications in these studies were attributable to tPA since critically ill neonates are at risk for hemorrhage in the absence of thrombolytic therapy.

●Management of bleeding – Treatment of bleeding during tPA infusion involves the following steps:

•Stop the tPA and heparin infusions

•Administer cryoprecipitate

•Transfuse platelets, if needed

The half-life for tPA is very short, and bleeding usually responds to these measures.

SPECIAL CIRCUMSTANCES

Neonatal purpura fulminans — Purpura fulminans in newborns is a rare life-threatening condition characterized by disseminated intravascular coagulation and hemorrhagic skin necrosis. (See "Neonatal thrombosis: Clinical features and diagnosis", section on 'Purpura fulminans'.)

●Initial management – Neonatal purpura fulminans is initially treated with a source of exogenous protein C; heparin and antiplatelet agents are ineffective [60-66]. Initial empiric treatment is often started before results of protein C and S levels are available. In this setting, administration of fresh frozen plasma (FFP; given at a dose of 10 to 20 mL/kg every 12 hours) is the appropriate intervention. Once protein C and S levels are resulted, subsequent therapy is as follows:

•Protein C deficiency – For infants with protein C deficiency, either FFP or protein C concentrate has been used with success:

-FFP is given at a dose of 10 to 20 mL/kg every 12 hours [1,67]. Frequent dosing is necessary because the half-life of protein C in the circulation is only approximately 6 to 16 hours. However, administration of FFP on a frequent basis is limited by the development of hyperproteinemia, hypertension, loss of venous access, and potential for exposure to infectious viral agents [68,69].

-A highly purified concentrate of protein C (Ceprotin [70]) is given at a starting dose of 100 units/kg intravenously (IV), followed by 50 units/kg IV every six hours [71-73]. Protein C concentrate is available in the United States and Canada for compassionate use in this condition.

Subsequent dosing of FFP or protein C concentrate depends upon the patient's response because the half-life of protein C may be shortened considerably during acute thrombosis. The dose is titrated to achieve a trough level of protein C activity of 50 international units/dL [73]. Treatment is continued until the lesions resolve (typically within six to eight weeks), and the infant is transitioned onto other anticoagulants. Protein C concentrate should not be confused with recombinant activated protein C (drotrecogin alfa), which is associated with bleeding complications in young infants and is no longer available.

•Protein S deficiency – For infants with protein S deficiency, FFP is used. The initial dose is 10 to 20 mL/kg every 12 hours (the same dose that is used for protein C deficiency). The half-life of protein S is approximately 36 hours (plasma levels of protein S are 23 percent at two hours and 14 percent at 24 hours after an infusion of FFP 10 mL/kg) [74,75]. The FFP dose titrated to a trough level of free protein S level of 30 international units/dL should be more than adequate.

●Long-term management – Infants with purpura fulminans must be treated indefinitely to prevent thrombosis [62,76-79].

Options for long-term management include systemic anticoagulation (eg, with low molecular weight heparin [LMWH], warfarin, or a direct oral anticoagulant [DOAC]) and/or protein C supplementation (given subcutaneously) [1]. If LMWH is used, the target anti-factor Xa concentration is 0.5 to 1 units/mL. If warfarin is used, the international normalized ratio (INR) usually should be maintained between 2.5 to 3.5. A lower INR of 1.5 to 2.5 is appropriate if the patient is also treated with protein C concentrate; a higher INR of 3 to 4.5 is appropriate if the patient has warfarin-induced skin necrosis [80]. Because LMWH has a more predictable and stable anticoagulation response in young patients, we generally prefer it over warfarin. We also prefer LMWH over DOACs because there is more experience using LMWH in infants and young children. (See 'Choice of agent' above.)

Subcutaneous administration of protein C concentrate has been described in several case reports [81-85]. Optimal dosing is not established. Subcutaneous administration avoids the potential hazards of long-term central venous access.

Liver transplantation can correct homozygous protein C deficiency and has been used for a patient for whom protein C replacement therapy was not available [86]. A combined liver and renal transplant was successfully used for a patient who developed renal failure due to renal vein thrombosis (RVT) [87].

Congenital nephrotic syndrome — Infants with congenital nephrotic syndrome are at increased risk for developing venous thromboembolism (VTE). For infants with nephrotic syndrome who develop VTE, we suggest continuing anticoagulant therapy beyond the usual three-month course, at either therapeutic or prophylactic doses, as long as the nephrotic syndrome persists [1]. For infants who have not experienced VTE, the role of anticoagulant therapy for primary prophylaxis has not been established [88]. Decisions about the treatment of such patients typically depend on the severity of the nephrotic syndrome and presence of other risk factors. As an example, the authors of this topic review would initiate primary prophylaxis for an infant with severe nephrotic syndrome and one or more other risk factors (eg, an inherited thrombophilia or central venous catheter [CVC]). Patients with congenital nephrotic syndrome tend to have a low antithrombin (AT) level, and, thus, the dose of LMWH required to achieve an adequate anti-Xa level is substantially higher than is typically used (eg, enoxaparin 3 mg/kg per dose). In patients with renal insufficiency, the dose of LMWH should be adjusted. (See "Congenital nephrotic syndrome".)

PREVENTION OF CATHETER-ASSOCIATED THROMBOSIS

●Arterial catheters – It is standard practice in most neonatal intensive care units (NICUs) to use a low-dose heparin infusion to maintain patency of arterial catheters, including both umbilical artery catheters and peripheral arterial catheters. This typically consists of an infusion of normal saline fluid containing unfractionated heparin (UFH) at a concentration of 0.25 to 1.0 units/mL at a rate of 0.5 to 1 mL per hour [1].

This practice is supported by clinical trials and observational data [89-91]. In a meta-analysis of five trials, low-dose heparin decreased the risk of umbilical artery catheter occlusion (relative risk 0.20, 95% CI 0.11-0.35) [89]. The risk of other serious complications (aortic thrombosis, intraventricular hemorrhage, death, or clinical ischemic events) did not appear to be affected, although there were too few events to draw firm conclusions. Data supporting the use of heparin for maintenance of peripheral arterial catheters in neonates are more limited [90,91].

●Central venous catheters (CVCs) – Heparin flushes (either as a continuous low-dose infusion or intermittent flushes) are commonly used in the NICU setting to maintain patency of umbilical venous catheters (UVCs) and peripherally inserted central catheters. In a meta-analysis of three small clinical trials (n = 267), a continuous heparin infusion reduced the risk of catheter occlusion (relative risk 0.28, 95% CI 0.15-0.53) but did not reduce rates of thrombosis or catheter-related sepsis [92].

Obstructed CVCs can be cleared with local instillation of tissue-type plasminogen activator (tPA; 0.25 to 0.50 mg) [48]. It is important to limit the volume infused to the dead space of the catheter to avoid systemic administration of tPA. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Blocked central venous catheter'.)

OUTCOME — The reported mortality rate associated with neonatal thrombosis ranges from 10 to 30 percent, depending upon the population studied [93,94]. The mortality rates in these reports are difficult to interpret as most neonates in these studies had underlying critical illness, which likely contributed to the poor outcome.

Long-term complications associated with neonatal thrombosis depend on the location and type of thrombus:

●Catheter-associated thrombosis – Most infants with asymptomatic catheter-associated thrombus do not develop long-term sequelae. For infants with occlusive deep vein thrombosis (DVT), there is potential risk of developing post-thrombotic syndrome (PTS), a disorder characterized by edema and impaired viability of subcutaneous tissue in an extremity. The condition is caused by incompetent perforating valves, resulting in blood flow directed from deep to peripheral veins. PTS is increasingly recognized in older infants and children, but it is less common following neonatal thrombosis. In one series of 95 neonates with catheter-related iliofemoral DVT who were followed for a median of four years, approximately 40 percent developed evidence of mild PTS; however clinically relevant PTS (ie, greater than mild) occurred in only 1 percent of patients [95]. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Post-thrombotic syndrome'.)

Severe arterial thrombosis in an extremity can result in long-term arterial insufficiency. This may impair growth of the affected limb [96].

●Portal vein thrombosis (PVT) – Long-term complications of PVT are uncommon but may include hepatic lobar atrophy and/or portal hypertension [10,97,98]. (See "Neonatal thrombosis: Clinical features and diagnosis", section on 'Portal vein thrombosis'.)

●Renal vein thrombosis (RVT) – Neonatal RVT can be associated with considerable morbidity, including chronic kidney disease and systemic hypertension [9,99-101]. In a systematic review of 13 case series that included 271 patients with neonatal RVT, there were nine reported deaths, all of which were related to comorbid conditions (eg, respiratory failure, multiorgan failure, sepsis) [6]. In the studies that reported long-term outcome, 20 percent of surviving patients developed hypertension and 71 percent had chronic kidney disease, including eight patients who required chronic renal replacement therapy (eg, dialysis and transplantation).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Thrombotic diseases in infants and children".)

SUMMARY AND RECOMMENDATIONS

●Removal of indwelling catheters – Most thrombotic events in neonates are catheter associated. Thus, management should generally include removal of the catheter, if possible. (See 'Catheter-associated thrombosis' above.)

●Rationale for anticoagulant therapy – Because prothrombotic risk factors in neonates usually are transient (eg, indwelling catheter, critical illness), the recurrence risk is low. Therefore, the primary goals of treatment are to prevent thrombus extension and minimize end-organ damage. (See 'General approach' above.)

●Patient selection – When choosing between conservative management (ie, supportive care and close monitoring) versus initiating anticoagulation, we suggest the following approach based upon the location of the thrombus:

•Renal vein thrombosis (RVT) – For most neonates with RVT, we suggest anticoagulation (Grade 2C). However, conservative management is reasonable if the RVT is unilateral without extension into inferior vena cava (IVC) and renal function is normal. Infants with bilateral RVT or extension into the IVC are more likely to benefit from anticoagulation; thrombolytic therapy can also be considered in such neonates. (See 'Renal vein thrombosis' above.)

•Portal vein thrombosis (PVT) – For most neonates with PVT that is limited to the left portal vein, we suggest conservative management (Grade 2C). If the thrombus extends into the main portal vein, we suggest anticoagulation (Grade 2C). (See 'Portal vein thrombosis' above.)

•Right atrial (RA) thrombosis – For most neonates with RA thrombosis, we suggest anticoagulation (Grade 2C). Conservative management is a reasonable alternative if the neonate is asymptomatic and the thrombus has low-risk features (as described above). If the thrombus is compromising cardiac function, thrombolytic therapy can be considered. (See 'Right atrial thrombosis' above and 'Thrombolytic therapy' above.)

•Catheter-associated venous thrombosis in other locations – For most neonates with catheter-associated venous thrombosis in locations other than the RV, PV, or RA who are asymptomatic, we suggest conservative management initially (Grade 2C). For neonates with symptomatic catheter-associated thrombosis and those with asymptomatic thrombosis that extends during conservative management, we suggest anticoagulation (Grade 2C). (See 'Catheter-associated thrombosis' above.)

•Arterial thrombosis – For neonates with arterial thrombosis causing clinically significant impairment of blood flow to an extremity or vital organ, we recommend anticoagulation (Grade 1C). Any associated arterial catheter should be removed. Thrombolytic therapy may be warranted if the thrombosis is life-threatening or if the viability of a limb or organ is jeopardized. A surgical consultation should be obtained in such cases. (See 'Arterial thrombosis' above.)

•Central nervous system – Management of neonatal stroke is discussed separately. (See "Stroke in the newborn: Management and prognosis".)

●Pretreatment evaluation – Before starting anticoagulant therapy, pretreatment testing includes (see 'Pretreatment evaluation' above):

•Baseline coagulation tests

•Complete blood count with platelet count

•Kidney and liver function tests

•Cranial ultrasound

●Choice of anticoagulant – For most neonates requiring anticoagulation therapy, we suggest low molecular weight heparin (LMWH) rather than other agents (eg, unfractionated heparin [UFH], direct oral anticoagulants [DOACs]) (Grade 2C). Compared with UFH, LMWH has a more predicable response in neonates, requires less laboratory monitoring and dose adjustment, and is administered subcutaneously (and therefore does not require a dedicated intravenous [IV] catheter). LMWH is preferred over DOACs because there are few data on DOACs in the neonatal population. (See 'Choice of agent' above and 'Low molecular weight heparin' above.)

UFH may be preferred for initial therapy in some circumstances, such as in patients with renal failure or those with bleeding risks who require finely tuned titration and the ability to quickly turn on or off the infusion. (See 'Unfractionated heparin' above.)

●Dosing, monitoring, and adjustment – Pediatric dosing for different LMWH agents is summarized in the table (table 1). Dose adjustment is necessary for patients with kidney impairment. (See 'Dose' above.)

The LMWH dose is adjusted according to the anti-factor Xa level measured four to six hours after the dose. For patients receiving therapeutic anticoagulation, the target range for anti-factor Xa levels is 0.5 to 1 units/mL. (See 'Monitoring and dose adjustment' above.)

If UFH is selected, the initial dose is 28 units/kg per hour IV. The approach to adjusting the infusion based upon anti-factor Xa level and aPTT is summarized in the algorithm (algorithm 1). (See 'Unfractionated heparin' above.)

●Duration of therapy – The usual duration of anticoagulant therapy is six weeks to three months. Our approach is to monitor the thrombus with ultrasound and continue therapy until the thrombus has resolved and the patient is asymptomatic or for three months, whichever is shorter. If the thrombus was related to a central venous catheter (CVC), the CVC should be removed before stopping therapy. (See 'Treatment based on thrombus location' above.)

●Limited role of thrombolytic therapy – Thrombolytic therapy is rarely required in the management of neonatal thrombosis; its use is limited to patients in whom major vessel occlusion is causing critical compromise of organs or limbs. Decisions about thrombolytic therapy in newborns should ideally be made by a multidisciplinary team including input from surgical and hematology specialists. When thrombolytic therapy is used, we suggest recombinant tissue-type plasminogen activator (tPA) rather than other agents (Grade 2C). The approach is summarized in the algorithm (algorithm 2). (See 'Thrombolytic therapy' above.)

●Prevention of catheter-associated thrombosis – For neonates with indwelling arterial or central venous catheters, we suggest low-dose UFH (Grade 2B) to prevent thrombosis and maintain catheter patency. For arterial catheters, UFH is given as a low-dose continuous infusion (0.25 to 1.0 units/mL in normal saline at a rate of 0.5 to 1 mL per hour); for CVCs, UFH can be given either as a continuous low-dose infusion or intermittent flushes. The available clinical trial data suggest that low-dose heparin reduces the risk of catheter occlusion, though it is uncertain whether this practice reduces catheter-associated thrombotic complications. (See 'Prevention of catheter-associated thrombosis' above.)

●Outcome – Long-term complications associated with neonatal thrombosis depend on the location and type of thrombus. Most infants with asymptomatic catheter-associated thrombus have no long-term sequelae, though there is potential risk of developing post-thrombotic syndrome (PTS). Long-term complications of PVT are uncommon but may include hepatic lobar atrophy and/or portal hypertension. RVT can be associated with considerable morbidity, particularly chronic kidney disease and hypertension. (See 'Outcome' above.)