1. Thrombin is the primary procoagulant protein, converting fibrinogen into a fibrin clot. The intrinsic and extrinsic pathways of the coagulation cascade result in formation of active thrombin from prothrombin.

2. Inhibitors of coagulation include antithrombin, heparin cofactors, protein C, protein S, α2-macroglobulin, and tissue factor pathway inhibitor. Antithrombin activity is potentiated by heparin.

3. Plasmin is the primary fibrinolytic enzyme, degrading fibrin in a reaction that produces fibrin degradation products and D-dimers. Plasmin is formed from plasminogen by numerous enzymes, most important of which is tPA.

4. In neonates, factors affecting blood flow, blood composition (leading to hypercoagulability), and vascular endothelial integrity can all contribute to thrombus formation.

1. In utero, coagulation proteins are synthesized by the fetus as early as 10 weeks gestational age and do not cross the placenta.

2. Both thrombogenic and fibrinolytic pathways are altered in the neonate compared with the older child and adult, resulting in increased vulnerability to both hemorrhage and pathologic thrombosis. Under normal physiologic conditions, however, the hemostatic system in preterm and term newborns is in balance, and healthy neonates do not clinically demonstrate hypercoagulable or bleeding tendencies.

3. Concentrations of most procoagulant proteins, particularly vitamin K-dependent coagulation factors, are reduced in neonates compared with adult values; levels of some procoagulant factors such as factor VIII and fibrinogen are typically normal or even increased. Compared to adults, neonates have a decreased ability to generate thrombin, and values for the prothrombin time (PT) and the activated partial thromboplastin time (PTT) are prolonged.

4. Concentrations of most antithrombotic and fibrinolytic proteins are also reduced, including protein C, protein S, plasminogen, and antithrombin, although α2-macroglobulin concentration is increased. Thrombin inhibition by plasmin is diminished compared with adult plasma.

5. Platelet number and life span appear to be similar to that of adults. The bleeding time, an overall assessment of platelet function and interaction with vascular endothelium, is shorter in neonates than in adults, suggesting more rapid platelet adhesion and aggregation.

1. Thrombosis occurs more frequently in the neonatal period than at any other age in childhood.

2. The presence of an indwelling vascular catheter is the single greatest risk factor for arterial or venous thrombosis. Indwelling catheters are responsible for more than 80% of venous and 90% of arterial thrombotic complications.

3. Autopsy studies show 20% to 65% of infants who expire with an umbilical venous catheter (UVC) in place are found to have a thrombus associated with the catheter. Venography suggests asymptomatic thrombi are present in 30% of newborns with a UVC.

4. Umbilical arterial catheterization (UAC) appears to result in severe symptomatic vessel obstruction requiring intervention in approximately 1% of patients. Asymptomatic catheter-associated thrombi have been found in 3% to 59% of cases by autopsy and 10% to 90% of cases by angiography or ultrasound.

5. Multiple maternal, perinatal, and neonatal risk factors are thought to contribute to thrombotic events in newborns. Maternal factors
include infertility, oligohydramnios, preeclampsia, diabetes, intrauterine growth restriction (IUGR), prolonged rupture of membranes, chorioamnionitis, and autoimmune and prothrombotic disorders. Perinatal risk factors include emergent cesarean section or instrumented delivery and fetal heart rate abnormalities. Neonatal risk factors include congenital heart disease, sepsis, birth asphyxia, respiratory distress syndrome, dehydration, polycythemia, congenital nephritic/nephrotic syndrome, necrotizing enterocolitis, pulmonary hypertension, and prothrombotic disorders.

6. Infants undergoing surgery involving the vascular system, including repair of congenital heart disease, are at increased risk for thrombotic complications. Diagnostic or interventional catheterizations also increase the risk of thrombosis.

7. Renal vein thrombosis is the most common type of non-catheterrelated pathologic thrombosis in newborns.

8. Registries from Canada, Germany, The Netherlands, and Italy have described series of cases of neonatal thrombosis.

a. Incidence of clinically significant thrombosis among infants in neonatal intensive care units (NICUs) was reported as 2.4 per 1,000 NICU admissions in Canada, 6.8 per 1,000 NICU admissions in The Netherlands, and 5.8 and 6.6 per 1,000 NICU admissions at two large centers in Italy. Incidence among live births was estimated at 5.1 per 100,000 births in Germany, 14.5 per 10,000 neonates in The Netherlands, and 3.4 and 6.5 per 10,000 live births at the Italian centers.

b. Three series examined both venous and arterial thromboses. Among all thrombotic events, the percentage of renal vein thrombosis ranged from 19% to 44%, other venous thrombosis ranged from 33% to 40%, and arterial thrombosis from 24% to 34%.

c. Excluding cases of renal vein thrombosis, 67%, 89%, and 94% of venous thromboses were found to be associated with indwelling central lines in three series.

d. Mortality was rare and generally restricted to very premature infants or infants with large arterial or intracardiac thromboses.

1. Inherited prothrombotic disorders are characterized by positive family history, early age of onset, recurrent disease, and unusual or multiple locations of thromboembolic events. Although it is estimated that a genetic risk factor can be identified in 10% to 50% of children with thrombosis, the incidence of these disorders in newborns with thrombosis is not well known.

2. Important inherited prothrombotic disorders include the following:

a. Deficiencies of protein C, protein S, and antithrombin appear to have the largest increase in relative risk for thromboembolic disease but are relatively rare.

b. Activated protein C resistance, including factor V Leiden mutation and prothrombin G20210A mutation, have a high incidence, particularly in certain populations, but appear to have low risk of thrombosis in neonates.

c. Hyperhomocysteinemia, increased lipoprotein (a) levels, and polymorphism in the methylene tetrahydrofolate reductase (MTHFR) gene are relatively common, but their significance in neonatal thrombosis is still poorly understood.

3. Multiple other defects in the anticoagulation, fibrinolytic, and antifibrinolytic pathways have been identified, including abnormalities in thrombomodulin, tissue factor pathway inhibitor, fibrinogen, plasminogen, tPA, and plasminogen-activator inhibitors. The frequency and importance of these defects in neonatal thrombosis is poorly understood.

4. The incidence of thrombosis in patients heterozygous for most inherited thrombophilias is small; however, increasing evidence suggests that the presence of a second risk factor substantially increases the risk for thrombosis. This second risk factor can be an acquired clinical condition or another inherited defect. Patients with single defects for inherited prothrombotic disorders rarely present in neonatal period, unless another pathologic event occurs.

5. Patients who are homozygous for a single defect or double heterozygotes for different defects can present in the neonatal period, often with significant illness due to thrombosis. The classic presentation of homozygous prothrombotic disorders is purpura fulminans associated with homozygous protein C or S deficiency, which presents within hours or days of birth, often with evidence of in utero cerebral damage.

6. Overall, the importance of inherited thrombophilias as independent risk factors for neonatal thrombosis is still undetermined. It appears that the absolute risk of thrombosis in the neonatal period in all patients with an inherited non-homozygous thrombophilia is low. Among neonates with thrombotic disease, however, the incidence of an inherited thrombophilia appears to be substantially increased compared to that of the general population, and evaluation for thrombophilia should be considered.

1. Newborns can acquire significant coagulation factor deficiencies due to placental transfer of maternal antiphospholipid antibodies, including lupus anticoagulant and anticardiolipin antibodies.

2. These neonates can present with significant thrombosis, including purpura fulminans.

3. Mothers should potentially be screened for the presence of autoimmune antibodies as part of a thrombophilia evaluation for neonates presenting with clinically significant thrombosis.

a. Most venous thrombosis occur secondary to central venous lines (CVLs). Spontaneous (i.e., non-catheter-related) venous thrombosis can occur in renal veins, adrenal veins, superior or inferior vena cava, portal vein, hepatic veins, and the venous system of the brain.

b. Spontaneous venous thrombi usually occur in the presence of another risk factor. Less than 1% of clinically significant venous thromboembolic events in neonates are idiopathic.

c. Thrombosis of the sinovenous system of the brain is an important cause of neonatal cerebral infarction.

d. Surgical repair of complex congenital heart disease has been associated with an increased risk of thrombosis, particularly of the superior vena cava.

e. It is likely that the frequency of pulmonary embolism in sick neonates is underestimated because signs and symptoms would be similar to other common neonatal pulmonary diseases.

f. Short-term complications of venous catheter-associated thrombosis include loss of access, pulmonary embolism, superior vena cava syndrome, and specific organ impairment.

g. Long-term complications of venous thrombosis are poorly understood. Inferior vena cava thrombosis, if extensive, can be associated with a high rate of persistent partial obstruction and symptoms such as leg edema, abdominal pain, lower extremity thrombophlebitis, varicose veins, and leg ulcers. Other complications can include chylothorax, portal hypertension, and embolism.

i. The most common initial sign of catheter-related thrombosis is usually difficulty infusing through or withdrawing from the line.

ii. Additional signs of venous obstruction include swelling of the extremities, head and neck, or distended superficial veins.

iii. The onset of thrombocytopenia in the presence of a CVL also raises the suspicion of thrombosis.

i. Ultrasound with Doppler is diagnostic in most cases of significant venous thrombosis. In smaller infants or low-flow states; however, ultrasound may not provide sufficient information about the size of the thrombus, and a significant false-negative rate has been documented.

ii. Contrast studies, including a radiographic line study or venography through peripheral vessels, may assist with the diagnosis of catheter-associated thrombosis. However, these studies are rarely performed secondary to improvements in ultrasound technology and associated risks in neonates.

i. Unfractionated heparin 0.5 U/mL is added to all compatible infusions through CVLs.

ii. UVCs should be removed as soon as clinically feasible and should not remain in place for longer than 10 to 14 days. A peripherally inserted central catheter (PICC) line is typically placed if the anticipated need for central access is >7 days.

i. Nonfunctioning CVL. If fluid can no longer be easily infused through the catheter, remove the catheter unless the CVL is
absolutely necessary. If continued central access through the catheter is judged to be clinically necessary, however, clearance of the blockage with thrombolytic agents (e.g., tPA) can be considered.

ii. Local obstruction. If a small occlusive catheter-related thrombosis is documented, a low-dose infusion of thrombolytic agent through the catheter can be considered for localized site-directed thrombolytic therapy. If infusion through the catheter is not possible, the CVL should be removed and heparin therapy considered.

iii. Extensive venous thrombosis. It is currently recommended that UVCs and CVLs associated with confirmed extensive thrombosis by ultrasound be left in place for 3 to 5 days of therapeutic anticoagulation and subsequently removed in order to reduce the risk of paradoxical emboli. Systemic thrombolytic therapy should be reserved for extensive non-catheter-related organ-, limb-, or lifethreatening venous thrombosis.

a. Renal vein thrombosis occurs primarily in newborns and young infants and most often presents in the first week of life. A significant proportion of cases appear to result from in utero thrombus formation.

b. Affected neonates are usually term and often large for gestational age. There is an increased incidence among infants of diabetic mothers, and males are more often affected than females. A recent review demonstrated bilateral renal vein thrombus formation in up to 30% of cases.

c. Additional risk factors include perinatal asphyxia, hypotension, polycythemia, increased blood viscosity, and cyanotic congenital heart disease.

d. Presenting symptoms in the neonatal period include flank mass, hematuria, proteinuria, thrombocytopenia, and renal dysfunction. The diagnosis is made by ultrasound with Doppler interrogation. Coagulation studies may be prolonged, and fibrin degradation products are usually increased.

e. Complications can include hypertension, renal failure, adrenal hemorrhage, extension of the thrombus into the inferior vena cava, and death.

f. Retrospective studies have demonstrated that 43% to 67% of neonates with renal vein thrombosis had at least one or more prothrombotic risk factors. A thrombophilia evaluation of infants with renal vein thrombosis is warranted.

g. Management is generally based on the extent of thrombosis.

i. Unilateral renal vein thrombosis without significant renal dysfunction or extension into the inferior vena cava is often managed with supportive care and close radiologic monitoring.

ii. Unilateral renal vein thrombosis with renal dysfunction or extension into the inferior vena cava and bilateral renal vein thrombosis should be considered for therapeutic anticoagulation with unfractionated heparin or LMWH for a total duration of 6 weeks to 3 months. Note that dosing of LMWH may need to be reduced in patients with renal insufficiency.

iii. Bilateral renal vein thrombosis with significant renal dysfunction should be considered for thrombolysis with tPA followed by anticoagulation with unfractionated heparin or LMWH.

a. Portal vein thrombosis is primarily associated with sepsis, omphalitis, exchange transfusion, and the presence of a UVC.

b. Diagnosis is made by ultrasound with Doppler, and reversal of portal flow is an indication of severity.

c. Spontaneous resolution is common (30% to 70% of cases); however, portal vein thrombosis can be associated with later development of portal hypertension.

d. There are currently no data to suggest that anticoagulation decreases the time to resolution or the risk of developing portal hypertension.

a. Thrombosis of the sinovenous system of the brain is an important cause of neonatal cerebral infarction and is associated with significant morbidity including epilepsy, cerebral palsy, and cognitive impairment in 10% to 80% of cases. Reported mortality rates range between 2% and 24%.

b. Major presenting clinical features of cerebral sinovenous thrombosis in neonates include seizures, lethargy, irritability, and poor feeding. The majority of cases present within the first day to week of life.

c. The superior sagittal sinus, transverse sinuses, and straight sinus are most commonly affected.

d. Hemorrhagic infarction is a frequent complication of sinovenous thrombosis and noted in 50% to 60% of cases on initial imaging.

e. The majority of cases of neonatal sinovenous thrombosis are associated with maternal conditions including preeclampsia, diabetes, and chorioamnionitis as well as acute systemic illness in the neonate.

f. Inherited thrombophilias have been reported in 15% to 20% of neonates with sinovenous thrombosis.

g. Ultrasound and computed tomography (CT) scan can identify sinovenous thrombosis, but magnetic resonance imaging (MRI) with venography is the imaging modality of choice for optimal detection of sinovenous thrombosis and associated cerebral injury.

h. Data on management remains limited. In general, neonates with cerebral sinovenous thrombosis without associated hemorrhage should be considered for anticoagulation therapy initially with unfractionated heparin or LMWH and subsequently LMWH for a total of 6 weeks to 3 months. If significant hemorrhage is present, anticoagulation should be reserved for cases with propagation of the thrombus.