INTRODUCTION — Thrombotic disease is uncommon in newborns; however, it is increasingly recognized as a complication of contemporary neonatal care. Thrombosis contributes to neonatal morbidity and mortality.
The pathogenesis, clinical features, and diagnosis of neonatal thrombosis, excluding the central nervous system, are reviewed here. Central nervous system thromboembolic disease and the management of neonatal thrombosis are discussed separately. (See "Stroke in the newborn: Classification, manifestations, and diagnosis" and "Neonatal thrombosis: Management and outcome".)
COAGULATION IN NEWBORNS — Plasma concentrations of the components of the coagulation cascade (figure 1) and fibrinolytic pathway (figure 2) in newborns differ markedly from older children and adults. Concentrations of these factors change from birth through infancy (table 1) [1-4]. (See "Overview of hemostasis".)
In newborns, the following procoagulant, anticoagulant, and fibrinolytic factors differ considerably compared with adult levels:
●Vitamin K-dependent coagulation factors (II, VII, IX, X) and contact factors (XI, XII, prekallikrein, high molecular weight kininogen) are 50 to 70 percent of adult levels [5]. These factors increase rapidly after birth, reaching adult levels of most components by six months of age [1].
●Factors V, VIII, and XIII; von Willebrand factor; and fibrinogen are at least 70 percent of adult levels [1].
●Coagulation inhibitors (antithrombin, heparin cofactor II, protein C, protein S) are approximately 50 percent of adult levels [1]. However, the concentration of alpha-2-macroglobulin is greater in newborns than in adults.
●The rate of thrombin generation in newborn plasma is 30 to 50 percent of adult values [6].
●Fibrinolytic factors plasminogen and alpha-1 antiplasmin are lower than adult values [1]. However, levels of tissue plasminogen activator and plasminogen activator inhibitor-1 are higher.
●Infants born preterm have even lower levels of vitamin K-dependent clotting factors as compared with those born at term (table 2) and also lower values for inhibitors of coagulation including antithrombin and protein C [2,7]. Because of their immature coagulation system, preterm infants are particularly at risk for developing bleeding or thrombotic complications in response to perinatal risk factors or iatrogenic events.
Due to the altered levels of procoagulant, anticoagulant, and fibrinolytic factors, newborns are at increased risk of bleeding or thrombotic complications compared with older children, especially in the presence of other hemostatic challenges such as indwelling catheters.
EPIDEMIOLOGY
Incidence — Reported estimates of the incidence of neonatal thrombosis range from 3 to 5 cases per 100,000 live births [8-10]. In studies performed in the neonatal intensive care unit (NICU) setting, rates of thrombosis range from 0.7 to 1.5 percent of NICU admissions [11-14]. Reported incidence rates of neonatal thrombosis in the contemporary era are higher than in studies from the 1990s to early 2000s. Improved detection and advances in management and survival of very preterm neonates likely explain the increase.
In a large multicenter observational study involving nearly 40,000 neonates cared for at 30 NICUs in Canada from 2014 to 2016, 1.5 percent of patients had at least one documented thrombosis during their NICU stay [14]. Among patients with thrombosis, 75 percent of cases were venous (most commonly involving the portal vein), 19 percent were arterial (most commonly arterial stroke), and 5 percent were mixed.
Risk factors — Important risk factors for thrombosis in newborns include:
●Central venous or arterial catheter – Thrombosis occurs in up to 10 percent of neonates with central venous catheters; however, most of these are asymptomatic [15]. Arterial thrombosis occurs in up to 20 percent of neonates with umbilical arterial catheters (UACs) [16]. The risk of thrombosis is influenced by location of the catheter (femoral location has the greatest risk) and how long the catheter remains in place [13,14,17-19]. (See 'Catheter-associated thrombosis' below.)
●Polycythemia [20]. (See "Neonatal polycythemia".)
●Infections [13].
●Major surgery.
●Other underlying conditions (eg, metabolic disorders, congenital heart disease, congenital nephrotic syndrome) [21,22].
●Inherited thrombophilia– The inherited thrombophilias for which the pathogenic link is most clearly established include [23-25]:
•Antithrombin deficiency
•Protein C deficiency
•Protein S deficiency
•Factor V Leiden mutation
•Prothrombin G20210A
However, the incidence of these disorders in newborns with thrombosis is not known and the contribution of the prothrombotic state to the pathogenesis of neonatal thrombosis is uncertain [26]. The approach to testing for thrombophilia in a newborn with clinically significant thrombosis is discussed below. (See 'Coagulation studies' below.)
CLINICAL FEATURES — The clinical presentation of thrombosis is variable. Signs and symptoms depend upon the location and size of the thrombus. The most common predisposing factor for thrombosis is the presence of a central venous or arterial catheter [8,9]. In thrombosis unrelated to a catheter, renal vein thrombosis (RVT) is the most common [9].
Catheter-associated thrombosis — Central venous catheters are usually placed through the umbilical vein or major vessels such as the jugular vein. Peripherally inserted central catheters are placed through peripheral veins in the arms, legs, or scalp. Central venous catheters are widely used to provide intravenous fluids, parenteral nutrition, and medications to term and preterm infants who require intensive care. In a series of 193 infants with central venous catheters, central venous or intracardiac thrombosis occurred in 13 percent [27]. The location of the tip of the catheter may have an effect on the incidence of thrombosis.
Venous thrombosis — Many cases of venous thrombosis are asymptomatic and detected incidentally [23,28]. Most are associated with central venous catheters [8,22,24]. The presenting sign may be loss of patency of the catheter. Other signs may include swelling and/or color changes in the affected extremity.
Symptomatic thrombosis in the inferior vena cava typically presents as swelling of the lower limbs and lower body [29]. Superior vena cava thrombosis typically presents as swelling of the arm, neck, and head. The severity of the swelling depends upon the size of the thrombus. Chylothorax may be the presenting sign of superior vena cava thrombosis [30-32].
The long-term outcome of venous thromboembolic disease in newborns depends upon the location. Portal vein thrombosis (PVT) related to umbilical venous catheterization may result in portal hypertension [33-35]. Long-term sequelae of RVT include systemic hypertension, renal insufficiency, and renal tubular dysfunction [36,37].
A potential complication is post-thrombotic syndrome, a disorder characterized by edema and impaired viability of subcutaneous tissue in an extremity [24]. The condition is caused by incompetent perforating valves, resulting in blood flow directed from deep to peripheral veins. This disorder is increasingly recognized in older infants and children, but it appears to be less common following neonatal thrombosis. Clinically relevant post-thrombotic syndrome only occurs in 1 percent of the neonates [16,38]. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Post-thrombotic syndrome'.)
Right atrial thrombosis — Right atrial thrombosis is associated with central venous catheter placement. In one report, this disorder was detected by prospective echocardiography in the first few days after birth in 4 of 76 (5 percent) very low birth weight infants who had umbilical catheters [39]. Symptomatic intracardiac thrombosis can present as a new murmur or heart failure, as well as malfunction of the catheter [24].
Arterial thrombosis — Nearly all cases of arterial thrombosis in neonates are associated with arterial catheters [24]. Umbilical arterial catheters (UACs) and peripheral arterial catheters (radial, posterior tibial) are typically used for monitoring of blood pressure and blood gases; the femoral artery is often used for cardiac catheterization.
The incidence of arterial thrombosis associated with arterial catheters in neonates is variable and depends in part upon the method of detection used. Prophylactic heparin infusion may reduce the risk of thrombosis, as discussed separately. (See "Neonatal thrombosis: Management and outcome", section on 'Prevention of catheter-associated thrombosis'.)
Umbilical artery catheter — The reported incidence of arterial thrombosis in neonates with UACs in place is approximately 8 to 20 percent [16,40,41]. Most UAC-associated thromboses are asymptomatic. However, some present with signs of severe ischemia or organ dysfunction. Depending upon the location of the thrombus, signs can include coolness; poor perfusion; and blanching of a toe, one or both limbs, or the buttocks. Hypertension may also be noted. In some cases, the presentation can mimic that of severe aortic coarctation. (See "Clinical manifestations and diagnosis of coarctation of the aorta".)
Renal failure, necrotizing enterocolitis, and spinal cord infarction are rare complications of UAC-associated thrombosis that can occur if the thrombosis extends into the renal, mesenteric, or branches of the spinal arteries [42-44].
Peripheral artery occlusion — There are limited data on thrombosis associated with peripheral artery catheterization in neonates. In the available reports, incidence rates ranged from 3 to 63 percent [16]. Clinical signs include decreased or absent peripheral pulses; diminished perfusion with a prolonged capillary refill time; and a cool, pale extremity. The diagnosis can be confirmed by Doppler ultrasound.
Severe thrombosis in an extremity can result in long-term arterial insufficiency. This may impair growth of the affected limb [45].
Portal vein thrombosis — In the neonate, umbilical venous catheterization is associated with an increased risk of PVT [33,34,46,47]. Most cases are asymptomatic and regress spontaneously.
Reported rates of PVT in studies using routine ultrasound surveillance for all patients with umbilical venous catheters range from 22 to 75 percent [40,48,49]. In these studies, spontaneous resolution at one year was >95 percent among patients who underwent serial ultrasound monitoring [48,49].
The majority of PVTs in neonates are asymptomatic. However, a small minority of patients may develop long-term complications such as hepatic lobar atrophy and/or portal hypertension [33,47,50-52]. The precise incidence of and risk factors for these complications are unknown. In a retrospective study of 74 patients with neonatal PVT, 60 percent had complete resolution demonstrated on sequential ultrasound imaging over an average follow-up of 16 months; the remaining 40 percent had either partial resolution or stable appearance on follow-up ultrasound [52]. In this study, only 4 percent of patients experienced complications of PVT (hepatomegaly in two patients, splenomegaly in one patient); no patients in this series developed lobar atrophy or portal hypertension. By contrast, an earlier study of 133 patients with neonatal PVT reported higher rates of hepatic lobar atrophy (23 percent) and portal hypertension (4.5 percent) [47].
Renal vein thrombosis — RVT accounts for approximately 10 percent of venous thrombosis in newborns and is the most common form of thrombosis not associated with a vascular catheter [8,37].
The proposed mechanisms resulting in RVT include reduced renal blood flow, hyperosmolality, hypercoagulability, and increased blood viscosity [53,54]. Risk factors associated with RVT include prematurity, perinatal asphyxia, shock, dehydration, sepsis, polycythemia, cyanotic congenital heart disease, respiratory distress syndrome, and maternal diabetes [37,53,55,56]. In addition, the prevalence of inherited thrombophilia (eg, antithrombin deficiency, protein C or S deficiency, factor V Leiden mutation, and prothrombin G20210A) is higher in infants with RVT compared with the general population [53,56].
RVT, which may occur as an extension of inferior vena cava thrombosis, typically presents with one of the following cardinal features of RVT: flank mass, hematuria, or thrombocytopenia. However, in one series of 23 cases of which 83 percent were diagnosed in the first month after birth, the complete triad was seen in only 13 percent [36].
The clinical presentation of neonatal RVT was demonstrated by a systematic review of the literature from 1992 to 2006 that identified 271 patients from 13 case series [57]. The following findings were noted:
●The time of presentation varied and occurred in utero (7 percent), by three days of life (67 percent), and after three days of life but before one month of age (26 percent). Most of the patients were born full term (71 percent), and there was a male predominance (67 percent).
●Patients had one or more of the following findings at presentation: gross hematuria (56 percent), thrombocytopenia (48 percent), and/or a palpable abdominal mass (45 percent).
●Approximately 70 percent of cases were unilateral, which involved the left kidney in two-thirds of these patients.
●The thrombus extended into the inferior vena cava in approximately 44 percent of patients, and adrenal hemorrhage occurred in 15 percent.
●Perinatal risk factors including asphyxia were identified in 32 percent of cases. Other reported risk factors included maternal diabetes mellitus (8 percent) and dehydration (2 percent).
●Among the 149 patients in whom prothrombotic factors were investigated, 53 percent had at least one risk factor identified.
Purpura fulminans — Purpura fulminans in newborns is a rare, life-threatening condition characterized by disseminated intravascular coagulation and hemorrhagic skin necrosis [58]. It usually is caused by homozygous or compound heterozygous deficiency in protein C or S, a mechanism that is consistent with the observation of consanguinity in some affected families [58-64]. The heterozygous parents of these infants have type 1 protein C deficiency but infrequently have a history of thrombosis.
Purpura fulminans also can result from acquired protein C deficiency due to consumptive coagulopathy, as in meningococcemia [58]. (See "Clinical manifestations of meningococcal infection", section on 'Purpura fulminans' and "Protein C deficiency", section on 'Control of protein C levels'.)
Clinical presentation — Neonatal purpura fulminans usually occurs on the first day of life. Affected infants present with ecchymoses, extensive venous and arterial thromboses (initially at sites of trauma), laboratory evidence of disseminated intravascular coagulation (thrombocytopenia, hypofibrinogenemia, and increased prothrombin time and activated partial thromboplastin time times), and extremely low levels of protein C or protein S antigen (less than 1 percent of normal) [59-61,65-70]. Delayed presentation of the disorder (after six months of age) has been reported [71].
Diagnosis — The diagnosis of protein C or S deficiency is made by testing a citrated plasma sample for protein C and S activity [58]. The sample must be collected prior to initiation of treatment, but treatment should not be delayed while awaiting the results. Results should be compared with age-specific reference ranges because protein C and S activity in healthy neonates is substantially lower than in older children or adults [1,2]. Ideally, the diagnosis is confirmed with genetic testing; a list of clinical laboratories that perform genetic testing for this disorder is available at the GeneTests website.
LABORATORY FINDINGS — Neonatal thrombosis is often associated with thrombocytopenia. Thus, the diagnosis of thrombosis should be considered in neonates with thrombocytopenia who lack an alternative explanation for the low platelet count. Other causes of neonatal thrombosis are summarized in the table (table 3) and discussed separately. (See "Neonatal thrombocytopenia: Etiology".)
DIAGNOSIS
Imaging
●Doppler ultrasound – Doppler ultrasound examination is the imaging test of choice to confirm thrombosis in most cases. The advantages of this technique are that it is noninvasive, does not require exposure to ionizing radiation, and can be performed at the bedside. Contrast angiography is considered the gold standard. However, it is rarely used because of its invasive nature.
The accuracy of ultrasound may be reduced by the presence of a catheter because reduced compressibility of the vessel lumen by the ultrasound probe (a sign of thrombosis) is difficult to assess [24]. Interpretation may also be limited by the low pulse pressure in preterm and sick newborns.
In one series of 47 infants with umbilical venous catheters, the accuracy of Doppler ultrasonography was poor compared with contrast venography in detecting asymptomatic thrombus [28]. Thrombi were detected by venogram in 14 patients (30 percent). The sensitivity and specificity of echocardiographic diagnosis for the three cardiologists who interpreted the studies ranged from 21 to 43 and 76 to 94 percent, respectively. However, the relative accuracy of these techniques to detect symptomatic thrombosis is not known.
●Renal vein thrombosis (RVT) imaging – Doppler ultrasound is the most commonly used imaging technique to confirm the diagnosis of RVT. The ultrasound features depend upon the timing of the examination [72-74]. During the first few days, echogenic streaks appear in a peripheral focal segment of the affected kidney. During the first week, the kidney appears swollen and echogenic, with prominent and less echogenic medullary pyramids. As the swelling decreases, the kidney appears heterogeneous with loss of corticomedullary differentiation. The kidney may subsequently atrophy with focal scarring or recover. Color Doppler ultrasonography may show absent intrarenal and renal venous flow in the early stages of RVT [72]. Indeed, the sonographic findings can be used to predict outcome [75].
●Pretreatment cranial ultrasound – If anticoagulation therapy is planned, we suggest performing a baseline pretreatment cranial ultrasound to rule out intracranial or intraventricular hemorrhage. This is especially important for preterm infants. (See "Neonatal thrombosis: Management and outcome", section on 'Pretreatment evaluation'.)
Coagulation studies
●Testing for thrombophilia – Decisions regarding testing for thrombophilia in newborns with clinically significant thrombosis are made on a case-by-case basis. The utility of testing newborns with catheter-related thrombosis is minimal [76]. However, patients with thrombosis that is not catheter related and those with recurrent thrombosis generally should be evaluated. Because it is difficult to interpret values of coagulation and fibrinolytic factors in the neonatal period and in the setting of acute thrombosis, we prefer to delay testing for prothrombotic disorders in most cases until the child is older, except when the thrombosis is severe or recurrent. The benefits of testing are uncertain. Inherited thrombophilias are associated with a risk of recurrence. However, among patients who present with thrombosis as a neonate, the recurrence risk is low (3 to 5 percent) and often a distant event, occurring at the earliest in the teenage years [25,77]. (See "Thrombophilia testing in children and adolescents", section on 'Children with venous thromboembolism'.)
When the decision is made to perform thrombophilia testing in a neonate, the results should be interpreted using reference values for the appropriate postnatal and gestational age [78]. Abnormal results should be repeated in four to six weeks, and parents should be counseled about the results. Consultation with a pediatric hematologist is advised.
Tests to perform to evaluate for thrombophilia in neonates are generally the same as for older children, as summarized in the table (table 4). The one difference is that testing for antiphospholipid antibodies should be performed on a maternal blood sample rather than testing the neonate. Thrombophilia testing in infants and children is discussed in greater detail separately. (See "Thrombophilia testing in children and adolescents".)
●Pretreatment coagulation tests – If anticoagulation therapy is planned, we suggest performing baseline pretreatment laboratory testing, including the following:
•Prothrombin time and international normalized ratio
•Activated partial thromboplastin time
•Platelet count
•Fibrinogen level
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
●Risk factors – In healthy newborns, thrombosis is rare, occurring in approximately 3 to 5 out of 100,000 live births. However, among patients admitted to the neonatal intensive care unit (NICU), approximately 1 percent develop thrombosis. Important risk factors for thrombosis in neonates include central venous or arterial catheters, polycythemia, infections, major surgery, other underlying conditions (eg, metabolic disorders, congenital heart disease, congenital nephrotic syndrome), and inherited thrombophilia. Procoagulant, anticoagulant, and fibrinolytic factors differ considerably in neonates compared with older children and adults. (See 'Epidemiology' above and 'Coagulation in newborns' above.)
●Presentation – Most cases of neonatal thrombosis are asymptomatic. However, the presentation varies depending upon the location of the thrombus:
•Catheter-associated thrombosis – A common presenting symptom of catheter-associated thrombosis is loss of catheter patency. If the thrombosis occludes the inferior vena cava or superior vena cava, the neonate may present with swelling and/or discoloration of the affected extremities. If the catheter tip is in the right atrium, a right atrial thrombosis can form, which may present as a new murmur or signs of heart failure. (See 'Venous thrombosis' above and 'Right atrial thrombosis' above.)
•Arterial thrombosis – Arterial thrombosis in neonates is usually associated with arterial catheters. Thrombosis associated with umbilical artery catheters may be asymptomatic or may present with ischemia or organ dysfunction, depending on the location of the thrombus. Thrombosis associated with peripheral artery catheters may present with decreased or absent peripheral pulses; diminished perfusion with a prolonged capillary refill time; and a cool, pale extremity. (See 'Arterial thrombosis' above.)
•Portal vein thrombosis (PVT) – PVT is a complication of umbilical vein catheterization. Most are asymptomatic and regress spontaneously. In a minority of patients, PVT may lead to hepatic lobar atrophy and/or portal hypertension. (See 'Portal vein thrombosis' above.)
•Renal vein thrombosis (RVT) – RVT accounts for approximately 10 percent of venous thrombosis in newborns and is the most common form of thrombosis not associated with a vascular catheter. RVT typically presents with flank mass, hematuria, or thrombocytopenia. Risk factors for RVT include prematurity, perinatal asphyxia, dehydration, sepsis, polycythemia, cyanotic congenital heart disease, maternal diabetes, and inherited thrombophilia. (See 'Renal vein thrombosis' above.)
•Severe neonatal purpura – Neonatal purpura fulminans in newborns is a rare, life-threatening condition characterized by disseminated intravascular coagulation and hemorrhagic skin necrosis. It usually occurs on the first day of life and is characterized by ecchymoses, extensive venous and arterial thromboses, laboratory evidence of disseminated intravascular coagulation, and extremely low levels of protein C or protein S antigen. (See 'Purpura fulminans' above.)
●Diagnosis – The diagnosis of thrombosis is confirmed by Doppler ultrasound. (See 'Imaging' above.)
●Testing for thrombophilia – Decisions regarding evaluation for thrombophilia in newborns with clinically significant thrombosis are made on a case-by-case basis. We pursue such testing only in neonates with recurrent or unprovoked (ie, not catheter-associated) thrombosis. If testing is performed, the results should be interpreted using reference values for the appropriate postnatal and gestational age. (See 'Coagulation studies' above and "Thrombophilia testing in children and adolescents".)
