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Neonatal thrombosis: Clinical features and diagnosis

Neonatal thrombosis: Clinical features and diagnosis
Literature review current through: Jan 2024.
This topic last updated: Oct 02, 2023.

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

The epidemiology, risk factors, 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 1A) [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 1B) 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 'Additional testing' 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]. For thromboses unrelated to a catheter, renal vein thrombosis (RVT) is the most common location [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].

Long-term complications of neonatal venous thromboembolic disease depend upon the location:

Portal vein thrombosis (PVT) may result in portal hypertension. (See 'Portal vein thrombosis' below.)

RVT can cause systemic hypertension and/or chronic kidney disease. (See 'Renal vein thrombosis' below.)

Occlusive deep venous thrombosis (DVT) can result in post-thrombotic syndrome (PTS), a disorder characterized by edema and impaired viability of subcutaneous tissue in an extremity. PTS is increasingly recognized in older infants and children, but it is less common following neonatal thrombosis. (See "Neonatal thrombosis: Management and outcome", section on 'Outcome' and "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Post-thrombotic syndrome'.)

Portal vein thrombosis — In the neonate, umbilical venous catheterization is associated with an increased risk of PVT [33-37]. 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 [38-40]. In these studies, spontaneous resolution at one year was >95 percent among patients who underwent serial ultrasound monitoring [38,40].

Most PVTs in neonates are asymptomatic and do not have long-term consequences. However, a small minority of patients may develop long-term complications such as hepatic lobar atrophy and/or portal hypertension [33,36,41-44]. 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 [44]. 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) [36].

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 [45]. 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 [16,24]. 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. In a systematic review of 22 observational studies, the pooled incidence of catheter-related arterial thrombosis in neonates with arterial catheters was 21 percent [16]. Presenting signs may include evidence of acute limb ischemia (ie, pale or discolored extremity) and/or arterial hypertension [16].

Prophylactic heparin infusion into arterial catheters may reduce the risk of thrombosis, as discussed separately. (See "Neonatal thrombosis: Management and outcome", section on 'Prevention of catheter-associated thrombosis'.)

Umbilical artery catheters – The reported incidence of arterial thrombosis in neonates with UACs in place is approximately 8 to 20 percent [16,39,46]. 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 [47-49].

Peripheral arterial catheters – Clinical signs of peripheral arterial thrombosis include decreased or absent peripheral pulses; diminished perfusion of the distal extremity with a prolonged capillary refill time; and a cool, pale extremity. Severe thrombosis in an extremity can result in long-term arterial insufficiency. This may impair growth of the affected limb [50].

Renal vein thrombosis — RVT accounts for approximately 10 percent of venous thrombosis in newborns and is the most common form of neonatal thrombosis not associated with a vascular catheter [8,51].

The proposed mechanisms resulting in RVT include reduced renal blood flow, hyperosmolality, hypercoagulability, and increased blood viscosity [52,53]. Risk factors associated with RVT include prematurity, perinatal asphyxia, shock, dehydration, sepsis, polycythemia, cyanotic congenital heart disease, respiratory distress syndrome, and maternal diabetes [51,52,54,55]. 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 [52,55].

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 [56].

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.

Long-term sequelae of RVT include systemic hypertension and chronic kidney disease [51,56].

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.

ASSOCIATION WITH THROMBOCYTOPENIA — 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 2) and discussed separately. (See "Neonatal thrombocytopenia: Etiology".)

DIAGNOSIS — Doppler ultrasonography is the imaging test of choice to confirm the diagnosis of venous or arterial thrombosis in most cases. The advantages of ultrasound are that it is noninvasive, does not require exposure to ionizing radiation, and can be performed at the bedside. Alternative imaging modalities are available (eg, contrast angiography, contrast magnetic resonance imaging, computed tomography); however, they are rarely necessary.

Catheter-associated thrombosis – Noncompressibility of the vessel with or without visible intraluminal thrombus confirms the diagnosis of catheter-associated thrombosis on ultrasound. However, the presence of a catheter may impact the sensitivity of ultrasound for detecting thrombus since the catheter itself may reduce the compressibility of the vessel lumen, thereby making it difficult to definitely determine if a thrombus is present [24]. In addition, preterm and critically ill neonates may have low pulse pressure, and therefore interpretation of the Doppler flow when assessing for an arterial thrombus can be challenging.

Renal vein thrombosis (RVT) – The ultrasound features of RVT 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].

ADDITIONAL TESTING

Testing for thrombophilia — The utility of thrombophilia testing in neonates with thrombosis is uncertain. Inherited thrombophilias are associated with a risk of recurrence. However, among patients who present with thrombosis in the neonatal period, the risk of recurrence is low (3 to 5 percent) and it when it does occur, it is most often a distant event, occurring at the earliest in the teenage years [25,76]. Consultation with a pediatric hematologist is advised when making decisions regarding testing for thrombophilia. (See "Thrombophilia testing in children and adolescents", section on 'Children with venous thromboembolism'.)

Who to test – Decisions regarding testing for thrombophilia in newborns with clinically significant thrombosis are individualized. We generally do not perform testing in newborns with a single episode of catheter-related thrombosis, since the utility of testing in this setting is minimal [77]. However, an evaluation for thrombophilia is generally warranted for patients with recurrent episodes and/or thrombosis unrelated to a catheter.

Timing of testing – Unless the thrombosis is severe or recurrent, we generally prefer to delay thrombophilia testing until the infant is older. This is because it is difficult to interpret non-DNA-based coagulation and fibrinolytic tests in the neonatal period and in the setting of acute thrombosis. (See "Thrombophilia testing in children and adolescents", section on 'Timing of testing'.)

Tests to perform – When the decision is made to perform thrombophilia testing in a neonate, the tests to perform are generally the same as for older children, as summarized in the table (table 3). 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", section on 'Tests to perform'.)

Interpretation – Reference values for functional assays and tests that measure protein levels vary somewhat by age. Thus, results of these tests should be interpreted using reference values for the appropriate postnatal and gestational age [78]. This limitation does not apply molecular tests (eg, DNA-based tests for factor V Leiden of prothrombin 20210 mutations).

Abnormal results should be repeated in four to six weeks, and parents should be counseled about the results.

Pretreatment evaluation — If anticoagulation therapy is planned, we suggest performing baseline pretreatment laboratory evaluation and cranial ultrasound. (See "Neonatal thrombosis: Management and outcome", section on 'Pretreatment evaluation'.)

Laboratory tests – Baseline pretreatment laboratory testing includes the following:

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)

Pretreatment cranial ultrasound – We suggest performing a baseline pretreatment cranial ultrasound to rule out intracranial or intraventricular hemorrhage. This is especially important for preterm infants. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis", section on 'Cranial ultrasound'.)

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. Procoagulant, anticoagulant, and fibrinolytic factors differ considerably in neonates compared with older children and adults (table 1A-B). As a result, newborns are at increased risk of both bleeding and thrombotic complications compared with older children, especially in the presence of other risk factors. Important risk factors for thrombosis in neonates include (see 'Coagulation in newborns' above and 'Risk factors' above):

Central venous or arterial catheters

Polycythemia

Infections

Major surgery

Other underlying conditions (eg, metabolic disorders, congenital heart disease, congenital nephrotic syndrome)

Inherited thrombophilia

Presentation – Most cases of neonatal thrombosis are asymptomatic. When present, signs and symptoms vary 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.)

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.)

Arterial thrombosis – Arterial thrombosis in neonates is usually associated with indwelling 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 arterial 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.)

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 presents 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 venous or arterial thrombosis is confirmed by Doppler ultrasonography. (See 'Diagnosis' 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 'Additional testing' above and "Thrombophilia testing in children and adolescents".)

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Topic 5912 Version 20.0

References

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