Neonatal Thrombosis
Munish Gupta
I. PHYSIOLOGY
Physiology of thrombosis
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.
Inhibitors of coagulation include antithrombin, heparin cofactor I, protein C, protein S, and tissue factor pathway inhibitor (TFPI). Antithrombin activity is potentiated by heparin.
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 tissue plasminogen activator (tPA).
In neonates, factors affecting blood flow, blood composition (leading to hypercoagulability), and vascular endothelial integrity can all contribute to thrombus formation.
Unique physiologic characteristics of hemostasis in neonates
In utero, coagulation proteins are synthesized by the fetus and do not cross the placenta.
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. However, under normal physiologic conditions, the hemostatic system in premature and term newborns is in balance, and healthy neonates do not clinically demonstrate hypercoagulable or bleeding tendencies.
Concentrations of most procoagulant proteins are reduced in neonates compared with adult values, although fibrinogen levels are normal or even increased. Compared with 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.
Concentrations of most antithrombotic and fibrinolytic proteins are also reduced, including protein C, protein S, plasminogen, and antithrombin. Thrombin inhibition by plasmin is diminished compared with adult plasma.
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.
II. EPIDEMIOLOGY AND RISK FACTORS
Epidemiology
Thrombosis occurs more frequently in the neonatal period than at any other age in childhood.
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.
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.
Umbilical arterial catheterization (UAC) appears to result in clinically 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.
Other risk factors for thrombosis include infection, increased blood viscosity, polycythemia, dehydration, hypoxia, hypotension, maternal preeclampsia, maternal diabetes, chorioamnionitis, and intrauterine growth restriction (IUGR).
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.
Renal vein thrombosis (RVT) is the most common type of noncatheter-related pathologic thrombosis in newborns.
Registries from Canada, Germany, and the Netherlands have described series of cases of neonatal thrombosis.
Incidence of clinically significant thrombosis were estimated as 2.4 per 1,000 admissions to the neonatal intensive care unit in Canada, 5.1 per 100,000 births in Germany, and 14.5 per 10,000 neonates aged 0 to 28 days in the Netherlands.
Two series examined both venous and arterial thromboses. Among all thrombotic events, percentage of RVT, other venous thrombosis, and arterial thrombosis were 44%, 32%, and 24%, respectively, in one series; and 22%, 40%, and 34% in the other series.
Excluding cases of RVT, 89% and 94% of venous thromboses were found to be associated with indwelling central lines in two of the studies.
Other commonly identified risk factors included sepsis, perinatal asphyxia, congenital heart disease, and dehydration.
Mortality was uncommon, but present, and was generally restricted to very premature infants or infants with large arterial or intracardiac thromboses.
Inherited thrombophilias
Inherited thrombophilias are characterized by positive family history, early age of onset, recurrent disease, and unusual or multiple locations of thromboembolic events. It is estimated that a genetic risk factor can be identified in approximately 70% of patients with thrombophilia.
Important inherited thrombophilias include:
Deficiencies of protein C, protein S, and antithrombin, which appear to have the largest increase in relative risk for thromboembolic disease, but are relatively rare.
Activated protein C resistance, including the factor V Leiden mutation, and the prothrombin G20210A mutation, which have high incidence, particularly in certain populations, but appear to have a low risk of thrombosis in neonates.
Hyperhomocysteinemia, increased lipoprotein(a) levels, and polymorphism in the methylene tetrahydrofolate reductase (MTHFR) gene, which are relatively common but whose significance in neonatal thrombosis is still poorly understood.
Multiple other defects in the anticoagulation, fibrinolytic, and antifibrinolytic pathways have been identified, including abnormalities in thrombomodulin, TFPI, fibrinogen, plasminogen, tPA, and plasminogen-activator inhibitors. The frequency and importance of these defects in neonatal thrombosis is poorly understood.
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 of thrombosis. This second risk factor can be an acquired clinical condition or illness, or another inherited defect. Patients with single defects for inherited prothrombotic disorders rarely present in neonatal period, unless another pathologic process or event occurs.
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 with homozygous protein C or S deficiency, which presents within hours or days of birth, often with evidence of in utero cerebral damage.
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 inherited thrombophilia (nonhomozygous) is actually quite small; however, among neonates with thrombotic disease, the incidence of an inherited thrombophilia appears to be substantially increased compared with incidence in the general population, and evaluation for thrombophilia should be considered (see V.A.).
Acquired thrombophilias
Newborns can acquire significant coagulation factor deficiencies due to placental transfer of maternal antiphospholipid antibodies, including the lupus anticoagulant and anticardiolipin antibody.
These neonates can present with significant thrombosis, including purpura fulminans.
III. SPECIFIC CLINICAL CONDITIONS
Venous thromboembolic disorders
General considerations
Most venous thrombosis occur secondary to central venous catheters. Spontaneous (i.e., noncatheter-related) venous thrombosis can occur in renal veins, adrenal veins, inferior vena cava, portal vein, hepatic veins, and the venous system of the brain.
Spontaneous venous thrombi usually occur in the presence of another risk factor. Less than 1% of significant venous thromboembolic events in neonates are idiopathic.
Thrombosis of the sinovenous system of the brain is an important cause of neonatal cerebral infarction.
Short-term complications of venous catheter-associated thrombosis include loss of access, pulmonary embolism, superior vena cava syndrome, and specific organ impairment.
It is likely that the frequency of pulmonary embolism in sick neonates is underestimated, as signs and symptoms would be similar to multiple other common pulmonary diseases.
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.
Major venous thrombosis—signs and symptoms
Initial sign of catheter-related thrombosis is usually difficulty infusing through or withdrawing from the line.
Signs of venous obstruction include swelling of the extremities, possibly including the head and neck, and distended superficial veins.
The onset of thrombocytopenia in the presence of a central venous line (CVL) also raises the suspicion of thrombosis.
Major venous thrombosis—diagnosis
Ultrasound is diagnostic in most cases of significant venous thrombosis. In smaller infants or low-flow states, however, the ultrasound may not provide sufficient information about the size of the thrombus, and a significant falsenegative rate for ultrasound diagnosis has been documented.
Contrast studies. A radiographic line study can be helpful for diagnosis of catheter-associated thrombosis. Venography through peripheral vessels may be needed for diagnosis of thrombosis proximal to the catheter tip, for spontaneous thrombosis in the upper body, and for thrombosis not seen by other methods (see IV.).
Prevention of catheter-associated venous thrombosis
Heparin 0.5 units/mL is added to all infusions (compatability permitting) through CVLs.
UVCs should be removed as soon as clinically feasible and should not remain in place for longer than 10 to 14 days. Our usual practice is to place a peripherally inserted central catheter (PICC) line if anticipated need for central access is more than 7 days.
Management of major venous thrombosis
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, clearance of the blockage with thrombolytic agents or HCl can be considered (see V.F.).
Local obstruction. If a small occlusive catheter-related thrombosis is documented, a low-dose infusion of thrombolytic agents through the catheter
can be considered for localized site-directed thrombolytic therapy (see V.E.). If infusion through the catheter is not possible, the CVL should be removed and heparin therapy should be considered.
Extensive venous thrombosis. Consider leaving the catheter in place and attempting local site-directed thrombolytic therapy. Otherwise, remove the catheter and begin heparin therapy. Systemic thrombolytic therapy should be reserved for extensive non—catheter-related venous thrombosis and for venous thrombosis with significant clinical compromise.
In cases of catheter-related venous thrombosis, some clinicians suggest delaying catheter removal until after 3 to 5 days of anticoagulation in order to reduce risk of paradoxical emboli at time of catheter removal. Data is limited to evaluate this practice.
Aortic or major arterial thrombosis
General considerations
Spontaneous arterial thrombi in absence of a catheter are unusual but may occur in ill neonates.
Acute complications of catheter-related and spontaneous arterial thrombi depend on location, and can include renal hypertension, intestinal necrosis, peripheral gangrene, and other organ failure.
Thrombosis of cerebral arteries is an important cause of neonatal cerebral infarction.
Long-term effects of symptomatic and asymptomatic arterial thrombi are not well studied, but may include increased risk for atherosclerosis at the affected area and chronic renal hypertension.
Aortic thrombosis—signs and symptoms
Initial sign is often isolated dysfunction of umbilical arterial catheter (UAC).
Mild clinical signs include hematuria in absence of transfusions or hemolysis, hematuria with red blood cells (RBCs) on microscopic analysis, hypertension, and intermittent lower extremity decreased perfusion or color change.
Strong clinical signs include persistent lower extremity color change or decreased perfusion, blood pressure differential between upper and lower extremities, decrease or loss of lower extremity pulses, signs of peripheral thrombosis, oliguria despite adequate intravascular volume, signs of necrotizing enterocolitis (NEC), and signs of congestive heart failure.
Aortic thrombosis—diagnosis
Ultrasound with Doppler flow imaging should generally be performed in all cases of suspected aortic thrombosis; if signs of thrombosis are mild and resolve promptly after removal of the arterial catheter, an ultrasound may not be necessary. Ultrasound is diagnostic in most cases, although a significant false-negative rate has been documented.
Contrast study. If an ultrasound is negative or inconclusive, and major arterial thrombosis is suspected, a radiographic contrast study can be performed via the arterial catheter.
Prevention of catheter-associated arterial thrombosis
Heparin 0.5 to 1 unit/mL is added to all infusions (compatibility permitting) through arterial catheters; heparin infusion through arterial catheters has been shown to prolong patency and to likely reduce incidence of local thrombus, without the risk of significant complications.
Review of the literature suggests “high” umbilical arterial lines (tip in descending aorta below left subclavian artery and above diaphragm) are preferable to “low” lines (tip below renal arteries and above aortic bifurcation), with fewer clinically evident ischemic complications, an apparent trend to reduced incidence of thrombi, and no difference in serious complications such as NEC and renal dysfunction (see Chap. 66).
Consider placing a peripheral arterial line rather than an umbilical arterial line in infants weighing >1,500 g.
Monitor carefully for clinical evidence of thrombus formation when an UAC is present.
Monitor for evidence of UAC dysfunction, including waveform dampening and difficulty flushing or withdrawing blood.
Monitor lower extremity color and perfusion.
Check all urine for heme.
Check upper and lower extremity blood pressure three times daily.
Monitor for hypertension and decreased urine output.
UACs should be removed as soon as clinically feasible. Our general practice is to leave UACs in place for no longer than 5 to 7 days, and to place a peripheral arterial line should continued arterial access be needed.
Management of aortic and major arterial thrombosis
Minor aortic thrombi. Small aortic thrombi with limited mild symptoms can often be managed with prompt removal of the UAC, with rapid resolution of symptoms.
Large but nonocclusive thrombus. For large thrombi that are nonocclusive to blood flow (as demonstrated by ultrasound or contrast study) and that are not accompanied by signs of significant clinical compromise, the arterial catheter should be removed and anticoagulation with heparin considered. Close follow-up with serial imaging studies is indicated.
Occlusive thrombus or significant clinical compromise. Large occlusive aortic thrombi or thrombi accompanied by signs of significant clinical compromise, including renal failure, congestive heart failure, NEC, and signs of peripheral ischemia, should be managed aggressively:
If catheter is still present and patent, consider local thrombolytic therapy through the catheter (see V.E.).
If catheter has already been removed or is obstructed, consider systemic thrombolytic therapy. The catheter should be removed if still in place and obstructed.
Surgical thrombectomy is generally not indicated, since the mortality and morbidity are considered to exceed that of current medical management. Some recent experience suggests thrombectomy and subsequent vascular reconstruction may have utility in significant peripheral arterial thrombosis, although this experience is limited.
Peripheral arterial thrombosis
Congenital occlusions of large peripheral arteries are seen, although rare, and can present with symptoms ranging from a poorly perfused, pulseless extremity to a black, necrotic limb, depending on duration and timing of occlusion.
Common symptoms include decreased perfusion, decreased pulses, pallor, and embolic phenomena that may manifest as skin lesions or petechiae.
Diagnosis can often be made by Doppler flow ultrasound.
Peripheral arterial catheters, including radial, posterior tibial, and dorsalis pedis catheters, are rarely associated with significant thrombosis.
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