Management of Vascular Thrombosis and Spasm in the Newborn

Abstract

After completing this article, readers should be able to: Vascular thromboembolic disease has been increasingly recognized in newborns in the past decade, in part because venous and arterial catheters are indispensable in the management of smaller and sicker neonates, but also because of heightened awareness of the problem.Transient vascular spasm due to arterial constriction may be difficult to distinguish from more serious thrombosis in the early stages, when pallor or cyanosis of extremities follows insertion of arterial catheters. Arterial and venous thromboses are serious complications associated with potential dangers of ischemic injury to the affected limbs or organs, thrombus propagation and embolization to other areas, and infection. Thromboembolism (TE) may affect renal, portal, mesenteric, or hepatic veins; the inferior and superior vena cava; pulmonary veins; and cerebral sinuses. Arterial TE may involve the aorta and its branches, any of the limb arteries, and the cerebral circulation. This review focuses on the management of vascular spasm and TE in the neonate, but excludes neonatal central nervous system-related TE, which merits a separate review.Among children, neonates are particularly susceptible to thromboembolic disease because of the relative immaturity of the hemostatic system, small vessel diameter, and the presence of serious underlying disease. Perinatal asphyxia, hypovolemia, septicemia, dehydration, polycythemia, congenital heart disease, and other conditions are associated with disturbances in the hemostatic balance and may lead to a prothrombotic state. (1)(2) About 90% of venous TEs in neonates are associated with central venous catheters. (2) Low placement of umbilical arterial catheters is associated with an increased incidence of limb blanching and cyanosis. (3)Vascular catheters may cause vasospasm or thrombosis by several mechanisms: intimal injury by the catheter, infusion of hyperosmolar fluids, or disruption in blood flow. When the vascular endothelium is disrupted, platelet activation and aggregation are triggered, leading to the release of thromboxane A2, a potent vasoconstrictor, that can result in vasospasm and ischemia. Tissue factor released from the vascular subendothelium binds activated factor VII and triggers coagulation by converting factors IX and X to their active forms (Fig. 1). FXa converts prothrombin to thrombin in the presence of factor Va, calcium, and a phospholipid surface. Thrombin cleaves fibrinopeptides from fibrin, which subsequently are cross-linked to produce a stable clot by factor XIIIa. Thrombin amplifies its own generation by activating factors V, VIII, and XI and promotes fibrin cross-linking by activating factor XIII. Thrombin is inhibited directly by antithrombin (AT), alpha2-macroglobulin (alpha2-M), and heparin cofactor II and indirectly by protein C, protein S, and tissue factor pathway inhibitor (Fig. 2). In an intact vascular system, thrombin functions as an anticoagulant by binding to thrombomodulin and activating protein C. Activated protein C, with its cofactor protein S, inactivates factors Va and VIIIa.Insoluble fibrin is broken down into soluble fibrin degradation products by interaction with serine proteases, again precisely regulated by activators and inhibitors (Fig. 3). During fibrin formation, plasminogen binds to fibrin and is incorporated into the thrombus. The binding of tissue plasminogen activator (TPA) to fibrin results in the conversion of plasminogen to plasmin, which splits fibrin into degradation products. The activity of fibrin-bound TPA is modulated by plasminogen activator inhibitor-1. Fibrinolysis also is modified by alpha2-antiplasmin and alpha2-macroglobulin.The neonatal hemostatic system differs quantitatively and qualitatively from that of older children and adults, affecting the response to antithrombotic agents. (4) The capacity of neonatal plasma to generate thrombin is reduced to about 50% of adult values due to decreased levels of prothrombin. (5) The concentration of the anticoagulants AT and protein C is decreased, particularly in sick infants, potentially increasing the risk of thrombosis. (6) The neonatal fibrinolytic system also shows age-dependent variation, which may impair the neonate’s ability to lyse thrombi if they are formed. The fibrinolytic system is activated transiently at birth, but the overall rate of plasmin generation in neonatal plasma is reduced compared with adult values. This may be due to the reduced plasminogen values as well as reduced functional activity of neonatal plasminogen. At birth, plasminogen concentrations are about 50% of adult values, and they remain low throughout the neonatal period, increasing to adult concentrations gradually by 6 months of age. Plasma concentrations of alpha2-antiplasmin are approximately 80% of adult values, but plasminogen activator inhibitor type 1 values are similar or slightly reduced compared with adult concentrations.The delicate hemostatic balance in the neonatal period prevents spontaneous hemorrhage or TE in the healthy term infant, but it is disturbed easily in sick or preterm newborns, making such neonates vulnerable to both hemorrhage and TE and making therapy extremely challenging.The role of congenital prothrombotic disorders in neonatal TE is being increasingly recognized. Deficiencies in protein C, protein S, and AT and the presence of prothrombin gene 20210A and factor V Leiden mutation have been identified in neonatal TE. (1)(2)(7) Homozygous protein C and protein S deficiency present in the neonatal period with purpura fulminans. Heterozygous prothrombotic disorders have been detected in 6% to 20% of neonates who have TE, usually in the presence of other factors that predispose the infants to TE. (1)(2)The incidence of thromboembolic disease in the newborn is dependent on the zeal with which surveillance is conducted, the timing and frequency of monitoring, and the diagnostic method used. A German prospective nationwide 2-year registry of symptomatic TE (venous and arterial) in newborns reported an incidence of 0.51 per 10,000 births, with about 25% being arterial and 75% venous. (1) In the Netherlands, a similar prospective registry of venous TE estimated an annual incidence in newborns from 0 to 28 days of age to be 14.5 per 100,000 infants. Neonatal venous TE was almost exclusively catheter-related and asymptomatic. (2) In 32 of 37 neonates who had catheter-related thrombosis, no signs or symptoms were present. Thrombosis was diagnosed by echocardiography prior to removal of a central venous line or discovered coincidentally during investigations for other reasons, such as cardiac evaluation.A much higher incidence of TE is reported in studies involving active surveillance for thrombosis in infants who have indwelling catheters. One set of investigators detected asymptomatic thrombi in 14 of 47 newborns who had indwelling umbilical venous catheters by contrast venography. (8) Other researchers found clinically silent portal venous thrombosis in 43 of 100 neonates who had serial ultrasonography, with complete or partial resolution in 20 of 36 babies who were followed up for 2 to 73 days. (9) The resolution of thrombi with time may explain the much lower incidence of portal venous thrombosis described by Schwartz and associates, (10) who detected portal venous thrombosis by color Doppler ultrasonography in only 1 of 100 neonates in whom umbilical venous catheterization was attempted.Vascular spasm probably is diagnosed best retrospectively, after confirmation of the transient nature of ischemic changes and complete recovery of circulation, usually within minutes to a few hours. The clinical signs associated with arterial or venous TE are shown in Table 1. Clinical signs may be subtle or absent in many cases. Persistent bacteremia or thrombocytopenia may be associated with vascular thrombosis at any site.Few studies have compared diagnostic tests in neonatal vascular TE. Contrast angiography is the recommended “gold standard,” but it is difficult to perform in sick neonates. (11) Doppler ultrasonography is readily available, noninvasive, and may be repeated to monitor progress over time, but the sensitivity and specificity of this method remains uncertain. For neonates who have umbilical arterial and venous catheters, Doppler ultrasonography has been found to give both false-positive and false-negative results compared with contrast angiography. (8)(12)A detailed family history should be obtained in all cases of unusual or extensive TE. In the absence of predisposing risk factors for thrombosis or TE in multiple or unusual sites, investigations to rule out a thrombophilic disorder may be required. (13)(14) Although heterozygous prothrombotic disorders have been identified in neonates who have TE, it is not clear if all affected infants should be investigated for congenital prothrombotic disorders, particularly in the presence of other risk factors that predispose to thrombosis. It is difficult to diagnose heterozygous congenital prothrombotic disorders in neonates because physiologic values of anticoagulant proteins are decreased compared with adults and may be reduced further in disease states. Prothrombotic disorders may be diagnosed only if protein-based assay results (such as protein C activity, free protein S antigen, and AT) are outside the limits of age-dependent normal reference ranges during the acute stage as well as on a confirmatory test performed 3 to 6 months after the acute thrombotic episode. (4)(15) Screening for genetic mutations and polymorphisms associated with congenital thrombophilia, such as factor V G1691A, prothrombin G20210A, and MTHFR C677T, may be performed at any time after the thrombotic event. Table 2 lists the tests that may be considered in neonates being investigated for possible thrombophilia.When blanching or cyanosis of extremities occurs following insertion or manipulation of peripheral or umbilical arterial lines, the first step is to determine if the arterial catheter is absolutely essential for care or if it may be removed. In the case of umbilical arterial catheters, vasospasm occasionally may be corrected by reflex vasodilatation through warming the contralateral leg. Tissue ischemia may persist even after umbilical and peripheral arterial catheters are removed, either because of persistent vasospasm or because of small clots in the distal end arteries. Use of anticoagulants or thrombolytics is not recommended in these situations. Nevertheless, diagnostic testing for vascular thrombosis should be initiated if signs of tissue ischemia persist despite catheter removal, contralateral warming, and volume expansion.Topical nitroglycerin has been demonstrated to reverse peripheral and umbilical artery catheter-induced ischemic injury in isolated case reports (Table 3). (16)(17)(18)(19) Nitroglycerin is a potent vasodilator that is postulated to work by intracellular bioconversion to nitric oxide, which relaxes smooth muscle directly, or indirectly by the activation of the intracellular enzyme soluble guanylyl cyclase. (20) Nitroglycerin is well absorbed across intact skin. The 4-mm/kg dose of 2% nitroglycerin ointment used in the neonatal case reports is calculated to be equivalent to 0.2 to 0.5 mcg/kg per minute administered intravenously. In adults, the onset of action is within 1 hour, and the hemodynamic effect may last up to 6 hours. The pharmacokinetics of nitroglycerin have not been studied in neonates. Vasodilatation may lead to hypotension, and transient decreases in blood pressure were noted in two of the case reports.The management of TE in neonates is controversial. In the absence of adequate controlled trials, recommendations for anticoagulation therapy in neonates largely are extrapolated from recommendations for older children and adults or based on observational studies in neonates. Recognizing the paucity of information in the management of children who have thromboembolic disease, the International Children’s Thrombophilia Network was established in Canada to develop international collaborative research, education, and clinical services. A free consultative service, maintained 24 h/d for physicians caring for children who have thromboembolic disease, provides current management protocols and links to the network and its services. The toll-free number in the United States is 1-800-NO-CLOTS.Infants who have thromboembolic disease should be managed in a suitably staffed and equipped neonatal center, where anticoagulant or thrombolytic therapy may be administered and monitored appropriately and where laboratory, blood bank, and surgical support is readily available. Consultation with a pediatric hematologist and vascular/plastic surgeon is expedient.Treatment options anticoagulant therapy with or heparin or heparin thrombolytic and such as are not used in neonates because of in The risk of serious associated with antithrombotic therapy in neonates be the of or limb or even of of thrombosis the of required. For in thrombosis or into the inferior vena care with for may be anticoagulation therapy with or may be with or is recommended for thrombosis that into the inferior vena or in thrombosis. therapy should be considered for thrombosis and care with to resolution of the thrombus may be in asymptomatic catheter-related venous TE, with the of anticoagulation therapy if the thrombus shows signs of all who have TE, of volume and thrombocytopenia and of is The removal of catheters associated with TE is catheters occasionally are in when through the catheter is be after possible to within the last days and of or are to the risk of concentration coagulation and are relative may be initiated these conditions are or and catheterization should be in neonates anticoagulant or thrombolytic and other are neonates are at increased risk for ultrasonography at is recommended during is a that decreases the plasma concentration of factors and is no information on the of in neonates, because its is with of therapy in pediatric that infants 1 and 1 of age were the difficult to on compared with other age increased a with of time to international more and more dose and had values in the and more values the neonates are to because of low levels of in infants are to because is with to disease of the is in a and its and when in for to neonates is therapy in changes in other and have a potential on its anticoagulant its is not recommended in neonates. heparin or the ability of AT to coagulation particularly studies in children have shown that the dose of to a activated partial time is in neonates and children compared with adults, the in neonates remains uncertain. A for heparin and for pediatric a dose of over minutes followed by a dose of 28 per for infants 1 of with in the heparin infusion rate to at to to an of to for of should be obtained after of the heparin dose and after in infusion and complete blood may be monitored a when values are The of anticoagulation with heparin is but therapy usually is for to 14 with of the thrombus both during and following of heparin therapy and with The incidence of with heparin therapy in children is reported to be to but the risk of may be higher in anticoagulation with heparin to be because of the heparin infusion usually because of its may be used to heparin The dose of to heparin is based on the of heparin in the 2 with 1 per 100 of heparin if the last heparin dose was administered minutes and per 100 heparin if the last heparin dose was administered as as minutes an by persistent thrombocytopenia and thrombosis due to platelet is difficult to diagnose in neonates in care when thrombocytopenia and thrombosis the of heparin or when these conditions are due to other The incidence of this in neonates from to in the thrombocytopenia is by of all heparin therapy and by the of such as or platelet has not been studied in are from by or to produce that have of approximately in their and in to in have a activity in factor with activity therapy is monitored by an not by the of are by binding to AT and AT of serine of over and potentially the for In adults, is associated with a lower incidence of thrombocytopenia and and a decreased frequency of recommended dose of in infants 2 months of age is with the of levels of 0.5 to in a blood to 6 following for based on levels are in Table The dose of to levels is higher in the dose of is compared with of about a for older a prospective of infants 2 months of age who were with preterm infants a higher dose term infants to the concentration in the who had congenital heart disease a lower dose of compared with infants who not have congenital heart disease The of the of therapy in neonates. In contrast with adults and older children, the dose of to levels had to be because of the rate of and in the neonates. of all values were the 2% were the in infants who had infants and serious in infants, hemorrhage in was not to concentrations being the and of TE in newborns, a who from thrombotic of the despite an concentration within the were noted in of in preterm infants who had venous or arterial thrombosis. The dose of to concentrations was per to per and 14 to days were to this concentrations were in only clot resolution was in of the had a history of prior to who had a but to be no of the hemorrhage during with with had to be for 36 in who is from these studies that decreased for is as an of in is at ranges are and remain of has been by the of a catheter which the number of from to Although used in many infants, at the that has been reported in infants. anticoagulation with be for any of the usually is At two of should be and if prior to the of and other the activity only but has been shown to reverse due to in The recommended dose of is 1 for 100 of within hours. therapy should be considered in the presence of extensive thrombosis when or limb is in (13)(14) by converting plasminogen to plasmin, in cleaves and fibrin to fibrin degradation products. The of thrombolytic may be in neonates because of their low plasminogen and with plasminogen may be to the of the agents. and thrombolytic used in the largely have been by tissue type plasminogen activator no has been noted in the rate of the thrombolytic are no their and in neonates. a protein from C is a plasminogen It has been associated with and in adults and older children, and is information on its in neonates. The dose is followed by dose of per for 6 to prothrombin time, thrombin time, and values. The dose is not clot of umbilical artery thrombi has been demonstrated at an of days in neonates with an infusion of of with in A smaller dose of per administered directly into the clot was in preterm infants who had thrombosis to indwelling umbilical artery catheters. from of from neonates, has not been in the United States when the United States and a about that had the potential risk for of agents. is recommended for in the United A dose of followed by dose of per for 6 to usually is with similar to that for (13)(14) as as 10,000 per have been administered clot from to per was in thrombi in extremely preterm infants who had to fibrinolytic of neonates who had catheter-related central venous thrombosis a rate of only 50% with of at a dose of per has several over and particularly for sick for fibrin should fibrinolytic activity to the of thrombosis, and it has a if number of case reports the of for the of neonatal thrombosis, but only or two have been in by and Table case in the last 6 for the of with from to and infusion from to 0.5 per The of heparin also the of complete of the clot was noted in of the and partial in to dose and of up to hours. has been for days at a dose of per in a who had vascular of both lower in complete recovery of to both and no or other The dose of remains recommendations of to 0.5 per were by the and a of in children was initiated to per the neonates with per in per in dose to to per Although was in preterm neonate, was increased to per because of clot a response during therapy studies to to of thrombolytic as as clot is Thrombin time, and plasminogen and fibrin products or should be prior to 3 to after of fibrinolytic and to (11) Neonatal fibrinolytic response is by a in concentration and in concentrations of fibrin degradation products. Although the fibrin degradation and concentrations can is no and no hemostatic and of thrombolytic levels should be maintained at a of 100 to of plasminogen with plasma may be to is a of thrombolytic even with therapy where is to at the thrombus in of children with with the of fibrinolytic therapy in newborns, has been described in at neonates with A of and the incidence of hemorrhage in children who had thromboembolic disease and fibrinolytic therapy with a of thrombolytic agents. The incidence of hemorrhage was 1 in term neonates compared with 2 in children after the neonatal In preterm neonates, the incidence of hemorrhage was in with of preterm neonates in the first hemorrhage not be to fibrinolytic therapy because preterm infants are to have a incidence of occasionally is for or A of are available, venous with the of and for is in neonatal care to to in central catheters to and TE. A of controlled that of the in a concentration of to in umbilical arterial catheters catheter and decreased the incidence of to be due to TE. The frequency of thrombosis not to be but because only a small number of were for this up to a 50% in thrombosis have been of peripheral arterial catheters is by infusion of The of in central venous catheters has not been in controlled in neonates, it is in and is by studies in infusion of has been associated with an increased risk of hemorrhage in newborns in but by anticoagulation with has been in central venous thrombosis in adult The the first at the only controlled of for the of central venous thrombotic complications in children, was early because of of In the was to infants 3 months of making the to in the incidence of thrombosis was noted when central venous catheters were used in children, but a controlled of umbilical artery catheters compared with catheters not a in clinical complications or of acute complications of central arterial and venous catheters, catheter-related of venous and for repeated of in infants are well The risk of pulmonary in neonates probably is because the symptoms of this may not be easily from other of in neonates. The of umbilical venous catheter-related TE portal and and thrombosis may lead to of a and the risk of and of TE following neonatal thrombosis is are no recommendations for in such infants. artery catheter-related TE has been to in and in and after resolution of the thrombosis. for further to for the and of TE in the was recognized more Although has been a the to therapy is based on studies or case Deficiencies remain in diagnostic and anticoagulants that in the coagulation and have pharmacokinetics and are in clinical in adults and may have an on the and of TE in neonates in the particularly if they are shown to have and