REVIEW

http://dx.doi.org/10.5546/aap.2016.eng.159

Thrombosis in newborn infants

 

Viviana Bacciedoni, M.D.^ab, Myriam Attie, M.D.^c, and Hugo Donato, M.D.^d' National Committee of Hematology, Oncology and Transfusion Medicine

a Hospital Pediátrico A. Fleming, Department of Hematology.
b. Hospital L. Lagomaggiore, Neonatal Hematology City of Mendoza, Mendoza.
c. Hospital de Niños Ricardo Gutiérrez, Department of Hematology.
d. Pediatric Hematology Outpatient Offices. City of Buenos Aires.
e. Hospital del Niño de San Justo, Division of Hematology and Oncology, San Justo, Buenos Aires.

E-mail address: Hugo Donato, M.D.: hcdonato@gmail.com

Funding: None.

Conflict of interest: None

Received: 7-28-2015
Accepted: 8-6-2015

 

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ABSTRACT

The incidence of thrombosis is higher among newborn infants than in any other stage of pediatric development. This fact is the consequence of labile characteristics of the neonatal hemostatic system, in addition to exposure to multiple risk factors and the wide use of vascular catheters. Venous thromboses, which mainly affect the limbs, the right atrium and renal veins, are more frequently seen than arterial thromboses. A stroke may be caused by the occlusion of the arterial flow entering the brain or by occlusion of its venous drainage system. Purpura fulminans is a very severe condition that should be treated as a medical emergency, and is secondary to severe protein C deficiency or, less frequently, protein S or antithrombin deficiency. Most thrombotic events should be managed with antithrombotic therapy, which is done with unfractionated and/or low molecular weight heparins. Purpura fulminans requires protein C replacement and/or fresh frozen plasma infusion. Thrombolytic therapy is done using tissue plasminogen activator and should only be used for life-, or limb-, or organ-threatening thrombosis.

Key words: Thrombosis; Newborn infant; Heparin; Anticoagulants; Thrombolytic therapy.

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INTRODUCTION

During the first month of life, the likelihood of thrombotic complications is 40 times higher than at any other pediatric age, especially in critically-ill children or those who have a central catheter in place. Catheterization is undoubtedly the most important risk factor for both arterial and venous thromboembolism. Approximately 90% of thromboembolic events are catheter-related.^1,2 The presence of a catheter favors the occurrence of thrombosis by different mechanisms, either isolated or combined. Catheters may cause mechanical damage to the vascular wall and slowing or interruption of the blood flow, they are manufactured with potentially-thrombogenic material, or they are used to infuse agents that damage the vascular wall.³ Other predisposing factors include perinatal asphyxia, prematurity, heart conditions, sepsis, hypoxia, and maternal diabetes. Congenital prothrombotic disorders play an irrelevant role in this period.⁴

The overall incidence of thromboembolism in hospitalized newborn infants is approximately 2.4 per 1000 admissions.^2,5 It has been reported that 1% of newborn infants with catheters have symptoms indicative of thrombosis,⁶ and it is estimated that the incidence of catheter-associated asymptomatic thrombosis is 20-30%.^7-11

An adequate management of thrombosis is generally complicated due to the extrapolation of adult management techniques. However, over the past years, major differences related to age have been observed in this condition (epidemiology, diagnostic tests, pharmacokinetics of antithrombotic agents), which have favored the use of diagnostic and therapeutic procedures appropriate for this period in life.

FEATURES OF THE HEMOSTATIC SYSTEM IN NEWBORN INFANTS

The hemostatic system of newborn infants has a series of special characteristics different from that of adults, which make it especially labile.¹² A reduced synthesis of several coagulation proteins (factors II, VII, IX, X, XI and XII, high molecular weight kininagen, antithrombin III, proteins S and C), an altered function of other coagulation proteins (fibrinogen, plasminogen), an accelerated clearance of factors, and differences in platelet functioning are some of the specific differences between the hemostatic system of adults and newborn infants. In addition, both

stimuli occurred during childbirth (acidosis, hypoxia, thermal changes, release of tissue factor) and a frequent exposure to trauma and manipulation result in a coagulation mechanism that is more active than that of adults. Although components of the hemostatic system start synthesizing during the tenth week of gestation and increase gradually, values reached at birth are remarkably different among them (Table 1).^9,13-17

Table 1. Normal average values of procoagulant, inhibitory and fibrinolytic factors at 24 hours of life and approximate time needed to reach normal values

Below we present the most important information regarding coagulation factors in newborn infants:^7,16,18-24

• Vitamin K-dependent factors (II, VII, IX, X) and contact factors (XII, XI, prekallikrein and high molecular weight kininagen) are reduced to varying degrees.
• Fibrinogen and factors V, VIII and XIII levels are similar to those of adults.
• Von Willebrand factor level is almost twice that of adults.

The time necessary for reduced factors to reach normal values is variable and may range from a few days to several months.^{14-16,19,25,26} Most factors reach 80% of the value of adults by six months old.

In addition, fibrinogen is quantitatively normal, but has qualitative differences because it has a higher sialic acid content and a shorter half life.^27-30

In spite of these alterations, newborn infants maintain a hemostatic balance because natural inhibitors are also different from those of adults:^{13-15,19,25,26,31-35}

• Antithrombin is reduced by 50%, and proteins C and S, by 60%.
• Protein S circulates absolutely freely (active form) because newborn infants lack C4b, a binding protein of protein S.
• Alpha-2-macroglobulin is high, approximately twice the level of adults.

Fibrinolytic activity is also altered, with plasminogen levels reduced by 50%.

Many of the above mentioned differences in the hemostatic system are even sharper among preterm infants.

CLINICAL PRESENTATIONS

Venous thrombosis

Deep vein thrombosis

This is a common condition in patients hospitalized in the Critical Care Unit; its incidence has been reported to be 2-22%. Superior vena caval thrombosis may be asymptomatic or accompanied by edema in the neck, face and/or upper chest, collateral circulation and, eventually, acute heart failure.³⁶ Limb thrombosis may appear as a change in skin color, swelling, edema, pain, elevated temperature and cyanosis. In the case of upper limb involvement, superior vena cava syndrome may also develop.^{18,19,26,37,38}

Post-thrombotic syndrome is a long-term complication that may develop as a result of neonatal thrombosis, as of one month after the event and up to 10 years later. It is characterized by chronic edema in the limbs together with skin discoloration, impaired wound healing, skin ulcers and, commonly, functional incapacity. It is the result of extravasation of RBCs and inflammatory mediators following damage to venous valves caused by the thrombus.³⁹

Renal vein thrombosis

It accounts for 10% of venous thrombosis cases in the neonatal period.^1,40 It is the most common type of thrombosis not related to a central venous catheter. Its clinical presentation starts as a palpable mass in the flank, hematuria, proteinuria, thrombocytopenia, renal failure and/ or arterial hypertension.^1,35 The classical triad of symptoms -palpable mass, hematuria and renal failure- is seen only in 13% of patients.⁴¹ If thrombosis reaches the vena cava (approximately in 50% of cases), it may also be accompanied by edema, hypothermia and lower limb cyanosis.^41-45 Approximately 25% of cases are bilateral.^5,46

Renal vein thrombosis occurs in the first month of life, generally, in the first three days of life (67% of cases), but it may also develop in utero ^{1,13,25,32-35,42,43,47,48}

Risk factors associated with this condition include asphyxia, dehydration, acidosis, arterial hypotension, polycythemia, and maternal diabetes.

Diagnosis is made by Doppler ultrasound, which shows a loss of renal corticomedullary differentiation or, preferably, a color Doppler ultrasound, which allows to observe absence of flow in the involved vein.^35,49-51

Anticoagulant therapy with unfractionated or low molecular weight heparin has improved survival remarkably, which at present is approximately 85%,^1,40 and prevents renal atrophy in two thirds of patients.⁴¹

Right atrial thrombosis

It accounts for approximately 6% of neonatal thromboses. A central venous catheter is present in almost all cases.⁵² Its clinical presentation is variable and includes signs of right-sided heart failure, persistent sepsis, sudden manifestation of murmur, bradycardia, tachyarrhythmia or respiratory distress.^1,20 The diagnostic method of choice is transthoracic echocardiogram.

Its most serious complications are pulmonary thromboembolism, which becomes apparent due to acute respiratory distress, and stroke.

Arterial thromboses

Arterial thromboses are, in general, iatrogenic complications of umbilical, peripheral or femoral artery catheterization. Its actual incidence in newborn infants is unknown and varies depending on the method used for assessment: 1-3% based on clinical signs, 14-35% based on ultrasonography, and 64% based on angiography.^1,53-56

Symptoms depend on thrombus location and size, and may go from no symptoms at all (malfunctioning catheter) to limb-threatening massive ischemia, arterial hypertension with or without renal failure (renal artery occlusion), necrotizing enterocolitis (mesenteric artery occlusion) or even stroke (due to patent foramen ovale).^1,57,58

The study of choice for this condition in older children and adults is an angiography, but it is not routinely used in newborn infants due to its risks. For this reason, a Doppler ultrasound is generally used to confirm diagnosis, although its actual specificity has not been validated and, in some cases, it may show false negative results.^1,2,4,28

Its management is a difficult issue. Catheter removal is mandatory, except in isolated exceptional cases. The risk/benefit ratio of using anticoagulant and thrombolytic agents has not been clearly defined, so every case should be assessed individually.¹ In general, non-occlusive thrombosis may resolve by removing the catheter and with no anticoagulant therapy; however, in the case of significant occlusion, the initial treatment is heparin.⁴ In some specific life-, organ, or limb-threatening circumstances, thrombolytic therapy should be attempted.¹

Stroke

A stroke may be caused by the occlusion of the arterial flow entering the brain or by the occlusion of its venous drainage system -venous sinus thrombosis (VST)-. It typically presents with seizures or lethargy. Focal signs are uncommon, and hemiparesis occurs in less than 25% of children with ischemic stroke and in less than 10% of VST cases.^4,40,59-64A tense anterior fontanelle, diastasis of the cranial sutures and engorged scalp veins in cases of VST have also been observed.^40,60,62,65

Ischemic stroke diagnosis is confirmed by angiography or angio-MRI.^40,66 For VST diagnosis, an MRI is the study of choice, but highly satisfactory results have also been observed with transfontanellar Doppler ultrasound and conventional ultrasound.^67-70

Survival with no neurological sequelae is approximately 33-50%.^40,60,71,72

Anticoagulant therapy is not recommended for stroke, unless it is a cardioembolic stroke, in which case heparin should be used.^40,73 For VST with no extensive ischemic areas or intracerebral hemorrhage, heparinization is recommended. In the case of extensive ischemic areas or intracerebral hemorrhage, brain monitoring is necessary, together with anticoagulation if the thrombus increases in size.^40,73

Purpura fulminans

This is a very severe condition that should be managed as a medical emergency. It occurs in children with severe protein C deficiency or, less frequently, protein S or antithrombin deficiency.^74-76 Lesions appear in the capillary vessels of the skin, brain and kidneys because protein C works mainly in microcirculation.

Its clinical presentation is characteristic.^40,74,75'^77-81 Children with this condition usually have brain and/or ophthalmic damage secondary to intrauterine thrombosis and, in the first hours of life, evidence the complete clinical picture in a catastrophic manner. Skin lesions start as small ecchymoses that gradually extend following a radial pattern, with reddish/blackish color, that turn into bullae and finally become necrotic and gangrenous. Lesions are mainly located in the limbs, but may appear in any other site. The presence of other hemorrhagic manifestations secondary to disseminated intravascular coagulation is practically continuous. Sometimes, large vessel thrombosis may occur.

A definitive diagnosis is based on low or undetectable levels of protein S or C, a high suspicion when facing this clinical presentation, and recognition of a heterozygote status in both parents.^40,81,82

This condition improves with the administration of protein C (60 IU/kg every 6-8 hours, with a subsequent customized dose adjustment) or, if this approach fails, fresh frozen plasma (10-20 mL/kg every 8-12 hours). For protein S deficiency, replacement therapy is done using fresh frozen plasma.^79,83 Treatment is administered until lesions resolve completely, which usually occurs in 6-8 weeks.⁴⁰ Long-term treatment should include oral anticoagulation (maintaining an international normalized ratio [INR] between 2.5 and 4.5) or with low molecular weight heparin (LMWH), together with protein C (or S) replacement, depending on the patient's symptoms.^40,80 The option for a definitive cure is liver transplant.^40,75

TREATMENT

General management of thromboses

Asymptomatic thrombosis is managed with supportive care and clot size monitoring. If a central venous catheter is associated with a thrombus, it should be removed. If the thrombus advances, an anticoagulant therapy is required.⁷³ Symptomatic thrombosis should be managed with anticoagulant therapy and/or, rarely, thrombolytic agents. If central or umbilical venous catheters are associated with the thrombus, they should be removed, if possible, after three to five days of anticoagulant therapy.^73,84When peripheral arterial catheters are associated with thrombosis, they should be removed immediately.⁷³Surgical thrombectomy is rarely indicated in newborn infants because of their small vessels and clinical instability.⁸⁵

Anticoagulant therapy

Not enough randomized controlled trials have been conducted on anticoagulation in children, so therapeutic schemes used in these patients are based on studies conducted in a small number of cases and guidelines that were adapted from adult treatments. At present, the most commonly used recommendations are evidence-based recommendations provided by experts, considering that most pieces of evidence are grade 2C.^26,73,86

Newborn infants pose two additional hurdles. On one side, it is hard to find an adequate venous access to collect the samples necessary for treatment monitoring. On the other side, the milk fed to these newborn infants contains different levels of vitamin K, a complication for oral anticoagulant use.

The most commonly used drugs are unfractionated heparin and LMWH. In general, thrombolytic agents are not recommended, except in life-threatening conditions. New anticoagulant agents are under investigation and cannot be recommended for use in newborn infants.

The optimal duration of treatment has not been clearly established but, in general, it should last between six weeks and three months, depending on the clinical condition.^73,87

Before starting antithrombotic therapy, prothrombin time, activated partial thromboplastin time (aPTT), platelet and fibrinogen levels should be checked. During anticoagulant therapy, platelet count should be maintained above 50 x 10⁹/L, while fibrinogen should be over 100 mg/dl. It is also advisable to do a head ultrasound before treatment, especially in preterm infants.

Unfractionated heparin

Unfractionated heparin enhances antithrombin activity, thereby inactivating thrombin and activated factor X (aFX). In order to work, an adequate amount of antithrombin is required. Taking into account that, at birth, the level of antithrombin and the ability to generate thrombin are physiologically reduced (even more in preterm infants), sometimes it is necessary to administer antithrombin to reach an adequate anticoagulant response.^88,89

The initial bolus dose is 75 IU/kg (10 minutes), followed by a maintenance dose of 28 IU/kg/ hour. The objective is to achieve an anti-aFX level of 0.3-0.7 IU/mL four hours after administration, and an aPTT activity of 1.5-2 times the normal value.^88,90 Once an adequate therapeutic range has been achieved, aPTT and platelet count should be controlled every 24 hours.

The most common secondary effects include bleeding due to an excessive dose and heparin-induced thrombocytopenia. If bleeding occurs, discontinue the drug and, if necessary, administer protamine sulfate (1 mg of protamine per 100 IU of heparin, intravenous infusion over 10 minutes).

The main advantages of unfractionated heparin are its low cost and the fast reversibility of its effect, if necessary, because its half life is one hour.

Low molecular weight heparin

The advantages of LMWH over unfractionated heparin include subcutaneous administration, a dose administered every 12-24 hours, minimum monitoring requirements, a more predictable response, and a lower risk of bleeding and heparin-induced thrombocytopenia.⁴

The most commonly LMWH used in newborn infants is enoxaparin. For thrombosis management, a 1.5 mg/kg subcutaneous dose every 12 hours is recommended;⁷³ however, at present, evidence indicates that the dose required to reach an adequate therapeutic range is approximately 1.7 mg/kg in term infants and 2 mg/kg in preterm infants.⁹¹ The goal is to achieve an anti-aFX level of 0.5-1 IU/ml. For prophylaxis purposes, a half of the therapeutic dose is recommended to reach an anti-aFX level of 0.1-0.3 IU/ml.

Oral anticoagulants

The most commonly used oral anticoagulants are vitamin K antagonists, which act by reducing functional activity of vitamin K-dependent coagulation factors (II, VII, IX and X). Considering that these factors are physiologically reduced in newborn infants, using these drugs in infants is problematic, especially given the great variability of vitamin K in milk, which in turn conditions treatment response: while infant formulas contain vitamin K supplements to prevent vitamin K deficiency bleeding, which renders formula-fed infants to be relatively resistant to this medication, breast milk contains a very low level of vitamin K, making these infants very sensitive to treatment.^1,73,92 In addition, this treatment requires frequent monitoring, making it difficult to find adequate venous accesses for sample collection.¹

Therefore, based on the available evidence, vitamin K antagonists should be avoided in newborn infants as far as possible.¹ However, in order to make a decision, it should be considered that maintaining anticoagulation with LMWH for several weeks is an invasive procedure, which sometimes leads to an inadequate treatment adherence. Considering every precaution and with controls done as often as necessary based on the patient's characteristics, oral anticoagulation may be indicated for long-term management. During treatment, special attention should be paid to variations in the type or amount of feeding, infectious complications (especially gastrointestinal complications), and antibiotic therapy.³ Among exclusively breastfed infants, the low intake of vitamin K provided by breast milk may be compensated by the administration of prophylactic doses of vitamin K or small amounts of formula administered on a daily basis.^1,73

Warfarin or acenocumarol may be used. The recommended initial dose is 0.2 mg/kg/day to reach an INR between 2 and 3,⁴⁰ although it has been observed that the average useful dose for infants is approximately 0.33 mg/kg/day.⁹³ If bleeding is caused by an excessive dose, vitamin K may be administered to neutralize the effect.⁴⁰

An indication of alternative oral anticoagulants, such as argatroban, bivalirudin or fondaparinux, has not yet been established in newborn infants.⁹⁴

Thrombolytic therapy

Thrombolytic agents generally act by converting plasminogen into plasmin, which acts on fibrin by breaking it down and contributing to thrombus lysis. Since thrombolytic activity may be reduced in these patients due to a decreased plasminogen level, the therapeutic effect of these agents may be limited. Plasminogen supplementation with the administration of fresh frozen plasma may improve fibrinolytic activity.

Considering the high risk of bleeding associated with this treatment, it should be reserved only to infants whose thrombosis is life-, organ-, or limb-threatening.^1,95,96 It is contraindicated in the following situations: active bleeding, major surgery or bleeding in the previous 10 days, neurosurgery in the previous 3 weeks, severe asphyxia in the previous 7 days, invasive procedure in the previous 3 days, seizures in the past 48 hours, gestational age younger than 32 weeks.⁹⁷

The drug of choice is tissue plasminogen activator (TPA). It is administered in a continuous infusion at a dose of 0.1-0.6 mg/kg/hour over 6 hours using a central or peripheral line.⁷³ No specific lab tests are available to define its therapeutic range or monitoring. A strict clinical, lab and radiological supervision is required. An increase in prothrombin time, aPTT, fibrin degradation products (FDPs) or D-dimer, and a reduction in fibrinogen evidence a response to thrombolytic therapy. It is recommended to maintain fibrinogen values above 100 mg/dL. If bleeding occurs, it is recommended to administer cryoprecipitates (5-10 mL/kg) or fibrinogen and, in life-hreatening situations, intravenous antifibrinolytics should be added.

Mortality is not clearly defined and varies between 1.2% and 13% of patients receiving TPA.^98,99 Treatment effectiveness with complete clot resolution ranges between 65% and 94%.^100-102

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