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Venous thromboembolism in children and adolescents
(Portuguese PDF version)

Francisco H. de A. Maffei¹, Winston B. Yoshida², Sidnei Lastória²

1. Professor, Department of Surgery and Orthopedics, School of Medicine of Botucatu (UNESP).
2. Associate Professor, Department of Surgery and Orthopedics, School of Medicine of Botucatu (UNESP).

Correspondence:
Francisco Humberto de Abreu Maffei
Caixa Postal 590 - Rubião Jr
CEP 18618-970 - Botucatu-SP
E-mail: fmaffei@fmb.unesp.br

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ABSTRACT

Venous thromboembolism (VTE) is a rare illness in childhood, with an estimated prevalence of 0.07 cases per 10,000 children in Canada. The frequency of VTE increases in adolescence, mainly in females, with either the use of oral contraceptives or during pregnancy and puerperium. VTE diagnostic approach is similar for children and adults. Ultrasonography is the exam of choice, and venography is indicated in case of doubt. The anticoagulant therapy is the preferable treatment and dosages must be adjusted according to age, weight and laboratory tests. Nomograms are helpful for heparin, low molecular weight heparin and warfarin dosage adjustments. Reports of fibrinolytic treatment, thrombectomy or vena cava filters are uncommon. This review focuses on the specific characteristics of diagnosis, treatment, follow-up and prophylaxis of VTE in children and adolescents, and the associated morbidity and mortality, which are important aspects to guide general practitioners and specialists regarding the management of VTE in this particular age group.

Key words: aneurysm, aorta, cardiovascular diseases
Palavras-chave: trombose de veia profunda, embolia pulmonar, criança, adolescente.

J Vasc Br 2002;1(2):121-8.

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INTRODUCTION

Venous thromboembolism (VTE), either spontaneous or triggered off by risk factors in adults, is rare among children, even in those with hereditary thrombophilia.¹ The Canadian Registry of VTE, including 15 tertiary pediatric centers, shows a prevalence of 5.3 cases per 10,000 hospital admissions and an incidence of 0.07 cases per 10,000 children in Canada. Among 137 children, 115 were diagnosed with deep vein thrombosis (DVT), eight presented pulmonary embolism (PE) with undocumented DVT, and 14 had DVT with PE.² The frequency of VTE according to surveys conducted in Germany and Canada is 0.24 to 0.26 cases per 10,000 live births.^1-4 After lower extremity or vertebral column surgeries, the incidence was less than 1%.⁵ Among VTE cases, only 1% in newborns and 5% in children are idiopathic; most cases are secondary to premature birth, cancer, surgeries, traumas, congenital heart diseases, and lupus erythematosus.¹,⁶ Some studies have shown genetic thrombophilia in most children with DVT and PE.⁷,⁸

We have no information about the frequency of VTE in Brazilian children. In our hospital, an incidence of 5% of PE was observed in autopsied children.⁹ Between 1971 and 1998, 33 children diagnosed with DVT of lower extremities were treated in our hospital.¹⁰

Both DVT and PE are more frequent among adolescents, especially among female adolescents. In this case, they are often caused by the use of oral contraceptives, pregnancy or puerperium.¹¹

The low incidence of VTE in children has been ascribed to low production of thrombin by the child,¹²,¹³ presence of circulating anticoagulants¹⁴,¹⁵ and to an increase in the antithrombotic potential by the vascular endothelium.¹⁶

In addition, the frequency of PE and DVT in upper extremities is not negligible. In this case, PE and DVT are caused by the insertion of catheters for parenteral nutrition or for anticancer therapy. This accounts for 50% of VTE cases in children and 80% of VTE cases in newborns.¹,^17-19 Just like in adults, the frequency of VTE in children depends, in these cases, on the diagnostic method used, ranging from 1% in clinical diagnosis to 75% in routine venography.¹⁸ The incidence of DVT, detected by venography, in children with acute lymphoblastic leukemia treated with L-asparaginase was 37%.²⁰ VTE resulting from catheter-related complications has remarkable morbidity and mortality rates: a prospective study of 244 with postcatheterization DVT has shown an incidence of 9.5% of postphlebitic syndrome and a mortality rate of 3.7%.¹⁹ A study with children on home anticancer therapy has shown a PE incidence of 35%, with a mortality rate of 12%.¹⁷

DIAGNOSIS

The first and foremost step in establishing the clinical diagnosis of DVT and PE, both in children and adults, is to remember that these diseases exist and can occur in these age groups, even at a lower frequency.

DVT should be suspected whenever a unilateral edema, accompanied or not by pain and visible collateral circulation, is present. In more rare cases of vena cava thrombosis, a bilateral edema with visible collateral circulation in the abdomen occurs. In some cases, especially in older children and adolescents, the first symptom is pain. This should not be overlooked by the physician.

PE symptoms are the same presented by adult patients: dyspnea, pleuritic pain, coughing, hemoptysis and cyanosis.¹ Bernstein et al. have found pleuritic pain as the most frequent symptom among adolescents.¹¹

Medical histories help with the diagnosis: recent history of trauma or surgery, neoplasia and, in female adolescents, use of oral contraceptives, pregnancy or puerperium. In newborns and children at any age, the presence of edema on a limb with intravenous catheter or development of local collateral circulation is a strong indicative sign of thrombosis of the catheterized vein. The family history of VTE, although infrequent, helps with the diagnosis.

When DVT is clinically suspected, diagnostic confirmation is important, given the inconvenience and risks of anticoagulant therapy. The diagnosis can be confirmed by duplex ultrasonography; in this case, an ultrasonographer with vast experience with venous diagnosis is required. In cases in which it is not possible to carry out ultrasonography or in which ultrasonographic results are not conclusive, venography should be performed. The diagnosis of PE is confirmed by ventilation-perfusion pulmonary scintigraphy, usually associated with the investigation for peripheral DVT by ultrasonography. In doubtful cases, with great clinical suspicion, pulmonary arteriography can be used.¹,²,¹¹

If thrombosis of a catheterized vein, without catheter obstruction, is suspected, the careful injection of a radiologic contrast medium through the catheter allows confirming thrombosis venographically and determining its extension. With regard to the diagnosis of DVT in upper extremities, ultrasonography seems to be less sensitive than venography. This procedure should be performed when ultrasonography shows normal or doubtful results.²¹

TREATMENT

Anticoagulant therapy

As VTE is quite rare in children, there are few studies on this topic and there exists no standardized procedure for its treatment. In general, the treatment of VTE, at our hospital and in the cases referred to in the literature, is based on that which is used for adult patients.¹ In most cases, except for children at a high risk for hemorrhage, the treatment initially consists of heparin or low molecular weight heparin (LMWH) and is maintained with antagonists of vitamin K (AVK). A small number of cases refererenced in the literature has been treated with fibrinolytic agents and, in more rare cases, thrombectomy or vena cava filter placement can be indicated.

Heparin treatment

The treatment always consists of an initial intravenous (IV) bolus of 75 to 80 IU/kg, maintained in the first six hours with 20 to 30 IU/kg/hour, IV. The dose is later adjusted in order to maintain the activated partial thromboplastin time (APTT) between 1.5 and 2.5 times the normal value. Some authors recommend standardizing ATTP in such a way that these values are equivalent to an anti-factor Xa (a-FXa) between 0.3 and 0.7.²² This exam should be repeated every six to 12 hours until the values become stable and every day thereafter. Along with heparin, warfarin therapy should be implemented one or two days later, maintained for five to 10 days and discontinued when prothrombin time (PT), expressed in international normalized ratio (INR), has reached a level of 2-3, for at least two days. For yet unclear reasons, younger children (aged less than two months or weighing less than five kilos) need slightly greater doses of heparin than older children.²²,²³ This should be considered before initiating the treatment.

Andrew et al.²³ have tested a protocol used with adults on children and have obtained good results. Table 1 shows this protocol, with some slight modifications. In the protocol, the bolus doses were increased with the aim of achieving anticoagulation levels more quickly.²² Quite recently, we have used this nomogram for children treated at our hospital and we obtained good results. In addition, the use of the nomogram facilitates the prescription of heparin therapy by resident doctors or doctors who are not so acquainted with anticoagulation control.

Table 1 - Protocol for administration of intravenous heparin in children

I - Bolus= 75 IU/kg in 10 minutes II - Initial maintenance dose: < 1 year: 28 IU/kg/h; > 1 year: 20 IU/kg/h III - APTT 1.5 - 2x
APPT	Bolus	Waiting time	% of change	Repeat APTT
< 1.5x	50	0	+ 10	4hrs
1.5 - 1.75	0	0	+ 10	4hrs
1.76 - 2.5	0	0	0	next day
2.6 - 3.0	0	0	-10	4hrs
3.1 - 4.0	0	30 min	-10	4hrs
> 4,0	0	60 min	-15	4hrs
IV - APTT 4hrs after bolus and 4hrs each time the dose was altered V - Daily APTT after stabilization
Adapted from Michelson et al.24

Hemorrhage is the major complication of heparin therapy; however, when heparin is carefully administered in children, greater risk of hemorrhage seems to decrease, showing a frequency between 0% and 2%.²²,²³ Heparin-induced thrombocytopenia (HIT) can be another complication. It has been described in some cases regarding the therapeutic and prophylactic use of heparin, but its frequency is not known.²² Therefore, platelet count is required every two days, when heparin is administered.²⁵ Osteoporosis can also develop in children, as occurs with adults, when heparin is used for a long time.²²

Low molecular weight heparin therapy

The higher bioavailability and hematological stability of LMWH, which permits subcutaneous administration with less frequent laboratory control, and the good results obtained for adult patients, has encouraged several health services, including ours, to use this type of heparin in the treatment of children with VTE. The doses are based on those used for adults. Also, in the case of LMWH, doses seem to be age-dependent; younger children need higher doses of LMWH.²²,²⁶ The LMWHs most widely used in children and most commonly referenced in the literature are enoxaparin and reviparin (of which, the latter is still unavailable in Brazil). There is only one study about the use of dalteparin in different types of thrombosis in children; however the results are good.²⁷ Very likely, other types of heparin may also be used in children; nonetheless, there is not enough information in the currently available literature about their use. The recommended initial doses of enoxaparin are shown in Table 2.

Table 2 - Doses of enoxaparin for children, given every 12 hours*

	< 2 months	> 2 months
Treatment	1.5 mg/kg	1.0 mg/kg
Prophylaxis	0.75 mg/kg	0.5 mg/kg
*Massicotte26

Several authors²²,²⁵,²⁸ have proposed the individual determination of LMWH doses for each child, by using the determination of a-FXa, which should be maintained between 0.5 and 1.0 U/ml, and measured by means of chromogenic substrate. The necessity of monitoring LMWH doses in children is justified by their growth and weight gain; thus, the doses should be recalculated so as to ensure optimal a-Fxa levels. Another reason would be severe disease, such as kidney failure and thrombocytopenia, which enhance the risk of hemorrhage. A nomogram for the control of the doses to be administered to each child has been proposed.²²,²⁸ (Table 3). Punzalan et al.²⁹ have attained therapeutic levels of LMWH in most children by using 1 mg/kg of enoxaparin every 12 hours, but they have recommended that the activity of plasmic a-FXa at the beginning of treatment be carefully monitored and that the dose be adjusted with the aim of attaining a therapeutic level, especially in newborns.

Table 3 - Nomogram for adjustment of LMWH dose in children*

Anti-factor Xa (U/ml)	Discontinue dose?	Change dose?	Repeat a-FXa
< 0.35	no	+ 25%	4hrs after dose
0.36 - 0.49	no	+ 10%	4hrs after dose
0.5 - 1.0	no	no	Next day, after 1 wk.-> month
1.1 - 1.5	no	- 20%	Before next dose
1.6 - 2.0	3hrs	- 30%	before next dose -> 4hrs afterwards
> 2.0	Up to a-FXa 0.50/ml	- 40%	Before next dose, if 0.5-1 U/ml, repeat 12hrs
*Massicotte et al.28

We used fixed doses of enoxaparin in the children treated at our hospital, since venous access was difficult to obtain. The results were apparently good and we could reduce the number of punctures and the treatment costs with laboratory control. The use of LMWH in children clearly shows the necessity for further studies in order to determine whether we should have laboratory control of all these children. Until we find more consistent data, we will continue to use this control in very young children, in cases with higher risks of hemorrhage or in those under prolonged LMWH therapy.³⁰ Complications such as thrombocytopenia and osteoporosis seem to be minimized by the use of LMWH comparatively to heparin therapy.²⁶

AVK therapy

Long-term AVK therapy usually follows the recommendations used for adult patients. Warfarin is the most widely used medication, whose experience in children has been largely gathered. Since newborns have deficiency of coagulation factors and vitamin K, which causes a delayed production of thrombin similarly to what occurs in adults after the ingestion of these anticoagulants, the prescription of AVK should be avoided in infants up to their first month of life, due to the high risk of bleeding. In these cases, the anticoagulant therapy must be maintained only with heparin. On the other hand, there exists a reverse, dose-dependent relationship with age after the first month of life, in which younger children need higher doses than older children and adolescents. The initial dose, also based on that of adults, is 0.1 - 0.15 mg/kg, and the INR is then maintained between 2 and 3 in most cases. In order to facilitate the control of AVK therapy, a nomogram was proposed for the correction of the initial dose and of the maintenance dose. This nomogram has proved very useful³¹,²⁴ (Table 4).

Table 4 - Protocol for the treatment of children with warfarin with the aim of maintaining INR between 2 and 3

I - Day 1= baseline INR 1.0 - 1.3: dose 0.2 mg/kg
II - Initial dose days 2 - 3
INR	Action
1.1 - 1.3	Repeat initial dose
1.4 - 1.9	50% initial dose
2.0 - 3.0	50% initial dose
3.1 - 3.5	25% initial dose
> 3.5	Discontinue up to INR < 3.5 -> 50% dose
III - Correction of maintenance dose according to INR
1.1 - 1.4	+ 20% of the dose
1.5 - 1.9	+ 10% of the dose
2.0 - 3.0	No alteration
3.1 - 3.5	- 10% of the dose
> 3.5	Discontinue up to INR < 3.5 restart with 20% lower
Michelson et al.24

The incidence of rethrombosis during the treatment is estimated at 1.3% of patients per year. The most common complication is hemorrhage, which has been estimated at approximately 20% in cases regarded as slightly hemorrhagic and 1.7% patients/year in severe cases.³¹ Other complications, described in children submitted to long-term anticoagulant therapy, albeit rare, include: hair loss, tracheal calcification and bone density disorders, whose clinical significance has not been clearly established so far. ²²,³²

The duration of anticoagulant therapy depends on the triggering mechanism, on the extension and persistence of risk factors. In catheter-related thrombosis, four to six weeks are probably sufficient; in cases triggered by surgeries or clinical diseases, the duration of treatment is three to six months, depending on the severity of the condition and on the presence of pulmonary embolism; in cases with no triggering mechanism and associated with PE, the treatment is maintained for six months; and in cases in which the triggering factor persists (i.e., use of chemotherapy), the treatment is maintained for as long as the cause exists.

Approximately two months after the discontinuation of anticoagulant therapy, children should be investigated for thrombophilia, except children in which DVT was caused by the use of catheter and children with cancer. Permanent anticoagulant therapy should be considered for children with deficiencies of antithrombin, protein C, protein S, homozygous for factor V Leiden or prothrombin 20210, anticardiolipin antibodies or those with associated disorders. Permanent anticoagulant therapy is more important if thrombosis is spontaneous, followed by PE, or if it is a case of rethrombosis.

Fibrinolytic therapy

There are few reports on the use of fibrinolytic agents in children. In the Canadian Registry of VTE, 15 of 137 children (20.2%) were treated with streptokinase (SK), urokinase (UK) or tissue plasminogen activator (tPA). The indication consisted of thrombus extension during heparin therapy in 12 patients and central catheter placement in three. Total thrombolysis only occurred in one child; in nine of them thrombolysis was partial.²

In another case series,³³,³² children from one to 18 years with VTE were submitted to initial treatment with UK, and the results were checked by ultrasonography and pulmonary scintigraphy. In nine children with vena cava thrombosis or thrombosis in the lower extremities, in which resolution of the thrombus was greater than 75% in the first 48 hours, we observed total resolution of the thrombus and absence of signs of post-thrombotic syndrome after one year. On the other hand, in seven of 12 children in which thrombolysis was less than 50% in the first 48 hours, the thrombi persisted after one year. The authors, by comparing their results with those of the Canadian Registry, treated only with heparin,² reported a similar number of complications and better results in relation to thrombus extension and to the symptoms of PTS one year after treatment. They therefore suggested that a controlled study that compares fibrinolytic therapy with exclusive anticoagulant therapy should be carried out.

Manco-Johnson et al.³⁴ have reviewed cases published in the literature of children and newborns treated with tPA. They have found 43 cases of children with DVT treated with doses between 0.03 and 0.1 mg/kg/h and with 70% of total thrombolysis, 9% of partial thrombolysis and 5% cases with no thrombolysis. There were 44% of slight bleeding, 3% of large hemorrhage and 6% of mortality. In 23 newborns, total thrombolysis was observed in 56% of the cases, partial thrombolysis in 35% and absence of thrombolysis in 9%. In these cases, there was 13% of large hemorrhage, with three cases of cerebral hemorrhage. A rate of 87% of central catheter patency was reported with the instillation of tPA at 0.25 to 0.5 mg in children.

Since UK is not currently available in the market and SK seems to be less active in children due to the high prevalence of anti-SK antibodies,³⁴ other studies on the use of tPA are still required in order to show validity or not of the use of this fibrinolytic agent in children. In our opinion, until we get new information, this treatment should be restricted to severe cases of thromboembolism progression (in the presence of adequate anticoagulant therapy) or to cases of phlegmasia cerulea dolens.

The use of fibrinolytic agents has been well established in the treatment of PE in adults, when cardiovascular involvement is present. There is no report in the literature on their use in children, but only reference to their occasional use in adolescents.¹¹

Surgical treatment

Trombectomy. It can be recommended for children, based on the same technique used for adults. The major indication is the presence of phlegmasia cerulea dolens. It can also be indicated for older children with phlegmasia alba, when the history is less than four days. In these cases, blood loss should be avoided as much as possible, as abundant bleeding may occur during this surgery and also due to the problems caused by polytransfusion. The possibility of permanent anticoagulation therapy should be considered in order to prevent recurrence of DVT, with loss of the benefits of the surgery.

Only one child (nine years old at the time) at our center had to operated on due to phlegmasia alba. The initial results were good, but the disease recurred after three years. In the second episode, the patient was clinically treated with anticoagulants, eventually evolving into PTS.

Vena cava filter placement The indications for vena cava filter placement are the same as those recommended for adults: patients with extensive DVT and/or PE, with contraindication for the use of anticoagulation therapy; PE even in the presence of adequate anticoagulation; thrombosis extending to the vena cava; and, prophylactically, in patients with high risk for PE and contraindication for pharmacological prophylaxis.

In adolescents with well developed vena cava, the placement of a vena cava filter does not present any special problem. In younger children, there are problems such as obtaining appropriate filters and growth of structures with age. Cahn et al.³⁵ have reported a good outcome in 15 children and adolescents aged between eight and 18 years, in which a Greenfield filter was placed. After a period of 19 months to 16 years, pulmonary embolism, inferior vena cava thrombosis, significant signs of SPT or filter migration were not observed; therefore, the authors have concluded that the use of this filter in children is as safe and efficient as in adults.

According to the literature, the youngest child to receive a vena cava filter was six years old.³⁶ In this case, it was referred that, depending on the diameter of the vena cava, this age would be the youngest one for the placement of commercial filters.³⁵ In younger children, if filter placement is mandatory for this vein, one should consider surgical ligation or plication.

PROPHYLAXIS

Prophylaxis should be recommended in situations of risk for children with previous history of VTE and for whom continuous anticoagulation therapy was not implemented. In children with thrombophilia without thromboembolic events, prophylaxis should also be indicated, although there are no studies that validate this recommendation. The recommended dosage of LMWH, in these cases, is half the dose used in the treatment.²⁵ Another indication, which is still being analyzed, is the use of prophylaxis in children on anticancer treatment.³⁷

OUTCOME

Among the 137 children in the Canadian study, followed up for six months to three years, 13 (9.5%) died: two from PE, one from thrombus extension to the vena cava, and another 10 due to underlying diseases. Of the 124 children who survived, 23 (18.5%) presented VTE recurrence, and 26 children (21%) had post-thrombotic syndrome, of whom seven had had recurrence.² In a later review of the children from the same study, the authors could follow the outcome of 356 children in a period from two weeks to six years and have found a total mortality rate of 16%, of which 14% (2.25% of the total) were caused by VTE. There was rethrombosis at the same site or a second episode of thrombosis in 8.1% of the children. Fifty children (12.4%) presented signs of post-thrombotic syndrome (PTS), among whom 35 had had DVT in the lower extremities and 18% of those with PTS had had recurrent thrombosis.³⁸

At our center, we could observe the outcome of 17 of 33 children with DVT in the lower extremities, after a period of three to 18 years after the first episode. One patient died from liver cancer. Of the remaining 16 patients, four had recurrent VTE. Nine patients (56%) had post-thrombotic syndrome, three of whom presented venous ulcers. Among the 14 patients tested for thrombophilia, we found one patient heterozygous for V Leiden factor, one with protein S deficiency, associated with antiphospholipid (APL) antibody and only two with APL antibodies, all of them with history of recurrence.¹⁰

To conclude with, we can affirm that, albeit rare, venous thromboembolism also occurs in children, with remarkable morbidity and mortality. Thus, it is essential that every physician that treats children or adolescents be familiar with this disease, consider this diagnosis in the presence of suggestive signs or symptoms and refer the child to a specialist as soon as possible for confirmation of the diagnosis and guidance on the treatment.

It is also important to be aware of family predisposition to VTE (thrombophilia). The family history of thrombosis justifies the analysis of thrombophilic disorders and should warn of the possible necessity for prophylaxis in situations of risk, and should also guide the prescription of estrogen to adolescents.

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