Revista Adolescência e Saúde

Revista Oficial do Núcleo de Estudos da Saúde do Adolescente / UERJ

NESA Publicação oficial
ISSN: 2177-5281 (Online)

Vol. 16 nº 3 - Jul/Sep - 2019

Original Article Imprimir 

Páginas 70 a 79


Deep vein thrombosis of the lower limbs in adolescence - a 12 years' perspective

Trombosis venosa profunda de las extremidades inferiores en la adolescencia: una perspectiva de 12 años

Trombose venosa profunda dos membros inferiores na adolescência - uma perspectiva de 12 anos

Autores: Isabel Ayres Pereira1; Andreia Ribeiro2; Cátia Vilas Boas Leitão3; Ana Catarina Maia4; Isabel Carvalho5; Ana Sofia Garrido6

1. Vila Nova de Gaia e Espinho Hospital Center, Pediatrics Service - Vila Nova de Gaia - Portugal
2. Vila Nova de Gaia e Espinho Hospital Center, Pediatrics Service - Vila Nova de Gaia - Portugal
3. Vila Nova de Gaia e Espinho Hospital Center, Pediatrics Service - Vila Nova de Gaia - Portugal
4. Vila Nova de Gaia e Espinho Hospital Center, Pediatrics Service - Vila Nova de Gaia - Portugal
5. Vila Nova de Gaia e Espinho Hospital Center, Pediatrics Service - Vila Nova de Gaia - Portugal
6. Vila Nova de Gaia e Espinho Hospital Center, Pediatrics Service - Vila Nova de Gaia - Portugal

Maria Isabel Pereira
(isabbap@gmail.com)
Centro Hospitalar Vila Nova de Gaia e Espinho, Serviço de Pediatria
Rua Conceição Fernandes, 1079
Vila Nova de Gaia - Portugal. CEP: 4434-502 Vila Nova de Gaia

Submitted on 12/28/2018
Approved on 2/9/2019

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Keywords: Venous Thrombosis; Adolescent; Risk Factors; Thrombophilia
Palabra Clave: Trombosis venosa; Adolescente; Factores de riesgo; Trombofilia
Descritores: Trombose Venosa; Adolescente; Fatores de Risco; Trombofilia.

Abstract:
OBJECTIVE: Assess a clinical and epidemiological descriptive analysis of Deep venous thrombosis (VTE) cases of lower limbs, of patients admitted to the Pediatric Service Portuguese hospital, between 2004-2016.
METHODS: Observational retrospective longitudinal study the deep vein thrombosis of the lower limbs in children with over one month old month admitted in a level II hospital from 2004-2016.
RESULTS: Eight cases were analyzed, all of them related to adolescents (mean age 16.4 years), 75% female. All had = 1 risk factor: oral contraceptive (75%), family history of deep vein thrombosis (37.5%), hereditary thrombophilia (37.5% - protein S deficiency, factor V Leiden and prothrombin mutations), immobility (25.0%), smoking (25%), Antiphospholipid syndrome (12.5%), infection (12.5%), recent major surgery (12.5%) and obesity (12.5%). Doppler sonography confirmed the diagnosis of proximal thrombosis in all; 25% had the diagnosis of a pulmonary embolism at admission. Therapy was started uneventfully with enoxaparin and warfarin, with discontinuation of the first after adjusted INR. Oral contraceptives were discontinued and compression stockings were introduced in all; 37.5% had early ambulation. Minimum time of anticoagulation was six months, and it was maintained indefinitely in the Antiphospholipid syndrome and PS deficiency subjects. Meantime of follow-up on vascular surgery consultation was 18 months; one case suggests post-thrombotic syndrome and thrombosis recurred on the Antiphospholipid syndrome case at 12 months of follow-up.
CONCLUSION: Adolescents are a population with intrinsic risk factors for deep vein thrombosis and should be consider in regular health consultations, promoting healthy lifestyles and prescribing oral contraceptives. The authors emphasize adjunctive therapies and long-term follow-up.

Resumen:
OBJETIVO: realizar el análisis descriptivo clínico y epidemiológico de los casos de trombosis venosa profunda (TVP) de las extremidades inferiores de pacientes ingresados en el Servicio de Pediatría de un hospital portugués de nivel II entre 2004-2016. Caracterización de la presentación, enfoque diagnóstico y terapéutico y evolución.
MÉTODOS: estudio observacional longitudinal retrospectivo. Se buscaron casos usando la codificación ICD-10 para trombosis venosa, y se seleccionaron casos de trombosis venosa profunda de las extremidades inferiores en niños mayores de 1 mes, ingresados en el hospital en cuestión entre 2004-2016.
RESULTADOS: Se analizaron ocho casos, todos relacionados con adolescentes (promedio 16.4 años), siendo 75% mujeres. Todos tenían al menos un factor de riesgo: anticonceptivos orales (75%), antecedentes familiares de trombosis venosa (37.5%), trombofilia hereditaria (37.5% - déficit de proteína S, mutaciones del factor V de Leiden y protrombina) , inmovilización (25%), tabaquismo (25%), síndrome antifosfolípido (12.5%), infección (12.5%), cirugía reciente (12.5%) y obesidad (12.5%). La ecografía Doppler confirmó la trombosis proximal en todos los casos, y en el 25% se diagnosticó tromboembolismo pulmonar bilateral al ingreso. La enoxaparina y la warfarina se iniciaron sin complicaciones, la primera se suspendió después de una INR adecuada; todos introdujeron medias elásticas y anticonceptivos orales suspendidos, y el 37.5% movilizó la extremidad temprano. El tiempo mínimo de tratamiento fue de seis meses, permaneciendo indefinidamente para el síndrome antifosfolípido y el déficit de PS. El seguimiento promedio en cirugía vascular fue de 18 meses; un caso presentó síndrome post-trombótico a los 12 meses, y la recurrencia ocurrió en el caso. La TVP ha recurrido al síndrome antifosfolípido. El seguimiento promedio en cirugía vascular fue de 18 meses; un caso presentó síndrome post-trombótico a los 12 meses, y la recurrencia ocurrió en el caso. La TVP ha recurrido al síndrome antifosfolípido.
CONCLUSIÓN: los adolescentes son un subgrupo con sus propios factores de riesgo de trombosis que deben considerarse en consultas de rutina, orientación para estilos de vida saludables y prescripción de anticonceptivos orales. Se destacan las medidas adyuvantes y el seguimiento a largo plazo con búsqueda regular de complicaciones.

Resumo:
OBJETIVO DO TRABALHO: Realizar a análise descritiva clínico-epidemiológica dos casos de Trombose venosa profunda (TVP) dos membros inferiores de pacientes internados no serviço de Pediatria de um hospital português nível II entre 20042016. Caracterização da apresentação, abordagem diagnóstica e terapêutica e evolução.
MÉTODOS: Estudo observacional retrospectivo longitudinal. Os casos foram pesquisados através da codificação ICD-10 para trombose venosa, sendo selecionados os casos de trombose venosa profunda dos membros inferiores em crianças com idade maior que 1 mês, internados no hospital em causa entre 2004-2016.
RESULTADOS: Foram analisados oito casos, todos relativos à adolescentes (média 16,4 anos), sendo 75% sexo feminino. Todos apresentavam ao menos um fator de risco: anticoncepcionais orais (75%), história familiar de trombose venosa (37,5%), trombofilia hereditária (37,5% - déficit de proteína S, mutações do fator V de Leiden e Protrombina), imobilização (25%), tabagismo (25%), Síndrome antifosfolipídico (12,5%), infecção (12,5%), cirurgia recente (12,5%) e obesidade (12,5%). O ecodoppler confirmou trombose proximal em todos os casos, e em 25% foi diagnosticado tromboembolismo pulmonar bilateral à admissão. Iniciou-se enoxaparina e varfarina sem complicações, suspendendo-se a primeira após INR adequado; todos introduziram meia elástica e suspenderam os anticoncepcionais orais, e 37,5% mobilizaram precocemente o membro. O tempo mínimo de tratamento foram seis meses, mantendo-se indefinidamente nos casos de Síndroma antifosfolipídico e déficit PS. A média de seguimento na cirurgia vascular foi de 18 meses; um caso apresentou Síndrome pós-trombótica aos 12 meses, e ocorreu recorrência no caso. A TVP recorreu no caso de Síndroma antifosfolipídico.
CONCLUSÃO: Os adolescentes são um subgrupo com fatores de risco próprios para trombose que devem ser considerados nas consultas de rotina, na orientação de estilos de vida saudáveis e na prescrição de anticoncepcionais orais. Salientam-se as medidas adjuvantes e o seguimento a longo prazo com pesquisa regular de complicações.

INTRODUCTION

Although rare in children, Venous Thromboembolism (VTE) has an increasing incidence and is associated with significant morbidity and mortality1,2. Its etiology at pediatric age is multifactorial and includes inherited and acquired risk factors (RF), whose identification is crucial for the optimization of the therapeutic approach and strategy for preventing complications and recurrence2,3,4,5.

However, the scarcity of studies makes it difficult to elaborate action protocols, and most recommendations are extrapolated from adults, with inherent limitations1,2.

The objective of this study is the clinical and epidemiological descriptive analysis of cases of deep vein thrombosis (VTE) of the lower limbs of patients admitted to the pediatric service of a Portuguese hospital between 2004 and 2016.


METHODS

Longitudinal retrospective observational study of cases of acute lower limb VTE in children aged between one month and 17 years and 365 days, admitted to the Pediatric Service of a Portuguese hospital between January 2004 and October 2016 . Cases were searched using ICD-10 coding for venous thrombosis, and cases of deep vein thrombosis of the lower limbs in this age group were selected. Clinical-epidemiological data were retrospectively extracted through each patient's individual electronic process, maintaining anonymity. Its clinical evolution until July 2017 was included. Demographic variables, personal and family history of VTE and hereditary thrombophilia, smoking, habitual medication, previous illnesses, history of trauma, recent surgery or immobilization (up to three months before admission), VTE clinic, body mass index were analyzed, laboratory and imaging tests, and treatment and evolution to date. SPSS v20 was used. In the data analysis, frequencies, means and medians were evaluated according to the variables under study. The study was approved by the Ethics Committee of the Hospital concerned.


RESULTS

Eight cases were identified, whose main characteristics are listed in table 1. All occurred in adolescents (minimum age 14.25 years; mean age 16.37 +/- 3.99 years), with 75% being female.




In all cases more than one risk factor (RF) was identified and in 87.50% more than two RF for VTE, whose distribution by sex is shown in figure 1 below. Overall, the following stand out: oral contraceptive use (OAC) (100% of adolescents), family history of VTE in first-degree relatives (37.5%), hereditary major thrombophilia (37.5%), immobilization (25 %) and smoking (25%; 25% without registration); one case (12.5%) occurred in a teenager with antiphospholipid syndrome (SAFL) and previous episodes of VTE, hypocoagulated with warfarin but with subtherapeutic INR on admission (INR 1.45); isolated cases of acute infection and obesity were identified.


Figure 1. Summary graph of VTE RF identified in the sample and its distribution by gender.



OACs were used for less than one year by all adolescents, with a mean of 5.5 months (DIQ 1.63-7.5); all were combined OAC: 66.70% 3rd generation (gestodene) and 33.3% 4th generation (cyproterone acetate).

The presentation of VTE was unilateral in 100% of cases (75% in the left MI). The mean time to evolution until diagnosis was 2.18 ± 1.46 days (minimum 12 hours, maximum 5 days), and the most reported symptoms were pain (100%), limb volume change (75%) and functional limitation (37.5%). Objectively, edema and pain on palpation of the affected area (87.5%), mobility limitation and pulse reduction (37.5%) stand out. The color change of the limb occurred in two cases (25%), and one case was isolated with heat and another with a positive sign of hommans.

Doppler ultrasound confirmed the diagnosis of proximal VTE (reaching the iliac, femoral or popliteal segments) in all cases, being considered extensive (ilio-femoropopliteal) in 75%; The occlusion was total in 25%, partial in 25% and mixed in 12.5%.

Laboratory investigation with blood count, coagulation study, renal function, ionogram, glucose, TGO/TGP and C-reactive protein (CRP) was performed in all cases upon admission, occurring after the first dose of low molecular weight heparin (LMWH) by 37.5%. Mild leukocytosis was identified in 12.5%, mild neutrophilia in 50%, and CRP elevation in 62.5%. There was a decrease in INR, an increase in aPTT or PT in cases already under anticoagulation and in cases associated with prothrombin mutation (PT) and PS deficit.

D-dimers were required in the acute phase in 75% of cases, being increased by 83%. Antiphospholipid antibodies were normal in all cases.

In all cases acute hereditary major thrombophilias were investigated in the acute phase (Table 2), and major thrombophilic defects were identified in 37.5%: n = 1 heterozygous FVL mutation, n = 1 heterozygous PT G20210A mutation and n = 1 deficit of PS with mutation in PROS 1 gene in heterozygote.




All cases started double anticoagulation with LMWH (1mg/Kg12/12h subcutaneously) and warfarin (0.2mg/Kg/day orally), the first remaining for five days and, until therapeutic INR, two consecutive days (median nine days (DIQ: 5.5-12)). The median length of stay was 11 days (DIQ 6.25-12.75), and all were discharged with warfarin. Total duration of treatment ranged from 6-41 months, remaining at the last assessment date in three cases. In no case were complications associated with treatment. In addition to the pharmacological treatment, all started stocking elastic in the hospital, 37.5% early mobilized limb and OAC were suspended.

Regarding acute complications, two cases of PTE were identified on admission in female adolescents (25%). No deaths, hemorrhages, early recurrences, or acute venous insufficiency of the limb occurred. Thoracic CT angiography was performed on admission in 37.5% of cases, confirming PTE in one symptomatic and one asymptomatic case with intra-abdominal extension of VTE, and excluding it in the adolescent without suggestive clinic, but with SAFL and previous VTE. In both cases, PTE was bilateral, affecting three or more vessels in lobar/segmental branches, and in one case the main pulmonary arteries. The symptoms reported were chest pain, dyspnea and cough.

At discharge, all cases were referred for immunohemotherapy and vascular surgery, and 50% were referred for pediatric consultation. The average follow-up time at the vascular surgery consultation was 17.75 +/- 3.16 months. At 12 months, one case presented symptoms and signs of post-thrombotic syndrome (PTS) (edema and collateral vessels in the affected limb) and VTE recurred in the contralateral limb in the SAFL adolescent with therapeutic INR (2.4).


DISCUSSION

After the neonatal period, adolescence is the second peak in the age distribution of pediatric VTE, with an estimated incidence of 1.1/10,000 adolescents/year1,2,6,7,8, about three times higher than the rest of the pediatric population9. Although rare, its incidence has increased due to improved care for critically ill children, more frequent use of invasive procedures, improved diagnostic techniques, and increased alertness for this condition1,4,5,6,7, 8.9,10. This trend seems more expressive in adolescence, for which a 49% increase in the prevalence of VTE between 2001-200711 is described. In this age group, smoking, OAC, and pregnancy are additional factors for this phenomenon3, and therefore more prevalent in females (incidence of 1.49 vs 0.81 / 10,000 adolescents/year in males)1,2,4.

Unlike adults, where 40% of VTE is idiopathic4,6, in pediatric age it is usually multifactorial, with ≥1 RF in 90% 2 and only 0-5% of idiopathic cases4, as in this sample. After the central venous catheter, responsible for 50-60% of VTE in pediatric age, chronic diseases are the most prevalent acquired RF (70%), especially cardiovascular disease, neoplasia, neuromuscular disease, nephrotic syndrome, and chronic inflammatory states, such as inflammatory bowel disease and rheumatoid arthritis3,5,9,12. In adolescence, in turn, acute conditions - such as infection/sepsis, trauma/major surgery with prolonged immobilization, dehydration and pregnancy/postpartum - and the use of OAC, obesity, physical inactivity and smoking seem to be of particular importance1, 3,4,7,8,11 as represented in the study population. Antiphospholipid antibodies (lupus anticoagulant, 2 microglobulin and anticardiolipin), present alone in primary SAFL or in the context of systemic disease, such as systemic lupus erythematosus, significantly increase the risk of VTE and its recurrence and should be systematically screened in all cases3,12. OOCs, significantly represented in this sample, increase about 3-4 times the risk of VTE, with an incidence of 1: 12500/women/year without OAC vs 1: 3500/women/year with OAC6,12. The risk seems higher in the first 6-12 months of treatment6 and is 2-4 times higher for the 3rd and 4th generation compared to the 2nd generation6,13. The coexistence of other risk factors such as smoking, FVL mutation, obesity, and major surgery, this substantially increases risco7,11, being present in 50% of adolescents. In this context, practical guidelines for its prescription were developed. These contraindicate combined OAC if acute or prior VTE, personal/family history of hereditary thrombophilia and/or surgery with prolonged immobilization, with progestative OCs and the progestative intrauterine device (IUD) being a lower risk option and considered safe only the copper IUD. In asymptomatic cases with a family history (1st degree) of VTE, combined/progestative OAC may be used although copper/progestative IUDs are preferred. In obese women, estrogen contraception is discouraged and progestative OAC or IUDs should be preferred14. In addition, OAC suspension is recommended at least four weeks before major surgery with prolonged immobilization2, which was not the case for our sample.

Hereditary thrombophilic defects occur in about 10-78% of pediatric VTE2. Although the risk of VTE and its recurrence increase, its identification does not affect its acute approach2,5, and the overall risk conferred is very low (0.07/100000 children/year), depending on the defect, and does not appear to be significant in the absence of other acquired RF2,12. However, the potential implications for treatment time, at-risk anti-thrombotic prophylaxis, clarification of the acute situation, and family counseling and healthy lifestyles seem to justify its systematic research in unprovoked cases, particularly in adolescence2,10,11,12,15,16. The most common inherited thrombophilic defects are the FVL mutation and the PT G20210A gene mutation, respectively present in 5% and 2% of Caucasians. PC, PS and ATIII deficits are rarer and are associated with a higher risk of VTE and recurrence15. Elevation of factor VIII and hyperhomocysteinemia may be hereditary or acquired and also increase this risk 2,3,9. Except for genetic mutations and FVIII, whose increase in the acute and posttreatment phase has prognostic value, the remaining evaluation should be delayed to avoid false positives related to the acute phase of the disease and treatment6,12,16, as occurred in this sample. Hereditary thrombophilic defects were identified in 37.5% of the cases, all associated with acquired RF, which is in accordance with the literature10. Although frequent in the general population, the risk of VTE associated with MTHFR and PAI-1 mutations alone is not proven, and its routine research is not recommended16. The history of VTE in first-degree relatives was present in 37.5% of cases and constitutes an independent RF for VTE, highlighting the importance of this data in the collection of clinical history6.

The multifactorial pathophysiology of VTE and the RF profile identified in this sample thus underline the importance of its systematic assessment in routine consultations with adolescents, particularly in planning risk situations such as hospitalization and/or major surgery with immobilization, and in candidates for ACO3. In this population, an early and risk-adjusted approach could have led to a change in attitude and eventually to the risk of VTE in 37.5% of cases, non-prescription of OAC in obese, smoking or major surgery adolescents and/or prolonged immobilization as well as prolonged antithrombotic prophylaxis in the latter.

Regarding the clinic, the unilateral presentation of VTE with predominance of the proximal segment of the MI is in agreement with the literature6, as well as the symptoms and the average time to diagnosis1. Doppler ultrasonography is the recommended diagnostic exam, and it allows to evaluate the extent and degree of occlusion and follow-up control2,6. Blood counts and coagulation studies are recommended before the beginning of treatment to detect coagulation disorders, avoiding false negatives associated with therapy2, as verified in the three cases in which the harvest occurred under these conditions.

In addition to antiphospholipid antibodies, basic biochemical evaluation is indicated to exclude systemic pathology that may underlie VTE and to guide the choice of anticoagulant2, and was normal in all cases. Elevation of CRP in 62.5% of cases, only one of which has a proven infection, may be related to the state of local and systemic inflammation associated with VTE.

Most current recommendations for treatment of VTE at pediatric age are extrapolated from adults, with inherent limitations2,3,5,6. The objectives are symptomatic relief, promotion of thrombus resolution and prevention of thrombus extension, embolization, recurrence and complications2,6. The recommended first-line regimen is LMWH (1mg/kg12/12h) due to its high bioavailability, blood stability and subcutaneous use, with less need for laboratory monitoring2,6. It should be started with warfarin (initial dose 0.2 mg/kg oral), maintaining the combination for at least five days and up to INR between 2-3 consecutive days2,6. In the adolescent population, frequent poor adherence to treatment, concomitant habitual medication, dietary variations, and occasional but potentially heavy alcohol consumption may make it difficult to control warfarin anticoagulation levels. Thus, while the efficacy and safety of new oral therapies (eg direct factor Xa inhibitors) are not proven at pediatric age, these are aspects that should be given particular attention in their regular surveillance1,3.

The treatment time depends on the etiology2,5,15. For VTE in the context of reversible RF, 3-6 months of anticoagulation2,3,5,15 are recommended. In our sample two cases performed more than 12 months taking into account clinical and epidemiological factors, stressing the importance of a case-by-case decision based on experience. Given the increased risk of VTE and its lifetime recurrence, SAFL is considered a major thrombophilia that advocates indefinite anticoagulation2,3,5,12,15, as in this sample. When VTE occurs in the context of an irreversible RF, indefinite anticoagulation is recommended, and if idiopathic it should be maintained 6-12 months3. In the context of PTE anticoagulation is advised six months3. Given the still poorly understood role of hereditary thrombophilia in the risk of VTE and its recurrence, the anticoagulation time in this context is not formally defined and may depend on the defect in question and the concomitant presence of other RF10,12. Thus, as they are heterozygous, cases associated with PT and FVL gene mutations underwent six months of treatment. For the case associated with PS deficit, given the higher risk of recurrence and its coexistence with persistent smoking and a history of familial VTE, it was decided to continue treatment indefinitely. In no case was treatment complications observed, reinforcing the safety of these drugs at pediatric age3.

In addition to pharmacological treatment, other general measures are recommended to prevent early recurrence and late complications of VTE, including early mobilization of the affected limb and ambulation, and the use of elastic restraint socks for symptomatic relief3,6. In this sample, ambulation and early mobilization of the affected limb occurred in only 37.5% of cases, being an important measure to reinforce. On the other hand, although all cases started elastic stocking during hospitalization, it was not possible to measure their long-term use in 37.5%, and in one case adherence was sporadic.

Although the prevalence of PTE as a complication of VTE is in accordance with the literature (16.0-31.0%), it may be underestimated since its research was not systematic. The clinical suspicion of PTE in children is difficult because it is often asymptomatic3,17,18; In addition, unlike adults, the use of D-dimers and scores to determine the pretest probability of PTE is not proven at pediatric age1,2,3,17,18. Thus, its diagnosis will continue to require a high level of suspicion and depend on clinical, imaging and team experience18.

PTS and recurrence are the main comorbidities associated with VTE, being of particular importance in pediatric age due to longer life expectancy after an event with potential disability and deterioration of quality of life in adulthood5. Thus, the identification and modification of RF for them, and their early diagnosis and early treatment are crucial in follow-up consultations19.

Recurrence of pediatric VTE is estimated at 5-10% 2,5,8, and is higher in adolescents (19-22%) 4,5,7,11 and in idiopathic cases15. In addition, it depends on the follow-up time and degree of occlusion4. In this sample, it occurred in the case of SAFL (12.5%) one year after the index event, which maintained hypocoagulation although at therapeutic levels.

PTS is the most common chronic complication of VTE and is characterized by chronic venous insufficiency of the affected limb5,19. It has an estimated prevalence of 10-70% (weighted average 26%) 2,15,19, being mild-moderate in most cases2,19. The greater number of affected vessels, longer follow-up after VTE, complete vein occlusion, elevation of D-dimers and factor VIII at diagnosis and after anticoagulation, and non-complete resolution or extension of the thrombus appears to increase the risk of PTS19. Its pathophysiology presupposes chronic vascular alterations and the clinic should not be confused with the acute phase symptoms; thus, the diagnosis assumes its presence in two evaluations at least three months apart and (6-) 12 months after the initial event20. Your research should be done at each follow-up appointment by applying one of two validated and modified pediatric age scales - Modified Villalta Scale and Manco-Johnson Instrument20. In the sample studied, only one case showed any signs/symptoms of PTS, reinforcing regular long-term follow-up.

Patient orientation at discharge highlights the importance of follow-up immunohemotherapy consultation for anticoagulation control, vascular surgery for thrombus resolution and regular surveillance of complications, and Pediatrics for a holistic centralization and approach of each case with advice and intervention on modifiable RF. Pulmonology consultation follow-up of PTE cases is important in the surveillance of complications such as pulmonary hypertension.


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