Bivalirudin and argatroban are possible alternatives for UFH (for example, in the case of suspected or confirmed HIT).11,15

The decision to treat should take into account the clinical condition of the patient, the potential benefits (pain control, prevention of clinical extension or recurrence, and reduction of the risk of post-thrombotic syndrome [PTS]), and the risk of bleeding.

The key factors are the location of the VTE and the clinical manifestations.23 In patients with symptomatic VTE, initiating anticoagulation is recommended, especially in cases of proximal DVT, PE, occlusive thrombosis, or persistent risk factors (CVC, cancer, infection, etc).4 In contrast, for cases of clinically unsuspected thrombosis, the current evidence suggests a low risk of progression; therefore, the decision to initiate treatment should be individualized, taking into account the location (higher risk of persistence in femoral thrombosis), comorbidities, the need to maintain the CVC in cases of CVC-related VTE, and the importance of preserving the venous capital for future vascular access or for previous clots.24 If treatment is not initiated, the patient should be closely monitored, especially if a recent VTE is suspected (Fig. 1).

Figure 1.

General management of pediatric venous thromboembolism (VTE) and recommendations regarding treatment duration.

Abbreviations: APS, antiphospholipid syndrome; CVC, central venous catheter; DOAC, direct-acting oral anticoagulant; LMWH, low-molecular-weight heparin; PE, pulmonary thromboembolism; SLE, systemic lupus erythematosus; UFH, unfractionated heparin; VKA, vitamin K antagonist.

The use of thrombectomy and thrombolysis (Table 4)25 is infrequent in pediatrics and their indication must be agreed on by a multidisciplinary care team.4,6

The duration of treatment depends on the presence of a known trigger, the risk of recurrence, the resolution of the thrombosis, as well as other factors such as the characteristics of the patient and the thrombosis (Fig. 1).4,26,27 Indefinite treatment is not recommended in pediatric patients due to its impact on quality of life and the lack of evidence in support of it.4,6

The presence of a CVC is the main risk factor for VTE in the pediatric population.28 The decision to initiate treatment is based on the etiology and the presence of symptoms (Fig. 1). The decision not to treat can be considered in cases of unsuspected (asymptomatic) CVC-related VTE.4,6

With regard to the CVC, the management depends on whether it is a functioning CVC and the treatment needs to continue (Fig. 2). To reduce the risk of embolic phenomena, it is recommended to delay removal until at least 48hours of anticoagulation have been delivered, especially in patients with extensive thrombosis or with right-to-left shunts.6,28

Figure 2.

Management of central venous catheter-associated thrombosis, cerebral venous sinus thrombosis, and pulmonary embolism.

Abbreviations: BNP, B-type natriuretic peptide; CVC, central venous catheter; DVT, deep vein thrombosis; ECMO, extracorporeal membrane oxygenation; PE, pulmonary embolism; RV, right ventricle; UFH, unfractionated heparin.

A watchful waiting approach is recommended for CVC-associated superficial venous thrombosis of the upper extremities.4 However, anticoagulation should be considered in cases of symptomatic thrombosis associated with a peripherally inserted central catheter.

Cerebral venous sinus thrombosis is a rare and heterogeneous condition (1.1 per 100 000 children per year) that is associated with permanent neurological sequelae in up to 35% of cases. Head and neck infections (mastoiditis or sinusitis) are the most frequent cause, but it has also been reported in the context of cancer (related to chemotherapy), autoimmune and inflammatory diseases, and congenital or acquired prothrombotic conditions. Its clinical presentation varies, ranging from mild headache to seizures, altered level of consciousness, focal neurologic deficits, or signs of intracranial hypertension.29

International guidelines recommend the use of anticoagulation in pediatric patients with CVST with or without associated bleeding (secondary to a complication of CVST, not due to other causes), but there are situations in which anticoagulation must be individualized due to a high risk of bleeding: newborn infant, CVST associated with infection (requiring surgery), trauma, a history of neurosurgery, or cancer.4,6,29

Thrombolysis is not recommended in pediatric patients. It may be considered in the case of an ischemic event or if there is neurologic deterioration despite anticoagulation. Mechanical thrombectomy may be considered depending on the experience and resources of the facility.4,6

Although underreported, PE is rare in the pediatric population (5.1–9.2 per 10 000 intensive care unit admissions). Its significance lies in the associated mortality (9%–10%) and the high recurrence rate (up to 12.5%).3,6

Pulmonary embolism can result from a circulating clot or from in situ pulmonary artery thrombosis secondary to local causes, such as congenital heart disease. In addition to the previously described risk factors (Table 1), there are peculiarities in adolescents: a higher incidence of unprovoked PE and greater prevalence of hereditary thrombophilia, as well as other risk factors such as obesity, hormonal contraception, autoinflammatory diseases, or anatomical predisposition (see “thrombosis secondary to anatomical abnormalities”).30

The diagnosis is not always straightforward, either because the patient reports nonspecific symptoms (shortness of breath, anxiety, pleurisy, or cough), or because, despite the presence of florid symptoms, PE is not included in the differential diagnosis due to its rarity. Acute and severe forms are characterized by varying degrees of pulmonary artery obstruction, pulmonary hypertension, and acute right-sided heart failure or dysfunction, which may progress to left-sided heart failure, obstructive shock, and cardiac arrest. Less severe forms present with mild, often self-limiting signs and symptoms that may be attributed to another condition.30

Early initiation of treatment is associated with a reduced mortality. The therapeutic approach depends on the patient’s hemodynamic status and the presence of cardiac dysfunction; therefore, performing an urgent echocardiogram and laboratory tests (including troponin) is essential. Although anticoagulation is the first-line treatment in the vast majority of cases, decisions regarding thrombolysis and thrombectomy in specific situations should be made jointly by a multidisciplinary care team (Fig. 2).4,6,30

Intracardiac thrombosis is rare in children, but it is associated with increased morbidity and mortality (10%–15%, although this is related to the presence of an underlying condition). It is associated with the use of CVCs, congenital or acquired heart disease, dilated cardiomyopathy, hypercoagulable states, and cancer.31

Transthoracic echocardiography is the imaging modality of choice for initial diagnosis. Transesophageal echocardiography offers a greater sensitivity (for example, in congenital heart disease). In complex cases or when visualization is inadequate, CT angiography may be useful (Fig. 3).32

Figure 3.

Management of intracardiac thrombosis, portal thrombosis and thrombosis secondary to anatomical abnormalities.

Abbreviations: CHD, congenital heart disease; CVC, central venous catheter; DVT, deep vein thrombosis.

The decision whether to treat or not to treat depends on the risk of thrombosis or bleeding.4 Anticoagulation is recommended as the treatment of choice in patients at high risk of thrombosis: a thrombus ≥ 2cm in size or occupying a large portion of the atrium, mobile or pedunculated, associated with a functioning CVC that cannot be removed or with evidence of progression in a patient with low bleeding risk (Fig. 3).4–6,32 Thrombolysis or thrombectomy should be reserved for exceptional situations (life-threatening hemodynamic instability) at experienced facilities.4,6

Portal vein thrombosis is a rare event. In pediatrics, it is usually associated with abdominal surgery (liver transplantation, splenectomy), sepsis, and prothrombotic conditions (such as thrombophilia or sickle cell disease).33 Its management depends on the extent and impact of the thrombosis. Anticoagulation is not generally recommended, and it is reserved for obstructive thrombosis, post-liver transplant thrombosis, or idiopathic thrombosis (Fig. 3).4 Spontaneous resolution without treatment has been reported in 30% to 70% of cases, but complications such as hepatic lobe atrophy, portal hypertension, cavernomatous transformation of the portal vein, and esophageal varices have also been reported.33

Splenic and mesenteric vein thrombosis are extremely rare conditions. They are associated with pancreatitis, surgery, trauma, and the use of oral contraceptives.34 Anticoagulation is associated with a recanalization rate of 55% (compared to 29% without treatment), a low incidence of bleeding (3.8%), and a reduced mortality.35 There is insufficient evidence to support thrombolysis.34

Thoracic outlet syndrome is caused by the compression of the left subclavian vein at the level of the costoclavicular passage. In adolescents, it is associated with sporting activities (swimming, volleyball) due to hypertrophy of the scalene or subclavian muscles, but it may also result from the presence of a cervical rib or other causes. The management focuses on recanalizing the vessel and reducing the size of the thrombus, definitive treatment with surgical decompression, preventing recurrence and PE, and facilitating resumption of athletic activity (Fig. 3).36 Acute phase (0–14 days): consider catheter-directed thrombolysis or mechanical thrombectomy. Subacute or chronic phase (>14 days): consider staged endovascular recanalization and planning for surgical decompression (resection of the first rib and/or scalene resection or venolysis).37 There is a high risk of rethrombosis if the anatomical cause is not resolved.

May-Thurner syndrome is an anatomical variant that results in the compression of the left iliac vein against the lumbar spine by the overlying right iliac artery. Anticoagulation is indicated in the presence of associated thrombosis, but will not resolve the venous occlusion secondary to the anatomical abnormality (Fig. 3).38 Thrombolysis or thrombectomy should be considered in cases with acute iliofemoral VTE and significant limb compromise (severe pain/swelling, risk of loss of function or phlegmasia) to reduce the risk of PTS. Endovascular revascularization (angioplasty with/without stent placement) may be indicated in the presence of significant compression and persistent symptoms or recurrent thrombosis despite anticoagulation.38

Post-thrombotic syndrome is a chronic complication that can develop following a VTE. It affects mobility and limits physical activity and activities of daily living, with an impact on quality of life. The symptoms vary according to the affected territory: in the extremities, pain, swelling, skin changes, ulceration, pruritus, paresthesia, nighttime cramps, venous claudication; in PE, chronic dyspnea, limitation of aerobic activities, impaired pulmonary or heart function, chronic pulmonary hypertension; in portal vein thrombosis, portal hypertension and gastroesophageal varices.9,39 Its etiology is multifactorial (Appendix B, Supplemental material, Fig. 1)39 and its frequency varies from series to series (26% in a systematic review, higher in prospective studies). Individualized follow-up is recommended for high-risk patients (unresolved VTE, cancer, portal vein thrombosis).4,39

The diagnosis is based on the evaluation of signs and symptoms (Table 5).9,39,40 The usefulness of various therapeutic strategies, such as the use of elastic compression stocking with moderate pressure, physical therapy, and supervised exercise, is still under debate.40