Pediatrics

Thrombotic Disorders

OVERVIEW: What every practitioner needs to know

Are you sure your patient has a thrombotic disorder? What are the typical findings for this disease?

Thrombotic disorders in children are not common and usually present in one of two ways. The patient may develop a venous thrombosis characterized by painful swelling of a limb (Figure 1) or signs of venous congestion of the head and neck with swelling and pain in the head and neck. Alternatively, the patient may present with an abnormal genetic test when they are screened after another family member was found to have a genetic thrombotic disorder (thrombophilia).

Figure 1.

Right lower extremity deep vein thrombosis. Note the swelling of the right leg.

Common symptoms are:

  1. Painful swelling of one limb (Figure 1)

  2. Swelling of the head and neck

  3. Cough and shortness of breath (associated with a pulmonary embolism)

What other disease/condition shares some of these symptoms?

Painful swelling of the limb can be the sign of infection, malignancy (although this is quite rare), or vasculitis.

The symptoms of pulmonary embolism are cough and shortness of breath, sometimes accompanied by chest pain. There are many conditions that can mimic a pulmonary embolism, including reactive airway disease, infections of the respiratory tract, and pleurisy.

What caused this disease to develop at this time?

  • In children, the most common cause of thrombosis is presence of a vascular catheter. These include central venous catheters placed in ICU settings or for cardiac catheterization, or long-term catheters placed for management of chronic or life-threatening conditions such as cancer, chronic infection requiring long-term antibiotics, malnutrition requiring total parenteral nutrition, or other serious chronic disorders.

  • The other causes of thrombosis in children include:

    • local infections such as head and neck infections (e.g., sinusits leading to cerebral venous sinus thrombosis) or osteomyelitis leading to local venous thrombosis

    • use of oral contraceptive pills in teenage girls and young women.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • The basic laboratory evaluation includes a CBC to check the platelet count, and a prothrombin time (PT), partial thromboplastin time (PTT) and fibrinogen.

  • Typically, additional laboratory studies are not required for the diagnosis of a thrombiosis, but an elevated D-dimer is highly suggestive of the presence of a venous thrombosis.

  • If a venous thrombosis is found, then an evaluation for genetic risk factors could be undertaken depending on the situation. Typically, if there are no other risk factors present ,such as the presence of central venous catheters, cancer, oral contraceptive pill use, then an evaluation for a genetic cause should be undertaken (see below.) If other risk factors are present, then searching for genetic risk factors is more controversial.

Would imaging studies be helpful? If so, which ones?

  • Imaging studies are required to diagnose a venous thrombotic event. Typically for a swollen limb, a Doppler ultrasound is ordered first.

  • Ultrasound has high sensitivity for thromboses in the lower extremities, while in the upper extremities the sensitivity is much lower. For upper extremity venous thrombosis, Doppler ultrasound may have a sensitivity as low as 37%.

  • In a patient with a suspected thrombosis of an upper extremity in which the ultrasound is normal, a venogram may be required to definitively rule out thrombosis.

  • If one suspects cerebral venous sinus thrombosis, an MRI and MR venogram should be ordered.

  • For thrombosis of visceral structures such as hepatic veins, splenic or renal veins, an MR or CT venogram are the best tests to order.

  • For patients with suspected pulmonary embolism, a CT angiogram should be performed.

If you are able to confirm that the patient has a thrombotic disorder, what treatment should be initiated?

  • Venous thromboses that are uncomplicated should be treated with anticoagulation. Anticoagulation is required to prevent embolization and prevent clot extension while the body's natural thrombolytic mechanisms dissolve the clot over time. Clots that do not dissolve readily put patients at risk for developing the post-thrombotic syndrome, which is characterized by long-term painful swelling of the affected extremity and can be quite debilitating. The choice of anticoagulants in children includes heparin followed by warfarin or low molecular weight heparin (LMWH), or LMWH followed by warfarin. Many children who develop thrombosis have serious chronic medical disorders and are receiving multiple medications; therefore, it may be advantageous to continue the LMWH for the duration of treatment because it has no drug interactions and requires less therapeutic drug monitoring than warfarin.

    Recently, the use of fondaparinux for anticoagulation has been reported; this medication has advantages over LMWH, as follows. First, it is dosed once-daily as opposed to LMWH which must be dosed twice daily for treatment of deep vein thrombosis (DVT). Second, fondaparinux has essentially no risk for inducing heparin-induced thrombocytopenia, a serious but rare complication of LMWH. Third, in vitro and animal data suggest that fondaparinux has no effect on bone mineralization, while LMWH is known to cause osteopenia, particularly if used for many months. Lastly, fondaparinux is a synthetic compound while LMWH is a purified biologic product derived from porcine intestine, which could potentially be affected by biologically active contaminants (as occurred in 2007). The only major limitation of fondaparinux compared with LMWH is that it cannot be reversed by protamine, while protamine is at least partially effective at reversing the effects of LMWH.

  • In patients with more severe symptoms and/or complications, treatment with thrombolytic therapy may be indicated. The recently published American College of Chest Physician Guidelines recommend thrombolysis only for life-threatening DVT; however, that suggestion is not evidence-based and may be overly conservative. The risk for bleeding with thrombolysis compared with anticoagulation is considerably higher; therefore, the potential increased benefits of thrombolysis (rapid clot resolution) must be balanced with the increased risk for bleeding.

  • The recommended duration of therapy depends somewhat on the clinical situation; however, anticoagulation for a minimum of 3 months is common. For more serious events or if there is an ongoing risk factor such as the presence of a central venous catheter, treatment can be much longer, and sometimes even indefinite.

  • The main treatment options include the anticoagulants unfractionated heparin, low molecular weight heparin (LMWH), warfarin, and fondaparinux. The properties of anticoagulants commonly used in children are shown in Table I.

Table I.

Properties of anticoagulants used in children
Anticoagulant Dosage Administration Side effects Comments
Unfractionated heparin Bolus: 50-75 units/kg followed by continuous infusion of 15-28 units/kg.hour (start with higher dose in neonates and lower dose in adolescents) IV bolus followed by continuous infusion Bleeding, heparin-induced thrombocytopenia, osteopenia with long-term (weeks to months) use Monitor with aPTT aiming for 1.5-3 times baseline
LMWH 1 mg/kg q12 (1.5 mg/kg q12 in children<2 months of age) Subcutaneous Bleeding, heparin-induced thrombocytopenia (rare), osteopenia Monitor with anti-factor Xa level aiming for a level of 0.5-1 anti-Xa units
Warfarin 0.1 mg/kg once daily (max starting dose is 5 mg) Oral (tablets only, i.e. no liquid formulation available) Bleeding, hair loss (uncommon and mild), fatigue, osteopenia (rare) Monitor with the PT/INR aiming for a level of 2-3.When initiating warfarin, it must be co-administered with another anticoagulant until the INR is >2 on two consecutive days.Warfarin has numerous food and drug interactions making it exceptionally difficult to use in children, particularly younger children.
Fondaparinux 0.1 mg/kg once daily Subcutaneous Bleeding Monitored with a fondparinux-based anti-Xa assay with unit conversion to mg/L aiming for a level of 0/5-1 mg/L

What are the adverse effects associated with each treatment option?

N/A

What are the possible outcomes of thrombosis?

Most children with thrombosis will recover with no sequelae if treated properly. The benefits of treatment are a reduced risk of pulmonary emboli and the prevention of post-thrombotic syndrome. However, if untreated or not treated properly, there is a high risk for post-thrombotic syndrome. Post thrombotic syndrome is a serious and debilitating condition whereby there is venous hypertension leading to chronic pain and swelling of the affected extremity, most often involving the legs.

For children who suffer from cerebral sinus thrombosis, there can be cognitive dysfunction and even permanent neurologic sequelae.

Uncommonly, children can develop pulmonary emboli, which can be fatal. Pulmonary emboli in children are usually, but not always, associated with a deep vein thrombosis.

The major risk of anticoagulant therapy is bleeding. Fortunately, this risk is relatively small in children. It is highest with warfarin, mostly because of the inconsistency with maintaining therapeutic levels.

The other risks of therapy are relatively minor and include the potential for osteopenia with long-term use of unfractionated or low molecular weight heparin and the rare, although potentially devastating, complication of heparin-induced thrombocytopenia.

What causes this disease and how frequent is it?

  • Venous thrombosis is increasing significantly in frequency as a result of the use of central venous catheters and other technologies and the improved survival of children with serious and chronic diseases. Most of the children who develop thrombosis have serious and chronic disorders such as congenital heart disease, cancer, or serious gastrointestinal or autoimmune conditions. The exact incidence of venous thrombosis is not known; however, it appears to occur in upwards of 60 per 10,000 hospital admissions.

  • Most cases of venous thrombosis in children are due to the use of central venous catheters. Other causes include congenital heart disease, along with its interventions (surgeries, cardiac catheterizations), cancer, antiphospholipid antibody syndrome, trauma, surgery, prolonged immobilization, and the use of oral contraceptive pills.

  • Some relatively common genetic conditions can be associated with an increased risk for thrombosis. These include:

    • Factor V Leiden (present in ~5% of Caucasians)

    • Prothrombin mutation (present in ~2% of Caucasians)

    • Deficiencies of protein C, protein S, or antithrombin. Collectively, these latter three present in about 1 per 1000 persons of all races.

  • There are extremely rare genetic disorders that can lead to severe thrombotic complications in the neonatal period, presenting as purpura fulminans (homozygous protein C or S deficiency) or stroke (homocystinuria).

  • Other conditions that have may have a genetic or acquired basis include hyperhomocysteinemia and elevated lipoprotein(a).

How do these pathogens/genes/exposures cause the disease?

  • The genetic conditions described above all lead to an increased risk for thrombosis by tilting the hemostatic balance towards thrombosis. For example, factor V Leiden results in a version of factor V that can be activated which leads to clot formation when bleeding occurs; however, it cannot then be deactivated. Similarly, the natural inhibitors to clot formation, proteins C and S and antithrombin, if deficient, cannot inhibit the formation of pathologic thrombi, as is their role.

Other clinical manifestations that might help with diagnosis and management

N/A

What complications might you expect from the disease or treatment of the disease?

The main complications of venous thromboses are pulmonary emboli and post-thrombotic syndrome.

The main complications from treatment of venous thromboses are bleeding, osteopenia, and heparin-induced thrombocytopenia.

Are additional laboratory studies available; even some that are not widely available?

A more elaborate and expensive panel of tests is required to evaluate for the genetic disorders described, as well as to check for antiphospholipid syndrome. Depending on the specific situation, one may elect to perform this panel, known as the thrombophilia panel.

For example, in children with clear risk factors, such as a child with cancer and a central venous catheter-associated thrombosis, no tests may be ordered, while for a child with an idiopathic thrombosis, all the tests for the conditions described above would be ordered.

This is a highly controversial area, and there is significant variance in recommendations even among pediatric thrombosis experts. It is suggested that the decision to perform these assays be made in conjunction with a pediatric hematologist with expertise in pediatric thrombosis.

How can thrombosis be prevented?

In general, venous thrombosis cannot be prevented because it is a rare and unexpected finding in children. In rare instances when there is a high likelihood of developing a thrombus, prophylactic anticoagulation can prevent thrombosis. For example, in a patient with a family history of thrombosis who is known to carry a genetic mutation increasing the risk for thrombosis who then suffers a broken bone and will be immobilized for a long period of time, prophylactic anticoagulation could be considered.

Genetic counseling is only needed in situations in which a strong family history exists. Even in such cases, most genetic counselors are not equipped with the knowledge to recommend treatment approaches. Such recommendations should come from pediatric hematologists with expertise in pediatric thrombosis.

Nutritional factors are not a significant factor in pediatric thrombosis save for the rare patient with elevated homocysteine levels, for whom supplementation with folic acid +/- vitamin B12 might be indicated.

What is the evidence?

There is very limited high-level evidence for the management of venous thromboembolism in pediatrics. Published guidelines from expert panels provide recommendations for the management of patients, which are based in part on the published literature and in part on the personal opinions of the panel members.

The following are all excellent reviews that offer suggestions for diagnosis and management of such patients:

Monagle, P, Chan, AKC, Goldenberg, NA. "Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines". Chest. vol. 141. 2012. pp. e737S-e801S.

Chalmers, E, Ganesen, V, Liesner, R. "Guidelines on the investigation, management, and prevention of venous thrombosis in children". Br J Haematol. vol. 154. 2010. pp. 196-207.

Young, G. "Diagnosis and treatment of thrombosis in children: general principles". Pediatr Blood Cancer. vol. 46. 2006. pp. 540-6.

Ongoing controversies regarding etiology, diagnosis, treatment

There are numerous controversies in this area including:

- the best imaging methods for diagnosis,

- the choice and duration of a specific anticoagulation regimen

In general, the approach to therapy that is used in adults is applied to children. However, it is not clear at all whether this is the optimal strategy.

- which patients should undergoing testing with the diagnostic thrombophilia panel.

If a genetic mutation is identified, it is not clear what should be done vis-à-vis counseling, prophylaxis, or treatment.

Therefore, it is best not to test for such mutations unless there is a clear reason to do so.

Further research is required to answer these many questions.

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