What is thrombophilia in children?

Thrombophilia in children is a disorder that increases the tendency of blood to clot abnormally.³ It can be inherited or acquired and may lead to venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE).¹ While rare in the pediatric population, its incidence is rising, particularly in hospitalized children due to central venous catheters and other medical conditions. 

The incidence of pediatric VTE has increased significantly over the past two decades, with an estimated rate ranging from 0.07 to 0.49 per 10,000 children.¹ Hospitalized children have a much higher incidence, with rates between 4.9 and 21.9 per 10,000 hospital admissions.¹ The rise in cases is primarily due to improved survival of children with chronic conditions, increased use of medical devices like central venous catheters, and heightened awareness leading to better diagnosis. 

While thrombophilia in children can be concerning, understanding the underlying causes, symptoms, and diagnostic approaches can facilitate early detection and effective management. Keep reading for a comprehensive guide.

Causes 

Thrombophilia can be classified into two types:  inherited and acquired, each with specific risk factors and mechanisms.

Inherited thrombophilia

This form results from genetic mutations affecting coagulation factors or natural anticoagulants.²

Protein C and protein S deficiencies

These deficiencies lead to a decreased ability to prevent excessive clotting, increasing the risk of thrombosis. Severe deficiencies can result in life-threatening clotting disorders.²

Antithrombin deficiency

This condition impairs the body’s ability to inhibit thrombin, a key enzyme in clot formation, leading to prolonged clotting activity and an increased risk of recurrent thrombotic events.²

Factor V Leiden mutation

Factor V Leiden mutation is a genetic mutation causing resistance to activated protein C, leading to an increased risk of clot formation in both veins and arteries. It is one of the most common inherited thrombophilias.³

Prothrombin 20210A mutation

Leads to elevated levels of prothrombin, increasing the likelihood of clotting in veins, particularly deep veins of the legs. This mutation is associated with an increased risk of first and recurrent VTE.³

MTHFR C677T mutation

Associated with elevated homocysteine levels, which contribute to endothelial damage and an increased risk of thrombosis, particularly in combination with other risk factors.²

Lipoprotein(a) elevation

Contributes to increased clotting risk by interfering with fibrinolysis, the body's natural clot breakdown process, and is associated with arterial thrombosis as well.²

Acquired thrombophilia

This form is triggered by external factors that alter normal blood flow or clotting balance.

Central Venous Lines (CVLs)

Common in hospitalized children, these devices disrupt normal blood flow, leading to clot formation, especially in young infants.³

Congenital heart disease

Children with structural heart abnormalities may have altered blood flow, increasing thrombosis risk in venous or arterial circulation.³

Septicemia and dehydration

Infection-induced clotting disorders and dehydration-related blood concentration contribute to clot formation, particularly in critically ill children.³

Total parenteral nutrition

May cause an imbalance in clotting factors, leading to increased thrombosis risk due to altered blood viscosity.¹

Pediatric Antiphospholipid Syndrome (APS)

Pediatric Antiphospholipid Syndrome is an autoimmune condition causing recurrent thrombosis due to autoantibodies targeting clotting proteins, often leading to severe thrombotic events.²

Symptoms of thrombophilia in children

Symptoms vary depending on the location and severity of the clot:

Swelling and pain in limbs

Common with deep vein thrombosis, often accompanied by warmth and redness in the affected limb. The affected area may feel heavy or tender.¹

Shortness of breath and chest pain

May indicate pulmonary embolism, particularly if sudden breathing difficulties or coughing up blood occur. Rapid heart rate and low oxygen levels can also be warning signs.¹

Neurological symptoms

Stroke-like symptoms in cases of cerebral venous sinus thrombosis (CSVT) include headaches, seizures, and altered mental status. In some cases, vision problems or weakness in limbs may occur.²

Recurrent or unexplained clots

Repeated episodes of thrombosis without clear external triggers can be an indication of an underlying thrombophilic disorder and require further investigation.²

Unusual clot locations

Clots in the abdomen, kidneys, or brain, which are not common in healthy children, may indicate thrombophilia and should prompt immediate medical attention.³

Diagnosis 

A combination of clinical evaluation and laboratory testing is used for diagnosis.

When to test?

Thrombophilia testing is not routinely recommended for all children with a single thrombotic event. Testing should be considered in the following cases:

• Children with recurrent thrombosis
• Thrombosis occurring in atypical sites like the brain (cerebral venous sinus thrombosis), abdomen (portal vein thrombosis), or kidneys
• Newborns with unexplained blood clots may require genetic testing for severe inherited thrombophilias. If a parent or sibling has known inherited thrombophilia, testing may be warranted
• Adolescents assigned females at birth with a family history of thrombosis should be tested before initiating hormonal contraceptives²

Diagnostic tests

Clotting factor assays

Protein C, Protein S, and Antithrombin levels are essential to assess the levels of natural anticoagulants. These tests help identify deficiencies that may contribute to thrombosis. A deficiency in any of these proteins can disrupt the delicate balance of clot formation and dissolution, increasing the risk of clot-related complications. Factor VIII activity is another important measure, as elevated levels of this clotting factor have been associated with an increased risk of thrombosis.³ High Factor VIII levels can lead to excessive clotting, which may result in conditions such as DVT or PE.³

Genetic testing

Factor V Leiden mutation analysis is performed to identify the presence of a common genetic mutation that leads to activated protein C resistance. This mutation increases the risk of developing abnormal blood clots, particularly in veins.³ If you have this mutation, you may require special considerations for anticoagulation therapy. Instead, Prothrombin 20210A mutation analysis detects a genetic predisposition to elevated prothrombin levels. This mutation can lead to an increased risk of clot formation, particularly in the venous system. Testing for this mutation helps in assessing your likelihood of developing thrombotic events. The MTHFR Gene Mutation test evaluates for polymorphisms associated with hyperhomocysteinemia, a condition characterized by elevated homocysteine levels.¹ Certain variations in the MTHFR gene can impair the body's ability to process homocysteine efficiently, increasing the risk of cardiovascular disease and thrombosis.

Hypercoagulability markers

Homocysteine levels are measured to assess your risk of thrombosis.¹ Elevated homocysteine is linked to an increased tendency for blood clot formation, especially if you have MTHFR mutations.¹ Addressing elevated homocysteine levels through dietary or medical interventions can help mitigate associated risks. Lipoprotein(a) measurement is another key marker of hypercoagulability. High levels of lipoprotein(a) are associated with an increased risk of clot formation and cardiovascular events.³ Since lipoprotein(a) levels are largely determined by genetics, high levels may require targeted risk-reduction strategies.

Antiphospholipid antibody testing

Lupus Anticoagulant testing assesses for antibodies that interfere with normal clotting regulation. The presence of these antibodies can indicate an increased risk of developing APS, 

which predisposes you to recurrent clot formation.¹ Anticardiolipin antibodies testing detects autoantibodies that contribute to blood clot formation.¹ These antibodies target phospholipids, which play a crucial role in coagulation, and their presence can indicate an underlying autoimmune disorder associated with thrombosis. Anti-β2 Glycoprotein Antibodies testing confirms the presence of antibodies linked to APS. These antibodies directly target β2 glycoprotein I, a protein involved in clotting regulation.¹ The detection of these antibodies helps in diagnosing APS, a condition that significantly increases the risk of both arterial and venous thrombosis.

Summary 

Thrombophilia in children is a complex condition influenced by genetic and acquired factors. Early diagnosis through clinical evaluation and targeted testing is essential for managing risks and preventing complications. While routine screening is not recommended for all children, those with significant family history or risk factors should be evaluated carefully. Ongoing research continues to refine our understanding and improve management strategies.

FAQs

What activities should children with thrombophilia avoid?

Children with thrombophilia should avoid prolonged immobility, dehydration, and high-impact activities with a risk of injury. However, regular low-impact exercise is encouraged to support healthy circulation.

Can a child outgrow thrombophilia?

Some aspects of thrombophilia may change with age, particularly acquired forms linked to temporary risk factors like central venous catheters or infections. However, inherited thrombophilia is generally lifelong, though its impact may vary depending on additional risk factors encountered over time.

Should all children with a family history of thrombophilia be tested?

Routine screening is not recommended for asymptomatic children.² Testing is advised only in high-risk situations, such as when making medical decisions related to surgery, long-term immobility, or hormonal therapy. 

What is the treatment for pediatric thrombophilia?

Treatment depends on the severity and type of thrombophilia.¹ In cases of acute clotting, anticoagulant medications such as heparin or warfarin may be used. Long-term management includes risk reduction through lifestyle modifications and, in some cases, preventive anticoagulation.¹