What Labs Should Know About Pediatric Thrombosis

What are the most common causes of thrombosis in children?

The incidence of hospital-associated pediatric thrombosis has risen over the last 2 decades. This is due to improved survival of children with chronic conditions and a concomitant increase in the use of central venous catheters—the most common cause of thrombosis in children—and other lifesaving technology.

The presence of inherited thrombophilia in children is more of a risk factor for than a cause of thromboembolism and is usually of greater importance in adolescent children who develop venous thromboembolism without any triggers or who develop an exaggerated response compared to the trigger. Hereditary thrombophilia are classified mainly into the high or low risk for thrombosis groups. The high-risk group includes: deficiencies of the coagulation inhibitors anti-thrombin, protein C, and protein S, while the low-risk group includes factor V Leiden and prothrombin gene mutation.

What does testing for hereditary thrombophilia involve?

The most common tests performed in cases of hereditary thrombophilia include those for anti-thrombin, protein C, and protein S activity, as well as factor V Leiden and prothrombin mutation analysis done via polymerase chain reaction. All of these tests together constitute the hypercoagulable panel at my institution. We might also test for plasma homocysteine concentrations, especially if a patient has arterial thrombosis.

Hereditary thrombophilia testing does not influence the immediate care of patients with thrombosis and should be deferred for approximately 3–6 months after an acute episode and after anticoagulant therapy has ceased. This is because both the thrombotic consumptive process and anticoagulants affect tests for coagulation inhibitor activity. However, labs can run molecular testing for factor V Leiden and prothrombin gene mutation at any time.

While labs should perform this testing on a case-by-case basis, it is generally reserved for children with unprovoked thrombotic episodes and a family history of thrombosis. Hereditary thrombophilia testing is usually not recommended if a thrombotic episode is provoked by strong risk factors like major surgery, catheter use, immobility, major trauma, or malignancy. Additionally, comprehensive testing based on a positive family history alone is controversial but might be necessary when prescribing oral contraceptives. In all scenarios, communication between the laboratory and clinicians is essential for deciding when, whom, and what to test.

Labs should always remember that the purpose of these tests is primarily for risk assessment, not for identifying a cause of thrombosis. This means that a patient with a positive result might never actually have a thrombotic episode.

What is the biggest challenge with hemostasis testing in children?

The coagulation system of neonates and children evolves with age, which means that pediatric concentrations for a majority of coagulation factors and inhibitors differ markedly from adult concentrations. For example, protein C levels at birth could be anywhere from 17% to 53% of adult levels. These levels usually rise to >50% of adult levels by 6 months, with some reports indicating that full adult levels may not be reached until around 16 years of age.

Differences like this between children and adults have significant biological and clinical implications. In an ideal world, diagnostic laboratories processing pediatric samples would therefore use age, analyzer, and reagent-appropriate reference ranges—but currently this is not always possible. Many hemostatic reference values for preterm infants are lacking, and the ones that researchers have already reported rely on small study groups. Because of this knowledge gap, adult-based reference ranges are often used for the diagnosis of pediatric patients.

Are direct oral anticoagulants (DOACs) approved for use in children?

None of the newer DOACs have been approved for use in children. Several clinical trials are still ongoing that will hopefully soon result in guidelines for pediatric DOAC use. These drugs would particularly benefit children on long-term therapy since new DOACs do not need to be monitored and also have fewer food and drug interactions.