HEMATOLOGY: Kids and clots

Part of Contemporary Pediatrics’ coverage of the 2015 AAP Annual Conference. For more coverage, click here.

As the number of clots in hospitalized children continues climbing, said Shannon L Carpenter, MD, MS, pediatricians must know when and how to screen for risk factors.¹ With many serious chronic illnesses now being treated more effectively, pediatricians are seeing increasing numbers of children who previously might not have survived very long, she said during the presentation “Clots and Kids: An Increasing Problem.”

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In such children and others who may be at risk, it is imperative to take a thorough history of risk factors for the child and/or family. For example, if a teenage girl who is considering oral contraceptives has a strong family history of clotting, that patient may need to be worked up or at least evaluated. An oral contraceptive containing estrogen may not be ideal for her.

If the patient has a history of clotting in a first-degree relative, start the workup by checking for deficiencies in anticoagulant proteins such as antithrombin, protein C, and protein S. Although factor V Leiden and prothrombin 20210 mutations have grabbed recent headlines and are indeed risk factors for clotting, they pose less risk than anticoagulant protein deficiencies do, according to Dr Carpenter’s presentation.

In patients who may have abnormally prolonged activated partial thromboplastin time (aPTT), a mixing study often helps point the way. Prolonged aPTT may be evidence of a clotting factor deficiency, but it also could indicate an inflammatory response to infection, which could lead to lupus anticoagulant. Or, in a patient with a connective tissue disorder and an antiphospholipid antibody, prolonged aPTT may indicate a risk for clotting.

Patients with a history of clotting require close monitoring because they are at risk for post-thrombotic syndrome, which causes swelling of the affected limb and possible long-term sequelae. Conversely, families of patients who have an abnormal lab value but are otherwise normal may need simple reassurance.

We do not yet know all the answers regarding clot prevention in hospitalized children. However research has revealed a strong association between clotting in children and use of central venous lines.² So, we should start by minimizing the amount of time a child has a central venous line and ensuring against infection.

References

1. Raffini L, Huang YS, Witmer C, Feudtner C. Dramatic increase in venous thromboembolism in children’s hospitals in the United States from 2001 to 2007. Pediatrics. 2009;124(4):1001-1008.

2. Male C, Kuhle S, Mitchell L. Diagnosis of venous thromboembolism in children. Semin Thromb Hemost. 2003;29(4):377-390.

Shannon L Carpenter, MD, MS, is an associate professor of pediatrics, University of Missouri-Kansas City School of Medicine Hematology/Oncology, and section chief, hematology, Children’s Mercy Hospital, Kansas City, Missouri.

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Commentary

Dr Carpenter provides an excellent review of the current literature and trends in pediatric thrombosis. The increased incidence of venous thrombosis in hospitalized children is widely appreciated and likely multifactorial. In addition to improved survival, increased awareness of this problem and increased utilization of catheters and procedures in pediatric care are likely contributors.

One of the more controversial questions is when and how to consider a laboratory evaluation for thrombophilia. Some believe that any thrombotic complication in a child warrants comprehensive evaluation. Some believe that siblings and children of patients with thrombosis should be tested for thrombophilia. I take a different approach.

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I consider thrombophilia in pediatric patients with unprovoked thrombosis, recurrent thrombosis, and/or extensive thrombosis. For patients with a strong family history, I recommend evaluation of the affected family member (when possible) to allow tailoring of laboratory testing in an unaffected relative. In general, I do not screen for thrombophilia in a child without a thrombotic complication. The World Health Organization argues against screening before prescribing hormonal contraception, because we’d have to screen tens of thousands of young women to prevent a severe blood clot or death.¹ Further, screening would significantly limit contraceptive prescriptions, leading to an increase in teen pregnancy. Pregnancy doubles the risk of clotting compared to hormonal contraception.

I find the estimation of absolute risk for an individual patient is far more valuable than relative risk assessments.² Let’s take the example of a 16 year old who is an unknown carrier for factor V Leiden and is starting hormonal contraception. The relative risk of venous thrombosis for a carrier of factor V Leiden (~5-fold) and hormonal contraception (~3-fold) in the same patient is not 15-fold, but is up to 35-fold. Despite this 35-fold increase in relative risk, her absolute risk is still only 0.35% per year (35 x 10/100,000 annual risk for venous thrombosis in a teenager). Remember that 90% of factor V Leiden carriers never experience thrombosis in their lifetime, and that 5% of Caucasians in the United States are carriers of this mutation. This means that 1 in 20 prescriptions for birth control pills is unsuspectedly given to carriers of factor V Leiden. It is important to consider the indication for these products (eg, acne, dysmenorrhea, contraception) and the fact that some options have less thrombotic risk than others.

In my experience with thrombophilia evaluations, there are several important pitfalls. Even in 2015, no list of laboratory tests for thrombophilia can rule out all hereditary and acquired blood clotting risk. “Normal” results often lead to false reassurance. Abnormalities in tests of minor or unclear clinical significance may lead to heightened anxiety and over-vigilance. Laboratory testing is expensive, ranging from several hundreds to thousands of dollars, depending on how many tests (especially genetic) are included.

Active areas of research interest in this field include: studies of direct oral anticoagulants and length of therapy in children with thrombosis; understanding when to consider interventional approaches, prevention, and treatment of post-thrombotic syndrome; and risk stratification and prevention of thrombosis in hospitalized children. For most pediatric patients, a single risk factor is insufficient to cause thrombosis. The risk factors for thrombosis are well established: central lines, immobility, inflammation, obesity, hormonal contraception, personal/family history, and several specific disease or anatomic states. Standardized risk assessment and improved calculation of combined risk factors for pediatric thrombosis would be a significant improvement in our field.

References

1. World Health Organization. WHO medical eligibility criteria wheel for contraceptive use–2008 update. Geneva, Switzerland: World Health Organization; 2009. http://apps.who.int/iris/bitstream/10665/44096/1/9789241547710_eng.pdf. Accessed October 6, 2015.

2. Trenor CC 3rd, Chung RJ, Michelson AD, et al. Hormonal contraception and thrombotic risk: a multidisciplinary approach. Pediatrics. 2011;127(2):347-357.

Cameron Trenor, MD, is an assistant professor of pediatrics, Harvard Medical School, and Division of Hematology/Oncology, Boston Children’s Hospital, Massachusetts.