November 10-15

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Pediatric clots more common than rheumatologists realize


4 minutes

The conventional wisdom that children are less likely to have thrombotic events than are adults is largely true — except in rheumatology.

Children with early onset lupus and other conditions associated with antiphospholipid antibodies have a dramatically elevated risk of thrombosis.

Patricia Massicotte, MD

“Children with antiphospholipid antibodies behave as adults in terms of thrombosis,” said Patricia Massicotte, MD, Peter Olley Endowed Chair of Pediatric Thrombosis at the University of Alberta Stollery Children’s Hospital in Edmonton. “These children suffer morbidity and mortality the way adults do from clots.”

Dr. Massicotte will discuss the latest data on treating pediatric clots during a clinical symposium on Clots in Children: Where They Come From and What to Do With Them from 8:30 – 10:00 am Sunday. Children are relatively protected from thrombotic events compared to adults, she said, but that relative protection disappears in high-risk groups. Children with organ transplants, severe infections, central lines, antiphospholipid syndrome, and other serious conditions are at elevated risk for thrombotic events.

Tadej Avcin, MD, PhD

“Antiphospholipid antibodies can cause either venous or arterial or small vessel thrombosis in any organ,” said Tadej Avcin, MD, PhD, Head of Allergy, Rheumatology and Clinical Immunology at Children’s Hospital, Ljubljana University Hospital in Slovenia. “Some coagulation disorders show some preference in the vascular tree, but antiphospholipid antibodies can cause thrombosis in any organ and in any size vessel. Antiphospholipid antibodies are the most common autoimmune coagulation disorder in children.”

Antiphospholipid antibodies have multiple cellular and molecular effects, said Dr. Avcin, who will present during this symposium. They can activate endothelial cells, platelets, and leukocytes such as monocytes and neutrophils. Antiphospholipid antibodies also promote complement activation, inhibit physiological anticoagulants such as activated protein C and antithrombin, and interfere with fibrinolysis.

From a clinical perspective, not all antiphospholipid antibodies are equally pathogenic. The most clinically relevant are antibodies to cardiolipin, beta-2 glycoprotein 1, and lupus anticoagulants. Thrombotic risk is related to the level of antiphospholipid antibodies and the persistence of antibodies. Children who consistently test positive for all three subtypes of antiphospholipid antibodies are at highest risk for future thrombotic events.

“Every child who presents with thrombosis should be tested for antiphospholipid antibodies,” Dr. Avcin said. “And we suggest that every child who presents with early onset SLE be tested at the time of diagnosis and at least once yearly thereafter. And every child who presents with nonthrombotic clinical features associated with antiphospholipid antibodies should be tested. That includes features like unexplained thrombocytopenia, hemolytic anemia, livedo reticularis, Raynaud’s phenomenon, and neurologic manifestations such as chorea.”

Treatment of antiphospholipid antibodies can be a moving target. Dr. Avcin said asymptomatic children whose antiphospholipid antibodies were identified accidentally are more appropriate for observation than active treatment. Those with early onset lupus and no history of thrombosis should receive primary thromboprophylaxis, most often hydroxychloroquine and possibly low-dose aspirin. Children with a history of thrombosis who test positive for antiphospholipid antibodies need anticoagulation therapy.

“Treatment is usually based on adult guidelines because nearly all of the studies have been in adults,” Dr. Massicotte said. “The problem is that none of these formulations are tailored for children. You have to smash them and remix them to create something that is more appropriate for a child-sized patient.”

A second problem in calculating pediatric dosing is differences in both pharmacodynamics and pharmacokinetics between adults and children. A pediatric dose that appears to be appropriate based on body weight may be dramatically wrong based on pediatric absorption and clearance rates.

“Children are very different from adults as far as hemostasis goes,” Dr. Massicotte said. “We are giving adult drugs to non-adults, knowing that they absorb these drugs and clear them in ways that are very different from adults. We are fooling ourselves if we think we can treat children in the same ways we treat adults using the same medications.”

The relative lack of pediatric dosing data is beginning to change, she said. Several new oral anticoagulants have been approved in recent years. And while they were initially approved for adults, manufacturers are conducting global pediatric trials.

“Regulatory bodies have required pharma companies to come up with pediatric formulations of their new products,” she said. “These formulations have to be easy to give from neonates to adolescents, they have to taste good, and they have to be easy for parents to administer because many of these medications will be continued at home. We are studying these new blood thinners in children in terms of absorption and excretion so we can home in on a pediatric dosing range and not try to scale down an adult dose for a child who weighs less.”