Pediatric Syncope

Hx: A young teenager presents with syncope. Parents note he had 2 episodes today without any preceding problems but the patient notes some mild lightheadedness prior to both episodes. He denies any other symptoms and has no complaints now. No pain. Medical history is positive only for mild reactive airway disease. Parents note a family history of hypercoagulability involving only one parent, possibly anti-thrombin III deficiency, but the patient has no history of testing or symptoms.

Exam:
Vitals: HR 75, BP 120/70, Resp 12, sat 100% on room air, temp 98.6 F (37C)
General: no distress, sitting up.
HEENT: normal
Resp: clear bilaterally
Cardiovascular: regular, no murmurs, normal pulses all extremities
Abdomen: non-tender, no masses.
Extremities: warm, no deformity.
Neuro: awake, alert, normal motor and sensory.

ED evaluation:

• EKG #1- ST elevation in III and aVF with T wave inversion and ST depression in I and aVL. Sinus, rate 75

• A troponin I and d-dimer are ordered due to the abnormal EKG and show: trop <0.01 (normal) and D-Dimer 1.5 (elevated)
• CT pulmonary angiogram is performed and is normal.
• EKG #2 one hour later – Slightly improved ST elevation in III and aVF with new q wave in III and improving ST depressions in I and aVL

• EKG #3 at 2 hours- improving ST elevation in III and aVF with persistent q wave in III and improving ST depressions in I and aVL

• Troponin I# 2 at 2 hours = elevated at 0.1 (nl <0.04)
• EKG #4 and 5 – resolution of ST elevation in III and aVF with deep q wave in III. Also improved changes in I and aVL

• Troponin I #3 = elevated at 1.5 (nl<0.04)
• During this evaluation consultation is made with pediatric cardiology and the patient is flown to a children’s hospital for further evaluation.

Hospital Evaluation:

• The patient is admitted to a children’s hospital ICU
• An echo demonstrates focal inferior wall motion abnormality leading to emergent heart catheterization
• Heart cath demonstrates 100% occluded RCA which is successfully re-perfused and stented. Comment is made that a smooth plaque is seen at the stenosis point leading to a diagnosis of primary coronary thrombosis, not an embolic thrombosis. No congenital anomalies are noted.

Discussion:
This case is exceptionally rare. However, it serves as an excellent example of how easy it can be to dismiss a diagnosis because it is rare, also known as the “zebra retreat” cognitive bias. The physician caring for this patient could easily have dismissed the complaint of syncope in a teenager and diagnosed a far more common, vasovagal episode. In addition, the physician might have dismissed the initial EKG and stopped before ordering lab work. Lastly, repeating the EKG and following the changes could have easily been criticized as unnecessary given the patient’s age. However, following the standard (adult) protocol of repeating EKGs and troponins led to the correct diagnosis. The “zebra retreat” bias simply states that a physician may “retreat” or avoid investigating a diagnosis due to its classification as rare. This may occur as a result of pressures to reduce diagnostic testing or utilization, or pressures to complete more rapid evaluations. Regardless of the cause, a physician making this cognitive bias will withhold further investigation and dismiss the possibility of a rare diagnosis in the face of evidence to the contrary.

Antithrombin III deficiency is a defect in the antithrombin gene. The antithrombin anticoagulant inactivates thrombin, and clotting factors IXa, Xa, XIa and XIIa. The deficiency can be inherited or acquired. Inherited deficiency is autosomal dominant and genetic testing can determine homozygous or heterozygous states. Typically, homozygous states present early in childhood and lead to more severe thromobotic complications, especially involving the arterial system. The disease is rare, reported as 1:2000 to 1:5000 symptomatic patients (those with clots).

The disease is further categorized into two types:

• Type 1- decreased levels of AT3 as well as decreased activity. Homozygous type I is fatal.
• Type 2- normal levels of the protein, but decreased activity. This type is further sub-categorized into two groups depending on the heparin binding site activity of the AT3 protein.

It is important to note that mutation at the gene does not necessarily result in clinical disease. A number of mutations of the gene have been reported and are currently collected in the antithrombin mutation database.

Inherited anti-thrombin III deficiency occurs when the protein production is impaired due to liver disease, coumadin therapy, or asparginase (chemotherapy) use. It can also occur due to protein loss as occurs in nephrotic syndrome, or due to a consumptive state like disseminated intravacular coagulopathy (DIC) or thrombosis.

When to test? Generally, testing for hypercoagulability is not performed unless certain conditions exist.
1) Thrombosis with a family history of disease.
2) Thrombosis with an atypical presentation
3) Child with thromboemblism
4) Suspected heparin resistance.
5) Asparginase chemotherapy or ECMO use
6) Asymptomatic patient with a family member who has hereditaary AT3 deficiency and complications.
(Levels should be tested when the acute thrombotic event has resolved and the patient is not on an anticoagulant.)

References:
https://lifeinthefastlane.com/ccc/cognitive-dispositions-to-respond/
https://www.ncbi.nlm.nih.gov/pubmed/22961244
https://www.ncbi.nlm.nih.gov/pubmed/10930236
https://www.ijsr.net/archive/v5i8/ART2016597.pdf 
https://www.hemophilia.org/sites/default/files/document/files/InheritedAntithrombinDeficiency.pdf
http://www.ihtc.org/medical-professionals/blood-disorders/clotting-disorders/inherited-causes-of-thrombosis/#antithrombin
https://www.imperial.ac.uk/department-of-medicine/research/experimental-medicine/haematology/haemostasis-and-thrombosis/database/
https://www.uptodate.com/contents/antithrombin-deficiency (subscription required)