Protein S Deficiency and Pulmonary Embolism in Children: A Case Report and Review of Literature

Oxygen 1 Abstract Protein S deficiency is a major risk factor for venous thromboembolism. Unprovoked life-threatening pulmonary embolism is uncommon in children; however, it can pose a diagnostic challenge, presenting in a non-specific and subtle way, masked by lack of typical presentation. Therefore, it is important for pediatrician to consider pulmonary embolism as a differential diagnosis for young patients presenting with severe unexplained parasternal chest pain with strong family history of thrombophilia and to have a low threshold for requesting appropriate investigations. Here we present a young patient with acute pulmonary embolism who was finally diagnosed as Type III Protein S deficiency.

were no red blood cells. A thrombophilia screening profile of this patient identified protein S deficiency (free protein S activity: 23%, and normal total protein S level). The activity of protein C and antithrombin III was within the normal limits (80% and 111%, respectively). Other results, including levels of homocysteine, factor II Prothrombin mutation G20210, factor V Leiden G1691A, anti-cardiolipin antibody, and anti-β2-glycoprotein IgM and IgG, all were negative. Therefore, a diagnosis of type III protein S deficiency (low free protein S activity and normal total protein S level) was established.
CT angiography showed picture suggestive of sub-massive acute pulmonary embolism including segmental and sub-segmental branches of both pulmonary arteries bilaterally (right more than left). There is patchy consolidation of the basal segment of the left lung with mild left pleural effusion. Furthermore, Leg veins color Doppler ultrasound was done and demonstrated no evidence of Deep Venous Thrombosis; moreover, in addition to, non-contrast Brain CT showed no acute abnormalities. The patient's father had been thrombosis-free, but he was also found to have PS deficiency with low PS activity (25%). No additional abnormalities were found in any of the subjects after testing for anticardiolipin antibodies, protein C level and activity, APCR-assay, factor V Leiden, and prothrombin G20210A.

Differential Diagnosis
Due to the degree of hypoxia, family history of thrombophilia and right heart strain, massive pulmonary embolism remained the most likely diagnosis that was confirmed with High resolution CT pulmonary angiography chest Table 1. Other differentials were also considered, such as community-acquired pneumonia with pleurisy due to hypoxia and chest pain, but this did not explain the significant chest pain and the patient did not have fever, productive cough or patchy shadowing on chest x-ray. A patient presenting with shortness of breath and low oxygen saturations raises the possibility of a pneumothorax, but clinical examination and chest x-ray did not correlate with this diagnosis. Importantly, cardiac causes such as an inherited cardiomyopathy or connective tissue disease causing acute valvular pathology or dissection should remain a high differential diagnosis but ECG, Echocardiography, and CT pulmonary angiography excluded cardiac causes. Thrombophilia profile confirmed diagnosis of acute pulmonary embolism with Type III Protein S deficiency.

Treatment and Outcome
His symptoms and signs subsided after treatment with Enoxaparin 1mg/kg/dose, every 12 hours and then maintenance 1mg/kg once daily. He has also been offered genetic counselling advice in the future, should he wish to start a family. Hematology consultation was done and planned for follow up and genetic counselling for the family.

Background
Pulmonary embolism is defined as a blockage of a pulmonary artery or one of its vessels by thrombus, fat, amniotic fluid or air.
A massive pulmonary embolism is characterized by hypotension, shock, right ventricular dysfunction and/or myocardial injury [1].
Venous thromboembolism (VTE) in a young, healthy patient is uncommon in the absence of a provoking factor. VTE occurs when ≥1 component of Virchow's triad is activated: stasis of blood flow, injury to the endothelial lining, and hypercoagulability of blood components. This is the most useful pathophysiological construct for thinking about thromboembolism in children [2]. Protein S (PS) deficiency contributes to 2% of all venous thromboembolisms presenting to accident and emergency and its deficiency is a major risk factor for venous thrombosis [3]. Studies of families with thrombophilia revealed that individuals with PS deficiency have a five to ten-folds higher risk for VTE than healthy relatives [4].
PS, a vitamin K-dependent glycoprotein, circulates in plasma in two forms: a complex with C4b-binding protein (bound form 60 % of total PS) and, in part as the functionally active form "free" protein S (40 %) [5]. PS, mainly synthesized in the liver and endothelial cells, is a cofactor of activated protein C (PC deficiency, the prophylaxis of VTE should be done in the presence of a major acquired risk factor for thrombosis [9].

Discussion
Unprovoked life-threatening pulmonary embolism is uncommon in children. They can pose a diagnostic challenge, presenting in a non-specific and subtle way, masked by lack of typical presentation. Interestingly, in the case described above, the patient presented with pulmonary embolism without any other acquired risk factors, indicating a potential abnormality in anticoagulation mechanisms. In our opinion, children presented with pulmonary embolism in the absence of precipitating factors need to be tested to identify whether there is a deficiency of PC, PS, or antithrombin III (AT III). In this case, the patient was found to be PS deficient.
Current evidence indicates that screening for inherited thrombophilia is appropriate in cases of VTE without obvious cause for VTE in patients with a positive family history of thrombosis; recurrent VTE; thrombosis at an unusual location; and developing blood, stasis and injury to the vessel wall [11]. Hereditary thrombophilias are associated with blood abnormalities and are characterized by venous thromboembolic events at a young age.
These are often unprovoked and recurrent, occurring at unusual locations and associated with a family history. Protein S deficiency predisposes to higher risk of venous thromboembolism than the general population with normal protein S level [12].
Obtaining a thorough family history on admission is very crucial to aid diagnosis. Interestingly, the patient's father had also PS deficiency, but was thrombosis-free, suggesting that a triggering event might have been involved in the patient's thrombus formation or the existence of a protective mechanism in the patient's father.

Summary
In summary, our report supports the view that PS deficiency should be taken into consideration for children with pulmonary embolism presenting with unexplained chest pain without obvious predisposing factors. Family history is extremely important in such cases and genetic studies could be valuable in the identification of PROS1 mutations for the PS deficient patients. Following the confirmation of massive pulmonary embolism, the patient received enoxaparin and genetic testing for the family is requested.

Learning Points
A. Protein S deficiency is a rare but important cause for venous thromboembolism in children. as thrombophilia, provides a very significant guidance in creating differential diagnoses, prioritizing investigations and providing the best care for the patient.
D. Pulmonary emboli can present with non-specific symptoms.
Meticulous clinical assessment of the patient as well as a low threshold for investigation on admission can be lifesaving.
E. children presenting with unprovoked pulmonary emboli, clinicians should consider inherited prothrombotic factors as a potential cause. A thrombophilia screen not only allows for better management of the patient, but also enables diagnosis of family members.
F. DNA-based testing is a useful diagnostic approach to diagnose protein S deficiency when more than one family member is affected with thrombosis.