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CASE REPORT PEER REVIEWED | OPEN ACCESS Venous thromboembolism in children: A rare case report

Ashnita Ashvini Krishna, Alok Kumar Dubey

ABSTRACT How to cite this article

Introduction: Venous thromboembolism (VTE) Krishna AA, Dubey AK. Venous thromboembolism in is an uncommon presentation in the pediatric children: A rare case report. Int J Case Rep Images population. Although its incidence is 60 times less 2019;10:101054Z01AK2019. in children compared to adults, VTE is gaining increased importance due to the difficulty in investigating its cause, lack of evidence-based Article ID: 101054Z01AK2019 established treatment guidelines, and increased morbidity and mortality. Case Report: This is a case report of a 3-year-old child who was ********* being treated for pneumonia and was noticed doi: 10.5348/101054Z01AK2019CR to have diffuse edema on right chest wall and right upper extremity. Doppler ultrasound confirmed thrombosis of right subclavian and internal jugular veins. The patient was treated INTRODUCTION with anticoagulants but succumbed before the actual cause of VTE could be found. Bone Venous thromboembolism (VTE) is relatively marrow biopsy results obtained five days later uncommon in the pediatric population. The annual showed findings suggestive of myelodysplastic incidence of VTE in children is 0.07–0.14 per 10,000 syndrome (MDS) versus reactive causes such as children, or 5.3 per 10,000 hospital admissions of systemic lupus erythematosus (SLE) and human children, and 24 per 10,000 admissions to neonatal immunodeficiency virus (HIV). Conclusion: intensive care units (ICUs) [1] compared to 8.8 per This case has been reported for the rarity of the 10,000 in adults [2]. Although the incidence of VTE condition, the many difficulties faced in working is remarkably lower in children compared to adults, up to reach a diagnosis and the absence of pediatric VTE is gaining increasing importance because standardized guidelines for treatment in children of the difficulty in investigating its cause, lack of validated compared to adults. methods of treatment, and the severity of disease leading to serious morbidity and mortality. Keywords: Anticoagulant therapy, Pediatrics, We report a case of VTE for its rarity and highlight the Venous thromboembolism challenges in investigating, diagnosing, and treating this patient.

Ashnita Ashvini Krishna1, Alok Kumar Dubey2 CASE REPORT Affiliations: 1Registrar, Department of Paediatrics, Lautoka Hospital, Lautoka, Fiji; 2MD, Paediatrics, MPhil (HHSM), Pro- A 3-year-old Fijian of Indian descent previously fessor, Department of Paediatrics, College of Medicine, Nurs- well female presented with fever, shortness of breath, ing and Health Sciences, Fiji National University, Suva, Fiji. and bilateral periorbital puffiness for three days. There Corresponding Author: Ashnita Ashvini Krishna, Department was no other remarkable past history of any significant of Paediatrics, Lautoka Hospital, Lautoka, Fiji; E-mail: krish. illness. The child was born to non-consanguineous [email protected] parents after an uneventful antenatal period. Birth, nutritional, developmental history were all unremarkable. Immunizations was up-to-date. There Received: 15 August 2019 Accepted: 06 September 2019 was no significant family history. Initially assessed as Published: 26 September 2019 clinical nephrotic versus nephritic syndrome however

International Journal of Case Reports and Images, Vol. 10, 2019. ISSN: 0976-3198 Int J Case Rep Images 2019;10:101054Z01AK2019. Krishna et al. 2 www.ijcasereportsandimages.com this was ruled out by urine examination and absence of hypoalbunemia and hyperlipidemia. She was diagnosed as a case of pneumonia clinically and radiologically, and was being treated with crystalline penicillin and gentamicin. On day four of admission she developed swelling of her right eyes, upper and lower limbs that progressively increased over the next day to involve neck, shoulder, and chest wall on the right side. Given the clinical suspicion of vascular occlusion a right upper limb Doppler study was done which showed jugular vein thrombosis with no definite vascular flow within. Subclavian vein was also completely thrombosed and incompressible. The patient was immediately transferred to ICU and commenced on heparin infusion. Examination revealed weight of 14 kg on admission but she gained more as her edema progressed specially on the right (Figure 1). The patient developed bilateral pleural effusion necessitating ventilation. She also developed ascites. Liver was palpable four finger breadths below the right costal margin, smooth, and non-tender. Genitalia was normal but right labia (Figure 2) was massively swollen by day 14 of admission. Fluid was oozing from all procedural sites. Initial investigation profile showed hemoglobin (Hb) of 8.5 g/dL with microcytosis and hypochromia. Some atypical and increased platelets were noted. culture grew Staphylococcus aureus sensitive to penicillin. Erythrocyte sedimentation rate (ESR) Figure 1: Generalized edema over face, chest, abdomen, and using the Westergrens method was normal (20 mm/h). limbs mostly on the right. Reticulocytes were 7.9%. Hepatitis and venereal disease research laboratory (VDRL) serology were negative. Pleural aspirate had red cells with 1600 white blood cells/mm3 which reduced to 320 white blood cells/mm3 on a repeat tap five days later. Biochemistry analysis [glucose 6.7 mmol, total protein 1 g/L, albumin 18, lactate dehydrogenase (LDH) 234 U/L] showed effusion was transudative in nature. No malignant cells seen. Culture was negative and no acid-fast bacilli (AFB) were seen. Ascitic fluid also had red blood cells and 160 white cells/ mm3, cultures were negative, glucose 6.7 mmol, total protein 19 g/L, Alb 10.2 g/L, LDH 234 U/L. The serum ascites albumin gradient was >1.1 g/dL indicating portal hypertension, negative for malignant cells. Her liver functions deteriorated over the course of admission. Antinuclear antibodies (ANA) and double stranded DNA (DsDNA) done to rule out SLE were also negative. Computed tomography (CT) scan revealed multifocal segments of venous thrombosis involving right internal jugular vein (Figure 3), left brachiocephalic, main portal vein, superior mesenteric, and hepatic veins. There was no obvious neck thoracic or abdominopelvic mass. Moderate ascites were with bilateral pleural effusion. Liver showed inhomogeneous enhancements/nutmeg liver with thrombosis of hepatic veins (Figure 4). Liver biopsy was contemplated, however poor general condition Figure 2: Right labial swelling and distended abdomen. and deranged coagulation profile precluded the invasive procedure.

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Figure 3: Thrombosis of right internal jugular vein.

Figure 5: Marrow fragment which is hypocellular for the age of patient.

Figure 4: Contrast CT scan of liver showing inhomogeneous enhancements/nutmeg liver appearance (A), with thrombosis of hepatic veins (absence of contrast in portal veins) (B).

Troponin was normal. Echo study was also normal. Uric acid (UA) 616 umol/L and LDH 3498 U/L were extremely elevated which lead to the clinical suspicion of lymphoreticular malignancy mainly Burkitt’s (BL) as a cause of the thrombosis. Burkitt’s are known to present either by obstruction of the structures with lumen like blood vessels, bones, compression of structures, infiltration, or by tumor lysis with LDH and Figure 6: (A) Large agranular lymphoblast with cytoplasmic urate rise. In view of systemic vein thrombosis and vacoulation, (B) myeloid cell with abnormal cytoplasmic picture of tumor lysis, possibility of lymphoreticular vacoulation, (C) dysplastic monolobed . malignancy and autoimmune disorder were entertained. Vanillylmandelic acid (VMA) estimation was requisitioned to rule out an occult neuroblastoma, however, could not be done for want of facility. Protein C, protein S, and DISCUSSION antithrombin III deficiency and factor V Leiden and prothrombin gene mutation could not be determined for The incidence of VTE in children is low, due to the same reason. Bone marrow aspirate was done after 14 them having protective mechanisms, e.g., deficiency of days of investigations and while awaiting official reports coagulation factors leading to decreased generation of the patient was started on hyperhydration 125 mL/BSA/h thrombin, increased capacity of α2-macroglobulin to and methylprednisolone. inhibit thrombin, enhanced antithrombotic potential of The patient continued to deteriorate each day with vessel wall, and children not being exposed to thrombotic no success in finding the cause of thrombosis. Warfarin predictors like smoking and antiphospholipid antibodies was commenced along with heparin on the second day (aPL) [3]. of heparin itself, coagulation profile was monitored and Among the many causes of thromboembolism on day nine heparin was ceased. Warfarin continued to (TE) in children, central venous catheter is the most maintain international normalized ratio (INR) within 2–3. important acquired trigger contributing to more than The patient succumbed on day 17 of admission 90% of neonatal venous thrombosis and more than without answers to her illness. The bone marrow biopsy 50% of all cases in other age groups [4, 5]. More than result (Figures 5 and 6) obtained five days after the loss of 90% of children with VTE have ≥2 predisposing factors patient was suggestive of hematological malignancy like [6]. Other risk factors include malignancy, infection, MDS versus autoimmune disorders like HIV/SLE. trauma, surgery, congenital heart disease, and lupus.

International Journal of Case Reports and Images, Vol. 10, 2019. ISSN: 0976-3198 Int J Case Rep Images 2019;10:101054Z01AK2019. Krishna et al. 4 www.ijcasereportsandimages.com Congenital prothrombotic conditions include factor V VTE is higher in the presence of lower CD4+ cell counts, Leiden mutation (G1691A), prothrombin gene mutation, there are reports of thrombosis occurring with CD4+ cell and deficiencies of antithrombin III (G20210A), protein counts as high as 800 cells/mm3, suggesting that the C, and protein S. risk of thrombosis is not completely confined to patients Acute lymphoblastic leukemia (ALL) is the most with end-stage disease [14]. Advanced HIV disease and common cancer associated with thrombosis in children opportunistic infections is a risk factor for thrombosis with rates varying from 1.1% to 36.7% and an average of [17, 18]. Venous thromboembolism is most common with 3.2% [7]. cytomegalovirus and Pneumcystis jirovecii pneumonia In one retrospective study of 726 children with cancer, (PCP) and Mycobacterium avium-intracellulare [19, the risk of TE was highest with ALL, followed by sarcoma 20]. In fact, P. jirovecii pneumonia patients with HIV and lymphoma, and the lowest risk was seen in children have been shown to have a high rate of concurrent with brain tumors [8]. Data based on small studies antiphospholipid syndrome that may increase the risk for estimate that the prevalence of TE is 11% in children with developing VTE [21]. acute myeloid leukemia (AML) and 12% in those with Pediatric patients with SLE and aPL, specifically lupus lymphoma [9, 10]. The clinical suspicion of BL was high anticoagulants (LAC) are at high risk of developing TE in this patient as serum LDH and UA were high. Burkitt’s [22]. According to some authors, thrombotic events are lymphoma typically presents with rapidly growing tumor the first complications of SLE after reactivation (“flares”) masses and has very high serum LDH and elevated UA of the disease and infections [23]. A study by Levy et al. levels. Burkitt’s lymphoma comprises 30% of pediatric reviewed data on 149 pediatric SLE patients treated over lymphomas [11]. Bone marrow was not suggestive of 10 years. In all, 24 patients (16%) were LAC positive, and malignancy but of MDS versus autoimmune disorders 21 TE occurred in 13 of these LAC positive patients (54% like SLE/HIV. This patient could well be having HIV, incidence of TE in LAC positive patients). Systemic lupus one test that was missed in our investigation while in erythematosus, however, was ruled out in our patient. search for more complicated diseases. Systemic lupus For the diagnosis of VTE, Doppler ultrasonography erythematosus was ruled out. The evidence for VTE in (USS), venography, CT, and magnetic resonance imaging pediatric patients with MDS is lacking. Adult studies state (MRI) can be used. Venography is rarely used as it is that the cause of death in MDS patients is usually related invasive, painful, and difficult to access in children. to the consequences of the leukemic evolution or to clinical Noninvasive Doppler USS should be the first modality events outside leukemia, such as cardiac failure, infection, to diagnose thrombosis in children, especially in lower hemorrhage, and hepatic cirrhosis [12]. Myelodysplastic extremities. Doppler USS may not detect thrombosis in syndrome patients have a low baseline risk of thrombosis upper extremities or pelvis in children [24]. Computed due to the high frequency of thrombocytopenia and severe tomography with intravenous contrast is used to evaluate anemia. The vascular risk seems to increase significantly the upper venous system and abdominal and pelvic when chemotherapeutic drugs, such as thalidomide or venous systems. Ventilation-perfusion radionucleotide lenalidomide, are used in association with erythropoiesis lung scanning and helical or spiral CT or MRI angiography stimulating agents, which do not seem to increase the are used to diagnose pulmonary embolism. Magnetic thrombotic risk when used alone [13]. Whether this resonance imaging and magnetic resonance angiography patient was a true case of MDS or not is still a question in (MRA) are recommended to confirm the diagnosis of our minds given the lack of data. cerebrovascular occlusion, superior vena cava, and Human immunodeficiency virus infection has also proximal subclavian veins. Echocardiography can detect been recognized as a prothrombotic condition and is cardiac and proximal superior vena cava thrombi [6]. associated with a two- to tenfold increased risk of venous The mainstay of treatment for pediatric VTE is thrombosis in comparison with a general population of anticoagulation. Recommendations for antithrombotic the same age. Studies on pediatric HIV versus VTE are treatment are based on small-scale studies in children and not available. In general, VTE frequency among HIV- most of the guidelines are adopted from adult protocols infected patients ranges from 0.19% to 7.63%/year [3]. Unfractionated heparin (UFH) is mostly used for [14]. Abnormalities leading to hypercoagulable state the initial treatment because of its short half-life [6]. such as presence of aPL and the lupus anticoagulant; Heparin acts by enhancing the activity of antithrombin. deficiencies of protein C, protein S, heparin cofactor II, Low molecular weight heparin (LMWH) with anti-Xa and antithrombin; and increased levels of von Willebrand activity can also be used and is preferred in the pediatric factor and D dimers have been reported in patients with population as it can be administered subcutaneously and HIV who had thrombotic disease. These abnormalities has lower risk of heparin-induced thrombocytopenia correlate with the severity of HIV-associated and osteoporosis [24]. Its pharmacokinetics are more immunosuppression as measured by CD4+ cell counts. predictable than UFH, thereby minimizing the frequency Several studies confirmed that there is a higher incidence of monitoring. Low molecular weight heparin does not of venous thrombosis in patients with low CD4 counts interfere with diet or drugs, a recurrent problem with oral [15, 16], however, the exact mechanisms by which this anticoagulants [6]. However UFH is preferred in patients phenomenon occurs is unclear. Although the frequency of with risk of bleeding and compromised renal function

International Journal of Case Reports and Images, Vol. 10, 2019. ISSN: 0976-3198 Int J Case Rep Images 2019;10:101054Z01AK2019. Krishna et al. 5 www.ijcasereportsandimages.com [24]. The therapeutic range of UFH is 0.3–0.7 anti-Xa The recurrence rate of VTE is approximately 3% activity units/mL and LMWH is 0.5–1.0 anti-Xa activity of neonates, 8% in older children, and 21% of children units/mL [24], however, this is not how monitoring was with idiopathic VTE, and the mortality rate of pediatric carried out for this patient out of want of facility. Activated pulmonary embolism is 2.2% [29]. partial thromboplastin time (aPTT) was used. Obtaining The short-term complications are major hemorrhage samples for coagulation profile was also a challenge for us due to thrombosis or secondary to anticoagulation and as the patient was very edematous. Vitamin K antagonists post-thrombotic syndrome characterized by edema, pain, act through inhibition of vitamin K dependent, post- skin pigmentation, and ulceration of affected limb. translational carboxylation of coagulation factors II, VII, IX, and X [25]. The most commonly used agent is warfarin. The anticoagulant activity is measured by the CONCLUSION prothrombin time (PT)/INR. Warfarin is, in general, not used in newborns and young infants because of the This case has been reported for the rarity of the difficulty of keeping the patient in the therapeutic range. condition, the many difficulties faced in working up Newborns have physiologically low levels of vitamin to reach a diagnosis and the absence of standardized K-dependent factors and variable intake of vitamin K (low guidelines for treatment in children compared to adults. in breast milk, high in formula, and the total parenteral Authors wish to raise the awareness of the practicing infusions); the blood sampling for INR monitoring is pediatricians about occurrence of VTE, the importance often difficult and there is no liquid formulation for of ruling out of thrombophilic abnormalities, HIV testing warfarin [25]. 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All relevant data are within the paper and its Supporting 26. Young G, Boshkov LK, Sullivan JE, et al. Argatroban Information files. therapy in pediatric patients requiring nonheparin anticoagulation: An open-label, safety, efficacy, and pharmacokinetic study. Pediatr Blood Cancer Copyright 2011;56(7):1103–9. © 2019 Ashnita Ashvini Krishna et al. This article is distributed under the terms of Creative Commons

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