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Clinical Conundrum: A toddler presenting with emesis and altered mental status
Amit Salkar, MD Nicole Bernard, MD Bhairav Patel, MD Robert Mignacca, MD Dell Children’s Medical Center of Central Texas 7th Annual Pediatric Conference Saturday, April 12, 2014
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Goals and Objectives Discuss what was learned from each step in obtaining this child's diagnosis Identify areas of improvement in patient care Explain areas of group learning from the case presentation
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Initial Presentation 22-month-old, previously healthy male presents to an outside hospital with 2 days of emesis He is appropriately fluid resuscitated for mild-to-moderate dehydration CBC reveals a Hgb of 4.7, MCV of 45.6, RDW of 26.6, and platelets of 525 Transferred to DCMC for further evaluation
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Initial Presentation Review of systems is negative
Child is otherwise healthy His mother states that he is a “picky eater” and consumes ~ ½ gallon of cow’s milk per day for the last several months Family history is unremarkable
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Initial Presentation Vital signs are significant for tachycardia
Physical exam reveals a pale, fussy but consolable toddler Otherwise, his physical exam is normal
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Initial Presentation Child continues to have emesis and low urine output Additional fluid resuscitation is given His mother seems worried, stating that he has been “very sleepy” and “not himself”
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Evaluation Acute emesis and altered mental status, and severe anemia raised suspicion for an intracranial process CT Head without contrast was ordered STAT, which led to the diagnosis
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Noncontrast CT Head
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GRE Sequence
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T1 Post-gadolinium Contrast
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Dynamic Post-gadolinium Contrast MR Venography
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Maximum Intensity Projection (MIP) Imaged from Postgad MRV
Vein of Trolard (lateral)
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DWI Sequence
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Diagnosis Deep cerebral venous thrombosis
Associated bilateral deep white matter and right caudate nucleus venous infarctions
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Hospital Course Hypercoagubility work-up was initiated
Transfused with 5 ml/kg of pRBCs Post-transfusion Hgb 4.3 (lower than initial value) Started on iron supplementation and Lovenox therapy Transfused again with pRBCs
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Hospital Course Although lethargy improved, patient continued to have some bouts of emesis and began complaining of headache Repeat imaging showed stable findings Symptoms were attributed to increase intracranial pressure from cerebral sinus venous thrombosis (CSVT)
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Hospital Course Symptoms of increased ICP gradually improved
Discharged home 8 days after admission Instructed to follow-up with Hematology for ongoing management of Lovenox therapy and iron deficiency anemia (IDA)
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Hypercoagulability Work-up
Hypercoagulability work-up initiated while inpatient reveals heterozygous mutation of the PT20210A allele
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Goals and Objectives Review CSVT in children, including definition, epidemiology, clinical manifestations, imaging, and risk factors Discuss the relationship between the PT20210A prothrombin gene mutation and CSVT Explore the association between IDA and CSVT
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Cerebral Sinus Venous Thrombosis in Children
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Definition of Ischemic Stroke
Ischemic stroke consists of Arterial ischemic stroke (AIS) Cerebral sinus venous thrombosis (CSVT) [1] Childhood stroke Cerebrovascular event in patients 30 days to 18 years of age [2] [1] Kirton A, deVeber G. Therapeutic Approaches and Advances in Pediatric Stroke. The Journal of the American Society for Experimental NeuroTherapeutics. 2006;3: [2] Lynch JL, Hirtz DG, deVeber G, Nelson KB. Report of the National Institue of Neurological Disorders and Stroke Workshop on Perinatal and Childhood Stroke. Pediatrics. 2002;109:
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Cerebral Venous Thrombosis
Defined as thrombotic occlusion of cerebral veins or sinuses Associated with venous infarction in ~ 50% of cases Proportion of AIS to CSVT is ~ 3:1 Venous congestion leads to focal cerebral edema progressing to venous infarction and hemorrhage [1] [1] Kirton A, deVeber G. Therapeutic Approaches and Advances in Pediatric Stroke. The Journal of the American Society for Experimental NeuroTherapeutics. 2006;3:
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Cerebral Sinus Venous Thrombosis
Reported incidence of 0.67 per 100,000 children per year CSVT was more common in neonates [3] [3] deVeber G, Andrew M, Adams C, et al. Cerebral sinovenous thrombosis in children. N Engl J Med. 2001;345:417–423.
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Neurologic Manifestations of CSVT in Children
Decreased level of consciousness Headache Focal neurological signs such as hemiparesis Cranial nerve palsies [3] [3] deVeber G, Andrew M, Adams C, et al. Cerebral sinovenous thrombosis in children. N Engl J Med. 2001;345:417–423.
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Deep Cerebral Venous System
Drains majority of deep gray nuclear structures Located in the ventricles and deep basal cisterns Choroidal, septal, and thalamostriate veins converge to form the paired internal cerebral veins Internal cerebral veins and basal veins of Rosenthal join to form the great vein of Galen, which joins the inferior sagittal sinus to form the straight sinus
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Deep Cerebral Venous System
Straight sinus drains to the torcular and subsequently to the transverse sinuses sigmoid sinuses internal jugular veins Variations of drainage are extremely common, which in part determines variable brain injury to thrombosis
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Figure 5 The spectrum of presentations of venous infarction caused by deep cerebral vein thrombosis. van den Bergh, Walter; van der Schaaf, Irene; van Gijn, Jan Neurology. 65(2): , July 26, 2005. Figure 5 Anatomy of the deep cerebral venous system. (A, B) Axial and sagittal view of deep venous system and basal ganglia: 1. caudate nucleus; 2. thalamus; 3. basal veins (veins of Rosenthal); 4. internal cerebral veins; 5. great cerebral vein (vein of Galen). (C, D) Axial and sagittal maximum intensity projection (MIP) images of the deep venous system. (E-F) Axial and sagittal MIP images; the deep venous system is demarcated in red. ©2005 American Academy of Neurology. Published by LWW_American Academy of Neurology. 2
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Normal Intracranial Venous Anatomy
Superior sagittal sinus Inferior sagittal sinus Superior sagittal sinus Straight sinus Internal cerebral veins Torcular Transverse sinus Basal vein of Rosenthal Sigmoid sinus Torcular
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Postcontrast MRV
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Venous Drainage
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Imaging Evaluation of Cerebral Venous System
Catheter angiography - gold standard Invasive (complications of stroke, groin hematoma, femoral artery injury) Highest radiation exposure CT angiography Excellent sensitivity Requires administration of iodinated contrast Radiation exposure
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Imaging Evaluation of Cerebral Venous System
MR venography Excellent sensitivity Can be done without contrast (although not as good as contrast enhanced MRV and not great for partial thrombosis) Typically contrast is given Ultrasound - acceptable for dural sinuses in neonate
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Two Additional Cases from the Past Two Years
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Risk Factors for CSVT in Children
Head and neck disorders 38% (of which 61% were infections) Otitis media, mastoiditis, and sinusitis (preschool children) Acute systemic diseases 31% Dehydration, sepsis [3] [3] deVeber G, Andrew M, Adams C, et al. Cerebral sinovenous thrombosis in children. N Engl J Med. 2001;345:417–423.
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Risk Factors for CSVT in Children
Chronic systemic diseases 54% Connective-tissue disorders Hematologic disorders Malignancy Cardiac disease Disorders requiring indwelling catheter [3] [3] deVeber G, Andrew M, Adams C, et al. Cerebral sinovenous thrombosis in children. N Engl J Med. 2001;345:417–423.
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Risk Factors for CSVT in Children
Coagulation disorders 32% Deficiencies in protein C, protein S, and antithrombin III, Factor V Leiden and PT20210A prothrombin gene mutations Presence of anticardiolipin antibody and Lupus anticoagulant [3] [3] deVeber G, Andrew M, Adams C, et al. Cerebral sinovenous thrombosis in children. N Engl J Med. 2001;345:417–423. The most common risk factors for CSVT are dehydration and prothrombotic disorders with others including infection, trauma, cancer/ chemotherapy, and systemic disease [deVeber 2001, Heller, Sebire] A number of risk factors are linked to the development of SVT, including head and neck infections, dehydration, perinatal complications, and coagulation disorders. In one study, prothrombotic abnormalities were present in half of children with SVT and many of these children had multiple risk factors. [19] deVeber G, Monagle P, Chan A, et al. Prothrombotic disorders in infants and children with cerebral thromboembolism. Arch Neurol. 1998;55:1539–1543. Five coagulation abnormalities are associated with thrombosis in children, including deficiencies in protein C, protein S, and antithrombin III, and the fVL and prothrombin A mutations. A study of cerebral thromboembolism that included 92 children from the Hospital for Sick Children in Toronto found coagulation abnormalities in 38% of children studied. [19] deVeber G, Monagle P, Chan A, et al. Prothrombotic disorders in infants and children with cerebral thromboembolism. Arch Neurol. 1998;55:1539–1543. Other studies report the frequency of prothrombotic states in children with CSVT is between 12 to 50%
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Risk Factors for CSVT in Children
Iron-deficiency anemia 2005 review of 42 cases of children with CSVT by Sebire et al. published in Brain 50% had probable IDA [4] Increasing number of case reports and reviews describing IDA as a risk factor for CSVT [5-9] [4] Sebire G, Tabarki B, Saunders D, et al. Cerebral venous sinus thrombosis in children: risk factors, presentation, diagnosis and outcome. Brain. 2005;128:477–489. [5] Hartfield DS, Lowry NJ, Keene DL, Yager JY. Iron Deficiency: A Cause of Stroke in Infants and Children. Pediatr Neurol.1997;16:50-53. [6] Benedict SL, Bonkowsky JL, Thompson JA, et al. Cerebral Sinovenous Thrombosis in Children: Another Reason to Treat Iron Deficiency Anemia. J Child Neurol. 2004;19: [7] Maguire JL, deVeber G, Parkin PC. Association Between Iron-Deficiency Anemia and Stroke in Young Children. Pediatrics. 2007;120: [8] Mehta PJ, Chapman S, Jayam-Trouth A, et al. Acute Ischemic Stroke Secondary to Iron Deficiency Anemia: A Case Report. Case Reports in Neurological Medicine. 2012; 2012: Article ID , 5 pages. doi: /2012/487080 [9] Azab SFA, Abdelsalam SM, Saleh SHA, et al. Iron deficiency anemia as a risk factor for cerebrovascular events in early childhood: a case-control study. Ann Hematol. 2014;93:
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MTHFR and Homocysteine
Common Low risk for pathology unless homocysteine is elevated If homocysteine is elevated, improvement can be seen with folic acid.
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Other Risk Factors for Thrombus
Obesity Inactivity Pregnancy hormones Anesthesia/surgery Crush injury Tobacco
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Overall Risk Assessment
Clinically, the balance between bleeding and clotting requires a significant change (or multiple less significant ones) to result in pathology
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Relationship between PT20210A Gene Mutation and CSVT
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Coagulation Cascade
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G20210A mutation Prothrombin (Factor II) functional point mutation on Cr 11 of non-coding region of prothrombin Increased protein expression [16-19] Increased protein stability [20] G20210A is a single nucleotide polymorphism (Guanine to adenine) at position located at the 3’ untranslated region of the non-coding region of the prothombin gene on chromosome 11. AT this time there is an unknown mechanism of increased thrombotic risk. 1)Functional mutation causing enhanced 3’-end formation, increased mRNA, and protein expression - Increased plasma concentration of prothrombin up to 30% in adults, however this is not reproduced in pediatric literature A pediatric study by Balasa et al. was not able to reproduce this, shows that increased prothrombin levels were not shown to be associated with this mutation alone. “Developmental homeostasis” : protein levels vary with age. Age related differences in amount of serum proteins between children and adults. May play a protective role against prothrombotic states, and why there are different rates of thrombosis in adult vs pediatric populations. 16. Andrew M. Developmetal homestasis: relevance to thromboembolic complications in pediatric pateints. Thromb Haemost. 1995; 47: 17. Kenet G, Nowak-Gottl U. Venous thromboembolism in neonates and children. Best Practice and research clinical haematology Sept; 25(3): 18. Balasa V, Gruppo RA, Glueck CJ, Stroop D, Becker A, Pillow A, Wang P.The relationship of muation in the MTHFR, prothrombin, and PAI-1 genes to plasma levels of homocysteine, prothrombin, and PAI-1 in children and adults. Thromb Haemost 1999: 81: 19. Poort SR, Rosendaal FR, Reigsma PH, Bertina RM. A common genetic variant in the 30-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 2) While one other study (Gelfi et al) proposes that increased glycosylation might in fact increase the stability of the protein. 20. Gelfi C, Vigano A, rpamonti M, Wait R, Begum S, Biguzzi E, Castaman G, Faioni EM. A proteomic analysis of changes in prothrombin and plasma proteins associated with the G20210A mutation. Proteomics, 2005 Jul; 4(7):2151-9 Bibio: Ceelie H, Sparrgaren-an Riel CC, Bertina RM, Vos HL. G20210A is a function mutation in the prothrombin gene; Effect on protein levels and 3’-end formation. J Thromb Haemos Jan; 2(1) Increased stability: The G-->A mutation at position of the prothrombin gene, localized in the 3'-polyadenylation untranslated region of the mRNA, is a recognized genetic risk factor for venous thromboembolism. The mechanism by which this base change confers an increased risk of thrombosis compared to noncarriers is undefined. Studies on the mRNA suggest enhanced cleavage site recognition and a change in the location of the 3'-cleavage/polyadenylation reaction, but no defined model has been proposed. The present study, based on proteomic investigation by two-dimensional gel electrophoresis and electrospray ionization (ESI) tandem mass spectrometry (MS/MS) protein identification, suggests that the G20210A mutation is associated with increased glycosylation of prothrombin, which confers greater stability to the protein. Additionally, proteomic investigation of pooled plasma showed that expression levels of six spots, three of them identified by ESI MS/MS, were altered in subjects carrying the mutation, suggesting a possible cooperative effect in the thrombotic risk increment induced by the mutation.
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Prevalence G20210A G20210a mutation 1-3% of general population
Prevalence rates of G20210a in pediatric patients with thrombosis have shown to be 4-10% Population Caucasians, with few Middle Eastern, and Hispanic incidence Rare in Asian and African American [20-22] Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associ- ated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996;88:3698–3703. [21] Rosendaal FR. Venous thrombosis: the role of genes, environment, and behavior. Hematology Am Soc Hematol Educ Program. 2005;1:1–12. [20] Coen Herak D, Radic Antolic M, Lenicek Krleza J, Pavic M, Dodig S, Duranovic V, et al. Inherited prothrombotic risk factors in children with stroke, transient ischemic attack, or migraine. Pediatrics April 2009; 123:4 e653-e660. Haywood S, Liesner R, Pindora S, Ganesan V. Thrombophilia and first arterial ischaemic stroke: a systematic review. Arch Dis Child 2005;90:402-5. [22] Kenet G, Lutkhoff LK, Albisetti M, Bernard T, Bonduel M, Brandao L, et al. Impact of thrombophilia on arterial ischemic stroke or cerebral sinovenous thrombosis in children: a systematic review & meta analysis of observational studies. Circulation 2010; Laugesaar R, Kahre T, Kolk A, Uustalu U, Kool P, Talvik T. Factor V Leiden and prothrombin 20210G>A [corrected] mutation and paediatric ischaemic stroke: a case-control study and two meta-analyses. Acta Pediatr 2010;99:
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Published frequencies of inherited prothrombotic risk factors and magnitude of association in childhood cerebral sinovenous thrombosis relative to healthy controls in different populations. Zadro R, Herak DC. Inherited prothrombitc risk factors in children with first ischemic stroke. Biochem Med (Zagreb). 2012;22 (3): Zadro R, Herak DC. Inherited prothrombitc risk factors in children with first ischemic stroke. Biochem Med (Zagreb). 2012;22 (3): [23]
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Inherited Risk Factor for CSVT
CSVT is associated with inherited prothrombotic risk Laugesaar et al. showed 3 fold increase risk of CSVT in children with PT G20210A, showing significant risk both on Meta-analysis (OR 11.9; 95%CI) and Case-control (OR 3.3; 95% CI) studies [24] While Arterial ischemic stroke (AIS) association with G20210a has mixed evidence. Have seen strong association with inherited prothrombotic risk alone, and even more strongly in conjunction with other risk factors. Cover: associated risk for prothrobotic RF for venous thromb, more in caucasians, older kids, commonly with other risk factors which are synergistic Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associ- ated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996;88:3698–3703. Rosendaal FR. Venous thrombosis: the role of genes, environment, and behavior. Hematology Am Soc Hematol Educ Program. 2005;1:1–12. Coen Herak D, Radic Antolic M, Lenicek Krleza J, Pavic M, Dodig S, Duranovic V, et al. Inherited prothrombotic risk factors in children with stroke, transient ischemic attack, or migraine. Pediatrics April 2009; 123:4 e653-e660. Haywood S, Liesner R, Pindora S, Ganesan V. Thrombophilia and first arterial ischaemic stroke: a systematic review. Arch Dis Child 2005;90:402-5. Kenet G, Lutkhoff LK, Albisetti M, Bernard T, Bonduel M, Brandao L, et al. Impact of thrombophilia on arterial ischemic stroke or cerebral sinovenous thrombosis in children: a systematic review & meta analysis of observational studies. Circulation 2010; [24] Laugesaar R, Kahre T, Kolk A, Uustalu U, Kool P, Talvik T. Factor V Leiden and prothrombin 20210G>A [corrected] mutation and paediatric ischaemic stroke: a case-control study and two meta-analyses. Acta Pediatr 2010;99:
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Clinical Manifestations
Retrospective review (Young et al.) of 374 thrombotic events in 26 hospital centers, 10% (38 children) had G20210A mutation [25] 92% of VT had an acquired risk factor 54% had an additional inherited risk factor Majority of VTE were older children (96% > 2 years) Prevalence rates of G20210a in pediatric patients with thrombosis have been shown to be 4-10%. In a retrospective review by Young et al. looking specifically at patients with thrombotic events in 26 hospital centers, 374 thrombotic events 10% (38 children) had G20210A mutation. (12% CVT) - 92% of venous thrombi had an additional acquired risk factor (catheter, malignancy, infection, immobilization, dehydration, ocp, lupus anticoagulant or anticardiolipin antibodies, trauma, congenital heart disease, nephrotic sydrome) - 54% had inherited risk factors: MTHFR, FVL, deficiency protein C/S, PAI-1, AT deficiency - Only 33% of arterial thrombosis had additional risk factors. Age association of arterial thrombi tended to be younger (75%) <2yo, whereas the majority of VTE were older children (96% >2yo). When excluding neonates the mean age were 3.3years and 10.6 years old respectively. OF 34 total venous thrombotic events 6 were CSVT 17.6% More common in extremities with half in extremities vs central. Location: Arterial 8 of 12 were CNS Venous 16 of 24 extremities, 9/34 central venous, 6/24 were CVT {CSVT manifested in 6 of 34 thrombotic events} all of these had an additional risk factor of dehydration, sinusitis, or malignancy The 3 PEs were all associated with DVT. Bibio: Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associ- ated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996;88:3698–3703. [25] Young G, Manco-Johnson M, Gil JC, Dimichele DM, Tarantino MD, Abshire T, Nugent DJ. Clinical Manifestations of the prothrombin G20210A mutation in children : A pediatric coagulation cosortium study. J Thromb Haemost. 2003; Rosendaal FR. Venous thrombosis: the role of genes, environment, and behavior. Hematology Am Soc Hematol Educ Program. 2005;1:1–12. Coen Herak D, Radic Antolic M, Lenicek Krleza J, Pavic M, Dodig S, Duranovic V, et al. Inherited prothrombotic risk factors in children with stroke, transient ischemic attack, or migraine. Pediatrics April 2009; 123:4 e653-e660. Haywood S, Liesner R, Pindora S, Ganesan V. Thrombophilia and first arterial ischaemic stroke: a systematic review. Arch Dis Child 2005;90:402-5. Kenet G, Lutkhoff LK, Albisetti M, Bernard T, Bonduel M, Brandao L, et al. Impact of thrombophilia on arterial ischemic stroke or cerebral sinovenous thrombosis in children: a systematic review & meta analysis of observational studies. Circulation 2010; Laugesaar R, Kahre T, Kolk A, Uustalu U, Kool P, Talvik T. Factor V Leiden and prothrombin 20210G>A [corrected] mutation and paediatric ischaemic stroke: a case-control study and two meta-analyses. Acta Pediatr 2010;99: Young G, Manco-Johnson M, Gill JC, Dimichele DM, Tarantino MD, Abshire T, Nugent DJ. Clinical Manifestations of the prothrombin G202010a mutation in children: a pediatric coagulation consortium study. J Thromb Haemost 2003;
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Clinical Manifestations
Excluding neonates the mean age was 10.6 years Only 25% with FH thrombotic event CSVT manifested in 6 of 34 thrombotic events Prevalence rates of G20210a in pediatric patients with thrombosis have been shown to be 4-10%. In a retrospective review by Young et al. looking specifically at patients with thrombotic events in 26 hospital centers, 374 thrombotic events 10% (38 children) had G20210A mutation. (12% CVT) - 92% of venous thrombi had an additional acquired risk factor (catheter, malignancy, infection, immobilization, dehydration, ocp, lupus anticoagulant or anticardiolipin antibodies, trauma, congenital heart disease, nephrotic sydrome) - 54% had inherited risk factors: MTHFR, FVL, deficiency protein C/S, PAI-1, AT deficiency - Only 33% of arterial thrombosis had additional risk factors. Age association of arterial thrombi tended to be younger (75%) <2yo, whereas the majority of VTE were older children (96% >2yo). When excluding neonates the mean age were 3.3years and 10.6 years old respectively. OF 34 total venous thrombotic events 6 were CSVT 17.6% More common in extremities with half in extremities vs central. Location: Arterial 8 of 12 were CNS Venous 16 of 24 extremities, 9/34 central venous, 6/24 were CVT {CSVT manifested in 6 of 34 thrombotic events} all of these had an additional risk factor of dehydration, sinusitis, or malignancy The 3 PEs were all associated with DVT. Bibio: Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associ- ated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996;88:3698–3703. [25] Young G, Manco-Johnson M, Gil JC, Dimichele DM, Tarantino MD, Abshire T, Nugent DJ. Clinical Manifestations of the prothrombin G20210A mutation in children : A pediatric coagulation cosortium study. J Thromb Haemost. 2003; Rosendaal FR. Venous thrombosis: the role of genes, environment, and behavior. Hematology Am Soc Hematol Educ Program. 2005;1:1–12. Coen Herak D, Radic Antolic M, Lenicek Krleza J, Pavic M, Dodig S, Duranovic V, et al. Inherited prothrombotic risk factors in children with stroke, transient ischemic attack, or migraine. Pediatrics April 2009; 123:4 e653-e660. Haywood S, Liesner R, Pindora S, Ganesan V. Thrombophilia and first arterial ischaemic stroke: a systematic review. Arch Dis Child 2005;90:402-5. Kenet G, Lutkhoff LK, Albisetti M, Bernard T, Bonduel M, Brandao L, et al. Impact of thrombophilia on arterial ischemic stroke or cerebral sinovenous thrombosis in children: a systematic review & meta analysis of observational studies. Circulation 2010; Laugesaar R, Kahre T, Kolk A, Uustalu U, Kool P, Talvik T. Factor V Leiden and prothrombin 20210G>A [corrected] mutation and paediatric ischaemic stroke: a case-control study and two meta-analyses. Acta Pediatr 2010;99: Young G, Manco-Johnson M, Gill JC, Dimichele DM, Tarantino MD, Abshire T, Nugent DJ. Clinical Manifestations of the prothrombin G202010a mutation in children: a pediatric coagulation consortium study. J Thromb Haemost 2003;
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Association between IDA and CSVT
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IDA and Risk of CSVT 2007 case-controlled study published in Pediatrics by Maguire JL, et. al. Studied children aged 12 to 38 months who were previously healthy with no identifiable risk factors for stroke Case patients had lower median hemoglobin levels and MCV and higher platelet counts [7] [7] Maguire JL, deVeber G, Parkin PC. Association Between Iron-Deficiency Anemia and Stroke in Young Children. Pediatrics. 2007;120: Case-controlled study conducted at University of Toronto Study looked at children aged 12 to 38 months who were previously healthy with no identifiable risk factors for stroke Stroke was defined as arterial ischemic stroke and sinovenous thrombosis Case patients had a lower median hemoglobin level and MCV and a higher platelet count Iron deficiency anemia was significantly more common among case patients Previously healthy children with stroke were 10 times more likely to have IDA (< 11 g/dl) than healthy children without stroke Children with IDA accounted for more than half of all stroke cases in children without underlying medical illness, suggesting IDA is a significant risk factor for stroke in healthy children Although healthy children who developed stroke were 5 times more likely to have thrombocytosis than children who did not develop stroke, there was no significant interaction between IDA and thrombocytosis
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IDA and Risk of CSVT 2007 case-controlled study published in Pediatrics by Maguire JL, et. al. Children with IDA accounted for more than half of all stroke cases Children with stroke were 10 times more likely to have IDA than controls [7] [7] Maguire JL, deVeber G, Parkin PC. Association Between Iron-Deficiency Anemia and Stroke in Young Children. Pediatrics. 2007;120: Case-controlled study conducted at University of Toronto Study looked at children aged 12 to 38 months who were previously healthy with no identifiable risk factors for stroke Stroke was defined as arterial ischemic stroke and sinovenous thrombosis Case patients had a lower median hemoglobin level and MCV and a higher platelet count Iron deficiency anemia was significantly more common among case patients Previously healthy children with stroke were 10 times more likely to have IDA (< 11 g/dl) than healthy children without stroke Children with IDA accounted for more than half of all stroke cases in children without underlying medical illness, suggesting IDA is a significant risk factor for stroke in healthy children Although healthy children who developed stroke were 5 times more likely to have thrombocytosis than children who did not develop stroke, there was no significant interaction between IDA and thrombocytosis
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IDA and Risk of CSVT 2014 case-controlled study published in Annals of Hematology Very similar to study by Maguire, except for having a higher number of case patients 57.1% of stroke cases had IDA and no other identified cause, compared to 26% of controls [9] [9] Azab SFA, Abdelsalam SM, Saleh SHA, et al. Iron deficiency anemia as a risk factor for cerebrovascular events in early childhood: a case-control study. Ann Hematol. 2014;93: Case-controlled study published this year, which is very similar to the study by Maguire, except for having a higher n 57.1% of stroke cases had IDA and no other identified cause, compared to 26% of controls Previous healthy children who developed stroke are 3.8 times more likely to have IDA than healthy children who do not develop stroke Significant interaction between IDA and thrombocytosis among studied cases
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IDA and Risk of CSVT 2014 case-controlled study published in Annals of Hematology Previous healthy children who developed stroke were 3.8 times more likely to have IDA than healthy children who did not develop stroke Significant interaction between IDA and thrombocytosis among studied cases [9] [9] Azab SFA, Abdelsalam SM, Saleh SHA, et al. Iron deficiency anemia as a risk factor for cerebrovascular events in early childhood: a case-control study. Ann Hematol. 2014;93: Case-controlled study published this year, which is very similar to the study by Maguire, except for having a higher n 57.1% of stroke cases had IDA and no other identified cause, compared to 26% of controls Previous healthy children who developed stroke are 3.8 times more likely to have IDA than healthy children who do not develop stroke Significant interaction between IDA and thrombocytosis among studied cases
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Mechanisms to Explain Association between IDA and CSVT
Hypercoaguable state directly related to iron-deficiency and/or anemia IDA causes microcytosis and reduced RBC deformability Turbulence replaces laminar blood flow, allowing platelets to come in contact with endothelium, initiating coagulation cascade and development of thrombus [6] [6] Benedict SL, Bonkowsky JL, Thompson JA, et al. Cerebral Sinovenous Thrombosis in Children: Another Reason to Treat Iron Deficiency Anemia. J Child Neurol. 2004;19: Mechanisms to explain association between IDA and childhood stroke Hypercoaguable state directly related to iron-deficiency and/or anemia • IDA causes microcytosis and reduced red blood cell deformability • Turbulent blood flow disrupts the usual laminar blood flow and allows platelets to come in contact with the endothelium, initiating the coagulation cascade and the development of thrombus Thrombocytosis secondary to IDA • Iron usually acts as an inhibitor of platelet production • This inhibition is lost in IDA, allowing a rise in megakaryocytes and an increase in platelet production • Iron is also required for the synthesis of essential platelet components and therefor is necessary for maximum platelet production above steady-state levels • When iron is replaced, there is an initial overcompensation of platelet production • EPO, which is increased in anemia, also stimulates megakaryocytes Anemic hypoxia • Mismatch between oxygen supply and end-artery oxygen demand leads to ischemia and infarction *Some case reports conjecture that venous stasis from dehydration is major factor in the development of venous thrombus
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Mechanisms to Explain Association between IDA and CSVT
Thrombocytosis secondary to IDA Iron inhibits platelet production, which explains thrombocytosis in IDA Iron also required for synthesis of essential platelet components and therefore needed for maximum platelet production above steady-state levels Bump in platelets observed when iron is initially replaced [6] [6] Benedict SL, Bonkowsky JL, Thompson JA, et al. Cerebral Sinovenous Thrombosis in Children: Another Reason to Treat Iron Deficiency Anemia. J Child Neurol. 2004;19: Mechanisms to explain association between IDA and childhood stroke Hypercoaguable state directly related to iron-deficiency and/or anemia • IDA causes microcytosis and reduced red blood cell deformability • Turbulent blood flow disrupts the usual laminar blood flow and allows platelets to come in contact with the endothelium, initiating the coagulation cascade and the development of thrombus Thrombocytosis secondary to IDA • Iron usually acts as an inhibitor of platelet production • This inhibition is lost in IDA, allowing a rise in megakaryocytes and an increase in platelet production • Iron is also required for the synthesis of essential platelet components and therefor is necessary for maximum platelet production above steady-state levels • When iron is replaced, there is an initial overcompensation of platelet production • EPO, which is increased in anemia, also stimulates megakaryocytes Anemic hypoxia • Mismatch between oxygen supply and end-artery oxygen demand leads to ischemia and infarction *Some case reports conjecture that venous stasis from dehydration is major factor in the development of venous thrombus
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Mechanisms to Explain Association between IDA and CSVT
Anemic hypoxia Mismatch between oxygen supply and end-artery oxygen demand leads to ischemia and infarction [2] [2] Benedict SL, Bonkowsky JL, Thompson JA, et al. Cerebral Sinovenous Thrombosis in Children: Another Reason to Treat Iron Deficiency Anemia. J Child Neurol. 2004;19: Mechanisms to explain association between IDA and childhood stroke Hypercoaguable state directly related to iron-deficiency and/or anemia • IDA causes microcytosis and reduced red blood cell deformability • Turbulent blood flow disrupts the usual laminar blood flow and allows platelets to come in contact with the endothelium, initiating the coagulation cascade and the development of thrombus Thrombocytosis secondary to IDA • Iron usually acts as an inhibitor of platelet production • This inhibition is lost in IDA, allowing a rise in megakaryocytes and an increase in platelet production • Iron is also required for the synthesis of essential platelet components and therefor is necessary for maximum platelet production above steady-state levels • When iron is replaced, there is an initial overcompensation of platelet production • EPO, which is increased in anemia, also stimulates megakaryocytes Anemic hypoxia • Mismatch between oxygen supply and end-artery oxygen demand leads to ischemia and infarction *Some case reports conjecture that venous stasis from dehydration is major factor in the development of venous thrombus
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Case Wrap-up Patient continues to follow-up with Hematology for ongoing management of anticoagulation (6 months duration) and IDA Repeat MRV Brain with contrast ~ 1 month after discharge showed resolution of thrombosis
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Case Wrap-up No evidence of neurologically sequelae
Due for repeat imaging around the time of discontinuation of Lovenox
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Lessons for the Clinician
Include intracranial process on differential for children presenting with emesis Recognize risk factors for CSVT Consider IDA as potential risk factor for CSVT, although the literature is still evolving Prevention of IDA can be simple as taking a good diet history and educating parents about proper nutrition
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References [1] Kirton A, deVeber G. Therapeutic Approaches and Advances in Pediatric Stroke. The Journal of the American Society for Experimental NeuroTherapeutics. 2006;3: [2] Lynch JL, Hirtz DG, deVeber G, Nelson KB. Report of the National Institue of Neurological Disorders and Stroke Workshop on Perinatal and Childhood Stroke. Pediatrics. 2002;109: [3] deVeber G, Andrew M, Adams C, et al. Cerebral sinovenous thrombosis in children. N Engl J Med. 2001;345:417–423. [4] Sebire G, Tabarki B, Saunders D, et al. Cerebral venous sinus thrombosis in children: risk factors, presentation, diagnosis and outcome. Brain. 2005;128:477–489. [5] Hartfield DS, Lowry NJ, Keene DL, Yager JY. Iron Deficiency: A Cause of Stroke in Infants and Children. Pediatr Neurol.1997;16: [6] Benedict SL, Bonkowsky JL, Thompson JA, et al. Cerebral Sinovenous Thrombosis in Children: Another Reason to Treat Iron Deficiency Anemia. J Child Neurol. 2004;19: [7] Maguire JL, deVeber G, Parkin PC. Association Between Iron-Deficiency Anemia and Stroke in Young Children. Pediatrics. 2007;120: [8] Mehta PJ, Chapman S, Jayam-Trouth A, et al. Acute Ischemic Stroke Secondary to Iron Deficiency Anemia: A Case Report. Case Reports in Neurological Medicine. 2012; 2012: Article ID , 5 pages. doi: /2012/487080
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References [9] Azab SFA, Abdelsalam SM, Saleh SHA, et al. Iron deficiency anemia as a risk factor for cerebrovascular events in early childhood: a case-control study. Ann Hematol. 2014;93: [10] Barron TF, Gusnard DA, Zimmerman RA, Clancy RR. Cerebral venous thrombosis in neonates and children. Pediatr Neurol. 1992;8: [11] Carvalho KS, Bodensteiner JB, Connolly PJ, Garg BP. Cerebral venous thrombosis in children. J Child Neurol. 2000;16: [12] Bonduel M, Sciuccati G, Hepner M, Torres AF, Pieroni G, Frontroth JP. Prethrombotic disorders in children with arterial ischemic stroke and sinovenous thrombosis. Arch Neurol. 1999;56: [13] Heller C, Heinecke A, Junker R, Knofler R, Kosch A, Kurnik K, et al. Childhood Stroke Study Group. Cerebral venous thrombosis in children: a multifactorial origin. Circulation. 2003;108: [14] Barnes C, Newall F, Furmedge J, et al. Cerebral sinus venous thrombosis in children. J Paediatr Child Health. 2004;40: [15] Yager JY, Hartfield DS. Neurologic Manifestations of Iron Deficiency in Childhood. Pediatr Neurol. 2002;27:85-92.
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References [16] Andrew M. Developmetal homestasis: relevance to thromboembolic complications in pediatric pateints. Thromb Haemost. 1995; 47: [17] Kenet G, Nowak-Gottl U. Venous thromboembolism in neonates and children. Best Practice and research clinical haematology Sept; 25(3): [18] Balasa V, Gruppo RA, Glueck CJ, Stroop D, Becker A, Pillow A, Wang P.The relationship of muation in the MTHFR, prothrombin, and PAI-1 genes to plasma levels of homocysteine, prothrombin, and PAI-1 in children and adults. Thromb Haemost 1999: 81: [19] Poort SR, Rosendaal FR, Reigsma PH, Bertina RM. A common genetic variant in the 30-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: [20] Gelfi C, Vigano A, rpamonti M, Wait R, Begum S, Biguzzi E, Castaman G, Faioni EM. A proteomic analysis of changes in prothrombin and plasma proteins associated with the G20210A mutation. Proteomics, 2005 Jul; 4(7):2151-9 [20] Rosendaal FR. Venous thrombosis: the role of genes, environment, and behavior. Hematology Am Soc Hematol Educ Program. 2005;1:1–12. [21] Coen Herak D, Radic Antolic M, Lenicek Krleza J, Pavic M, Dodig S, Duranovic V, et al. Inherited prothrombotic risk factors in children with stroke, transient ischemic attack, or migraine. Pediatrics April 2009; 123:4 e653-e660.
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References [22] Kenet G, Lutkhoff LK, Albisetti M, Bernard T, Bonduel M, Brandao L, et al. Impact of thrombophilia on arterial ischemic stroke or cerebral sinovenous thrombosis in children: a systematic review & meta analysis of observational studies. Circulation 2010; [23] Zadro R, Herak DC. Inherited prothrombitc risk factors in children with first ischemic stroke. Biochem Med (Zagreb). 2012;22 (3): [24] Laugesaar R, Kahre T, Kolk A, Uustalu U, Kool P, Talvik T. Factor V Leiden and prothrombin 20210G>A [corrected] mutation and paediatric ischaemic stroke: a case-control study and two meta-analyses. Acta Pediatr 2010;99: [25] Young G, Manco-Johnson M, Gil JC, Dimichele DM, Tarantino MD, Abshire T, Nugent DJ. Clinical Manifestations of the prothrombin G20210A mutation in children : A pediatric coagulation cosortium study. J Thromb Haemost. 2003;
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