1. 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

2. 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

3. 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

4. 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

5. Initial Presentation Vital signs are significant for tachycardia
Physical exam reveals a pale, fussy but consolable toddler
Otherwise, his physical exam is normal

6. 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”

7. 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

8. Noncontrast CT Head

9. GRE Sequence

10. T1 Post-gadolinium Contrast

11. Dynamic Post-gadolinium Contrast MR Venography

12. Maximum Intensity Projection (MIP) Imaged from Postgad MRV
Vein of Trolard (lateral)

13. DWI Sequence

14. Diagnosis Deep cerebral venous thrombosis
Associated bilateral deep white matter and right caudate nucleus venous infarctions

15. 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

16. 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)

17. 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)

18. Hypercoagulability Work-up
Hypercoagulability work-up initiated while inpatient reveals heterozygous mutation of the PT20210A allele

19. 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

20. Cerebral Sinus Venous Thrombosis in Children

21. 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:

22. 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:

23. 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.

24. 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.

25. 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

26. 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

27. 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

28. 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

29. Postcontrast MRV

30. Venous Drainage

31. 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

32. 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

33. Two Additional Cases from the Past Two Years

42. 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.

43. 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.

44. 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%

45. 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:

46. MTHFR and Homocysteine
Common
Low risk for pathology unless homocysteine is elevated
If homocysteine is elevated, improvement can be seen with folic acid.

47. Other Risk Factors for Thrombus
Obesity
Inactivity
Pregnancy hormones
Anesthesia/surgery
Crush injury
Tobacco

48. Overall Risk Assessment
Clinically, the balance between bleeding and clotting requires a significant change (or multiple less significant ones) to result in pathology

49. Relationship between PT20210A Gene Mutation and CSVT

50. Coagulation Cascade

51. 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.

52. 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:

53. 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]

54. 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:

55. 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;

56. 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;

57. Association between IDA and CSVT

58. 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

59. 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

60. 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

61. 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

62. 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

63. 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

64. 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

65. 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

66. Case Wrap-up No evidence of neurologically sequelae
Due for repeat imaging around the time of discontinuation of Lovenox

67. 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

68. 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

69. 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.

70. 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.

71. 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;