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Thromb Haemost 1999; 81(05): 690-694
DOI: 10.1055/s-0037-1614555
Rapid Communication
Schattauer GmbH

Factor V Leiden, Prothrombin 20210 G → A and the MTHFR C677T Mutations in Childhood Stroke

M. D. McColl
1   From the Royal Hospital for Sick Children, Yorkhill, Glasgow, Scotland, UK
,
E. A. Chalmers
1   From the Royal Hospital for Sick Children, Yorkhill, Glasgow, Scotland, UK
,
A. Thomas
2   Edinburgh Sick Childrens NHS Trust, Scotland, UK
,
A. Sproul
1   From the Royal Hospital for Sick Children, Yorkhill, Glasgow, Scotland, UK
,
C. Healey
2   Edinburgh Sick Childrens NHS Trust, Scotland, UK
,
I. Rafferty
1   From the Royal Hospital for Sick Children, Yorkhill, Glasgow, Scotland, UK
,
R. McWilliam
1   From the Royal Hospital for Sick Children, Yorkhill, Glasgow, Scotland, UK
,
P. Eunson
2   Edinburgh Sick Childrens NHS Trust, Scotland, UK
› Author Affiliations
Further Information

Publication History

Received 23 October 1998

Accepted after resubmission 27 January 1999

Publication Date:
09 December 2017 (online)

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Summary

Ischaemic stroke is a rare occurrence in children and in a proportion of cases the aetiology remains unknown. We have investigated the role of thrombophilia in the aetiology of this condition. Of 50 cases identified at two centres, 37 were available for detailed haematological analysis. No cases were identified with deficiencies of antithrombin, protein C or protein S. One case had elevated IgG anticardiolipin antibodies at low titre. The prevalence of the prothrombin 20210 G→A mutation, factor V Leiden (FVL) mutation and the C677T mutation in the MTHFR gene was compared in cases to that observed in random unselected cord blood controls. The odds ratio for stroke was not significantly increased in carriers of the prothrombin mutation (OR 1.2; 95% CI 0.1-10.7), FVL (OR 2.5; 95% CI 0.5-13.5), or the C677T mutation (OR 1.7; 95% CI 0.6-4.5). Our findings suggest that thrombophilia may not play a significant role in the aetiology of stroke in children, although a large prospective study is required to investigate this area further.

 

  • References

  • 1 deVeber G, Andrew M. Canadian Pediatric Ischemic Stroke Registry.. 29th Canadian Congress of Neurological Sciences. 1994. abstract.
    Search in Google Scholar
  • 2 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.. Blood 1996; 88: 3698-703.
    PubMedSearch in Google Scholar
  • 3 Kapur RK, Mills LA, Spitzer SG, Hultin MB. A prothrombin gene mutation is significantly associated with venous thrombosis.. Arter Thromb Vasc Biol 1997; 17: 2875-9.
    CrossrefPubMedSearch in Google Scholar
  • 4 Hillarp A, Zoller B, Svensson PJ, Dahlbäck B. The 20210 A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis.. Thromb Haemost 1997; 78: 990-2.
    Thieme ConnectPubMedSearch in Google Scholar
  • 5 Cumming AM, Keeney S, Salden A, Bhavnani M, Shwe KH, Hay CR. The prothrombin gene G20210A variant: prevalence in a U.K. anticoagulant clinic population.. Br J Haematol 1997; 98: 353-5.
    CrossrefPubMedSearch in Google Scholar
  • 6 Brown K, Luddington R, Williamson D, Baker P, Baglin T. Risk of venous thromboembolism associated with a G to A transition at position 20210 in the 3’-untranslated region of the prothrombin gene.. Br J Haematol 1997; 98: 907-9.
    CrossrefPubMedSearch in Google Scholar
  • 7 De Stefano V, Chiusolo P, Paciaroni K, Casorelli I, Rossi E, Molinari M, Servidei S, Tonali PA, Leone G. Prothrombin G20210A mutant genotype is a risk factor for cerebrovascular ischemic disease in young patients.. Blood 1998; 91: 3562-5.
    PubMedSearch in Google Scholar
  • 8 Rosendaal FR, Siscovick DS, Schwartz SM, Psaty BM, Raghunathan TE, Vos HL. A common prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women.. Blood 1997; 90: 1747-50.
    PubMedSearch in Google Scholar
  • 9 Watzke HH, Schuttrumpf J, Graf S, Huber K, Panzer S. Increased prevalence of a polymorphism in the gene coding for human prothrombin in patients with coronary heart disease.. Thromb Res 1997; 87: 521-6.
    CrossrefPubMedSearch in Google Scholar
  • 10 Doggen CJ, Cats VM, Bertina RM, Rosendaal FR. Interaction of coagulation defects and cardiovascular risk factors: increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A.. Circulation 1998; 97: 1037-41.
    CrossrefPubMedSearch in Google Scholar
  • 11 Arruda VR, Siquiera LH, Chiaparini LC, Coelho OR, Mansur AP, Ramires A, Annichino-Bizzacchi JM. Prevalence of the prothrombin gene variant 20210 G→A among patients with myocardial infarction.. Cardiovasc Res 1998; 37: 42-5.
    CrossrefPubMedSearch in Google Scholar
  • 12 Arruda VR, Annichino-Bizzacchi JM, Goncalves MS, Costa FF. Prevalence of the prothrombin gene variant (nt20210A) in venous thrombosis and arterial disease.. Thromb Haemost 1997; 78: 1430-3.
    Thieme ConnectPubMedSearch in Google Scholar
  • 13 Corral J, Gonzalez-Conejero R, Lozano ML, Rivera J, Heras I, Vicente V. The venous thrombosis risk factor 20210 A allele of the prothrombin gene is not a major risk factor for arterial thrombotic disease.. Br J Haematol 1997; 99: 304-7.
    CrossrefPubMedSearch in Google Scholar
  • 14 Ferraresi P, Marchetti G, Legnani C, Cavallari E, Castoldi E, Mascoli F, Ardissino D, Palareti G, Bernardi F. The heterozygous 20210 G/A prothrombin genotype is associated with early venous thrombosis in inherited thrombophilias and is not increased in frequency in artery disease.. Arterio Thromb Vasc Biol 1997; 17: 2418-22.
    CrossrefPubMedSearch in Google Scholar
  • 15 Longstreth WT, Rosendaal Jr FR, Siscovick DS, Vos HL, Schwartz SM, Psaty BM, Raghunathan TE, Koepsell TD, Reitsma PH. Risk of stroke in McColl et al.: Thrombophilic Abnormalities in Childhood Stroke young women and two prothrombotic mutations: factor V Leiden and pro-thrombin gene variant (G20210A).. Stroke 1998; 29: 577-80.
    CrossrefPubMedSearch in Google Scholar
  • 16 Martinelli I, Franchi F, Akwan S, Bettini P, Merati G, Mannucci PM. The transition G to A at position 20210 in the 3’-untranslated region of the pro-thrombin gene is not associated with cerebral ischemia.. Blood 1997; 90: 3806
    PubMedSearch in Google Scholar
  • 17 Dahlbäck B, Hildebrand B. Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of factor V.. Proc Nat Acad Sc 1994; 91: 1396-400.
    CrossrefPubMedSearch in Google Scholar
  • 18 Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C.. Nature 1994; 369: 64-7.
    CrossrefPubMedSearch in Google Scholar
  • 19 Koster T, Rosendaal FR, de Ronde H, Briët E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study.. Lancet 1993; 342: 1503-6.
    CrossrefPubMedSearch in Google Scholar
  • 20 Ganesan V, Kelsey H, Cookson J, Osborn A, Kirkham FJ. Activated protein C resistance in childhood stroke.. Lancet 1996; 347: 260
    PubMedSearch in Google Scholar
  • 21 Rosendaal FR, Siscovick DS, Schwartz SM, Beverly RK, Psaty BM, Long-streth WT, Raghunathan J TE, Koepsell TD, Reitsma PH. Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women.. Blood 1997; 89: 2817-21.
    PubMedSearch in Google Scholar
  • 22 Holm J, Zoller B, Berntorp E, Erhardt L, Dahlbäck B. Prevalence of factor V gene mutation amongst myocardial infarction patients and healthy controls is higher in Sweden than in other countries.. J Int Med 1996; 239: 221-6.
    CrossrefPubMedSearch in Google Scholar
  • 23 De Lucia D, Nina P, Papa ML, Belli A, Conte M, Renis V, Di Mauro C, Masi S, Franco A, Schisano G. Activated protein C resistance due to a factor V mutation associated with familial ischemic stroke.. J Neurosurg Sc 1997; 41: 373-8.
    PubMedSearch in Google Scholar
  • 24 Demarmels Biasiutti F, Merlo C, Furlan M, Sulzer I, Binder BR, Lammle B. No association of APC resistance with myocardial infarction.. Blood Coag Fibrinol 1995; 6: 456-9.
    CrossrefPubMedSearch in Google Scholar
  • 25 Press RD, Liu XY, Beamer N, Coull BM. Ischemic stroke in the elderly. Role of the common factor V mutation causing resistance to activated protein C.. Stroke 1996; 27: 44-8.
    CrossrefPubMedSearch in Google Scholar
  • 26 Prohaska W, Mannebach H, Schmidt M, Gleichmann U, Kleesiek K. Evidence against heterozygous coagulation factor V 1691 G→A mutation with resistance to activated protein C being a risk factor for coronary artery disease and myocardial infarction.. J Molec Med 1995; 73: 521-4.
    PubMedSearch in Google Scholar
  • 27 Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men.. NEJM 1995; 332: 912-7.
    CrossrefPubMedSearch in Google Scholar
  • 28 Cushman M, Rosendaal FR, Psaty BM, Cook EF, Valliere J, Kuller LH, Tracy RP. Factor V Leiden is not a risk factor for arterial vascular disease in the elderly: results from the Cardiovascular Health Study.. Thromb Haemost 1998; 79: 912-5.
    Thieme ConnectPubMedSearch in Google Scholar
  • 29 Kontula K, Ylikorkala A, Miettinen H, Vuorio A, Kauppinen-Makelin R, Hamalainen L, Palomaki H, Kaste M. Arg506Gln factor V mutation (factor V Leiden) in patients with ischaemic cerebrovascular disease and survivors of myocardial infarction.. Thromb Haemost 1995; 73: 558-60.
    Thieme ConnectPubMedSearch in Google Scholar
  • 30 Catto A, Carter A, Ireland H, Bayston TA, Philippou H, Barrett J, Lane DA, Grant PJ. Factor V Leiden gene mutation and thrombin generation in relation to the development of acute stroke.. Arterio Thromb Vasc Biol 1995; 15: 783-5.
    CrossrefPubMedSearch in Google Scholar
  • 31 Iniesta JA, Corral J, Fernandez-Pardo J, Gonzalez-Conejero R, Vicente V. Factor-V (Arg506→Gln) mutation in ischemic cerebrovascular disease.. Haemostasis 1997; 27: 105-11.
    PubMedSearch in Google Scholar
  • 32 Ardissino D, Peyvandi F, Merlini PA, Colombi E, Mannucci PM. Factor V (Arg 506→Gln) mutation in young survivors of myocardial infarction.. Thromb Haemost 1996; 75: 701-2.
    Thieme ConnectPubMedSearch in Google Scholar
  • 33 Nowak-Gottl U, Strater R, Dubbers A, Oleszuk-Raschke K, Vielhaber H. Ischaemic stroke in infancy and childhood: role of the Arg506 to Gln mutation in the factor V gene.. Blood Coag Fibrinol 1996; 7: 684-8.
    CrossrefPubMedSearch in Google Scholar
  • 34 Simioni P, de Ronde H, Prandoni P, Saladini M, Bertina RM, Girolami A. Ischemic stroke in young patients with activated protein C resistance. A report of three cases belonging to three different kindreds.. Stroke 1995; 26: 885-90.
    CrossrefPubMedSearch in Google Scholar
  • 35 Thorarensen O, Ryan S, Hunter J, Younkin DP. Factor V Leiden mutation: an unrecognized cause of hemiplegic cerebral palsy, neonatal stroke, and placental thrombosis.. Annals Neurol 1997; 42: 372-5.
    CrossrefPubMedSearch in Google Scholar
  • 36 Riikonen RS, Vahtera EM, Kekomaki RM. Physiological anticoagulants and activated protein C resistance in childhood stroke.. Acta Paediatrica 1996; 85: 242-4.
    CrossrefPubMedSearch in Google Scholar
  • 37 Deguchi K, Tsukada T, Iwasaki E, Wada H, Murashima S, Miyazaki M, Shirakawa S. Late-onset homozygous protein C deficiency manifesting cerebral infarction as the first symptom at age 27.. Int Med 1992; 31: 922-5.
    CrossrefPubMedSearch in Google Scholar
  • 38 Kato H, Shirahama M, Ohmori K, Sunaga T. Cerebral infarction in a young adult associated with protein C deficiency. A case report.. Angiology 1995; 46: 169-73.
    CrossrefPubMedSearch in Google Scholar
  • 39 Matsushita K, Kuriyama Y, Sawada T, Uchida K. Cerebral infarction associated with protein C deficiency.. Stroke 1992; 23: 108-11.
    CrossrefPubMedSearch in Google Scholar
  • 40 Brown DC, Livingston JH, Minns RA, Eden OB. Protein C and S deficiency causing childhood stroke.. Scot Med J 1993; 38: 114-5.
    PubMedSearch in Google Scholar
  • 41 Israels SJ, Seshia SS. Childhood stroke associated with protein C or S deficiency.. J Pediatrics 1987; 111: 562-4.
    CrossrefPubMedSearch in Google Scholar
  • 42 Kohler J, Kasper J, Witt I, von Reutern GM. Ischemic stroke due to protein C deficiency.. Stroke 1990; 21: 1077-80.
    CrossrefPubMedSearch in Google Scholar
  • 43 Koller H, Stoll G, Sitzer M, Burk M, Schottler B, Freund HJ. Deficiency of both protein C and protein S in a family with ischemic strokes in young adults.. Neurology 1994; 44: 1238-40.
    CrossrefPubMedSearch in Google Scholar
  • 44 Uysal S, Anlar B, Altay C, Kirazli S. Role of protein C in childhood cerebrovascular occlusive accidents.. Eur J Pediatrics 1989; 149: 216-8.
    CrossrefPubMedSearch in Google Scholar
  • 45 van Kuijck MA, Rotteveel JJ, van Oostrom CG, Novakova I. Neurological complications in children with protein C deficiency.. Neuropediatrics 1994; 25: 16-9.
    Thieme ConnectPubMedSearch in Google Scholar
  • 46 Simioni P, Battistella PA, Drigo P, Carollo C, Girolami A. Childhood stroke associated with familial protein S deficiency.. Brain & Development 1994; 16: 241-5.
    CrossrefPubMedSearch in Google Scholar
  • 47 Halbmayer WM, Haushofer A, Schon R, Fischer M. The prevalence of poor anticoagulant response to activated protein C (APC resistance) among patients suffering from stroke or venous thrombosis and among healthy subjects.. Blood Coag Fibrinol 1994; 5: 51-7.
    CrossrefPubMedSearch in Google Scholar
  • 48 Kodish E, Potter C, Kirschbaum NE, Foster PA. Activated protein C resistance in a neonate with venous thrombosis.. J Pediatrics 1995; 127: 645-8.
    CrossrefPubMedSearch in Google Scholar
  • 49 de Bruijn SF, Stam J, Koopman MM, Vandenbroucke JP. Case-control study of risk of cerebral sinus thrombosis in oral contraceptive users who are carriers of hereditary prothrombotic conditions. The Cerebral Venous Sinus Thrombosis Study Group.. BMJ 1998; 316: 589-92.
    CrossrefPubMedSearch in Google Scholar
  • 50 Martinelli I, Sacchi E, Landi G, Taioli E, Duca F, Mannucci PM. High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives.. NEJM 1998; 338: 1793-7.
    CrossrefPubMedSearch in Google Scholar
  • 51 Bloem BR, van Putten MJ, van der Meer FJ, van Hilten JJ, Bertina RM. Superior sagittal sinus thrombosis in a patient heterozygous for the novel 20210 A allele of the prothrombin gene.. Thromb Haemost 1998; 79: 235
    Thieme ConnectPubMedSearch in Google Scholar
  • 52 Siegert CE, Smelt AH, de Bruin TW. Activated protein C resistance and factor V Leiden mutation are risk factors for cerebral sinus thrombosis.. Stroke 1997; 28: 1291-2.
    PubMedSearch in Google Scholar
  • 53 Deschiens MA, Conard J, Horellou MH, Ameri A, Preter M, Chedru F, Samama MM, Bousser MG. Coagulation studies, factor V Leiden, and anti-cardiolipin antibodies in 40 cases of cerebral venous thrombosis.. Stroke 1996; 27: 1724-30.
    CrossrefPubMedSearch in Google Scholar
  • 54 Zuber M, Toulon P, Marnet L, Mas JL. Factor V Leiden mutation in cerebral venous thrombosis.. Stroke 1996; 27: 1721-3.
    CrossrefPubMedSearch in Google Scholar
  • 55 Brey RL, Coull BM. Cerebral venous thrombosis. Role of activated protein C resistance and factor V gene mutation.. Stroke 1996; 27: 1719-20.
    CrossrefPubMedSearch in Google Scholar
  • 56 Kimber TE, Lloyd JV, Brophy BP, Thompson PD. Cerebral venous sinus thrombosis associated with factor V gene mutation.. J Neurology, Neurosurgery & Psychiatry 1996; 61: 204-5.
    PubMedSearch in Google Scholar
  • 57 Martinelli I, Landi G, Merati G, Cella R, Tosetto A, Mannucci PM. Factor V gene mutation is a risk factor for cerebral venous thrombosis.. Thromb Haemost 1996; 75: 393-4.
    Thieme ConnectPubMedSearch in Google Scholar
  • 58 Becker S, Heller C, Gropp F, Scharrer I, Kreuz W. Thrombophilic disorders in children with cerebral infarction.. Lancet 1998; 352: 1756-7.
    PubMedSearch in Google Scholar
  • 59 Zenz W, Bodo Z, Plotho J, Streif W, Male C, Bernert G, Rauter L, Ebets-berger G, Kaltenbrunner K, Kurnik P, Lischka A, Paky F, Ploier R, Hofler G, Mannhalter C, Muntean W. Factor V Leiden and Prothrombin Gene G20210A Variant in Children with Ischemic Stroke.. Thromb Haemost 1998; 80: 763-6.
    Thieme ConnectPubMedSearch in Google Scholar
  • 60 Baca V, Garcia-Ramirez R, Ramirez-Lacayo M, Marquez-Enriquez L, Martinez I, Lavalle C. Cerebral infarction and antiphospholipid syndrome in children.. J Rheumatol 1996; 23: 1428-31.
    PubMedSearch in Google Scholar
  • 61 Nencini P, Baruffi M, Abbate R, Massai G, Amaducci L, Inzitari D. Lupus Anticoagulant and Anticardiolipin Antibodies in Young Adults with Cerebral Ischaemia.. Stroke 1992; 23: 189-93.
    CrossrefPubMedSearch in Google Scholar
  • 62 Kluijtmans LAJ, Van den Heuvel L, Boers GHJ, Stevens EMB, Frosst P, Van Oost BA, Trijbels JMF, Rozen R. Molecular genetic analysis in mild hyperhomocysteinaemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease.. Am J Hum Genet 1996; 58: 35-41.
    PubMedSearch in Google Scholar
  • 63 Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GHJ, Den Heijer M, Kluijtmans LAJ, Van den Heuvel LPWJ, Rozen R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.. Nature Genet 1995; 10: 111-3.
    CrossrefPubMedSearch in Google Scholar
  • 64 de Franchis R, Mancini FP, DA A, Sebastio G, Fermo I, de Stefano V, Mar-gaglione M, Mazzola G, di Minno G, Andria G. Elevated total plasma homocysteine and 677C→T mutation of the 5,10-methylenetetrahydrofolate reductase gene in thrombotic vascular disease.. Am J Hum Genet 1996; 59: 262-4.
    PubMedSearch in Google Scholar
  • 65 Simioni P, Prandoni P, Burlina A, Tormene D, Sardella C, Ferrari V, Benedetti L, Girolami A. Hyperhomocysteinaemia and Deep-Vein Thrombosis.. Thromb Haemost 1996; 76: 883-6.
    Thieme ConnectPubMedSearch in Google Scholar
  • 66 Arruda V, Zuben P, Chiaparini L, Annichino-Bizzachi J, Costa F. The mutation Ala677-Val in the methylene tetrahydrofolate reductase gene: a risk factor for arterial disease and venous thrombosis.. Thromb Haemost 1997; 77: 818-21.
    Thieme ConnectPubMedSearch in Google Scholar
  • 67 den Heijer M, Koster T, Blom HJ, Bos GM, Briët E, Reitsma PH, Vandenbroucke JP, Rosendaal FR. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis.. NEJM 1996; 334: 759-62.
    CrossrefPubMedSearch in Google Scholar
  • 68 Bienvenu T, Ankri A, Chadefaux B, Montalescot G, Kamoun P. Elevated total plasma homocysteine, a risk factor for thrombosis. Relation to coagulation and fibrinolytic parameters.. Thromb Res 1993; 70: 123-9.
    CrossrefPubMedSearch in Google Scholar
  • 69 Malinow MR. Plasma homocyst(e)ine: a risk factor for arterial occlusive diseases.. J Nutrition 1996; 126: 1238S-43S.
    PubMedSearch in Google Scholar
  • 70 Perry IJ, Refsum H, Morris RW, Ebrahim SB, Ueland PM, Shaper AG. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men.. Lancet 1995; 346: 1395-8.
    CrossrefPubMedSearch in Google Scholar
  • 71 Dudman NP, Wilcken DE, Wang J, Lynch JF, Macey D, Lundberg P. Disordered methionine/homocysteine metabolism in premature vascular disease. Its occurrence, cofactor therapy, and enzymology.. Arterio Thromb 1993; 13: 1253-60.
    CrossrefPubMedSearch in Google Scholar
  • 72 van den Berg M, Stehouwer CD, Bierdrager E, Rauwerda JA. Plasma homocysteine and severity of atherosclerosis in young patients with lower-limb atherosclerotic disease.. Arterio Thromb Vasc Biol 1996; 16: 165-71.
    CrossrefPubMedSearch in Google Scholar
  • 73 Kluijtmans LAJ, den Heijer M, Reitsma PH, Heil SG, Blom HJ, Rosendaal FR. Thermolabile Methylenetetrahydrofolate Reductase and Factor V Leiden in the Risk of Deep-Vein Thrombosis.. Thromb Haemost 1998; 79: 254-8.
    Thieme ConnectPubMedSearch in Google Scholar