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Thromb Haemost 2009; 101(01): 145-150
DOI: 10.1160/TH07-12-0754
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

Ischaemic stroke patients with heterozygous factor V Leiden present with multiple brain infarctions and widespread atherothrombotic disease

Elena Haapaniemi
1   Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
,
Johanna Helenius
1   Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
,
Dimitrije Jakovljeviâ
1   Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
,
Lauri Soinne
1   Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
,
Martti Syrjälä
2   Laboratory Services, Helsinki University Central Hospital, Helsinki, Finland
,
Markku Kaste
1   Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
,
Riitta Lassila
2   Laboratory Services, Helsinki University Central Hospital, Helsinki, Finland
3   Department of Hematology, Helsinki University Central Hospital, Helsinki, Finland
,
Turgut Tatlisumak
1   Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
› Author AffiliationsFinancial support: This study was supported by the Finnish Medical Foundation, the Finnish Cultural Foundation, the Paulo Foundation, the Aarne Koskelo Foundation, the Biomedicum Foundation, and the Helsinki University Central Hospital.
Further Information

Publication History

Received: 27 December 2007

Accepted after major revision: 17 October 2008

Publication Date:
23 November 2017 (online)

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Summary

Factor V Leiden (FVL) mutation is a risk factor for venous and, to a degree, arterial thrombosis. It is unknown whether and how FVL affects the manifestations of ischaemic stroke (IS). We assessed the clinical, laboratory, radiological, and prognostic characteristics in an observational study with adult IS patients having FVL. We tested 860 patients with first-ever IS for FVL and found 48 FVL positive patients. Detailed clinical, laboratory, and radiological evaluation were compared with that of 144 (1:3) gender and age matched IS patients without FVL. All patients underwent a prognostic evaluation at an average of five years follow-up. Despite the relatively young age (mean 48.5 years, range 44–54 years) of the FVL positive IS patients, peripheral arterial occlusive disease (PAOD), coronary artery disease (CAD), and previous transient cerebrovascular event occurred more frequently compared with controls. Family history of cardiovascular disease (CVD) and multiple silent brain infarctions were revealed in half of the FVL positive patients, whereas these were seldom encountered among controls. Stroke severity, long-term recovery, and recurrence rates seemed similar irrespective of FVL status. Our findings indicate that the clinical profile of IS patients with FVL associated with wider manifestation of atherothrombosis, positive family history of arterial thrombosis, and presence of multiple silent infarctions on brain images.

Keywords

Factor V Leiden mutation - ischaemic stroke - coagulation - cardiovascular disease - peripheral arterial occlusive disease
 

  • References

  • 1 Bertina R, Koeleman B, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67.
    CrossrefPubMedGoogle Scholar
  • 2 Dahlbäck B. Activated protein C resistance and thrombosis: molecular mechanism of hypercoagulable state due to FVR506Q mutation. Semin Thromb Hemost 1999; 25: 273-289.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Kim R, Becker R. Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system: a meta-analysis of published studies. Am Heart J 2003; 146: 948-957.
    CrossrefPubMedGoogle Scholar
  • 4 Marcucci R, Sofi R, Fedi S. et al. Thrombophilic risk factors in patients with severe carotid atherosclerosis. J Thromb Haemost 2005; 03: 502-507.
    CrossrefPubMedGoogle Scholar
  • 5 Juul K, Tybjærg-Hansen A, Steffensen R. et al. Factor V Leiden: the Copenhagen City Heart Study and 2 meta-analyses. Blood 2002; 100: 3-10.
    CrossrefPubMedGoogle Scholar
  • 6 Casas J, Hingorani A, Bautista L. et al. Mate-analysis of genetic studies in ischemic stroke: thirty-two genes involvimg approximately 18,000 cases and 58,000 controls. Arch Neurol 2004; 61: 1652-1661.
    CrossrefPubMedGoogle Scholar
  • 7 Kenet G, Sadetzki S, Murad H. et al. Factor V Leiden and antiphospholipid antibodies are significant risk factors for ischemic stroke in children. Stroke 2000; 31: 283-1288.
    PubMedGoogle Scholar
  • 8 Martinelli I, Battaglioli T, Burgo I. et al. Oral contraceptive use, thrombophilia and their interaction in young women with ischemic stroke. Haematologica 2006; 91: 844-847.
    PubMedGoogle Scholar
  • 9 Rosendaal F, Siscovick D, Schwartz S. et al. Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood 1997; 89: 2817-2821.
    PubMedGoogle Scholar
  • 10 Slooter A, Rosendaal F, Tanis B. et al. Prothrombotic conditions, oral contraceptives, and risk of ischemic stroke. J Thromb Haemost 2005; 03: 1213-1217.
    CrossrefPubMedGoogle Scholar
  • 11 Kontula K, Ylikorkala A, Miettinen H. et al. Arg506Gln factor V mutation (factor V Leiden) in patients with ischaemic cerebrovascular disease and survivors of myocardial infarction. Thromb Haemost 1995; 73: 558-560.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Lalouschek W, Suess E, Aull S. et al. Clinical and laboratory data in heterozygous factor V Leiden mutation positive versus negative patients with TIA and minor stroke. Stroke 1995; 26: 1963-1964.
    PubMedGoogle Scholar
  • 13 Zunker P, Hohenstein C, Plendl H-J. et al. Activated protein C resistance and acute ischemic stroke: relation to stroke causation and age. J Neurol 2001; 248: 701-704.
    CrossrefPubMedGoogle Scholar
  • 14 Hankey G, Eikelboom J, van Bockxmeer F. et al. Inherited thrombophilia in ischemic stroke and its pathogenic subtypes. Stroke 2001; 32: 1793-1799.
    CrossrefPubMedGoogle Scholar
  • 15 Goldstein L, Adams R, Alberts M. et al. Primary prevention of ischemic stroke. Stroke 2006; 37: 1583-1633.
    CrossrefPubMedGoogle Scholar
  • 16 European stroke initiative recommendations for stroke management-update 2003. Cerebrovasc Dis 2003; 16: 311-337.
    CrossrefPubMedGoogle Scholar
  • 17 Bamford J, Sandercock P, Dennis M. et al. Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet 1991; 337: 1521-1526.
    CrossrefPubMedGoogle Scholar
  • 18 Blennow K, Wallin A, Uhlemann C. et al. Whitematter lesions on CT in Alzheimer patients: relation to clinical symptomatology and vascular factors. Acta Neurol Scand 1991; 83: 187-193.
    CrossrefPubMedGoogle Scholar
  • 19 Szolnoki Z, Samogyvári F, Kondacs A. et al. Evalution of the interactions of common genetic mutations in stroke patients. J Neurol 2002; 249: 1391-1397.
    CrossrefPubMedGoogle Scholar
  • 20 Haapaniemi E, Tatlisumak T, Soinne L. et al. Natural anticoagulants (antithrombin III, protein C, and protein S) in patients with mild to moderate ischemic stroke. Acta Neurol Scand 2002; 105: 107-114.
    CrossrefPubMedGoogle Scholar
  • 21 Haapaniemi E, Helenius J, Soinne L. et al. Serial measurements of plasma homocysteine levels in early and late phases of ischemic stroke. Eur J Neurol 2007; 14: 12-17.
    CrossrefPubMedGoogle Scholar
  • 22 Gruber A, Griffin J. Direct detection of activated protein C in blood from human subjects. Blood 1992; 79: 2340-2348.
    PubMedGoogle Scholar
  • 23 Sampram E, Lindblad B, Dahlback B. Activated protein C resistance in patients with peripheral vascular disease. J Vasc Surg 1998; 28: 624-629.
    CrossrefPubMedGoogle Scholar
  • 24 Reny J, Alhenc-Gelas M, Fontana P. et al. The factor II G20210A gene polymorphism, but not factor V Arg506Gln, is associated with peripheral arterial disease results of a case-control study. J Thromb Haemost 2004; 02: 1334-1340.
    CrossrefPubMedGoogle Scholar
  • 25 Mueller T, Marschon R, Dieplinger B. et al. Factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations are not associated with chronic limb ischemia: the Linz Peripheral Arterial Disease (LIPAD) study. J Vasc Surg 2005; 41: 808-815.
    CrossrefPubMedGoogle Scholar
  • 26 Sofi F, Lari B, Rogolino A. et al. Thrombophilic risk factors for symptomatic peripheral arterial disease. J Vasc Surg 2005; 41: 255-260.
    CrossrefPubMedGoogle Scholar
  • 27 Gardemann A, Arsic T, Katz N. et al. The factor II G20210A and factor V G1691A gene transitions and coronory heart disease. Thromb Haemost 1999; 81: 208-213.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Mansourati J, Da Costa A, Munier S. et al. Prevalence of factor V Leiden in patients with myocardial infarction and normal coronary angiography. Thromb Haemost 2000; 83: 822-825.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Voetsch B, Damasceno B, Camargo E. et al. Inherited thrombophilia as a risk factor for the development of ischemic stroke in young adult. Thromb Haemost 2000; 83: 229-233.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Ye Z, Liu E, Higgins J. et al. Seven haemostatic gene polymorphisms in coronory disease: meta-analysis of 66,155 cases and 91,307 controls. Lancet 2006; 367: 651-658.
    CrossrefPubMedGoogle Scholar
  • 31 Eskandari M, Bontempo F, Hassett A. et al. Arterial thromboembolic events in patients with the factor V Leiden mutation. Am J Surg 1998; 176: 122-125.
    CrossrefPubMedGoogle Scholar
  • 32 Rallidis L, Belesi C, Manioudaki H. et al. Myocadrial infarction under the age of 36: prevalence of thrombophilic disorders. Thromb Haemost 2003; 90: 272-279.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Glueck C, Wang P, Fontaine R. et al. Estrogen replacement therapy, thrombophilia, and atherothrombosis. Metabolism 2002; 51: 724-732.
    CrossrefPubMedGoogle Scholar
  • 34 Hobikoglu G, Akyuz U, Akyuz F. et al. Factor V Leiden is a risk factor for myocardial infarction in young Turkish men. Acta Cardiol 2004; 59: 594-597.
    CrossrefPubMedGoogle Scholar
  • 35 Sabino A, Ribeiro D, Carvalho M. et al. Factor V Leiden and increased risk for arterial thrombotic disease in young Brazilian patients. Blood Coagul Fibrinolysis 2006; 17: 271-275.
    CrossrefPubMedGoogle Scholar
  • 36 Willeit J, Kiechl S, Oberhollenzer F. et al. Distinct risk profiles of early and advanced atherosclerosis: prospective results from the Bruneck Study. Arterioscler Thromb Vasc Biol 2000; 20: 529-537.
    CrossrefPubMedGoogle Scholar
  • 37 Provenzale J, Barboriak D, Davey I. et al. Cerebrovascular disease risk factors: neuroradiologic findings in patients with activated protein C resistance. Radiology 1998; 207: 85-89.
    CrossrefPubMedGoogle Scholar
  • 38 Szolnoki Z, Somogyvari F, Kondacs A. et al. Evaluation of the roles of the Leiden V mutation and ACE I/D polymorphism in subtypes of ischemic stroke. J Neurol 2001; 248: 756-761.
    CrossrefPubMedGoogle Scholar
  • 39 Adachi T, Kobayashi S, Yamaguchi S. Frequency and pathogenesis of silent subcortical brain infarction in acute first-ever ischemic stroke. Intern Med 2002; 41: 103-108.
    CrossrefPubMedGoogle Scholar
  • 40 Pohjasvaara T, Mäntylä R, Aronen H. et al. Clinical and radiological determinations of prestroke cognitive decline in a stroke cohort. J Neurol Neurosurg Psychiatry 1999; 67: 742-748.
    CrossrefPubMedGoogle Scholar
  • 41 Mok V, Wong A, Lam W. et al. Cognitive impairment and functional outcome after stroke associated with small vessel disease. J Neurol Neurosurg Psychiatry 2004; 75: 560-566.
    CrossrefPubMedGoogle Scholar
  • 42 Vermeer S, Longstreth Jr W, Koudstaal P. Silent brain infarcts: a systematic review. Lancet Neurol 2007; 06: 611-619.
    CrossrefPubMedGoogle Scholar
  • 43 Knuiman M, Folsom A, Chambless L. et al. Association of hemostatic variables with MRI-detected cerebral abnormalities: the atherosclerosis risk in communities study. Neuroepidemiology 2001; 20: 96-104.
    CrossrefPubMedGoogle Scholar
  • 44 Pruissen D, Kappelle L, Algra A. Polymorphisms and risk of ischemic stroke (POLARIS) study: rationale and design. Eur Neurol 2004; 51: 30-34.
    CrossrefPubMedGoogle Scholar