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Semin Neurol 2006; 26(1): 057-064
DOI: 10.1055/s-2006-933309
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Disorders of Coagulation in Stroke

Salina P. Waddy1
  • 1Assistant Professor in Neurology, Emory University, Atlanta, Georgia
Further Information

Publication History

Publication Date:
15 February 2006 (online)

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ABSTRACT

The roles of the coagulopathies in thrombosis have been well established; however, the role in ischemic stroke is poorly understood. This article reviews the recent advances in the genetics of coagulation, the recently identified interactive roles of the coagulation and anticoagulation proteins, and the literature supporting protein dysregulation as a causative agent in cerebral venous thrombosis and ischemic stroke.

KEYWORDS

Coagulation - stroke - protein

REFERENCES

  • 1 Spronk H M, Govers-Riemslag J W, ten Cate H. The blood coagulation system as a molecular machine.  Bioessays. 2003;  25 1220-1228
    CrossrefPubMedGoogle Scholar
  • 2 Haberl R L, Biniasch O, Ott M, Peinemann A, Wick M, Kempter B. Infrequency of stroke caused by specific coagulation disorders.  Cerebrovasc Dis. 1995;  5 391-396
    PubMedGoogle Scholar
  • 3 Catto A, Carter A, Ireland H et al.. Factor V Leiden gene mutation and thrombin generation in relation to the development of acute stroke.  Arterioscler Thromb Vasc Biol. 1995;  15 783-785
    PubMedGoogle Scholar
  • 4 Mann K G, Kalafatis M. Factor V: a combination of Dr Jekyll and Mr Hyde.  Blood. 2003;  101 20-30
    CrossrefPubMedGoogle Scholar
  • 5 Lutze G, Frick U, Topfer G, Urbahn H. Hereditaere Dysprothrombinaemie mit geringer Blutungsneigung (Prothrombin Magdeburg).  Dtsch Med Wochenschr. 1989;  114 288-292
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Poort S R, Rosendaal F R, Reitsma P H, Bertina R M. A common genetic variation in the 3-prime-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.  Blood. 1996;  88 3698-3703
    CrossrefPubMedGoogle Scholar
  • 7 Dahlbäck B. The discovery of activated protein C resistance.  J Thromb Haemost. 2003;  1 3-9
    CrossrefPubMedGoogle Scholar
  • 8 Nicolaes G A, Tans G, Thomassen M C et al.. Peptide bond cleavages and loss of functional activity during inactivation of factor Va and factor VaR506Q by activated protein C.  J Biol Chem. 1995;  270 21158-21166
    CrossrefPubMedGoogle Scholar
  • 9 Dahlbäck B. The discovery of activated protein C resistance.  J Thromb Haemost. 2003;  1 3-9
    CrossrefPubMedGoogle Scholar
  • 10 Váradi K, Rosing J, Tans G et al.. Factor V enhances the cofactor function of protein S in the APC-mediated inactivation of factor VIII: influence of the factor VR506Q mutation.  Thromb Haemost. 1996;  76 208-214
    PubMedGoogle Scholar
  • 11 Thorelli E, Kaufman R J, Dahlbäck B. Cleavage of factor V at Arg 506 by activated protein C and the expression of anticoagulant activity of factor V.  Blood. 1999;  93 2552-2558
    PubMedGoogle Scholar
  • 12 Ridker P M, Miletich J P. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke and venous thrombosis in apparently healthy men.  N Engl J Med. 1995;  332 912-917
    CrossrefPubMedGoogle Scholar
  • 13 Catto A, Carter A, Ireland H et al.. Factor V Leiden gene mutation and thrombin generation in relation to the development of acute stroke.  Arterioscler Thromb Vasc Biol. 1995;  15 783-785
    PubMedGoogle Scholar
  • 14 Press R D, Liu X-Y, Beamer N et al.. Ischaemic stroke in the elderly. Role of the common factor V mutation causing resistance to activated protein C.  Stroke. 1996;  27 44-48
    PubMedGoogle Scholar
  • 15 Castaman G, Tosetto A, Ruggeri M, Rodeghiero F. Pseudohomozygosity for activated protein C resistance is a risk factor for venous thrombosis.  Br J Haematol. 1999;  106 232-236
    CrossrefPubMedGoogle Scholar
  • 16 Castoldi E, Brugge J M, Nicolaes G A et al.. Impaired APC-cofactor activity of factor V plays a major role in the APC resistance associated with the factor V Leiden (R506Q) and R2 (H1299R) mutations.  Blood. 2004;  103 4173-4179
    CrossrefPubMedGoogle Scholar
  • 17 Bernardi F, Faioni E M, Castoldi E et al.. A factor V genetic component differing from factor V R506Q contributes to the activated protein C resistance phenotype.  Blood. 1997;  90 1552-1557
    PubMedGoogle Scholar
  • 18 Castaman G, Lunghi B, Missiaglia E, Bernardi F, Rodeghiero F. Phenotypic homozygous activated protein C resistance associated with compound heterozygosity for Arg506Gln (factor V Leiden) and His1299Arg substitutions in factor V.  Br J Haematol. 1997;  99 257-261
    CrossrefPubMedGoogle Scholar
  • 19 Williamson D, Brown K, Luddington R et al.. Factor V Cambridge: a new mutation (Arg306→Thr) associated with resistance to activated protein C.  Blood. 1998;  91 1140-1144
    PubMedGoogle Scholar
  • 20 Chan W P, Lee C K, Kwong Y L et al.. A novel mutation of Arg306 of factor V gene in Hong Kong Chinese.  Blood. 1998;  91 1135-1139
    PubMedGoogle Scholar
  • 21 Gehring N H, Frede U, Neu-Yilik G et al.. Increased efficiency of mRNA 3′ end formation: a new genetic mechanism contributing to hereditary thrombophilia.  Nat Genet. 2001;  28 389-392
    PubMedGoogle Scholar
  • 22 Rosendaal F R. High levels of factor VIII and venous thrombosis.  Thromb Haemost. 2000;  83 1-2
    PubMedGoogle Scholar
  • 23 Bertina R M. Elevated clotting factor levels and venous thrombosis.  Pathophysiol Haemost Thromb. 2003;  33 395-400
    CrossrefPubMedGoogle Scholar
  • 24 Sebire G, Tabarki B, Saunders D E et al.. Cerebral venous sinus thrombosis in children: risk factors, presentation, diagnosis and outcome.  Brain. 2005;  128 477-489
    CrossrefPubMedGoogle Scholar
  • 25 Williamson D, Brown K, Luddington R, Baglin C, Baglin T. Factor V Cambridge: a new mutation (Arg306→Thr) associated with resistance to activated protein C.  Blood. 1998;  91 1140-1144
    PubMedGoogle Scholar
  • 26 Kalafatis M, Simioni P, Tormene D et al.. Isolation and characterization of an anti-factor V antibody causing activated protein C resistance from a patient with severe thrombotic manifestations.  Blood. 2002;  99 3985-3992
    CrossrefPubMedGoogle Scholar
  • 27 Henkens C M, Bom V J, van der Meer J. Lowered APC-sensitivity ratio related to increased factor VIII-clotting activity.  Thromb Haemost. 1995;  74 1198-1199
    PubMedGoogle Scholar
  • 28 Laffan M A, Manning R. The influence of factor VIII on measurement of activated protein C resistance.  Blood Coagul Fibrinolysis. 1996;  7 761-765
    PubMedGoogle Scholar
  • 29 Reitsma P H, Bernardi F, Doig R G et al.. Protein C deficiency: a database of mutations, 1995 update. On behalf of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization Committee of the ISTH.  Thromb Haemost. 1995;  73 876-889
    PubMedGoogle Scholar
  • 30 Reitsma P H. Protein C deficiency: summary of the 1995 database update.  Nucleic Acids Res. 1996;  24 157-159
    CrossrefPubMedGoogle Scholar
  • 31 Gladson C L, Scharrer I, Hach V et al.. The frequency of type 1 heterozygous protein S and protein C deficiency in 141 unrelated young patients with venous thrombosis.  Thromb Haemost. 1988;  59 18-22
    PubMedGoogle Scholar
  • 32 Grewal R P, Goldberg M A. Stroke in protein C deficiency.  Am J Med. 1990;  89 538-539
    CrossrefPubMedGoogle Scholar
  • 33 Kohler J, Kasper J, Witt I et al.. Ischaemic stroke due to protein C deficiency.  Stroke. 1990;  21 1077-1080
    CrossrefPubMedGoogle Scholar
  • 34 Camerlingo M, Finazzi G, Caato L et al.. Inherited protein C deficiency and non-haemorrhagic arterial stroke in young adults.  Neurology. 1991;  41 1371-1373
    PubMedGoogle Scholar
  • 35 Thomas D P, Roberts H R. Hypercoagulability in venous and arterial thrombosis.  Ann Intern Med. 1997;  126 638-644
    CrossrefPubMedGoogle Scholar
  • 36 Martinelli I, Mannucci P M, De Stefano V et al.. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families.  Blood. 1998;  92 2353-2358
    PubMedGoogle Scholar
  • 37 Kalafatis M, Rand M D, Mann K G. The mechanism of inactivation of human factor V and human factor Va by activated protein C.  J Biol Chem. 1994;  269 31869-31880
    PubMedGoogle Scholar
  • 38 Nicolaes GAF, Tans G, Christella M et al.. Peptide bond cleavages and loss of functional activity during inactivation of factor Va and factor Va R506Q by activated protein C.  J Biol Chem. 1995;  270 21158-21166
    CrossrefPubMedGoogle Scholar
  • 39 Heeb M J, Mesters R M, Tans G, Rosing J, Griffin J H. Binding of protein S to factor Va associated with inhibition of prothrombinase that is independent of activated protein C.  J Biol Chem. 1993;  268 2872-2877
    PubMedGoogle Scholar
  • 40 Hackeng T M, van't Veer C, Meijers J C, Bouma B N. Human protein S inhibits prothrombinase complex activity on endothelial cells and platelets via direct interactions with factors Va and Xa.  J Biol Chem. 1994;  269 21051-21058
    PubMedGoogle Scholar
  • 41 Koppelman S J, Hackeng T M, Sixma J J, Bouma B N. Inhibition of the intrinsic factor X activating complex by protein S: evidence for a specific binding of protein S to factor VIII.  Blood. 1995;  86 1062-1071
    PubMedGoogle Scholar
  • 42 van Wijnen M, Stam J G, van't Veer C et al.. The interaction of protein S with the phospholipid surface is essential for the activated protein C-independent activity of protein S.  Thromb Haemost. 1996;  76 397-403
    PubMedGoogle Scholar
  • 43 Dahlbäck B. Protein S and C4b-binding protein: components involved in the regulation of the protein C anticoagulant system.  Thromb Haemost. 1991;  66 49-61
    PubMedGoogle Scholar
  • 44 van de Poel R H, Meijers J C, Bouma B N. C4b-binding protein inhibits the factor V-dependent but not the factor V-independent cofactor activity of protein S in the activated protein C-mediated inactivation of factor VIIIa.  Thromb Haemost. 2001;  85 761-765
    PubMedGoogle Scholar
  • 45 Rezende S M, Simmonds R E, Lane D A. Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S-C4b binding protein complex.  Blood. 2004;  103 1192-1201
    PubMedGoogle Scholar
  • 46 Gandrille S, Borgel D, Sala N et al.. Protein S deficiency: a database of mutations-summary of the first update. For the Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis.  Thromb Haemost. 2000;  84 918
    PubMedGoogle Scholar
  • 47 Bertina R M. Nomenclature proposal for protein S deficiency. XXXVI Annual meeting of the Scientific and Standardization Committee of the ISTH Barcelona, Spain; 1990
    Google Scholar
  • 48 Israels S J, Seshia S S. Childhood stroke associated with protein C or protein S deficiency.  J Pediatr. 1987;  111 562-564
    CrossrefPubMedGoogle Scholar
  • 49 Barinagarrementeria F, Cant A, Cant-Brio C et al.. Prothrombotic states in young people with idiopathic stroke: a prospective study.  Stroke. 1994;  25 287-290
    PubMedGoogle Scholar
  • 50 Mayer S A, Sacco R L, Hurlet-Jensen A, Shi T, Mohr J P. Free protein S deficiency in acute ischemic stroke: a case-control study.  Stroke. 1993;  24 224-227
    PubMedGoogle Scholar
  • 51 Kurnik K, Kosch A, Sträter R et al.. Recurrent thromboembolism in infants and children suffering from symptomatic neonatal arterial stroke.  Stroke. 2003;  34 2887-2892
    CrossrefPubMedGoogle Scholar
  • 52 Green D, Otoya J, Oriba H, Rovner R. Protein S deficiency in middle-aged women with stroke.  Neurology. 1992;  42 1029-1033
    PubMedGoogle Scholar
  • 53 Golub B M, Sibony P A, Coller B S. Protein S deficiency associated with central retinal artery occlusion.  Arch Ophthal. 1990;  108 918
    PubMedGoogle Scholar
  • 54 Hakimi K N, Massagli T L. Anterior spinal artery syndrome in two children with genetic thrombotic disorders.  J Spinal Cord Med. 2005;  28 69-73
    PubMedGoogle Scholar
  • 55 Espinosa-Parrilla Y, Morell M, Souto J C et al.. Protein S gene analysis reveals the presence of a cosegregating mutation in most pedigrees with type I but not type III PS deficiency.  Hum Mutat. 1999;  14 30-39
    CrossrefPubMedGoogle Scholar
  • 56 Makris M, Leach M, Beauchamp N J et al.. Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S.  Blood. 2000;  95 1935-1941
    PubMedGoogle Scholar
  • 57 Borgel D, Gandrille S, Aiach M. Protein S deficiency.  Thromb Haemost. 1997;  78 351-356
    PubMedGoogle Scholar
  • 58 Restrepo L, McArthur J. Stroke and HIV infection.  Stroke. 2003;  34 e176-e177
    CrossrefPubMedGoogle Scholar
  • 59 Stahl C P, Wideman C S, Spira T J, Haff E C, Hixon G J, Evatt B L. Protein S deficiency in men with long-term human immunodeficiency virus infection.  Blood. 1993;  81 1801-1807
    PubMedGoogle Scholar
  • 60 Majluf-Cruz A, Silva-Estrada M, Sanchez-Barboza R et al.. Venous thrombosis among patients with AIDS.  Clin Appl Thromb Hemost. 2004;  10 19-25
    CrossrefPubMedGoogle Scholar
  • 61 Rosenberg R D, Damus P S. The purification and mechanism of action of human antithrombin-heparin cofactor.  J Biol Chem. 1973;  248 6490-6505
    PubMedGoogle Scholar
  • 62 Rosenberg J S, McKenna P W, Rosenberg R D. Inhibition of human factor IXa by human antithrombin.  J Biol Chem. 1975;  250 8883-8888
    PubMedGoogle Scholar
  • 63 Seegers W H, Holt E. An antithrombin reaction related to prothrombin activation.  Am J Physiol. 1954;  176 97
    PubMedGoogle Scholar
  • 64 Biggs R, Denson K W, Akman N, Borrett R, Hadden M. Antithrombin III, antifactor X and heparin.  Br J Haematol. 1970;  19 283-305
    PubMedGoogle Scholar
  • 65 Damus P S, Hicks M, Rosenberg R D. Anticoagulant action of heparin.  Nature. 1973;  246 355-357
    PubMedGoogle Scholar
  • 66 Stead N, Kaplan A, Rosenberg R D. Inhibition of activated factor XII by antithrombin-heparin cofactor.  J Biol Chem. 1976;  251 6481-6488
    PubMedGoogle Scholar
  • 67 Olson S T, Björk I, Sheffer R, Craig P A, Shore J D, Choay J. Role of the antithrombin-binding pentasaccharide in heparin acceleration of antithrombin-proteinase reactions. Resolution of the antithrombin conformational change contribution to heparin rate enhancement.  J Biol Chem. 1992;  267 12528-12538
    PubMedGoogle Scholar
  • 68 Stein P E, Carrell R W. What do dysfunctional serpins tell us about molecular mobility and disease?.  Nat Struct Biol. 1995;  2 96-113
    CrossrefPubMedGoogle Scholar
  • 69 Vomberg P P, Breederveld C, Fluery P, Arts W F. Cerebral thromboembolism due to antithrombin III deficiency in two children.  Neuropediatrics. 1987;  18 42-44
    PubMedGoogle Scholar
  • 70 Simioni P, Zanardi S, Saracino A et al.. Occurrence of arterial thrombosis in a cohort of patients with hereditary deficiency of clotting inhibitors.  J Med. 1992;  23 61-64
    PubMedGoogle Scholar
  • 71 Arima T, Motomura M, Nishiura Y et al.. Cerebral infarction in a heterozygous with variant antithrombin III.  Stroke. 1992;  23 1822-1825
    CrossrefPubMedGoogle Scholar
  • 72 Graham J A, Daly H M, Carson P J. Antithrombin III deficiency and cerebrovascular accidents in young adults.  J Clin Pathol. 1992;  45 921-922
    PubMedGoogle Scholar
  • 73 Martinez H R, Rangel Guerra R A, Marfil L J. Ischemic stroke due to deficiency of coagulation inhibitors: report of 10 young adults.  Stroke. 1993;  24 19-25
    CrossrefPubMedGoogle Scholar
  • 74 Barinagarrementeria F, Cantu-Brito C, De La Pena A, Izaguirre R. Prothrombotic states in young people with idiopathic stroke. A prospective study.  Stroke. 1994;  25 287-290
    PubMedGoogle Scholar
  • 75 Ernerudh J, Olsson J E, von Schenck H. Antithrombin-III deficiency in ischemic stroke.  Stroke. 1990;  21 967
    PubMedGoogle Scholar
  • 76 Munts A G, van Genderen P J, Dippel D W, van Kooten F, Koudstaal P J. Coagulation disorders in young adults with acute cerebral ischaemia.  J Neurol. 1998;  245 21-25
    PubMedGoogle Scholar
  • 77 Ridker P M, Hennekens C H, Lindpaintner K, Stampfer M J, Eisenberg P R, Miletich J. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men.  N Engl J Med. 1995;  332 912-917
    CrossrefPubMedGoogle Scholar
  • 78 Markus H S, Hambley H. Neurology and the blood: haematological abnormalities in ischaemic stroke.  J Neurol Neurosurg Psychiatry. 1998;  64 150-159
    PubMedGoogle Scholar
  • 79 Haberl R L, Biniasch O, Ott M, Peinemann A, Wick M, Kempter B. Infrequency of stroke caused by specific coagulation disorders.  Cerebrovasc Dis. 1995;  5 391-396
    PubMedGoogle Scholar
  • 80 Catto A, Carter A, Ireland H et al.. Factor V Leiden gene mutation and thrombin generation in relation to the development of acute stroke.  Arterioscler Thromb Vasc Biol. 1995;  15 783-785
    PubMedGoogle Scholar
  • 81 Press R D, Liu X, Beamer N, Coull B M. Ischemic stroke in the elderly: role of the common factor V mutation causing resistance to activated protein C.  Stroke. 1996;  27 44-48
    PubMedGoogle Scholar
  • 82 Hankey G J, Eikelboom J W, van Bockxmeer F M, Lofthouse E, Staples N, Baker R. Inherited thrombophilia in ischemic stroke and its pathogenic subtypes.  Stroke. 2001;  32 1793-1799
    CrossrefPubMedGoogle Scholar
  • 83 Jerrard-Dunne P, Evans A, McGovern R et al.. Ethnic differences in markers of thrombophilia: implications for the investigation of ischemic stroke in multiethnic populations: the South London Ethnicity and Stroke Study.  Stroke. 2003;  34 1821-1827
    CrossrefPubMedGoogle Scholar
  • 84 Martinez H R, Rangel Guerra R A, Marfil L J. Ischemic stroke due to deficiency of coagulation inhibitors: report of 10 young adults.  Stroke. 1993;  24 19-25
    CrossrefPubMedGoogle Scholar
  • 85 Barinagarrementeria F, Cantu-Brito C, De La Peria A, Izaguirre R. Prothrombotic states in young people with idiopathic stroke: a prospective study.  Stroke. 1994;  25 287-290
    PubMedGoogle Scholar
  • 86 Munts A G, van Genderen P J, Dippel D W, van Kooten F, Koudstaal P J. Coagulation disorders in young adults with acute cerebral ischaemia.  J Neurol. 1998;  245 21-25
    PubMedGoogle Scholar
  • 87 Kroon U B, Silfverstolpe G, Tengborn L. The effects of transdermal estradiol and oral conjugated estrogens on haemostasis variables.  Thromb Haemost. 1994;  71 420-423
    PubMedGoogle Scholar
  • 88 Shen Y M, Frenkel E P. Thrombosis and a hypercoagulable state in HIV-infected patients.  Clin Appl Thromb Hemost. 2004;  10 277-280
    CrossrefPubMedGoogle Scholar

Salina P WaddyM.D. 

Department of Neurology, Emory University, Woodruff Memorial Research Building, Suite 600, 101 Woodruff Circle, Atlanta, GA 30322

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