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Thromb Haemost 2017; 117(09): 1808-1815
DOI: 10.1160/TH17-03-0189
Stroke, Systemic or Venous Thromboembolism
Schattauer GmbH

Haemostasis biomarkers and risk of intracerebral haemorrhage in the REasons for Geographic and Racial Differences in Stroke Study

Neil A. Zakai
1   University of Vermont College of Medicine Department of Medicine, Burlington, Vermont, USA
2   University of Vermont College of Medicine Department of Pathology and Laboratory Medicine, Burlington, Vermont, USA
,
Nels C. Olson
2   University of Vermont College of Medicine Department of Pathology and Laboratory Medicine, Burlington, Vermont, USA
,
Suzanne E. Judd
3   University of Alabama at Birmingham, Birmingham, Alabama, USA
,
Dawn O. Kleindorfer
4   University of Cincinnati, Cincinnati, Ohio, USA
,
Brett M. Kissela
4   University of Cincinnati, Cincinnati, Ohio, USA
,
George Howard
3   University of Alabama at Birmingham, Birmingham, Alabama, USA
,
Mary Cushman
1   University of Vermont College of Medicine Department of Medicine, Burlington, Vermont, USA
2   University of Vermont College of Medicine Department of Pathology and Laboratory Medicine, Burlington, Vermont, USA
› Author Affiliations Financial support: This research project is supported by a cooperative agreement U01 NS041588 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Service (Bethesda, MD, USA). Additional funding was provided by K08HL096841 (principle investigator NAZ) and K99HL129045 (principle investigator NCO) from the National Heart, Lung, and Blood Institute (Bethesda, MD, USA).
Further Information

Publication History

Received: 17 March 2017

Accepted after major revision: 26 May 2017

Publication Date:
28 November 2017 (online)

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Summary

Pathologic alterations in haemostasis cause bleeding disorders, but it is unknown if variation within the normal range relates to intracerebral haemorrhage (ICH) risk. It was our objective to assess the prospective associations of haemostasis biomarkers with ICH risk. The REasons for Geographic and Racial Differences in Stroke study (REGARDS) recruited 30,239 U. S. individuals aged ≥45 years. ICH was ascertained through biannual telephone contact and review of deaths followed by medical record evaluation. Haemostasis biomarkers (factor VIII (FVIII), factor IX (FIX), factor XI (FXI), fibrinogen, protein C, and D-dimer) were measured in a case cohort study consisting of ICH and a 1,104 person cohort random sample. The hazard ratio (HR) and 95 % confidence interval (CI) by biomarker were estimated using Cox models and adjusted for ICH risk factors. Individuals with a prior history of stroke, ICH or on warfarin were excluded. Over a median 5.8 years 66 ICH occurred. Fibrinogen, FVIII, FXI, and protein C were not associated with ICH risk in any analysis. Lower FIX increased risk of ICH with the bottom versus the top tertile of FIX associated with an HR of 5.68 (95 % CI 2.30, 14.05). D-dimer demonstrated a non-linear relationship with a potential threshold effect with increased risk only in the top 5th percentile (HR 3.22; 95 % CI 1.01, 10.31; pnon-linear = 0.04).In conclusion, low FIX levels within the normal range were associated with increased ICH risk. These data suggest non-pathologic alterations in haemostasis impact intracranial bleeding risk.

Keywords

Cerebral haemorrhage - cohort studies - continental population groups - epidemiology - haemostasis
 

  • References

  • 1 Sturgeon JD, Folsom AR, Longstreth Jr. WT. et al. Risk factors for intracerebral hemorrhage in a pooled prospective study. Stroke 2007; 38: 2718-2725.
    CrossrefPubMedGoogle Scholar
  • 2 Rincon F, Mayer SA. The epidemiology of intracerebral hemorrhage in the United States from 1979 to 2008. Neurocrit Care 2013; 19: 95-102.
    CrossrefPubMedGoogle Scholar
  • 3 Howard G, Cushman M, Howard VJ. et al. Risk factors for intracerebral hemorrhage: the REasons for geographic and racial differences in stroke (REGARDS) study. Stroke 2013; 44: 1282-1287.
    CrossrefPubMedGoogle Scholar
  • 4 Woo D, Sauerbeck LR, Kissela BM. et al. Genetic and environmental risk factors for intracerebral hemorrhage: preliminary results of a population-based study. Stroke 2002; 33: 1190-1195.
    CrossrefPubMedGoogle Scholar
  • 5 Feldmann E, Broderick JP, Kernan WN. et al. Major risk factors for intracerebral hemorrhage in the young are modifiable. Stroke 2005; 36: 1881-1885.
    CrossrefPubMedGoogle Scholar
  • 6 Ariesen MJ, Claus SP, Rinkel GJ. et al. Risk factors for intracerebral hemorrhage in the general population: a systematic review. Stroke 2003; 34: 2060-2065.
    CrossrefPubMedGoogle Scholar
  • 7 Srivastava A, Brewer AK, Mauser-Bunschoten EP. et al. Guidelines for the management of hemophilia. Haemophilia 2013; 19: e1-47.
    CrossrefPubMedGoogle Scholar
  • 8 Cushman M. Epidemiology and risk factors for venous thrombosis. Semin Hematol 2007; 44: 62-69.
    CrossrefPubMedGoogle Scholar
  • 9 Adam SS, Key NS, Greenberg CS. D-dimer antigen: current concepts and future prospects. Blood 2009; 113: 2878-2887.
    CrossrefPubMedGoogle Scholar
  • 10 Howard G, Cushman M, Kissela BM. et al. Traditional risk factors as the underlying cause of racial disparities in stroke: lessons from the half-full (empty?) glass. Stroke 2011; 42: 3369-3375.
    CrossrefPubMedGoogle Scholar
  • 11 Howard VJ, Cushman M, Pulley L. et al. The reasons for geographic and racial differences in stroke study: objectives and design. Neuroepidemiol 2005; 25: 135-143.
    CrossrefPubMedGoogle Scholar
  • 12 Gillett SR, Boyle RH, Zakai NA. et al. Validating laboratory results in a national observational cohort study without field centers: the Reasons for Geographic and Racial Differences in Stroke cohort. Clin Biochem 2014; 47: 243-246.
    CrossrefPubMedGoogle Scholar
  • 13 Barlow WE, Ichikawa L, Rosner D. et al. Analysis of case-cohort designs. J Clin Epidemiol 1999; 52: 1165-1172.
    CrossrefPubMedGoogle Scholar
  • 14 Kulathinal S, Karvanen J, Saarela O. et al. Case-cohort design in practice - experiences from the MORGAM Project. Epidemiol Perspect Innov 2007; 04: 15.
    CrossrefPubMedGoogle Scholar
  • 15 Cushman M, Judd SE, Howard VJ. et al. N-terminal pro-B-type natriuretic peptide and stroke risk: the reasons for geographic and racial differences in stroke cohort. Stroke 2014; 45: 1646-1650.
    CrossrefPubMedGoogle Scholar
  • 16 Zakai NA, Judd SE, Alexander K. et al. ABO blood type and stroke risk: the REasons for Geographic And Racial Differences in Stroke Study. J Thromb Haemost 2014; 12: 564-570.
    CrossrefPubMedGoogle Scholar
  • 17 Quinones-Hinojosa A, Gulati M, Singh V. et al. Spontaneous intracerebral hemorrhage due to coagulation disorders. Neurosurg Focus 2003; 15: pE3.
    PubMedGoogle Scholar
  • 18 Plug I, Mauser-Bunschoten EP, Brocker-Vriends AH. et al. Bleeding in carriers of hemophilia. Blood 2006; 108: 52-56.
    CrossrefPubMedGoogle Scholar
  • 19 Woo D, Falcone GJ, Devan WJ. et al. Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage. Am J Hum Genet 2014; 94: 511-521.
    CrossrefPubMedGoogle Scholar
  • 20 Hirsh J, Dalen J, Anderson DR. et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001; 119 (Suppl. 01) 8S-21S.
    CrossrefPubMedGoogle Scholar
  • 21 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
    CrossrefPubMedGoogle Scholar
  • 22 Investigators E-P, Buller HR, Prins MH. et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366: 1287-1297.
    CrossrefPubMedGoogle Scholar
  • 23 Granger CB, Alexander JH, McMurray JJ. et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992.
    CrossrefPubMedGoogle Scholar
  • 24 Adams NB, Lutsey PL, Folsom AR. et al. Statin therapy and levels of hemostatic factors in a healthy population: the Multi-Ethnic Study of Atherosclerosis. J Thromb Haemost 2013; 11: 1078-1084.
    CrossrefPubMedGoogle Scholar
  • 25 Peralta CA, Shlipak MG, Judd S. et al. Detection of chronic kidney disease with creatinine, cystatin C, and urine albumin-to-creatinine ratio and association with progression to end-stage renal disease and mortality. J Am Med Assoc 2011; 305: 1545-1552.
    CrossrefPubMedGoogle Scholar
  • 26 Zakai NA, Katz R, Jenny NS. et al. Inflammation and hemostasis biomarkers and cardiovascular risk in the elderly: the Cardiovascular Health Study. J Thromb Haemost 2007; 05: 1128-1135.
    CrossrefPubMedGoogle Scholar
  • 27 Di Castelnuovo A, Agnoli C, de Curtis A. et al. Elevated levels of D-dimers increase the risk of ischaemic and haemorrhagic stroke. Findings from the EPI-COR Study. Thromb Haemost 2014; 112: 941-946.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Warren HS, Suffredini AF, Eichacker PQ. et al. Risks and benefits of activated protein C treatment for severe sepsis. N Engl J Med 2002; 347: 1027-1030.
    CrossrefPubMedGoogle Scholar
  • 29 Clouse LH, Comp PC. The regulation of hemostasis: the protein C system. N Engl J Med 1986; 314: 1298-1304.
    CrossrefPubMedGoogle Scholar
  • 30 Martinelli I, Mannucci PM, 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
  • 31 Ljung RC. Intracranial haemorrhage in haemophilia A and B. Br J Haematol 2008; 140: 378-384.
    CrossrefPubMedGoogle Scholar
  • 32 de Tezanos Pinto M, Fernandez J, Perez Bianco PR. Update of 156 episodes of central nervous system bleeding in hemophiliacs. Haemostasis 1992; 22: 259-267.
    PubMedGoogle Scholar
  • 33 Peyvandi F, Palla R, Menegatti M. et al. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thromb Haemost 2012; 10: 615-621.
    CrossrefPubMedGoogle Scholar
  • 34 Casini A, Blondon M, Lebreton A. et al. Natural history of patients with congenital dysfibrinogenemia. Blood 2015; 125: 553-561.
    CrossrefPubMedGoogle Scholar
  • 35 Buller HR, Bethune C, Bhanot S. et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med 2015; 372: 232-240.
    CrossrefPubMedGoogle Scholar
  • 36 Rasche H. Haemostasis and thrombosis: an overview. Eur Heart J Suppl 2001; 03 (Q) Q3-Q7.
    CrossrefPubMedGoogle Scholar