Molecular pathogenesis of subarachnoid haemorrhage
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Molecular pathogenesis of subarachnoid haemorrhage. Baiping Zhang, Kaare Gugleholm, Lorna B. Day, Shu Ye, Roy O. Weller, Ian N.M. Day 5 November 2002. Pathogenesis and the stages involved in the formation of saccular aneurysm Cellular and molecular architecture of the vessel wall

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Molecular pathogenesis of subarachnoid haemorrhage

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Molecular pathogenesis of subarachnoid haemorrhage

Baiping Zhang, Kaare Gugleholm, Lorna B. Day, Shu Ye, Roy O. Weller, Ian N.M. Day

5 November 2002


  • Pathogenesis and the stages involved in the formation of saccular aneurysm

  • Cellular and molecular architecture of the vessel wall

  • Molecular pathology

    • PKD1 gene and polycystin

    • COL3A1 and type III collagen

    • Fibrillin-1

    • Collagen IV and other basement membrane constituents

    • Alpha1-Antitrypsin (protease inhibitor)

  • Future focus


Subarachnoid haemorrhage (SAH)

  • Condition caused by the escape of blood from a cerebral artery into the subarachnoid space along the surface of the brain.

http://instruct.uwo.ca/anatomy/530/SagSin.gif


  • Mortality of diagnosed cases is about 40% within the first 30 days

  • Less then 25% have a good functional outcome and the disease has dramatic impact on the lives of carers and relatives.

Pritchard, Foulkes, Lang, & Neil-Dwyer. 2001


Schematic overview of contributory factors to subarachnoid haemorrhage

B. Zhang et al./ The International Journal of Biochemistry & Cell Biology 35 (2003) 1341-1360


Commonest sites for Saccular Aneurysms

B. Zhang et al./ The International Journal of Biochemistry & Cell Biology 35 (2003) 1341-1360


B. Zhang et al./ The International Journal of Biochemistry & Cell Biology 35 (2003) 1341-1360


Etiology involved in the formation of saccular aneurysms

  • Majority of aneurysms occur between the ages of 40 and 70

    • Ageing effects on the arteries

  • Increased incidence of saccular aneurysms in families with

    • Polycystic kidney disease

    • Fibromuscular dysplasia

    • Moyamoya disease

    • Marfan Syndrome

    • EDS type IV


PKD1 gene and polycystin

  • Adult polycystic kidney disease is an autosomal dominant disorder in which renal cysts form, leading to progressive loss of glomerular filtration and subsequently to renal failure and end-stage renal disease.

  • PKD1 gene causing (PKD)

    • Encodes for a protein named polycystin

  • Polycystin - participates in protein-protein and protein-carbohydrate interactions in the extracellular matrix

adpkd.cimr.cam.ac.uk/ buttons/pkd1_hs_350.gif


COL3A1 and type III collagen

  • Ehlers-Danlos Syndrome Vascular Type

    • Arterial rupture risk

    • Thin transparent skin

    • Early bruising

    • Joint laxity

    • Ligament weakness

    • Bowel rupture

  • (EDS type IV)

    • Defective collagen III synthesis

    • Vascular expression on COL3A1


Collagen IV and other basement membrane constituents

  • Collagen IV defects cause Alport’s syndrome.

  • Alports syndrome characterized sensorineural hearing loss and haematuria.

    • Its is therefore plausible new hypothesis that defects in the basement membrane as well as defects in the elastic and medial layer may predispose intracranial aneurysms


Protease inhibitor (alpha1-Antitrypsin)

  • Most abundant and potent natural inhibitor of elastase.

  • Alpha1-Antitrypsin activity has been claimed to be reduced in both intracranial and abdominal aortic aneurysm.


Future focus


Fibrillin-1 and FBN1

  • Marfan syndrome is an autosomal dominant heritable disorder of connective tissue with prominent manifestations affecting the skeletal, ocular and cardiovascular systems.

  • Progressive dilation of the aortic root and aortic dissection and rupture are frequent, and mitral and aotic valve insufficiency may also occur early.

    • Caused by mutations in FBN1 gene encoding fibrilin-1

      • Mutations of this gene also cause type I fibrillinopathies


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