Advanced

The molecular basis of thrombolysis and its clinical application in stroke

Murray, V.; Norrving, Bo LU ; Sandercock, P. A. G.; Terent, A.; Wardlaw, J. M. and Wester, P. (2010) Stockholm Stroke Symposium - From Genes to Acute Care In Journal of Internal Medicine 267(2). p.191-208
Abstract
The rationale for thrombolysis, the most promising pharmacological approach in acute ischaemic stroke, is centred on the principal cause of most ischaemic strokes: the thrombus that occludes the cerebral artery, and renders part of the brain ischaemic. The occluding thrombus is bound together within fibrin. Fibrinolysis acts by activation of plasminogen to plasmin; plasmin splits fibrinogen and fibrin and lyses the clot, which then allows reperfusion of the ischaemic brain. Thrombolytic agents include streptokinase (SK) and recombinant tissue-type plasminogen activator (rt-PA) amongst others under test or development. SK is nonfibrin-specific, has a longer half-life than tissue-type plasminogen activator (t-PA), prevents re-occlusion and... (More)
The rationale for thrombolysis, the most promising pharmacological approach in acute ischaemic stroke, is centred on the principal cause of most ischaemic strokes: the thrombus that occludes the cerebral artery, and renders part of the brain ischaemic. The occluding thrombus is bound together within fibrin. Fibrinolysis acts by activation of plasminogen to plasmin; plasmin splits fibrinogen and fibrin and lyses the clot, which then allows reperfusion of the ischaemic brain. Thrombolytic agents include streptokinase (SK) and recombinant tissue-type plasminogen activator (rt-PA) amongst others under test or development. SK is nonfibrin-specific, has a longer half-life than tissue-type plasminogen activator (t-PA), prevents re-occlusion and is degraded enzymatically in the circulation. rt-PA is more fibrin-specific and clot-dissolving, and is metabolized during the first passage in the liver. In animal models of ischaemic stroke, the effects of rt-PA are remarkably consistent with the effects seen in human clinical trials. For clinical application, some outcome data from the Cochrane Database of Systematic Reviews which includes all randomized evidence available on thrombolysis in man were used. Trials included tested urokinase, SK, rt-PA, pro-urokinase, or desmoteplase. The chief immediate hazard of thrombolytic therapy is fatal intracranial bleeding. However, despite the risk, the human trial data suggest the immediate hazards and the apparent substantial scope for net benefit of thrombolytic therapy given up to 6 h of acute ischaemic stroke. So far the fibrin-specific rt-PA is the only agent to be approved for use in stroke. This may be due to its short half-life and its absence of any specific amount of circulating fibrinogen degradation products, thereby leaving platelet function intact. The short half-life does not leave rt-PA without danger for haemorrhage after the infusion. Due to its fibrin-specificity, it can persist within a fibrin-rich clot for one or more days. The molecular mechanisms with regards to fibrin-specificity in thrombolytic agents should, if further studied, be addressed in within-trial comparisons. rt-PA has antigenic properties and although their long-term clinical relevance is unclear there should be surveillance for allergic reactions in relation to treatment. Although rt-PA is approved for use in selected patients, there is scope for benefit in a much wider variety of patients. A number of trials are underway to assess which additional patients - beyond the age and time limits of the current approval - might benefit, and how best to identify them. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Chapter in Book/Report/Conference proceeding
publication status
published
subject
keywords
molecular aspects, fibrinolysis, animal data, clinical effect, stroke, thrombus
in
Journal of Internal Medicine
volume
267
issue
2
pages
191 - 208
publisher
Wiley-Blackwell
conference name
Stockholm Stroke Symposium - From Genes to Acute Care
external identifiers
  • wos:000273771200005
  • scopus:74849106257
ISSN
0954-6820
DOI
10.1111/j.1365-2796.2009.02205.x
language
English
LU publication?
yes
id
bcf66b3d-daec-4ce4-926f-ecd5593f8758 (old id 1547277)
date added to LUP
2010-02-24 09:12:35
date last changed
2018-07-08 03:41:43
@inproceedings{bcf66b3d-daec-4ce4-926f-ecd5593f8758,
  abstract     = {The rationale for thrombolysis, the most promising pharmacological approach in acute ischaemic stroke, is centred on the principal cause of most ischaemic strokes: the thrombus that occludes the cerebral artery, and renders part of the brain ischaemic. The occluding thrombus is bound together within fibrin. Fibrinolysis acts by activation of plasminogen to plasmin; plasmin splits fibrinogen and fibrin and lyses the clot, which then allows reperfusion of the ischaemic brain. Thrombolytic agents include streptokinase (SK) and recombinant tissue-type plasminogen activator (rt-PA) amongst others under test or development. SK is nonfibrin-specific, has a longer half-life than tissue-type plasminogen activator (t-PA), prevents re-occlusion and is degraded enzymatically in the circulation. rt-PA is more fibrin-specific and clot-dissolving, and is metabolized during the first passage in the liver. In animal models of ischaemic stroke, the effects of rt-PA are remarkably consistent with the effects seen in human clinical trials. For clinical application, some outcome data from the Cochrane Database of Systematic Reviews which includes all randomized evidence available on thrombolysis in man were used. Trials included tested urokinase, SK, rt-PA, pro-urokinase, or desmoteplase. The chief immediate hazard of thrombolytic therapy is fatal intracranial bleeding. However, despite the risk, the human trial data suggest the immediate hazards and the apparent substantial scope for net benefit of thrombolytic therapy given up to 6 h of acute ischaemic stroke. So far the fibrin-specific rt-PA is the only agent to be approved for use in stroke. This may be due to its short half-life and its absence of any specific amount of circulating fibrinogen degradation products, thereby leaving platelet function intact. The short half-life does not leave rt-PA without danger for haemorrhage after the infusion. Due to its fibrin-specificity, it can persist within a fibrin-rich clot for one or more days. The molecular mechanisms with regards to fibrin-specificity in thrombolytic agents should, if further studied, be addressed in within-trial comparisons. rt-PA has antigenic properties and although their long-term clinical relevance is unclear there should be surveillance for allergic reactions in relation to treatment. Although rt-PA is approved for use in selected patients, there is scope for benefit in a much wider variety of patients. A number of trials are underway to assess which additional patients - beyond the age and time limits of the current approval - might benefit, and how best to identify them.},
  author       = {Murray, V. and Norrving, Bo and Sandercock, P. A. G. and Terent, A. and Wardlaw, J. M. and Wester, P.},
  booktitle    = {Journal of Internal Medicine},
  issn         = {0954-6820},
  keyword      = {molecular aspects,fibrinolysis,animal data,clinical effect,stroke,thrombus},
  language     = {eng},
  number       = {2},
  pages        = {191--208},
  publisher    = {Wiley-Blackwell},
  title        = {The molecular basis of thrombolysis and its clinical application in stroke},
  url          = {http://dx.doi.org/10.1111/j.1365-2796.2009.02205.x},
  volume       = {267},
  year         = {2010},
}