Zusammenfassung
Ziel: Zu überprüfen, ob der Erfolg einer Lyse mit rekombinantem Gewebe-Plasminogenaktivator
(rt-PA) vom Erythrozyten- und Fibringehalt eines Thrombus abhängt. Methode: 30 Minuten nach Verschluss der A. cerebri media mit 20 Stunden alten roten oder weißen
Emboli wurde bei 23 Kaninchen eine intraarterielle Thrombolyse mit 3 mg rt-PA/kg Körpergewicht
durchgeführt. 20 Kaninchen dienten als Kontrolle. Die zerebrale Perfusion wurde MR-tomographisch
überwacht. Ergebnisse: rt-PA entfaltete nur bei Gefäßverschlüssen mit roten Emboli eine thrombolytische
Wirkung. In dieser Gruppe sank die mittlere Transitzeit des Kontrastmittels durch
das Hirngewebe (NFM; p < .05), das relative regionale Blutvolumen (rrCBV) normalisierte
sich (p < .05), und die Infarktgröße nahm ab (p < .01). Bei weißen Emboli hatte rt-PA
keinen Einfluss auf die Hirndurchblutung und die Infarktgröße. Schlussfolgerungen: In unserem Tierversuch nahm die thrombolytische Wirkung von rt-PA mit dem Erythrozytengehalt
der Gefäßverschlüsse zu und mit ihrem Fibringehalt ab. Sollte dieses Ergebnis auch
auf Schlaganfallpatienten zutreffen, wäre es denkbar, dass der Erfolg einer Lyse noch
vor Therapiebeginn abgeschätzt werden kann, denn rote und weiße Thromben lassen sich
durch ihre Röntgendichte unterscheiden.
Abstract
Purpose: It is known from autopsy studies that thromboembolic stroke can be caused by red,
white and mixed clots. We therefore examined whether the efficacy of thrombolysis
with recombinant tissue-type plasminogen activator (rt-PA) depends on the proportions
of fibrin and erythrocytes within thromboembolic material. Methods: In 23 rabbits intraarterial thrombolysis with 3 mg rt-PA/kg body weight was started
30 minutes after middle cerebral artery occlusion with either red or white autologous
emboli 20 hours old. 20 rabbits served as control. Cerebral perfusion was monitored
by MRI. Results: rt-PA enhanced lysis of red but not of white emboli and decreased the infarct volume
only if vascular occlusion was due to red emboli (p < .01). Cerebral perfusion improved
only in the red treatment group where the normalized first moment (NFM) decreased
(p < .05) and the relative regional cerebral blood volume (rrCBV) reached normal values
(p < .05). Conclusion: We suggest that in our animal model the efficacy of thrombolysis increases with
the proportion of erythrocytes within thromboembolic material and decreases with its
content of fibrin. lf these findings would also be applicable to patients, pretherapeutic
estimation of the efficacy of thrombolysis might become feasible because the CT values
of red and white thrombi differ.
Key words
Experimental thrombolysis - rabbit - stroke - erythrocytes - fibrin
Literatur
1
Bednar M M, Mc Auliffe T, Raymond S, Gross C E.
Tissue plasminogen activator reduces brain injury in a rabbit model of thromboembolic
stroke.
Stroke.
1990;
21
1705-1709
2
Benes V, Zabramski J M, Boston M, Puca A, Spetzler R F.
Effect of intra-arterial tissue plasminogen activator and urokinase on autologous
arterial emboli in the cerebral circulation of rabbits.
Stroke.
1990;
21
1594-1599
3
Hamilton M G, Lee J S, Cummings P J, Zabramski J M.
A comparison of intra-arterial and intravenous tissue-type plasminogen activator on
autologous arterial emboli in the cerebral circulation of rabbits.
Stroke.
1994;
25
651-656
4
Gross C E, Raymond S J, Howard D B, Bednar M M.
Delayed tissue-plasminogen activator therapy in a rabbit model of thromboembolic stroke.
Neurosurgery.
1995;
36
1172-1177
5
The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group
.
Tissue plasminogen activator for acute ischemic stroke.
N Engl J Med.
1995;
333
1581-1587
6
Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, Kummer R von, Boysen G, Bluhmki E,
Höxter G, Mahagne M H, Hennerici M. for the ECASS Study Group .
Intravenous thrombolysis with recombinant tissue plas-minogen activator for acute
hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS).
JAMA.
1995;
274
1017-1025
7
Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E,
Davis S, Donnan G, Schneider D, Diez-Tejedor E, Trouillas P. for the Second European-Australasian
Acute Stroke Study Investigators .
Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous
alteplase in acute ischaemic stroke (ECASS II).
Lancet.
1998;
352
1245-1251
8
Steiner T, Bluhmki E, Kaste M, Toni D, Trouillas P, von Kummer R, Hacke W. for the
ECASS Study Group .
The ECASS 3-hour cohort. Secondary analysis of ECASS data by time stratification.
Cerebrovasc Dis.
1998;
8
198-203
9
del Zoppo G J.
Clinical trials in acute stroke: why have they not been successful?.
Neurology.
1998;
51
(3 Suppl 3)
S 59-S 61
10
Hacke W, Brott T, Caplan L, Meier D, Fieschi C, Kummer R von, Donnan G, Heiss W D,
Wahlgren N G, Spranger M, Boysen G, Marler J R.
Thrombolysis in acute ischemic stroke: controlled trials and clinical experience.
Neurology.
1999;
53
(7 Suppl. 4)
S 3-S 14
11
Vanderschueren S, Van Vlaenderen I, Collen D.
Intravenous thrombolysis with recombinant staphylokinase versus tissue-type plasminogen
activator in a rabbit embolic stroke model.
Stroke.
1997;
28
1783-1788
12
Yenari M A, Lee L K, Beaulieu C, Sun G H, Kunis D, Chang D, Albers G W, Moseley M E,
Steinberg G K.
Thrombolysis with reteplase, an unglycosylated plasminogen activator variant, in experimental
embolic stroke.
J Stroke Cerebrovasc Dis.
1998;
7
179-186
13
Castaigne P, Lhermitte F, Gautier J C, Escourolle R, DerouesneŽ C.
Internal carotid artery occlusion. A study of 61 instances in 50 patients with post-mortem
data.
Brain.
1970;
93
231-258
14
Jörgensen L, Torvik A.
Ischaemic cerebrovascular diseases in an autopsy series. Part 2. Prevalence, location,
pathogenesis, and clinical course of cerebral infarcts.
J Neurol Sci.
1969;
9
285-320
15
Torvik A, Jörgensen L.
Thrombotic and embolic occlusions of the carotid arteries in an autopsy series. Part
2. Cerebral lesions and clinical course.
J Neurol Sci.
1966;
3
410-432
16
Kirchhof K, Welzel T, Zoubaa S, Lichy C, Sikinger M, Lorbacher de Ruiz H, Sartor K.
New method of embolus preparation for standardized embolic stroke in rabbits.
Stroke.
2002;
33
2329-2333
17
Golanov E V, Reis D J.
Contribution of cerebral edema to the neuronal salvage elicited by stimulation of
cerebellar fastigial nucleus after occlusion of the middle cerebral artery in rat.
J Cereb Blood Flow Metab.
1995;
15
172-174
18
Urban I, Richard P.
A stereotaxic atlas of the New Zealand rabbit's brain.
Springfield, Illinois, USA C C Thomas.
1972;
1
76-81
19
Fisel C R, Ackerman J L, Buxton R B, Garrido L, Belliveau J W, Rosen B R, Brady T J.
MR contrast due to microscopically heterogeneous magnetic susceptibility: numerical
simulations and applications to cerebral physiology.
Magn Reson Med.
1991;
17
336-347
20
Rosen B R, Belliveau J W, Vevea J M, Brady T J.
Perfusion imaging with NMR contrast agents.
Magn Reson Med.
1990;
14
249-265
21
Blinc A, Keber D, Lahajnar G, Stegnar M, Zidansek A, Demsar F.
Lysing patterns of retracted blood clots with diffusion or bulk flow transport of
plasma with urokinase into clots - a magnetic resonance imaging study in vitro.
Thromb Haemost.
1992;
68
667-671
22
Carr M E, Hardin C L.
Fibrin has larger pores when formed in the presence of erythrocytes.
Am J Physiol.
1987;
253
H 1069-H 1073
23
Jørgensen L.
Experimental platelet and coagulation thrombi.
Acta Path et Microbiol Scandinav.
1964;
62
189-223
24
Chapman I.
Morphogenesis of occluding coronary artery thrombosis.
Arch Path.
1965;
80
256-261
25
Rodman N F, Painter J C, Mc Devitt N B.
Platelet disintegration during clotting.
J Cell Biol.
1963;
16
225-241
26
Brown B G, Gallery C A, Badger R S, Kennedy J W, Mathey D, Bolson E L, Dodge H T.
Incomplete lysis of thrombus in the moderate underlying atherosclerotic lesion during
intracoronary infusion of streptokinase for acute myocardial infarction: quantitative
angiographic observations.
Circulation.
1986;
73
653-661
27
Ueda T, Hatakeyama T, Kumon Y, Sakaki S, Uraoka T.
Evaluation of risk of hemorrhagic transformation in local intra-arterial thrombolysis
in acute ischemic stroke by initial SPECT.
Stroke.
1994;
25
298-303
28
Xi G, Hua Y, Bhasin R R, Ennis S R, Keep R F, Hoff J T.
Mechanisms of edema formation after intracerebral hemorrhage: effects of extravasated
red blood cells on blood flow and blood-brain barrier integrity.
Stroke.
2001;
32
2932-2938
29
Kirchhof K, Welzel T, Mecke C, Zoubaa S, Sartor K.
Differentiation of white, mixed, and red thrombi: value of CT in estimation of the
prognosis of thrombolysis - phantom study.
Radiology.
2003;
228
126-130
30
Kirchhof K, Mecke C, Lichy C, Sartor K.
Die Röntgendichte am Ort thrombembolischer zerebraler Gefäßverschlüsse: Prognostischer
Faktor für eine Lysetherapie?.
Fortschr Röntgenstr.
2003;
175
1130-1137
Dr. Klaus Kirchhof
Klinik für Diagnostische Radiologie und Neuroradiologie, Zentralklinikum Augsburg
Stenglinstraße 2
86156 Augsburg
Phone: ++49/821/400-2441
Fax: ++49/821/400-3312
Email: Klaus.Kirchhof@radiologie.zk.augsburg-med.de