Microthrombosis and Fibrin Deposition

In ischemia the microcirculation is impaired by hemorrheological failure: the microthrombosis (Pe-tito 1979; Obrenovitsch and Hallenbeck 1985). The thrombi are composed of platelets, and a network of fibrin. In some vessels there is only a thick layer of fibrin coating the endothelium and surrounding the platelets. The number of microthrombi increases in humans as the necrotic process ages, and peaks in such stages in which acute ischemic changes coexist with the beginning of phagocytosis: between 7 and 15 days (Figols et al. 1987).

Extravascular fibrin deposition was significantly increased by 24 h of reperfusion in adolescent male baboons (Okada et al. 1994) after 2 h or 3 h of middle artery occlusion. These results suggest that microvascular fibrin deposition accumulates in a time-dependent manner during focal cerebral is-chemia/reperfusion and that exposure of plasma to

rations, i.e., edema, congestion, and perivascular hemorrhages, in the pons (a) and medulla (b)

a perivascular tissue factor is partially responsible for occlusion formation. During ischemia the large plasma protein fibrinogen extravasates and interacts with parenchymal tissue factor, forming significant extravascular fibrin by 24 h of reperfusion.

14.3.4 Neurons

In the reperfusion type of ischemia ischemic nerve cell alterations in Nissl stain are characterized by tigrolysis (loss of Nissl bodies) and/or microvacuo-lation (Fig. 13.4c) within 1-3 h (Steegmann 1968). In H&E stain ischemic cortical nerve cell necrosis in layers III, V, and VI is seen within 4 h (Schröder 1983) or 5 h (Horn and Schlote 1992) marked by a homogenizing cell change consisting of eosinophilic or dark Luxol fast blue cytoplasm, a hyperchromatic, pyknotic nucleus, and a pericellular space as described in Chapter 4 (Figs. 4.5c, d, 13.4). After 5 min of ischemia and 1-2 days of recirculation, numerous calcium-containing neurons appeared in the CA4 sector, but only a few were present in the CA1 sector (Bonnekoh et al. 1992).

Fig. 14.7a, b. Ischemia induced edema in the cerebral cortex. a tershed edema) as well as b along the subpial cortical vessels Edema in the sulcus between the 1st and 2nd frontal gyri (wa- (H&E; magnification a, b x50)

Two relevant clinicopathologic investigations of ischemic neuronal death in human autopsy material (Petito et al. 1987; Horn and Schlote 1992) gave evidence of an early and delayed neuronal death, as had already been demonstrated by animal experiments (Ito et al. 1975). In 1982, Kirino demonstrated that the CA1 damage in the gerbil hippocampus takes place with a delay of about 48 h after brief forebrain ischemia, and is completed by the fourth day following an ischemic insult. Horn and Schlote (1992) evaluated 26 human brains and observed the earliest manifestations of ischemic neuronal necrosis by 5 h following cardiac arrest in cortical layers III, V, and VI, whereas hippocampal CA1 and Purkinje cell layers did not yet reveal any definite ischemic cell damage. CA1 pyramidal cell death does not occur until 4 days following global ischemia (cardiac arrest) but afterwards develops rapidly, exceeding the extent of neocortical neuronal injury by about 5 days post arrest. Finally, it seems to be completed no earlier than 7 days after the ischemic insult.

These findings allow the conclusion to be drawn that two types of neuronal damage, an early and a delayed one, exist in human brain too. Additional ly it is known that the current data substantiate that the cell process determining the fate of CA1 neurons - delayed death or recovery - is related to the first 40 min of post-ischemic reperfusion, thus underlining the particular clinical importance of delayed neuronal death as a therapeutic window of post-ischemia treatment (Kuroiwa et al. 1990). Within the Purkinje cell layers neuronal death takes place significantly earlier and more gradually than in CA1 of the hippocampus.

A retrograde reaction of neuronal perikaryon, i.e., a neuronal swelling, a central chromatolysis, and an eccentric localization of the nucleus (Fig. 3.1b), is seen within 35 h and 15 months after ischemia (Schröder 1983; see also Schlote 1970; Torvik and Skjörten 1971); Jacob and Pyrkosch (1951) described "neuronal necrosis" in 3 of 20 cases of hanging. We agree with Schröder (1983) that these alterations may be supravital or postmortem phenomena. Though is-chemic changes are mainly consistent with necrosis of neurons we have to accept that DNA fragmentation (apoptosis) occurs after the development of neuronal death in CA1 neurons subjected to 10 min of global ischemia (Petito et al. 1997; Love et al. 2000).

Fig. 14.8a-c. Astrocytic reaction in ischemic cornu Ammonis and cerebral cortex. a Intact, non-injured cornu Ammonis; b activation, i.e., astrocytic proliferation and upregulation of GFAP, in the CA4 sector; c upregulation of GFAP in the cerebral cortex (GFAP immunoreactivity; magnification a x10; b, c X500)

Fig. 14.9a-c. Selective neuronal injury in the cornu Ammonis (CA1 sector) and reactive astrocytes. a Edema with selective neuronal loss; b neuronal loss without visible edema; c astrocytic reaction (a, c H&E, b Nissl stain; magnification a-c X300)

The temporal profile of neuronal, astrocytic, and microglial cells was studied in rats (Lin et al. 1998). In the striatum, normal neuron counts were first decreased significantly at 2 weeks after the ischemic event. In the CA1 hippocampus, a decreased number of normal neurons was seen at 1 week post ischemia, together with a significant increase in immunore-active microglia at that time; the latter normalized after 2 weeks. Reactive astrocytes in the CA1 hippocampus and cerebral cortex were significantly increased at 1-2 weeks after ischemia (see also Figs. 14.8, 14.9c).

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