Fibrin formations in vascular fibrinoid change in experimental hypertension: An electron microscopic study

EXPERIMENTAL

Fibrin

AND

MOLECULAR

Formations

PATHOLOGY

in Vascular

Hypertension: ISTV~N IInd

Fibrinoid

An Electron

H~TTNER,

Department

(1968)

9, 30%-321

HARRY

of Pathology, Received

Microscopic

JELLINEK, Medical May

Change

AND TIBOR

University,

Budapest,

in Experimental Study BER~NYI Hungary

10, 1968

It has been demonstrated by conventional microscopy bhat in malignant hypertension the fibrin precipitates are formed in the walls of arteries as a result of alterations in the permeability of the arterial wall (Schiirmann and McMahon, 1933; Soustek, 1956; Lendrum, 1963; Kergnyi et al., 1966a). The presence of fibrinogen in t,he vascular lesion in hypertension has been demonstrated indirectly by immunofluorescence (Fennel et al., 1961; Paronetto, 1965). Direct demonstration of fibrin by electron microscopy (Geer et al., 1958; Spiro el al., 1965; Wiener et al., 1965; Ooneda et al., 1965) has been based on its characteristic axial periodicity (Hall, 1949; Hall and Slayter, 1959). In this laboratory rapidly developing malignant hypertension was produced in albino rats by artificial compression of the renal cortex on both kidneys. In the small arteries of these animals, electron microscopy revealed fibrin formation in various structures, corresponding to fibrinoid lesions visible by light microscopy, in the different layers of the vessel wall depending on t,he lesion’s age and localization (Jellinek et al., 1967). The present report deals with t,hesevarious stages of fibrin deposition. MATERIALS

AND

METHODS

Artificial hypertension was produced in albino rats of 150-200 gm body weight by bilateral compression of the kidney with a rubber envelope as described by Liirincz and Go&z (1954). The systolic blood pressure of the animals increased to 1SOmm Hg 3-4 days following the operation, as comparedto the control mean value of lO(r130 mm Hg. In an additional few days, the blood pressure of the operated animals was an average of 190-200 mm Hg, and occasionally as high as 240 mm Hg. To prevent cardiac insufficiency caused by rapid elevation of blood pressure, the animals were given daily intramuscular dosesof 0.05 mg Isolanid (desacethyl-lanatoside-C, G. Richter Chemical Works, Hungary). Starting on postoperative days 4 and 5, t,he survivors (22 rats) were killed in ether narcosis by intravasal perfusion with Holt formalin (Holt and Hicks, 1961) in successionon days 5, 7, 9, 35 and 42 after the operation. Based on the results of previous light microscopic studies by Gor&cz (1962) and ourselves (Kerhnyi et al., 1966a), the arteries best suited for the exa,mination of fibrinoid lesions are branches of the mesenteric arteries, small submucosal arteries of the intestine, and the small branches of the coronary arteries. These specimenswere subjected to fixation for 3 hours in a 1: 3 mixture (v/v) of 25 %, glutaraldehyde and 4% Holt’s formalin (T6r6 Jr., and Jock, 1966). After 309

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JELLINEK,

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KERtiNYI

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washing, postfixation was achieved for 1 hour in 1% Os04, buffered according to Millonig (1962). All specimens were dehydrated in ethanol and embedded in Araldite (Durcupan ACM, Fluka, Switzerland). Sections of 0.5 CL thickness were cut and stained with methylene blue. These preparations were examined by light microscopy to select specimens for preparation of ultrathin sections by an LMB ultrotome. These were stained for 20 minutes with saturated uranil acetate solution in methanol (Gibbons and Grimstone, 1960) and for an additional 20 minutes in lead citrate (Reynolds, 1963). Electron microscopic studies were performed with a JEM 6-C apparat)us. RESULTS In the large and small arteries exhibiting fibrinoid lesions by light microscopy, the following fibrin formations were demonstrable by the electron microscope, depending on the age of the lesion: I. Loose, vaguely contoured fibdlar fibrin forming bundles of various directions and curvatures (Fig. 1, 2, 3). Some bundles exhibited transverse striation, most of them, however, had no periodic structure at all. In bundles with transverse striat,ion, the longitudinal fibrillar structure was usually poorly defined. The axial periodicity giving the transverse striation was found to be in certain areas 160-170 8, while in others 200-220 A. II. Compact sharply contoured wystal-like jbrin formations. They were often present in hexagonal forms (Fig. 4, 5), or in bundles with straight contours, or in clumps. Transverse striation of the periodicities given above was best demonstrated in the sharply contoured fibrin (Fig. 5). In the polygonal bodies, two or three linear structures, at 60” angles, were present having a periodicity of 90-115 8, occasionally SO8, with predominants of the periodicity of one or the other type

FIG. 1. Light-microscope picture of a submucosal small intestinal artery of an experimentally hypertensive albino rat 7 days after the operation. Fig. 2 and 3 are electron micrographs of areas indicated by arrows. The intensively stained regions in the wall of the small artery with fibrinoid change represent sites of fibrin precipitation. The preparat,ion was 0.5-r thick section of an Araldite-embedded material. Methylene blue stain. X250. FIG. 2. Part of the wall of the small artery shown in Fig. 1. In the dilated subendothelial space bordered by the endothelial cells (E) and the lamina elastica interna (ILE), finely granulated, occasionally filamentous matrix surrounds the longitudinal and cross sections of loose fibrillar fibrin bundles (F). Znset: Part of the sltbendothelial loose fibrin bundles seen at the upper part, in longitudinal (L), while at the lower part, in cross (Q) section. In the longitudinal section, the longitudinal fibrillar structure is recognizable, but no transverse striation is seen. At the upper part of the picture, part of an endothelial cell, is seen pinocytotic vesicles (arrows). X5400. FIG. 3. Another part of the same small artery. In the subendothelium (SE) between the endothelial cells (E) and the lamina elastica interna (ILE) a granular material of plasma density is apparent, containing here and there loose, vaguely contoured fibrin bundles (F). Beneath the lamina elastica interna, in the media some details of degenerated muscle cells are seen (MC) surrounded by granular cloudy substance of plasma density. This matrix forms a thick coat beneath the degenerating media and contains several fibrin bundles of loose consistency (F). FC: Fibroblasts of the adventitia. X10,000. Znset: Magnified image of a fibrin b~mdle from the media. The bundle exhibit,s a transverse striation of 165 A periodicity. X42,000.

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(Fig. 5). The linear structure of 90-115 H periodicity was recognizable also in certain fibrin bundles with typical transverse striation, the two structures mostly at a 60’ angle with respect to each other (Fig. 6). III. Crystal-like j&in formations with striation of broacl perioclicity. These are structures similar to the polygonal fibrin crystal bodies odescribed above, exhibiting, however, a superimposed broad striation of 600-1500 A periodicity. This striation usually enclosed a right angle with the basal striation of 90-115 A perioc@ity (Fig. 5 and 7). The limit values of striation ranged from approximately 200 A to 40005000 A, including all possible variations within this range. The width of the dense lines varied parallel to the periodicity distance. In early, 5- to 7-day-old vessel lesions, loose fibrillar fibrin formations were most frequently encountered (Fig. l-3). Parallel to the length of time after the operation, the occurrence of crystal-like forms became more frequent. Polygonal crystal formations with striations of broad periodicity were particularly conspicuous in the dilated subendothelial space between the endothelial cells and the internal elastic lamina of the mesenteric arteries (Fig. 4-8). Dense, sharply contoured crystalline fibrin formations also occurred, however, in the early phase, together with loose fibrillar fibrin in certain vascular areas. In these cases the loose fibrillar formations were usually present in the peripheral part of the vessel wall, the site of earliest fibrin precipitation, whereas the crystalline forms were present in the regions close to the lumen, representing the relatively older sites of damage (Fig. 9,10). In many regions of mesenteric arteries in 42-day specimens, particular patt’erns of electron dense fields were visible, filling tightly the subendothelial space and consisting of fibrin crystal bodies with striations of various directions and periodicities (Fig. 11). The basic structure and the borders of the crystal were quite vague and the crystalline mass was surrounded by highly electron dense material. Simultaneously, the endothelial cells exhibited intensive pinocytotic activity. Pinocytotic vesicles on t’he subendothelial surface of endothelium contained a substance of high electron density similar to that of the matrix surrounding the crystals in the subendothelium (Fig. 11). This might be considered a sign of onset of fibrinolysis and homogenization. The muscle cells in the media of the examined arteries and small arteries exFIG. 4. Light microscopic picture of portion of a mesenteric artery 42 days after the operation. Between the endothelial cells and the lamina elastica interna, intensively stained fibrin clumps are visible in the subendothelial fibrinoid accumulation. The section was prepared from an Araldite-embedded material. Thickness: 0.5 h. Methylene blue staining. X250. FIG. 5. Subendothelial layer of the mesenteric artery portion shown in Fig. 4. The subendothelial space between the endothelial cells (E) and the lamina elastica interna (ILE) is filled with a granular matrix of plasma density, containing bundles and polygonal fibrin crystal bodies of sharp contours. The majority of polygonal crystal-like bodies exhibit striation of varying periodicity. Ly: Lymphocytes in the lumen and in the subendothelium. MC: Intact muscle cell portion in the media. X10125. Inset il, Longitudinal section of a sharply demarcated fibrin fiber with 210 K axial periodicity and polygonal fibrin crystal bodies with 102-112 A distance two directions linear structures apparently cross sections of fibrin fibers. X65,000. Inset B, Fibrin crystal body with broad-periodicit,y striation. The periodicity of the broad striation is 1300 K, that of the other striation, enclosing approximately right angle with the former is 102 ,&. X65,000.

FIG. 6. Dense, sharply contoured fibrin fibzr exhibiting transverse striation of 207 A periodicity and another linear structure of 103 A periodicity, enclosing a 60” angle with the former. Close to this, a probably transversal section of a fiber, exhibiting a crystal-like hexagonal formation, consisting of a striation of 103 d periodicity. X43,000. FIG. 7. Fibrin crystals with a 1600 A broad periodicity striation. The directions of the linear structures forming the basic structure enclose about a 60” angle and are indicated by arrows. X43,000. 314

FIG. 8. View of the wall of a mesenteric artery on day 42 aft,er the operat,ion. In the sukendothelial space between t,he endothelial cells (E) and the lamina elastiea interna (ILE), fibrin crystal bodies of broad-periodicity striation (F) are seen. The muscle cells in the media exhibit various degrees of necrobiosis. In the cent,er, an edematous pale muscle cell (EMC), and at the left, osmiophilic cell debris (arrow) are visible. Among t,he muscle cells, the COW nect.ive tissue fibers and connective tissue matrix have accumulated. Ly: Lymphocytes ill t.he lnmen. X7650. FIG. 9. Light microscopic picture of a coronary artery exhibiting periarteritia-like lesions on day 7 after the operation. In the total length of the vessel wall and radially arollnd it, there are fibrinous precipitates visible. The preparation is a 0.5-r thick section from an Araldite-embedded material. Methylene blue staining. X250. FIG. 10. Electron microscopic view of a section of the coronary arteries shown in Fig. 9. In t,he peripheral layers of the vessel wall loose fibrin formations are seen (Inset B), whereas beneath the endothelinm (E), there are dense sharply contoured crystal-like fibrin formations (Inset A). X9100 (Inset A, B X48,000).

FIG. 11. Densely arranged fibrin crystal masses with broad-periodicity striation in the subendothelial space (42 days after the operation). E: endothelial cells, ILE: lamina elastica interna. Intensive pinocytot,ic activity along the margins of the endothelial cells. The vesicles of the endothelial surface facing the crystals contain highly electron dense substance (arrows). x15,ooo. FIG. 12. Detail of the media 42 days after the operation. Bottom: intact muscle cell portion (MC) with regular myofibrillar st,ructure, and vivid pinocytosis (arrows). Top left: edematous muscle cell portion (EMC) with hypertrophic Golgi apparatus (GA) and smooth endoplasmic reticulum (ER). The myofilaments are broken down into granules and no pinocytosis is observable in the cell membrane. Middle right: osmiophilic shrunken muscle cell portion (OMC). X16,800. Znset: Enlarged detail of the muscle cell with osmiophilic degeneration (OMC). Conglomerated myofilaments. X25,750. 316

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hibited, prior to or parallel with fibrin precipitation, various degrees of necrobiosis, progressing even to necrosis. The typical lesion of muscle cells was the “necrotic edema” (Korb, 1965) of various grades. The cytoplasm of the muscle cells cleared up, the myofibrils separated and finally lysed, while mitochondria exhibited various degrees of degeneration. In the edematous muscle cells, masses of tubulo-vesicular, smooth endoplasmic reticulum, and hypertrophized Golgi vesicles were often detectable (Fig. 12). This phenomenon suggested the possibly increased fluid or plasma matrix uptake by the impaired muscle cells (Gardner 1963; Hatt et al., 1966; Kent, 1967). In other muscle cells, unlike those mentioned above, the myofibrils were agglomerated; the total cell was shrunken and exhibited increased osmophilia (Fig. 12). This type of degeneration may be the explanation of increased double refraction in certain areas of the vessel walls in the initial phase of damage (KerBnyi et al., 1966a; Veress et al., 1966). Finally the cells exhibiting edematous or osmiophilic degeneration were equally fragmented and macrophages and connective tissue cells made their appearance in the area. DISCUSSION Certain authors (Vassalli et al., 1963; Vassalli and McCluskey, 1964) used the term “fibrinoid” in a more restrictive sense to designate t’he electron dense, microscopically granular, incompletely polymerized, or partially decomposed fibrin characterized by an electron density lower than that of the typical fibrillar fibrin. The majority of the authors, however, use “fibrinoid” as a light microscopic collect#ive term that connotates substances whose essential constituent is fibrin, which together with other plasma proteins, conrlective tissue matrix, and necrotic cell debris produces the homogeneously eosinophilic light microscopic pict’ure (Gitlin el al., 1957; Movat and More, 1957; Churg, 1963; Lendrum, 1963; Hiittner et al., 1966; Jellinek, 1967). The term “fibrinoid” has been interpreted in this wider sense also in the present paper; hence, the fibrin formations demonstrated in vascular lesions of various localizations are uniformly referred to as “fibrinoid.” I. The loose fibdlur fibrin structure both in its striated and nonstriated form has been described by several authors in damaged vessel walls and in other tissue lesions with inflammation or blood coagulation (Vassalli et al., 1963; Vassalli and McCluskey, 1964; Hirano et al., 1965; Prose et al., 1965; Nam et al., 1965; Haust et al., 1965; Marshall and O’Neal, 1966; Still and Scott, 1966; Uriuhara and Mowat, 1966; Haust et al., 1967). The major$y of the authors have found the periodicity of t)ransverse striation to ,be 200-230 A. The perioodicities found in the present study were greater (200-220 A) and smaller (160-170 A), in accordance with the results of KGppel (1967), who has similarly found two different axial periodicities, 200-208 b and 165-170 d, respectively. According to the theoretical model of Kijppel(1967), the periodicity of fibrin is a result of overlapping of the peptide chain boundaries and their intermolecular spaces associated to the edges of the pentagon dodecahedron like fibrinogen molecules. Should this overlapping be absent, no periodic structure of fibrin fibers will be detectable. Nevertheless, the part of the loose bundles with no periodic structure may reasonably be supposed to be incompletely polymerized fibrin appearing in the initial stage-of fibrin precipitation. II. Compact crystal-like Jibyin foymutions have been described by Wiener et al.

318

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AND

KERfiNYI

1965) and Ben-Ishay et al. (1966) in the vessel wall with hypertensive lesions and in glomerular lesions of similar origin. The osmiophilic bodies in the subendothelium of renal arteries described by Esterly and Glagov (1963), or minimally some of them, may be supposed to represent also that group of fibrin format#ions. In those bodies, Wiener et al. (1965) have describe:, in addition to the 230 8 periodicity characteristic of fibrin, a periodicity of 115 A. These crystal-like fibrin formations are, in our opinion, of a considerably more organized structure than the loose fibrillar fibrin. It is extremely probable that the polygonalfibrin crystal bodies exhibiting striation of 90-115 d periodicity are cross sections of the fibrillar fibrin structures with sharp contours. This 90-115 8 periodicity was detectable in certain obliquely cut fibrin fibers in which transverse striation was still detectable (Fig. 6). In cross sections of loose fibrillar fibrin bundles, the geometric structure observed in similar sections of sharply demarcated contact bundles was absent. Data available in the literature concern mostly the loose bundles of fibrillar fibrin; this may explain why detailed analysis of cross sectional pictures has not been made. Walls of vessels characterized by the presence of elastic lamellae exhibit a particular type of fibrin-containing lesion, as compared to other sites of similar lesions; these vessel walls apparently offer favorable conditions for the format’ion of highly ordered fibrin bundles. Wiener et al. (1965), in their studies on fibrin formations in the vessel wall were the first to suggest the possibility that the 115 i periodicity in the fibrin formations might represent cross sections of the structure. The clumped crystalline formations in the subendothelial space might represent an arrangement of the fibrin bundles parallel to the vessel’s axis, yielding identical pictures in serial sections. Nevertheless, the existence of an independent clumpy structure cannot be definitely excluded. III. CVystalline bodies with striations of broad periodicity have been found in our earlier studies at low ma,gnifications in vascular lesions of experimental hypertension (Ker&vi et al., 196613). These observations correlate well with t’hose by Ooneda et al. (1965). Based on their periodicity and morphology, they were initially compared to the periodically structured bodies of collagenous origin, localized paravascularly close to the basal mtmkrane, as described by Wetzstein et al. (1963) and Pillai (1964), but their collagenous nat’ure has been excluded on the basis of their polarization-optizal and topochemical reactions (Jobst, 1954). In micrographs of higher resolution, the basic structure of 90-115 A periodicity characteristic of the cross-sections of fibrin bundles was recognizable also in cryetai bodies with broadperiodicity striation. This, and the polarization-optical effect are both suggestive of the fibrin nature of these bodies. Ooneda et al. (1965) designated the similar periodically striated structures as “fibrinoid substance” and supposed their fibrinous origin on the basis of the 230 B transverse striation, characteristic of the fibrin and demonstrable within the dark lines. In contrast to Ooneda, we have never seen the 230 8 periodicity of fibrin transverse striation, but we could always detect the 90115 B periodicity linear structure typical of the cross-sections of fibrin fiber. The latter, however, was detectable not only in the dark lines, but also in the total area of the crystal body. As to the possible origin of broad-periodicity striation, several explanations are

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available: (1) The average periodicity of broad-periodicity striation in the crystals was 600-1500 8, nevertheless, a wide variety of periodicities from 200 8, the axial periodicity of the fibrin fiber, to 4000-5000 & was also detectable in the crystal bodies. This and the presence of the basal structure of a cross-sectioned fiber in these bodies suggested the possibility that these variations represent different planes of sectioning of a three-dimensional basic fibrin structure. The broadperiodicity may conceivably be a summation phenomenon depending on the actual plane of sectioning. However, the occurrence of these bodies exclusively in the subendothelial space, as well as the increase of their incidence parallel to the age of fibrin precipitation, cannot be explained on the basis of differences in the planes of sectioning. (2) The possibility of a ring-like fibrin precipitation has also emerged, but the different periodicities of adjacent crystal bodies and the uniformity of periodicities within the same crystal body are against this hypothesis. (3) Incorporation of other plasma substances into the fibrin crystal structure cannot be excluded. The possible role of pulsation effect of the functioning vessel should also be considered. Based on the model of the fibrinogen molecule by Kijppel (1937), a wide variety of possible projection of the protein chains may be visualized. It should be noted, however, that Koppel has stated that for the time being the threedimensional structural model of the typical fihrillar fibrin fiber cannot be accurately imagined, thus the particular structures found in the vessel wall can only be described in two-dimensions. SUMMARY Fibrin formations in the small arteries with fibrinoid degeneration in albino rats with experimentally produced malignant hypertension by bilateral compression of renal cort,eces were examined. In the initial phase, the vessel’s wall showed generally loose fibrillar fibrin formations. In sites of the longitudinal sections of these structures, transverse striation of ZOO-220 i or 160-170 A periodicity was discerned. In preparations from the later phase, the occurrence of dense sharply defined crystal-like fibrin increased. The appearance of these formations was Partly that of bundles with sharp straight contours and partly that of polygonal clumps. In the majority of bundles characteristic transverse striation, while in the polygonal formations a 90-115 i periodicity linear structure was demonstrable. In part of the polygonal crystal-like fibrin formations, striation of broad periodicity (6OIt1500 A) was often detectable, superimposed on the basic structure. Fibrin crystal bodies of broad periodicitystriation accumulated in the subendothelial fibrinoid, localized between the endothelial cells and the lamina elastica interna. It is proposed that the polygonal structures with 90-116 8 periodicity represent transverse sections of highly organized crystal-like fibrin bundles. In these structures, striation of broad periodicity may be the result either of summation phenomena at certain planes of sectioning or that of the pulsation effect of the functioning vessel. This does not exclude, however, the possibility of incorporation of other plasma components into the fibrin crystal structure. REFERENCES Z., SPIRO, P., and WIENER, J. (1966). The cellular pathology of experimental hypertension. III. Glomerular Alterations. Am. J. Pathol. 49, 773-794. CHURG, J. (1963). Renal and renoprival vascular disease in the rat. Arch. Pathol. 75, 547-557. ESTKRLY, J. A., and GLAGOV, S. (1963). Altered permeability of the renal artery of the hypertensive rat: an electron microscopic study. Am. J. Pathol. 43, 619-638.

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FENNEL, R. H., REDDY, C. R. R. M., and VUQUEZ, J. J. (1961). Progressive systemic sclerosis and malignant hypertension. Immunohistochemical study of renal lesions. A.M.A. Arch. Pathol. 72, 209-215. GARDNER, D. L. (1963). Arteriolar necrosis and the prenecrotic phase of experimental hypertension. Quart. J. Exp. Physiol. 48, 156-163. GEER, J. C., SKELTON, F. R., and MACGILL, H. C. (1958). Observations with the electron microscope of arterial lesions in hypertensive rats. Federation Proc. 17, 438. GIBBONS, I. R., and GRIMSTONE, A. V. (1960). On flagellar structure in certain flagellates. J. Biophys. Biochem. Cytol. 7, 697-716. GITLIN, D., CRAIG, J. M., and JANEWAY, C. A. (1957). Studies on the nature of fibrinoid in the collagen diseases. Am. J. Pathol. 33, 55-78. GORACZ, G. (1962). Geflssverlnderungen bei experimenteller maligner hypertonie. In “Metabolismus Parietis Vasorum” Comptes Rendus du VIP Congres International d’AngCiologie, (B. Prusik, Z. Rein%, and 0. Riedl, eds.), pp. 459-462. Statni zdravotnick6 nakladatelstvi, Praha. HALL, C. E. (1949). Electron microscopy of fibrinogen and fibrin. J. Biol. Chem. 179, 857864. HALL, C. E., and SLAYTER, H. S. (1959). The fibrinogen molecule: its size, shape, and mode of polymerization. J. Biophys. Biochem. CytoZ. 5, 11-16. HATT, P-Y., BERJBL, G., and BONVALET, j.-P. (1966). Structures arterielle et arteriolaires au COWS de l’hypertension experimentale du rat. Etude au microscope Blectronique. In “11~ reunion de Club International sur I’Hypertension artbrielle.” Vol. l., pp. 460478. Expansion scientifique FranCaise Bd., Paris. HAUST, M. D., WYLLIE, J. C., and MORE, R. H. (1965). Electron microscopy of fibrin in human atherosclerotic lesions. Immunohistochemical and morphologic identification. Exptl. Mol. Pathol. 4, 205-216. HAUST, M. D., MORE, R. H., BENCOSME, S. A., and BALIS, J. U. (1967). Electron microscopic studies in human atherosclerosis extracellular elements in aortic dots and streaks. Exptl. Mol. Pathol. 6, 300-313. HIRANO, A., ZIMMERMAN, H. M., and LEVINE, S. (1965). The fine structure of cerebral fluid accumulation. IX. Edema following silver nitrate implantation. Am. J. Pathol. 47, 531-548. HOLT, S. J., and HICKS, R. M. (1961). Studies on formalin fixation for electron microscopy and cytochemical staining purposes. J. Biophys. Biochem. Cyiol. 11, 3146. H~~TTNER, I., JELLINEK, H., KER~NYI, T., and SZEMENYEI, KLARA. (1966). Fibrinoid necrosis of the vascular wall induced by painting with acid. Acta Morphol. Acad. Sci. Hung. 14, 169-174. JELLINEK, H. (1967). Fibrinoid vascular changes showing the same morphological pattern following induction by various experimental conditions. Angiology 18, 547-555. JELLINE~, H., H~TTNER, I., KAD~~R, ANNA., KER~NYI, T., and VERESS, B. (1967). Vergleichende histologische und elektronenmikroskopische Untersuchungen von Gefiissveriinderungen verschiedenen Ursprungs. Verhandl. Deut. Ges. Pathol. 51, Tagung, 243-247. JOBS~, K. (1954). Beitrlge zur submikroskopischen Struktur der fibrinoiden degeneration. Acta Morphol. Acad. Sci. Hung. 4, 333-344. KENT, H. P. (1967). Diffusion of plasma proteins into cells: a manifestation of cell injuring in human myocardial ischemia. Am. J. Pathol. 50, 623-638. KER~NYI, T., JELLINEB, H., H~~TTNER, I., GOR~CZ, G., and KONY~R, EVA. (1966a). Fibrinoid necrosis of the vascular wall in experimental malignant hypertension. Acta Morphol. Acad. Sci. Hung. 14, 175-182. KER~NYI, T., H~~TTNER, I., and JELLINEK, H. (1966b). nber die Entwicklung der periodischen Struktur im Subendothelialen Fibrinoid. 2. M&r.-Anat. Forsch. 74, 121-131. KORB, G. (1965). Elektronenmikroskopische Untersuchungen zur Aludrin (Isoproterenolsulfat)-Schldigung des Herzmuskels. Virchows Arch. Pathol. Anat. 339, 136-150. K~PPEL, G. (1967). Elektronenmikroskopische Untersuchungen zur Gestalt und zur makromolekularen Bau des Fibrinogenmolekiils und des Fibrinfasern. Z. Zclljorsch. 77, 443517.

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