Organization of mural thrombi

J.B. Duguid promoted the idea that atherosclerotic plaques develop from organization of mural or “parietal”14 thrombi in the 1940's and 50's.13 Arterial thrombi tend to remain localized to the low shear environment of the arterial wall because of high blood velocity present on the opposite side of the artery.

parietal thrombus 100xFigure 4.  This is a mural or parietal thrombus.  This is the precursor lesion to the atherosclerotic plaque.  Note the eccentric location.  This is because the thrombus forms in the area of low shear.  The high shear on the opposite wall of the vessel protects that side of the artery from thrombosis.

In the presence of a marked hemodynamic abnormality caused by an obstruction such as an atherosclerotic plaque, an occlusive thrombus can form. In veins, the velocity gradient between the center of the vessel and the vessel wall is small. Thus, thrombi in veins are more likely to become occlusive, as in deep venous thrombosis. This is why atherosclerosis is limited to arteries.

If thrombi persist, whether in arteries or veins, they undergo organization, in which circulating fibrocytes 15, 16, 17 colonize the thrombus and differentiate into cells capable of producing collagen and markers of smooth muscle differentiation, such as smooth muscle actin.

It is well-accepted that LDL (the “bad cholesterol”) increases blood viscosity, and HDL (the “good cholesterol”) decreases blood viscosity.  It is also well-accepted that increased blood viscosity predisposes to thrombosis.  Therefore, the main impediment to acceptance of the hemorheologic-hemodynamic theory is the notion that an atherosclerotic plaque develops from organization of a mural thrombus. 

Figure 5 shows a femoral artery in the upper left and femoral artery in the lower right.  Thrombi in arteries remain localized to areas of slow flow (low shear), rapid flow (high shear) prevents thrombosis.  Three layers of successive thrombosis are found in the artery.  The oldest thrombosis, the outer pale layer against the artery wall (blue triangle), has been organized into an atherosclerotic plaque.  Superimposed on the plaque is a layer of organizing thrombus (green diamond), which is more recent.  Superimposed on this, and occupying the remaining lumen (white circle) is fresh thrombus.  In the vein, thrombus occupies the entire lumen, because blood flow is slow and relatively uniform across the lumen.  Bands of organization (yellow stars) focally span the lumen.  Photograph courtesy of Kerry Johnson. 

Figure 6 is a photomicrograph of an organizing eccentric thrombus obtained from an anterior tibialis artery.  The small vessels which allow the influx of fibrocytes and subsequent collagen deposition are visible as small clear spaces in the organizing thrombus (green arrows). 



Figure 7 is a simple drawing of the organization process.  It is incomplete because it doesn’t show vessels growing from the surface of the thrombus, only from the interface with the vessel wall.  In reality, stem cells within the thrombus are the most important source of endothelial cells and fibrocytes in the organization process.  (Majno G, and Joris I.  Cells, Tissues, and Disease, Blackwell Science, 1996, p. 634)

The eccentric location of organized arterial thrombi is well-recognized in the diagnostic pathology literature. Figure 8 shows a photomicrograph of an organized thrombus in a large branch of the pulmonary artery.  According to the text, “A helpful feature that should alert the pathologist to the presence of thrombi and emboli is the finding of eccentric intimal proliferation and/or intimal fibrosis in arterial vessels; these lesions represent old small organizing thrombi.”  (Churg A, Wright JL.  Pulmonary Hypertension.  In:  Leslie KO, and Wick MR, eds.  Practical Pulmonary  Pathology, Churchill Livingstone, 2005, p.  390-1)    

Figures 9a and 9b are photomicrographs of an arterial lesion from a 22 week gestation monochorionic placenta with twin-twin transfusion syndrome.  In this condition,there is unequal distribution of blood between the identical twins, with one twin being overperfused and the second underperfused.  The overperfused twin is at risk for thrombosis as a consequence of polycythemia and increased viscosity.  Again, note the eccentric location of the organized thrombus.  The placental pathology literature also recognizes the eccentric location of organized arterial thrombi. 


Figure 10 shows a mural thrombus in a case of fetal thrombotic vasculopathy.  (Kraus FT, et al.  Placental Pathology, American Registry of Pathology, 2004, p. 144)    

It is interesting and enlightening to look at how the medical establishment has viewed the thrombotic theory of atherogenesis.  From Pathology of the Heart, published in 1960:

Indeed, Duguid (1946, 1955) has revived the hypothesis of Rokitansky by suggesting that coronary atherosclerosis…can be more satisfactorily explained as a late sequel of coronary thrombosis.  As a result of histologic studies, Duguid believes that all the features of atherosclerosis, with fibrous intimal overgrowth and deposition of fat, can be produced by organizing thrombi.  In these cases, fat is deposited as a result of softening and fatty degeneration of red blood cells and fibrin within thrombi.  Although there is no doubt that atherosclerosis and certain stages of organizing arterial thrombi are often indistinguishable, the importance of thrombosis as a cause of coronary atherosclerosis still remains to be determined. (Gould SE.  Diseases of the Coronary Arteries.  In: Gould SE, ed.  Pathology of the Heart, Charles C Thomas, publisher, 1960, p. 563)

His [Duguid’s] encrustation theory assumes that atheromata are the result of deposition of fibrin on the intima, mural thrombosis, and organization by endothelium with formation of new capillaries from the lumen.  This process leads to crescentic thickening at one or more foci. (Ibid., p. 576)

It has been noted that an old, organized mural thrombus may not always be readily distinguished from the changes of arteriosclerosis [atherosclerosis].  The same may be true of old organized hemorrhage, and the distinction between the end stage of thrombosis and hemorrhage, as well as arteriosclerotic [atherosclerotic] disease, is at times impossible.  (from Wartman WB.  Types of Coronary Obstruction and Their Morphological Characteristics.  In:  The Etiology od Myocardial Infarction, James TN, Keyes JW, eds.  Little, Brown and Company, 1963, p, 237)    

Comments from the participants of a symposium sponsored by Henry Ford Hospital in 1961 are enlightening regarding the status of the hypothesis that organization of mural thrombi leads to an atherosclerotic plaque.

Chairman William B. Wortman, M.D.:  Dr. Horn, the thought occurs to me that the English workers (in accordance with Duguid’s theories) have remarked that the hemorrhages found in coronary arteries, instead of representing bleeding into the wall might represent thrombi which are organized and incorporated into the wall.  Do you have any comment about this from your own study?

Dr. Robert C. Horn, Jr.,:  I do not believe we actually have any data on this at all, but I think Duguid stated that evidence of vessels extending from the lumen of the artery into the arteriosclerotic [atherosclerotic] plaque is evidence that the plaque really began its existence as an organized mural thrombus.  This hypothesis seems reasonable to me, although I have no data bearing on it. (Ibid. p. 243)

Thus, until at least the early 1960’s, the idea that atherosclerotic plaques were organized mural thrombi was viewed favorable yet cautiously.  Contrast this with the following, published in 1982:

Thrombosis may be important in the origin and growth of lesions as well as acting as a secondary occlusive phenomenon….It was demonstrated that atherosclerotic lesions of a sort could be produced by thrombi (or thromboemboli) alone….It was also obvious that organized mural thrombi (frequently found on advanced lesions) added to the mass of the atherosclerotic lesion and could be considered an integral part of it.

However, except for the specifics above and in spite of extensive efforts, no convincing evidence has been found to indicate that thrombosis played a great role in the origin and development of atherosclerotic lesions in man. This theory has been abandoned by most investigators. (Thomas WA, et al.  Pathogenesis of Atherosclerosis: An Evaluation of Several Competing Theories.  In:  The Coronary Artery, Kalsner S., ed.  Oxford University Press, 1982, p. 445)

Of course, the last paragraph brings to mind the words of Osler, also quoted on the opening page of this website:  “The philosophies of one age have become the absurdities of the next, and the foolishness of yesterday has become the wisdom of tomorrow.”The penultimate sentence is curious, given that Duguid’s work was performed on humans.  I am unfamiliar with any published work which refuted Duguid’s work or failed to confirm it, although negative results are not always published, despite the extensive efforts sometimes exerted.  Nevertheless, the statement strikes me as disingenuous, motivated by rising awareness that hypercholesterol is a risk factor for atherosclerosis, and no obvious way to reconcile this with the notion that atherosclerotic plaques were organized mural thrombi.  The hemorheologic-hemodynamic theory reconciles the two by recognizing that LDL increases blood viscosity and predisposes to thrombosis.

What sorts of lesions are produced by organizing thrombi?  The next series of figures are photomicrographs of varying stages of organizing thrombi in small muscular arteries in prostate glands.  Figure 11 shows an organizing thrombus which is more mature than the one seen in Figure 6, meaning it is less vascular and contains more collagen..  The vascular lumen is indicated by the white star, and the organizing atherosclerotic plaque is outlined by black arrows.



Figure 12 is a detail from the organizing thrombus showing collagen (black star), a capillary (green arrow), extravasated erythryocytes, lipid-containing foamy macrophages (black arrows), and hemosiderin (red arrow).  The ongoing hemorrhage is one source of the lipid in the foamy macrophages, the other being platelet plasma membrane and circulating lipoproteins, which bind to collagen.   The hemosiderin accumulation is from previous episodes of hemorrhage or from erythrocytes which were part of the original thrombus.  The collagen is synthesized by fibrocytes which arrive in the organizing thrombus via the capillaries.

Figure 13 shows a more mature organizing thombus.  No capillaries are seen.  Collagen is denser (black circle).  There is a layer of foamy macrophages at the periphery of the lesion (black arrows). 



Figure 14 shows the end result of the organization process: a mature atherosclerotic plaque.  No capillaries or foamy macrophages are present.  The collagen (black circle) is dense.  This plaque would be classified as a type Vc lesion in the classification of Stary, et al.  Those authors write:  “Fibrotic lesions could be the result of one or more processes, including organization of thrombi, extension of the fibrous component of an adjacent fibroatheroma, or resorption (regression) of lipid cores.”  (Stary HC, et al.  A Definition of Advanced types of Atherosclerotic Lesions and a Histologic Classification of Atherosclerosis.  (Circulation 1995; 92:  1355-1374).  Note that the origin of atherosclerotic plaques from organization of mural thrombi is accepted by these mainstream authorities.