Fibrin is found in the pulmonary interstitium and alveolar spaces in acute and chronic inflammatory forms of lung diseases, and may be an important mediator of inflammation during the active and resolving phases of these diseases. Fibrin and its degradation products may promote and propagate inflammation by increasing vascular permeability, producing endothelial cell retraction, and promoting inflammatory cell chemotaxis. Fibrin in the extravascular spaces of the lung may also provide a “provisional matrix” in which inflammatory cells and fibroblasts adhere, migrate, and initiate later stages of tissue repair that can lead to pulmonary fibrosis.
Fibrin deposition in the lung is controlled by several factors, the most important of which is likely the changes in alveolar-capillary membrane permeability that regulate the influx of plasma fibrinogen into the extravascular spaces of the lung. Marked alterations of procoagulant and fibrinolytic activities at sites of inflammation within the pulmonary compartment may regulate the rate at which fibrin is formed and degraded. Profound increases in procoagulant activity accompanied by decreases in fibrinolytic activity have been found in the BAL fluids of patients with adult respiratory distress syndrome and chronic interstitial lung disease (ILD), such as idiopathic pulmonary fibrosis and sarcoidosis.
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Elevated D Dimer in the Lungs and Blood of Patients With Sarcoidosis (1)
The Role of Coronary Arteriography in Demonstration of Mural Thrombosis after Angioplasty (12)
Implications
Despite significant advances in intravascular imaging techniques, contrast arteriography is likely to retain its unique value for exploration of the entire anatomy of the vascular tree. Better knowledge of the limitations and capabilities of this method will clarify the specific indications for novel techniques, such as angioscopy and ultrasound, which improve anatomic definition of individual lesions.
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The Role of Coronary Arteriography in Demonstration of Mural Thrombosis after Angioplasty (11)
Limitations of This Model
Although the present data provide insights into the role of arteriography in thrombus detection, several limitations should be taken into account. First, this study was performed in intact arteries. In the presence of an atherosclerotic plaque, smaller thrombi could become visible due to further arterial lumen reduction. This limitation, however, does not seem to be crucial, since arteriography is also insensitive for identification of mural thrombi superimposed on atherosclerotic plaques in unstable angina. On the other hand, the observed 100 percent specificity of arteriography in this study may be much smaller clinically, because commonly occurring plaque dissection may appear as an intraluminal filling defect at arteriography and be taken for a thrombus. Biplane angiography and high-power magnification, not used in this study, might enhance sensitivity for thrombosis detection. It should be pointed out, however, that the inaccuracies of arteriography found in the above-mentioned studies occurred despite use of such technical improvements; also, the single projection used in the present study was highly optimized for viewing of injured arterial segments.
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The Role of Coronary Arteriography in Demonstration of Mural Thrombosis after Angioplasty (10)
Yet 33 percent of AT— thrombi were of the same size as AT + values, ranging from 27 percent to 75 percent of the arterial lumen area. In these cases, negativity of the arteriogram must be explained by factors other than small thrombus size or the lumen-stretching effect of arterial distention.
Our data indicate that the composition of thrombus may influence its arteriographic demonstration, fibrin-rich thrombi being more likely to be detected than fibrin-poor ones. However, the information given by this variable is not independent of size alone.
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The Role of Coronary Arteriography in Demonstration of Mural Thrombosis after Angioplasty (9)
Therefore, univariate analysis showed that thrombus size, presence of slowed flow, and fibrin composition were associated with a positive angiogram. Fitting of a logistic regression model incorporating all three variables in 26 specimens confirmed the abovementioned influence of thrombus size on the outcome of arteriography. Neither fibrin composition nor slowed flow added independent information on the outcome of arteriography, suggesting that their contribution is already shared by the variable thrombus size.
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The Role of Coronary Arteriography in Demonstration of Mural Thrombosis after Angioplasty (8)
Considering the 50 dogs with histologic mural thrombosis, thrombus sizes were significantly greater in AT+ dogs than in AT— dogs, despite a wide range of similar values in both groups (62.9 ± 5.1 vs 20.8 ±3.9 percent of arterial lumen area, respectively [p<0.001]). To analyze the correlation between outcome of arteriography and thrombus size (percentage of arterial lumen area), the following univariate logistic regression model was fitted: log pj 1 — p, = — 4.02 + 0.08 size, where p{ = probability of i dog being AT+. The standard errors of the coefficients for size and the constant were, respectively, 0.02 and 0.88 (p<0.0001 for both), thus showing a significant effect of this variable.
Slowed or interrupted flow was present in none of the 33 AT— dogs with histologic thrombus, whereas it was present in 12 of the 17 AT + dogs. This difference was significant (p<0.001).
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The Role of Coronary Arteriography in Demonstration of Mural Thrombosis after Angioplasty (7)
Accuracy of Arteriography
The overall sensitivity of arteriography for detection of mural thrombi was 34 percent (17 of 50 dogs were AT+). The specificity was 100 percent (none of the 27 AT + dogs was without histologic thrombosis). Figure 3 depicts the histologic extent of mural thrombosis in AT — and AT + dogs. The lower limit of the 95 percent interval for thrombus size distribution in AT + dogs was 21.8 percent of the arterial lumen area. Arteriography consistently missed thrombi smaller than 25 percent of the arterial lumen area (22 of 23 dogs were AT—); this value was chosen from a preliminary cohort before this study. Even considering as significant only thrombi larger than this value, 11 of 27 mural thrombi were still missed by arteriography (sensitivity, 59 percent; specificity, 98 percent); this occurred despite thrombus sizes ranging between 27 percent and 75 percent of arterial lumen area.
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The Role of Coronary Arteriography in Demonstration of Mural Thrombosis after Angioplasty (6)
Arteriographic Findings
Seventeen dogs (22.1 percent) exhibited one or more findings indicative of intracoronary thrombosis (Fig 1). Frequency of arteriographic findings was as follows: minor lumen irregularities, 0 (0.0 percent); discrete filling defects, 12 (15.6 percent); staining of thrombus, 5 (6.5 percent); slowed or interrupted flow, 12 (15.6 percent). Slowed or interrupted flow always coexisted with either a discrete filling defect or contrast retention. Total interruption of flow was present in three dogs 2 h after angioplasty. For purposes of analysis, the presence of at least one of the above signs was considered indicative of thrombosis at arteriography; this state was designated AT -I-, as opposed to AT—, which denoted absence of all arteriographic signs of thrombosis. Analysis of the evolution of all arteriograms showed no differences from the results of the 120-min arteriogram (before death); however, this analysis allowed better interpretation of this injection.
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The Role of Coronary Arteriography in Demonstration of Mural Thrombosis after Angioplasty (5)
Statistical Analysis
Data are presented as mean±SEM, unless stated otherwise. Student s t test and one-way analysis of variance were used to assess differences among two and more than two means, respectively. The correlation between arteriographic positivity and thrombus size was assessed through logistic regression in all 77 dogs, with a program designed for IBM PC-compatible computers. In the 26 dogs with scanning electron microscopic analysis, a similar model was fitted with the variables thrombus size, fibrin composition, and angiographically slowed flow. Scanning electron microscopic specimens were systematically analyzed by two blinded observers for presence of platelets, red blood cells, and fibrin. Arbitrary scores of 1 to 4 were given to each of these findings; both the average and the maximal scores were considered for all sections of each dog. Thrombi with average or maximal scores of 3 to 4 were considered fibrin-rich; those with average or maximal scores of 1 to 2 were considered fibrin-poor (Fig 2).
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The Role of Coronary Arteriography in Demonstration of Mural Thrombosis after Angioplasty (4)
Histologic Analysis
The injured area was easily identified by the presence of vessel dilation and small periarterial hematoma. Diagonal branches and the distal LAD were tied; the proximal LAD was perfused through the ostium with 4.0 percent glutaraldehyde in phosphate-buffered saline (pH, 7.4) for 20 to 30 min at low pressure and flow. In preliminary experiments, we verified that perfusion at systemic pressure with the distal artery open was associated with high coronary flow and disruption of thrombi in some animals. The myocardial fragment containing the injured area and the 2.0-cm segments proximal and distal to it were immersion-fixed in glutaraldehyde, cut into 2-mm slices, and stained for light microscopy by the Verhoeff-van Gieson method, as well as with hematoxylin-eosin.
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