series of consecutive autopsies and the relation of such thrombi to pulmonary embolism.

Transcription

1 THE AMERICAN JOURNAL OF CLINICAL PATHOLOGY Copyright 1969 by The Williams & Wilkins Co. Vol. 52, No. 5 Printed in U.S.A. FEMORAL-POPLITEAL VENOUS THROMBOSIS AND PULMONARY EMBOLISM RAYMOND E. BECKERING, JR., M.D., AND JACK L. TITUS, M.D., PH.D. Section of Experimental and Anatomic Pathology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota ABSTRACT Beckering, Raymond E., Jr., and Titus, Jack L.: Femoral-popliteal venous thrombosis and pulmonary embolism. Am. J. Clin. Path., 52: 50-57, In an unselected series of 9 autopsies, femoral-popliteal vessels were removed by means of a new technic and were evaluated by gross morphologic and histologic studies. The origin and manner of propagation of venous thrombi were evaluated and the relations of such thrombi to pulmonary embolism, disease states, and clinical features of the patients were studied. Thrombi in thigh veins were noted in 26.9% of the cases and 49.1% of the thrombi were situated in the sinuses of venous valves. A large percentage (82.4%) of the thrombi were primary in the thigh veins; 40% were bilateral. Thrombi that totally occluded thigh veins usually originated in the involved veins, often from the sinus of a valve, with subsequent retrograde thrombosis; propagation from thrombi in the calf veins was infrequent. Inflammation was associated infrequently with thrombosis. Thrombosis of the thigh veins was related to the length of confinement to bed. A statistically significant increase in frequency of thrombosis in thigh veins was found in women. In patients who had had congestive heart failure and in those who had had nonbacterial thrombotic endocarditis, increased frequencies of such thrombi were not statistically significant. Pulmonary embolism was present in 22.6% of the total series and in.2% it was fatal. Pulmonary emboli were found in 60 % of the cases having thrombi in the thigh, but in only 9 % of the other cases. Since Virchow's 18 description of pulmonary thromboemboli originating chiefly in the iliac and femoral veins, only a few studies have attempted to determine the site of origin of pulmonary emboli by anatomic dissections, 2 " 12,14 ' 16, " 19 in spite of voluminous literature on the subject of venous thrombosis and pulmonary embolism. Some investigators 2, 6> * 14 concluded that venous thrombi arose in the veins of the calf or foot and not in the femoral-popliteal system, except as an extension from thrombi in tributary veins. Others held that iliac and femoral thrombosis could occur and be unrelated to thrombi in the veins of the calf. The present study is concerned with the frequency of thrombosis of the femoral and popliteal venous system in an unselected Received March 27, 1969; accepted for publication May 14, series of consecutive autopsies and the relation of such thrombi to pulmonary embolism. METHODS AND MATERIALS Morphologic Studies In order to evaluate the femoral and popliteal vascular system at autopsy, a simple and rapid technic was devised for removal of these vessels. 1 The technic utilized a simple metal tube and did not require external dissection of the lower extremities. After removal, the arteries and veins of the thigh were opened longitudinally and were inspected, measured, and photographed. Thrombi were evaluated for color, firmness, dryness, attachment, and origin. Changes in the venous wall were noted and such regions were examined histologically. The tissues around the thigh vessels were examined for hemorrhage, edema, fibrosis, or inflammation.

2 Nov VENOUS THROMBOSIS AND PULMONARY EMBOLISM 51 The pulmonary arteries were dissected peripherally as far as possible, and all parts of the lung were examined for embolism or infarction. The percentage of the pulmonary arterial tree obstructed by emboli was estimated. When more than two-thirds of the pulmonary arterial area was obstructed, the cause of death was attributed to pulmonary embolism. Histologic studies were made of all organs, including each lobe of the lung. Representative histologic sections were made of all thrombotic or embolic lesions. Histologic examination of the femoral vessels was done routinely 5 and 10 cm. distal to the inguinal ligament and the popliteal vessels were examined routinely 5 to 45 cm. below the inguinal ligament. Histologic sections were made of all thrombi of the femoral and popliteal veins and multiple or serial histologic sections were made of all thrombi to evaluate the origin of the thrombi and to estimate their ages by use of histologic criteria. The stains employed were hematoxylin and eosin, elastic and van Gieson, von Kossa, Brown-Gram, and Prussian blue for iron. The histologic criteria of endothelization, ingrowth of fibroblasts, presence of macrophages, vascularization, necrosis of nucleated blood cells, and presence of inflammatory cells were used to establish the antemortem nature of thrombi. Cases studied. The technic for removal of the femoral-popliteal vessels was performed on both legs in 100 consecutive unselected autopsies of patients who were 12 years or older at the time of death. The vessels were removed after arterial embalming. In most cases, the entire femoral-popliteal vascular system was obtained; the case was included in the study if at least 15 cm. of thigh vessels were obtained. This criterion was fulfilled in 9 of the 100 cases and data from these 9 cases form the basis of this report. The clinical record in each of the 9 cases was reviewed to ascertain past episodes of thrombosis or venous disorders such as varicose veins. Data concerning the terminal illness that were recorded included: (1) length of terminal illness requiring bed rest; (2) number of days hospitalized; () TABLE 1 CLASSIFICATION OF THROMBI IN 25 CASES Type of thrombi Large, occlusive thrombosis of the femoral or popliteal vein or both veins Loose, unattached thrombotic material Small or moderate sized thrombi related directly to venous valves Microscopic thrombi Total No. of thrombi Per cent major medical problem of patient or, if postoperative, length of time since operation; (4) clinical diagnosis of thrombosis or embolism; (5) presence of disease states or medical conditions known to be associated frequently with thrombosis; (6) anticoagulant therapy; (7) laboratory coagulation studies; (8) radiographic evidence of embolism. In each of the 9 cases, the autopsy findings of thrombosis or embolism were compared with the historical, clinical, and autopsy data. All observations were submitted to statistical evaluation for significance by X 2 analysis.* RESULTS Incidence of thrombosis of the femoralpopliteal veins. Of the consecutive autopsies, 21 (22.6 %) had grossly evident thrombi in these veins. In four other cases (4.%), microscopic thrombi were found on histologic examination. The total incidence of thrombosis of the femoral-popliteal veins was 26.9% (25 of 9 cases). Morphologic features of thrombi of the femoral-popliteal veins. In the 25 cases in which there were thrombi, 57 separate thrombi were found. These thrombi were classified into four groups according to their size and location (Table 1). Bilateral throm- * Dr. Lila R. Elveback of the Section of Medical Statistics, Epidemiology and Population Genetics supervised the statistical analysis.

3 52- BECKERING AND TITUS Vol. 52 FIG. 1. Diagram of pathogenesis and fate of thrombi in venous valve sinuses. A, small thrombus in sinus of venous valve formed by deposition of fibrin, platelets, and erythrocytes on vein wall is present. B, growth of thrombus continues, with extension from valve sinus into lumen proper of vein. C, slight intimal thickening, fibrosis, and hemosiderin-laden macrophages are evidence of thrombus of venous valve sinus that has been resorbed almost completely. D, continued growth of thrombus in venous valve sinus has blocked venous return and has caused secondary thrombosis of entire venous segment; venous valve thrombus has been incorporated into larger segmental thrombus. bosis was noted in 10 of these 25 cases (40%). In the 16 large occlusive thrombi, the gross and histologic features of the thrombi and the vessels were studied in an attempt to establish the point of origin and the direction of propagation of the thrombus. In 10 of these 16 cases, the vessel of origin was established; in nine of the 10 cases, the origin was a thigh vein and in four of the nine cases the origin Avas a venous valve sinus. In one case, the thrombus originated in the calf, with thrombosis extending first into the popliteal vein and then into the femoral vein. In the other six cases of total occlusive thrombosis of the thigh veins, the origin and direction of propagation of the thrombus could not be established with certainty. Study of the 28 thrombi limited to the sinuses of venous valves and of the four large occlusive thrombi that originated from venous valves revealed a consistent pathogenetic pattern (Fig. 1). The thrombus had its origin in the sinus of the venous valve, with the deposition of fibrin, platelets, and erythrocytes on the wall of the vein in the FIG. 2. Three thrombi of venous valves emerging from venous valve sinuses. The two thrombi in the right femoral vein are developing in opposing venous valve sinuses.

4 Nov VENOUS THROMBOSIS AND PULMONARY EMBOLISM 5 HF'*j EEK \ \ Bv * VMK'^JUJS v.; t I fflbtk FIG. (upper left). Cross-section of thrombus in venous valve sinus revealing attachment of thrombus to vein wall {right) and an intact venous valve {left). Hematoxylin and eosin. X 40. FIG. 4 (upper right). Longitudinal section of thrombus of venous valve sinus demonstrating its emergence from sinus (to right), its small area of attachment to vein wall, and intact venous valve {below and left). Hematoxylin and eosin. X 10. FIG. 5 (lower left). Bilateral venous valve thrombi. Area of attachment is seen in thrombus at bottom. Thrombus at top is sectioned above its attachment. Hematoxylin and eosin. X 10. FIG. 6 (lower right). Thrombus of venous valve showing advanced organization and resorption into vein wall {right). Valve is thin structure to left of thrombus. Elastic and van Gieson. X 25.

5 54 BECKEEING AND TITUS Vol. 52 valve sinus. The venous valves themselves were intact and no pathologic alteration was found. Inflammation of the wall of the vein or the valve was not a contributing factor to the thrombus. Additional layers of thrombotic material were laid down until the valve sinus was filled, after which the thrombus extended out of the sinus into the lumen proper of the vein (Figs. 2 through 5). The point of attachment to the venous wall usually was small in comparison to the size of the thrombus and was limited to the region of the venous wall in the valve sinus (Figs. 4 and 5). Organization of the thrombus with ingrowth of fibroblasts, macrophages, and capillaries took place at the site at which the thrombus originally formed (Fig. 6). Thrombi in the sinuses of venous valves had one of three outcomes: (1) dislodgement from the attachment and embolism; (2) organization and nearly complete absorption into the wall of the vein, occurring apparently over a period of weeks; () growth of the thrombus by means of continued thrombosis, leading to blockage of the vein by a large segmental thrombus (Figs. 5, 7, and 8). Venous inflammation and femoral-popliteal thrombosis. In only two cases did thrombi have an associated inflammatory response in the walls of the veins. In one case, a small branch of the femoral vein had a microscopic thrombus. In the other, a continuous thrombus of the femoral and popliteal veins was present. The latter case was that of a patient who had died 0 days after internal fixation of a pathologic fracture of the femur. This case was the only one of the 25 in which thrombosis was associated with trauma, specific immobilization, or surgery on a lower extremity. Other thromboembolic phenomena. All 9 cases were evaluated for thromboembolic phenomena other than femoral-popliteal thrombosis and for pulmonary embolism and pulmonary infarction. Other thromboembolic phenomena were seen in 14 (56%) of the 25 cases in which there was venous thrombosis of thigh vessels and in 21 (0.9 %) of the 6S cases in which there was no thrombosis. This difference was statistically significant (7) < 0.005). There were three cases (12%) of nonbacterial thrombotic endocarditis in the group with FIG. 7. Two venous valve thrombi. Larger one on left was.5 cm. long and almost completely obstructed femoral vein. Thrombus also blocked origin of deep femoral vein and extended into deep femoral vein for 1 cm.

6 Nov VENOUS THROMBOSIS AND PULMONARY EMBOLISM 55 TABLE 2 PULMONARY EMBOLISM AND THROMBOSIS OP THE FEMORAL-POPLITEAL VEINS Thigh veins Pulmonary embolism With thrombosis (25 cases) Without thrombosis (68 cases) Total (9 cases) No. Per cent No. Per cent No. Per cent Gross Fatal Gross and microscopic Pulmonary infarct 12* 15* * 0 6* * Significant difference (p < 0.005). FIG. 8. Bilateral, totally occluding thrombi of femoral and popliteal veins. Segments of origin on both sides were femoral veins and origins of both thrombi could be traced to thrombi in sinuses of venous valves. Thrombosis of popliteal veins was retrograde. thigh thrombosis compared with only one case (1.4%) in the group without thigh thrombosis, but this difference was not statistically significant. Pulmonary embolism. Pulmonary emboli were classified as gross (found by gross dissection of the pulmonary vessels at autopsy) and microscopic (found only on histologic examination of the lungs). Gross pulmonary emboli were present in 12 cases (48%) and gross and microscopic emboli were found in 15 (60 %) of the 25 cases with thrombosis of the thigh (Table 2). In contrast, pulmonary emboli, either gross or microscopic, were found in only six (9%) of the 68 cases in which there were no thrombi in the leg veins. A relationship between pulmonary emboli and thrombosis of the thigh veins was indicated; the difference in incidence between the two groups was statistically significant (p < 0.005). Histologic evidence of pulmonary vascular hypertensive disease or multiple recurrent pulmonary emboli was not found in any of the 9 cases. Clinical features. There was no significant difference in the age of those patients with thigh thrombi compared to those without thigh thrombi (Fig. 9). Chi-square analysis revealed an increase in femoral-popliteal venous thrombosis in females as compared with males (p < 0.05). No females in this study were taking any form of oral contraceptives prior to death. There was an increased incidence of thrombosis in patients with congestive heart failure compared with other conditions, but this difference was not statistically significant by X 2 analysis. Statistically, there were no differences in the incidence of thrombi between the left and the right thighs, in the presence or absence of malignant disease or recent surgery, or in instances of previous episodes of venous disease (thrombosis, varicose veins) or no prior episodes.

7 56 BECKERING AND TITUS Vol i 20 Th gh thrombosi - No throrr bos is i 0 * / I 40 f. y ' * i AGE -YEARS t «i FIG. 9. Comparison of age and femoral-popliteal vein thrombosis. A significant relationship existed between the occurrence of thigh thrombosis and the duration of bed rest. The median duration of bed rest prior to death was 7 days in the group without thigh thrombosis, whereas it was 2 days in the group with thigh thrombosis. Other findings. In only one case was there focal calcification of a femoral or popliteal vein that could represent a phlebolith. A correct clinical diagnosis of thrombosis of thigh veins had been made in two of the 25 cases (8%). The clinical diagnosis of pulmonary embolism had been made in four of 21 cases (19%). DISCUSSION Venous thrombosis of the femoral-popliteal veins frequently is found at autopsy if specific examination of the lower extremities is performed. The incidence of 26.9 % in this series is similar to reported incidences..8, i2,17 Localization of thrombi to the sinuses of venous valves was found in nearly one-half of the cases in which there was thrombosis of femoral-popliteal veins. Stein and Evans 17 observed that thigh thrombi were found in this location in 46% of their series and Gibbs and McLachlin and Paterson 8 previously had pointed out this localization. It appeared that primary occlusive thrombosis of the thigh veins resulted from growth of a small thrombus in a valvular sinus and resulted in retrograde thrombosis of the vein. The majority (82%) of the thrombi were primary within the femoral-popliteal veins, including thrombi in nine of 16 cases of continuous femoral-popliteal venous thrombosis. Gibbs and Roberts 12 previously emphasized that massive thrombosis of thigh veins could be limited to these veins and was not necessarily an extension from tributaries in the calf. These findings are at variance with others " who believe that most occlusive thrombi in the thigh veins are the result of proximal extension from the thrombi in calf veins. The absence of acute inflammation in relation to femoral-popliteal thrombi supports the contention that inflammation is infrequently a component of femoralpopliteal thrombosis. Surgery or trauma of the lower extremity appears to predispose to venous thrombosis because of immobilization and venous inflammation. There was a statistically significant increase in femoral-popliteal venous thrombosis in women as compared with men (p < 0.05). An increased frequency of leg thrombosis in women was noted by Roberts 12 in his dissections. In other dissections, men more frequently had leg thrombi. - 6 The findings of three instances of nonbacterial thrombotic endocarditis associated with occlusive femoral-popliteal thrombosis are suggestive of a possible relationship between these conditions, but the number of cases is small. A relationship among venous thrombosis, nonbacterial thrombotic endocarditis, and mucinous malignancies was suggested recently by Rohner and coworkers. 1 In one case in our series, a mucinous adenocarcinoma of the pancreas was found to be associated with venous thrombosis of the thigh and nonbacterial thrombotic endocarditis. Heart disease, especially congestive heart failure, frequently was associated with venous thrombosis, but the relationship was not statistically significant. An association of heart disease and thrombosis of the veins of the lower extremity has been noted frequently in the past. In this study of thrombosis of the thigh vein, the most important concomitant factor was bed rest for 2 to weeks or more. The importance of bed rest in the etiology of venous thrombosis also was stressed by

8 Nov VENOUS THROMBOSIS AND PULMONARY EMBOLISM 57 Raebum, 11 Gibbs, and Hunter and associates. 6 Pulmonary embolism remains a common and difficult medical problem. Rousuck 15 found at autopsy a 10% frequency of gross pulmonary emboli and a 4.46% frequency of fatal pulmonary embolism at our institution between 1940 and The 15 % frequency of gross pulmonary emboli and the.2 % frequency of fatal pulmonary embolism in the present study of 9 consecutive autopsies indicate no essential change in the magnitude of the problem as observed at autopsy during the last 25 years. REFERENCES 1. Beckering, R. E., Jr., and Titus, J. L.: A method for the autopsy study of the femoralpopliteal vessels. Am. J. Clin. Path., Ifl: 652, Frykholm, R..: Om ventrombosens patogenes och mekaniska profylax. Nord. med., 4: , Gibbs, N. M.: Venous thrombosis of the lower limbs with particular reference to bed-rest. Brit. J. Surg., 45: , Greenstein, J.: Thrombosis and pulmonary embolism. South African M. J., 19: 50-56, 77-80, Hunter, W. C, Krygier, J. J., Kennedy, J. C, and Sneeden, V. D.: Etiology and prevention of thrombosis of the deep leg veins: a study of 400 cases. Surgery, 17: , Hunter, W. C, Sneeden, V. D., Robertson, T. D., and Snyder, G. A. C.: Thrombosis of the deep veins of the leg: its clinical significance as exemplified in three hundred and fifty-one autopsies. Arch. Intern. Med., 68: 1-17, Ingraham, E. S., Jr.: The distribution of thrombi in veins of the pelvis and legs in relation to the possible value of ligation of the femoral vein. Canad. M. A. J., ^7: , McLachlin, J., and Paterson, J. C: Some basic observations on venous thrombosis and pulmonary embolism. Surg. Gynec. & Obst., 98: 1-8, Neumann, R.: Ursprungszentren und Entwicklungsformen der Bein-Thrombose. Arch. path. Anat., S01: , Putzer, Rita: Die Wadenvenenthrombose in ihrer Beziehung zur Architektur der Wade. Arch. Gyniik., 169: , Raebum, C: The natural history of venous thrombosis. Brit. M. J., 2: , Roberts, G. H.: Venous thrombosis in hospital patients: a postmortem study. Scot. M. J., 8: 11-15, Rohner, R. F., Prior, J. T., and Sipple, J. H.: Mucinous malignancies, venous thrombosis and terminal endocarditis with emboli. Cancer, 19: , Rossle, R.: tlber die Bedeutung und die Entstehung der Wadenvenenthrombosen. Arch, path Anat., 800: , Rousuck, A. A.: Fatal and non-fatal pulmonary embolism with and without thrombosis: a clinical and pathological study. Rochester, Minnesota: Thesis, Mayo Graduate School of Medicine, University of Minnesota, Sevitt, S., and Gallagher, N. G.: Prevention of venous thrombosis and pulmonary embolism in injured patients. Lancet, 2: , Stein, P. D., and Evans, H.: An autopsy study of leg vein thrombosis. Circulation, SB: , Virchow, R.: Neuer Fall von todtlicher Embolic der Lungenarterien. Arch. path. Anat., 10: , Voegt, H.: Veranderungen der Wadenmuskulatur bei Venenthrombose und langem Krankenlager. Arch. path. Anat., 00: , 197.