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Cardiac Evaluation of Vascular Patients
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Deep Vein Thrombosis, Anticoagulation and the Location of Fatal Pulmonary Emboli

Although the pathophysiology of venous thromboembolic disease has been known for years, deep vein thrombosis remains a major source of morbidity in hospitalized patients. Short-term morbidity occurs in the form of pulmonary emboli, which are a common cause of death. Pulmonary emboli account for about 5% of hospital deaths, or approximately 60 000-200 000 deaths per year in the United States depending on the diligence of search for this cause of death.1 Long-term morbidity occurs primarily due to the sequellae of the postphlebitic leg and due to the development of chronic pulmonary hypertension as a result of the embolization. Only about 30% of the fatal cases of pulmonary emboli are diagnosed before death. This is a consistent figure across many autopsy series. The statistics on incidence and consequence of pulmonary emboli are highly variable thru the literature. One important unifying feature of this vast literature, however, is that the incidence of deep vein thrombosis and pulmonary embolism is critically dependant on the diligence with which these diagnoses are sought. Pulmonary emboli are often asymptomatic, so reports of the incidence of "clinical embolism," meaning patients found by history and physical examination to have pulmonary embolus, will not accurately reflect the true incidence. Autopsies in which only proximal pulmonary arteries are examined will underestimate the incidence. Venous diagnostic tests which do not evaluate the entire venous system of the lower extremities will underestimate the incidence of deep venous obstruction. Such studies are common.

Role of Deep Venous Thrombosis (DVT) in Pulmonary Embolus

Over 90% of pulmonary emboli originate from clots in the deep veins of the pelvis and leg. Of patients admitted for DVT, 40% have experienced pulmonary emboli before admission according to a careful study by Moser et al.2 While they consider the figure of 40% to be a minimal figure, they studied patients more thoroughly than is usually done, and studied only patients in whom DVT was suspected, making their incidence higher. Remember that DVT is often present when in is not suspected. Clearly the extent of pretreatment embolization determines the amount of additional clot burden which is tolerable should further embolization occur. Of the patients with DVT, the incidence of pulmonary emboli varies according to location. Proximal clots, designated in the literature as ileofemoral thrombosis, have the highest incidence and calf veins have the least incidence. Norris,3 for example, studied the occurrence of clinically evident pulmonary emboli in 78 patients with ileofemoral thrombosis treated with adequate heparin anticoagulation. Almost 10% of these patients had clinically evident pulmonary emboli documented by lung scan in spite of adequate anticoagulation. Had he studied all patients with lung scans, he probably would have found more. Kistner noted that when phlebitis extended into the iliac veins, pulmonary embolism occurred in 50% of patients, many before the diagnosis of DVT was recognized.4 In his entire series, 15% of patients experienced embolism after the onset of anticoagulation. Since he tended to perform thrombectomy on patients with iliac thrombosis, the incidence would have been a bit higher had this high risk group been included. Moser also noted a much higher incidence of thromboembolism in patients with more proximal deep vein thrombosis.5 Free floating thrombi were found to be particularly dangerous and were associated with a 60% incidence of embolization in spite of treatment.3 At the other end of the spectrum, calf vein thrombosis appears to have a 20% incidence of embolization if untreated, and some believe that the incidence is even less.

Mechanisms of Death from Pulmonary Emboli

Several mechanisms contribute to death from pulmonary emboli. Increased pulmonary vascular resistance leads to decreased blood flow thru the pulmonary vascular bed and decreased pumping ability on the part of the heart. There is impaired gas exchange due to loss of blood flow and loss of functioning units of lung tissue. There is spasm of the bronchi and pulmonary vessels causing obstruction out of proportion to the clot burden. The lungs become stiff due to edema, hemorrhage and loss of surfactant. These mechanisms are discussed in most major textbooks.6 Although these secondary factors may be contributing, patients die for mechanical reasons. Fifty per cent or more of their pulmonary vascular bed is occluded, and the heart simply can not pump enough blood thru the obstruction to provide oxygen to the body. It does not matter which 50% is occluded, and this 50% number is consistent across the medical literature.7,13

Goldhaber suggests that 30% of the vascular bed can be occluded by multiple emboli without major compromise. Obviously an additional clot thrown in on top of an asymptomatic 30% obstruction of the pulmonary bed carries a worse prognosis that one landing in a normal vascular bed. "Obviously, the volume and orientation of the embolus dictate the effects on the pulmonary circulation.8" Proximal emboli require a smaller volume of clot to occlude the requisite 50% of the vascular bed and cause "massive pulmonary embolism." The literature on transfemoral pulmonary embolectomy confirms that dramatic effects are often produced by removing small amounts of critically placed clot.9 This has been my experience with this technique as well. When the critical volume has been removed the patient notes a sudden improvement in breathing and pulmonary hemodynamics are much improved. Follow-up angiography often demonstrates multiple pruned distal branches, indicating distal embolization. Sometimes improvement is produced by simply breaking up the thrombus and dispersing it into the periphery--providing that the peripheral vessels aren't already overloaded. Death from overloading the distal pulmonary circulation is not uncommon (see autopsy info).

Autopsy Findings in Fatal Pulmonary Embolus.

"Differences in size of thromboemboli have great consequences not only for the clinical effects and for mortality, but also for the evaluation of the prevalence of pulmonary thromboembolism. Large emboli obstructing pulmonary trunk or main pulmonary arteries will not remain undetected when these vessels are opened at autopsy. However, lobar and segmental pulmonary arteries are not regularly cut systematically, so that emboli in these vessels may escape detection. This explains that the percentage of grossly recognizable emboli in routine autopsies of adult patients varies widely, from 1.5% to almost 30%.10"

Although anticoagulation has been remarkably effective in preventing pulmonary emboli in patients with deep vein thrombosis, all patients are not protected. Kistner believed it to be 89% effective for clots at the inguinal ligament and belowiv Schafer (1999) reported that anticoagulants are up to 90% effective in preventing repeated episodes of pulmonary embolism.11 Sandler12 reported an autopsy study from the Royal Hallamshire Hospital in 1989. Unfortunately he did not describe the location of the fatal pulmonary emboli, but he did note that 6% of the 239 fatal pulmonary emboli occurred while the patient was anticoagulated. Dismuke et al13 reported, in an autopsy study from North Carolina Memorial Hospital, that the use of anticoagulants increased dramatically between the start of the study in 1966 and the end of the study in 1980. Although the proportion of patients dying from pulmonary emboli decreased as a result, 40% of the patients who died (17/43) during the last 5 years of the study were receiving anticoagulants when they experienced their fatal pulmonary embolus. They too did not report the locations of the emboli found. Anticoagulation may not be the best treatment for DVT, however. Marder's studies14 show that when DVT is treated with heparin 50% of patients retain the same clot burden, 25% lyse some of the clot, but fully 25% experience clot propagation.

Morpurgo summarized his extensive studies on the pathology of pulmonary embolism as follows: "Often a fatal embolus is relatively small but hardly tolerated because of the underlying cardiopulmonary situation. For this reason also, an hemodynamic rather than anatomic stratification of prognosis proves to be suitable. In 1948 Neuhof already wrote the following: 'Embolism of peripheral branches of the pulmonary arteries, leaving the main branches free, may produce symptoms of marked severity and may even cause death.' Also in our experience covering 49 cases of sudden and unexpected death, pulmonary embolization often involved only peripheral and unilateral vessels.15"

Most autopsy studies do not give the locations of the fatal pulmonary emboli found. Since studies of this type are carried out using the same technology as would be used today, and since they are studies of the natural history of the disease, older articles remain relevant. An extensive autopsy survey of pulmonary embolism published by Coon and Coller in 195916 studied 4391 consecutive autopsies done at the University of Michigan on hospitalized patients. A careful search was made for all pulmonary emboli. Pulmonary embolism was found in 606 patients (13.8%) and was considered the cause of death in 198, or 4.5%. An additional 190 patients (4.3%) had emboli which contributed to death but were not the cause. In patients whose cause of death was pulmonary embolism, 33% had thrombi in the main pulmonary artery, left or right pulmonary arteries. In 48% the thrombi were in lobar arteries, and in 19% they were in smaller arteries only. These patients died suddenly. Twenty-two per cent died immediately, 47% were dead within 15 minutes from the onset of symptoms, and 62% were dead in one hour. In the patients with emboli contributing to death the percentages were 19% in the main, right or left pulmonary artery, 43% in lobar arteries, and 38% in even smaller arteries. They concluded that "Massive occlusion with myriads of microscopic emboli to almost all of the terminal branches of the pulmonary arterial system appear to be responsible for almost one-fifth of the deaths attributed to pulmonary embolism.....Very frequently, routine microscopic section of various areas of grossly normal lung is the only way to detect this entity."

The most pertinent autopsy series defining the location of fatal pulmonary emboli is the series reported by the Mayo Clinic in 1995.17 These authors studied autopsy cases from the Mayo clinic between 1985 and 1989. Among 2427 autopsies, death was clinically and pathologically judged to be caused by pulmonary embolism in 92 or 3.8% of autopsies. Of these 92 patients, 46% were on some form of thrombophlebitis prophylaxis. 7% were fully anticoagulated. 8% had vena cava filters in place. Sudden death occurred in 26% without any symptoms. If you include patients unable to report symptoms (coma, respirators, etc) then the incidence rose to 35%. In this group of patients pulmonary embolism was considered as a diagnosis by the physicians caring for the patient in 49% and was correctly assigned as the cause of death on the death certificate or in the medical records in only 32%. Half of these patients had several generations of pulmonary emboli. The importance of complete autopsy was emphasized by the locations of the fatal emboli. 27 patients had saddle emboli, meaning emboli occluding both main pulmonary arteries. 9 had occlusions of one main pulmonary artery. The remainder, or 60% had their emboli confined to lobar or sublobar pulmonary arteries. These data are Strikingly similar to those reported by Coon and Coller in 1959.

Surgical papers have commented on the impossibility of saving patients with massive peripheral pulmonary emboli by emergency pulmonary embolectomy. The trouble, of course, is in identifying these patients preoperatively, as the lung scan is unable to make the differentiation.18, 21

Fragmentation of Pulmonary Emboli

As can be seen by the diagram of the pulmonary vasculature, the volume of clot required to occlude the pulmonary vasculature depends on where it located and how much of the pulmonary vascular bed has previously been occluded. The main pulmonary artery divides in three dimensions so that by the time the capillary bed is reached distally, the cross sectional area of the vascular bed in huge compared to the main pulmonary artery. Since deep vein thrombosis is commonly associated with asymptomatic pulmonary emboli it is difficult to know how much of the vascular bed is involved at the time of diagnosis.

"...thromboemboli may break up into numerous small fragments, either mechanically or during the process of endogenous thrombolysis."

"Thrombotic microembolism al-most certainly may give rise to extensive pulmonary arterial obstruction and to thrombo-embolic pulmonary hyper-tension. Cases of widespread peripheral pulmonary arterial occlusion by post thrombotic lesions which are clearly of embolic origin, may be masquerading as primary pulmonary hypertension.10" Clearly if widespread enough, death may occur before chronic pulmonary hypertension is a consideration.

Fragmentation of pulmonary emboli is a well-known phenomenon. Coon and Coller reported "A difficult problem is the explanation for sudden death in a patient with occlusion of only one major pulmonary artery or several secondary branches which one would not expect to be fatal on the basis of mechanical obstruction of the arterial tree alone. This has usually been attributed to the generalized reflex changes mentioned previously. [also mentioned above in this paper]. Another equally logical explanation would be that a large embolus had fragmented at the bifurcation of the main pulmonary artery with secondary undetected microscopic obstruction of the smaller branches to the other lung. We believe that such fragmentation occurs frequently in pulmonary embolism and is very often fatal, although difficult to detect unless one examines routine sections from each pulmonary lobe."

In fact a proximal clot can lead to cardiac arrest and then be broken up into the periphery during CPR, thus disappearing from the major pulmonary vessels. Brady mentioned this phenomenon in describing a technique for mechanical disruption of the occluding thrombus as a means of therapy.19 "Because the volume of thrombus is large relative to that of the main pulmonary arteries, but small when compared with the total volume of the smaller vessels, dispersing the clot into the distal branches will substantially increase pulmonary blood flow." His critics noted failure with this technique, presumably because distal vessels were already overloaded in their patient.20 Elliott (1995)21 Noted that "Because chest compression may fragment large central pulmonary emboli, the need for embolectomy following a successful cardiopulmonary resuscitation for acute pulmonary embolism remains less certain. Indeed, a number of centers do not perform embolectomies for patients whose condition has stabilized." As far as I can tell, formal studies on clot fragmentation during CPR have not been carried out. To demonstrate this phenomenon due to CPR, one would have to know the exact location of the clot before CPR was started and then document where it was after CPR was concluded. The impossibility of obtaining such data in humans is obvious. Nonetheless, Price noted that "If cardiac arrest occurs, external cardiac massage should be undertaken as it is sometimes successful and disseminates and fragments the clot in the pulmonary artery.22"

Thus fatal pulmonary emboli found only in the periphery may be the natural presentation of fatal pulmonary embolism, or may be due to fragmentation of the clot as a part of its natural history or as the result of instrumentation or resuscitation.

Dr Brantigan wrote this paper in December 2000.

1 I have not referenced much of this basic data, as it appears at the beginning of most articles on the subject.

2 Moser, KM, Fedullo, PF, LittleJohn, JK, Crawford, R, Frequent asymptomatic pulmonary embolism in patients with deep vein thrombosis, J Amer Med Ass (1994) 271:223-5.

3 Norris, CS, Greenfield, LJ, Free-floating iliofemoral thrombus, Arch Surg (1985) 120:806-808.

4 Kistner, RL, Ball, JJ, Nordyke, RA, Freeman, GC, Incidence of pulmonary embolism in the course of thrombophlebitis of the lower extremities, Amer J Surg (1972) 124:169-176.

5 Moser, KM, LeMoine, JR, Is embolic risk conditioned by location of deep venous thrombosis?, Ann Int Med (1981) 94 (part 1): 439-444.

6 Goldhaber, SZ, Pulmonary embolism, in Braunwald, E, Heart Disease, WB Saunders, Philadelphia 1997 p1585.

7 Goldhaber, SZ in Braunwald op cit. table 46-7.

8 Greenfield, LJ, Zocco, JJ, Intraluminal management of acute massive pulmonary thrombembolism, J Thor Cardiovasc Surg (1979)77:402-410.

9 See Greenfield's other articles on the subject, such as Greenfield, LJ, Reif, ME, Guenter, CE, Hemodynamic and respiratory responses to transvenous pulmonary embolectomy, J Thor Cardiovasc Surg (1971) 62:890-7.

10 Wagenvoort, CA, Pathology of pulmonary thromboembolism, Chest (1995) 107:10s-17s. Note that this article is against us in some respects when it notes that most PE's that cause sudden death are located in major arteries. He does go on to describe fragmentation of clots and distal embolization as a cause of major problems, however. Note that this is not an article with data, just opinions.

11 Schafer, AI, Editorial: Venous thrombosis as a chronic disease, New Engl J Med (1999) 340:955-6.

12 Sandler, DA, Martin, JF, Autopsy proven pulmonary embolism in hospital patients: are we detecting enough deep vein thrombosis, J Roy Soc Med (1989) xxxxxxxx

13 Dismuke, SE, Wagner, EH, Pulmonary embolism as a cause of death; The changing mortality in hospitalized patients, JAMA (1986) 255:2039-2042.

14 I remember these articles-they are on a slide from my DVT lecture-but do not remember the reference.

15 Morpugo, M, Schmid, C, The spectrum of pulmonary embolism: clinicopathologic correlations, Chest (1995) 107:18s-20s. He refers to Morpurgo, Clinico-pathological correlation in pulmonary embolism;a posteriori evaluation. Progr Respir Res (1980) 13:8-15, and Neuhof, H, Venous thrombosis and pulmonary embolism, Grune and Stratton, 1948, p 92-105, references that I don't have.

16 Coon, WW, Coller, FA, Clinicopathological correlation in thromboembolism, Surg Gynec Obstet (1959) 109:259-269.

17 Morgenthaler, TI, Ryu, JH, Clinical characteristics of fatal pulmonary embolism in a referral hospital, Mayo Clin Proc (1995) 70:417-424.

18 Stulz, P, Schlapfer, R, Feer, R, Habicht, J, Gradel, E, Decision making in the surgical treatment of massive pulmonary embolism, Eur J Cardio-thorac Surg (1994), 8:188-93.

19 Brady, AJB, Crake, T, Oakley, CM, Percutaneous catheter fragmentation and distal dispersion of proximal pulmonary embolus, Lancet (1991) 338:1186-89.

20 Meyer, G et al, Letter to the editor, Chest (1992) 102:1306.

21 Elliott, CG, Embolectomy, catheter extraction, or disruption of pulmonary emboli: editorial review, Current Opinion in Pul Med (1995) 1:298-302.

22 Price, DG, Pulmonary embolism. Prophylaxis and treatment, Anaesthesia (1977) 31:925-32.


2003-2004 Dr. Charles Brantigan,  Vascular Surgery Practice
2253 Downing Street, Denver, CO 80205
303.830.8822 fax: 303.830.7068 or 800.992.4676  inquiries@drbrantigan.com

Last Updated: 07/15/2004