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Pulmonary thromboendartectomy (PTE) for chronic thromboembolic pulmonary hypertension may be complicated by reperfusion lung injury. This has previously been demonstrated to be neutrophil-mediated. We postulated that blocking selectin-mediated adhesion of neutrophils to the endothelium with Cylexin (CY-1503) would prevent reperfusion lung injury in this patient population. In this double-blind, randomized, placebo-controlled, parallel study, 26 patients received Cylexin the day of surgery and 25 received placebo. Significantly fewer patients in the treated group (31%) compared with the placebo group (60%) developed lung injury (p = 0.036). However, the average number of days of mechanical ventilation, days in the intensive care unit (ICU) and hospital, as well as mortality were not significantly different between the treatment groups. Those with reperfusion lung injury had significantly elevated percent neutrophils, total protein, and soluble P-selectin in bronchoalveolar lavage fluid compared with those without lung injury. We conclude that reperfusion lung injury after PTE is a high-permeability lung injury and its incidence can be reduced by the administration of Cylexin on the day of surgery.

Patients with sickle cell disease have been reported to have an increased risk of thromboembolism and pulmonary hypertension. Some of these patients may benefit from pulmonary thromboendarterectomy (PTE), a procedure that requires profound hypothermia, cardiopulmonary bypass, and periods of circulatory arrest, factors that may potentially increase the risk of sickling. Two patients with sickle cell disease (sickle-thalassemia [Hb S/beta+] and Hb SS) presented to the Pulmonary Vascular Center of UCSD Medical Center with significant shortness of breath and limitation of daily activities. Both of these patients were found to have surgically accessible chronic thromboembolic disease with pulmonary hypertension. PTE was performed in both patients using exchange transfusion, with avoidance of anemia, hypoxia, and acidosis. A successful outcome with resolution of pulmonary hypertension was achieved in both cases. To our knowledge this is the first report of patients with sickle cell disease who successfully underwent PTE for chronic thromboembolic pulmonary hypertension.

Purpose The purpose of this consensus report was to address clinically relevant questions related to the diagnosis and management of acute pulmonary embolism and deep venous thrombosis. Background Physicians are often forced to make decisions about the diagnosis and management of pulmonary thromboembolism even though there are only limited data to guide them. Methods We assessed the relevant literature regarding clinical trials according to levels of evidence. The data on which the opinions of the committee were made were sparse. The consensus opinions, therefore, were often based on experience or intuition, rather than firm data. Results Consensus opinions were given in regard to eight clinically relevant questions. Conclusion We hope that the consensus opinions of this committee will assist others in making clinical decisions while we all await prospective investigations.

Background The presence of patent neovessels within vascular occlusions in chronic thromboembolic pulmonary hypertension suggests that local mechanisms exist to regulate the coagulation system. This study investigated the expression of a potent inhibitor of Factor IXa and Factor XIa (ie, protease nexin-2/amyloid β-protein precursor, AβPP) in the organized vascular occlusions harvested from patients with this disease. Methods and Results Immunohistochemical analysis revealed intense immunoreactivity for AβPP in the single layer of cells that line the neovessels. A positive signal was also detected by in situ hybridization analysis with the use of a 35 S-UTP–labeled antisense riboprobe that recognizes the various alternatively spliced mRNA forms of this molecule. To identify the forms of AβPP produced within the thrombi, total RNA was extracted from the thrombi, reverse transcribed, and subjected to amplification with the use of the polymerase chain reaction (PCR) and primers that flank the region encoding the alternatively spliced 56–amino acid Kunitz-type protease inhibitor (KPI) domain. The major PCR products consisted of 255 bp and 312 bp and corresponded to transcripts encoding this domain (ie, AβPP 751 and AβPP 770 ). In situ hybridization analysis with the use of a 35 S-UTP–labeled antisense riboprobe complementary to the region encoding the KPI domain confirmed the presence of these mRNA species in nucleated cells lining the neovessels. Conclusions The expression of KPI-containing isoforms of AβPP in thrombus endothelial cells may represent one mechanism utilized in this disease to shift the local hemostatic balance and preserve regional vessel patency.

The finding of a restrictive pulmonary defect may divert clinicians from considering the diagnosis of chronic thromboembolic pulmonary hypertension because lung volumes are usually normal in this disorder. We have, however, encountered a significant number of these patients with reduced lung volumes. Furthermore, we have observed many patients who have developed parenchymal scars and/or pleural thickening. To determine whether such findings are associated with lung volume restriction, we analyzed patients evaluated at our institution for chronic thromboembolic pulmonary hypertension over a 20-month period in whom thoracic high-resolution CT scans and pulmonary function testing had been performed. Patients with obstructive or restrictive lung disease from another cause were excluded. We compared the presence of lung restriction (total lung capacity below 80% of predicted) with the extent of parenchymal scarring, pleural thickening, and pulmonary artery diameter on CT scans. Of 191 patients evaluated, 51 met criteria for entry. Eleven patients (22%) had lung restriction. Parenchymal scarring was highly associated with lung restriction (p=0.01). Neither pleural thickening (p=0.08) nor pulmonary artery diameter (p=0.80) was associated with lung restriction. Conclusions A significant number of patients with chronic thromboembolic pulmonary hypertension may have restrictive lung defects. The restriction may be due to parenchymal scarring.

Rationale and Objectives. We evaluated the accuracy of contrast-enhanced magnetic resonance (MR) angiography in demonstrating the findings of chronic pulmonary thromboembolism (CPTE) compared with conventional pulmonary angiography. Methods. We examined 18 patients with CPTE proved by conventional pulmonary angiography and 16 healthy control patients. T1-weighted and single-breathhold, two-dimensional multiplanar spoiled gradient-recalled pulmonary images were obtained after injection of gadopentetate dimeglumine. Images were interpreted independently by two radiologists. Results. All patients with CPTE were identified on MR angiography images by both readers. Sensitivity and specificity for MR angiography in diagnosing abnormal segments were 76% and 95% for reader 1 and 68% and 93% for reader 2, respectively. Sensitivity and specificity for MR angiography in depicting abnormal lobes were 83% and 96% for reader 1 and 82% and 93% for reader 2, respectively. Interobserver agreement was high; kappas for abnormal segments and abnormal lobes were .72 and .84, respectively. The T1-weighted spin-echo images demonstrated a mosaic signal intensity pattern in all patients with CPTE. Conclusion. Contrast-enhanced MR angiography accurately depicts abnormal segments and lobes in occlusive vascular disease and clearly distinguishes between patients with CPTE and those with healthy lungs.

BACKGROUND Chronic thromboembolic pulmonary hypertension is the result of nonresolving pulmonary emboli that lead to chronic obstruction of the central pulmonary arteries. METHODS AND RESULTS To determine if the failure to lyse pulmonary thromboemboli is caused by an abnormality in the endothelial cell (EC)-associated fibrinolytic system, conditions were established to culture ECs from patient main pulmonary arteries during surgical pulmonary thromboendarterectomies and to analyze the conditioned media for levels of tissue-type plasminogen activator (TPA) and type 1 plasminogen activator inhibitor (PAI-1). Our data indicate that the levels of TPA antigen and PAI-1 activity in media conditioned by primary ECs harvested from areas free of thrombus were not significantly different between patients with chronic thromboemboli and organ donors. In 13 consecutive patients, no correlation was obtained in either the TPA antigen or PAI-1 activity level in a patient's plasma and the respective levels in media conditioned by the patient's pulmonary ECs. Moreover, patient pulmonary arterial ECs were observed to increase the secretion of TPA and PAI-1 in response to thrombin in a fashion similar to donor pulmonary artery ECs. CONCLUSIONS The data suggest that an inherent EC-mediated fibrinolytic imbalance is not a generalized phenomenon observed in pulmonary arteries of patients with chronic pulmonary thromboemboli.

BACKGROUND Chronic thromboembolic pulmonary hypertension is the result of nonresolving pulmonary emboli that lead to chronic obstruction of the central pulmonary arteries. METHODS AND RESULTS To determine if the failure to lyse pulmonary thromboemboli is caused by the local expression of the primary inhibitor of tissue-type plasminogen activator (type 1 plasminogen activator inhibitor, PAI-1), levels of PAI-1 antigen and mRNA were analyzed by immunohistochemistry and in situ hybridization in specimens harvested from a series of patients during pulmonary thromboendarterectomies. Red, fibrin-rich thrombi within the thromboendarterectomy specimens were lined with a single layer of endothelial cells exhibiting high levels of PAI-1 antigen. Quantitation of the in situ hybridization signal revealed that a significant increase in PAI-1 mRNA was present in the endothelial cells lining the fresh thrombi in comparison to the signal present in the endothelial cells from noninvolved areas of patients' pulmonary arteries (n = 16, P < .001). In contrast, tissue-type plasminogen activator antigen levels were low in all samples. Yellowish-white thrombi were composed of smooth muscle cells and endothelial cells in numerous vessels that stained prominently for PAI-1 antigen. Both types of cells within the highly organized tissues also exhibited elevated PAI-1 mRNA levels in comparison to patient pulmonary artery specimens that were free of thrombus (n = 16, P < .02). CONCLUSIONS The prevalence of PAI-1 expression within pulmonary thromboemboli suggests that this inhibitory may play a role in the stabilization of vascular thrombi.

A program to alleviate chronic, major vessel thromboembolic pulmonary hypertension by pulmonary thromboendarterectomy was initiated at this institution in 1970. Multiple evolutionary changes in the diagnostic evaluation, surgical approach, and postoperative management have been implemented over the series of 323 thromboendarterectomies performed through March 1992. A sequence of five surgeons at the University of California at San Diego have performed these procedures, with the last 150 having been performed by one surgeon. We report here the changes in surgical approach developed over the last 150 cases and the results obtained. The operation involves a median sternotomy incision, the institution of cardiopulmonary bypass, and deep hypothermia with circulatory arrest periods. Incisions are made in both pulmonary arteries into the lower lobe branches. Pulmonary thromboendarterectomy is always bilateral, with removal of both organized thrombus and an endarterectomy plane from all involved vessels. The right atrium is routinely explored for atrial septal defects. Current techniques appear to allow more thorough revascularization and shorter circulatory arrest times. The surgical mortality of 8.7% over this span is below that previously reported from this and other institutions. Among survivors, the hemodynamic and functional results have been excellent. Surgically correctable chronic thromboembolic pulmonary hypertension likely remains underdiagnosed. The diagnostic, surgical, and postoperative management evolution provided by the coordinated team involved at this institution has established that pulmonary thromboendarterectomy can be performed with an acceptable risk and good hemodynamic and symptomatic results.

The pulmonary angiograms of 250 patients evaluated for chronic thromboembolic pulmonary hypertension were reviewed. Pulmonary thromboendarterectomy was performed in each of these individuals, and the surgical findings were correlated with abnormal angiographic patterns. The pulmonary angiographic findings suggestive of chronic thromboembolic disease included "pouching" defects, webs or bands, intimal irregularities, abrupt vascular narrowing, and complete vascular obstruction. Pouching is reported by the authors to be a previously undescribed angiographic feature of this disease. Carefully obtained and properly interpreted pulmonary angiograms are necessary to confirm the diagnosis of operable chronic thromboembolic disease. Differential diagnostic possibilities should be considered prior to a decision to perform surgical correction.

Pulmonary thromboendarterectomy is being performed with increasing frequency for incapacitating pulmonary hypertension caused by chronic large-vessel pulmonary embolism. However, patient-related risk factors and procedural complications associated with morbidity and mortality have not been fully defined. From Oct. 1, 1984, to April 10, 1989, we performed pulmonary thromboendarterectomy using deep hypothermia and circulatory arrest in 127 consecutive patients (62.2% male, mean age 50 ± 16 [standard deviation], range 20 to 82 years) in whom the exposure and dissection of the pulmonary arteries and methods for myocardial protection have been standardized. End points for univariate and multivariate analyses of risk factors were reperfusion pulmonary edema leading to respiratory insufficiency as defined by ventilator dependency (≥5 days) (31.5%, 39/124) and hospital mortality (12.6%, 16/127). Multivariate analyses showed that ascites and need for 4 units of blood or more predicted ventilator dependency (p

This study evaluated long-term outcome of pulmonary thromboendarterectomy (PTE) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Survival, functional status, quality of life, health care utilization, and relationships between these parameters and postoperative pulmonary hemodynamics were assessed. Questionnaires were mailed to 420 patients who were more than 1 yr post-PTE; 308 responded (mean age, 56 yr [range, 19-89 yr]; mean years since PTE, 3.3 [range, 1- 16]). Survival after PTE was 75% at > 6 yr. After surgery, symptoms were markedly reduced. Median distance walked was 5,280 ft; 56 patients could walk "indefinitely." Of the working population, 62% of patients unemployed before PTE returned to work. Post-PTE patients scored several quality of life components of the Rand SF-36 slightly lower than reported normals but significantly higher than did pre-PTE patients. Ten percent of patients used oxygen. Ninety-three percent were in NYHA Class I or II. Disease-related hospitalizations/ER visits were minimal. A relationship was shown between 48 h postoperative pulmonary vascular resistance (PVR) and walking and stair-climbing ability, NYHA class, dyspnea scores, and the physical function and general health quality of life components. These data indicate that PTE offers most CTEPH patients substantial improvement in survival, function, and quality of life, with minimal disease-related health care utilization.

Abstract —Information is lacking on the mechanisms involved in the organization, resolution, and repair of the vascular lumen after acute pulmonary thromboembolism. Because recent data suggest that the balance between plasminogen activators (PAs) and type 1 plasminogen activator inhibitor (PAI-1) plays a role in regulating cell migration within the extracellular matrix, we investigated the expression of these molecules by immunohistochemical and in situ hybridization analysis of pulmonary artery specimens from patients suffering fatal pulmonary embolism. The data were compared with the expression of these molecules in both patients’ noninvolved pulmonary arteries and organ donor pulmonary arteries. Regions of initial organization and vascular remodeling were identified by a modified trichrome stain and by the presence of proliferating cell nuclear antigen (PCNA), a cell marker of proliferation. Staining for tissue-type PA antigen was low to undetectable in endothelial cells directly in contact with the fibrin-platelet thromboembolus and in areas in which the endothelial cell lining was replaced by cell growth into the thrombus. Urokinase-like PA (u-PA) expression was detected in mononuclear cells within the thrombus in the initial phase of thromboembolism and within cells migrating into the thrombus during the later stages of organization. PAI-1 expression was elevated in the monolayer of endothelial cells underlying the fresh platelet-fibrin thromboembolus and in a PCNA-positive cell population present between the pulmonary arterial intima and the thromboembolus that represents early organization. Increased expression of PAI-1 may play a role in inhibiting proteolysis and fostering the localization of the acute fibrin-platelet thrombus to the vascular wall, which is followed by the upregulation of u-PA in migrating cells during the reorganization process.

A reduced diffusing capacity for carbon monoxide (DCO) is common among patients with chronic thromboembolic pulmonary hypertension (CTEPH) and often persists for more than a year following successful pulmonary thromboendarterectomy (PTE). To determine the relative contribution the pulmonary membrane diffusing capacity (DM) and pulmonary capillary blood volume (VC) make to the reduction in DCO, we measured both in 29 patients with CTEPH before and approximately 3 weeks after PTE. Mean preoperative DM was reduced in patients with CTEPH (28 mL min-1 mm Hg-1 vs 43 mL min-1 mm Hg-1 in control subjects; p0.001) and dropped significantly following PTE (21 mL min-1 mm Hg-1; p0.001). Mean preoperative VC was mildly reduced in the CTEPH group compared with healthy control subjects (57 vs 67 mL; p = 0.044) and did not rise following PTE (57 mL pre-PTE vs 54 mL post-PTE; p0.05) despite substantial reduction in mean pulmonary artery pressure and increase in cardiac output after surgery. We conclude that the low DCO observed in patients with CTEPH before and after PTE is principally caused by a reduced DM and to a lesser extent by a low VC. The mechanisms responsible remain speculative but may reflect pathophysiologic changes in the pulmonary microcirculation caused by chronic pulmonary hypertension that did not improve in the postoperative period studied.

The characteristics and postoperative outcomes of a unique group of eleven patients with total unilateral pulmonary artery (PA) thromboembolic occlusion were compared with those of some 400 patients who underwent bilateral thromboendarterectomies during the same time period. Preoperative historical, physical, and laboratory features and postoperative outcomes of these two groups were analyzed. The unilateral group had no distinct historical features. However, they were younger (32 +/- 10 yr) than the bilateral group (51 +/- 15 yr), dominantly female (10 of 11) versus a male predominance (62%) in the bilateral group; had significantly lower preoperative PA mean pressures (30 +/- 12 versus 46 +/- 12 mm Hg) and calculated pulmonary vascular resistance (360 +/- 293 versus 901 +/- 467 dynes/s/cm-5); and small lung by chest radiograph was common (8 of 11). Postoperatively, four unilateral patients developed unilateral rethrombosis (two immediate; two late, at several years postsurgery); this occurred in only one bilateral patient. Furthermore, of six patients with unilateral occlusion present more than 1 yr, reperfusion was poor in four despite an adequate thromboendarterectomy in all. Postoperative pulmonary angiograms in two of these disclosed apparent atrophy of central and distal pulmonary arteries. Prior animal investigation models indicate that unilateral PA occlusion is followed by development of a postobstructive arteriopathy in the resistance arteries of the occluded lung. The unusual outcomes in these 11 patients suggest that they may develop a similar arteriopathy which requires special management considerations at surgery and postoperatively.

Chronic obstruction of pulmonary arteries can be due to a variety of disease processes, including chronic thromboembolic disease, fibrosing mediastinitis, or neoplasia. Large vessel arteritis is another unusual cause of pulmonary artery obstruction and can be difficult to distinguish from the above-listed etiologies. We present four patients referred to our institution with the provisional diagnosis of chronic thromboembolic pulmonary hypertension who were subsequently diagnosed with Takayasu's arteritis involving the pulmonary arteries. We review the historical, physical examination, and radiologic characteristics that help distinguish Takayasu's arteritis from chronic thromboembolic disease.

All doctors with patients suspected of having an acute deep venous thrombosis or a pulmonary embolism would love a diagnostic magic bullet. They long for a test that would rule in or rule out the diagnosis of venous thromboembolism with a high degree of certainty. Ideally, such a test would be rapid, non-invasive, and widely available. The search for a reliable test has continued because the clinical diagnosis of thromboembolism is neither sensitive nor specific. Neither symptoms nor examination of the legs are reliable; nor can clinical signs or symptoms define the presence or absence of pulmonary embolism. Clinical signs and symptoms can only suggest these diagnoses—and asymptomatic venous thrombosis and pulmonary embolism are both fairly common. Not surprisingly, then, over the years a succession of simple, relatively non-invasive tests has been explored. Blood tests have included measurement of the “diagnostic” triad of lactic dehydrogenase, bilirubin, and glutamic oxaloacetic transaminase; immunoglobulin E1; …

BACKGROUND The brisk fibrinolytic response of canines has impaired efforts to develop a canine model of chronic thromboembolic pulmonary hypertension. Difficulties in retaining chronic embolic residuals were partially overcome by administration of tranexamic acid (TXA) (Circulation. 1991;83:1272-1279.). In this study, we used type 1 plasminogen activator inhibitor (PAI-1), a major inhibitor of the endogenous fibrinolytic system, to determine its efficacy in the suppression of thrombolysis in canines. METHODS AND RESULTS Thrombus was induced in the inferior vena cava of anesthetized mongrel dogs with thrombin and a special double-balloon catheter; 2 hours later, the thrombus was embolized. In one group of dogs, activated type 1 plasminogen activator inhibitor (PAI-1) (130 micrograms) was delivered directly into the forming thrombus; in another, TXA (110 mg/kg) was given intravenously before thrombus formation; in controls, thrombus was induced without inhibitors. Cross-linked fibrin degradation product (D-dimer) appeared in the blood of control animals within 1 hour of thrombus induction (176 +/- 62.5 versus 1.02 +/- 0.39 ng/mL baseline; mean +/- SEM), was maximal by 4 hours (413 +/- 110 ng/mL) and remained elevated at 24 hours (90.8 +/- 19.5 ng/mL). Compared with controls, PAI-1 and TXA suppressed D-dimer release by 80% and 85%, respectively, over the first 24 hours. One week later, animals were killed, and residual emboli were harvested. Perfusion scan defects persisted in all animals at this time, but there were no scan defect differences among groups. However, emboli recovered from animals receiving PAI-1 still harbored immunoreactive PAI-1 and were, on average, more than twofold greater in mass (393 +/- 56 mg) than emboli recovered from either controls (183 +/- 76 mg) or animals receiving TXA (180 +/- 80 mg). CONCLUSIONS Intravenous TXA and intrathrombus PAI-1 effectively suppress thrombolysis for 24 hours in canines. Thromboemboli enriched with PAI-1 appear to resist lysis for longer periods of time (up to 1 week). These findings are consistent with the hypothesis that PAI-1 remains associated with the embolus, where it continues to inhibit lysis, whereas TXA eventually diffuses out of the embolus, allowing lysis to ensue.

PURPOSE: To study the relationship of regional hypoperfusion and areas of decreased lung attenuation on computed tomographic (CT) scans of patients with chronic pulmonary thromboembolism. MATERIALS AND METHODS: Preoperative CT scans of five patients (four men and one woman, aged 29-72 years) with chronic pulmonary thromboembolism were reviewed and compared with axial single photon emission CT (SPECT) perfusion scans obtained at similar levels. Regions of varying attenuation and perfusion were scored on a three-point scale. RESULTS: In the five patients, 198 regions were identified. Of 176 abnormal regions at SPECT, 133 were abnormal at CT (sensitivity, 75.6%). Eleven of 22 regions interpreted as normal at SPECT were judged to have normal attenuation at CT (specificity, 50%). The overall accuracy of CT for detecting areas of hypoperfusion was 72.7% (P = .011). CONCLUSION: A mosaic pattern of lung attenuation at CT is a sign of variable regional perfusion and may suggest chronic pulmonary thromboembolism as...

BACKGROUND Numerous investigators have observed that pulmonary emboli are rapidly lysed in a canine model system. This study was undertaken to delineate the unique mechanism that accounts for the rapid dissolution of pulmonary emboli in mongrel dogs. METHODS AND RESULTS Canine plasminogen activator (PA) activity (2.6 +/- 1.1 IU/mL acidified platelet-poor plasma [PPP], < 0.3 IU/mL acidified whole blood serum [WBS], mean +/- SD; n = 6) and PA inhibitor activity (6.1 +/- 2.6 U/mL PPP, 35.4 +/- 7.8 U/mL WBS; n = 6) were determined in standard plasminogen-based chromogenic assays. Analysis of canine PPP, WBS, platelet lysates, and primary canine endothelial cell (EC) cultures by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fibrin autography revealed a plasminogen-dependent lytic zone at 45-kd relative molecular mass that was shown to be related to urokinase-type PA (u-PA) by its selective inhibition through amiloride. Analysis of canine platelets on standard 125I fibrin plate assays revealed a net fibrinolytic activity. In a clot lysis assay system, canine platelets were able to stimulate fibrinolysis when layered on the outside of fibrin clots containing autologous PPP. Moreover, net fibrinolytic activity of primary canine pulmonary artery endothelial cells was higher than the activities expressed by canine aortic or carotid artery endothelial cells. CONCLUSIONS Rapid lysis of pulmonary emboli in mongrel dogs appears to be a result of 1) the high u-PA activity in canine PPP and 2) the predominant association of u-PA activity with canine platelets and canine pulmonary artery endothelial cells.

The status of small pulmonary arteries may influence diagnosis, surgical selection and postoperative outcome of patients with chronic major vessel thromboembolic pulmonary hypertension (CTEPH). Therefore, in patients with the established diagnosis of CTEPH, lung tissue was obtained by biopsy (15 patients) or at autopsy (16 patients) to assess the histopathologic composition of small pulmonary arteries. Pathologic examination disclosed the full range of pulmonary hypertensive lesions in the small arteries, including plexogenic lesions. The type and extent of hypertensive lesions did not relate to preoperative hemodynamic values, to patient age, or to symptom duration. The findings indicate that primary pulmonary hypertension cannot be differentiated from potentially correctable CTEPH on the basis of histopathologic findings in small pulmonary arteries. Furthermore, none of the histologic findings preclude a positive hemodynamic and clinical result from pulmonary thromboendarterectomy. However, development of these hypertensive changes may explain the deterioration which these patients experience preoperatively over time.

BACKGROUND Chronic thromboembolic pulmonary hypertension (CTEPH) is a disorder characterized by pulmonary arterial hypertension as a consequence of organized thrombotic material in the central pulmonary arteries. Incomplete resolution of acute pulmonary emboli is believed to be pathogenically important; however, the mechanism for poor thrombus dissolution remains to be explained. We undertook this study to assess the major determinants of plasma fibrinolysis in patients with CTEPH (n = 32). METHODS AND RESULTS Immunological and functional levels of tissue-type plasminogen activator (t-PA) and type 1 plasminogen activator inhibitor (PAI-1) were quantified in platelet-poor plasma (PPP) from patients with CTEPH as well as age-matched controls. Although basal PPP t-PA antigen levels (CTEPH mean, 29.5 ng/ml; control mean, 2.7 ng/ml) and PAI-1 antigen levels (CTEPH mean, 55.8 ng/ml; control mean, 21.0 ng/ml) were higher in the CTEPH group, no between-group differences were detected in the enzymatic activities of these two molecules. The CTEPH group demonstrated a greater rise in t-PA antigen (CTEPH mean rise, 53.0 ng/ml; control mean rise, 5.6 ng/ml) and PA activity (CTEPH mean rise, 10.5 IU/ml; control mean rise, 1.2 IU/ml) than controls in response to an experimentally induced venous occlusion. Immunoprecipitation and fibrin autography of PPP from two patients with markedly elevated basal t-PA antigen levels demonstrate that the t-PA antigen was present in PPP primarily in complex with PAI-1. CONCLUSIONS Although abnormalities of the fibrinolytic system were detected, neither a high resting plasma PAI-1 activity nor a blunted response of t-PA to venous occlusion can be invoked as an etiology for CTEPH

BACKGROUND Many questions remain regarding the pathogenesis, natural history, diagnosis, and treatment of chronic thromboembolic pulmonary hypertension in patients. To answer such questions, we developed an animal model of this disorder. The brisk thrombolytic response of canines to acute embolism has, previously, prevented the establishment of such a model. METHODS AND RESULTS The fibrinolytic inhibitor tranexamic acid was given orally to canines before, and for intervals after, pulmonary emboli were released from venous thrombi formed in vivo in femoral veins or the inferior vena cava. Preliminary studies disclosed that embolic residuals from femoral vein thrombi were not sufficient to cause significant, persistent pulmonary hypertension. With repetitive, larger thrombi embolized from the inferior vena cava, however, persistent pulmonary hypertension was achieved in most animals. CONCLUSIONS Resolution of emboli in the canine can be inhibited by tranexamic acid. As in humans, a spectrum of embolic residuals is encountered, and the perfusion lung scan consistently underestimates the extent of embolic residuals. Studies of this animal model continue.

Pulmonary thromboendarterectomy is now the treatment of choice for pulmonary hypertension due to chronic pulmonary thromboemboli. A precise assessment of location and extension of these thrombi is important because only proximal chronic pulmonary thromboemboli are accessible to surgery. Because intravascular ultrasound imaging can assess not only arterial luminal size, but also wall thickness, its value as a complement to angiography was assessed in 11 patients aged 35 to 64 years with severe pulmonary hypertension (systolic pulmonary artery pressure, mean ± standard deviation 70 ± 19 mm Hg; pulmonary artery resistance, 609 ± 297 dynes·s· cm −5 ). Intravascular ultrasound was obtained in 10 of 11 patients and no complication occurred. Intravascular ultrasound identified 10 segments with suspected chronic pulmonary thromboemboli in 7 patients, all confirmed at operation. Nine segments were considered normal, all of which (except 1) were free of chronic pulmonary thromboemboli at operation. Image quality was highly dependent on pulmonary artery size and position of the catheter. Therefore, intravascular ultrasound of pulmonary arteries is feasible and safe in patients with pulmonary hypertension. It may help to assess the location and extension of the pathologic process involving pulmonary arteries.

To map global epicardial repolarization patterns and test the "SI" model of T wave generation, the patterns of epicardial activation and repolarization in patients with chronic pulmonary thromboembolism and right ventricular hypertrophy were studied by computerized mapping techniques and monophasic action potential (MAP) recording. The ventricular activation patterns were characterized by delayed right ventricular activation and the absence of normal early epicardial ventricular breakthrough in some cases. The repolarization patterns were characterized by nonuniform distribution of T wave morphologies. The T waves were predominantly positive over the left ventricular epicardium and negative or biphasic over the right ventricular epicardium. The activation-recovery (A-R) intervals were measured from the local activation to the maximal dV/dt of the upstroke of the T waves (Wyatt method). The difference between the A-R intervals and the MAP from onset of activation to 90% repolarization (MAP90) varies according to T wave morphology and could be as high as 96 msec with positive T waves, despite significant correlations (r = 0.56-0.90) between MAP90 and A-R intervals for each morphology. Better overall correlations were found if the minimal dV/dt on the downslope of the positive T waves was chosen to estimate the time of local repolarization (alternative method). Using this method, the mean A-R intervals were the same over the right and left ventricles. Cardiopulmonary bypass significantly prolonged the action potential duration equally at all parts of the epicardium. We conclude that in patients with right ventricular hypertrophy, the time of local repolarization can be estimated by our alternative method; the right ventricle completes activation and repolarization later than the left ventricle, and the distribution of T wave morphologies is nonuniform, with predominantly positive T waves observed over the left ventricle and negative or biphasic T waves observed over the right ventricle. These findings are compatible with the SI model of the generation of T waves.

After pulmonary thromboendarterectomy, performed for relief of chronic thromboembolic pulmonary hypertension, perfusion lung scans have frequently disclosed new perfusion defects in segments served by undissected pulmonary arteries. Our hypotheses were that these new postoperative defects occurred with great frequency and did not represent postoperative vessel occlusion. We retrospectively reviewed the preoperative and postoperative perfusion scans of 33 consecutive patients undergoing pulmonary thromboendarterectomy. New postoperative perfusion defects were noted in 23 of 33 patients. The incidence of new defects was increased tenfold in segments that had (1) normal preoperative angiographic findings, (2) normal preoperative radionuclide perfusion, and (3) not been entered at the time of surgery. Postoperative angiograms, available in 15 of 33 patients, documented the nonembolic, nonocclusive nature of the new perfusion scan defects. The most plausible alternate explanation for this previously undescribed finding is a redistribution of pulmonary arterial resistance induced by the thromboendarterectomy, namely, a pulmonary vascular "steal."

Thromboendarterectomy is the treatment of choice for chronic large vessel thromboembolic pulmonary hypertension. To identify the mechanisms responsible for the improvement in gas exchange following thromboendarterectomy, we studied nine patients with chronic thromboembolic pulmonary hypertension before and eight to 18 months after surgery using the multiple inert gas elimination technique. Preoperatively, all subjects had pulmonary hypertension and were hypoxemic or had an elevated P(A-a)O 2 . The V · A / Q · distribution was widened with an elevated V D /V T and a low cardiac index. After thromboendarterectomy, significant improvement had occurred. The V · A / Q · distribution had narrowed to near normal, and the cardiac index increased. It was concluded that thromboendarterectomy improved gas exchange both by improving V · A / Q · relationships and by increasing cardiac output.

Some patients with chronic pulmonary embolism causing severely symptomatic pulmonary hypertension have been managed by heart-lung transplantation with an associated hospital mortality of 24%. To allow comparison with pulmonary thromboendarterectomy (PTE), we have reviewed the hospital morbidity and mortality in 149 consecutive patients. From 1 October 1984 to 18 September 1989, these patients underwent PTE utilizing a standardized procedure consisting of median sternotomy, cardiopulmonary bypass, deep hypothermia and circulatory arrest for bilateral PTE in 91% (136/149) of the procedures with 7.4% (11/149) and 1.3% (2/149) undergoing right or left PTE, respectively. Ventilator dependency (greater than or equal to 5 days on respirator) occurred in 28.3% (41/146). Hospital mortality (death within 30 days or in hospital) was 11.4% (17/149). The most common causes of death were respiratory and multiorgan failure, 10 (59% of deaths) and acute pulmonary hemorrhage, 3 (17% of deaths). We conclude that PTE with an operative mortality of half that of heart-lung transplantation (11.4% vs. 24%) should be the procedure of choice for significantly symptomatic chronic pulmonary embolism. Furthermore, the hazards of immunosuppression and chronic graft rejection are avoided.

Objective. —To determine the frequency of pulmonary embolism in patients admitted for treatment of deep venous thrombosis. Design. —An open, multicenter, dose-ranging study to assess the safety and pharmacokinetic characteristics of tissue-type plasminogen activator in deep venous thrombosis and pulmonary embolism. Perfusion and ventilation lung scans, chest roentgenograms, and venograms (in deep venous thrombosis) or pulmonary angiograms (in pulmonary embolism) were obtained before and 24 hours after inception of therapy. Heparin therapy was then administered. Settings. —Five tertiary-care hospitals. Patients. —All patients with suspected deep venous thrombosis or pulmonary embolism seen from August 1987 through November 1988 entered the study if they met inclusion criteria and if the diagnosis was confirmed by venogram (deep venous thrombosis) or pulmonary angiogram (pulmonary embolism). Interventions. —All patients received tissue-type plasminogen activator followed by intravenous heparin therapy. Main Outcome Measures. —The primary measure was the frequency of pulmonary embolism in patients with deep venous thrombosis who had no symptoms of pulmonary embolism. This was not the original purpose of the study but emerged as an important finding as the data were analyzed. Results. —Nearly 40% of patients with deep venous thrombosis who had no symptoms of pulmonary embolism had evidence of pulmonary embolism based on ventilation-perfusion scan and chest roentgenogram findings. Conclusions. —Because all of those considered to have embolism had so-called high-probability scan results, the frequency of embolism reported likely represents the minimum incidence of pulmonary embolism in patients with deep venous thrombosis who have no embolic symptoms. These data emphasize that venous thromboembolism is one disorder. ( JAMA . 1994;271:223-225)

There is widespread acceptance of the thesis that in a patient with suspected embolism, a normal perfusion lung scan excludes the diagnosis of acute pulmonary embolism. However, limited published data exist which validate this thesis. We have explored this question by longitudinal follow-up of 68 patients who were referred for lung scanning to rule out embolism and proved to have normal perfusion lung scans. Risk factors for venous thromboembolism among these patients were similar to those reported in prior series of patients with pulmonary embolism. Our data support the widely-held views that: 1) a normal perfusion lung scan excludes the diagnosis of clinically significant pulmonary emboli; 2) the diagnostic work-up for suspected pulmonary embolism need not extend beyond a normal perfusion scan; 3) anticoagulant therapy can be discontinued after a normal perfusion scan, except in the presence of documented venous thrombosis; and 4) a normal lung scan has the same value in ruling out embolism in man as does a normal pulmonary angiogram.

Pulmonary thromboendarterectomy is an innovative surgical technique for treating pulmonary hypertension caused by chronic thromboembolism. The procedure uses cardiopulmonary bypass but necessitates dramatically longer bypass times than coronary artery bypass grafting or valve operations. We prospectively evaluated 22 patients undergoing pulmonary thromboendarterectomy to determine the incidence of delirium and its relationship to certain preoperative and postoperative medical variables as well as to duration of cardiopulmonary bypass, deep hypothermia, and circulatory arrest. Delirium occurred in 77% of patients with a peak incidence around 72 hours postoperatively. No preoperative or postoperative medical variable distinguished delirious from nondelirious patients. Total bypass time was not associated with delirium, but deep hypothermia time and total circulatory arrest time were both strongly associated. Overall prediction of delirium was 81% when total circulatory arrest time was considered. Further analysis suggested that a total circulatory arrest time greater than 55 minutes was both sensitive to (82%) and specific for (80%) delirium. Implications for the mechanism of postcardiotomy delirium and future research directions are discussed.

Major vessel chronic thromboembolic pulmonary hypertension is potentially remediable by thromboendarterectomy. The diagnosis often has been delayed because a lung perfusion scan demonstrated modest defects thought to be incompatible with severe vascular obstruction. To define the relationships between perfusion scan abnormalities, angiographic findings, and hemodynamic data, we analyzed 25 consecutive patients with chronic major vessel thromboembolic pulmonary hypertension who subsequently underwent thromboendarterectomy. We found that the perfusion lung scan consistently caused us to underestimate the severity of pulmonary arterial obstruction as defined by pulmonary angiography. Furthermore, there was no significant correlation between the severity of hemodynamic compromise and the extent of obstruction defined by perfusion scan or angiogram. These findings suggest that, when pulmonary hypertension is known or suspected, the diagnosis of correctable, chronic major vessel obstruction should be pursued by angiography and hemodynamic assessment even though the perfusion scan may demonstrate only two segmental defects.

Fifteen dogs were studied by perfusion scan, angioscopy and autopsy. In 10, emboli were formed in leg veins and released before study; five dogs were not embolized and served as controls. In controls, angioscopy disclosed no emboli, perfusion scans were normal after angioscopy and autopsy disclosed no emboli. Among the embolized dogs, 23 emboli were identified at autopsy. Perfusion scans disclosed 23 defects, but in three dogs there was a disparity between scan and autopsy localization. Angioscopy identified 21 of the 23 autopsy-defined emboli and localized them correctly; two emboli in vessels less than 1 mm in diameter were not visualized. Angioscopy may provide a useful new approach in animal investigations of pulmonary embolism and perhaps, after additional study, in selected patients.

Failure of pulmonary emboli to undergo fibrinolytic resolution generates a small but significant patient population progressively disabled by hypoxemia, chronic pulmonary hypertension, and eventual right heart failure. Medical management of these patients has not been effective. In the few patients treated surgically, no clear picture has emerged regarding the most effective surgical approach or the late results. Four male patients with chronic pulmonary embolism were managed operatively. Extrapericardial dissection, cardiopulmonary bypass, deep hypothermia, and intermittent circulatory arrest were utilized to perform pulmonary thromboendarterectomy. All patients, ages 30 to 65 years, had had severe dyspnea with minimal exertion for 1 to 20 years. Angiograms showed 50% to 75% of the pulmonary vasculature to be occluded, with frequent involvement of the segmental arteries. Preoperative pulmonary pressures varied from 60/33 to 74/24 mm Hg. Pulmonary vascular resistance values ranged from 450 to 750 dynes-sec-cm-5. All patients survived the operative procedure. The eldest patient died 3 weeks postoperatively following an acute posteroseptal myocardial infarction. The remaining patients had a 20 to 50 mm Hg decrease in pulmonary systolic pressure with a 50% to 75% reduction in pulmonary vascular resistance. Neither static nor dynamic lung volumes were changed appreciably. Follow-up angiograms in all patients confirmed significant increase in pulmonary perfusion. Each patient had improvement in functional capacity; one is completely asymptomatic. The primary advantage of the surgical approach described is the more complete removal of distally located thrombofibrotic material. The late results suggest that this surgical approach should be considered in the management of patients disabled by chronic pulmonary embolism.

SUMMARY There is no question that a substantial risk of venous thrombosis, pulmonary embolism, and lethal pulmonary embolism exists among patients undergoing urologic surgery. Available prophylactic strategies should sharply reduce this risk. Acceptable treatment options exist for patients who develop thromboembolism despite, or in the absence of, prophylaxis. Accurate diagnosis, however, is essential in order to select the most appropriate option. Finally, it should be noted that in making judgments, the comments provided can offer only general guidelines for patients undergoing urologic surgery. Individual patients may have a particular constellation of circumstances that dictates a rational deviation in decision-making from these general guidelines. However, one pivotal decision from which there should be no deviation without extraordinarily special justification is that some form of prophylaxis for deep venous thrombosis should be offered to all patients undergoing major urologic surgical procedures.

Trauma patients are at exceedingly high risk for the development of deep venous thrombosis and pulmo nary embolism. The incidence, pathophysiology, diag nosis, prophylaxis, and therapy of deep venous throm bosis and pulmonary embolism in the trauma patient are reviewed. The type of injury, systemic pertubations, and enforced immobility are important factors in pathogenesis. Patients with lower extremity injuries and spine fractures with paraplegia appear to be at highest risk. Orthopedic devices used to treat these injuries of ten preclude the conventional noninvasive diagnostic modalities. Further, hemorrhagic risk often impacts the judgment regarding the use of prophylactic measures as well as the therapy once deep venous thrombosis is diagnosed. Better data regarding the incidence of ve nous thromboembolism and the applicability of existing diagnostic, prophylactic, and treatment approaches in this population are needed. Accidents are responsible for over 140,000 deaths and approximately 70 million nonfatal injuries an nually in the United States [1]. Most of the fatalities occur within hours of injury as a result of exsangui nation or a lethal head injury, but approximately 20% survive for days or weeks [2], usually in the intensive care unit. The primary causes of late death are sepsis and multiple-organ failure [2]. Increasing evidence, however, suggests that pulmonary embo lism (PE) is now becoming a leading cause of late death, especially in some high-risk groups [3-5]. The increase in the incidence of PE is due in part to improvements in trauma care, which have lowered the early mortality rate [6-8], leaving more patients at risk for late death. In addition, autopsy examina tions, used more frequently to audit trauma care systems [6,9], have documented an increase in clini cally unsuspected deep venous thrombosis (DVT) and PE. This review was prompted because of the appar ent increase in DVT and PE in the trauma popula tion, and because the trauma patient presents very difficult and unique problems compared with the nontrauma patient with regard to the diagnosis, prophylaxis, and treatment of these disorders. In this review, we address the incidence, pathophys iology, diagnosis, treatment, and prophylaxis of DVT and PE in the trauma patient. We do not con sider the entities of fat embolism or pulmonary microemboli as a cause of late pulmonary failure.

A case is reported of chronic massive thromboembolic occlusion of major pulmonary arterial branches successfully treated with embolectomy and endarterectomy. The historic features, physical signs and pathophysiologic alterations which form the basis for the diagnosis of this disorder are reviewed.

Ten patients with clinical-laboratory evidence suggesting extensive acute or chronic pulmonary thromoboembolism were studied by pulmonary photoscan and by utilizing radiolabeled macroaggregates of human serum albumin (R-MAA) and by angiographic technics. A high degree of correlation between the inactive areas of the radioscan and the nonperfused areas of the angiogram was noted. The radioscan accurately reflected the pattern of arteriolarcapillary blood flow, whereas the angiogram provided precise information regarding the pulmonary vascular anatomy. The two procedures should be considered complementary rather than competitive. Lung radioscanning was found to offer a readily available, safe, rapid and reliable screening technic for definition of nonperfused pulmonary areas. Problems in radioscan interpretation, including “false positives,” lack of anatomic precision and limitations of resolution are discussed. Such problems underscore the basic tenet that accurate evaluation of the radioscan requires that it be viewed in proper clinical context.

1.1. Cases are presented to illustrate sickle cell anemia and sickle variants complicated by pulmonary infarction which could not be explained on an embolic basis. Pulmonary thrombosis is postulated. 2.2. Physiologic mechanisms through which the sickling process may be intensified within the venous blood are discussed. 3.3. It is indicated that the pulmonary vascular bed, aside from being the passive receptor of intensely sickled venous blood, may be subject to intrapulmonary influences which tend to promote the development of thrombosis in situ and infarction. 4.4. Pathologic evidence regarding the occurrence of pulmonary thrombosis and infarction in sickle subjects is reviewed. 5.5. Cor pulmonale may be an ultimate consequence of such multiple recurrent infarctions. The necessity for increased cardiac output may be a contributory factor. 6.6. The importance of maintaining a high index of suspicion regarding this association between pulmonary infarction, cor pulmonale and the sickle states is stressed.

The time course and locus of radiolabelled fibrinogen (RLF) incorporation into venous thrombi were studied in dogs. Incorporation of radiolabelled fibrinogen (RLF) into fresh venous thrombi induced in vivo was studied by serial autoradiography, well-counting and surface counting. Autoradiographs disclosed diffuse incorporation of RLF into thrombi formed before and after RLF injection. Well-counting data also reflected thrombus RLF accumulation in both instances, although this accumulation was discernible earlier in thrombi induced in the presence of circulating RLF. Thrombi induced prior to RLF injection were detectable by surface counting after six hours. These studies support the potential value of RLF in detecting human venous thrombosis but also point out the limitations of the technique as well as questions which require clarification.