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Pulmonary thrombotic arteriopathy in patients with sickle cell disease.

Pulmonary complications are a major cause of morbidity and mortality in patients with sickle cell disease (SCD). Acute pulmonary complications consist of the acute chest syndrome that presents a differential diagnosis between pneumonia, pulmonary infarction, fat embolism from infarcted bone marrow, and parvovirus infection. (1-5) Chronic pulmonary complications are thought to be the result of repeated episodes of the acute chest syndrome and include pulmonary fibrosis, pulmonary hypertension (PH), and cor pulmonale. (6-8) Most deaths among SCD patients with chronic lung disease are the result of PH and cor pulmonale. (6, 9, 10)

The pathogenetic mechanisms underlying the PH in SCD are poorly understood. (6, 9, 10) It has been suggested that PH is the result of arterial occlusion secondary to pulmonary thromboemboli (PE) or in situ thrombosis, but it has been noted that the pathologic findings in SCD are often indistinguishable from those seen in primary PH. (7-11) Other possibilities include increased intravascular shear forces, as a result of the adherence of sickled erythrocytes or injury by free fatty acids released from infarcted bone marrow. Such factors may produce vasospasm and elevated pulmonary blood pressures with the subsequent development of hypertensive vascular changes. (10) The present study investigates the pulmonary pathology of patients dying with SCD. This study was undertaken to determine whether a pathologic analysis of the pulmonary arteries may discriminate between these pathophysiologic considerations and contribute to understanding the pathogenesis of PH in SCD.

MATERIALS AND METHODS

Autopsies were performed on 12 patients with SCD between 1991 and 2001 at the Department of Pathology, University of Mississippi Medical Center, Jackson. The clinical records of these patients were reviewed for the following information: age, sex, hemoglobin electrophoresis, and clinical complications of SCD, including stroke, acute chest syndrome, and bone pain crisis. Lungs were examined for pneumonia, fibrosis, and infarcts and for atherosclerosis, thrombi, and intraluminal fibrous webs in large pulmonary arteries. Hearts were examined for right ventricular hypertrophy. Right ventricular hypertrophy was diagnosed on the basis of gross autopsy findings when the right ventricle was more than 0.4 cm thick and there was notable thickening of the right ventricular trabecular muscles.

Six to 10 blocks of tissue from each lung were cut in a series of 4-[micro] m sections and stained with hematoxylin-eosin, Masson trichrome, and Verhoeff van Gieson stains. The pulmonary arteries were divided into elastic (>1000 [micro] m) and small muscular arteries (100 to 1000 [micro] m) on the basis of cross-sectional diameter. (12) The elastic arteries were examined for recent and organized thrombi and for atherosclerosis.

The muscular arteries were evaluated for the changes of PH, as described by Heath and Edwards, (13) and for a thrombotic arteriopathy as defined by Katzenstein. (12) Fat emboli were identified as intravascular marrow fragments containing fat cells causing luminal occlusion or the distension of arterioles and alveolar capillaries by large clear fat vacuoles.

Immunohistochemical stains were performed to evaluate the cellular components of fresh and organizing small artery thrombi. The antibodies employed were the endothelial markers factor VIII-related antigen (Signet Laboratories, Dedham, Mass) and CD34 (BioGenex, San Ramon, Calif); smooth muscle-specific [alpha]-actin (Dako Corporation, Carpinteria, Calif); and inflammatory cell markers myeloperoxidase (Dako), leukocyte common antigen (Ventana Medical Systems Inc, Tucson, Ariz), and CD68 (Dako) for macrophages. Immunostaining was performed using the Ventana 320 automated immunostainer using biotinylated secondary antibodies followed by avidin-peroxidase. Color was developed using diaminobenzidine as substrate. Negative controls consisted of the SCD lung sections with the primary antibody omitted.

RESULTS

The clinical and pathologic findings of this study are summarized in the Table. The ages of the patients ranged from 8 to 47 years (mean 27 years). There were 7 males and 5 females. Nine patients had homozygous hemoglobin SS (HbSS) disease and 3 had sickle cell and hemoglobin C (HbSC) disease. Eleven patients had episodes of pain crisis before death, and 10 died at the time of a pain crisis. A clinical diagnosis of PH was made in 1 patient (patient 1). One patient (patient 7) was diagnosed as having PE after hip replacement surgery several months prior to death, but evidence for deep leg vein thrombosis was not investigated clinically. Four patients were diagnosed clinically as having an acute chest syndrome.

Six patients had recent or organized thrombi in the proximal elastic pulmonary arteries (Figure 1). Only 2 patients in this group had an acute chest syndrome, and none were clinically diagnosed as having PE. Deep leg vein thrombosis was found at autopsy in the 1 patient (patient 6)in whom it was investigated. In all patients with elastic artery thrombi, widespread recent and organized thrombi or organized thrombi alone were found in small muscular arteries (Figure 2). Concentric intimal fibrosis was present in the small arteries of 5 of these patients (Figure 3). Pulmonary infarcts were found in 4 patients with large artery thrombi. Wedge-shaped areas of sub-pleural pulmonary fibrosis from scarred infarcts were observed in 4 patients, all of whom had large artery thrombi (Figure 4).

[FIGURE 1-4 OMITTED]

Of the 6 patients who did not have thrombi in elastic pulmonary arteries, 3 had widespread recent and organized thrombi in small muscular arteries (Figure 5). These 3 patients also had concentric intimal hyperplasia of the small arteries. Plexiform-like lesions and fibrinoid necrosis were found at branch points of a few small arteries in 1 of these 3 cases (case 9) (Figure 6). In this clinical setting, the plexiform-like lesions could not be clearly discriminated from recanalized thrombi, (14) therefore they were not regarded as being identical to the plexiform lesions of primary PH. Two of the patients with small artery thrombi, including the patient with plexiform-like lesions, showed extensive intravascular sickling and alveolar wall necrosis (Figure 7). This alveolar wall necrosis was different from pulmonary infarcts in that it was patchy and multicentric rather than wedge-shaped and subpleural. Patient 7, who was diagnosed clinically as having postoperative PE, did not have large artery thrombi at autopsy. In cases with thrombi in muscular pulmonary arteries, including those with large artery thrombi, sickled erythrocytes were frequently enmeshed in and adherent to the small arterial thrombi.

[FIGURE 5-7 OMITTED]

Three of the patients who did not have large artery thrombi also did not have hypertensive changes or thrombi in muscular arteries. In one of these patients, there was extensive pulmonary intravascular sickling that was associated clinically with a pain crisis, but there was no necrosis of alveolar walls, no fat emboli, and no discernible pathology other than a marked collection of sickled erythrocytes in the lung vasculature.

Right ventricular hypertrophy was seen in 9 patients (Figure 8), including the 6 patients with large artery thrombi and the 3 patients with only small artery thrombi. The patients who did not have any pulmonary arterial thrombi did not have right ventricular hypertrophy. Fat emboli were found in a few small muscular arteries or arterioles in 4 of the 12 patients. In patient 2, who had large artery thrombi, fat emboli containing the cellular elements of bone marrow were widespread and were found in small arteries and arterioles in which there were fresh thrombi (Figure 9). Fresh thrombi associated with erythrocyte sickling or fat emboli showed large numbers of myeloperoxidase-, CD45-, and CD68-positive inflammatory cells enmeshed in and surrounding the developing thrombus (Figure 10). Organized thrombi showed recanalized vessels lined by factor VIII-related antigen- and CD34-positive cells, and proliferative fibrointimal tissue containing smooth muscle actin-positive cells. CD45-positive cells were rarely present, and CD68-positive cells were not seen in organized thrombi.

[FIGURE 8-10 OMITTED]

COMMENT

The most common finding among these SCD cases was a thrombotic arteriopathy of small pulmonary arteries. Such arteriopathy was found in 9 of the 12 autopsies and consisted of widespread recent or organized thrombi, eccentric intimal fibrosis, multiple recanalized lumina, or intravascular webs. (12) All patients with this thrombotic arteriopathy had right ventricular hypertrophy, and the small arterial changes of PH were seen in 8 of the 9 cases.

The thrombi within large elastic pulmonary arteries are most certain to be PE and are designated as such throughout this article. Deep leg vein thrombosis as a source of PE was found in the 1 autopsy where it was sought. All of the 6 patients with PE had a small artery thrombotic arteriopathy. In addition to a thrombotic arteriopathy, all patients with PE had chronic cor pulmonale and hypertensive changes of small pulmonary arteries. This included 1 patient in whom only fresh thrombi were found in elastic arteries. These findings indicate that PE are likely to be a late complication of PH and cor pulmonale, and that the predominant cause of PH in patients with SCD is widespread small arterial thrombosis.

The small artery thrombi may be derived from recurrent small PE. Histologically, however, fresh thrombi in the small arteries commonly demonstrated sickled erythrocytes enmeshed within the fibrin of developing clots. Together with the absence of clinical histories suspicious of emboli, the findings suggest that rather than PE, the thrombotic arteriopathy is the result of in situ thrombosis promoted by erythrocyte sickling. (6,10,12) In 1 patient, who died in a pain crisis, fresh thrombi in small arteries contained fat emboli, providing evidence that in some cases the embolization of infarcted bone marrow causes the small artery thrombosis.

Our findings support the hypothesis of Powars et al, (6) who emphasized the local rather than the embolic nature of the process and proposed that the PH of SCD is caused primarily by an obstructive arteriopathy resulting from in situ thrombosis. This point of view was also held by Collins and Orringer, (7) who performed bilateral venograms on 2 SCD patients. Although old and recent PE were found in 1 case, the patient had severe small artery disease, and the authors thought that PE developed because of advanced cor pulmonale due to microvascular occlusion.

The pathogenetic mechanisms underlying the vascular occlusions are thought to be multifactorial and to be a long-term consequence of the sickling disorder. (11) The rigidity of the sickled erythrocytes and increased adherence of erythrocytes to each other and to endothelium have been considered principal factors leading to acute vasoocclusion. (11) The release into the lungs of free fatty acids from infarcted bone marrow is thought to be an additional cause of vascular damage. (11) Although 11 of our patients were in pain crisis prior to death, fat emboli associated with microvascular thrombosis extensive enough to have contributed to death were found in only 1 case. This would suggest that fat emboli are a relatively uncommon cause of the thrombotic arteriopathy. If, however, free fatty acids could initiate microvascular thrombosis in the absence of histologically demonstrable fat emboli, our method of study would make little contribution toward evaluating this pathophysiologic process.

Normal blood flow may be altered by other factors. Coagulation is activated in the microvasculature of SCD patients, and the cytokine activation of platelets and endothelium promotes clotting, vasoconstriction, and inflammatory cell adherence. (15) By immunohistochemistry, we find large numbers of inflammatory cells in the fresh thrombi associated with both fat emboli and erythrocyte sickling, which supports the concept that inflammatory cell adherence is important in the development of these acute lesions.

Only 1 of the patients in our study was clinically diagnosed as having PH, representing an underdiagnosis of PH in SCD patients that has been observed clinically. (6, 10) This underscores the fact that PH is silent until late in its course and frequently requires pulmonary arterial catheterization to be adequately evaluated. Less invasive techniques may also be used. By echocardiography, Sutton et al (10) evaluated right ventricular dysfunction in 60 patients with SCD as a means of diagnosing PH and found evidence for PH in 12 patients (20%), although it was suspected in only 6 (10%).

Chronic lung disease is reported in approximately 5% of patients with SCD. (6,7) It tends to occur in patients at an average age of 25 to 33 years and consists of perfusion and diffusion defects, indicating that pulmonary fibrosis as well as vascular occlusion contribute to the disorder. (6,7) The range and average age of the patients in our study were nearly identical to data reported in clinical series of sickle cell lung disease. We found that significant pulmonary fibrosis occurred only in patients with PE and that most of the areas of fibrosis were old infarcts.

While our study supports in situ small artery thrombosis as underlying the development of PH in SCD, it also shows that thromboemboli contribute substantially to the morbidity and mortality of chronic sickle cell lung disease. Autopsy studies, while valuable, usually capture this illness in its final stages and certainly do not unequivocally resolve the question of the role that thromboembolism may play in the initiation of PH. The definitive studies will probably require an investigation of PH earlier in its course. The evaluation of patients for deep vein thrombosis and pulmonary perfusion defects in the beginning stages of PH would help clarify whether PE or an in situ thrombotic arteriopathy is the cause of PH in SCD.
Summary of Clinical and Pathologic Findings in 12 Sickle Cell
Disease Patients *

 Age,
Case y/Sex Hb

With Large Artery Thrombi

1 8/M SS
2 34/M SC
3 47/M SC
4 15/F SS
5 21/M SS
6 46/F SS

Without Large Artery Thrombi

7 22/M SS
8 21/F SS
9 23/M SS
10 26/F SS
11 45/M SC
12 18/F SS

 Clinical
 Diagnosis at Other Clinical
Case Time of Death Diagnosis

With Large Artery Thrombi

1 Pain crisis, CVA, pulmonary
 CHF hypertension
2 Pain crisis Systemic
 hypertension
3 Pain crisis, Schizophrenia
 ACS
4 Pain crisis None
5 Pain crisis Cerebral palsy
6 Pain crisis, CVA, pneumonia
 ACS

Without Large Artery Thrombi

7 Pain crisis, Pulmonary
 ACS, CHF embolism
8 Pain crisis None
9 Pain crisis, None
 ACS, CHF
10 Pain crisis None
11 Septicemia, Pneumonia,
 DIC CVA
12 Pain crisis CVA

 RVT,
Case cm Elastic Arteries

With Large Artery Thrombi

1 0.8 Recent and
 organized
 thrombi,
 atherosclerosis
2 0.6 Recent and
 organized
 thrombi,
 atherosclerosis
3 0.5 Organized
 thrombi, fibrous
 webs,
 atherosclerosis
4 0.4 Recent and
 organized
 thrombi, fibrous
 webs
5 0.6 Recent thrombi
6 0.5 Recent and
 organized
 thrombi,
 atherosclerosis

Without Large Artery Thrombi

7 0.6 Atherosclerosis
8 0.5 No change
9 0.6 Atherosclerosis
10 0.3 No change
11 0.3 No change
12 0.3 No change

 Muscular Arteries
Case Hypertensive Thrombotic

With Large Artery Thrombi

1 Concentric intimal Organized thrombi,
 fibrosis luminal webs
2 Concentric intimal Recent and organized
 fibrosis thrombi
3 Concentric intimal Organized thrombi
 fibrosis
4 Concentric intimal Organized thrombi
 fibrosis
5 None Recent and organized
 thrombi
6 Concentric intimal Recent and organized
 fibrosis thrombi

Without Large Artery Thrombi

7 Concentric intimal Recent and organized
 fibrosis thrombi
8 Concentric intimal Recent and organized
 fibrosis thrombi
9 Concentric intimal Recent and organized
 fibrosis, thrombi
 plexiform-like
 lesions, fibrinoid
 necrosis
10 Focal intimal None
 fibrosis
11 None None
12 None None

 Marrow Other Lung
Case Emboli Findings

With Large Artery Thrombi

1 No Infarct, fibrosis,
 edema, extensive
 sickling
2 Many Edema, infarct
3 No Fibrosis, pneumonia
4 No Edema, extensive
 sickling, fibrosis
5 No Infarct, edema
6 Rare Infarct, fibrosis,
 edema, pneumonia

Without Large Artery Thrombi

7 Rare Edema
8 No Edema, extensive
 sickling,
 alveolar wall
 necrosis,
 pneumonia
9 Rare Edema, extensive
 sickling,
 alveolar wall
 necrosis
10 No Extensive sickling
11 No Pneumonia
12 No Edema

* HbSS indicates homozygous hemoglobin SS; HbSC, sickle cell and
hemoglobin C; CHF, congestive heart failure; ACS, acute chest syndrome;
DIC, disseminated intravascular coagulation; CVA, ischemic stroke; and
RVT, right ventricular thickness.


Illustrations were prepared by John Coleman PhD, MD.

References

(1.) Kirkpatrick MB, Bass JB. Pulmonary complications in adults with sickle cell disease. Pulm Perspect. 1989;6:6-10.

(2.) Charache S, Scott JC, Charache P. Acute chest syndrome in adults with sickle cell anemia. Arch Intern Med. 1979;139:67-69.

(3.) Barrett-Conner E. Pneumonia and pulmonary infarction in sickle cell anemia. JAMA. 1973;244:997-1000.

(4.) Haynes J Jr, Allison RC. Pulmonary edema: complication in the management of sickle cell pain crisis. Am J Med. 1986;80:833-840.

(5.) Johnson CS, Verdgem TD. Pulmonary complications of SCD. Semin Respir Med. 1988;9:287-297.

(6.) Powars D, Weidman JA, Odom-Maryon T, Niland JC, Johnson C. Sickle cell chronic lung disease: prior morbidity and the risk of pulmonary failure. Medicine. 1988;67:66-76.

(7.) Collins FS, Orringer ER Pulmonary hypertension and cor pulmonale in sickle hemoglobinopathies. Am J Med. 1982;73:814-821.

(8.) Francis RB. Large vessel occlusions in sickle cell disease: pathogenesis, clinical consequences and therapeutic implications. Med Hypotheses. 1991;35:8895.

(9.) Gokhale S, Adegboyega P, Veasey S, Haque AK. Pulmonary changes in sickle cell hemoglobinopathy: an autopsy study. Mod Pathol. 2000;13:5A.

(10.) Sutton LL, Castro O, Cross DJ, Spencer JE, Lewis JF. Pulmonary hypertension in sickle cell disease. Am J Cardiol. 1994;74:626-628.

(11.) Weil JV, Castro O, Malik AB, Rodgers G, Bonds DR, Jacobs TP. Pathogenesis of lung disease in sickle hemoglobinopathies. Am Rev Respir Dis. 1993;148: 249-256.

(12.) Katzenstein AA. Pulmonary hypertension and other vascular disorders. In: Katzenstein and Askin's Surgical Pathology of Non-Neoplastic Lung Disease. 3rd ed. Philadelphia, Pa: WB Saunders Co; 1997:332-360: Major Problems in Pathology Vol 13.

(13.) Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease: a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation. 1958;18: 533-547.

(14.) Moser KM, Bloor CM. Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension. Chest. 1993; 103:685-692.

(15.) Francis RB, Johnson CS. Vascular occlusion in sickle cell disease: current concepts and unanswered questions. Blood. 1991;77:1405-1414.

Accepted for publication June 8, 2001.

From the Department of Pathology, University of Mississippi Medical Center, Jackson.

Presented at the annual meeting of the United States and Canadian Academy of Pathologists, Atlanta, Ga, March 5, 2001.

Reprints: Michael D. Hughson, MD, Department of Pathology, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216-4505 (e-mail: mhughson@pathology.umsmed.edu).
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No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2001 Gale, Cengage Learning. All rights reserved.

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Author:Adedeji, Moses O.; Cespedes, Julio; Allen, Kay; Subramony, Charu; Hughson, Michael D.
Publication:Archives of Pathology & Laboratory Medicine
Geographic Code:1USA
Date:Nov 1, 2001
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