Non-bacterial thrombotic endocarditis C L I N I C O P A T H O L O G I C CORRELATIONS
Ludwig M. Deppisch, M.D. A. Olusegun Fayemi, M.D.* New York, N. Y.
N o n b a c t e r i a l t h r o m b o t i c endocarditis ( N B T E ) is no longer considered merely a p o s t m o r t e m pathologic curiosity. R e c e n t emphasis has been affixed to the significant morbidity and m o r t a l i t y rates associated with this entity, mainly as a result of m a j o r arterial embolization from a cardiac valve t h r o m b u s . P r e m o r t e m clinical recognition has been stressed. 1-6 N B T E has been associated with a spectrum of u n d e r l y i n g diseases. 7, 8 However, it is seen most c o m m o n l y in patients with malignant neoplasms, p a r t i c u l a r l y adenocarcinomas. 1-4' ' M c K a y first associated N B T E with dissemin a t e d i n t r a v a s c u l a r coagulation (DIC). Infreq u e n t cases of N B T E , occurring in patients with DIC, have since been reported, b u t this relationship has received little emphasis. ~~ A retrospective clinicopathologic analysis was u n d e r t a k e n for all cases of N B T E diagnosed at a u t o p s y over a 10 year period at the M o u n t Sinai Hospital, New York City. A t t e n t i o n was focused u p o n (1) the distribution and clinical significance of peripheral organ thrombosis and infarction, (2) the diseases underlying N B T E , and (3) a b n o r m a l bleeding p a r a m e t e r s present and the relationship of N B T E with DIC. Materials and methods
T h e a u t o p s y files of the M o u n t Sinai Hospital for the 10 y e a r period 1965 to 1974 were examined From the Department of Pathology, Mount Sinai School of Medicine, New York, N. Y. Received for publication Sept. 9, 1975. Reprint requests: Ludwig M. Deppisch, M.D., Department of Laboratories, The Youngstown Hospital Association, Youngstown, Ohio 44501. *Present address: Department of Pathology, Holy Name Hospital, Teaneck, N: J. 07666.
December, 1976, Vol. 92, No. 6, pp. 723-729
to identify cases of N B T E . N B T E is the presence of a bland, fibrin-platelet t h r o m b u s upon a cardiac valve. Valve destruction or the presence of microorganisms within the t h r o m b u s indicated a diagnosis of infectious, r a t h e r t h a n nonbacterial, t h r o m b o t i c endocarditis. T h e p o s t m o r t e m diagnosis of N B T E was made in 102 cases. In 65, the diagnosis was confirmed upon review and b o t h pathologic material and clinical i n f o r m a t i o n were available for study. T h e histologic slides and the autopsy reports of all 65 cases were reviewed. Clinical information was derived from b o t h the hospital records and the clinical s u m m a r y t h a t forms a part of the p o s t m o r t e m record. Fibrin degradation products ( F D P ) were determined qualitatively by double-gel diffusion with antifibrinogen serum. Fibrinogen levels were determined by h e a t precipitation. Results Incidence. During the 10 y e a r period of s t u d y 4096 adult autopsies were performed in this institution. T h e incidence of N B T E in adult deaths is at least 1.6 per cent. Age and sex distribution. Of 65 patients with N B T E , 36 were men and 29 were women, ranging in age from 21 to 86 years; 50 patients were 50 years of age or older. Body habitus. Of 49 patients in whom a d e q u a t e description a b o u t nutritional state was available, 29 were cachectic or showed significant weight loss just prior to death. Eight patients were "obese." nine were "well nourished," one showed Cushingoid features, and two others were "thin." Primary diseases associated with NBTE. There were 51 patients with one or more malignant
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Table ]. S i t e s o f p r i m a r y n e o p l a s m in N B T E
Table lit. L o c a t i o n o f v e g e t a t i o n s in N B T E Location
Mitral
Aortic
Tricuspid
Pulmonary
Closure margin Free margin Nodule of Arantius Ventricular surface
17 5 -
10 5 5 2*
1 -1
---1"
NO. ~
Adenocarcinoma of pancreas Adenocarcinoma of colon Adenocarcinoma of lung Anaplastic carcinoma of lung Malignant melanoma Adenocarcinoma of prostate Adenocarcinoma of breast Adenocarcinoma of gall bladder Adenocarcinoma of unknown primary site Multiple myeloma
12 7 5 2 5 5 5 3 3 3
*Two patients each with transitional-cell carcinoma of urinary bladder, Hodgkin's disease. One patient each with gastric adenocarcinoma, hepatoma, hypemephroma, transitional-cell carcinoma of kidney, acute myelogenous leukemia, squamous-cell carcinoma of esophagus, malignant fibrous xanthoma.
Table It. F r e q u e n c y o f N B T E Neoplasm Adenocarcinoma of pancreas Multiple Myeloma Adenocarcinoma of prostate Adenocarcinoma of lung Hodgkin's disease Adenocarcinoma of colon Adenocarcinoma of breast Anaplastic carcinoma of lung Adenocarcinoma of stomach Leukemia Reticulum-cell sarcoma Lymphosarcoma Adenocarcinoma of ovary Glioblastoma Squamous carcinoma of lung
No. of cases 74 41 57 112 52 139 139 70 70 258 63 53 46 43 40
I
[ Frequency I (%) 16.2 7.3 7.0 4.5 3.9 3.6 2.8 2.8 1.4 0.4 0.0 0.0 0.0 0.0 0.0
n e o p l a s m s a t a u t o p s y . I n 10 p a t i e n t s t w o m a l i g n a n c i e s w e r e p r e s e n t . T a b l e I d e t a i l s t h e site a n d histologic type of the associated neoplasm. The f r e q u e n c y w i t h w h i c h N B T E is a s s o c i a t e d w i t h t h e s e t u m o r s a t a u t o p s y is l i s t e d ( T a b l e I I ) . I n c i d e n c e w a s d e t e r m i n e d o n l y for t h o s e t u m o r s o c c u r r i n g in 40 o r m o r e a u t o p s i e s . T h e g r e a t m a j o r i t y of a s s o c i a t e d n e o p l a s m s w e r e a d e n o c a r cinomas. Pancreatic adenocarcinoma showed the h i g h e s t i n c i d e n c e (16.2 p e r c e n t ) , w h i c h w a s f o u r times that of pulmonary adenocarcinoma. Squam o u s - c e l l c a r c i n o m a o f a n y site, l e u k e m i a , n o n Hodgkin lymphoma, and sarcoma were rarely associated with NBTE. I n 14 p a t i e n t s , n o n e o p l a s m w a s d e m o n s t r a t e d . Four had systemic lupus erythematosus (SLE).
724
*As described in autopsy protocol. May refer to free or closure margin or elsewhere on the valve leaflet.
Table IV. I n c i d e n c e o f t h r o m b i a n d i n f a r c t i o n in patients with NBTE
Organ
Thrombi without infarction
Thrombi with infraction
Spleen Kidney Heart Liver Adrenal Pancreas Thyroid Esophagxls Lung (bronchial artery) Breast Colon Stomach Skin Prostate Lymph node Bladder Vagina
5 4 16 7 11 8 6 4 3 2 2 2 2 2 1 2 1
22 22 5 3 1 1 2 -
The gross and microscopic appearances of NBTE in t h e s e c a s e s fulfilled t h e c r i t e r i a for N B T E ; t h e specific s u b v a l v u l a r m i t r a l a n d t r i c u s p i d l e s i o n s of L i b m a n - S a c h s e n d o c a r d i t i s w e r e a b s e n t . T h e remaining patients had the following diagnoses: p o s t c a r d i a c v a l v u l a r r e p l a c e m e n t (2), c i r r h o s i s (2), o n e p a t i e n t e a c h w i t h v o l v u l u s , g a s g a n g r e n e , coronary artery-saphenous vein bypass, interstit i a l p n e u m o n i a , p e r f o r a t e d d u o d e n a l ulcer, a n d chronic renal failure. Location of NBTE. T h e m i t r a l v a l v e w a s i n v o l v e d in 25 p a t i e n t s (38 p e r c e n t ) a n d t h e a o r t i c in 20 (31 p e r c e n t ) . I n t h r e e a n d o n e p a t i e n t s , r e s p e c t i v e l y , t h e l e s i o n w a s l o c a t e d on t h e t r i c u s p i d a n d p u l m o n i c valves. B i v a l v u l a r i n v o l v e m e n t w a s n o t e d in 15 p a t i e n t s - a o r t i c a n d m i t r a l {12), m i t r a l a n d t r i c u s p i d (2), a o r t i c a n d t r i c u s p i d (1). T w o p a t i e n t s s h o w e d t r i v a l v u l a r lesions involving the tricuspid, mitral, and
December, 1976, Vol. 92, No. 6
Nonbacterial thrombotic endocarditis Table V. Clinicopathologic correlations of p a t i e n t s with N B T E and m y o c a r d i a l infarction Age~Sex
Primary disease
61/M
Urinary bladder carcinoma
29/M
Hodgkin's disease
59/M
Pancreatic and renal cell carcinoma (occult)
49/M
Carcinomaof breast
54/F
Adenocarcinomaof gallbladder
Symptomatology
[ Location of NBTE
ECG diagnosis: myo- Aortic valve cardial infarction; aortic ejection murmur; + LDH Jt SGOT Systolicmurmur at Mitral valve left sternal border; thrombocytopenia with bleeding; septic shock with acute renal failure Clinicaldiagnosis of Aortic and mitral NBTE; predomivalves nantly neurologic; bowel infarction with surgical resection SystolicmurAortic and mitral mur; +CVP; conges- valves tive heart failure; convulsions ECG diagnosis: myo- Tricuspid, mitral, and cardial infarction; pulmonic valves SGOT; alkaline phosphatase; predominantly neurologic
pulmonic or aortic valves. There was no p a t i e n t with q u a d r i v a l v u l a r lesions.
Distribution and size of vegetations. Most vegetations were located on the closure margin of the valves. I n 10 cases, however, the vegetations were situated on the free edge {Table III). Vegetations were f o u n d on the nodule of Arantius in 5 patients and on the ventricular surface of aortic (2), tricuspid (1), and pulmonic valves (1). Of 38 patients in which there was a d e q u a t e m e a s u r e m e n t of size of vegetations, 31 were less t h a n 5 mm. in diameter a n d 7 ranged in size from 5 to 10 mm. T h e r e was no vegetation larger t h a n 10 mm. D a t a relating to the n u m b e r of vegetations were available in 54 patients. Of these 38 had multiple vegetations, and 12 (22 per cent) single vegetations. F o u r patients had two isolated vegetations. T h e size and the n u m b e r of vegetations could n o t be correlated with the frequency or severity of t h r o m b o s i s in peripheral locations. Associated valvular disease. In most instances (53 patients) N B T E was f o u n d on grossly n o r m a l h e a r t valves. It was associated with probable chronic r h e u m a t i c valvulitis in 8 patients (mitral
American Heart Journal
Location of MI
Vessels occluded
Posterior wall, 3 cm. in diameter
Branches of left circumflex, 2.5 cm. long thrombus
Apex, up to 1.5 cm. in diameter
Intramyocardial
No gross description
Intramyocardial
Posterolateral wall near apex
Intramyocardial
Anterolateral
Intramyocardial
7, aortic 1). T h e valvular d a m a g e was slight in more t h a n half of these. N B T E was superimposed on atherosclerotic mitral valves in 2 patients. In 2 others, it was n o t e d on prosthetic aortic valves. In b o t h these patients the valvular vegetations were indistinguishable from N B T E in o t h e r cases and occurred 6 m o n t h s after the valve replacement. C a r d i a c m u r m u r . M u r m u r s were heard in 31 patients during t h e course of their illness. However, in only 8 patients did the m u r m u r exhibit a probable relationship to N B T E . In 1 case, the m u r m u r increased in intensity during hospitalization and led to a p r e m o r t e m diagnosis of N B T E . Arterial thrombosis. Table IV shows the a u t o p s y distribution of arterial thrombi, with and w i t h o u t associated organ infarction. Infarcts, usually of recent origin, were m o s t frequently f o u n d within the spleen and kidney. Microt h r o m b i were c o m m o n l y n o t e d within the adrenal, liver, and pancreas, b u t related ischemic necrosis was u n c o m m o n in these organs. I n t r a m y o c a r d i a l arterial thrombosis was n o t e d in 21 patients; in 5 the vascular occlusion was
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Deppisch and Fayemi
Table Vi. N e u r o p a t h o l o g y findings in N B T E
Positive Infarction Recent or acute Old Thrombosis Hemorrhage
19
Negative
17
11 7 2 3
VII. Incidence of venous patients with N B T E (30 patients) Table
Vein
Iliac Mesenteric Femoral Inferior vena cava Splenic Portal Ovarian Prostatic Subclavian Renal Coronary Hepatic Jugular Pulmonary Pancreatic Skin
thrombi
in
No. of cases
7 5 5 5 4 4 3 3 2 2 2 2 1 1 1 1
severe e n o u g h to cause myocardial infarction. P a t i e n t s in w h o m infarction was due to atherosclerotic vascular disease were excluded. T h e clinical and pathologic findings in these five patients are t a b u l a t e d in T a b l e V. Nineteen of 36 brains examined showed recent or old infarction, hemorrhage, or arterial t h r o m bosis (Table VI). All lesions possibly related to arteriosclerotic cerebrovascular disease were excluded. Neurologic findings were noted in 18 patients; these included focal or segmental m o t o r deficits, convulsions, and obtundation. M a j o r vessel thrombosis was clinically n o t e d in the femoral (2 patients), and in the superior mesenteric a r t e r y (1 patient). T h r o m b o e m b o l i s m within the p u l m o n a r y arteries was a frequent occurrence, noted at a u t o p s y in 37 cases. In 6 patients, the diagnosis of p u l m o n a r y t h r o m b o e m b o l i s m was suspected clinically. V e n o u s t h r o m b o s i s . Nine patients had clinical lower e x t r e m i t y thrombophlebitis. In 30 cases,
726
there was gross a u t o p s y evidence of venous thrombosis. T a b l e VII details the location of venous thrombosis. T h e iliac vein was m o s t f r e q u e n t l y involved, followed by the femoral vein, mesenteric veins, and inferior vena cava. Venous thrombosis was c o m m o n l y associated with malign a n t neoplasms a n d / o r disseminated intravascular coagulation. Hemorrhage. H e m o r r h a g e was a significant p o s t m o r t e m finding; it occurred in 25 cases. Sites of h e m o r r h a g e included the lungs (13 cases), spleen (10), gastrointestinal t r a c t (8), skin (4), renal pelvis (3), u r i n a r y bladder (2), e n d o m e t r i u m (2), o v a r y (2).
Disseminated intravascular coagulation (DIC). Twelve patients (18.5 per cent) with N B T E manifested l a b o r a t o r y and occasionally clinical evidence of DIC (Table VIII). A diagnosis of D I C was based on the presence of hypofibrinogenemia, significant prolongation of the p r o t h r o m b i n time and partial t h r o m b o p l a s t i n time, t h r o m b o c y t o p e nia, and d e m o n s t r a t i o n of fibrin/fibrinogen degradation products. Six of these patients showed venous thrombosis in various organs and in 9 patients clinical or pathologic evidence of bleeding was found. Malignant neoplasia constit u t e d the c o m m o n e s t underlying disease (8 patients). S L E was present in 2 others. Antem o r t e m diagnosis of N B T E was suggested in 3 of these patients.
Comment In the present study, underlying malignant neoplasm was present in the great majority of cases. It has been postulated t h a t N B T E occurring in association with malignant neoplasms might be related to a "hypercoagulable state.,,o .... 1 4 - 1 6 M a n y coagulation abnormalities have been found in patients with malignant neoplasms including hypofibrinogenemia, TM 18 hyperfibrinogenemia,1,. ~0 thrombocytopenia, decreased levels of factors V, VIII, and XIII, 11 and i m p a i r m e n t of platelet function by circulating fibrin degradation products. :1 It has been suggested t h a t the probable cause of intravascular coagulation is the presence of clotp r o m o t i n g substance derived from neoplastic cells. ~ Less studied, however, is the mechanism of D I C in nonneoplastic conditions. T h e mechanisms postulated for the induction of DIC in those cases include bacterial capsular antigens (through antigen-antibody complexes) ~2 and en-
December, 1976, Voll 92, No. 6
Nonbacterial thrombotic endocarditis
Table VIII. Clinical, pathological, and laboratory findings in patients with NBTE and DIC* Laboratory data
Primary disease
Age~sex
68/F 24/F 42/F
Carcinoma of pancreas SLE
Fibrinogen
FDP
P/T
PTT
14.6/11.6
--
46
100
-
13.6/13.8
67.4/56.2
70
38
-
-
-
32
50-100
-
17.0/12.5
-
100
150
-
17.0/11.0 13.4/11.8
78.0/51.0 62.0/50.0
63
Ludwig M. Deppisch, M.D. A. Olusegun Fayemi, M.D.* New York, N. Y.
N o n b a c t e r i a l t h r o m b o t i c endocarditis ( N B T E ) is no longer considered merely a p o s t m o r t e m pathologic curiosity. R e c e n t emphasis has been affixed to the significant morbidity and m o r t a l i t y rates associated with this entity, mainly as a result of m a j o r arterial embolization from a cardiac valve t h r o m b u s . P r e m o r t e m clinical recognition has been stressed. 1-6 N B T E has been associated with a spectrum of u n d e r l y i n g diseases. 7, 8 However, it is seen most c o m m o n l y in patients with malignant neoplasms, p a r t i c u l a r l y adenocarcinomas. 1-4' ' M c K a y first associated N B T E with dissemin a t e d i n t r a v a s c u l a r coagulation (DIC). Infreq u e n t cases of N B T E , occurring in patients with DIC, have since been reported, b u t this relationship has received little emphasis. ~~ A retrospective clinicopathologic analysis was u n d e r t a k e n for all cases of N B T E diagnosed at a u t o p s y over a 10 year period at the M o u n t Sinai Hospital, New York City. A t t e n t i o n was focused u p o n (1) the distribution and clinical significance of peripheral organ thrombosis and infarction, (2) the diseases underlying N B T E , and (3) a b n o r m a l bleeding p a r a m e t e r s present and the relationship of N B T E with DIC. Materials and methods
T h e a u t o p s y files of the M o u n t Sinai Hospital for the 10 y e a r period 1965 to 1974 were examined From the Department of Pathology, Mount Sinai School of Medicine, New York, N. Y. Received for publication Sept. 9, 1975. Reprint requests: Ludwig M. Deppisch, M.D., Department of Laboratories, The Youngstown Hospital Association, Youngstown, Ohio 44501. *Present address: Department of Pathology, Holy Name Hospital, Teaneck, N: J. 07666.
December, 1976, Vol. 92, No. 6, pp. 723-729
to identify cases of N B T E . N B T E is the presence of a bland, fibrin-platelet t h r o m b u s upon a cardiac valve. Valve destruction or the presence of microorganisms within the t h r o m b u s indicated a diagnosis of infectious, r a t h e r t h a n nonbacterial, t h r o m b o t i c endocarditis. T h e p o s t m o r t e m diagnosis of N B T E was made in 102 cases. In 65, the diagnosis was confirmed upon review and b o t h pathologic material and clinical i n f o r m a t i o n were available for study. T h e histologic slides and the autopsy reports of all 65 cases were reviewed. Clinical information was derived from b o t h the hospital records and the clinical s u m m a r y t h a t forms a part of the p o s t m o r t e m record. Fibrin degradation products ( F D P ) were determined qualitatively by double-gel diffusion with antifibrinogen serum. Fibrinogen levels were determined by h e a t precipitation. Results Incidence. During the 10 y e a r period of s t u d y 4096 adult autopsies were performed in this institution. T h e incidence of N B T E in adult deaths is at least 1.6 per cent. Age and sex distribution. Of 65 patients with N B T E , 36 were men and 29 were women, ranging in age from 21 to 86 years; 50 patients were 50 years of age or older. Body habitus. Of 49 patients in whom a d e q u a t e description a b o u t nutritional state was available, 29 were cachectic or showed significant weight loss just prior to death. Eight patients were "obese." nine were "well nourished," one showed Cushingoid features, and two others were "thin." Primary diseases associated with NBTE. There were 51 patients with one or more malignant
American H e a r t J o u r n a l
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Deppisch and Fayemi
Table ]. S i t e s o f p r i m a r y n e o p l a s m in N B T E
Table lit. L o c a t i o n o f v e g e t a t i o n s in N B T E Location
Mitral
Aortic
Tricuspid
Pulmonary
Closure margin Free margin Nodule of Arantius Ventricular surface
17 5 -
10 5 5 2*
1 -1
---1"
NO. ~
Adenocarcinoma of pancreas Adenocarcinoma of colon Adenocarcinoma of lung Anaplastic carcinoma of lung Malignant melanoma Adenocarcinoma of prostate Adenocarcinoma of breast Adenocarcinoma of gall bladder Adenocarcinoma of unknown primary site Multiple myeloma
12 7 5 2 5 5 5 3 3 3
*Two patients each with transitional-cell carcinoma of urinary bladder, Hodgkin's disease. One patient each with gastric adenocarcinoma, hepatoma, hypemephroma, transitional-cell carcinoma of kidney, acute myelogenous leukemia, squamous-cell carcinoma of esophagus, malignant fibrous xanthoma.
Table It. F r e q u e n c y o f N B T E Neoplasm Adenocarcinoma of pancreas Multiple Myeloma Adenocarcinoma of prostate Adenocarcinoma of lung Hodgkin's disease Adenocarcinoma of colon Adenocarcinoma of breast Anaplastic carcinoma of lung Adenocarcinoma of stomach Leukemia Reticulum-cell sarcoma Lymphosarcoma Adenocarcinoma of ovary Glioblastoma Squamous carcinoma of lung
No. of cases 74 41 57 112 52 139 139 70 70 258 63 53 46 43 40
I
[ Frequency I (%) 16.2 7.3 7.0 4.5 3.9 3.6 2.8 2.8 1.4 0.4 0.0 0.0 0.0 0.0 0.0
n e o p l a s m s a t a u t o p s y . I n 10 p a t i e n t s t w o m a l i g n a n c i e s w e r e p r e s e n t . T a b l e I d e t a i l s t h e site a n d histologic type of the associated neoplasm. The f r e q u e n c y w i t h w h i c h N B T E is a s s o c i a t e d w i t h t h e s e t u m o r s a t a u t o p s y is l i s t e d ( T a b l e I I ) . I n c i d e n c e w a s d e t e r m i n e d o n l y for t h o s e t u m o r s o c c u r r i n g in 40 o r m o r e a u t o p s i e s . T h e g r e a t m a j o r i t y of a s s o c i a t e d n e o p l a s m s w e r e a d e n o c a r cinomas. Pancreatic adenocarcinoma showed the h i g h e s t i n c i d e n c e (16.2 p e r c e n t ) , w h i c h w a s f o u r times that of pulmonary adenocarcinoma. Squam o u s - c e l l c a r c i n o m a o f a n y site, l e u k e m i a , n o n Hodgkin lymphoma, and sarcoma were rarely associated with NBTE. I n 14 p a t i e n t s , n o n e o p l a s m w a s d e m o n s t r a t e d . Four had systemic lupus erythematosus (SLE).
724
*As described in autopsy protocol. May refer to free or closure margin or elsewhere on the valve leaflet.
Table IV. I n c i d e n c e o f t h r o m b i a n d i n f a r c t i o n in patients with NBTE
Organ
Thrombi without infarction
Thrombi with infraction
Spleen Kidney Heart Liver Adrenal Pancreas Thyroid Esophagxls Lung (bronchial artery) Breast Colon Stomach Skin Prostate Lymph node Bladder Vagina
5 4 16 7 11 8 6 4 3 2 2 2 2 2 1 2 1
22 22 5 3 1 1 2 -
The gross and microscopic appearances of NBTE in t h e s e c a s e s fulfilled t h e c r i t e r i a for N B T E ; t h e specific s u b v a l v u l a r m i t r a l a n d t r i c u s p i d l e s i o n s of L i b m a n - S a c h s e n d o c a r d i t i s w e r e a b s e n t . T h e remaining patients had the following diagnoses: p o s t c a r d i a c v a l v u l a r r e p l a c e m e n t (2), c i r r h o s i s (2), o n e p a t i e n t e a c h w i t h v o l v u l u s , g a s g a n g r e n e , coronary artery-saphenous vein bypass, interstit i a l p n e u m o n i a , p e r f o r a t e d d u o d e n a l ulcer, a n d chronic renal failure. Location of NBTE. T h e m i t r a l v a l v e w a s i n v o l v e d in 25 p a t i e n t s (38 p e r c e n t ) a n d t h e a o r t i c in 20 (31 p e r c e n t ) . I n t h r e e a n d o n e p a t i e n t s , r e s p e c t i v e l y , t h e l e s i o n w a s l o c a t e d on t h e t r i c u s p i d a n d p u l m o n i c valves. B i v a l v u l a r i n v o l v e m e n t w a s n o t e d in 15 p a t i e n t s - a o r t i c a n d m i t r a l {12), m i t r a l a n d t r i c u s p i d (2), a o r t i c a n d t r i c u s p i d (1). T w o p a t i e n t s s h o w e d t r i v a l v u l a r lesions involving the tricuspid, mitral, and
December, 1976, Vol. 92, No. 6
Nonbacterial thrombotic endocarditis Table V. Clinicopathologic correlations of p a t i e n t s with N B T E and m y o c a r d i a l infarction Age~Sex
Primary disease
61/M
Urinary bladder carcinoma
29/M
Hodgkin's disease
59/M
Pancreatic and renal cell carcinoma (occult)
49/M
Carcinomaof breast
54/F
Adenocarcinomaof gallbladder
Symptomatology
[ Location of NBTE
ECG diagnosis: myo- Aortic valve cardial infarction; aortic ejection murmur; + LDH Jt SGOT Systolicmurmur at Mitral valve left sternal border; thrombocytopenia with bleeding; septic shock with acute renal failure Clinicaldiagnosis of Aortic and mitral NBTE; predomivalves nantly neurologic; bowel infarction with surgical resection SystolicmurAortic and mitral mur; +CVP; conges- valves tive heart failure; convulsions ECG diagnosis: myo- Tricuspid, mitral, and cardial infarction; pulmonic valves SGOT; alkaline phosphatase; predominantly neurologic
pulmonic or aortic valves. There was no p a t i e n t with q u a d r i v a l v u l a r lesions.
Distribution and size of vegetations. Most vegetations were located on the closure margin of the valves. I n 10 cases, however, the vegetations were situated on the free edge {Table III). Vegetations were f o u n d on the nodule of Arantius in 5 patients and on the ventricular surface of aortic (2), tricuspid (1), and pulmonic valves (1). Of 38 patients in which there was a d e q u a t e m e a s u r e m e n t of size of vegetations, 31 were less t h a n 5 mm. in diameter a n d 7 ranged in size from 5 to 10 mm. T h e r e was no vegetation larger t h a n 10 mm. D a t a relating to the n u m b e r of vegetations were available in 54 patients. Of these 38 had multiple vegetations, and 12 (22 per cent) single vegetations. F o u r patients had two isolated vegetations. T h e size and the n u m b e r of vegetations could n o t be correlated with the frequency or severity of t h r o m b o s i s in peripheral locations. Associated valvular disease. In most instances (53 patients) N B T E was f o u n d on grossly n o r m a l h e a r t valves. It was associated with probable chronic r h e u m a t i c valvulitis in 8 patients (mitral
American Heart Journal
Location of MI
Vessels occluded
Posterior wall, 3 cm. in diameter
Branches of left circumflex, 2.5 cm. long thrombus
Apex, up to 1.5 cm. in diameter
Intramyocardial
No gross description
Intramyocardial
Posterolateral wall near apex
Intramyocardial
Anterolateral
Intramyocardial
7, aortic 1). T h e valvular d a m a g e was slight in more t h a n half of these. N B T E was superimposed on atherosclerotic mitral valves in 2 patients. In 2 others, it was n o t e d on prosthetic aortic valves. In b o t h these patients the valvular vegetations were indistinguishable from N B T E in o t h e r cases and occurred 6 m o n t h s after the valve replacement. C a r d i a c m u r m u r . M u r m u r s were heard in 31 patients during t h e course of their illness. However, in only 8 patients did the m u r m u r exhibit a probable relationship to N B T E . In 1 case, the m u r m u r increased in intensity during hospitalization and led to a p r e m o r t e m diagnosis of N B T E . Arterial thrombosis. Table IV shows the a u t o p s y distribution of arterial thrombi, with and w i t h o u t associated organ infarction. Infarcts, usually of recent origin, were m o s t frequently f o u n d within the spleen and kidney. Microt h r o m b i were c o m m o n l y n o t e d within the adrenal, liver, and pancreas, b u t related ischemic necrosis was u n c o m m o n in these organs. I n t r a m y o c a r d i a l arterial thrombosis was n o t e d in 21 patients; in 5 the vascular occlusion was
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Deppisch and Fayemi
Table Vi. N e u r o p a t h o l o g y findings in N B T E
Positive Infarction Recent or acute Old Thrombosis Hemorrhage
19
Negative
17
11 7 2 3
VII. Incidence of venous patients with N B T E (30 patients) Table
Vein
Iliac Mesenteric Femoral Inferior vena cava Splenic Portal Ovarian Prostatic Subclavian Renal Coronary Hepatic Jugular Pulmonary Pancreatic Skin
thrombi
in
No. of cases
7 5 5 5 4 4 3 3 2 2 2 2 1 1 1 1
severe e n o u g h to cause myocardial infarction. P a t i e n t s in w h o m infarction was due to atherosclerotic vascular disease were excluded. T h e clinical and pathologic findings in these five patients are t a b u l a t e d in T a b l e V. Nineteen of 36 brains examined showed recent or old infarction, hemorrhage, or arterial t h r o m bosis (Table VI). All lesions possibly related to arteriosclerotic cerebrovascular disease were excluded. Neurologic findings were noted in 18 patients; these included focal or segmental m o t o r deficits, convulsions, and obtundation. M a j o r vessel thrombosis was clinically n o t e d in the femoral (2 patients), and in the superior mesenteric a r t e r y (1 patient). T h r o m b o e m b o l i s m within the p u l m o n a r y arteries was a frequent occurrence, noted at a u t o p s y in 37 cases. In 6 patients, the diagnosis of p u l m o n a r y t h r o m b o e m b o l i s m was suspected clinically. V e n o u s t h r o m b o s i s . Nine patients had clinical lower e x t r e m i t y thrombophlebitis. In 30 cases,
726
there was gross a u t o p s y evidence of venous thrombosis. T a b l e VII details the location of venous thrombosis. T h e iliac vein was m o s t f r e q u e n t l y involved, followed by the femoral vein, mesenteric veins, and inferior vena cava. Venous thrombosis was c o m m o n l y associated with malign a n t neoplasms a n d / o r disseminated intravascular coagulation. Hemorrhage. H e m o r r h a g e was a significant p o s t m o r t e m finding; it occurred in 25 cases. Sites of h e m o r r h a g e included the lungs (13 cases), spleen (10), gastrointestinal t r a c t (8), skin (4), renal pelvis (3), u r i n a r y bladder (2), e n d o m e t r i u m (2), o v a r y (2).
Disseminated intravascular coagulation (DIC). Twelve patients (18.5 per cent) with N B T E manifested l a b o r a t o r y and occasionally clinical evidence of DIC (Table VIII). A diagnosis of D I C was based on the presence of hypofibrinogenemia, significant prolongation of the p r o t h r o m b i n time and partial t h r o m b o p l a s t i n time, t h r o m b o c y t o p e nia, and d e m o n s t r a t i o n of fibrin/fibrinogen degradation products. Six of these patients showed venous thrombosis in various organs and in 9 patients clinical or pathologic evidence of bleeding was found. Malignant neoplasia constit u t e d the c o m m o n e s t underlying disease (8 patients). S L E was present in 2 others. Antem o r t e m diagnosis of N B T E was suggested in 3 of these patients.
Comment In the present study, underlying malignant neoplasm was present in the great majority of cases. It has been postulated t h a t N B T E occurring in association with malignant neoplasms might be related to a "hypercoagulable state.,,o .... 1 4 - 1 6 M a n y coagulation abnormalities have been found in patients with malignant neoplasms including hypofibrinogenemia, TM 18 hyperfibrinogenemia,1,. ~0 thrombocytopenia, decreased levels of factors V, VIII, and XIII, 11 and i m p a i r m e n t of platelet function by circulating fibrin degradation products. :1 It has been suggested t h a t the probable cause of intravascular coagulation is the presence of clotp r o m o t i n g substance derived from neoplastic cells. ~ Less studied, however, is the mechanism of D I C in nonneoplastic conditions. T h e mechanisms postulated for the induction of DIC in those cases include bacterial capsular antigens (through antigen-antibody complexes) ~2 and en-
December, 1976, Voll 92, No. 6
Nonbacterial thrombotic endocarditis
Table VIII. Clinical, pathological, and laboratory findings in patients with NBTE and DIC* Laboratory data
Primary disease
Age~sex
68/F 24/F 42/F
Carcinoma of pancreas SLE
Fibrinogen
FDP
P/T
PTT
14.6/11.6
--
46
100
-
13.6/13.8
67.4/56.2
70
38
-
-
-
32
50-100
-
17.0/12.5
-
100
150
-
17.0/11.0 13.4/11.8
78.0/51.0 62.0/50.0
63
