Unusual Intravascular Material in the Brain
Autopsy Findings in a Patient Treated with
Antihemophilic Factor Concentrates
NITYA R. GHATAK, M.D.,
AND MUHAMMAD M. HUSAIN,
M.D.
From the Departments of Pathology (Neuropathology), Montefiore Hospital and Medical Center,
Bronx, New York, and Bowman Gray School of Medicine, Winston-Salem, North Carolina
ABSTRACT
Ghatak, Nitya R., and Husain, Muhammad M.: Unusual intravascular material
in the brain. Autopsy findings in a patient treated with antihemophilic factor
concentrates. Am J Clin Pathol 65: 508-512, 1976. Widespread vascular occlusion caused by unusual particulate material in the brain of a patient who was
intensively treated with antihemophilic factor (AHF) concentrates prior to
death is described. The intravascular particles were seen partially or completely
occluding both veins and arteries of small caliber in the brain and also to a much
lesser extent in other organs. T h e resultant small focal infarcts were predominantly distributed in the cerebral white matter. T h e pathogenesis of this
apparently unique vascular occlusive phenomenon and its relationship, if any,
to the massive AHF concentrate infusion in this patient remain unknown. (Key
words: Antihemophilic factor concentrates; Cerebral microinfarcts; Disseminated intravascular coagulation; Vascular occlusion.)
IN THIS REPORT we describe the occurrence
of unusual intravascular particulate material predominantly in the brain of a patient
who was treated with large amounts of andhemophilic factor (AHF) concentrates and
blood transfusion. We are not aware of a
similar phenomenon's having been reported previously. Although the precise
source and nature of the intravascular
material remain obscure, these observadons appear to be of particular interest in
view of the obvious importance of AHF
concentrates and their increasing use in the
current treatment of hemophilia.
Received May 19, 1975; received revised manu-
script July 14, 1975; accepted for publication July
• 4, 1975.
Report of a Case
A
51-year-old man with known hemodeficiency underwent a subtotal
gastrectomy for carcinoma
in A n l 1 9 7 L
P
Adequate hemostas.s was
achieved during and after the operation by
infusion of multiple units of cryoprecipiP
hlha d u e to factor VI11
tates a n d
after
w h o l e bloocL A b o u t
four
weeks
the
operation, the patient had an
P>sode of gastro.ntestmal bleeding which
was
> a S a i n > effectively controlled by cryoprecipitate infusion. In December 1971,
the
P a t , e n t w a s readmitted to the hospital
because of another episode of profuse
gastrointestinal bleeding.
e
°
.
.
.
,
On admission, there was no demonsuable plasma factor VIII. T h e patient was
Address reprint requests to Dr. Ghatak: Bowman
Gray School of Medicine, Winston-Salem, North
,
. , ,
«u c
r
t r e a t e d With l a r g e a m o u n t s o f A H F COn-
Carolina 27103.
centrate, including cryoprecipitates ob508
April 1976
UNUSUAL INTRAVASCULAR MATERIAL
509
Fie 1. Focal hemorrhagic and nonhemorrhagic infarcts in cerebral white matter.
tained from various sources. In addition,
multiple units of whole blood and packed
cells were transfused. Despite the intensive
treatment, the factor VIII levels ranged
between 10 and 50%, the hematocrit values
remained about 20%, and the patient continued to have gastrointestinal bleeding.
Coombs-positive hemolysis and circulating
factor VIII inhibitors also developed.
About two weeks after admission, the patient underwent laparotomy because of
persistent gastrointestinal bleeding, apparently refractory to infusion of AHF concentrates. However, no specific site of
bleeding could be identified at operation.
The subsequent course was complicated by
oozing of blood from the operative sites
and superimposed infection, necessitating
a re-exploration with removal of a large
amount of infected blood clot from the
peritoneal cavity. T h e patient's condition
continued to deteriorate, with obtundation and sustained hypotension, until he
died about four weeks after admission.
Throughout the entire period, he was continually treated with AHF concentrates and
blood transfusion. More specifically, about
two weeks prior to death the patient received cryoprecipitate for the last time, in
a dosage approximately equivalent to
10,000 units of AHF over a period of three
days. During the remaining ten days, he
received other forms of commercial AHF
concentrates in daily dosages ranging from
4,000 to 8,000 units. During the same
period the patient received nine units of
packed cells.
Autopsy Findings
The pertinent findings in the general
autopsy included massive submucosal
hematoma in the esophagus, blood in the
gastrointestinal tract and peritoneal cavity,
generalized peritonitis, and bronchopneumonia. In addition, metastatic carcinoma was found in the perigastric lymph
nodes.
The brain appeared swollen on external
examination. On sectioning the brain,
multiple small foci of hemorrhage were
seen almost exclusively in the white matter
(Fig. 1). Microscopic examination of these
and other apparently normal areas of the
510
GHATAK AND HUSAIN
A.J.C.P.—Vol.
65
farcts appeared fresh, as evidenced by
lack of reactive changes, and therefore,
presumably occurred shortly before the
patient's death. In view of the presence of
the particles in both arteries and veins,
the brain was re-examined for possible
vascular malformation conceivably underlying an abnormal arteriovenous shunt;
however, none was found. On rare occasions, similar intravascular material was
seen in the liver, spleen and lungs. T h e
renal glomeruli were remarkably free of
such material, probably because of the
relatively large size of the particles.
FIG. 2. Conglomerate particulate material occluding
a small artery in the brain. Masson's trichrome
stain. X240.
brain frequently showed unusual eosinophilic particulate material within the
lumens of both arteries and veins, predominantly those of small caliber. Compact
aggregates of the particles were often seen
plugging small arteries adjacent to microinfarcts (Fig. 2). More frequently, these
appeared loose and intermingled with normal cellular elements of blood (Fig. 3). T h e
particles were, by and large, elongated in
shape, and varied considerably in size (Fig.
3). Occasionally, several particles interconnected to one another, apparently forming
larger masses, were seen (Fig. 3). T h e staining properties of these particles were essentially similar to those of fibrin in Masson's trichrome, periodic acid-Schiff (PAS)
and phosphotungstic acid hematoxylin
(PTAH) stains. They remained unstained
with Sudan IV in frozen sections and were
not birefringent under polarized light.
Although partial or complete vascular
occlusion was present in different parts
of the brain, the small focal infarcts,
mostly hemorrhagic, were virtually limited
to the white matter. Furthermore, all in-
Paraffin-embedded blocks of brain tissue
were utilized for electron-microscopic
study. Portions of tissue corresponding to
the intravascular particles were isolated
and processed according to the methods
described by Morecki and Becker. 6 Despite
the poor preservation of tissue, the particulate material could be easily identified
within the vascular lumens and appeared
as electron-dense structures conforming to
the general size and shape of those seen
with the light microscope (Fig. 4). At a
higher magnification, the particles appeared homogeneous or finely granular,
with no discernible periodicity characteristically seen in fibrin. T h e particles were
frequently seen in close proximity to erythrocytes, from which they could be easily
distinguished by their much larger size, in
addition to other features. Due to poor
preservation, no meaningful observation
could be made with regard to their relationship to other cellular elements.
Discussion
Although the intravascular particulate
material was predominantly observed in
the microcirculation of the brain, it should
be emphasized that similar material was
present in other organs as well; however,
to a much lesser extent. Furthermore, the
occurrence of cerebral microinfarcts related to the occluded vessels would clearly
April 1976
511
UNUSUAL INTRAVASCULAR MATERIAL
^%^Pfi^ H
r
~****-i;<Z.
]
«k.0 *
W^<$Z€+\ ***
FIG. 3 (upper). Particles of variable size and shape in cerebral venous lumens mixed with blood cells. Note
partial adhesion between adjacent particles. Heniatoxylin and eosin. Left x 9 5 ; right X260.
FIG. 4 (lower). Electron micrograph, showing a small portion of an intravascular particle adjacent to poorly
preserved unidentifiable cell process. Uranyl acetate and lead citrate. X8.000.
512
GHATAK AND HUSAIN
indicate that the intravascular material
was not a postmortem artefact. Since the
origin of these particles could not be explained by the autopsy findings, it seems
reasonable to consider a possible relationship between these and the massive transfusions of AHF concentrates and blood in
this patient. It is conceivable that the
particles represented certain precipitates
or contaminants and were introduced into
the venous circulation during infusion.
Subsequently, these may have gained access
into the systemic circulation after transpulmonary passage in a manner similar to
that postulated in posttraumatic fat embolism, resulting in disseminated microinfarcts in the cerebral white matter. Such
an assumption, however, would fail to account for the presence of the particles
in both arterial and venous sides of the
cerebral circulation. Therefore, it seems
more likely that the particulate material
originated de novo in the circulating blood,
thus explaining its presence in arteries and
veins alike.
A.J.C.P.—Vol.
65
unlike the globular thrombi. Furthermore,
the fine structure of the particles failed
to provide any clue as to their mode of
formation. Nevertheless, their resemblance
to the globular thrombi cannot be ignored
altogether.
Whatever the nature of the particles
may be, their occurrence, apparently following prolonged infusion of several types
of AHF concentrates, raises the possibility
of a causal relationship. In that case, however, it would be difficult to explain why the
vascular occlusion occurred only at the
terminal stage of the patient's illness despite continued administration of AHF for
several weeks. So far as we know, among
various complications associated with AHF
concentrate therapy, 7 a similar phenomenon has not been reported. T h e role, if
any, of the combination of various types
of AHF concentrates administered to this
patient in the pathogenesis of vascular occlusion would, therefore, be entirely
speculative. Indeed, such an association
may have been merely coincidental. In
Several types of intravascular material either event, the source and mechanism
are known to occur in disseminated intra- underlying the occurrence of these unusual
vascular coagulation (DIC) under various intravascular particles remain intriguing.
circumstances. 2-4 T h e surgical procedures,
infection, or terminal shock in this case
References
may indeed, have provided a setting for 1. Hard RC Jr, Still JS: Intravascular fibrin deDIC after correction of the clotting defect
posits, hepatic infarcts and thrombocytopenia
in parent/F, mouse chimeras with host-versuswith treatment. Despite certain tinctorial
graftsyndrome. AmJ Pathol 7 9 : 1 3 1 - 142, 1975
similarities, the morphology, including the 2. Hardaway RM: Syndromes of Disseminated Intravascular Coagulation. Springfield, 111.,
fine structure, of the intravascular material
Charles C Thomas, 1966, pp 2 1 - 4 3
described in this report appeared quite 3. McGovern
VJ: Shock. Pathol Ann 6:279-298,
different from that of the usual fibrin
1971
thrombi characteristically seen in DIC. 1 ' 3,5 4. McKay DG: Tissue damage in disseminated intravascular coagulation: Mechanisms of localizaOf particular interest in this regard was
tion of thrombi in the microcirculation.
Thromb Diath Haemorrh (suppl 36):67-81,
the occurrence of globular thrombi in pa1969
tients dying of shock, described by Harda- 5. Margaretten
W, Csavossy I, McKay DG: An
2
way. These structures were round or ovoid
electron microscopic study of thrombin-induced disseminated intravascular coagulation.
and ranged from 10 to 100 /xm. or more
Blood 29:169-181, 1967
in diameter. It was concluded that the 6. Morecki R, Becker NH: Human herpes virus
infection: Its fine structure identification in
globular thrombi were the result of aggluparaffin-embedded tissue. Arch Pathol 86:
tination of fibrin-coated erythrocytes. Al292-296, 1968
though similar in certain respects, the intra- 7. Seeler RA: Complications of therapy in patients
with hemophilia, Hemophilia. Edited by D
vascular particles in this patient, were, by
Green. Springfield, 111., Charles C Thomas,
and large, elongated and homogeneous,
1973, pp 3 4 - 4 1