Neurosurgery 1992-98
July 1994, Volume 35, Number 1
26 Serial Changes in Hemostasis after Intracranial
Surgery
Clinical Study
AUTHOR(S): Fujii, Yukihiko, M.D.;
Tanaka, Ryuichi, M.D.; Takeuchi, Shigekazu, M.D.;
Koike, Tetsuo, M.D.; Minakawa, Takashi, M.D.;
Sasaki, Osamu, M.D.
Department of Neurosurgery, Brain Research
Institute, Niigata University (RT, ST, TK, TM), and
Department of Neurosurgery, Kuwana Hospital (YF,
OS), Niigata, Japan
Neurosurgery 35; 26-33, 1994
ABSTRACT: WE PERFORMED HEMOSTATIC
studies on eight patients undergoing clipping of
unruptured cerebral aneurysms to assess the influence
of intracranial surgery itself on hemostasis. Blood
samples were collected from each patient 10 times:
before and after the induction of anesthesia and 6, 12,
and 24 hours and 2, 3, 5, and 7 days immediately
after surgery. The changes and our interpretation of
them include the following: 1) the elevation of
thrombin antithrombin III complex levels (activation
of blood coagulation) was transient and monophasic;
2) the elevation of plasmin α2-antiplasmin complex
and D-dimer levels (activation of fibrinolysis) was
biphasic, despite the monophasic elevation of tissue
plasminogen activator or plasminogen activator
inhibitor-1 levels; 3) the elevation of β-
thromboglobulin and platelet-factor-4 levels
(activation of platelet) was also biphasic; 4)
fibrinogen level and α2-antiplasmin activity increased
in the acute phase of the postoperative course (acute
phase reaction); 5) the changes in hematocrit
appeared to parallel those in various other
parameters, especially platelet count, antithrombin
III, and plasminogen levels for 1 or 2 days after
surgery; 6) fibronectin appeared to be consumed in
the acute phase of postoperative course; and 7)
general anesthesia did not significantly affect
hemostasis. These serial changes seem to be related
to the activation of hemostatic systems after
intracranial surgery and the subsequent acute phase
reaction.
KEY WORDS: Blood coagulation; Fibrinolysis;
Hemostasis; Molecular markers; Neurosurgery;
Platelet; Postoperative state
Patients with neurosurgical diseases have a high risk
of developing a number of the disorders of
hemostasis, including disseminated intravascular
coagulation (DIC) (11,15,23) and deep venous
thrombosis complicated by pulmonary embolism (4,
24)
. Although many clinical studies and trials related
to hemostasis in neurosurgical patients have been
reported (2,3,5,8,25,28), none appears to have taken into
consideration the influence of surgery itself on
hemostasis. The lack of adequate information on
Downloaded from https://academic.oup.com/neurosurgery/article-abstract/35/1/26/2757331
by guest
on 26 March 2018
changes in hemostatic parameters associated with
neurosurgery may result in misinterpreting changes
in the hemostatic systems (7,11,19,26). Indeed, other
kinds of surgery have been noted to alter the
hemostatic systems (9,10,17). Therefore, it is important
to assess the dynamic changes in hemostasis after
intracranial surgery.
In this study, we performed hemostatic studies,
including assays of molecular markers of hemostatic
activation, i.e., substances produced by the activation
of hemostatic systems, on patients undergoing
clipping of unruptured cerebral aneurysms in order to
assess the influence of intracranial surgery itself on
hemostasis.
PATIENTS AND METHODS
Eight patients (5 men and 3 women) undergoing
clipping of unruptured cerebral aneurysms, who had
neither neurological deficits nor hemostatic
abnormalities, were studied. The patients ranged in
age from 41 to 71 (58.3 ± 10.6) years. The site of the
cerebral aneurysm was the anterior communicating
artery in three patients, the middle cerebral artery in
two, the distal anterior cerebral artery in one, the
upper basilar artery trunk in one, and the distal
superior cerebellar artery in one. All the patients
underwent clipping of the aneurysmal neck under
Redistribution of this article permitted only in accordance with the publisher’s copyright provisions.
general anesthesia with nitrous oxide and enflurane,
and the surgical procedures were completed within 4
hours. No patient received osmotic agents during
surgery. The total blood loss was less than 200 ml in
all cases. As a result, no patient was transfused. Each
patient was given a regular diet and approximately
1500 ml of isotonic solution intravenously daily.
Ten ml of blood was collected before (baseline)
and after the induction of anesthesia, immediately
after surgery, 6, 12, 24 hours, and 2, 3, 5, and 7 days
after surgery. No blood sample was drawn for this
study during the operation. Venipuncture was
performed with a 21-gauge siliconized butterfly
needle. Various tests were performed on blood
samples thus collected. Table 1 lists all tests and
parameters assessed in this study, giving their
meanings. Figure 1 briefly illustrates hemostatic
systems, i.e., interplay of blood coagulation,
fibrinolysis, platelets, and blood vessel. The first 1 ml
of blood was used for blood cell counts, including
white blood cell, red blood cell and platelet count,
hemoglobin, and hematocrit value, using S-PLUS JR
(Coulter, Hialeah, FL). The next 2 ml was used for
fibrin (-ogen) degradation products assay, using the
latex photometric immunoassay (LPIA, Iatron,
Tokyo, Japan). The next 2.5 ml was carefully placed
into a prechilled glass tube containing an antiplatelet
anticoagulant consisting of theophylline, adenosine,
dipyridamole, and sodium citrate, and the plasma
separated was stored frozen at -70°C and used for
batch analyses of β-thromboglobulin and platelet-
factor-4 by enzyme immunoassay (Asserachrom,
Diagnostica Stago, Paris, France). The last 4.5 ml was
transferred into a plastic tube containing 1 ml of 3.1%
citrated buffer, and the plasma was stored frozen at -
70°C until batch analyses were performed by the
following assays: 1) clot-based assays to determine
 prothrombin time (PT), activated partial
thromboplastin time, and fibrinogen level
(Thromboplastin C, Actin, Fibrinogen determination
set, Baxster-Dade, Miami, FL); 2) chromogenic
substrate assays to determine antithrombin III, α2-
antiplasmin and plasminogen activity (Berichrom,
Behringwerke, Marburg, Germany); 3) enzyme
immunoassay to estimate thrombin antithrombin III
complex (TAT) (Enzygnost TAT, Behringwerke),
plasmin α2-antiplasmin complex (PAP) (α2PI
Complex, Teijin, Tokyo, Japan), D-dimer
(Asserachrom, Diagnostica Stago), total tissue
plasminogen activator (t-PA), and free plasminogen
activator inhibitor-1 (PAI-1) levels (American
Diagnostica, Greenwich, CT); and 4) assay to
determine fibronectin level using a nephelometer
(NB100, Behringwerke). All assays were completed
within a month after the blood collection. All data
were expressed as mean ± standard deviation, and the
paired Student's t-test was performed to assess
statistical changes in hemostatic parameters after
surgery in comparison with baseline values.
RESULTS
Clinical outcome
No patients experienced postoperative neurological
deterioration, DIC, or clinical signs of deep vein
thrombosis.
Anesthesia
There were no significant differences in any tests
performed before or after the induction of anesthesia
(Figs. 2, 3, 4, 5, 6).
Blood coagulation system
The PT was significantly (P < 0.05) prolonged for
2 days after surgery (12.2-12.8 ± 0.6 sec), compared
with the baseline value (11.4 ± 0.6 sec), but no
significant changes in activated partial
thromboplastin time were observed after surgery.
Antithrombin III activity gradually decreased after
surgery, reaching its nadir 2 days after surgery
(87.3% of the baseline value), but soon returned to
the baseline value (Fig. 2A). There were no
significant changes in fibrinogen levels immediately
and 6 hours after surgery. The fibrinogen level started
to increase 12 hours after surgery, reached its highest
level 2 or 3 days after surgery (191.0% of the
baseline value), and decreased gradually thereafter.
However, its level remained significantly (P < 0.01)
higher than the baseline value until the end of the
study (Fig. 3). The TAT level (P < 0.01) rose
significantly immediately after surgery, then
gradually diminished, and returned to within the
normal range. Its level, however, remained
significantly (P < 0.05) higher than the baseline value
until the end of the study (Fig. 4).
Fibrinolytic system
Plasminogen activity rapidly decreased, reached its
lowest value 24 hours after surgery (77.3% of the
baseline value), and then gradually increased,
becoming significantly (P < 0.01) higher than the
baseline value (Fig. 2B). On the other hand, there
Downloaded from https://academic.oup.com/neurosurgery/article-abstract/35/1/26/2757331
by guest
on 26 March 2018
were no significant changes in α2-antiplasmin
activity for 3 days after surgery; however, significant
(P < 0.05) increases (116.5% of the baseline value)
were observed 5 and 7 days, postoperatively (Fig. 3).
The PAP level became considerably (P < 0.05)
elevated immediately after surgery and, after rapidly
returning to the baseline value, began to rise again 3
days after surgery, significantly (P < 0.05) exceeding
the baseline value. The D-dimer level (P < 0.01) rose
significantly immediately after surgery, reaching its
initial peak 6 hours after surgery, then gradually
decreased to its lowest value 2 days after surgery, and
subsequently increased to a higher level than the
initial peak. Its level remained considerably (P <
0.01) higher than the baseline value until the end of
the study (Fig. 4). The fibrin degradation product
level changed in parallel with changes in the D-dimer
level, and the values 6 hours and 7 days after surgery
were 4.3 ± 0.9 and 4.8 ± 2.0 µg/ml, respectively. Both
t-PA and PAI-1 levels (P < 0.05) increased
significantly immediately after surgery, compared
with the baseline values, then rapidly decreased and
reached the baseline values within 24 hours after
surgery. No significant elevations of t-PA and PAI-1
followed their initial increase (Fig. 5).
Platelet system
Redistribution of this article permitted only in accordance with the publisher’s copyright provisions.
The platelet count increased slightly immediately
after surgery, then gradually decreased, reaching its
nadir 2 days after surgery (81.2% of the baseline
value), after which it rapidly increased to become
significantly (P < 0.05) higher than the baseline value
(Fig. 2C). Both β-thromboglobulin and platelet-factor-
4 levels (P < 0.01) rose significantly immediately
after surgery, rapidly decreased, and returned to the
baseline values within 24 hours after surgery. They
then gradually increased again, becoming
significantly (P < 0.01) higher than the baseline
values 7 days after surgery (Fig. 6).
Fibronectin
The fibronectin level gradually decreased after
surgery, reached its lowest level (71.8% of the
baseline value) 24 hours after surgery, and returned to
the baseline value 5 days after surgery (Fig. 2C).
Blood cell counts
The white blood cell count significantly (P < 0.01)
increased over the baseline value immediately after
surgery, became peaked (246.9% of the baseline
value) 6 hours after surgery, gradually decreased
thereafter, and almost returned to the baseline value 5
days after surgery (Fig. 3). Although the red blood
cell count, hemoglobin, and hematocrit value did not
change immediately after surgery, they gradually
decreased, reaching their nadir 3 days after surgery
(80.0, 77.3, and 76.3% of the baseline values,
respectively), and remained significantly (P < 0.01)
lower than the baseline values until the end of the
study (Fig. 2).
DISCUSSION
A few studies on serial changes in limited numbers
of hemostatic parameters after abdominal surgery (9,
 10,17)
and cardiopulmonary bypass (6,14) have been
published. Intracranial surgery, however, differs from
other surgery in many ways, i.e., the brain contains
singularly high levels of tissue thromboplastin, and
intracranial surgery usually requires craniotomy.
Nevertheless, to the best of our knowledge, no studies
on postoperative changes in hemostasis after
intracranial surgery have been published. In this
study, we performed many hemostatic assays, which
enabled us to comprehensively evaluate hemostatic
systems, including the coagulation system,
fibrinolytic system, and platelet system. Moreover,
there have been no studies in any specialty in which
such a comprehensive evaluation of hemostatic
systems has been performed. We investigated only
patients with an unruptured aneurysm to assess
changes in hemostasis associated with intracranial
surgery because of the following two reasons: 1)
patients with other neurosurgical diseases, e.g.,
stroke, brain tumor, and trauma, are expected to have
hemostatic abnormalities before surgery; and 2) a
number of studies on vasospasm after the rupture of
cerebral aneurysm have been performed using various
hemostatic tests, such as β-thromboglobulin (7,19,26).
Influence of anesthesia
There were no significant changes in any of the
parameters we assessed after general anesthesia
(Figs. 2, 3, 4, 5, 6). Thus, it appears that the influence
of general anesthesia with nitrous oxide and
enflurane on the hemostatic systems before surgery is
of little significance.
Influence of hemodilution
The hematocrit values did not change immediately
after surgery probably because of a balance between
blood loss and rehydration during surgery; however,
they did gradually decrease by 23.7% of the baseline
value as a result of hemodilution after intravenous
infusion. The changes in hematocrit appeared to
affect various hemostatic parameters assessed in this
study, especially platelet count, antithrombin III, and
plasminogen levels (Fig. 2), although the possibility
of their consumption after surgery cannot be
completely excluded. Platelet count, antithrombin III,
and plasminogen levels decreased in parallel with the
changes in hematocrit for 1 or 2 days after surgery
and then started to increase. It is generally accepted
that concentration levels in various hemostatic
parameters, such as platelets, fibrinogen,
antithrombin III, α2-antiplasmin, and plasminogen,
change in parallel with the fall in hematocrit after
hemodilution (6,13,14,22). Thus, hematocrit seems to be
an important parameter in assessing changes in the
hemostatic systems. More significant decreases in
these parameters, especially in platelet count, than
those in hematocrit, may indicate pathological (not
physiological) consumption, e.g., DIC.
Influence of acute phase reaction
It is well known that increases in the concentration
of many hemostatic substances are observed shortly
after chemical, inflammatory, or physical stimulation,
i.e., acute phase reaction, because of the interaction of
Downloaded from https://academic.oup.com/neurosurgery/article-abstract/35/1/26/2757331
by guest
on 26 March 2018
cytokines, mainly interleukin-6 (12). The acute phase
reaction is a factor that should be considered in
postoperative changes in hemostatic systems. White
blood cell counts and fibrinogen levels increased in
the acute phase, and α2-antiplasmin did not decrease
despite significant decreases in hematocrit (Fig. 3).
Fibrinogen is also an important factor in the
diagnosis of DIC, and hence we have to bear in mind
that the plasma level of fibrinogen never decreases
significantly after surgery unless the hematocrit drops
precipitously, because fibrinogen is a representative
acute phase reactant.
Activation of the coagulation system
An elevation of TAT means the presence of
thrombin, a powerful enzyme that catalyzes the
conversion of fibrinogen into fibrin in the circulating
blood, i.e., activation of the coagulation system
(Table 1 and Fig. 1) (20). The TAT elevation after
surgery was rapid but transient and was followed by a
return to the normal range, although the levels were
significantly higher than the baseline value until the
end of the study (Fig. 4). From the fact that the
changes in the TAT level after intracranial surgery are
monophasic, it is considered that a second elevation
in TAT after surgery may indicate the occurrence of
coagulopathy, including DIC, deep vein thrombosis,
Redistribution of this article permitted only in accordance with the publisher’s copyright provisions.
and pulmonary embolism (4).
Activation of the fibrinolytic system
An elevation of PAP means the presence of
plasmin, a powerful fibrin-cleaving enzyme in blood
circulation, i.e., activation of the fibrinolytic system
(Table 1 and Fig. 1) (18). The level of PAP, which was
generated during surgery, rapidly decreased and
returned to the baseline value within 24 hours
(Fig. 4); however, it gradually increased again and
became significantly higher than the baseline value.
Thus, the changes in PAP were biphasic,
corroborating the findings of Mellbring et al. (17).
Increases in D-dimer levels indicate the presence of
both thrombin and plasmin in the blood, i.e., D-dimer
represents degradation products derived from cross-
linked fibrin but not from fibrinogen (Table 1 and
Fig. 1) (21). Changes in D-dimer were also biphasic
and followed the changes in PAP (Fig. 4), failing to
corroborate the study reported by Kang et al. who
claimed that the initial fibrinolytic reaction was not
associated with D-dimer elevation on the basis of
semiquantitative assay (10). Plasmin is generated by a
number of plasminogen activators, e.g., t-PA.
Although we investigated levels of t-PA and PAI-1
after surgery to assess the relationship between PAP
and t-PA or PAI-1, the changes were monophasic
rather than biphasic and did not correspond to those
in PAP (Fig. 5). It is unclear why the second
elevation of PAP was not associated with an elevation
of the t-PA or PAI-1 level. However, plasminogen
activators other than t-PA may activate plasminogen
(16)
, or fibrin deposits in wound healing after surgery
may contribute as potentiating agents in the process
of plasminogen activation (17). Hence, it seems very
important in assessing hemostatic disorders after
surgery to be aware that postoperative changes in
 PAP and D-dimer are biphasic, despite the for his valuable hematological suggestions; Dr.
monophasic changes in t-PA and PAI-1. Takayuki Koizumi, Dr. Yoshiho Honda, and Dr.
Yasusi Itoh for their clinical assistance; and Ms.
Platelet activation Noriko Sakai, Ms. Miho Suga, and Ms. Yoko Ishii for
Platelet factor 4 and β-thromboglobulin are their laboratory assistance.
proteins stored in the α- granules of platelets, and
their elevation in plasma indicates platelet activation Received, April 23, 1993.
(Table 1 and Fig. 1) (27). Changes in platelet-factor-4 Accepted, January 13, 1994.
and β- thromboglobulin levels were also biphasic, Reprint requests: Yukihiko Fujii, M.D.,
and their levels became significantly higher than the Department of Neurosurgery, Brain Research
baseline value in parallel with platelet counts 7 days Institute, Niigata University, 757 Asahimachi 1,
after surgery (Fig. 6). It is also unclear why a second Niigata, 951 Japan.
elevation of their levels was observed. The second
elevation, however, may be relevant to wound REFERENCES: (1-28)
healing and tissue repair after surgery.
1. Beckmann R, Geiger M, De Vries C,
Fibronectin Pannekoek H, Binder BR: Fibronectin
Fibronectin is an adhesive glycoprotein that is decreases the stimulation effect of fibrin and
involved in many biological processes, such as cell fibrinogen fragment FCB-2 on plasmin
adhesion to extracellular matrix, cross-linking of formation by tissue plasminogen activator. J
fibrin or collagen, and platelet aggregation (Table 1 Biol Chem 66:2227-2232, 1991.
and Fig. 1). It can be found on cell surfaces, in 2. Findlay JM: Subarachnoid fibrinolytic
extracellular matrix, and in plasma. The binding and treatment for the prevention of cerebral
cross-linking of fibronectin to fibrin seem to be vasospasm. Semin Neurol 11:400-410, 1991.
important for the attachment and ingrowth of cells 3. Fodstad H, Nilsson IM: Coagulation and
into clot and, therefore, for wound healing and tissue fibrinolysis in blood and cerebrospinal fluid
repair (1). The decrease in fibronectin level was after aneurysmal subarachnoid haemorrhage:

Redistribution of this article permitted only in accordance with the publisher’s copyright provisions.
greater than the fall in hematocrit (Fig. 2C), which Effect of tranexamic acid (AMCA) Acta
may indicate that the consumption of fibronectin is Neurochir 56:25-38, 1981.
for wound healing and tissue repair after surgery. 4. Fujii Y, Mammen EF, Farag A, Muz J,
Salciccioli GG, Weingerden ST: Thrombosis
CONCLUSION in spinal cord injury. Thromb Res 68:357-
It should always be borne in mind that changes in 368, 1992.
the hemostatic systems associated with intracranial 5. Glick R, Green D, Ts'ao C, Witt WA, Yu
surgery are dynamic and characteristic of the ATW, Raimondi AJ: High dose ε-
individual hemostatic parameters involved. The aminocaproic acid prolongs the bleeding time
following findings are particularly important: 1) the and increases rebleeding and intraoperative
elevation of the TAT level (activation of blood hemorrhage in patients with subarachnoid
coagulation) was transient and monophasic; and 2) hemorrhage. Neurosurgery 9:398-401, 1981.
the elevation of PAP and D-dimer levels (activation 6. Harker LA, Malpass TW, Branson HE, Hassel
of fibrinolysis) was biphasic despite the monophasic EA, Slichter SJ: Mechanism of abnormal
elevation of the t-PA or PAI-1 level; 3) the elevation bleeding in patients undergoing
of β-thromboglobulin and platelet-factor-4 levels cardiopulmonary bypass: Acquired transient
(activation of platelet) was also biphasic; 4) the platelet dysfunction associated with selective
fibrinogen level and α2-antiplasmin activity rose in a-granule release. Blood 56:824-834, 1980.
the acute phase of the postoperative state (acute phase 7. Hasegawa T, Watanabe H, Ishii S: Studies of
reaction); 5) the changes in hematocrit appeared to intravascular components in cerebral
parallel those in various other parameters, especially vasospasm following subarachnoid
platelet counts, antithrombin III, and plasminogen hemorrhage. Neurosurg Rev 3:93-100, 1980.
levels for 1 or 2 days after surgery; 6) the fibronectin 8. Hossmann V, Bewermeyer H, Auel H, Heiss
appeared to be consumed in the acute phase of the WD: Monitoring of antifibrinolytic treatment
postoperative state; and 7) general anesthesia did not in subarachnoid hemorrhage. Eur Neurol
significantly affect hemostasis. These serial changes 24:196-204, 1985.
seem to be related to the activation of hemostatic 9. Kambayashi J, Sakon M, Yokota M, Shiba E,
systems by intracranial surgery and subsequent acute Kawasaki T, Mori T: Activation of
phase reaction. Additional studies seem to be coagulation and fibrinolysis during surgery,
required to assess late postoperative changes in analyzed by molecular markers. Thromb Res
hemostatic systems, because, in this study, we noted 60:157-167, 1990.
some parameters still remained out of the normal 10. Kang J, Kambayashi J, Sakon M, Tsujinaka T,
range 7 days after surgery. Mori T: Postoperative changes in hemostasis
analyzed by the serial determination of
ACKNOWLEDGMENTS fibrinopeptides and D-dimer. Jpn J Surg
The authors thank Dr. Hoyu Takahashi, the 1st 19:262-268, 1989.
Department of Internal Medicine, Niigata University, 11. Kaufman HH, Hui KS, Mattson JC:

Downloaded from https://academic.oup.com/neurosurgery/article-abstract/35/1/26/2757331

by guest
on 26 March 2018
 Clinicopathological correlations of
disseminated intravascular coagulation in
patients with head injury. Neurosurgery
15:34-42, 1984.
12. Kishimoto T: The biology of interleukin-6.
Blood 74:1-10, 1989.
13. Laks H, Handin RI, Martin V, Pilon RN: The
effect of acute normovolemic hemodilution on
coagulation and blood utilization in major
surgery. J Surg Res 20:225-230, 1976.
14. Mammen EF, Koets MH, Washington BC,
Wolk LW, Brown JM, Burdick M, Selik NR,
Wilson RF: Hemostasis changes during
cardiopulmonary bypass surgery. Semin
Thromb Hemost 11:281-292, 1985.
15. Matjasko MJ, Ducker TB: Disseminated
intravascular coagulation associated with
removal of a primary brain tumor: A case
report. J Neurosurg 47:476-480, 1977.
16. Matsuda T, Asakura H, Ito K, Sato M, Jokaji
Y, Uotani C, Kumabashiri I: Changes in levels
of t-PA and α2 PI-plasmin complex in plasma
in patients with DIC. Thromb Res (Suppl)
VIII:143-151, 1988.
17. Mellbring G, Dahlgren S, Wiman B: Plasma
fibrinolytic activity in patients undergoing
major abdominal surgery. Acta Chir Scand
151:109-114, 1985.
18. Mimuro J, Koike Y, Sumi Y, Aoki N:
Monoclonal antibodies to discrete regions in
α2-plasmin inhibitor. Blood 69:446-453,
1987.
19. Ohkuma H, Suzuki S, Kimura M, Sobata E:
Role of platelet function in symptomatic
cerebral vasospasm following aneurysmal
subarachnoid hemorrhage. Stroke 22:854-
859, 1991.
20. Pelzer H, Schwarz A, Heimburger N:
Determination of human thrombin-
antithrombin III complex in plasma with an
enzyme-linked immunosorbent assay.
Thromb Haemost 59:101-106, 1988.
21. Rylatt DB, Blake AS, Cottis LE: An
immunoassay for human D-dimer using
monoclonal antibodies. Thromb Res 31:767-
778, 1983.
22. Six AJ, Tjon RM, Buys EM, Haas F,
Hollander van Zalk A, Haverkate F: The
influence of coronary angiography and
angioplasty on parameters of hemostasis and
fibrinolysis. Thromb Haemost 64:113-116,
1990.
23. Spallone A, Mariani G, Rosa G: Disseminated
intravascular coagulation as a complication of
ruptured intracranial aneurysms. J Neurosurg
59:142-145, 1983.
24. Swann KW, Black PM: Deep vein thrombosis
and pulmonary emboli in neurosurgical
patients: A review. J Neurosurg 61:1055-
1062, 1984.
25. Tokiyoshi K, Ohnishi T, Nii Y: Efficacy and
toxicity of thromboxane synthetase inhibitor
for cerebral vasospasm after subarachnoid
hemorrhage. Surg Neurol 36:112-118, 1991.
Downloaded from https://academic.oup.com/neurosurgery/article-abstract/35/1/26/2757331
by guest
on 26 March 2018
26. Toyoda O, Nakajima H, Nukui H: Changes in
coagulation and fibrinolysis and effects of
ticlopidine and cisternal drainage in the acute
phase following aneurysm rupture (in
Japanese, English abstr) Neurol Med Chir
(Tokyo) 30:670-675, 1990.
27. Walz DA: Platelet-released protein as
molecular markers for the activation process.
Semin Thromb Hemost 10:270-279, 1984.
28. Zabramski JM, Spetzler RF, Lee KS,
Papadopoulos SM, Bovill E, Zimmerman RS,
Bederson JB: Phase I trial of tissue
plasminogen activator for the prevention of
vasospasm in patients with aneurysmal
subarachnoid hemorrhage. J Neurosurg
75:189-196, 1991.
COMMENTS
The authors have made a substantial effort of
documenting the changes that occurred in several
hemostatic parameters immediately and up to 7 days
after intracranial surgery. The data demonstrate
evidence of the activation of the coagulation and the
fibrinolytic systems. However, the overall fibrinolytic
potential of the blood cannot be assessed because the
assays did not include a measurement of the
fibrinolytic capacity at the various time points. A
Redistribution of this article permitted only in accordance with the publisher’s copyright provisions.
fibrinolytic "shut-down" has been described in non-
neurosurgical patients and has included a rise in
plasminogen activator inhibitor-1 and a drop in tissue
plasminogen activator (1). The former is well
documented in this study, whereas the latter did not
occur.
It should be noted that this study has included only
patients with unruptured aneurysms who underwent
uncomplicated surgery and in whom the brain
parenchyma was not transgressed. It is anticipated
that with other more complicated circumstances, such
as in brain tumor patients, the hemostatic parameters
are much more likely to lead to coagulopathies and to
thromboembolism (2,3).
The lack of clinical evidence of deep venous
thrombosis in this study does not exclude its
occurrence at a subclinical level, and future studies
would be more clinically relevant if the significance
of the hemostatic changes were correlated with the
hemorrhagic as well as thromboembolic occurrences
during and after intracranial surgery.
Raymond Sawaya
Houston, Texas
REFERENCES: (1-3)
1. Kluft C: Fibrinolytic shut-down after surgery,
in Sawaya R (ed): Fibrinolysis and the
Central Nervous System. Philadelphia, Hanley
& Belfus, 1990, pp 127-140.
2. Sawaya R, Glas-Greenwalt P: Postoperative
venous thromboembolism and brain tumors:
Part II: Hemostatic profile. J Neurooncol
14:127-134, 1992.
3. Sawaya R, Ramo OJ, Glas-Greenwalt P, Wu
SZ: Plasma fibrinolytic profile in patients
 with brain tumors. Thromb Haemost 65:15-
19, 1991.

The authors have completed a detailed, systematic

evaluation of the hemostatic system in relation to
intracranial surgery. Changes in hemostasis in
neurosurgery are most commonly clinically
significant in trauma, where they are an issue in and
of themselves because of problems with intravascular
clotting and bleeding, which appear to be significant
enough to be related separately to outcome (1). This
article suggests the kinds of approach that could also
improve our understanding of coagulopathy in head
injury and can be used as a model for such work.

Howard H. Kaufman
Morgantown, West Virginia
REFERENCES: (1)

1. Olson JD, Kaufman HH, Moake J: The

incidence and significance of hemostatic
abnormalities in head injury. Neurosurgery
24:825-832, 1989.

Redistribution of this article permitted only in accordance with the publisher’s copyright provisions.

Downloaded from https://academic.oup.com/neurosurgery/article-abstract/35/1/26/2757331

by guest
on 26 March 2018
 Redistribution of this article permitted only in accordance with the publisher’s copyright provisions.
Figure 1. A simplified diagram of the hemostatic
systems, which is facilitated through harmonious
interplay of the blood coagulation system,
fibrinolytic system, platelet system, and blood vessel
wall. The tests and parameters assessed are printed in
bold type.

Downloaded from https://academic.oup.com/neurosurgery/article-abstract/35/1/26/2757331

by guest
on 26 March 2018
 Redistribution of this article permitted only in accordance with the publisher’s copyright provisions.
Figure 2. Graph showing serial changes in
antithrombin III activity (A), plasminogen activity
(B), platelet counts and fibronectin levels (C), as a
comparison with hematocrit levels after intracranial
surgery. Values are expressed as mean ± standard
deviation (vertical bars). Significant differences (P <
0.05 and P < 0.01) from baseline values are indicated
with * and **, respectively.

Downloaded from https://academic.oup.com/neurosurgery/article-abstract/35/1/26/2757331

by guest
on 26 March 2018
 Redistribution of this article permitted only in accordance with the publisher’s copyright provisions.
Figure 3. Graph showing serial changes in white
blood cell counts, fibrinogen levels, and α2-
antiplasmin activity after surgery. Values are
expressed as mean ± standard deviation (vertical
bars). Significant differences (P < 0.05 and P < 0.01)
from baseline values are indicated with * and **,
respectively.

Downloaded from https://academic.oup.com/neurosurgery/article-abstract/35/1/26/2757331

by guest
on 26 March 2018
 Figure 4. Graph showing serial changes in thrombin
antithrombin III complex (TAT), plasmin α2-
antiplasmin complex (PAP), and D-dimer levels after

Redistribution of this article permitted only in accordance with the publisher’s copyright provisions.
intracranial surgery. Values are expressed as mean ±
standard deviation (vertical bars). Significant
differences (P < 0.05 and P < 0.01) from baseline
values are indicated with * and **, respectively.

Figure 5. Graph showing serial changes in plasmin

α2-antiplasmin complex (PAP), tissue plasminogen
activator (t-PA), and plasminogen activator inhibitor-
1 (PAI-1) levels after intracranial surgery. Values are
expressed as mean ± standard deviation (vertical
bars). Significant differences (P < 0.05 and P < 0.01)
from baseline values are indicated with * and **,
respectively.

Downloaded from https://academic.oup.com/neurosurgery/article-abstract/35/1/26/2757331

by guest
on 26 March 2018
 Figure 6. Graph showing serial changes in platelet
counts, β-thromboglobulin, and platelet-factor-4
levels after intracranial surgery. Values are expressed

Redistribution of this article permitted only in accordance with the publisher’s copyright provisions.
as mean ± standard deviation (vertical bars).
Significant differences (P < 0.05 and P < 0.01) from
baseline values are indicated with * and **,
respectively.

Downloaded from https://academic.oup.com/neurosurgery/article-abstract/35/1/26/2757331

by guest
on 26 March 2018
 Redistribution of this article permitted only in accordance with the publisher’s copyright provisions.

Table 1. List of Tests Assessed in This Study and

Their Meanings

Downloaded from https://academic.oup.com/neurosurgery/article-abstract/35/1/26/2757331

by guest
on 26 March 2018