Fibrinogen Decrease after Intravenous Thrombolysis in

Ischemic Stroke Patients Is a Risk Factor for Intracerebral

Hemorrhage
Laura Vandelli, MD,* Marco Marietta, MD, Mariaelena Gambini, PhD,
Milena Cavazzuti, MD,* Tommaso Trenti, MD,x Maria A. Cenci, MD,x
Federica Casoni, MD,* Guido Bigliardi, MD,* Roberta Pentore, MD,*
Paolo Nichelli, MD, PHD,* and Andrea Zini, MD*

Background: Intravenous thrombolysis is an effective treatment in acute stroke

patients, but it increases the risk of intracerebral hemorrhages. Our aim is to establish if fibrinogen depletion increases the risk of intracerebral hemorrhage after intravenous thrombolysis for acute ischemic stroke. Methods: In 104 ischemic stroke
patients, treated with intravenous thrombolysis, we assessed the rate of intracerebral hemorrhages documented by computed tomographic scan at 24 hours and
within 7 days post-treatment. Fibrinogen levels were determined at 2 hours after
therapy: patients were classified as belonging to low fibrinogen group if levels
decreased to less than 2 g/L and/or by 25% or more. Fibrinogen levels and other
known hemorrhagic risk factors were studied using univariate and multivariate
analyses. Results: During the first 7 days, an intracerebral hemorrhage was detected
in 24 patients (23.1%), and only 6 of these (5.8%) experienced symptomatic bleeding;
41 patients were included in the low fibrinogen group. Among the 24 hemorrhages,
18 occurred in the low fibrinogen group and 6 in the normal fibrinogen group: the
bleeding rate in the low fibrinogen group was significantly higher (43.9%) than that
in the normal fibrinogen group (9.5%; odds ratio [OR] 7.43, P ,.001). Univariate and
multivariate analyses revealed that only clinical severity (OR 1.15, P , .001) and
hypofibrinogenemia (OR 7.47, P , .001) were significantly associated with brain
bleeding at 7 days and at 24 hours (P 5.008). Conclusions: An early fibrinogen reduction seems to increase the risk of intracerebral hemorrhage after rtPA treatment
in ischemic stroke. Fibrinogen assessment could be a rapid, inexpensive, and
widely available tool to help the identification of patients at higher risk of
bleeding. Key Words: Fibrinogenacute strokeintracerebral hemorrhagerisk
factorsthrombolysisrtPA.
2015 by National Stroke Association

From the *Stroke Unit, Department of Neuroscience, University of

Modena and Reggio Emilia, Nuovo Ospedale Civile S. AgostinoEstense, AUSL Modena, Modena; Section of Haematology,
Department of Oncology and Haematology, Policlinico of Modena,
University of Modena and Reggio Emilia, Modena; Environmental
Protection Agency, ARPA Emilia Romagna District of Reggio Emilia,
Reggio Emilia; and xClinical Pathology-Toxicology, Nuovo Ospedale
Civile S. Agostino-Estense, AUSL Modena, Modena, Italy.
Received March 21, 2014; revision received September 2, 2014;
accepted September 6, 2014.

394

Disclosure: The authors report no conflicts of interest.

Address correspondence to Andrea Zini, MD, Neurology Clinic,
Stroke Unit, Department of Neuroscience, University of Modena
and Reggio Emilia, Nuovo Ospedale Civile S.Agostino-Estense,
AUSL Modena, via Giardini, 1355 Baggiovara, 41100 Modena, Italy.
E-mail: andrea.zini@me.com.
1052-3057/$ - see front matter
2015 by National Stroke Association
http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.09.005

Journal of Stroke and Cerebrovascular Diseases, Vol. 24, No. 2 (February), 2015: pp 394-400

FIBRINOGEN DECREASE AFTER INTRAVENOUS THROMBOLYSIS IN STROKE PATIENTS

Introduction
Thrombolytic therapy with administration of intravenous recombinant tissue plasminogen activator (iv rtPA)
has been shown to improve long-term functional
outcome, and it is recommended for the treatment of
eligible acute ischemic stroke patients.1 This therapy,
however, is associated with an increased risk of symptomatic intracerebral hemorrhages (sICH). Symptomatic
intracranial bleeding in stroke patients treated with iv
rtPA is approximately 6%-8%2-4 and is associated with a
worse clinical outcome. It is, however, not known what
proportion of a worse outcome is attributable to sICH
as there is an overlap between the risk factors for
thrombolysis-associated sICH and those for poor
outcome after thrombolytic therapy with no sICH.2
Many studies have evaluated sICH risk factors in
patients receiving thrombolytic therapy, and 2 recent
systematic reviews identified the most relevant ones:
hyperglycemia, early ischemic changes on computed
tomography (CT)/magnetic resonance imaging scan,
clinical stroke severity assessed by the National Institutes
of Health Stroke Scale (NIHSS) score on admission,
advanced age, and high blood pressure.2,3,5-10
The pathophysiological mechanisms of hemorrhagic
cerebral transformations could result from the reperfusion of intracranial arteries whose integrity has been disrupted by cerebral ischemia, with an alteration in the
bloodbrain barrier and an increase in capillary permeability.3
Within this complex pathophysiological process, a central role is played by fibrinogen. rtPA binds to plasminogen within the clot, converting it to plasmin that is a
proteolytic enzyme capable of breaking cross-links between fibrin molecules and so dissolving clots, releasing
fibrin(ogen) degradation products (FDPs). It is important
to note, however, that plasmin is fairly nonspecific in its
activity and, besides fibrin, will also break down other
circulating proteins, including fibrinogen.11,12 In short,
although rtPA is relatively selective for clot-associated
fibrin, it can produce a systemic fibrinolytic state (with a
secondary hypofibrinogenemia and a D-dimer increase12)
and bleeding complications, which were first reported in
the setting of the treatment of acute myocardial infarction
(AMI). The Thrombolysis in Myocardial Infarction trial13
showed that both streptokinase and rtPA caused a
decrease in fibrinogen levels and an increase in FDP
and that the rate of hemorrhagic events was higher in patients with increased FDP in both treatment groups and in
patients with reduced fibrinogen levels in the rtPA group.
Moreover, there were more hemorrhages in patients with
greater plasma changes, underlining the importance of
coagulation parameters.13,14 Collen et al15 analyzed coagulation and fibrinolysis parameters during intravenous
rtPA infusions in patients with AMI and showed that
the extent of fibrinogen breakdown is occasionally very

395

important, with a decrease of fibrinogen level less than

1.0 g/L observed in 27% of rtPA-treated patients.
Experience and information on the subject of ischemic
stroke are poor and sparse. Only 1 recent work by Matosevic et al16 evaluated the extent of fibrinogen depletion
in rtPA thrombolysis in stroke patients and its association
with intracranial and extracranial bleeding: they showed
that a fibrinogen decrease is a significant predictor for
bleeding risk and that a temporal relationship exists
with the manifestation of hemorrhage.
For these reasons, we decided to study early modifications in fibrinogen levels pre- and post-thrombolysis, to
assess if they are significantly involved in iv rtPArelated ICH in ischemic stroke patients.

Materials and Methods

Study Population
We studied consecutive patients with acute ischemic
stroke treated with iv infusion of Alteplase (Actilyse, a
tPA produced by recombinant DNA technology) from
January 1, 2010, to January 1, 2011, in our stroke unit. Patients selection was made according to the Safe Implementation of Thrombolysis in Stroke-Monitoring Study
criteria and the European Cooperative Acute Stroke
Study-3 time window (,4.5 hours). A few of treated patients were included in randomized control trials, such
as International Stroke Trial-3, Synthesis Expansion, and
Thrombolysis in Elderly Stroke Patients in Italy trial, an
Italian randomised controlled trial in patients older than
80 years.
The following data were collected on each patient: age,
gender, clinical stroke severity assessed by NIHSS preand post-thrombolysis, fibrinogen level at admission
and 2 hours after the end of rtPA infusion, baseline glycemia, baseline platelet count, and blood pressure levels.

Plasmatic Fibrinogen Dosage

Peripheral blood samples were drawn from each patient, on entry to the emergency room and 2 hours after
the end of fibrinolytic infusion. Fibrinogen levels were
determined on fresh plasma obtained from blood
collected in 5-mL vacuum tubes containing .5 mL sodium
citrate (.129 mol/L). The assay was performed using the
HemosIL Fibrinogen-C kit assay based on the Clauss
method on ACL TOP Coagulation Systems (Instrument
Laboratory, Milan, Italy). The Fibrinogen-C kit uses
an excess of thrombin to convert fibrinogen to fibrin in
diluted plasma. At high thrombin and low fibrinogen
concentrations, the rate of reaction is a linear function of
the fibrinogen concentration.

Neuroimaging
On admission, all patients underwent a noncontrast
brain CT scan, which was repeated about 24 hours and

L. VANDELLI ET AL.

396

7 days post-treatment; an additional control scan was conducted whenever neurologic worsening was observed in
the first 7 days. We considered every intracranial bleeding
that occurred within the first 7 days post-thrombolysis,
including both symptomatic and asymptomatic hemorrhages, classifying them according to the Safe Implementation of Thrombolysis in Stroke radiological criteria.
Early hemorrhages (early ICH) were those occurring
within 24 hours post-thrombolytic treatment. Hemorrhagic transformations were categorized as sICH if
patients had neurologic deterioration with an NIHSS increase of more than 1 point and if the CT scan revealed
blood at any site in the brain irrespective of its extension
(National Institute of Neurological Disorders and Stroke
classification). All neuroimaging studies were reviewed
by 2 independent, certified, expert neurologists blinded
to fibrinogen-level assessment.

Statistical Analysis
We assessed fibrinogen-level changes after thrombolytic therapy. A threshold of fibrinogen plasma value critical for the development of bleeding is not reported in the
literature. Some studies13,15 have reported a correlation
between bleeding and fibrinogen values less than 1.5 or
1.0 g/L or less than 1.0 and .5 g/L. A more recent study,
which evaluated the role of fibrinogen concentrate
substitution therapy in patients with massive hemorrhage and low plasma fibrinogen concentrations, considered 2 g/L to be the threshold value.17
On these grounds, we performed a logistic regression
analysis that analyzed different levels of both absolute
fibrinogen plasma values and percentage decrease. We
analyzed the following absolute fibrinogen plasma levels
as independent variables: lower than 3, 2.5, 2, and 1. We
then tested the percentage decrease of fibrinogen values
calculated as the percentage of the proportion between
the difference of fibrinogen values after and before treatment, divided by the fibrinogen value before treatment:
% decrease5fibrinogen value after treatment2
fibrinogen value before treatment=
fibrinogen value before treatment%:
For the analysis, we considered only negative values that
indicate a decrease in the fibrinogen values after the treatment, and we chose to analyze decreases exceeding 45%,
40%, 35%, 30%, 25%, 20%, 15%, and 10%.
After these analyses, we set the cutoff values as fibrinogen absolute levels after treatment below 2 g/L and/or
25% decrease or more, between pre- and post-treatment.
This choice derives from the comparison of the logistic
regression results between the infarction (dependent
variable) and the different absolute values of fibrinogen
and between the infarction (dependent variable) and the
different values of percentage decrease in fibrinogen: in

both cases, we chose the values associated with the result

showing a greater statistical significance (lower P-value).
A Pubmed search was conducted looking for sICH risk
factors after thrombolytic therapy, focusing primarily on
systematic reviews.2,3,5-10 From these data, the following
variables were indicated as being most closely related
to hemorrhagic transformation: hyperglycemia, clinical
stroke severity assessed by baseline NIHSS, age, sex,
and high blood pressure. A logistic regression analysis
was then conducted on each single parameter.
The study population was splitted into 2 groups: a
low fibrinogen group and a normal fibrinogen group,
to compare important statistical data (eg, mean age,
mean NIHSS, mean fibrinogen level pre- and postthrombolysis) and to evaluate any significant differences
between the groups. The low fibrinogen group included
all patients with post-thrombolysis fibrinogen levels less
than 2 g/L and/or a 25% or more decrease of fibrinogen
levels respect to baseline, whereas all other patients were
included into the normal fibrinogen group. Univariate
and multivariate logistic regression analyses were performed to evaluate if fibrinogen levels and other parameters (age, sex, NIHSS, baseline glycemia, baseline blood
pressure) were independent risk factors for ICH.
We also analyzed the occurrence of ICH and sICH
(within 24 hours and 7 days), comparing low and normal
fibrinogen groups using contingency tables with Pearson
chi-square, to verify a possible association between fibrinogen levels and early onset of ICH or sICH.

Results
A total of 104 patients were included in this study, 66
(63.5%) men and 38 (36.5%) women. The mean age was
66.6 years (standard deviation [SD] 13.5; range 21-91)
and the mean baseline NIHSS was 10.9 (SD 7.2; range
2-34).
On the seventh day follow-up CT scan, 24 patients
(23.1%) presented ICH (3 HI1, 8 HI2, 2 PH1, 7 PH2, and
4 PHr1), 14 of which developed in the first 24 hours
(3 HI1, 3 HI2, 1 PH1, 4 PH2, and 3 PHr1). Only 6 patients
(5.8%) experienced sICH according to the NINDS classification.
Mean fibrinogen pretreatment level was 3.34 g/L (SD
1.1) with a significant decrease after thrombolysis
(2.47 g/L, 226%, SD .8; P , .001 respect to baseline).
Logistic analysis found a significant association between
baseline fibrinogen value and ICH (P 5 .048) that became
more significant when comparing ICH and fibrinogen
post-thrombolysis level (P 5 .029).
A logistic regression analysis of the most well-known
ICH risk factors (age, sex, baseline NIHSS, 24-hour
NIHSS, pre-rtPA arterial blood pressure, pre-rtPA glycemia; baseline platelet count) showed that only baseline
NIHSS (P , .001) and 24-hour NIHSS (P , .001) were
significantly associated with ICH (Table 1).

FIBRINOGEN DECREASE AFTER INTRAVENOUS THROMBOLYSIS IN STROKE PATIENTS

397

Table 1. Univariate logistic regression analysis: risk factors

for ICH post-thrombolysis
Variable
Fibrinogen level ,2.0 g/L
and/or .25% decrease
Fibrinogen level ,2.0 g/L
Fibrinogen level
decreased .25%
Platelet count
Sex
Age
Glycemia
Blood systolic pressure
Baseline NIHSS
24-h NIHSS

OR

95% CI

7.43 ,.001 2.620-21.100

2.83
.051 .994-8.075
8.36 ,.001 3.002-23.309
1.00
.485 .996-1.008
.83
.710 .318-2.180
1.19
.138 .945-1.499
1.01
.054 1.000-1.019
1.01
.569 .983-1.031
1.16 ,.001 1.082-1.253
1.11 ,.001 1.051-1.168

Abbreviations: ICH, intracerebral hemorrhage; NIHSS, National

Institutes of Health Stroke Scale.
Bold values indicate P , .05.

A subsequent logistic regression analysis comparing

different post-rtPA fibrinogen cutoff values (,1.0, ,2.0,
,2.5, and ,3.0 g/L) showed that a cutoff value less
than 2 g/L offered the best predictive risk factor for
ICH, although it did not reach a statistical significance
(P 5.051, odds ratio [OR] 5 2.83). The regression analysis,
after a class-based analysis with different rates of fibrinogen reduction (45%, 40%, 35%, 30%, 25%, 20%, 15%,
and 10%), showed that a higher ICH risk lies in a 25%
or more decrease in fibrinogen levels. Based on the results
of regression analysis, the patient cohort was divided in
the 2 main groups: low fibrinogen group and normal
fibrinogen group as described earlier.
The low fibrinogen group was composed of 41 patients
(39.4%); 6 of them (5.8% of the whole population) had
post-rtPA fibrinogen levels less than 2 g/L, 21 (20.2% of
the whole population) had a decrease of 25% or more
respect to baseline and 14 patients had a reduction in
both values (13.5%).
Among the 24 patients who presented ICH, 18 were in
the low fibrinogen group (Figs 1 and 2) and 6 were in the
normal fibrinogen group. The ICH rate during the first
7 days in the low fibrinogen group was significantly
higher (43.9%) than that (9.5%) in the normal fibrinogen
group (OR 7.43, P , .001; Table 1). The difference remained statistically significant when the analysis was
restricted to the patients showing only a fibrinogen
decrease greater than 25% (P , .001; OR 8.36; Table 1).
Patient characteristics included in the low fibrinogen
and normal fibrinogen groups are summarized in
Table 2, showing the absence of significant differences
except for baseline NIHSS scores and baseline fibrinogen
levels. A further subanalysis divided patients into mild
(NIHSS score 0-7), moderate (NIHSS score 8-15), and
severe (NIHSS score .15) clinical severity groups: similar

Figure 1. A noncontrast brain computed tomographic scan of a patient

belonging to low fibrinogen group that experienced post-thrombolysis parenchymal hematoma in the contest of a left frontotemporal ischemic lesion (PH2
type according to the Safe Implementation of Thrombolysis in Stroke radiological criteria), with associated intraventricular hemorrhage.

NIHSS values were found in each group, in particular in

the severe one (Table 3).
In conclusion, the univariate analysis showed that
the only variables significantly associated with ICH were
baseline NIHSS, 24-hour NIHSS, and belonging to the

Figure 2. A noncontrast brain computed tomographic scan of another low

fibrinogen group patient that presented multiple parenchymal hematomas after intravenous recombinant tissue plasminogen activator infusion: the
largest one in the contest of a left parieto-occipital ischemic lesion (PH2
type) and some other minor contralateral parenchymal hematomas, remote
from the ischemia (PHr1 type).

L. VANDELLI ET AL.

398

Table 2. Comparison of patient characteristics between

normal and low fibrinogen groups
Low
fibrinogen Normal
group, N group, N

Variable
Age (mean)
Sex (male %)
Baseline NIHSS (mean)
24-h NIHSS (mean)
Glycemia (mean)
Blood pressure (systolic)
Blood pressure (diastolic)
Platelet count
Fibrinogen-level
prethrombolysis (mean)

66.71
65.9
12.8
9.34
135.78
148.63
78.54
207.73
362.21

66.46
61.9
9.71
7.27
133.86
146.78
78.71
192.11
311.72

P
NS
NS
.031*
NS
NS
NS
NS
NS
.028*

Abbreviation: NIHSS, National Institutes of Health Stroke Scale.

Bold values indicate P , .05.
*P , .05.

low fibrinogen group (fibrinogen levels post-thrombolysis

,2 g/L and/or a $25% decrease). This finding was
confirmed by the multivariate analysis (Table 4).
Considering early ICH, 14 events were found, 10 in the
low fibrinogen group (71.4% of early ICH and 9.62% of
total ICH) and 4 in the normal fibrinogen group (28.6%
of early ICH and 3.85% of total ICH), showing that hemorrhagic risk remains significantly higher in the low
fibrinogen group when analyzing only ICH less than
24-hour subgroup (P 5 .008; Table 5).
Of the 6 sICH reported, 5 (83.3%) occurred during the
first 24 hours post-thrombolysis. The logistic regression
analysis for sICH and early sICH did not reveal statistical
significance between the normal and low fibrinogen
groups (P . .05; Table 5).

Discussion
The development of ICH is the most serious adverse
event related to iv rtPA as it carries a relevant morbidity

Table 3. Subgroup analysis of baseline clinical severity

between low and normal fibrinogen groups

Clinical severity
Mild (NIHSS
score 0-7)
Moderate (NIHSS
score 8-15)
Severe (NIHSS
sore .15)

Fibrinogen
group
Mean
Normal
Low
Normal
Low
Normal
Low

4.83
4.31
10.48
11.36
20.58
22.14

P*

SD

30
13
21
14
12
14

1.46
1.75 .319
2.58
2.50 .324
3.34
4.82 .355

Abbreviation: NIHSS, National Institutes of Health Stroke Scale.

*Significance P , .05.

Table 4. Multivariate logistic regression analysis of risk

factors for ICH post-thrombolysis
Variable

OR

95% CI

Fibrinogen level ,2.0 g/L

and/or .25% decrease
Baseline NIHSS
Glycemia
Blood systolic pressure

7.47

,.001

2.26-24.74

1.15
1.01
1.00

,.001
.131
.802

1.06-1.25
1.00-1.02
.97-1.03

Abbreviations: ICH, intracerebral hemorrhage; NIHSS, National

Institutes of Health Stroke Scale.
Bold values indicate P , .05.

and mortality.4 In our study, we found an overall ICH

rate within the first 7 days of 23.1%, which is lower
than that reported from previous studies.18 Similarly, we
found 6 patients with sICH (5.8%), a rate comparable
with those reported in the literature (6%-8%).2-4
Many studies in the literature have reported various
risk factors for ICH, the most relevant of which are age,
clinical severity, pre-rtPA arterial blood pressure, and
pre-rtPA glycemia.2,3
In our study, we found that the only already known
variables significantly associated with the development
of ICH are baseline NIHSS (OR 1.16, P , .001) and
24-hour NIHSS (OR 1.11, P , .001) (Table 1) because
neither baseline blood glucose nor systolic blood pressure
pretreatment attained the statistical significance.
On the other hand, we demonstrated by logistic
regression analysis that a decrease in post-thrombolysis
fibrinogen levels of less than 2 g/L and/or of 25% or
more (low fibrinogen group) was statistically significantly related with post-rtPA ICH. Indeed, in this patient
group, the ICH rate within 7 days was 43.9%, significantly higher than the 9.5% of the normal fibrinogen
group (OR 7.4, P , .001) (Table 1). When the 2 subgroups
of patients included in the low fibrinogen group
were separately analyzed, however, the results were

Table 5. Logistic regression analysis of fibrinogen decrease

as risk factor for ICH, early ICH, sICH, and early sICH
Low
Normal
Total
Subgroups of fibrinogen fibrinogen
hemorrhage (n 5 63) (n 5 41) (n 5 104)
ICH
Early ICH
sICH
Early sICH

6 (9.5%)
4 (28.6%)
2 (33.3%)
2 (40%)

18 (43.9%)
10 (71.4%)
4 (66.7%)
3 (60%)

24
14
6
5

P
,.001*
.008*
.586
.480

Abbreviations: ICH, intracerebral hemorrhage; sICH, symptomatic intracerebral hemorrhage.

Bold values indicate P , .05.
*P , .05.

FIBRINOGEN DECREASE AFTER INTRAVENOUS THROMBOLYSIS IN STROKE PATIENTS

somewhat different. Indeed, considering only patients

with fibrinogen decreases of 25% or more, the difference
remains statistically significant (OR 8.36, P , .001),
whereas those with fibrinogen levels less than 2 g/L
did not, although the results were at limit of significance
(OR 2.83, P 5 .051).
Our data are in line with results recently published by
Matosevic et al,16 which showed that a 6-hour reduction
in fibrinogen levels greater than 2 g/L after thrombolysis canas with stroke severity, diabetes, and subtherapeutic Vitamin K Antagonists pretreatmentheighten
the risk of sICH and systemic bleeding. Moreover, as
also reported in the Matosevic study, we found that a
higher baseline fibrinogen level seems to enhance the
risk of a more significant decrease post-treatment. This
suggests a correlation between extent of fibrinogen
depletion (delta pre- and post-rtPA) and baseline fibrinogen values that could be explained by a consumption
effect, that is, a more active early fibrinogen degradation coagulopathy.
These findings support the hypothesis that postthrombolysis intracranial bleedings are, at least partially,
linked to an early rtPA-related coagulopathy that causes
a fibrinogen breakdown because of rtPAs relative selectivity for clot-associated fibrin.11,12 This type of coagulopathy, with an early increase in FDP and fibrinogen
consumption, was first described in iv thrombolytic
therapy used for AMI.13-15 Some years later, Trouillas19
studied the possible correlation between acquired hypofibrinogenemia and sICH after thrombolysis in stroke patients and found that an increase in FDP, like D-dimer,
2 hours post-thrombolysis was statistically significant
and appeared to be a predictive factor for early parenchymal hematomas (,24 hours).
Nevertheless, we consider FDP a less specific parameter than fibrinogen of such coagulopathy: in fact,
D-dimer, which is the most frequently measured FDP,
always increases after a cerebral ischemic event, even
without thrombolysis12 as it is a by-product of clot degradation and remodeling that constantly occurs during
vessel occlusion.
Other factors have been implicated in the genesis of
rtPA-related sICH, such as the pretreatment levels of
fibrinolysis inhibitors (ie, plasminogen activator inhibitor-17,8 or matrix metalloproteinases-920), but studies
gave conflicting results. Moreover, the methods for
determining plasma levels of these biomarkers are
both very expensive and too slow for use in emergencies, and therefore, they cannot be used to stratify
sICH risk in rtPA therapy decision making. On the
contrary, determining fibrinogen levels is very quick,
easy, and cheap and can be performed in any hospital
laboratory.
The decrease in fibrinogen was demonstrated to be
a significant risk factor for bleeding, even when the
analysis was restricted only to early (ie, within 24 hours

399

from treatment) ICH (P 5 .008; Table 5). This aspect is

very important as some authors have suggested that
only early ICH can regarded as linked to thrombolysis because of the rtPA short plasma half-life (around
5 minutes).
Matosevic et al16 found that most of bleeding occurred
between 2 and 24 hours post-thrombolysis, an interval
that broadly overlaps with the period in which fibrinogen
degradation coagulopathy develops. For this reason, they
evaluated the fibrinogen decrease 6 hours post-rtPA therapy and its correlation with hemorrhages. On the other
hand, other studies on post-fibrinolysis hemostatic
changes in myocardial infarction patients have shown
that fibrinogen reaches its lowest point some time between 90 minutes and 3 hours.21,22 On these grounds,
and on the pharmacologic basis of the short rtPA halflife, we decided to restrict the analysis of fibrinogen levels
to 2 hours post-thrombolysis, assuming a very early
fibrinogen-related coagulopathy.
In our study, the analysis of sICH, either early or total,
failed to show a statistically significant correlation with
fibrinogen levels (Table 5), but this finding could be explained by the very small number of patients with
sICH, making it difficult to reach reliable conclusions.
One limitation of our study was the significant difference in baseline NIHSS score that existed between the
normal and low fibrinogen groups. This factor could
diminish the relevance of our results as it makes it
less clear whether the greater bleeding rate in the low
fibrinogen group was attributable to the fibrinogen
decrease itself or to clinical severity. As a final point,
the limited number of included patients did not allow
a reliable stratification of study population in several
subgroups of patients, such as those with sICH and
early sICH.
In conclusion, an early decrease in fibrinogen levels
seems to represent a risk factor for ICH within the first
7 days after rtPA therapy and even within the first
24 hours in ischemic stroke patients. This result confirms
the hypothesis that iv rtPA causes a related coagulopathy
because of relative selectivity of Alteplase for clotassociated fibrin, which results in fibrinogen breakdown.
We, therefore, recommend assessing fibrinogen levels
before and 2 hours postinfusion of rtPA in all thrombolyzed patients: this would allow the identification of patients at higher bleeding risk. The rapidity, cheapness,
and wide availability of such a test further reinforce the
utility value of this parameter.
Further RCT studies could assess the preventive role of
therapies like fibrinogen intravenous replacement or
plasma transfusion in the low fibrinogen group in avoiding post-thrombolysis ICH.
Acknowledgment: The authors thank all neurologists
and nurses working in Neurology Clinic at Nuovo Ospedale
Civile S.Agostino-Estense.

L. VANDELLI ET AL.

400

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