UUNNIIVVEERRSSIITTYY OOFF MMEEDDIICCIINNEE AANNDD PPHHAARRMMAACCYY [613418]

UUNNIIVVEERRSSIITTYY OOFF MMEEDDIICCIINNEE AANNDD PPHHAARRMMAACCYY
CCRRAAIIOOVVAA
DDOOCCTTOORRAALL SSCCHHOOOOLL

PPhhDD
TTHHEESSIISS

CCOONNTTRRIIBBUUTTIIOONNSS TTOO TTHHEE SSTTUUDDYY
OOFF TTHHEE CCLLIINNIICCAALL–MMOORRPPHHOOLLOOGGIICCAALL
PPRROOFFIILLEE OOFF CCEERREEBBRRAALL HHAAEEMMOORRRRHHAAGGEE
–AABBSSTTRRAACCTT–

Scientific Coordinator:
PPrrooffeessssoorr IIaannccuu EEmmiill PPLLEEȘȘEEAA
PhD Student: [anonimizat]
22001133

22
TTAABBLLEE OOFF CCOONNTTEENNTTSS
C O N T E N T S ………………………….. ………………………….. ..I
A B B R E V I A T I O N S ………………………….. ……………. VI
I N T R O D U C T I O N ………………………….. ………………… 1
B A C K G R O U N D ………………………….. …………………… 4
CHAPTER I BRAIN MOR PHOLOGY ELEMENTS ………… 5
CEREBRAL VASCULARIZAT ION ………………………….. ………………………….. …………. 6
Arterial vascularization ………………………….. ………………………….. …………….. 6
Cerebral Venous System ………………………….. ………………………….. ……….. 27
NEUROVASCULAR UNIT ………………………….. ………………………….. ………………… 33
Overview ………………………….. ………………………….. ………………………….. …. 33
Anatomical description ………………………….. ………………………….. …………… 34
Alteration of Junction ………………………….. ………………………….. …………….. 40
CEREBROSPINAL FLUID S PACES ………………………….. ………………………….. …….. 41
Spaces arising from primitive neural tube ………………………….. ……………… 41
Subarachnoid space ………………………….. ………………………….. ……………… 44
CHAPTERL II C E R E B R A L H A E M O R R A G E .. 47
INTRODUCTION ………………………….. ………………………….. ……………………… 48
DEFINITION AND CLASSI FICATION ………………………….. ………………………….. ……. 48
EPIDEMIOLOGY ………………………….. ………………………….. ………………………….. 49
RISK FACTORS ………………………….. ………………………….. ………………………….. . 49
Modifiable risk factors ………………………….. ………………………….. ……………. 49
Non – modifiable risk factors ………………………….. ………………………….. …… 50
AETIOLOGY ………………………….. ………………………….. ………………………….. ….. 51
Hypertension ………………………….. ………………………….. ………………………… 51
Amyloid angiopathy ………………………….. ………………………….. ……………….. 52
Vascular malformations ………………………….. ………………………….. …………. 52
TRIGGERS ………………………….. ………………………….. ………………………….. ……. 55
Endogenous triggers ………………………….. ………………………….. ……………… 55
Exogenous triggers ………………………….. ………………………….. ……………….. 55
PATHOGENESIS ………………………….. ………………………….. …………………………. 56
Hematoma formation ………………………….. ………………………….. …………….. 56
PATHOLOGY ………………………….. ………………………….. ………………………….. …. 57
Localisation ………………………….. ………………………….. ………………………….. 57
Other macroscopic aspects of ICH ………………………….. ………………………. 60
CLINICAL FEATURES OF ICH ………………………….. ………………………….. …………. 66
Clinical assessment scales ………………………….. ………………………….. …….. 67
IMAGING INVESTIGATIONS ………………………….. ………………………….. …………….. 69
Native Computed Tomography ………………………….. ………………………….. .. 69
Computed Tomography Angiography ………………………….. …………………… 69
Magnetic Resonance Imaging ………………………….. ………………………….. … 70
NEW THERAPEUTIC TREND S ………………………….. ………………………….. ………….. 70
EVOLUTION AND PROGNOS IS ………………………….. ………………………….. …………. 72
ICH PROFILAXY ………………………….. ………………………….. …………………………. 73

33
P E R S O N A L C O N T R I B U T I O N ………………….. 74
CHAPTER III MATERIA L AND METHODS ………………… 75
MATERIALS ………………………….. ………………………….. ………………………….. …… 76
Inclusion criteria ………………………….. ………………………….. ……………………. 76
Study groups ………………………….. ………………………….. ………………………… 77
Data sources ………………………….. ………………………….. ………………………… 78
METHODS ………………………….. ………………………….. ………………………….. ……. 78
Type of study ………………………….. ………………………….. ……………………….. 78
Aim of study ………………………….. ………………………….. …………………………. 78
Parameters ………………………….. ………………………….. ………………………….. 79
Acquisition of microscopic images ………………………….. ……………………….. 85
Statistical analysis ………………………….. ………………………….. …………………. 85
Scales of parameter stratification ………………………….. …………………………. 86
CHAPTER IV CLINICAL STUDY ………………………….. …. 91
CEREBRAL HAEMORRHAGE STATISTICS WORLDWIDE ………………………….. ……….. 92
TEMPORAL DISTRIBUTION ………………………….. ………………………….. ……………… 93
Annual variation ………………………….. ………………………….. ……………………. 93
Monthly variation ………………………….. ………………………….. …………………… 94
Seasonal Variation ………………………….. ………………………….. ………………… 95
GENDER ………………………….. ………………………….. ………………………….. ………. 96
SOCIAL ENVIRONMENT ………………………….. ………………………….. …………………. 97
AGE GROUPS ………………………….. ………………………….. ………………………….. … 98
HYPERTENSION SEVERITY ………………………….. ………………………….. …………… 100
OTHER RISK FACTORS ………………………….. ………………………….. ……………….. 101
IMPAIRMENT OF CONSCIO USNESS ………………………….. ………………………….. …. 103
STROKE SEVERITY ………………………….. ………………………….. ……………………. 104
NIHSS score at admission ………………………….. ………………………….. ……. 104
NIHSS score at discharge ………………………….. ………………………….. …….. 105
THROMBOEMBOLIC EVENTS ………………………….. ………………………….. …………. 107
TYPE OF DISCHRGE ………………………….. ………………………….. …………………… 109
LENGTH OF STAY ………………………….. ………………………….. ……………………… 110
FINAL COMMENTS ON THE CLINICAL STUDY ………………………….. ………………….. 112
CHAPTER V MORPHOLOGICAL STUDY ……………….. 114
MACROSCOPIC STUDY ………………………….. ………………………….. ………………. 115
Hemorrhagic foci topography ………………………….. ………………………….. … 115
Deep Intracerebral Hemorrhage ………………………….. ………………………… 118
Lobar Intracerebral Hemorrhage ………………………….. ………………………… 123
Brainstem and cerebellar hemorrhage ………………………….. ………………… 130
Dimensions of hemorrhagic foci ………………………….. …………………………. 132
Intraventricular haemorrhage and s ubarachnoid effusion…………………… 148
Perilesional edema and mass effect ………………………….. …………………… 150
MORPHOLOGICAL STUDY O F VESSEL WALL CHANGE S………………………….. ……… 153
Overview ………………………….. ………………………….. ………………………….. .. 153
Perilesional edema ………………………….. ………………………….. ……………… 159
Microbleeds presence ………………………….. ………………………….. ………….. 161
Changes of the large arteries wall ………………………….. ……………………… 163
Changes of the penetrant arteries and arterioles wall ………………………… 168
Capillary changes ………………………….. ………………………….. ……………….. 172

44
Genesis of hemorrhagic foci ………………………….. ………………………….. …. 177
FINAL COMMENTS ON THE MORPHOLOGICAL STUDY ………………………….. ……….. 178
CHAPTER VI CLINICAL – MORPHOLOGICAL
CORRELATIONS ………………………….. ………………………….. . 183
PROGNOSTIC IMPACT OF THERAPY ………………………….. ………………………….. .. 184
DISCHRGE STATUS – AGE ………………………….. ………………………….. ……………. 185
DISCHRGE STATUS – HYPERTENSION ………………………….. ………………………….. 186
DISCHRGE STATUS – GCS SCORE ………………………….. ………………………….. … 186
DISCHRGE STATUS – NIHSS SCORE ………………………….. ………………………….. 187
DISCHRGE STATUS – LENGTH OF HOSPITALISA TION ………………………….. ……….. 188
DISCHRGE STATUS – THROMBOEMBOLIC EVENTS ………………………….. ………….. 189
DISCHRGE STATUS – HEMATOMA TOPOGRAPHY ………………………….. ……………. 190
DISCHRGE STATUS – HEMATOMA VOLUME ………………………….. …………………… 191
DISCHRGE STATUS – INTRAVENTRICULAR HEMO RRHAGE ………………………….. …. 192
DISCHRGE STATUS – SUBARACHNOID EFFUSIO N ………………………….. ……………. 192
HEMATOMA TOPOGRAPHY – AGE ………………………….. ………………………….. ….. 193
HEMATOMA TOPOGRAPHY – HYPERTENSION ………………………….. ……………….. 194
HEMATOMA TOPOGRAPHY – GCS SCORE ………………………….. ……………………. 195
HEMATOMA TOPOGRAPHY – NIHSS SCORE ………………………….. ………………… 196
HEMATOMA TOPOGRAPHY – INTRAVENTRICULAR HEMO RRHAGE ……………………. 197
HEMATOMA TOPOGRAPHY – LENGTH OF HOSPITALISA TION ………………………….. 198
HEMATOMA VOLUME – HYPERTENSION ………………………….. ………………………. 199
HEMATOMA VOLUME – GCS SCORE ………………………….. ………………………….. . 200
HEMATOMA VOLUME – NIHSS SCORE ………………………….. ……………………….. 201
HEMATOMA VOLUME – INTRAVENTRICULAR HEMO RRHAGE ………………………….. .. 201
INTRAVENTRICULAR HEMO RRHAGE – HYPERTENSION ………………………….. …….. 202
INTRAVENTRICULAR HEMO RRHAGE – GCS SCORE ………………………….. ………… 203
INTRAVENTRICULAR HEMO RRHAGE – NIHSS SCORE ………………………….. ……… 204
FINAL COMMENTS ON THE CLINICAL – MORPHOLOGICAL CORREL ATIONS STUDY …. 205
C O N C L U S I O N S ………………………….. ………………. 207
R E F E R E N C E S ………………………….. …………………. 210
LITERATURE REFERENCES ………………………….. ………………………….. ………….. 211
PERSONAL REFERENCES ………………………….. ………………………….. ……………. 233

55
AABBBBRREEVVIIAATTIIOONNSS
ACA Anterior cerebral artery
ACC Common carotid artery
AchA Anterior choroidal artery
ACI Internal carotid artery
ACM Middle cerebral artery
ACoA Anterior communicating artery
ACoP Posterior communicating artery
ACP Posterior cerebral artery
ACS Superior cerebellar artery
AICA Anterior – Inferior cerebellar artery
AIT Transient ischemic attack
AngioCT Computer Tomography Angiography
AVC Stroke
BHE Blood -brain barrier
CT Computer Tomography
DZ Diabetes
ECG Electrocardiogram
GSC Glasgow Coma Scale
HE Hematoxylin – Eosin
HIC Intracranial hypertensions
HSA Subarachnoid hemorrhage
HTA Hypertension
HVS Left ventricular hypertrophy
ICH Intracer ebral hemorrhage
IHC Immunohistochemistry
IMA Acute Myocardial Infarction
IV Intraventricular
LCR Cerebrospinal fluid
MAV Arteriovenous malformation
NIHSS National Institutes of Health Stroke Scale
OMS World Health Organization
PICA Posterior – Inferior cerebellar artery
rFVIIa Recombinant activated factor VII
RMN Magnetic resonance imaging
TA Blood pressure
TEPA Pulmonary thromboembolism
Tn T Troponin T
TVP Deep vein thrombosis
VSH Erythrocyte sedimentation rate
KKEEYY WWOORRDDSS::
Intracerebral haemorrhage, hemostatic therapy, hematoma volume

66
IINNTTRROODDUUCCTTIIOONN
The c erebral h aemorrhage ( ICH ) is a devastating form of stroke , representing
one of the main cause of death nowadays . It has a major impact on the public health
not only by its enormous costs of the hospitalization and the patient management
but also by productivity reduction, the cerebral h aemorrhage being a n impairment
that outruns severe disability ( Earnshaw et al., 2006).
By its ethiopathogenic and topographic features, the cerebral haemorrhage
imposes a personalised treatment , sometimes with neurosurgical possibilities some
other time a strict conservative treatment.
Paradoxically , in spite of the fact that the percentage of the hospitalized patients
with cerebral haemorrhage has increased lately , there has n’t been registred
simultaneously any reduction of the mortality ( Lloyd -Jones et al., 2010).
This aspect is probably due to the lack of any specific medication treatment .
If until this present thesis there isn’t any hope to have a drug therapy able to
determine the rapid resorption of haemorrhage, there is the real possibility of a
therapy that aims at a frightening precious complication, that is the hematoma
expansion: rec ombinant activated Factor VII therapy.
Recombinant activated F actor VII or eptacog alpha is a protein got from genetic
engineering , structurally and functionally similar to Factor VII from human plasma ,
destined initial ly to the therapy of haemophilic pati ents.
This u se in neurology and neurosurgery has generated various controversials
for some time . It arrest ongoing bleeding but it also has thromboembolic side effects ,
it doesn’t improve long -term prognosis at all patients and the therapy is very
expensive , according to some clinicians.
The r esearchers agreed with the necessity of careful selection based on pre-
established criteria of the patients candidates for this kind of therapy and also the
reconsidering p osition regarding the effective therapy dose .
Monotherapy with rFVIIa has already been test ed in several clinical trials
(Mayer et al. 2005 , 2008).
The s tudies achieved recently as well as the ones ongoing in the world, have
already identified the selection potential criteria of the patients by adding to the well –
known clinical and biological criteria , a new paraclinic criterion : biomarker "spot sign "
highlighted by the examination of the Computer Tomography Angiog raphy (Demchuk
et al., 2012).
On the other hand there are discovered new properties to the vitamin K:
vasoprotective, neuroprotective and modulatory proprieties through the dependent
proteins of the stem cells proliferation at the level of the subventricular niche and
constitues a nece ssity to some patients with aquired Factor VII deficiency (Gely –
Pernot et al., 2012; Chou, Inks & Josey , 2013).
Taking into consideration these aspects as well as the fact that I haven’t found
information in the Romanian literature related to the morpho logical study of cerebral
haemorrhage according to the treatment , particularly the one treated with rFVIIa and
Vitamin K , I proposed myself to approach this subject.
Thus, the present thesis tries to be a modest contribution to the understanding
of this re doubtable disease.

77
SSTTAATTEE OOFF KKNNOOWWLLEEDDGGEE
In the first part of the paper consisting of two chapters, I have tried to outline a
formal introduct ion and a review regarding the elements of brain morphology on one
hand and on the other hand, a detailed description of the la test data regarding the
epidemiology , etiology, pathogenesis, diagnosis and treatment of cerebral
hemorrhage.
PPEERRSSOONNAALL CCOONNTTRRIIBBUUTTIIOONN
The second part of the paper, representing personal contribution is divided into
four main chapters linked in a classical sequence of a research project.
In the f irst chapter, we defined the study materia l , described the research
methodology that we used, including parameter stratification scales , the algorithm of
brain hemorrhage morphological investigation , both macroscopic and microscopic
evaluation and use of computerized quantitative analysis for some of the parameters.
SSTTUUDDYY DDEESSIIGGNN
The study was conducted in two main directions
̵ a retrospective analysis that targeted the cases hosp italized and
diagnosed in 200 8
̵ a prospective analysis that included patients newly admitted during the
period of the PhD, from 2009 to 2012
AAIIMM OOFF SSTTUUDDYY
̵ Assessment of hematoma behavior under different therapeutic protocols
̵ Identification of the mechanism that led to death by means of necropsy
MMAATTEERRIIAALL AANNDD MMEETTHHOODDSS
Based study consisted of 720 patients diagnosed with spontaneous
intracerebral hemorrhage , admitted to the Department of Neurology from Emergency
County Hospital of Slatina , during 2008 -2012 .
Patients with spontaneous intracerebral hemorrhage documented by brain
Computer Tomography examination performed at the admission were considered
potentially eligible.
The distribution of patients in the study groups was performed according to the
treatmen t protocol that w as applied ( Figure 1).
This afforded three study groups :
 Group A 319 cases that did not receive hemostatic treatment
 Group B 361 cases treated with standard doses of conventional
hemostatic s , in various combinations . Also , in this group there were
included cases that received rFVIIa therapy but where selection criteria,
imaging or treatment protocol was not fully respected
 Group C 40 cases selected based on pre-established criteria,
treated with a single dose of 20 µ g / kg of rFVIIa within 4 hours from the

88
symptoms onset followed by treatment with vitamin K 40 mg / day
divided in 4 doses , for 5 days
CCLLIINNIICCAALL SSTTUUDDYY
The second chapter of the special part included the analysis of the
epidemiological and clinical parameters; data were obtained both from clinical
observation sheets and rFVIIa cases report forms .

Figure 1: Algorithm for diagnosis and treatment of pati ents
MMOORRPPHHOOLLOOGGIICCAALL SSTTUUDDYY
The third chapter fo cused on morphological analysis; information was obtained
from :
̵ Computed Tomography images
̵ Autopsy – examining different parts of the brain during autopsy in order to
determine the diameters of the hematoma and collect tissue samples for
the microscopic examination.
Hematoma volume was determined by the ABC / 2 method. Although
this technique can result in errors, it was preferred do to the short time in
which hematoma volume was obtained ( Kothari et al. , 1996 Divani et al,
2011)

99
The samples were subjected to conventional histo logical processing techniques
Stains that we used were both classic and common for the different components of
the vascular structures : hematoxylin – eosin (HE ) for morphological evaluation and
van Gieson , Goldner , CD34 immunostaining for qualitative assessment of the
vascular structures .
Histopathological findings were selected using an Olympus microscope .
TTHHEE CCLLIINNIICCOO–MMOORRPPHHOOLLOOGGIICCAALL CCOORRRREELLAATTIIOONNSS
The last chapter of the special part aimed to establish correlations between
different parameters of morphological and clinical evaluation of cerebral hemorrhage.
SSttaattiissttiiccaall aannaallyyssiiss
For some of the clinical or morphological parameters scale of stratific ation were
used. Categorical data were analyzed using chi -square test and linear regression.
Some data with normal distribution were presented as mean ± SD and compared
using t test with two tails. P value of less than 0.05 was considered significant.
RREESSUULLTTSS AANNDD DDIISSCCUUSSSSIIOONN
CCLLIINNIICCAALL SSTTUUDDYY
The analysis of all clinical parameters in the three study groups yielded the
following results :
̵ Increased incidence of ICH in cold season, with peaks of incidence in
December and January
̵ Most patients were from count ryside areas , with a slight predominance of ICH
in male patients
̵ Cerebral hemorrhage occurs at relatively young age, immediately after the age
of 45 with upward trend until age of 65.
̵ Severe hypertension was present in most of the patients. Dyslipidemia ,
alcohol and smoking were the most frequent risk factors associated with ICH,
after hypertension
̵ Stroke severity was moderate to severe in most cases, often associated w ith
impairment of consciousness
̵ The best neurological improvement has been achieved i n patients of group C
̵ There were no thromboembolic events in the group C. The highest numb er of
thromboembolic events was observed in group A.
̵ A third of cases had poor outcome resulting in patients death or rapid
discharged at the request of their famil y/carers. Group B is where there have
been most unfavor able outcomes. The best outcome was recorded in patients
of group C where there have been no deaths or worsening of general condition
̵ Average length of stay in hospital for the patients treated with re combinant
activated Factor VII was 9.4 days. In the other study groups , the average
length of stay in hospital was shorter due to the deaths or the rapid discharges
on request after a short time of hospitalization.
MMOORRPPHHOOLLOOGGIICCAALL SSTTUUDDYY
Analysis of the macr oscopic morphological characteristics of the various forms of
cerebral hemorrhage has helped us to draw several conclusions:

1100
̵ The most common location of intracerebral hemorrhage was in the deep gray
matter . At this level, capsulo – thalamic area was the most common affected
with a hematoma volume below 30 ml in all study groups
̵ Lobar hemorrhages were located predominantly in the parietal area with a
hematoma volume below 30 ml . Massive lobar hemorrhages with volume of
over 60 ml affected the whole hemisp here in which they were located, with
poor outcome regardless of the therapy that we applied
̵ Brainstem haemorrhages were mainly very small pontine haemorrhages with
less tha n 3 ml volume , while most of the cerebellum bleedings were s mall and
did not requi re neurosurgical evacuation
̵ A significant number of cases had intraventricular haemorrhage from the
admission. Subarachnoid extension was one of the complication that we
identified to a number of multilobar haemorrhages that died.
̵ Vary degrees of perile sional edema was present on the CT images in more
than one third of the cases
̵ Some small and medium ̵ hemorrhages complicated themselves by hematoma
expansion causing the patient's death
̵ Rapid and significant reduction of the bleeding was achieved only fo r the
patients in group C
Regarding the microscopic aspects, some clarifications have to be made:
̵ Vast majority of the cases had hypertensive disease either as a major risk
factor or as a determining factor
̵ .Degenerative changes of arterial and a rteriolar wall did not suggest the
presence of abnormal deposits of focal, amorphous materia l. Therefore we did
not direct histopathological diagnosis toward to amyloid angiopathy and there
was no required to perform special stains for amyloid ( Congo red )
̵ We haven ’t found fibrinoid necrosis outbreaks in full healthy vascular wall .
Vascular lesions that we encountered and analyzed were interpreted as being
the result of the harmful effect of chronic hypertension on intraparenchymal
vascular structures
̵ The lesions that we described were encountered both in vascular structures in
the proximity of the hemorrhage, in the same hemisphere, as well as in its
counterpart
CCLLIINNIICCAALL – MMOORRPPHHOOLLOOGGIICCAALL CCOORRRREELLAATTIIOONNSS
The purpose of hemostatic therapy is to arrest ongoing bleeding and minimize
hematoma expansion, which is a major predictor of ICH death and disability
(Dowlatshahi et al., 2013 ).
The success of any therapy requires first of all to save the patient's life.
The question is what caused the unfavorable outcome of some pat ients?
What are the factors that directly or indirectly influenced the outcome ?
The fourth chapter records the possible correlations between the different
morphological and clinical parameters of cerebral hemorrhage .
The analysis revealed the following:
̵ The outcome of the patient with cerebral haemorrhage was directly influenced
by the severity of neurological impairment at admission expressed by GSC
and NIHSS scores.
̵ Thromboembolic events that occurred during the hospitalization weren't
treatment -relate d but they influenced the outcome and caused the death of the
patients

1111
̵ There was an inverse relationship between length of hospitalisation and the
severity of bleeding and a directly relationship between length of
hospitalisation and the patient positive o utcome, especially for the deep gray
matter location of haemorrhage.
̵ Cerebral haemorrhages larger than 60ml, arising from the deep gray matter
had poor outcome
̵ Poor outcome is associated with extension into the subarachnoid and
intraventricular spaces.
̵ Severity of the neurological impairment assessed by GCS and NIHSS scores
was dependent of hematoma volume, topography and the presence of
intraventricular haemorrhage
̵ Lobar hemorrhages were associated with severe impairment of consciousness
, while severity of the neurological deficit was related to the deep gray matter
ICH
̵ Massive, deep originated hemorrhages are directly influenced by the severity
of hypertension and frequently complicate themselves with intraventricular
extension
CCOONNCCLLUUSSIIOONNSS
Finally, we summarize d all clinical and morphological parameters from the three
study groups and we tri ed to draw the profiles that had emerged from their bundling
which in our opinion are as follows :
The most commonly encountered clinical profile of the patient with intracerebral
hemorrhage was: male, ave rage age 65, from countryside, known history of
neglected severe hypertensio n, dyslipidemia, almost always smoker and
alcohol drinker, bleeding occurred most frequently in the winter and was
associated with mode rate to severe neurological impairment.
The most commonly encountered morphological profile of the hemato ma was:
hematoma with volume less than 30 ml located in the capsulo -thalamic or
parietal area, in the left hemisphere, with perilesional edema present on
admission, with expansiv potential, sometimes complicated by intraventricular
haemorrhage, that can occur on a background of pr eexisting artheriosclerotic
lesions. The range of variation of this profile can stretch from very small
hemorrhages under 3 ml volume, such as the pontine ones, to the massive
lobar hemorrhages with volume of over 60 ml, complicated by intraventricular
and/or subarachnoid space extension.
The two fundamental aspects of the dynamic evolutiv profile of hematoma were:
̵ unfavorable cl inical outcome resulted in the death of patients of the massive
bleeding with volume of over 60 ml., regardless of the treatment protocol
that we applied
̵ hematoma expansion for small and medium bleedings, regardless of
location and unprotected by rFVIIa and Vitamin K therapy.

1122
Profile of an effective therapy addressed to hemorrhagic stroke can take three
aspects:
̵ therapeutic protocol free of hemostatic̵s
̵ therapeutic protocol with conventional hemostatic̵s
̵ therapeutic protocol with rFVIIa and Vitamin K
Analy zing all , our study showed that the l ast one may be the only effective
therapy which has been proven to significantly reduce hematoma expansion.
Profile of a potential candidate for rFVIIa and Vitamin K therapy may be as
follows: patients age under 65 years, w ho meets temporal and clinical
criteria , with severe hypertension on admission, with a moderate to sev ere
neurological impairment caused by a spontaneous intracerebral hemorrhage
located deep in the gray matter , with an average volume of 30 m l.
SSEELLEECCTTIIVVEE RREEFFEERREENNCCEESS
Chou, C.J., Inks, E.S. & Josey, B.J. 2013, "Vitamin K: a structural basis for the
design of novel neuroprotective agents?", Future medicinal chemistry, vol. 5, no.
8, pp. 857 -860.
Demchuk, A.M., Dowlatshahi, D., Rodriguez -Luna, D., Molina, C.A., Blas, Y.S.,
Dzialowski, I., Kobayashi, A., Boulanger, J., Lum, C. & Gubitz, G. 2012,
"Prediction of haematoma growth and outcome in patients with intracerebral
haemorrhage using the CT -angio graphy spot sign (PREDICT): a prospective
observational study", The Lancet Neurology, vol. 11, no. 4, pp. 307 -314.
Divani, A.A., Majidi, S., Luo, X., Souslian, F.G., Zhang, J., Abosch, A. & Tummala,
R.P. 2011, "The ABCs of accurate volumetric measurement of cerebral
hematoma", Stroke, vol. 42, no. 6, pp. 1569 -1574.
Dowlatshahi, D., Hogan, M.J., Sharma, M., Stotts, G., Blacquiere, D. & Chakraborty,
S. 2013, "Ongoing bleeding in acute intrace rebral haemorrhage", The Lancet,
vol. 381, no. 9861, pp. 152.
Earnshaw, S.R., Joshi, A.V., Wilson, M.R. & Rosand, J. 2006, "Cost -effectiveness of
recombinant activated factor VII in the treatment of intracerebral hemorrhage",
Stroke, vol. 37, no. 11, pp. 2751 -2758
Gely‐Pernot, A., Coronas, V., Harnois, T., Prestoz, L., Mandairon, N., Didier, A.,
Berjeaud, J.M., Monvoisin, A., Bourmeyster, N. & De Frutos, P.G. 2012, "An
Endogenous Vitamin K ‐Dependent Mechanism Regulates Cell Proliferation in
the Brain Subve ntricular Stem Cell Niche", Stem Cells, vol. 30, no. 4, pp. 719 –
731.
Kothari, R.U., Brott, T., Broderick, J.P., Barsan, W.G., Sauerbeck, L.R., Zuccarello,
M. & Khoury, J. 1996, "The ABCs of measuring intracerebral hemorrhage
volumes", Stroke, vol. 27, no. 8, pp. 1304 -1305.
Lloyd -Jones, D., Adams, R.J., Brown, T.M., Carnethon, M., Dai, S., De Simone, G.,
Ferguson, T.B., Ford, E., Furie, K. & Gillespie, C. 2010, "Heart disease and
stroke statistics —2010 update A report from the American Heart Association",
Circulation, vol. 121, no. 7, pp. e46 -e215
Mayer, S.A., Brun, N.C., Begtrup, K., Broderick, J., Davis, S., Diringer, M.N.,
Skolnick, B.E. & Steiner, T. 2005, "Recombinant activated factor VII for acute

1133
intracerebral hemorrhage", New England Journal of Medi cine, vol. 352, no. 8, pp.
777-785.
Mayer, S.A., Brun, N.C., Begtrup, K., Broderick, J., Davis, S., Diringer, M.N.,
Skolnick, B.E. & Steiner, T. 2008, "Efficacy and safety of recombinant activated
factor VII for acute intracerebral hemorrhage", New Englan d Journal of Medicine,
vol. 358, no. 20, pp. 2127 -2137.
PPEERRSSOONNAALL RREEFFEERREENNCCEESS
AArrttiicclleess ppuubblliisshheedd iinn MMEEDDLLIINNEE aanndd BBDDII jjoouurrnnaallss
Stancu, C.C., Pleșea, I., Enache, S., Diaconescu, R., Cameniță, A. & Tenovici, M.
2011, "Morphoclinical study of intracerebral hemor rhage with subarachnoid
effusion", Rom J Morphol Embryol , vol. 52, no. 1 Suppl, pp. 263 -271.
Stancu, C. C., Diaconescu, R. 2012, „Recombinant Activated Factor VII for bilateral
spontaneous basal ganglia haemorrhage with tetraventricular extension -case
report”, Analele Universitatii Dunarea de Jos din Galati , No 2, pp. 21 -23.
AAbbssttrraaccttss ppuubblliisshheedd iinn nnaattiioonnaall aanndd iinntteerrnnaattiioonnaall jjoouurrnnaallss
Diaconescu, R., Stancu, C. C., Coteanu M.F. 2013, „ Hemostatic therapy for acute
intracerebral hemorrhage”, Romanian Journal of Neurology/ Revista Romana de
Neurologie , vol. XII, no. 1 Suppl, pp. 49 -50.
Diaconescu, R., Stancu, C. C., Coteanu M.F. 2013, „ A comparative effectiveness
study of recombinant activated factor VII in off -label use: monotherapy versus
combination therapy for acute intracerebral haemorrhage”, Journal of the
Neurological Sciences , vol. 333, Supplement 1, pp. e279.
CCoommmmuunniiccaattiioonn iinn nnaattiioonnaall aanndd iinntteerrnnaattiioonnaall sscciieennttiiffiicc
mmeeeettiinnggss
Diaconescu, R., Stancu, C. C., Coteanu M.F. 25 septembrie 2013, „A comparative
effectiveness study of recombinant activated factor VII in off -label use:
monotherapy versus combination therapy for acute intracerebral haemorrhage”.
The XXI World Congress of Neurology, Viena, Austria.
Diaconescu, R., Stancu, C. C., Coteanu M.F. 15 -18 mai 2013, „Hemostatic therapy
for acute intracerebral hemorrhage”. Al XI -lea Congres al Societății de
Neurologie din România, București
Diaconescu, R., Stancu, C. C., Coteanu M.F. 7 -8 iunie 2013, „Studiul clinic al
hemoragiei intracerebrală spontană la Spitalul Județean de Urgență Slatina ȋn
perioada 2008 -2012”, Zilele UMF, Craiova