Arch Orthop Trauma Surg (2007) 127:485–491
DOI 10.1007/s00402-007-0367-y

123

B A S I C S C I E N C E

Interruption of the blood supply of femoral head: an experimental
study on the pathogenesis of Legg-Calve-Perthes Disease

A. Mumtaz Alpaslan · M. Cemalettin Aksoy ·
Muharrem Yazici

Received: 27 September 2006 / Published online: 28 June 2007

©

Springer-Verlag 2007

Abstract
Introduction

The etiology of LCPD still is not clear.

Thrombosis has been accused in the pathogenesis of LCPD
but it is not proven untill now. The aim of this study is to
evaluate the results of single episode of obstruction of
blood supply to the femoral heads of dogs.
Material and method

Blood supply femoral heads of 45

dogs was interrupted with embolisation with gel foam. The
radiologic appearances, macroscopic and microscopic spec-
imes of the hips were evaluated and compared with the
human specimens of 15 LCPD patients obtained at the time
of femoral osteotomies.
Results

After one infarct, we demonstrated changes in

femoral heads of puppies showing close resemblance to the
Wndings of LCPD in human.
Conclusion

Obstruction of the femoral head caused by

single arti

Wcial emboli caused changes in the femoral head

similiar to LCPD. The cause of the obstruction is obscure,
intravascular and/or extravascular pathologies need speci

Wc

attention, further studies focusing especially on the coagu-
lation system are needed.

Keywords

LCPD · Coagulation · Experimental study

Introduction

Legg–Calve–Perthes disease (LCPD) is a unique self-lim-
ited microvascular occlusive disease leading to the repeated
interruptions of the blood supply to the proximal femur
[

3

,

4

,

7

,

8

]. The immediate etiology of ischemia however,

has not yet been discovered. Two basic mechanisms block the
arterial system of proximal femoral epiphysis, one tampon-
ade produced by an aseptic in

Xammatory exudates as in

transient synovitis or more rarely by hemorrhage into the
joint causing an increase in extravascular pressure, two ces-
sation of circulation in the femoral head because of intra-
vascular clots [

4

,

9

,

11

,

20

,

22

,

23

,

26

,

31

,

36

,

38

,

39

,

42

].

Hemodynamic alterations, endothelial injury, thrombotic
tendency due to hypercoagulability and/or hipo

Wbrinolysis

have all been proposed as the possible pathogenetic factors
in the etiology of the LCPD [

12

,

13

,

16

,

17

,

30

,

32

,

43

,

46

].

We recently demonstrated a increase in Tissue factor path-
way inhibitor (TFPI), global

Wbrinolytic capacity (GFC)

and thrombomodulin (TM) levels in LCPD compared to
normal population [

1

,

2

]. These two studies indirectly re

X-

ect the presence of thrombosis and/or embolisation, which
in turn activating the

Wbrinolytic system.

Immunological and in

Xammatory processes together

with disturbed endothelial functions may take place in the
microvascular compromise and decreased blood

Xow of

LCPD. Histopathological and electron microscopic exam-
inations revealed perivascular collections of plasma cells
and lymphocytes in the synovial tissue of the LCPD
[

24

,

29

]. Signi

Wcant synovitis as the consequence of, or

preceding, the loss of blood supply and epiphyseal necrosis
is also an important feature in the LCPD [

21

]. In

Xamma-

tion, itself, is a potent prothrombotic stimulus. In

Xamma-

tory mechanisms up regulate procoagulant factors, down
regulate natural anticoagulants and inhibit

Wbrinolytic

A. M. Alpaslan · M. C. Aksoy (&) · M. Yazici
Faculty of Medicine,
Department of Orthopaedics and Traumatology,
Hacettepe University, Zemin kat,
Ankara 06100, Turkey
e-mail: [e-mail]

486

Arch Orthop Trauma Surg (2007) 127:485–491

123

activity. Increased blood viscosity with hemodynamic alter-
ations in LCPD could further complicate the diminution of
the blood

Xow to the capital femoral epiphysis by disturb-

ing endothelial functions, ultimately resulting in symptom-
atic disease and osteonecrosis [

18

,

44

].

The arterial blood of the femoral head is supplied by

medial and lateral femoral circum

Xex arteries. Medial cir-

cum

Xex artery usually originates from medial or posterior

of femoral artery whereas, lateral circum

Xex artery origi-

nates from the deep branch of femoral artery. Obstruction
of the femoral artery causes interruption of the blood sup-
ply of the femoral head [

15

,

45

]. The aim of this study is to

evaluate the results of embolisation causing one single inf-
arct in femoral arteries of dogs, which resulted in intravas-
cular obstruction of the blood supply.

Material and methods

Experimental animals

The Turkish shepherd dogs aged between 1 and 14 months
were used in the study. All the study group consisted of
brother animals born and grown-up at Hacettepe University
Experimental Animals Breeding Laboratory.

Experimental aseptic necrosis

All the animals were anesthesized with 15–20 mg kg

¡

1

nembutaline. Right inguinal are of the animals were
shaved. An “S” shaped incision starting from the lateral
part of pectineus muscle ending at the lower part of abdom-
inal muscles were made. After passing through skin and
subcutaneous tissue, femoral artery was visualized which
was followed until external iliac artery. After temporary
clamping of external iliac artery, femoral artery was
clamped just below the branching point of deep femoral
artery. After that, external iliac artery was catheterized and
previously prepared gelfoam was used for embolization.
Angiography was performed using urographin was used
before and after this procedure in order to con

Wrm the pres-

ence of obstruction if obstruction did not occur, gelfoam
was re-given. Clamps were removed, skin and fascia were

closed and animals were left to normal feeding and living
situations.

After 1, 2, 4, 8 and 12 weeks of surgery, the animals

were anesthesized again and angiography was repeated to
document the presence of revascularization and the animals
were terminated with high dose nembutaline. Through an
anterior incision on the thigh, femur was externalized. The
same procedure was applied to both sides. Head and neck
of femurs were divided in half on frontal plane. External
appearance of femoral head, shaft, growth plane were
examined. One half of the left and right femoral heads were
stored at ¡20°C. The other half was

Wxed at 10% formalin

solution for 24 h. Decalci

Wcation of the bone tissue was

obtained after application of 5% formic acid. Sections
obtained from para

Yn blocks were stained with hemotoxyl-

ene–eosin and toluidine blue than examined under light
microscope. Infarct areas were determined under light
microscope. Animals with only epiphysial necrosis were
grouped as A, the ones with epiphysial and metaphysical
necrosis as B and the ones with only metaphysical necrosis
as C.

Human biopsy materials

Specimens from the patients who underwent varus osteot-
omy for LCPD were obtained with needle biopsy from the
non-weight bearing parts of epiphysis and joint cartilage.
We could not obtain biopsies from the enchondral ossi

Wca-

tion part of the growth plate. Only subchondral parts were
used in order to make a conclusion. After

Wxation with for-

malin and formic acid decalci

Wcation, histologic specimens

were examined under light microscope.

This study was approved as Thesis in Orthopaedics and

Traumatology, by Hacettepe University.

Results

There were 29 (64.4%) animals in Group A 10 (22.2%) ani-
mals’ in-group B and 6 (13.3%) animals in Group C
(Table

1

). Bone biopsies of 15 patients were taken from

patients with LCPD all of whom were in the aseptic necro-
sis phase of the disease.

Table 1 Histological

Wndings, localization of the infarct and its distrubition

a

Weeks indicate the sacri

Wcation time of the animal

Localization
of Infarct

Number

Percent (%)

Number of the dogs

1st week

a

2nd week

a

4th week

a

8th wk

a

12th wk

a

GROUP A

29

64.4

6

5

5

7

6

GROUP B

10

22.2

4

5

1

0

0

GROUP C

6

13.3

2

1

2

1

0

Arch Orthop Trauma Surg (2007) 127:485–491

487

123

Radiological

Wndings

Group A: At fourth week there was an increase in medial
joint distance, shortening and thickening in femoral neck
and osteoporosis in epiphysis. At eighth week in six ani-
mals, irregularities in growth plate, an increase in epiphys-
ial density were present and coxa magna were visible.
Thickening of femoral neck was detected in all experimen-
tal animals. In animals, which were extinguished in 12th
week, radiological

Wndings were normal except coxa vara

but in two animals there were obvious radiodense appear-
ance in the radiogram (Fig.

1

).

Group B: In earlier period, in one hip coxa vara and lytic

lesion in the neck were detected.At 4th week, increase in
size of the femoral head, coxa vara, lytic areas in metaphy-
sis, thickening in growth plate and lengthening of trochan-
ter major were present.

Group C: Increase in metaphysial density, thickening in

growth plate and mild increase in size of femur neck were
common

Wndings in this group.

Macroscopic

Wndings

Group A: In specimens of the animals who were killed at
Wrst and second weeks there was no diVerence except a
slight increase in diameter compared to the normal femur
but in specimens of animals killed at fourth week, right
femoral head was larger than left, joint cartilage was
thicker, growth plate showed irregularity (Fig.

2

). In some

animals femur neck was found to be short. At eighth week
animals, femoral head was bigger and joint cartilage was
thicker than normal femur. Thickening and shortening of
the femoral neck was frequently encountered. There was
not much di

Verence other than slight increase in femoral

head and thickening in femoral neck in 12th week animals.

Group B: Compared to Group A deformities like

increase in femoral head, thickening and shortening in fem-
oral neck occurred earlier. Joint cartilage was apparently
thicker and passed the level of trochanter major in

Wrst

2 weeks. At fourth week, an increase in femoral head was
very signi

Wcant. Neck was thickened and femur neck was

visibly short compared to the left femur (Fig.

3

). Shorten-

ing ranged between 2 and 5 mm.

Group C: Although there was not an apparent change in

macroscopic appearance, there was thickening of growth
plate in sections. At 4th, 8th and 12th weeks, there was not

Fig. 1 Radiodense appearance of the right femoral head at the end of
the 12th week in a group A dog

Fig. 2 Macroscopic appearance of the both sides of femoral head at
the end of the fourth week. Obvious thickening of the cartilage at the
right femoral head. (Group A Dog)

Fig. 3 Coxa magna, and coxa breva on the right femoral head in a
Group B dog at the end of fourth week

488

Arch Orthop Trauma Surg (2007) 127:485–491

123

much di

Verence in size of the femoral heads but femur neck

was thicker compared to control side and growth plate was
very thickened as much as 2–2.5-fold compared to normal
femur.

Light microscopic

Wndings

Group A: Joint cartilage was similar in

Wrst weeks com-

pared to normal, but in epiphysis, bone marrow cells
became scarce and disappeared in some animals. There
were many giant cells in intertrabecular space. Osteoblasts
decreased in number and were totally lost in some. In

Wrst

week, there was irregularities in the resting layer of the
growth plate, deeper to this layer there were some pycnotic
cells. The growth plate was thinner compared to normal
side.

In second week animals, joint cartilage was thicker,

there were pycnotic cells located deeply and there was vas-
cularization and degeneration in cartilage in some areas.
Disappearance of the giant cells detected in

Wrst week, lack

of osteocytes in some lacunes of bone trabecules, hypocel-
lular bone marrow were present. There was late granulation
tissue around the periphery of the epiphysis. Thinning of
growth plate was more obvious, irregularity in the resting
cellular layer became prominent and there was destruction
in some areas. Just above these areas with above-mentioned
abnormalities, osteocytes disappeared in subepiphysial
bone. Loss of metachromasia was detected with toluidine
blue stain in joint cartilage and growth plate. At 4th week,
joint cartilage was thickened, pycnosis was detectable and
lacunae of bone trabecula were empty. Growth plate
showed too much irregularity especially around epiphysial
necrosis. There was destruction in growth plate in some
sections and there was granulation tissue growing from
metaphysis towards epiphysis (Fig.

4

). Patchy loss of meta-

chromasia in joint cartilage and growth plate were visible.

At eighth week the joint cartilage was very thick with pynk-
nosis in degenerated areas close to subchondral area and
empty lacunae with increased osteoblastic activity accom-
panying mature granulation tissue was present. In four ani-
mals at eighth week, irregularity of growth plate resulted in
destruction. A global thinning in the growth plate was pres-
ent but a more careful examination revealed a thicker rest-
ing cellular layer with numerous cells compared to control
femur. The hypertrophic part of growth plate was especially
thin. The destructed areas were surrounded by granulation
tissue and with the extension of the growth plate, they were
pulled towards metaphysis. At 12th week, however, joint
cartilage returned to normal thickness, chondrocytes around
subchondral area regained normal appearance. Pannus for-
mation was detectable in one animal and it destructed the
cartilage. There was osteoblastic overactivity in all animals
at this week. There was destroyed tissue remmants between
overthickened bone trabeculae. There was a thickened,
highly cellular germinal layer in some but not all animals.

Group B: The bone marrow was poor in cellularity and

present bone marrow cells were necrotic at

Wrst week.

There were empty lacunae in bone trabeculae in epiphysis.
The nucleus of some osteocytes were pycnotic and osteo-
blasts disappeared. Granulation tissue was not present in
any area. The resting layer of growth plate showed patchy
degeneration, proliferation layer was usually normal and
hypertrophied layer was overthickened. Periostium was
Wbrotic and cambium layer had normal appearance. There
was loss of metachromasia in joint cartilage and growth
plate with toluidine blue.

At second week, joint cartilage was thickened the cells

became pycnotic towards deeper parts of epiphysis, baso-
philia of cartilage interspace material decreased. Empty
lacunae were more frequent in bone trabeculae in epiphysis.
There was granulation tissue more at the periphery but in
between trabecular space as well. The resting cellular layer
of growth plate was irregular irregularity was prominent in
proliferative layer. Overall, growth plate was thick. Granu-
lation tissue, new bone formation and active necrosis in
wide areas were prominent. The periostium of the metaphy-
sis was normal.

At fourth week, there was osteoblastic activity in epiph-

ysis (Fig.

5

). Granulation tissue almost

Wlled all areas and

growth plate preserved its thickness. Hypertrophic layer,
which was visibly thickened showed cystic degeneration.

Group C: The most characteristical

Wndings of this

group were the abnormal thickening of the growth plate.
The thickening of growth plate persisted after 1st week
(Fig.

6

). There was partial metaphysical necrosis in one ani-

mal. The thickening of the growth plate corresponding to
the necrosis area continued but growth plate was normal
where metaphysial circulation was su

Ycient. Progression

of granulation tissue from epiphysis to metaphysis was not

Fig. 4 Appearance of granulation tissue from metaphysic to epiphy-
sis. (black arrow growth plate, white arrow: granulation tissue, e
epiphysis (Group A dog) (H.E. X75)

Arch Orthop Trauma Surg (2007) 127:485–491

489

123

present in any experimental animal. In this series with
metaphysial necrosis, periostium was intact and there was
no necrotic cells.

Microscopic

Wngings of LCPD patients

In light microscopic examination, there were bone trabecu-
lae with empty lacunae without osteocytes in 13 patients
(Fig.

7

). In some slides there were non-viable tissue and

irregular tissues between viable bone tissues. In most
patients there were necrotic bone trabeculae, disappearence
of osteoblasts in subchondral area where normally osteo-
blastic activity takes place was visible. Chondroctyes were
pycnotic in neighbouring joint cartilage and deformation
was evident in patchy fashion. In nine biopsies bone mar-
row was hypocellular even absent in some. There were
mesencyhmal cell in intertrabecular space in four biopsies.
In one biopsy, which was interesting, there were throm-
bosed vessels in joint cartilage. Cartilage cells around these

vessels were pycnotic. In two specimens increase in osteo-
blastic activity and new bone formation were apparent.

Discussion

In this study we evaluated the results embolisation causing
one single infart in femoral arteries of dogs, which resulted
in intravascular obstruction of the blood supply. We pre-
ferred to use young dogs because of the resemblance of
superior femoral vascularization to humans and spontane-
ous occurance of LCPD in dogs [

5

,

19

]. In fact the method

used in this study was di

Verent than other studies in creat-

ing avascular necrosis, the material gel-foam recanalizes in
2–5 days and does not create any reaction in the organism
so this method creates a situation with much more resem-
blance to naturally occuring LCPD [

14

,

25

,

34

,

35

,

37

,

48

].

We demonstrated an increase in the thickening of joint

cartilage of the femoral head. This increase in thickness
starting at

Wrst weeks reached its maximum layer at 4th and

8th weeks. Accompanying this enchondral ossi

Wcation was

interrupted in subchondral area. The interstitial substance
secreting cartilage, which gets its nutrition through syno-
vium was destroyed in subchondral area through enchondral
ossi

Wcation. The interruption of the enchondral ossiWcation

decreased the destruction of the cartilage and by this way
cartilage grew in size. The presence of pynknosis and degen-
eration in the cartilage cells close to subchondral area also
supports this hypothesis [

10

,

48

]. Our

Wndings in puppies

showed close resemblance to biopsy specimens obtained
from LCPD patients. There were necrosis in bone trabeculae
obtained from subchondral area, cartilage cells adjacent to
this area showed pynknosis and empty lacunae. These

Wnd-

ings proved that the frequently encountered increase in
medial joint distance is not due to hyperemia of ligamen-
tum teres and haversian path infarct but due to increase in

Fig. 5 Appearance of the obvious osteoblastic activity at the epiphysis
and irregular proliferation in the growth plate in a group B dog at the
end of the fourth week. (HE £75)

Fig. 6 Thickening of the growth plate in a group C dog (HE £30)

Fig. 7 In a human specimen, appearance of the pycnotic nucleus and
empty lacuna and amorf necrotic bone in the epiphysis. (HE £200)

490

Arch Orthop Trauma Surg (2007) 127:485–491

123

thickness of cartilage. This

Wnding is supported by the arte-

riographic studies of hips in LCPD [

3

].

The overall

Wndings in epiphysis were pycnotic osteo-

cytes in empty lacunae at 2nd week. At 8th week though
scarce pycnotic nuclei were visible, they disappeared at
12th week and increased osteoblastic activity was present.
The viability of osteocytes are still debatable. Twenty-four
hours to 1 week are the reported viability intervals for the
osteocytes after appearance of pynknosis [

6

,

33

,

47

].

Another issue, which needs to be cleared out, is the occu-
rance and timing of the granulation tissue. The stages of
granulation tissue was di

Verent in diVerent specimens.

These results showed concordance with the biopsy speci-
mens of LCPD some of which showed necrosis and others
osteoblastic activity on the other hand. These observations
support the idea that exact timing of LCPD after epiphysial
necrosis is impossible [

27

,

28

]

Repeated obstruction of the vascular supply had all been

supported as an etiology of LCPD [

7

,

8

,

40

,

41

]. This idea

was accepted as an evidence for the chronic nature of the
disease. Contrary to this presence of sclerosis at 12th week
in this study supports that chronicity can occur even after
one single infarct. In fact when we compare the size of the
femoral head in puppies and human, the disease may take
longer time to develop in humans. The changes in growth
plate demonstrated the sensitivity of this layer to anoxia.
The destruction of organisation of the growth plate and its
restoration depend largely on the severity of the necrosis
period. Growth plate has the ability to correct the deformi-
ties after restoration of the blood supply because of this,
prognosis of the LCPD is parallel to the duration and sever-
ity of the anoxic period.

In this study, non-recurrent arti

Wcal embolism caused

changes in the femoral head just like changes that we detect
in LCPD. The presence of thrombosis in vessels of one of
our patients also supports the idea. As the

Wndings persist

till 12th week this study, one single episode of interruption
of the blood supply may cause chronicity so chronic inter-
ruption of the blood supply may not be necessary. We dem-
onstrated an increase in GFC, TM and TFPI levels in LCPD
[

1

,

2

]. These results are consistent with the

Wndings that

coagulation is present in LCPD, which in turn leads to acti-
vation of the

Wbrinolytic system. The cause of the obstruc-

tion is obscure in LCPD intravascular and/or extravascular
pathologies need speci

Wc attention further studies focusing

especially on the coagulation system are needed.

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