Ther Adv Endocrinol
(2011) 2(6) 247 –255
© The Author(s), 2011.
Reprints and permission:
Therapeutic Advances in Endocrinology and Metabolism Original Research
The diabetic foot syndrome (DF) is a major
disabling complication with an estimated life-
time incidence of up to 25% in patients with dia-
betes mellitus [Singh et al. 2005] and peripheral
arterial disease (PAD) is one of the most com-
mon comorbidities in DF. However, despite the
frequency and importance of these pathological
conditions, clear epidemiological data with
respect to the combination of DF with critical
limb ischemia (CLI) are scarce. For example, in
the EURODIALE study [Prompers et al. 2007],
which included 1229 patients with diabetic
foot ulcers, 49% of the patients also had
PAD. However, this proportion is apparently
underestimated, as 32% of the subjects had an
ankle-brachial index (ABI) of >1.2, indicating
mediasclerosis. Therefore, we can assume a prev-
alence of >80% of PAD in DF. Moreover, in this
study, the proportion of patients with DF and
CLI with an ABI of <0.5 was 12%. In another
study from Milan [Faglia et al. 2009], data were
presented with respect to the long-term progno-
sis of patients with DF and CLI, in which 554
patients with this combination were observed
over a mean of 6 years. Peripheral angioplasty
was performed in 74% and vascular surgical
interventions in 21% of this selected group of
patients with DF and CLI. A negative option for
revascularization was given in only 5% of the
patients. These subjects were treated with pros-
tanoids (60–120 µg/day alprostadil) over 5 days
after arteriography. The initial major amputation
(MA) rate (‘early period’, within 30 days after
intervention) in this study was only 4.1%, corre-
sponding exactly to the early MA rate of our
interdisciplinary diabetic foot unit, based on 754
patients with different stages of DF [Weck et al.
2010]. During their follow up, the researchers
reported MA in 13% of all subjects, 8% in the
Noninvasive management of the diabetic foot
with critical limb ischemia: current options
and future perspectives
Mathias Weck, Torsten Slesaczeck, Hannes Rietzsch, Dirk Münch, Thomas Nanning,
Hartmut Paetzold, Hans-Joachim Florek, Andreas Barthel, Norbert Weiss and Stefan Bornstein
Abstract: Foot ulcers are a major complication in patients with diabetes mellitus and involve
dramatic restrictions to quality of life and also lead to enormous socio-economical loss due
to the high amputation rate. The poor and slow wound healing is often aggravated by the
frequent comorbidity of foot ulcers with peripheral arterial disease, making the treatment of
this condition even more complicated. While the local treatment of foot ulcers is mainly based
on mechanical relief and prevention or treatment of infection, improving perfusion of the
impaired tissue remains the major challenge in peripheral arterial disease. While focal arterial
stenosis is the domain of interventional angioplasty or vascular surgery, patients with critical
limb ischemia and lacking options for revascularization have a much worse prognosis, because
current treatment options avoiding amputation are scarce. However, based on recent research
efforts, there is rising hope for promising and more-effective therapeutic approaches for these
patients. Here, we discuss the current improvements of established therapies aimed at an
improvement of limb perfusion, as well as the development of novel cutting-edge therapies
based on stem-cell technology. The experiences of a ‘high-volume center’ for treatment of
diabetic foot syndrome with a current major amputation rate of 4% are discussed.
Keywords: autologous bone marrow transplantation, critical limb ischemia, diabetic foot,
prostaglandins, therapy, urokinase
Matthias Weck, MD
Medizinische Klinik III,
Bürgerstraße 7 01705
Torsten Slesaczeck, MD
Medizinische Klinik III,
Hannes Rietzsch, MD,
Norbert Weiss, MD,
Stefan Bornstein, MD
Medizinische Klinik und
Poliklinik III, Technische
Gustav Carus, Dresden,
Dirk Münch, MD,
Thomas Nanning, MD
Medizinische Klinik II,
Hartmut Paetzold, MD,
Hans-Joachim Florek, MD
Klinik für Gefäßchirurgie,
Andreas Barthel, MD
Medizinische Klinik und
Poliklinik III, Technische
Carl Gustav Carus,
Dresden, Germany and
427721 TAE262042018811427721M WeckTherapeutic Advances in Endocrinology and Metabolism
Therapeutic Advances in Endocrinology and Metabolism 2 (6)
group treated with angioplasty (percutaneous
transluminal angioplasty [PTA]), 21% in the
vascular surgery group and 59% in the group
without options for revascularization. In 40% of
the subjects, they found CLI of the contralateral
leg [Faglia et al. 2009]. This finding empha-
sizes the importance of a detailed angiological
examination of both legs.
Patients with a history of diabetic foot ulcers
alone already have high mortality rates, mainly
due to cardiovascular events but also other causes
such as cancer [Iversen et al. 2009]. However,
CLI further significantly increases the mortality
risk [Faglia et al. 2009]. On the other hand,
treatment options for this group of patients are
still very limited, demonstrating the imperative
need to develop novel therapeutic strategies.
Based on the current literature and our experi-
ence, we summarize the noninvasive treatment
options currently available for this highly morbid
group of patients with DF and CLI and draw
Therapeutic strategies in CLI without
options for revascularization
In subjects with DF, the accompanying PAD,
particularly of the lower leg arteries is apparently
the major risk factor for MA. Revascularization
appears to be possible in the large majority of
cases if these patients are referred in time to an
interdisciplinary organized center offering highly
skilled experience, not only in diabetology, but
also interventional angiology and vascular surgery
[Faglia et al. 2006, 2009; Sumpio et al. 2010]. In
these specialized units, a dramatic improvement
of healing rates and reduction of the frequency of
MA can be accomplished.
Endovascular treatment is mostly recommended
because the risk of infection is lower; subjects
with DF are older and have multiple comor-
bidities, representing additional risk factors for
vascular surgery [Zeller, 2007; Zeller et al. 2009;
Alexandrescu et al. 2009]. A clinical algorithm for
the diagnosis and treatment of DF with PAD is
illustrated in Figure 1. In patients with DF and
CLI without options for revascularization, further
therapeutic approaches must be considered in
order to avoid MA, although none of these nonin-
vasive strategies have been validated in rand-
omized clinical trials so far. This includes methods
aiming at an improvement of limb perfusion,
for example, prostaglandin treatment, low-dose
urokinase therapy and autologous bone marrow
transplantation into the affected limb.
Although the treatment of CLI with prostaglan-
dins is not a new option, this class of drugs needs
to be discussed here briefly, especially in the con-
text of other therapeutic strategies.
The impact of prostaglandins in the treatment
of PAD is still discussed in a controversial light
[Lawall et al. 2009a, 2009b; Amendt, 2005;
Norgren et al. 2007]. There is some evidence that
prostaglandin treatment improves claudication
and some evidence exists with respect to improve-
ment of walking capacity and quality of life
[Amendt, 2005]. Summarizing the literature, one
can assume an improvement of wound healing,
reduction of pain and a reduction of MAs in
~50% of subjects with CLI and lacking options
for revascularization after local infusion of prosta-
glandins. Prostaglandins are administered intra-
arterially or intra-venously for 3–4 or 7–28 days.
Prostaglandin E1 (PGE1) is commonly applied
with doses of 40 µg bid over 2–4 hours. The
majority of the current guidelines recommend
this procedure, but the intersociety consensus
for the management of PAD (TASC II) does not
[Norgren et al. 2007].
Short-term studies in subjects with CLI had no
clear results. In particular, there was no ulcer
healing or pain reduction in the majority of these
studies. In contrast to short-term studies [Belch
et al. 1983; Cronenwett et al. 1986; Schuler et al.
1984; Telles et al. 1984], the majority of long-term
studies in patients with CLI demonstrated a clear
reduction of pain and ulcer size, and some of
these studies indicate a reduced need for MA
[Norgen et al. 1990; Stiegler et al. 1992; ICAI
Study Group, 1999; UK Severe Limb Ischaemia
Study Group, 1991; Trübestein et al. 1987;
Duthois et al. 2003; Loosemore et al. 1994;
Altstaedt et al. 1993]. It should be noted that
these studies are older investigations with some
methodological problems and should be consid-
ered with caution.
A more recent meta-analysis of the administra-
tion of PGE1 for patients with PAD stage III or
IV not eligible for arterial reconstruction shows
that it not only has significant beneficial effects
over placebo on ulcer healing and pain relief, but
also increases the rate of patients surviving with
M Weck et al.
both legs after 6-months follow up [Creutzig et al.
2004]. Despite this positive statement, the com-
bined endpoint ‘MA and death after 6-month
follow up’ seems to be very high, at 22.6%.
However, in TASC II it is concluded that the cur-
rent data do not provide evidence for a significant
benefit of prostaglandins in CLI with respect to
amputation-free survival, whereas all other scien-
tific associations recommend the use of prosta-
glandins in CLI if revascularization is not possible
[Lawall et al. 2009a; Hirsch et al. 2006; Ryden
et al. 2007]. In the guidelines for the diagnosis
and treatment of PAD from the German Society
of Angiology and Vascular Surgery, the follow-
ing recommendation is given: ‘In consideration of
the meta-analysis about clinical efficiency of pros-
tanoides, the recommendation of administration
of prostanoids is given with level of evidence A.
This conclusion is based, (apart from the out-
come of the meta-analysis), on the assessment of
predominantly older studies and concordant
experiences of the authors (of this guideline)’
[Lawall et al. 2009b]. Special recommendations
of administration of prostaglandins on patients
with DF and CLI do not exist.
Hyperfibrinogenemia with the resulting increase
in plasma viscosity and erythrocyte aggregation
has been demonstrated in patients with coronary
heart disease and PAD [Leschke et al. 1986, 1997;
Peters et al. 1999; Partsch and Jochmann, 1993;
Weck et al. 2008; Rietzsch et al. 2008]. The increase
in plasma viscosity, in particular, can be a flow-
limiting factor and a critical determinant of oxy-
gen supply in the poststenotic microcirculation of
myocardium and diabetic foot. It has been shown
that urokinase is effective in improving the micro-
circulation in patients with coronary heart disease
[Peters et al. 1999; Leschke et al. 1996, 2003;
Figure 1. Clinical algorithm illustrating the currently available treatment options for patients with the diabetic
foot syndrome in combination with peripheral artery disease. PTA, percutaneous transluminal angioplasty,
diabetic osteoarthropathy (DOAP) [Weck et al. 2006, reproduced with permission from UNI MED].
Therapeutic Advances in Endocrinology and Metabolism 2 (6)
Leschke, 2008]. Plasma fibrinogen, plasma vis-
cosity and red blood cell aggregation were reduced
significantly in these studies. In another study,
low-dose urokinase was used to treat subjects
with nonhealing leg ulcers. The authors reported
a significant improvement of microcirculation
measured by an increase of laser-Doppler indices,
increase of tcpO2 and a significant decrease of
plasma viscosity and plasma fibrinogen [Partsch
and Jochmann, 1993].
In addition, it has been shown that urokinase is
effective in improving the microcirculation in dia-
betic patients with PAD stages III and IV accord-
ing to Fontaine (CLI) or Rutherford stages 4–6
[Leschke et al. 1997; Weck et al. 2001, 2008;
Hicken et al. 1995]. These preliminary data pro-
vide some evidence that diabetic patients appar-
ently benefit more from rheologic treatment of
PAD than nondiabetic patients. However, studies
on the effect of intravenous urokinase treatment
in patients with CLI and diabetic foot lesions are
mostly retrospective in small patient cohorts.
Therefore, we performed an open, prospective,
noncontrolled, multicenter cohort study in 77
type 2 diabetic patients with CLI and diabetic
foot ulceration [Weck et al. 2008]. Patients had no
surgical or endovascular treatment option based
on interdisciplinary consensus. Urokinase (1 IU if
plasma fibrinogen ≥2.5 g/l; 0.5 IU if fibrinogen
<2.5 g/l) was administered for 21 days as an intra-
venous infusion over 30 minutes. After 12 months,
33% of the surviving patients showed completely
healed ulcers without having MA (Figure 2). The
total survival rate was 85%, amputation-free sur-
vival 69% and the rate of MA was 21%. Within
the course of the study, 82% of patients experi-
enced ulcer healing at least once. It should be
noted that the mortality rate and also the rate of
MA in this study was surprisingly low as com-
pared with the literature and 33% of the patients
in this study even met the ultimate treatment
goal of freedom from amputation and residual
ulcers for at least 1 year. Although this study was
not controlled, randomized or blinded, it estab-
lishes a solid basis for the use of urokinase in this
special patient population. The specific reasons
for the low event rates in this study can be specu-
lated upon. For example, high levels of fibrinogen
have been associated with an increased cardio-
vascular risk and fibrinogen is known to rise as
an acute-phase protein in the acutely infected
diabetic foot. Alternatively, the effect of uroki-
nase therapy has been attributed to a decrease
in fibrinogen concentration with a subsequent
improvement of microcirculation [Leschke et al.
1996, 1997, 2003; Leschke, 2008]. In another
observational study, the heparin-induced extra-
corporeal LDL-precipitation (HELP) was used
as an alternative therapeutic approach in subjects
with diabetic foot, CLI and sepsis [Rietzsch et al.
2008]. The risk of limb loss in these patients was
extreme. HELP reduced the fibrinogen levels by
68%. Only 3 of 17 patients underwent MA, thus,
the HELP approach seems to be a proof of prin-
ciple for fibrinogen-lowering therapy.
Urokinase treatment in diabetic patients with
chronic foot lesions and CLI appears to be feasi-
ble, safe and effective. Based on our promising
clinical experience with low-dose urokinase in
the treatment of DF with chronic, nonhealing
ulcers and CLI without options for revasculariza-
tion, we have extended the application of uroki-
nase to the perioperative treatment of borderline
amputations in some cases. With this strategy,
we have seen an improvement in wound healing
in some subjects with fatal distal vascularization.
It should be noted that these are observational
data. Nevertheless, urokinase treatment in these
patients appears a reasonable option in order to
avoid MA. The data and theoretical considera-
tions on low-dose urokinase treatment in subjects
with diabetic foot presented here should be
treated with caution and considered as a strong
endorsement for the implementation of a pro-
spective randomized controlled study, which is
3 month6 month 9 month12 month
Percentage of’ patients (95%CI)
Figure 2. Ulcer healing rates in patients with diabetic
foot ulcers and critical limb injury after short time
urokinase treatment. The patients were monitored up
to 12 months after treatment. Data were obtained in an
open, prospective, noncontrolled multicenter cohort
study in 77 patients with type 2 diabetes [Weck et al. 2008,
reproduced with permission from Thromb Haemost].
M Weck et al.
Autologous bone marrow transplantation
A large body of experimental evidence in mice,
rats and larger animals has demonstrated the
feasibility and efficacy of stem cell therapies
in restoring blood flow to the critical ischemic
limb. These studies demonstrated that the
number of circulating endothelial precursor cells
(EPCs) increases in response to ischemia
[Shintani et al. 2001; Takahashi et al. 1999] and
that EPCs can be found incorporated into capil-
laries and interstitial arteries [Shintani et al.
2001]. It is assumed that EPCs may act in a par-
acrine manner by secreting vascular growth fac-
tors and cytokines [Asahara et al. 1999; Kamihata
et al. 2001]. In 2000, Kalka and colleagues
demonstrated that intracardial application of
human EPCs in nude mice improved the periph-
eral circulation [Kalka et al. 2000]. Recently,
Turan and colleagues demonstrated that intrac-
oronary transplantation of autologous freshly iso-
lated bone marrow cells (BMCs) improved global
ejection fraction and infarct size significantly in
patients with ischemic heart disease after 3 and
12 months of transplantation [Turan et al. 2011].
These results formed the basis for the rapid
growth in studies with stem cells in patients with
PAD. The Therapeutic Angiogenesis using Cell
Transplantation (TACT) study in 2002 was the
first report on application of bone-marrow
derived mononuclear cells (BMMNCs) in the
treatment of patients with CLI [Tateishi-Yuyama
et al. 2002]. After 24 weeks, the ABI was improved
by 31% and the pain-free walking distance was
increased by 80% following intramuscular injec-
tion of BMMNCs. Of course, the early TACT
study has been criticized for its lack of credibil-
ity, in particular with regard to all vascular infor-
mation (angiogram, ABI, walking distance).
Nevertheless, these studies raised considerable
interest in stem cell and/or BMMNC therapy
in PAD [Fadini et al. 2010; Lawall et al. 2010].
It can be argued that the data were based on a
wide variety of different experimental approaches.
Furthermore, the degree of ischemia was hetero-
geneous in these studies and CLI was not gener-
ally present. However, despite these limitations a
meta-analysis demonstrated a consistent improve-
ment of perfusion (based on quantitation of ABI,
wound healing, walking capacity, tcpO2) through-
out most of the studies [Fadini et al. 2010].
In the majority of studies in humans, the intra-
muscular injection of BMMNCs into the gastroc-
nemius muscle along a symmetric grid with fixed
number of injections (20–60) was the preferred
mode of application [Miyamoto et al. 2004;
Prochaska et al. 2009; Van Tongeren et al. 2008].
The density of preformed capillaries and collater-
als is highest in close proximity to the axial arteries
and collateral growth preferably occurs in these
regions. Therefore, it is rational to place injections
along the occluded vessels of the lower leg, as per-
formed in the studies by Amann and colleagues
[Amann et al. 2008, 2009]. A schematic display of
the injections is shown in Figure 3. Formation and
extension of small collateral vessels appears to be
the most important physiological repair mecha-
nism in PAD [Unthank et al. 2004], presumably
due to the local production of growth factors
by BMMNCs. These collaterals can form direct
connections between the axial main vessels.
Nevertheless, the growth capacity of these col-
laterals is reduced in atherosclerosis and espe-
cially in diabetic macroangiopathy [Helisch and
Schaper, 2003]. In contrast to intramuscular
injection, intra-arterial application guides the
injected BMMNCs to the border zone of maxi-
mum ischemia [Yoshida et al. 2003]. In order to
optimize the therapeutic procedure, Bartsch and
colleagues conducted an ischemic precondi-
tioning of the affected leg by means of exercise
and combined this procedure with intra-arterial
and intramuscular administration of BMMNCs
[Bartsch et al. 2007]. Recently, Kolvenbach
and colleagues applied BMMNCs as adjuvant
treatment in patients with PAD and CLI during
bypass surgery and/or endovascular interventions
[Kolvenbach et al. 2010]. In addition, BMMNCs
have also been locally applied to restore angio-
genesis and promote wound healing in type 2
diabetic patients with neuro-ischemic wounds
[Humpert et al. 2005].
In the majority of studies, bone marrow is the pri-
mary source of stem cell material and enrichment
of mononuclear cells from the crude aspirate can
be accomplished with different techniques such as
density gradient centrifugation (Ficoll™) [Boyum
et al. 2002] or other commercially available
blood-centrifugation and plasmapheresis systems
[Tateishi-Yuyama et al. 2002]. However, these are
laborious and require the background of a special-
ized and certified hematological or immunological
unit. In contrast, bedside centrifugation systems
have been developed (e.g. Smart Prep®, Harvest
Technol ogies, USA) that can be easily used on the
ward. These systems yield sufficient amounts of
purified BMMNCs in a short time (~1 hour) and
are considerably cheaper than the other tech-
niques mentioned [Amann et al. 2008].
Therapeutic Advances in Endocrinology and Metabolism 2 (6)
Relating to the clinical outcome of BMMNC
therapy in PAD, two major studies with regard to
the number of treated patients and duration of
follow up should be mentioned. In the TACT fol-
low-up study, mortality and amputation-free sur-
vival were analyzed as primary endpoints [Matoba
et al. 2008]. The 3-year overall mortality was only
20% and after 3 years 60% of the patients were
free of amputation. The BONMOT pilot study
included 51 subjects with CLI and impending
risk for amputation. During 3.2 years of follow
up, limb salvage was 53%. The improvement of
the mean Rutherford category from 4.9 at base-
line to 3.3 after 6 months appears to be clinically
important [Amann et al. 2009].
Based on the combined efforts in basic together
with clinical research, the therapeutic arsenal for
the treatment of patients with diabetic foot ulcers
and CLI is growing constantly. The current devel-
opment of novel techniques and clinical protocols
including stem cell-based approaches gives realis-
tic hope for the future to substantially improve
the prognosis of this multi-morbid and critically
ill group of patients.
This work was supported by the BMBF (grant
number FKZ01GI0924 to the Paul Langerhans
Institute Dresden - DZD e.V.), DFG SFB 655
‘from cells to tissues’ and by the Centre for
Regenerative Therapy Dresden (CRTD) to SRB.
Conflict of interest statement
The authors declare no conflicts of interest in
preparing this article.
Alexandrescu, V., Hubermont, G., Philips, Y.,
Guillaumie, B., Ngongang, C. and Coessens, V.
et al. (2009) Combined primary subintimal and
endoluminal angioplasty for ischaemic inferior-
limb ulcers in diabetic patients: 5-years practice in
a multidisciplinary ‘diabetic foot’ service. Eur J Vas
Endovasc Surg 37: 448–456.
Altstaedt, H., Berzewski, B., Breddin, H., Brockhaus,
W., Bruhn, H. and Cachovan, M. et al. (1993)
Treatment of patients with peripheral arterial
occlusive disease Fontaine stage IV with intravenous
iloprost and PGE1: a randomized open controlled
study. Prostaglandins Leukot Essent Fatty Acids
Amann, B., Luedemann, C., Ratei, R. and
Schmidt-Lucke, J. (2009) Autologous bone marrow
cell transplantation increases leg perfusion and
reduces amputations in patients with advanced critical
limb ischemia due to peripheral artery disease.
Cell Transplant 18: 371–380.
of A. fem. sup.
distal occlusion of
A. fem. sup./ A. poplitea
occlusion of the
arteries of lower leg
along the arteries of lower leg
Figure 3. Illustration of the intramuscular injection regime of bone marrow mononuclear cells in patients with
critical limb ischemia, as performed by Amann et al. [2008, 2009].
M Weck et al.
Amann, B., Luedemann, C., Rückert, R., Lawall, H.,
Liesenfeld, B. and Schneider, M. et al. (2008) Design
and rationale of a randomized, double-blind, placebo-
controlled phase III study for autologous bone
marrow cell transplantation in critical limb ischemia:
the BONe Marrow Outcomes Trial in Critical Limb
Ischemia (BONMOT-CLI). Vasa 37: 319–325.
Amendt, K. (2005) PGE1 and other prostaglandins
in the treatment of intermittent claudication: a
metaanalysis. Angiology 56: 409–415.
Asahara, T., Masuda, H., Takahashi, T., Kalka, C.,
Pastore, C. and Silver, M. et al. (1999) Bone marrow
origin of endothelial progenitor cells responsible
for postnatal vasculogenesis in physiological and
pathological neovascularization. Circulation Res 85:
Bartsch, T., Brehm, M., Zeus, T., Högler, G.,
Wernet, P. and Strauer, B. (2007) Transplantation of
autologous mononuclear bone marrow stem cells in
patients with peripheral arterial disease (The TAM-
PAD Study). Clin Res Cardiol 96: 891–899.
Belch, J., McKay, A., McArdle, B., Leiberman, P.,
Pollock, J. and Lowe, G. et al. (1983) Epoprostenol
(prostacycline) and severe arterial disease: A double-
blind trial. Lancet 1: 315–317.
Boyum, A., Brincker, F., Martinsen, I., Lea, T.
and Lovhang, D. (2002) Separation of human
lymphocytes from citrated blood by density gradient
(Nyco Prep) centrifugation: monocyte depletion
depending upon activation of membrane potassium
channels. Scand J Immunol 56: 76–84.
Creutzig, A., Lehmacher, W. and Elze, M. (2004)
Meta-analysis of randomised controlled prostaglandin
E1 studies in peripheral arterial occlusive disease
stages III and IV. Vasa 33: 137–144.
Cronenwett, J., Zelenock, G., Whitehous, W., Jr,
Lindenauer, S., Graham, L. and Stanley, J. (1986)
Prostacyclin treatment of ischemic ulcers and rest
pain in unreconstructible peripheral arterial occlusive
disease. Surgery 100: 369–375
Duthois, S., Cailleux, N., Benosman, B. and
Levesque, H. (2003) Tolerance of iloprost and results
of treatment chronic severe lower limb ischaemia
in diabetic patients. A retrospective study of 64
consecutive cases. Diab Metab 29: 36–43.
Fadini, G., Agostini, C. and Avogaro, A. (2010)
Autologous stem cell therapy for peripheral arterial
disease. Meta-analysis and systematic review of the
literature. Atherosclerosis 209: 10–17.
Faglia, E., Clerici, G., Clerissi, J., Gabrielli, L., Losa,
S. and Mantero, M. et al. (2006) Early and five-year
amputation and survival rate of diabetic patients with
critical limb ischemia: data of a cohort study of 564
patients. Eur J Vasc Endovasc Surg 32: 484–490.
Faglia, E., Clerici, G., Clerissi, J., Gabrielli, L.,
Losa, S. and Mantero, M. et al. (2009) Long-term
prognosis of diabetic patients with critical limb
ischemia: a population-based cohort study. Diabetes
Care 32: 822–827.
Helisch, A. and Schaper, W. (2003) Arteriogenesis:
The development and growth of collateral arteries.
Micocirculation 10: 83–97.
Hicken, G., Lossing, A., Rubin, B., Aro, L. and
Ameli, F. (1995) Intra-arterial infusion of urokinase
for acute, critical ischemia in the lower limb. Can J
Surg 38: 486–491.
Hirsch, A., Haskal, Z., Hertzer, N., Bakal, C.,
Creager, M. and Halperin, J. et al. (2006) ACC/
AHA 2005 Practical guidelines for the management
of patients with peripheral arterial disease (lower
extremity, renal, mesenteric, and abdominal aortic):
a collaborative report from the American Association
for Vascular Surgery/Society for Vascular Surgery,
Society for Cardiovascular Angiography and
Interventions, Society for Vascular Medicine and
Biology, Society of Interventional Radiology, and
the ACC/AHA Task Force on Practice Guidelines.
Circulation 113: e463–e654.
Humpert, P., Bärtsch, U., Konrade, I., Hammes,
H.-P., Morcos, M. and Kasper, M. et al. (2005)
Locally applied mononuclear bone marrow cells
restore angiogenesis and promote wound healing in
a type 2 diabetic patient. Exp Clin Endocrinol Diabetes
ICAI (Ischemia Cronica degli Arti Inferiori) Study
Group (1999) Prostanoids for chronic criticial leg
ischemia. A randomized, controlled, open-label trial
with prostaglandin E1. Ann Intern Med 130: 412–421.
Iversen, M., Tell, G., Riise, T., Hanestad, B.,
Østbye, T. and Graue, M. et al. (2009) History of
foot ulcer increases mortality among individuals with
diabetes: ten-year follow-up of the Nord-Trøndelag
Health Study, Norway. Diabetes Care 32: 2193–2199.
Kalka, C., Masuda, H., Takahashi, T., Kalka-
Moll, W., Silver, M. and Kearney, M. et al. (2000)
Transplantation of ex vivo expanded endothelial
progenitor cells for therapeutic neovascularization.
Proc Natl Acad Sci U S A 97: 3422–3427.
Kamihata, H., Matsubara, H., Nishihue, T.,
Fujiyama, S., Tsutsumi, Y. and Ozono, R. et al.
(2001) Implantation of bone marrow mononuclear
cells into ischemic myocardium enhances collateral
perfusion and regional function via side supply
of angioblasts, angiogenic ligands, and cytokines.
Circulation 104: 1046–1052.
Kolvenbach, R., Kreissig, C., Cagiannos, C., Afifi,
R. and Schmaltz, E. (2010) Intraoperative adjunctive
stem cell treatment in patients with critical limb
Therapeutic Advances in Endocrinology and Metabolism 2 (6)
ischemia using a novel point-of-care device. Ann Vasc
Surg 24: 367–372.
Lawall, H., Bramlage, P. and Amann, B. (2010) Stem
cell and progenitor cell therapy in peripheral artery
disease. A critical appraisal. Thromb Haemost 103:
Lawall, H., Diehm, C., Baler, K., Gail, D., Heidrich,
H. and Huppert, P.. (2009a) Deutsche Gesellschaft für
Angiologie/ Gesellschaft für Gefäßmedizin. Leitlinien
zur Diagnostik und Therapie der peripheren arteriellen
Verschlusskrankheit (PAVK). http://www.awmf.de/
Lawall, H., Gorriahn, H., Amendt, K., Ranft, J.,
Bramlage, P. and Diehm, C. (2009b) Long-term
outcomes after medical and interventional therapy of
critical limb ischemia. Eur J Intern Med 20: 616–621.
Leschke, M. (2008) Rheology and coronary heart
disease. Dtsch Med Wochenschr 133(Suppl. 8):
Leschke, M., Klimek, W. and Jung, F. (2003)
Rheological determinants of end-organ damage.
Internist 44: 853–863.
Leschke, M., Motz, W. and Strauer, B. (1986)
Hemorheologic therapy applications in coronary heart
disease. Wien Med Wochenschr 136: 17–24.
Leschke, M., Schoebel, F., Mecklenbeck, W., Stein,
D., Jax, T. and Müller-Gärtner, H. et al. (1996)
Long-term intermittent urokinase therapy in patients
with end-stage coronary artery disease and refractory
angina pectoris: a randomized dose-response trial.
J Am Coll Cardiol 27: 575–584.
Leschke, M., Schoebel, F. and Strauer, B. (1997)
Low-dose intermittent urokinase therapy in chronic
symptomatic end-stage arterial disease—clinical
relevance for patients with coronary artery disease or
peripheral arterial occlusive disease. Clin Hemorheol
Microcirc 17: 59–66.
Loosemore, T., Chalmers, T. and Dormandy, J. (1994)
A meta-analysis of randomized placebo controlled
trials in Fontaine Stages III and IV peripheral occlusive
arterial disease. Int Angiol 13: 133–142.
Matoba, S., Tatsumi, T., Murohara, T., Imaizumi,
T., Katsuda, Y. and Ito, M. et al. (2008) Long-term
clinical outcome after intramuscular implantation
of bone marrow mononuclear cells (Therapeutic
Angiogenesis by Cell Transplantation [TACT] trial)
in patients with chronic limb ischemia. Am Heart J
Miyamoto, M., Yasutake, M., Takano, H., Takagi,
H., Takagi, G. and Mizuno, H. et al. (2004)
Therapeutic angiogenesis by autologous bone marrow
cell implantation for refractory chronic peripheral
arterial disease using assessment of neovascularization
by 99m Tc-tetrofosmin (TF) perfusion scintigraphy.
Cell Transplant 13: 429–437.
Norgen, L., Alwmark, A., Angquist, K., Hedberg,
B., Bergqvist, D. and Takolander, R. et al. (1990)
A stable prostacyclin analogue (iloprost) in the
treatment of ischaemic ulcers of the lower limb. A
Scandinavian–Polish placebo controlled, randomised
multicenter study. Eur J Vasc Surg 4: 463–467.
Norgren, L., Hiatt, W., Dormandy, J., Nehler, M.,
Harris, K. and Fowkes, F. (2007) TASC II Working
Group. Inter-society consensus for the management
of peripheral arterial disease (TASC II). Eur J Vasc
Endovasc Surg 33(Suppl. 1): S1–S75.
Partsch, H. and Jochmann, W. (1993) [Urokinase in
refractory lower leg ulcers: therapy with retrograde
intravenous pressure infusion]. Wien Med Wochenschrs
Peters, A., Schoebel, F., Jax, T., Neubaur, T.
Strauer, B. and Leschke, M. (1999) Long-term
Urokinase Therapy and Isovolemic Hemodilution:
A Clinical and Hemodynamic Comparison in Patients
with Refractory Angina Pectoris. Int J Angiol 8: 44–49.
Prochaska, V., Gumulec, J., Chmelova, J.,
Klement, P., Klement, G. and Jonsza, T. et al. (2009)
Autologous bone marrow stem cell transplantation in
patients with end-stage chronical limb ischemia and
diabetic foot. Vnitr Lek 55: 173–178.
Prompers, L., Huijberts, H., Apelqvist, J., Jude,
E., Piaggesi, A. and Bakker, K. et al. (2007) High
prevalence of ischemia, infection and serious
comorbidity in patients with diabetic foot disease in
Europe. Baseline results from the Eurodiale Study.
Diabetologia 50: 18–25.
Rietzsch, H., Panzer, I., Selisko, T., Julius, U., Jabs,
N. and Reimann, M. et al. (2008) Heparin-induced
extracorporeal LDL precipitation (H.E.L.P.) in
diabetic foot syndrome-preventive and regenerative
potential? Horm Metab Res 40: 487–490.
Ryden, L., Standl, E., Bartnik, M., Van den
Berghe, G., Betteridge, J. and de Boer, M. et al.
(2007) Guidelines on diabetes, pre-diabetes, and
cardiovascular diseases: executive summary: The
Task Force on Diabetes and Cardiovascular Diseases
of the European Society of Cardiology (ESC) and of
the European Association for the Study of Diabetes
(EASD). Eur Heart J 28: 88–136.
Schuler, J., Flanigan, D., Holcroft, J., Ursprung,
J., Mohrland, J. and Pyke, J. (1984) Efficacy
of prostaglandin E1 in the treatment of lower
extremity ischemic ulcers secondary to peripheral
vascular occlusive disease. Results of a prospective
randomized, double-blind, multicenter clinical trial.
J Vasc Surg 1: 160–170.
Shintani, S., Murohara, T., Ikeda, H., Ueno, T.,
Honma, T. and Katoh, A. et al. (2001) Mobilization
of endothelial progenitor cells in patients with acute
myocardial infarction. Circulation 103: 2776–2779.
M Weck et al. Download full-text
Singh, N., Armstrong, D. and Lipsky, B. (2005)
Preventing foot ulcers in patients with diabetes.
J Am Med Assoc 293: 217–228.
Stiegler, H., Diehm, C., Grom, E., Martin, M.,
Morl, M. and Rudofsky, G. et al. (1992) Placebo
controlled, double-blind study of the effectiveness of
i.v. prostaglandin E1 in diabetic patients with stage IV
arterial occlusive disease. Vasa 35(Suppl.): 164–166.
Sumpio, B., Armstrong, D., Lavery, L. and
Andros, G., for the SVS/ APMA writing group (2010)
The role of interdisciplinary team approach in the
management of the diabetic foot: a joint statement
from the Society for Vascular Surgery and the
American Podiatric Medical Association. J Vasc Surg
Takahashi, T., Kalka, C., Masuda, H., Chen, D.,
Silver, M. and Kearney, M. et al. (1999) Ischemia-
and cytokine-induced mobilization of bone
marrow-derived endothelial progenitor cells for
neovascularization. Nat Med 5: 434–438.
Tateishi-Yuyama, E., Matsubara, H., Murohara, T.,
Ikeda, U., Shintani, S. and Masaki, H. et al. (2002)
Therapeutic angiogenesis for patients with limb
ischemia by autologous transplantation of bone-
marrow cells: a pilot study and a randomised
controlled trial. Lancet 360: 427–435.
Telles, G., Campbell, W., Wood, R., Collin, J., Baird,
R. and Morris, P. (1984) Prostaglandin E1 in severe
lower limb ischaemia: a double blind controlled trial.
Br J Surg 71: 506–508.
Trübestein, G., Diehm, C., Gruss, J. and Horsch, S.
(1987) Prostaglandin E1 in chronic arterial disease:
a multicenter study. Vasa 17(Suppl.): 39–43.
Turan, R., Ortakm, J., Akin, I., Kische, S.,
Schneider, H. and Turan, C. et al. (2011) Improved
mobilization of the CD 34+ and CD 133+ bone
marrow-derived circulation progenitor cells by
freshly isolated intracoronary bone marrow cell
transplantation in patients with ischemic heart disease.
Stem cells Dev 20: 1491–1501.
UK Severe Limb Ischaemia Study Group (1991)
Treatment of limb threating ischaemia with
intravenous iloprost: a randomised double-blind
placebo controlled study. Eur J Vasc Surg 5: 511–516.
Unthank, J., Sheridan, K. and Dalsing, M. (2004)
Collateral growth in the peripheral circulation: a
review. Vasc Endovascular Surg 38: 291–313.
Van Tongeren, R., Hamming, J., Fibbe, W., van
Weel, V., Frerichs, S. and Stiggelbout, A. et al.
(2008) Intramuscular or combined intramuscular/
intra-arterial administration of bone marrow
mononuclear cells: a clinical trial in patients with
advanced limb ischemia. J Cardiovasc Surg (Torino)
Weck, M., Laage, C., Schab, T. and Mölle, A.
(2001) Low-dose urokinase therapy in acute
angioneuropathic diabetic foot syndrome (DFS).
Diab Stoffw 10: 13–21.
Weck, M., Panzner, I. and Schellong, S.M. (2006)
Diagnostik und Therapie des diabetischen Fußes. UNI
MED: Bremen, Germany.
Weck, M., Rietzsch, H., Lawall, H., Pichlmeier, U.,
Bramlage, P. and Schellong, S. (2008) Intermittent
intravenous urokinase for critical limb ischemia
in diabetic foot ulceration. Thromb Haemost
Weck, M., Slesaczeck, T., Paetzold, H., Münch, D.,
Nanning, T. and von Gagern, G. et al. (2010)
Limb salvage experience in a Disease Management
Program for the diabetic foot. Diabetes 59(Suppl. 1):
Yoshida, M., Horimoto, H., Mieno, S., Nomura, Y.,
Okawa, H. and Nakahara, R. et al. (2003) Intra-arterial
bone marrow cell transplantation induces angiogenesis
in rat hindlimb ischemia. Eur Surg Res 35: 86–91.
Zeller, T. (2007) Current state of endovascular
treatment of femoro-popliteal artery disease. Vasc Med
Zeller, T., Sixt, S. and Rastan, A. (2009) New
techniques for endovascular treatment of peripheral
artery disease with focus on chronic critical limb
ischemia. Vasa 38: 3–12.
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