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The Vulnerable Patient with Diabetes
4
Vulnerable Blood with Diabetes
Hyperglycaemia
Metabolic changes TF expression
Oxidative stress Fibrinogen
Endothelial VWF and FVIII
dysfunction
TF expression Denser clot
Platelet Decreased NO
IFN structure /
dysfunction Production
IL-6 hypofibrinolysis
PAI-1
Increased
shedding
Increase
Increaseofof
Microparticles
microparticles
Vulnerable blood
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author
2012. For permissions please email: journals.permissions@oup.com
Platelet function and plasma coagulation factors with Diabetes,
favouring platelet aggregation and a propensity for thrombosis.
Tissue plasminogen
Platelet aggregability activator (t-PA)
Cytokines Activated
Insulin platelets
Proinsulin
High glucose
Modified LDL Glycation
Modified VLDL
PAI-1 Fibrin
deposits
Plasmin
Plasminogen
(-) t-PA t-PA
(-)
Collagenase
PAI-1
DM die
a thrombotic death.
Deaths due to
cardiovascular complications
Cerebrovascular Coronary
disease disease
7.4%
24.7% 29.9%
3.3%
3.8% 11.8%
19.2%
Rapid formation of
Stop bleeding quickly
mechanically sound clot
PT
XI XIa
Tissue Factor
IX IXa
PTT X Xa X
V Va XIII
Prothrombin Thrombin
XIIIa
Insoluble Fibrin
Coagulation and
Fibrinolysis
The coagulation cascade
FX
Prothrombin
Tissue
+
FXa Plasmin-mediated fibrinolysis
factor FVa +
FVIIa Plasminogen
Prothrombinase
complex + tPA
Thrombin aggregated
platelets
-
PAI-1
+
Fibrinogen
Fibrin Plasmin
Thrombus - ⍺-2-AP
+ TAFI
Fibrin
Degradation
Products
Fibrinolysis
Physiologic Plasminogen
Activators
α2 X Unbound Fibrin bound
-Tissue Plasminogen Activator
Anti Plasmin Plasmin Plasmin
- Urokinase
- Activated Clotting Factor XII
Fibrinogen
Split Products Fibrinogen Fibrin Fibrin – Split
Product
(D-dimer)
Fibrinogenolysis Fibrinolysis
20
Platelets
Platelets
▪ Stick to damaged blood vessels
• requires von Willebrand factor
▪ Spread out to cover damaged area
▪ Activate and release contents
• partly blocked by aspirin
▪ Aggregate
▪ Cause blood vessel constriction
▪ Cause retraction of clot to draw wound edges together
Endothelial abnormalities undoubtedly play a
role in the enhanced activation of platelets
and clotting factors seen in diabetes.
23
Circulating platelet aggregates,
Platelet aggregation in response to platelet agonists,
Platelet contractile force (PCF)
24
Higher plasma levels of platelet
release products;
-beta-thromboglobulin,
-platelet factor 4,
-thromboxane B(2),
demonstrate
platelet hyperactivity in diabetes.
25
This constellation of findings
supports the clinical observation
that diabetes is a
hypercoagulable state.
26
The result is an imbalance between
thrombus formation and dissolution,
favouring the former.
27
28
HYPERGLYCAEMIA
probably determines the onset
of these abnormalities through
three mechanisms:
1. Non-enzymatic glycation,
2. Increased oxidative stress
3. Decrease in the levels of
heparan sulphate.
Non-enzymatic glycation
seems to affect the
functionality of key
molecules of coagulation in
a negative sense.
Numerous studies have
shown that coagulation
abnormalities occur in the
course of DM, resulting in a
state of thrombophilia.
Thrombophilia
Tendency to form Thrombi
Hypercoagulable state
Arterial thrombi:
Usually in areas of
atherosclerotic plaques
Venous thrombi:
Thrombophlebitis, DVT,
Pulmonary embolism
These observations are
supported by epidemiological
studies which demonstrate
that thromboembolic events
are more likely to occur in
diabetic patients.
The abnormalities observed
involve
all stages of coagulation,
affecting both thrombus
formation and its inhibition,
fibrinolysis,
platelet
and
endothelial function.
Good metabolic control could play a key role in
controlling the coagulation irregularities in
diabetes.
However,
considering the difficulties in achieving such an
objective,
Pathogenesis Therapy
- Platelet Adhesion
Anti Platelet
- Platelet Agregasion
Anti Coagulant
- Blood Coagulation
- Thrombosis Thrombolitic
38
Therapy of Atherothrombosis
Plaque Rupture
or Erosion
Platelet-Rich
Thrombus Thrombolysis
1. Anti-coagulants
2. Anti-platelet Drugs
3. Thrombolytic Agents
Oral Trombolytic,
A challenging Opportunity
Atherothrombosis* is a
Leading Cause of Death Worldwide1†
AIDS 5.1
Pulmonary disease 6
Injuries 9.1
Cancer 12.6
Atherothrombosis* 28.7
0 5 10 15 20 25 30
Mortality (%)
* Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease
† Worldwide defined as Member States by WHO Region (Africa, Americas, Eastern Mediterranean, European,
South-East Asia and Western Pacific)
20
18
16
-7.4
14 tahun -9.2
tahun
12
-12
tahun
Tahun
10
6
4
2
0
Anti-thrombosis
Fibrinogenolytic
DISOLF
DLBS1033
Clot Lysis
Thrombolytic
Fibrinolytic
Anti-thrombosis
47
Mechanism of Actions
Anti-platelet
aggregation
Anti-thrombosis
Fibrinogenolytic
DISOLF
DLBS1033
Clot Lysis
Thrombolytic
Fibrinolytic
Anti-platelet
aggregation
Trombosit
DISOLF
Adenilat
PDE III
siklase
Ca2+ TXA2
Intracell cAMP
Primer Sekunder
Intracell Ca2+
ADP
Agregasi
trombosit
Platelet activation
inhibition
The Role of Platelets in Atherothrombosis
1 Adhesion 3 Aggregation
2 Activation Anti-platelet
aggregation
Anti-platelet
aggregation
Mechanism of Actions
Anti-platelet
aggregation
Anti-thrombosis
Fibrinogenolytic
DISOLF
DLBS1033
Clot Lysis
Thrombolytic
Fibrinolytic
Fibrinogenolytic
Trombin
Fibrinogen
X Fibrin
DISOLF
Anti-platelet
aggregation
Mechanism of Actions
Anti-platelet
aggregation
Anti-thrombosis
Fibrinogenolytic
DISOLF
DLBS1033
Clot Lysis
Thrombolytic
Fibrinolytic
Thrombolytic
54
Mechanism of Actions
Anti-platelet
aggregation
Anti-thrombosis
Fibrinogenolytic
Disolf
DLBS1033
Clot Lysis
Thrombolytic
Fibrinolytic
Clot Lysis
DISOLF
Clot Lysis
Anti-thrombosis
Fibrinogenolytic
Disolf
DLBS1033
Clot Lysis
Thrombolytic
Fibrinolytic
Fibrinolytic
Plasminogen
t-PA
Plasmin DISOLF
• Anticoagulation
Specific binding to fibrinogen (specific affinity with
fibrinogen)
Hydrolyze fibrinogen (generate soluble degraded
products)
* Decrease concentration of fibrinogen
Lumbrokinase Oral Function
• Antiplatelet
It decreases significantly the levels of Gmp-140,
TXB2 and S-HT
*Inhibiting platelet activation and vasoconstriction
Different mechanism
Common Sense of Daily Practices
Lumbrokinase
✂
Fibrinogen
Plasminogen
Li G, Wang KY, Li D, Wang N, et al. (2012) Cloning, Expression and Characterization of a Gene from Earthworm Eisenia
fetida Encoding a Blood-Clot Dissolving Protein. PLoS ONE 7(12): e53110. doi:10.1371/journal.pone.0053110
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0053110
Successful results of Lumbrokinase
in some cases:
1. Acute Limb Ischemia
2. Acute DVT
3. PAD
Medical Management of Acute Limb Ischemia
The Role of Lumbrokinase
Acute Limb Ischemia ( A L I )
Definition :
Pulselessness
Pallor
Paresthesia
Paralysis
• 60 yrs man
• Stage IIb Acute Limb Ischemia
• Atrial fibrilation with normoventricular response
• Moderate mitral stenosis
• Type-2 DM
• Stage-1 hypertension
CT Angiography (MSCT) 23 Sept 2008
• Kanan
Thrombus a. Femoralis superficial didua
tempat dengan panjang sumbatan 3,5 cm
dan 13 cm
Thrombus a. Poplitea distal sehingga a.
Tibialis ant, post, dan peronea tidak terisi
kontras
• Kiri
Thrombus a. Iliaka communis sepanjang
7,4 cm.
Thrombus a. Poplitea distal, hanya
sebagian a. Tibialis ant 13 proksimal
terisi kontras dan a. Peronea. Sedangkan
a. Tibilais post tidak terisi kontras
Treatment
Figure 2. Improvement of Ankle-Brachial Index (ABI) values from baseline. Improvement of Ankle-Brachial Index
(ABI) values in DLBS1033 group was significantly higher than that in Control group (p < 0.01)
UJI KLINIS
Sub Bagian Endokrin Metabolik FK Universitas Andalas /
RSUP Dr M Jamil Padang ( 2014 – 2015 )
Rerata kadar Tx B2 pada awal, minggu ke-4 dan ke-8 pada klp
Lumbrokinase dan kontrol (ng/mL), rerata(SB)
95
Changes of Fibrinogen level from baseline to Week 4
and 8
50
Placebo DLBS1033
38
Changes of fibrinolgen level (mg/dL)
25
13
11.5
5.0833
0
-21.56 -12.4
-13
-25 p = 0,298
p = 0,471
-38
-50
Week 4 Week 8
Pengaruh pemberian lumbrokinase terhadap penurunan
kadar fibrinogen serum pada DMT2
Conclusion
• Oral thrombolytics can be considered to treat and
prevent certain clinical conditions of arterial
thrombosis
in T2DM
• Risk and benefit of aspirin ( hemorrhage risk and
low of
effectiveness due to drug resistance ) make it
controversial.
• Based on study in its pharmacologic actions,
DLBS1033
( lumbrokinase, Disolf ) may be effective in the
treatment or prevention of atherothrombosis in
T2DM
• More clinical trials are needed to confirm its
efficacy and safety
● Almost all PAD subjects were females, mean age of
all subjects was 55.4 years old.
● The most prevalent independent risk factors for
PAD observed in the study were hypertension,
diabetes, dyslipidemia, and lack of exercise.
● DBLS1033 showed to improve ABI in patients
with intermittent claudication.
Oral Fibrinolytics can be considered in certain
clinical conditions of arterial and venous thrombosis
99
DiSOLF
Bioactive protein fraction DLBS1033
(Lumbrokinase) 490 mg
100