Defeat Thrombosis

Thrombosis
Formation, development, or presence of a
thrombus; this can happen whenever the flow
of blood in arteries or veins is impeded.
Arterial thrombosis Venous thromboembolism (VTE)
Mechanism Erosion or rupture of an atherosclerotic Interdependently of Virchow’s triad factors.
plaque, and through platelet-mediated
thrombin.

Manifestation Acute Coronary Syndrome Deep venous thrombosis (DVT)

Stroke Pulmonary embolism (PE)
Acute limb ischemia

Composition Mainly by Platelet Mainly by Fibrin

Treatment Antiplatelet (ASA, clopidogrel), Anticoagulants (heparins, warfarin),

anticoagulant, thrombolytic, statins, thrombolytic
antihypertensive.
 Venous
Thromboembolism (VTE)
 Venous Thromboembolism
(VTE)
Blood flow to
VTE is the most common the heart
vascular disease after AMI and and lungs

stroke.
It represented by two main Embolus
clinical events : Deep Vein released
Thrombosis (DVT) and
Pulmonary Embolism (PE).
DVT = Thrombus
formed/affecting in vein
that lie under the fascia

Previtali E. Bloodtranfus.2011
JSC Guidelines. Circ J 2011.
https://www.preferredvasculargroup.com/conditions/deep-vein-thrombosis-dvt/
 RISK FACTOR OF VTE

• Immobility
• Bed rest
• Anaesthetical • Surgery, tauma
procedure
• Congestive heart
failure
• History of vein
thrombosis

• Cancer
• Heparin-induced
Thrombositopenia
• Essential Thrombosistosis
• Nefrotic syndrome
• Protein C dan S deficiency
• ATIII deficiency
• Estrogen therapy

1) Goldhaber S. Risk factors for venous thromboembolism. J Amer Coll Cardiol. 2010; 56:1-7
 Management of VTE

 Anti-coagulants:
Objectives: 1. Unfractionated Heparin (UFH)
2. Low-Molecular Weight Heparin
Decrease the propagation of (LMWH)
the thrombus and prevent 3. Vit. K Antagonist
its complication: Pulmonary 4. Fondaparinux (Synthetics
pentasaccharides with selectives anti-
Embolism, reccurent deep factor Xa activity)
vein thrombosis (DVT), 5. Direct oral anticoagulan (DOAC)
post-thrombotic syndromes
(PTS), and death.  Thrombolitic

 Surgical intervention –
mechanical support

Min SK, et al. Vascular Specialist International. 2016. 32(3). 77-104

Gutt CN.The American Journal of surgery. 2005
Defeat Thrombosis
 Fondaparinux

 Synthetic polysaccharide (pentasaccharides)

 Indirect, selective factor Xa inhibitor
 Binds to antithrombin III
 Anticoagulants Mechanism of action
Intrinsic Pathway
Tissue Factor
(extrinsic) pathway
XII XIIa Tissue
Trauma
Factor
XI XIa
VIIa VII
IX IXa VIIIa VIII TF +
VIIa TFPI

X X AntiThrombin
aktivasi

inhibisi

Xa
Prothrombin (II) Thrombin (IIa)
Va
Common pathway
V XIIIa XIII
Fibrinogen (I) Fibrin (Ia)
(monomer)

Fibrin crosslinked
(polimer)
UFH
Menghambat Thrombin (IIa), IXa, Xa, XIa, & XIIa
LMWH Ketiganya :
Terutama menghambat Xa, sedikit pada IIa • Membutuhkan AT sebagai kendaraan
Fondaparinux • Tidak mempengaruhi thrombin yg terikat
Hanya mengambat Xa pada fibrin
Fondaparinux Mechanism of action
 Fondaparinux
• Pharmacologic benefits:
– Binds specifically to antithrombin III and not to
irrelevant plasma proteins
– Exhibits no inhibitory effect on platelet aggregation
– Favorable pharmacokinetic profile after SC
administration
• 100% absorption into plasma
• Maximal concentration (Cmax) in 2h
• Relatively long half-life (17h)
• Predictable dose response, independent of age or sex
Paolucci, et al. 2002.
Messmore, et al. 1989.
Donat, et al. 2002
 Pharmacologic comparison
Property UFH LMWH Fondaparinux

Source Animal (porcine) Animal (porcine) synthetic

T1/2 ~3h ~4h (variable) 17-21h
Bioavailability (SC) 30% >90% 100%

Reticuloendothelial
Elimination renal renal
and renal

Induced HIT 2-5% 1-2% Non reactive

aPTT
Monitoring Plt count nil
Plt count

Reversal Protamine Protamine FFP

Pharmacotherapy 23(6):772-787, 2003

Savi P, et al. Blood 2005;105(1):139–44.
Diviti PI
 Heparin-Induced Thrombocytopenia

4 in-vitro studies showed no platelet activation and no cross-

reactivity of fondaparinux to HIT antibodies

• Elalamy I. Thromb Haemost 1995;74(5):1384–5.

• Amiral J, et al. Blood Coagul Fibrinolysis 1997;8:114–17.

• Ahmad S, et al. Clin Appl Thromb Hemost 1999;5(4):259–66.

• Savi P, et al. Blood 2005;105(1):139–44.

VTE in Surgical Patient
 RISK FACTOR OF DVT

** incidence increased without prophylaxis

Gutt CN.The American Journal of surgery. 2005

 Prophylaxis of VTE
• Recommended
prophylaxis :
– Appropriate prevention
strategy based on risk factor
and thromboembolic level of
risk.
– Anti-coagulant agents can
be used as effective
prophylaxis (UFH, LMWH,
Pentasaccahrides).

Gutt CN.The American Journal of surgery. 2005

Clinical Study
Objective: To compare efficacy and safety of fondaparinux and enoxaparin
in prevention of venous thromboembolism in patients undergoing elective
hip-replacement surgery.

Method: 2.5 mg Fondaparinux

oncedaily SC injected 6 h
after the operation
Primary outcome
Subject 2309
Patients
Treatment scheduled for 5-9 days assessed between days Result
5 and 11
40 mg enoxaparin
injected 12 h before the
operation
Result Efficacy
Events of VTE
9%

Reduction
of VTE 56 %
4% Fonda
Enoxa

By 11 days, Significantly fewer patients on Fondaparinux

had VTE than those on Enoxaparin

Safety

Fondaparinux and enoxaparin used did

not differ in frequency of death or
clinically relevant bleeding.
Sullivan SD, et al. ISPOR 2006.
 Treatment of VTE

Objective
To evaluate the efficacy and safety of fondaparinux compared with enoxaparin in the initial treatment of
symptomatic DVT

2205 patients (mean age

61 years) with acute
symptomatic DVT and who
required antithrombotic
therapy
Endpoints
Primary efficacy endpoint: 3-month incidence of symptomatic recurrent VTE
complications (DVT and PE)
Primary safety endpoints: major bleeding during the initial treatment period and 3-
months mortality
Buller HR, et al. 2004. Ann Intern Med.
Result

Fondaparinux given subcutaneously once

daily is at least as effective and safe as
enoxaparin twice daily for initially treating
symptomatic DVT.

Buller HR, et al. 2004. Ann Intern Med.

VTE in non-Surgical Patient
 Hospital-Associated Venous Thromboembolism as a Public
Health Problem

High risk patients : VTE in non-surgical patient are

patient who is suffering
ischaemic stroke,
Patients who are
hospitalized and a history of VTE,
decompensated HF, acute and
immobilised for acute
medical illness (non- chronic lung disesase,
surgical patient) are at acute and chronic
an increased risk of inflammatory disease, active
cancer, or
developing VTE until
75%. patient with age over 60
years, and
sepsis, etc.
associated with extended
duration of inpatient stays.
A result from large cohort study
indicates that symptomatic VTE
risk is highest within the
first 19 days after
hospital admission
(most frequent during
days 0-9), with considerable
risk of VTE extending into the
periode after discharge.

Amin A, et al. Journal of Hospital Medicine. 2012

Fletcher J, et al. Prevention of VTE. The Australia and New Zealand Working Party 4th ed
Maynard G. Preventing hospital-associated VTE. AHRQ-US Dept. of Health and Human Services 2016.
Prophylaxis of VTE in Hospitalized Patients

ACCP 2012.
• Objective: To determine the efficacy and safety of the anticoagulant
fondaparinux in older acute medical inpatient at moderate to high risk of VTE

• Subject: 849 patients, aged 60 or more, admitted to hospital for CHF, acute
respiratory illnes or chronic lung disease, acute infectious or inflammatory
disease and expected to remain in bed for at least 4 days.

• Intervention: 2.5 mg fondaparinux or placebo sc, 1x per day, 6-14 days.

Cohen AT, et al. BMJ 2006

Result:

p=0.029
Cohen AT, et al. BMJ 2006
 Fondaparinux for VTE prophylaxis in patients with ischemic stroke is not
associated with an increased risk of major hemorrhage or total hemorrhage in
comparison to standard prophylaxis with UFH.

Hackett CT, et al. Thrombosis Research. 2015

Product Profile
Composition: Each syringe contains 2.5 mg of fondaparinux sodium in 0.5ml
solution for injection

Pharmacology : Fondaparinux is a synthetic and selective inhibitor of

activated factor X (Xa). The antithrombotic activity of fondaparinux is the
result of antithrombin III (AT III) mediated selective inhibition of factor Xa. By
binding selectively to AT III, fondaparinux potentiates (about 300 times) the
innate neutralization of factor Xa by AT III. Neutralization of factor Xa
interrupts the blood coagulation cascade and inhibits both thrombin
formation and thrombus development
 Indication
 Prevention of venous thromboembolic events (VTE) in
patients undergoing major orthopedic surgery of the lower
limbs such as hip fracture including extended prophylaxis,
knee replacement surgery, hip replacement surgery.
 Prevention of venous thromboembolic events (VTE) in
patients undergoing abdominal surgery who are at risk of
thromboembolic complications.
 Prevention of venous thromboembolic events (VTE) in
medical patients who are at risk for VTE and who are
thromboembolic complications due to restricted mobility
during acute illness.
 Contraindication

 Patients with known hypersensitivity to fondaparinux

sodium or any of the excipients of this drug.

 Active clinically significant bleeding

 Severe renal impairment defined by creatinine < 20

ml/minute
 Dossage and Administration
Orthopedic and abdominal surgery:
The recomended dose of fondaparinux sodium is 2.5 mg once daily,
administered postoperatively by subcutaneous injection.

The timing of the first dose should be no earlier than 6 hours following
surgical closure, and only after hemostasis has been established.

Treatment should be continued until the risk of venous

thromboembolism has diminished, usually until the patient is
ambulant, at least 5 to 9 days after surgery.
 Adverse Reaction
• Common: anemia, bleeding, purpura, edema
• Uncommon: thrombocytopenia, abnormal platetelets,
coagulation disorders, headache, nausea, vomiting, abnormal
liver function test, hepatic enzymes increased, rash, pruiritus,
fever, chest pain, flushing, dyspnea
• Rare: allergic reaction, postoperative wound infection,
hypokalemia, anxiety, confusion, vertigo, hypotension,
coughing.
CONCLUSION
 Pentasacharides syntetic
 Proven effective for VTE prophylaxis
and treatment
 Has comparable safety profile with
LMWH
 Simple dose regimen
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