DRUGS USE IN HEMOSTASIS

Setyo Purwono
Dept. of Pharmacology & Therapy

Faculty of Medicine, Universitas Gadjah Mada

 Hemostatic process
Coagulation cascade
Fibrinolysis
Medications

Coagulation disorders

Hemostasis

Ensure that coagulation mechanisms are

activated when there is injury
not unnecessarily activated

Restore tissue blood flow after repair of

injury (fibrinolysis)

Hemostasis
Subendothelial matrix

WBC

Hemostatic plug Endothelial cell

WBC
Fibrin
RBC
Platelets

Hemostatic Process

3 main steps

Primary hemostasis: local vasoconstriction &

platelet plug formation

Coagulation cascade

Fibrinolysis

Hemostatic Process

Platelet Plug Formation

vascular injury

release and binding of vWF to exposed

blood vessel collagen
glycoprotein IB on platelet surface
membrane binds to vWF
TxA2 vasoconstriction & platelet adhesion

platelet factor 3 (PF3) phospholipid layer

(procoagulant)

Platelet Activation & Aggregation

exposed endothelial surface
platelets exposed to collagen
activated
release contents of cytoplasmic granules

adenosine diphosphate (ADP)

accelerates platelet
aggregation/activation

thromboxane (Tx A2)

vasoconstriction
ADP release from platelets

Hemostatic Process

Coagulation Cascade

to stabilize and reinforce the weak platelet plug

fibrinogen fibrin

3 main steps:
1. formation of prothrombin activator
2. conversion of prothrombin into thrombin

3. conversion of fibrinogen to fibrin

Coagulation Pathways
Intrinsic Pathway

Extrinsic Pathway

IX

Tissue Factor + VII

X

Contact

XI

TF Pathway

TF-VIIa
PL

XIIa HKa

Common Pathway

Prothrombin

XIa
IXa

PL (Tenase)
VIIIa

Xa

(Prothrombinase)
Protein C, Protein
S, Antithrombin III

PL
XIII

Va
Thrombin

Fibrinogen

Fibrin
(weak)

XIIIa

Fibrin

(strong)

Coagulation Mechanism

activation of clotting factors

requires a phospholipid surface

tissue factor (TF) extrinsic to the blood
activated platelet (platelet factor 3 phospholipid)

intrinsic to blood

vitamin-K dependent factors (II, VII, IX, X)

formation of reaction complex

labile factors : factors V and VIII

Coagulation Factors
FACTORS

PLASMA t
(hrs)

Fibrinogen (I)

72-120

Prothrombin (II)

60-70

12-16

VII

3-6

VIII

8-12

FACTORS

PLASMA t
(hrs)

XI

52

XII

60

Protein C

Protein S (total)

42

Tissue factor

--

IX

18-24

Thrombomodulin

--

30-40

antithrombin

72

Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

Fibrinolysis

Plasminogen plasmin

Release of tPA by the endothelium

Lysis of clot FDPs or FSPs

Reopening of blood vessel

Drugs affecting Coagulation

HEMOSTATIC
PROCESS
AFFECTED

CLASS OF
DRUGS

SPECIFIC
DRUGS

1 platelet plug
formation inhibition

antiplatelet drugs

reversible: NSAID
irreversible: ASA

coagulation cascade

IV anticoagulants

standard and LMW

heparins
warfarin

oral anticoagulants
fibrinolysis

fibrinolytic agents

Streptokinase
Urokinase
t-PA

Platelet Activation Pathways (1)

COLLAGEN

THROMBIN
ADP

Aggregation

GpIIb/IIIa

GpIIb/IIIa
GpIIb/IIIa

Adrenaline

Platelet

Adhesion
vWF

Endothelium
Exposed Collagen

Prostaglandin Synthesis
arachidonic acid
cyclooxygenase

prostaglandin G2
prostaglandin H2
prostacyclin
synthetase

peroxidase

thromboxane
synthetase

prostacyclin

thromboxane A2

PG F1a

thromboxane B2

Mechanism of Action

ASPIRIN

arachidonic acid

ASPIRIN
cyclooxygenase

prostaglandin G2
prostaglandin H2
prostacyclin
synthetase

peroxidase

thromboxane
synthetase

prostacyclin

thromboxane A2

PG F1a

thromboxane B2

Mechanism of Action

ASPIRIN and NSAIDS

arachidonic acid

ASPIRIN
cyclooxygenase

prostaglandin G2
prostaglandin H2
prostacyclin
synthetase

NSAIDS
peroxidase

thromboxane
synthetase

prostacyclin

thromboxane A2

PG F1a

thromboxane B2

Platelet Receptor Mediated

Pathways: Drugs
Arachidonic Acid

ASA
NSAIDs
ADP
Ticlopidine
Clopidogrel
Thrombin
GP IIB/IIIA Inhibitors
-Final Common Pathway Abciximab (ReoPro)
-Promotes Platelet
Eptifibatide (Integrilin)
Adhesion (Fibrinogen,
Tirofiban
vWF)

Antiplatelet Medications
DRUG

SITE OF
ACTION

PLASMA METABOLISM
ROUTE t 1/2

PRIOR
PROCEDURE

PT /
PTT

ANTI
DOTE

Aspirin

COX 1
and 2

oral

20 min

hepatic

7 days

No/No

none

Dipyridamole

adenosine

oral

40 min

hepatic

24 hrs

No/No

none

Clopidogrel

ADP

oral

7 hrs

hepatic

5 days

No/No

none

ADP

oral

4 days

hepatic

10 days

No/No

none

GPIIb-IIIa

IV

30 min

renal

72 hrs

No/No

none

Eptifibatide

GPIIb-IIIa

IV

2.5 hrs

renal

24 hrs

No/No

none

Tiroban

GPIIb-IIIa

IV

2 hrs

renal

24 hrs

No/No

hemodialysis

(Plavix)

Ticlodipine
(Ticlid)

Abciximab
(ReoPro)

Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

Non-steroidal Anti-inflammatory Medications

DRUG

SITE OF
ACTION

PLASMA METABOLISM
ROUTE t 1/2

PRIOR
PROCEDURE

PT /
PTT

ANTI
DOTE

Piroxicam

COX 1 & 2

oral

50 hrs

hepatic

10 days

No/No

none

Indome
thacin

COX 1 & 2

oral/
supp

5 hrs

hepatic

48 hrs

No/No

none

Ketorolac

COX 1 & 2

oral /
IV

5-7 hrs

hepatic

48 hrs

No/No

none

Ibuprofen

COX 1 & 2

oral

2 hrs

hepatic

24 hrs

No/No

none

naproxen

COX 1 & 2

oral

13 hrs

hepatic

48 hrs

No/No

none

Diclofenac

COX 1 & 2

oral

2 hrs

hepatic

24 hrs

No/No

none

Celecoxib

COX 2

oral

10-17
hrs

hepatic

none

No/No

none

Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

ANTICOAGULANT

Anticoagulants & Thrombolytics

DRUG

SITE OF
ACTION

Unfractionated
heparin

IIa/Xa

LMWHs

Xa
IIIa

PT / ANTI
PTT DOTE

ROUTE

PLASMA
t 1/2

EXCRETION

PRIOR
PROCEDURE

IV/SC

1.5 hrs

hepatic

6 hrs

No/
Yes

protamine

SC

4.5 hrs

renal

12-24 hrs

No/No

protamine
(partial)

Strepto kinase

plasmi
nogen

IV

23 mins

hepatic

3 hrs

Yes/
Yes

antifibrinolytics

t-PA

plasmi
nogen

IV

<5 min

hepatic

1 hr

Yes/
Yes

antifibrinolytics

vit-K dep.
factors

Oral

2-4days

hepatic

Oral
Anticoagulants

Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

2-4 days

Yes/No Vit. K,
rFVIIa
Plasma,
Prothrom.
complex
conc.

Other Anticoagulants
DRUG

SITE
PLASMA METAOF
BOLISM
ROUTE t 1/2
ACTION

PRIOR
PROCEDURE

PT/
PTT

ANTI
DOTE

Pentasaccharide

Xa

IV

14-17
hrs

renal

4 days

No/No

rFVIIa?

Bivalirudin

IIa

IV

25 min

hepatic

2-3 hrs

Yes/
Yes

None

Argatroban

IIa

IV

45 min

hepatic

4-6hrs*

Yes/
Yes

None

Hirudin

IIa

IV

1.5 hr

renal

8 hrs*

Yes/
Yes

PMMA
dialysis

Va/
VIIIa

IV

2 hrs

hepatic

12 hrs

No/Yes

none

IIa

IV

3 hrs

renal

24 hrs

Yes/
Yes

none

Activated
Protein C
(APC)
Ximelagatran

PMMA= polymethyl-methyl acrylate

*Argatroban &lepirudin may the normal PT 4-5 secs

Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

Oral Anticoagulants

Warfarin

inhibits synthesis of vitamin - k dependent

factors II, VII, IX, X and protein C & S

reversal:
stopping medication and waiting for ~4 days
for PT normalization
vitamin K PO or IV (1-2mg)
immediate: rFVIIa, FFP (1-2 units),

prothrombin complex concentrate

check PT prior to surgery

Oral Anticoagulants
Warfarin

biphasic effect on PT and INR

initial : F VII (shortest t ) to 55 %
of normal
subsequent : F II and X therapeutic

anticoagulant

discontinuation
return to normal: F VII followed by F II & X
caution: INR =/< 1.4 no assurance of
normal coagulation

Warfarin - monitoring

International Normalized Ratio (INR)

The need for frequent testing and dose adjustments
detracts from warfarins ease of use in clinical
practice.

Anticoagulation Clinics
Coagucheck S

Unfractionated Heparin

negatively charged, water - soluble

glycosaminoglycan

extracted from porcine gut or bovine lung

binds and anti - thrombin III (AT III) activity

to 1,000 fold binds & inactivates factors IIa
and factor Xa

degree of inhibition: F Xa = IIa

LMWH inhibition of Xa > IIa

lesser inhibition on F XIa, XIa and F XIIa

Unfractionated Heparin

Low-dose or minidose

5,000 U SC q 12 hrs for thromboprophylaxis

peak action: 40 - 50 minutes

duration 4 - 6 hrs

low risk for hemorrhage during anesthesia

or surgery

Unfractionated Heparin

Standard Dose

regular doses for therapeutic anticoagulation

high risk of bleeding during & after surgery
stop at least 6 hrs before surgery
restarted ~ 12 hrs postop if needed with close
monitoring
immediate reversal: protamine

Low Molecular Weight Heparin (LMWH)

4,000-6,500 daltons (vs. standard heparin 3,000

-30,000 daltons

retains anti-Xa activity

less anti -IIa than standard heparin

enhances AT-III interaction with F IIa & F Xa

degree of inhibition: F Xa > IIa

Thrombin Inactivation: Heparin

IIa
ATIII
Pentasaccharide
sequence

Heparin/ATIII/IIa
Ternary complex accelerates
inactivation of IIa by ATIII
IIa

ATIII

Pentasaccharide
sequence

LMW Heparin/ATIII
No acceleration of
inactivation of IIa by
ATIII without ternary
complex

Factor Xa Inactivation:
LMWH/Heparin
Pentasaccharide
sequence

Xa

ATIII

LMW Heparin/ATIII
Ternary complex not
necessary to
accelerate inactivation
of Xa by ATIII

ATIII

Xa

Heparin/ATIII
Ternary complex not
necessary to
accelerate inactivation
of Xa by ATIII

LMWH in the U.S.

LMWH

TRADE
NAME

MOLECULAR
WEIGHT
(daltons)

HALF - LIFE
(minutes)

Dalteparin

Fragmin

5,000

120

2:1

Enoxaparin

Lovenox

4,500

150

2.7:1

Danaparoid

Orgaran

6,500

1,100

20:1

Ardeparin

Normiflo

6,000

200

2:1

14,000

60-90

Standard
Heparin

Anti Xa:
Anti IIa

1:1

Standard Heparin vs. LMWH

PARAMETERS

STANDARD HEPARIN

LMWH

MOLECULAR WEIGHT

3, 000 - 30,000 daltons

4,000-6,500 daltons

BIOAVAILABILITY

variable due to binding to

predictable

plasma protein &

macrophages

MONITORING

PTT
dose adjusted based on PTT

HALF LIFE

variable; dose-dependent

no need for monitoring

no dose adjustments
4-6 hrs

(30 min for 25 u/kg, 150

mins with 400 u/kg)
CLEARANCE

hepatic

renal

Standard Heparin vs. LMWH

PARAMETERS
EFFECT ON
PLATELETS

STANDARD HEPARIN

LMWH

Higher incidence of HIT

Lower incidence of HIT

Inhibition of platelet function

Less inhibition

Inhibits platelet-endothelium

No interaction

interaction

RISK OF BLEEDING

ANTI Xa: IIa

ACTIVITY
REVERSAL

higher

Lower

1:1

2:1

protamine

Only anti-IIa (90%) but

not anti-Xa (60%) activity
reversed by protamine (1
mg/100 anti-Xa units
LMWH

COST

inexpensive

expensive

Indications for and Contraindications to

Parenteral Anticoagulant Agents (contd)
Ardeparin

Low-molecular-weight
heparin

Approved; not being

marketed

Regional anesthesia

Lepirudin

Hirudin derivative

Heparin-induced
thrombocytopenia with
thrombosis

Thrombocytopenia other
than heparin-induced
thrombocytopenia

Argatroban

Direct thrombin inhibitor

Heparin-induced
thrombocytopenia with
thrombosis

Thrombocytopenia other
than heparin-induced
thrombocytopenia

Danaparoid

Heparinoid

Prophylaxis against
thrombosis in heparininduced
thrombocytopenia

Thrombocytopenia other
than heparin-induced
thrombocytopenia

Bivalirudin

Hirudin derivative

Unstable angina or
angioplasty

Unknown

Fondaparinux

Synthetic factor Xa
inhibitor

Prophylaxis in highrisk patients?

Unknown

Fibrinolysis

Antithrombotic Agents
Fibrinolytics
Streptokinase
Urokinase
Drotrecogin alpha activated
Tissue Plasminogen Activators
Alteplase / rt-PA
Tenecteplase

Contraindications to Antithrombotic
Therapy

General risk factors

-Pre-existing coagulation or platelet defect,
thrombocytopenia, or
other bleeding abnormality
-Inaccessible ulcerative lesion (e.g., gastrointestinal tract
lesion)
-Central nervous system lesion (e.g., caused by stroke,
surgery,
trauma)
-Spinal anesthesia or lumbar puncture
-Malignant hypertension
-Bacterial endocarditis
-Advanced retinopathy
-Old age (relative)
-Aspirin or other antiplatelet drugs
-Neoplastic disease

Contraindications to
Antithrombotic Therapy

Specific to warfarin (ambulatory patients)

-Early and late pregnancy
-Poor patient cooperation,
understanding, reliability
-Unsatisfactory laboratory or patient
follow-up
-Occupational risk to trauma

Contraindications to Antithrombotic
Therapy

Specific to thrombolytic agents

-Recent thoracic, abdominal, or central
nervous system surgery
-Recent cerebrovascular accident, trauma, or
neoplasm
-Bleeding ulcer
-Hypertension
-Anticipated invasive procedures (arterial
punctures, biopsies, central lines)
-Concurrent hemostatic dysfunction

References

Roberts HR, Monroe DM, Escobar MA. Current Concepts of Hemostasis.

Anesthesiology 2004; 100:722-30.
De Souza GJ. Anticoagulation and Central Neuraxial Anesthesia. Progress in
Anesthesiology. 2000;vol XIV, Chap 9: 132-148.
Petrovich, CT. An approach to the patient who may have a bleeding
disorder. 2005 ASA nnual Meeting Refresher Course Lectures. Atlanta, GA.
2006;241:1-6.
Kelly RE, Yao FF. Hemophilia and Coagulation Disorders. Yao & Artusios
Problem Oriented Anesthesiology 4th Ed. Lippincott Williams & Wilkins.
1998. Chapter 40, pp 763-774.
Fleisher LA. Evidence-based Practice of Anesthesiology. Saunders. 2004.
Stoelting RK,Dierdorf, SF. Coagulation Disorders. Anesthesia and Coexisting diseases 3rd Ed. Churchill Livingston. 1993. Chapter 25, p 407-426.