Drugs Use in Hemostasis

8/10/2019 Drugs Use in Hemostasis

1/47

DRUGS USE IN HEMOSTASISSetyo Purwono

Dept. of Pharmacology & TherapyFaculty of Medicine, Universitas Gadjah Mada


2/47


3/47

Hemostasis

Ensure that coagulation mechanisms are

activated when there is injury

not unnecessarily activated

Restore tissue blood flow after repair of

injury (fibrinolysis)


4/47

HemostasisSubendothelial matrix

Platelets

Hemostatic plugFibrin

Endothelial cellRBC

WBCWBC


5/47


6/47


7/47

Platelet Activation & Aggregation

exposed endothelial surfaceplatelets exposed to collagen

activated

release contents of cytoplasmic granules

adenosine diphosphate (ADP) thromboxane (Tx A 2)

accelerates platelet vasoconstrictionaggregation/activation ADP release from platelets


8/47

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


9/47

Contact Tissue Factor + VII

XIIIa

XIIIThrombin

Fibrin(strong)

Fibrinogen Fibrin(weak)

IX

XI

XIa

IXa

XaVa

XIIaProthrombin

TF-VIIa

(Prothrombinase)

PL

PL(Tenase)

VIIIaPL

X

Intrinsic Pathway

HKa

Extrinsic Pathway

Common Pathway

TF Pathway

Coagulation Pathways

Protein C, ProteinS, Antithrombin III


10/47


11/47

Coagulation Factors

FACTORS PLASMA t (hrs)

Fibrinogen (I) 72-120

Prothrombin (II) 60-70

V 12-16

VII 3-6

VIII 8-12

IX 18-24

X 30-40

FACTORS PLASMA t (hrs)

XI 52

XII 60

Protein C 6

Protein S (total) 42

Tissue factor --

Thrombomodulin --

antithrombin 72

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


12/47

Fibrinolysis

Plasminogen plasmin

Release of tPA by the endothelium

Lysis of clot FDPs or FSPs

Reopening of blood vessel


13/47


14/47


15/47


16/47

Adhesion

GpIIb/IIIa

Platelet Activation Pathways (1)

GpIIb/IIIa GpIIb/IIIa Aggregation ADP

Adrenaline Platelet

Exposed Collagen

Endothelium

vWF

COLLAGEN

GpIIb/IIIa GpIIb/IIIa Aggregation GpIIb/IIIa GpIIb/IIIa Aggregation

AdhesionAdhesion

ADP

Adrenaline

THROMBIN


17/47


18/47

Mechanism of Action ASPIRIN

arachidonic acid ASPIRINcyclooxygenase

prostaglandin G 2

peroxidaseprostaglandin H 2

prostacyclin thromboxane

synthetase synthetase

prostacyclin thromboxane A2

PG F1a thromboxane B2


19/47

Mechanism of Action ASPIRIN and NSAIDS

arachidonic acid ASPIRINcyclooxygenase

prostaglandin G 2 NSAIDS

peroxidaseprostaglandin H 2

prostacyclin thromboxane

synthetase synthetase

prostacyclin thromboxane A2

PG F1a thromboxane B2


20/47


21/47

Antiplatelet Medications

DRUGSITE OF

ACTION ROUTEPLASMAt 1/2

META-BOLISM

PRIORPROCEDURE

PT /PTT

ANTI DOTE

Aspirin COX 1and 2

oral 20 min hepatic 7 days No/No none

Dipyrida-mole

adenosine oral 40 min hepatic 24 hrs No/No none

Clopidogrel(Plavix)

ADP oral 7 hrs hepatic 5 days No/No none

Ticlodipine(Ticlid)

ADP oral 4 days hepatic 10 days No/No none

Abciximab(ReoPro)

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 hemo-dialysis



22/47

Non-steroidal Anti-inflammatory Medications

DRUGSITE OF

ACTION ROUTEPLASMAt 1/2

META-BOLISM

PRIORPROCEDURE

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 10-17hrs

hepatic none No/No none



23/47

ANTICOAGULANT


24/47

Anticoagulants & Thrombolytics

DRUG SITE OF ACTION ROUTE

PLASMA

t 1/2

EXCRE-

TION

PRIOR

PROCEDURE PT /

PTT ANTI

DOTE

Unfraction-atedheparin

IIa/Xa IV/SC 1.5 hrs hepatic 6 hrs No/ Yes

protamine

LMWHs Xa

IIIa

SC 4.5 hrs renal 12-24 hrs No/No protamine

(partial)Strepto -kinase

plasmi nogen

IV 23 mins hepatic 3 hrs Yes/ Yes

antifibri-nolytics

t-PA plasmi nogen

IV


25/47

Other Anticoagulants

DRUGSITEOF

ACTIONROUTE

PLASMAt 1/2

META-BOLISM

PRIORPROCEDURE

PT/PTT

ANTI DOTE

Pentasac-charide

Xa IV 14-17hrs

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

PMMAdialysis

ActivatedProtein C

(APC)

Va/ VIIIa

IV 2 hrs hepatic 12 hrs No/Yes none

Ximelagatran IIa IV 3 hrs renal 24 hrs Yes/ Yes

none

PMMA= polymethyl-methyl acrylate*Argatroban &lepirudin may the normal PT 4-5 secs



26/47

Oral Anticoagulants Warfarin

inhibits synthesis of vitamin - k dependentfactors II, VII, IX, X and protein C & S

reversal:

stopping medication and waiting for ~4 daysfor PT normalization

vitamin K PO or IV (1-2mg)

immediate: rFVIIa, FFP (1-2 units),prothrombin complex concentrate

check PT prior to surgery


27/47

Oral Anticoagulants Warfarin

biphasic effect on PT and INRinitial : F VII (shortest t ) to 55 %

of normal

subsequent : F II and X therapeuticanticoagulant

discontinuation

return to normal: F VII followed by F II & Xcaution: INR =/< 1.4 no assurance ofnormal coagulation


28/47

Warfarin - monitoring

International Normalized Ratio (INR) The need for frequent testing and dose adjustments

detracts from warfarins ease of use in clinicalpractice.

Anticoagulation ClinicsCoagucheck S


29/47

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


30/47

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


31/47

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


32/47

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


33/47


34/47

Factor Xa Inactivation:LMWH/Heparin

Heparin/ATIII Ternary complex notnecessary toaccelerate inactivationof Xa by ATIII

XaATIII

LMW Heparin/ATIII Ternary complex notnecessary toaccelerate inactivationof Xa by ATIII

Pentasaccharidesequence

Xa ATIII


35/47


36/47

LMWH in the U.S.LMWH TRADE

NAME

MOLECULARWEIGHT

(daltons)

HALF - LIFE(minutes)

Anti Xa: Anti IIa

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

StandardHeparin

14,000 60-90 1:1


37/47

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

plasma protein &

macrophages

predictable

MONITORING PTTdose adjusted based on PTT

no need for monitoring

no dose adjustments

HALF LIFE variable; dose-dependent

(30 min for 25 u/kg, 150

mins with 400 u/kg)

4-6 hrs

CLEARANCE hepatic renal


38/47

I di i f d C i di i


39/47

Indications for and Contraindications toParenteral Anticoagulant Agents (contd)

Ardeparin

Lepirudin

Argatroban

Danaparoid

Bivalirudin

Fondaparinux

Low-molecular-weightheparin

Hirudin derivative

Direct thrombin inhibitor

Heparinoid

Hirudin derivative

Synthetic factor Xainhibitor

Approved; not beingmarketed

Heparin-inducedthrombocytopenia withthrombosis

Heparin-inducedthrombocytopenia withthrombosis

Prophylaxis againstthrombosis in heparin-inducedthrombocytopenia

Unstable angina orangioplasty

Prophylaxis in high-risk patients?

Regional anesthesia

Thrombocytopenia otherthan heparin-inducedthrombocytopenia



Unknown

Unknown


40/47


41/47

Antithrombotic Agents

FibrinolyticsStreptokinaseUrokinaseDrotrecogin alpha activated

Tissue Plasminogen Activators Alteplase / rt-PATenecteplase


42/47


43/47


44/47


45/47

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


46/47

Contraindications to AntithromboticTherapy

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


47/47

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 bleedingdisorder. 2005 ASA nnual Meeting Refresher Course Lectures. Atlanta, GA.2006;241:1-6.Kelly RE, Yao FF. Hemophilia and Coagulation Disorders. Yao & ArtusiosProblem Oriented Anesthesiology 4 th 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 Co-existing diseases 3 rd Ed. Churchill Livingston. 1993. Chapter 25, p 407-426.

Documents

Drugs Use in Hemostasis