4. Common anticoagulants encountered in
the surgical setting.
1) Anti-platelet medications-
a) Aspirin, NSAIDs, COX-2 inhibitors
b)Thienopyridin derivatives- Clopidogrel,
Ticlopidine
c)GPIIb/IIIa inhibitors- Abciximab,
Eptifibatide, Tirofiban
2) Oral anticoagulants- Warfarin sodium, Dicumarol
3) Unfractionated Heparin
4) Low molecular weight heparin- Enoxaparin, Dalteparin, Tinzaparin
5) Specific Xa inhibitors- Fondaparinux
6) Direct Thrombin Inhibitors- Lepirudin, Bivalirudin, Ximelgatran,
Argatroban
7)Fibrinolytic/Thrombolytic drugs- Streptokinase, Urokinase, Reteplase,
Alteplase, Tenecteplase
8)Herbal Therapy- Garlic, Ginkgo, Ginseng
5. CYCLOOXYGENASE INHIBITORS
COX inhibitors include:
(1)Non selective inhibitors (Aspirin and NSAIDs) and
(2) Selective agents inhibiting only COX-2.
Aspirin irreversibly inhibits COX-1-mediated platelet granule
release over the platelet’s lifetime (7-10 days).
NSAIDs (naproxen, piroxicam, and ibuprofen) reversibly inhibit
platelet COX and prevent thromboxane A2 synthesis.
6. ASRA recommendations for Aspirin and NSAIDs
•Either medication alone does not increase risk.
•Need to scrutinize dosages, duration of therapy
and concomitant medications that may affect
coagulation.
•No wholly accepted laboratory tests. A normal
bleeding time does not indicate normal
homeostasis. An abnormal bleeding time does not
necessarily indicate abnormal homeostasis.
7. THIENOPYRIDINE DERIVATIVES
The thienopyridine derivatives ticlopidine and clopidogrel interfere with
platelet function by interfering with fibrinogen binding to platelets and thus
inhibiting ADP induced primary and secondary platelet aggregation.
ASRA recommendations: Clopidogrel- discontinue for 7 days
Ticlopidine- discontinue for 14 days
GPIIb/IIIa ANTAGONISTS
Available GPIIb/IIIa platelet receptor antagonists include abciximab,
eptifibatide, and tirofiban.
These drugs are potent inhibitors of platelet aggregation because binding of
fibrinogen and vWF to platelet GPIIb/IIIa receptors is blocked.
ASRA recommendations: Abciximab- 48hrs
Eptifibatide- 8hrs
Tirofiban- 8hrs
8. Medication Recommendation
NSAIDS No contraindication
Aspirin No contraindication
Ticlopidine Discontinue 14 days preoperative
Clopridogrel Discontinue 7 days preoperative
GP IIb/IIIa inhibitors
Abciximab Discontinue 48 hrs preoperative
Eptifibatide Discontinue 8 hours preoperative
Tirofiban Discontinue 8 hrs preoperative
ASA Practice Advisory 2010
9. Warfarin (Coumadin)
• MECHANISM OF ACTION:
Inhibits vitamin K formation by inhibiting the
enzyme Vitamin K epoxide reductase(VKOR).
Depletion of the vitamin K dependent proteins
(prothrombin and factors VII, IX and X) occurs.
• DURATION OF ACTION:
Onset is 8-12 hours with a peak at 36-72
hours.
10. Warfarin and General Anesthesia
Preoperative
• Discontinue warfarin at least 5 d before elective procedure
• Assess INR 1 to 2 d before surgery, if >1.5, consider 1-2 mg of
oral vitamin K
• Reversal for urgent surgery/procedure- consider 2.5-5 mg of
oral or intravenous vitamin K; for immediate reversal, consider
fresh-frozen plasma
• Patients at high risk for thromboembolism
Bridge with therapeutic subcutaneous LMWH (preferred) or
intravenous UFH
Last dose of preoperative LMWH administered 24 hrs before
surgery, administer half of the daily dose
Intravenous heparin discontinued 4 hrs before surgery
• No bridging necessary for patients at low risk for
thromboembolism
11. Postoperative
• Patients at low risk for thromboembolism
Resume warfarin on postoperative day
• Patients at high risk for thromboembolism (who
received preoperative bridging therapy)
Minor surgical procedure--resume therapeutic LMWH
24 hrs postoperatively
Major surgical procedure--resume therapeutic LMWH
48 to72 hrs postoperatively or administer low-dose
LMWH
• Assess bleeding risk and adequacy of
haemostasis when considering timing of the
resumption of LMWH or UFH therapy
14. Warfarin and Neuraxial Anesthesia
• The current ASRA guidelines recommends an INR value of ≤1.4 as
acceptable for the performance of neuraxial blocks
• The concurrent use of other medications, such as aspirin, NSAIDs,
and heparins that affect the clotting mechanism, increases the risk
of bleeding complications without affecting the INR.
• A controversy exists regarding whether or not the epidural catheter
can be removed on postoperative day 1, or 12-14 hours after
warfarin is started, when the INR is >1.4. In the absence of other
risk factors for increased bleeding, the catheter can probably be
removed.
• The factor VII activity should be determined if risk factors such as
low platelets, advanced age, kidney failure, or intake of other
anticoagulants are present
16. Standard Heparin
• MECHANISM OF ACTION:
Binds with antithrombin III, producing a
conformational change and scaffolding in it that
exposes the binding sites, thus inactivating factor
Xa and IIa respectively.
• DURATION OF ACTION:
The elimination half life for IV heparin is 56
minutes.
17. ASRA recommendations for Standard
Heparin
• Mini-dose subcutaneous heparin(5000 IU twice
daily) does not contraindicate a neuraxial block. The
administration of subcutaneous heparin should be
withheld until after the block.
• Patients should be screened for concurrent
anticoagulant medications that may impact clotting.
• Patients on heparin for more than 5 days should
have a platelet count assessed prior to neuraxial
blockade due to the risk of heparin induced
thrombocytopenia.
contd...
18. • Intravenous Heparin administration should be
delayed for 1 hour after neuraxial blockade.
• Indwelling catheters should be removed 2-4 hours
after the last dose and evaluation of APTT.
Intravenous Heparin should not be re-initiated until 1
hour has passed.
• If a “bloody tap” has occurred it should be
communicated to the surgeon. No data suggests the
mandatory cancellation of the surgical case.
19. Unfractionated Heparin
Sub –
Cutaneous
(usually given for
prophylaxsis)
Neuraxial
intervention
No contraindication, measure platelet count, if more
than 4 days of heparin treatment.
After
intervention
if more than 4 days of heparin treatment measure
platelet count before removing catheter.
Intra
venous
Vascular
surgery and
Neuraxial
intervention
Avoid in presence of other coagulopathies. Delay
heparin for 1 hour after catheter placement, no
restriction before procedure with dosing every 12
hours, delay if difficult catheter placement is
anticipated
After
intervention
Catheter removal 2 to 4 hours after heparin and
normal PTT & ACT
ASA Practice Advisory 2010
20. LOW MOLECULAR WEIGHT HEPARIN
LMWH is produced by cleaving heparin into shorter fragments.
LMWH only causes conformational change in ATIII and inhibits only factor
Xa. LMWH has a delayed onset of 20 to 60 minutes and a longer half-time
than heparin and can be administered subcutaneously either once or
twice daily and require less monitoring (anti-Xa levels) or no monitoring.
Have predictable pharmacokinetics and fewer effect on platelet function.
Disadvantages of LMWH include less reliable reversal with protamine and
increased risk of bleeding during long-term use compared to
unfractionated heparin.
21. ASRA recommendations for LMWH
1. Preoperative LMWH :
• If LMWH has been administered preoperatively, then LMWH should be held for 12 hrs
prior to a neuraxial technique.
2. Postoperative LMWH:
• Avoid other drugs that affect hemostasis.
• Presence of blood during needle or catheter placement does not necessitate
postponement of surgery. In those cases the first dose of LMWH should be delayed for 24
hrs postoperatively
• Twice daily dosing. It is recommended that the first dose of LMWH be administered no
earlier than 24 hours postoperatively. Indwelling catheters should be removed prior to
initiation of LMWH thromboprophylaxis.
• Single daily dosing. It is recommended that the first postoperative LMWH dose be
administered no sooner than 6-8 hours postoperatively. The second postoperative dose
should occur no sooner than 24 hours after the first dose.
22. LMWH
Before Neuraxial
intervention
Delay 10 – 12 hours after dose. Delay 24 hours after
traumatic (bloody) tap or with twice daily
dosing.
After intervention
Once daily dosing :
Remove catheter 10-12 hours after last dose and
start next dose 2 hours later
Twice daily dosing :
Remove catheter 2 hours before 1st dose.
23. Fondaparinux
• Antithrombotic medication for DVT prophylaxis
• Binds with antithrombin III which neutralizes factor Xa.
• Peak effect in 3 hours with half life of 17-21 hours
• Irreversible effect
• ASRA recommendation: if neuraxial procedure has to be
performed then it is recommended to do a single needle,
atraumatic placement, and avoid indwelling catheter
• Expert study recommends epidural placement/removal
to be done after 36hrs of fondaparinux dose and
subsequent dose to be given after 24hrs.
24. New anticoagulants
Direct Thrombin Inhibitors
• Bivalirudin- thrombin inhibitor used in interventional
cardiology.
• Lepirudin used to treat heparin-induced thrombocytopenia.
• Caution advised. No recommendations related to limited
clinical experience.
Direct Factor Xa Inhibitors-
• Rivaroxaban is an oral, reversible, direct factor Xa inhibitor
that is rapidly absorbed. Howerer apixaban also has the
same MOA but irreversible
25. Thrombolytic and Fibrinolytic Medications
• Thrombolytics are classified as native tissue
plasminogen activators, streptokinase and urokinase,
or as exogenous tissue plasminogen activator
formulations, alteplase ,reteplase, tenecteplase
• Original recommendation was to withhold neuraxial
blockade for 10 days.
• No data concerning the length of time that neuraxial
blockade should be withheld.
• If a patient has received a neuraxial block and
unexpectantly receives thrombolytic/fibrinolytic
therapy then monitor patient for neurological
complications.
• No recommendations related to the removal of
epidural catheters in the patient who unrepentantly
receives thrombolytic/fibrinolytic therapy.
27. Herbal Medications
Herbal Medicine Mechanism of Action Time to normal
haemostasis
1.) Garlic •Inhibits platelet
aggregation
•Increased Fibrinolysis
7 Days
2.) Ginkgo • Inhibits platet- activating
factor
36 hours
3.) Ginseng • Increased PT and aPTT 24 hours
ASRA recommendations: Neuraxial block not
contraindicated for single herbal medication use
28. Anticoagulation and peripheral
nerve blockade
• Case reports of major bleeding occurring with psoas
compartment and lumbar sympathetic blocks.
• Patients with neurological deficits had complete
recovery in 6-12 months. The key to this reversal
was the fact that bleeding occurred in expandable
and compressible tissue as opposed to the non-
expandable compartments associated with neuraxial
blockade.
29.
30. Type of Procedure Platelets in /uL
Minimally invasive procedures (central line placement,
angiography, thoracocentesis, and
paracentesis,endoscopy,biopsy)
>30,000
Epidural catheter insertion or removal Ranges from50,000 to
80,000
Operative procedures ordinarily associated with insignificant
blood loss
>50,000
Surgery within a closed space such as in neurosurgery and
ophthalmic surgery
>100000
Lumbar puncture or spinal or vaginal delivery >50,000
Microvascular bleeding attributed to platelet dysfunction, for
example, uremia, a post cardiopulmonary bypass, or in
association with massive transfusion
Clinical judgement
Proposed guidelines for platelet transfusion,BCMJ 2005
31. Epidural Space vs Intrathecal Space
• Epidural space is richly supplied with a venous plexus
• Area around the spinal cord is fixed. Bleeding results
in compression, ischemia, nerve trauma, and
paralysis.
• Bleeding into the intrathecal space is diluted by the
Cerebral Spinal Fluid (which is usually less
devastating)
32. Risk Factors for the Development of
Epidural Hematoma
• Anatomic abnormalities of the spinal cord or
vertebral column
• Vascular abnormalities
• Pathologic/medication induced alterations in
homeostasis
• Alcohol abuse
• Chronic renal insufficiency
• Difficult and traumatic needle placement
• Epidural catheter removal
33. Signs and Symptoms of an Epidural
Hematoma
• Low back pain (sharp and irradiating)
• Sensory and motor loss (numbness and
tingling/motor weakness long after block
should have abated)
• Bowel and/or bladder dysfunction
• Paraplegia
34. Treatment and Outcome
• Must be treated within 8-12 hours of onset of
symptoms
• Emergency decompressive laminectomy with
hematoma evacuation
• Outcome is generally poor
35. Anticoagulation in patients with prosthetic valve
INDICATIONS:-
• Lifelong for all patients with mechanical valves
• Lifelong for patients with bioprosthesis who have other indications for
anticoagulation, e.g. atrial fibrillation
• For the first 3 months after insertion in all patients with bioprosthesis with
a target INR of 2.5
RISK FACTORS
• The risk of embolization is greater with prosthetic mitral valve than
prosthetic aortic valve
• Atrial fibrillation, LV dysfunction, clotting disorder, prior embolic events
TARGET INR:- 2.5- 3.5
36. RECOMMENDATIONS:-
• Aspirin is recommended for all patients with bioprosthesis: aspirin alone
(75-100 mg per day) in patients with bioprosthesis and no risk factors or
aspirin combined with warfarin in patients with mechanical heart valves
and high-risk patients with bioprosthesis.
• For minor surgeries where bleeding is easily controlled, anticoagulation
should be given with a target of 2.0
• For major surgical procedures in which anticoagulation interruption is
considered essential(INR < 1.5) , patients should be admitted to the
hospital in advance and transferred to intravenous unfractionated heparin.
Heparin is stopped 6 hrs before surgery and resumed 6-12hrs after. This
technique is termed as ‘bridging anticoagulation’
37. Anesthetic implications of anticoagulants in patients
with coronary stents
• Elective surgery postponed for the following durations if
aspirin and thienopyridine (eg, clopidogrel) needs to be discontinued
o Bare metal stents: 4-6 wk
o Drug-eluting stents: 12 mo
• If surgery cannot be postponed, continue aspirin throughout
perioperative period
• Patients at high risk for cardiac events (exclusive of coronary stents)
o Continue aspirin throughout the perioperative period
o Discontinue clopidogrel at least 5 d (and preferably 10 d) before surgery
o Resume clopidogrel 24 hrs postoperatively
• Patients at low risk of cardiac events
o Discontinue antiplatelet therapy 7Y10 d before surgery
o Resume antiplatelet therapy 24 hrs postoperatively
38. PROSTHETIC VALVE IN PREGNANCY
Pregnancy in a woman with mechanical valve is associated with an
estimated maternal mortality of 1 to 4 % with death usually resulting from
complications of prosthetic valve thrombosis.
Before Conception:
• Clinical evaluation of cardiac functional status and previous cardiac events
• Echocardiographic assessment of ventricular and valvular function and
pulmonary pressure
• Discussion of risks associated with pregnancy and use of anticoagulation.
• Family planning
Conception
• Change to unfractionated heparin(APTT ratio should be maintained above
2.0) from time of confirmed pregnancy upto week 12.
39. Completion of First Trimester:
• Warfarin therapy, 12- 36 weeks
Week 36:
• Discontinue warfarin
• Change to unfractionated heparin titrated to a therapeutic APTT time or
factor Xa level.
Delivery:
• Heparin should be discontinued at the start of labour
• Oral anticoagulation should be resumed after 24hrs if no concerns
regarding bleeding
• Restart heparin therapy 4 to 6 hours after delivery if no contraindications
• If labour occurs preterm while the patient is till on anticoagulant use, a
caesarean section should be performed after reducing the INR to 2.0
• A vaginal delivery should be avoided under oral anticoagulation because
of danger of fetal intracranial bleeding.
42. 1. Following hypercoagulable states are classified
under high risk for peri-operative thrombosis
except:
1)Protein C deficiency
2)Protein S deficiency
3)Heparin-induced thrombocytopenia
4)Factor V Leiden genetic polymorphism
43. Answer: 4
Protein c, protein s deficiency is a
procoagulant state
In heparin induced thrombocytopenia,
there is relative decrease in platelets due
to consumptive coagulopathy but there is
increased venous thrombosis
Miller’s 8th ed
44. 2) Following are true about HIT (heparin induced
thrombocytopenia) except:
1)Absolute or relative (=/> 50 percent) reduction
in platelet count during or after heparin
administration.
2)A direct thrombin inhibitor (i.e., bivalirudin,
lepirudin, argatroban) is substituted for heparin
3)HIT manifests clinically as thrombocytopenia
occurring 5 to 14 days after initiating heparin
4)PF4/heparin immune complexes clear from the
circulation within 30 days.
45. Answer: 4
the first 3 options are correct
platelet immune complexes clear
much faster
Miller’s 8th ed
46. 3) Which of the following is true about ACT
(activated clotting time):
1)The ACT in normal individuals is 75-80 seconds
2)ACT measures clot formation by way of intrinsic
and common pathways
3)Celite is recommended for use in patients
receiving the antifibrinolytic drug aprotinin
4)After surgical incision, baseline ACT usually
increases
47. Answer:- 2
Normal ACT- 107+-13sec
Kaolin is recommended in pt receiving aprotinin
as celite shows false ACT in such pt
After surgical incision, ACT decreases
Miller’s 8th ed
48. 4)Correct statements about the action of warfarin
include:
A. warfarin is structurally similar to vitamin K and
competitively
inhibits liver synthesis of clotting factors
B. warfarin inhibits vitamin K epoxide reductase
C. the onset of warfarin action may be prolonged
due to the long half-life of factor VII
D. factors II, VII, IX, and X are not activated
(carboxylated) when warfarin is administered in
therapeutic doses
1. A,B,C
2. A,C
3. B,D
4. D only
5. All of the above
49. • Answer:- 3
Options B and D are correct
Warfarin inhibits VKOR vitamin K epoxide
reductase which is primarily responsible for
the regeneration of Vit k after its does gamma
carboxylation of factor 2,7,9,10
Factor 7 has the shortest half life-6hrs among all
the factors
Competitive pharmacology
50. 5)The mechanism of action of mini-dose heparin is correctly
described by:
A. factor X is more sensitive to heparin than are other serine
protease factors
B. mini-dose heparin is useful prophylactically rather than
during active clot formation
C. by inhibiting factor X activation, a relative block of the
clotting cascade develops, with less thrombin formed
D. the major action is to directly inhibit factor II, which is very
sensitive to heparin
1. A,B,C
2. A,C
3. B,D
4. D only
5. All of the above
51. Answer:- 1
Options a,b,c are correct
Mini dose heparin includes heparin 5000IU sc
It is used as thromboprophylaxis
Factor X is more sensitive to inhibition than
Factor 2
52. 6) Heparin does not cause:-
a) Osteoporosis
b) Factor V inhibition
c) Thrombocytopenia
d) Prolongs aPTT
53. Answer:- B
Heparin causes a decrease in calcium(Factor 4)
and hence all females of child bearing age
should receive calcium when the receive
heparin
Heparin induced thrombocytopenia is a well
known complication
Heparin prolongs aPTT
Competitve pharmacology
54. 7) You started a patient on oral warfarin. Which
of the following factors show the most rapid
decline in the blood levels after the initiation
of warfarin therapy?
a) Factor VII
b) Protein C
c) Factor X
d) Prothrombin
55. Answer:- 1
Factor 7 has the least half life i.e. 6 hrs
Whereas factor 2(prothrombin) has the highest
half life i.e. 60hrs
Competitve pharmacology
56. 8) Warfarin induced skin necrosis and
hypercoagulation is seen in:
a) Protein C deficiency
b) Protein S deficiency
c) Haemophilia
d) Antithrombin III deficiency
e) Factor VII deficiency
57. Answer:- 1
Heparin in addition to inhibition of factor
2,7,9,10 also inhibits protein C,S
Protein C,S are thrombolytics in our body
Protein C half life is 8hrs
Hence its inhibition causes a hypercoagulant
state known as Dermal Vascular Necrosis
Competitive pharmacology
58. 9) Excessive anticoagulant effect in bleeding due
to warfarin can be reversed by(multiple
answer) :
A) stopping the drug
B) large doses of vitamin K
C) factor IX concentrates
D) cholestyramine
E) diuretics
59. Answer:- 1,2,3
Stopping warfarin, vit K and Factor 9
concentrates can reverse the effects of
warfarin
For acute reversal FFP/Cryoppt
Competitve pharmacolgy
60. 10) Which of the following is NOT an advantage
of low molecular weight heparin over
unfractionated heparin?
a) Higher efficacy in arterial thrombosis
b) Less frequent dosing
c) Higher and more consistent subcutaneous
bioavailability
d) Laboratory monitoring of response not
required
61. Answer:- 1
Arterial thrombus is mainly formed by platelets
and hence anti-platelet drugs are indicated in
arterial thrombosis
Venous thrombus is mainly formed of fibrin and
hence anticoagulants are indicated in venous
thrombosis
Rest all are advantages of LMWH over UFH
Competitve pharmacology
