This document discusses the physiology of coagulation and various anticoagulant and thrombolytic agents. It covers the intrinsic and extrinsic pathways of coagulation and the mechanisms of several common anticoagulants including heparin, low molecular weight heparins, warfarin, and direct thrombin and factor Xa inhibitors. It also addresses considerations for reversing anticoagulation with protamine or newer antidotes and managing patients on anticoagulants who require surgery or procedures.

1. Sandra Ouellette,
CRNA, MEd, FAAN

2.  Physiology of Coagulation
 Anticoagulants
◦ Heparin/Protamine
◦ Low Molecular Weight Heparins
◦ Coumadin
◦ Thrombin Inhibitors
◦ Factor X Inhibitors
◦ Thrombolytic Agents
◦ Antiplatelet Agents
 Anesthetic Considerations
The Patient on Warfarin?
◦ Neuraxial Anesthesia and Anticoagulants

3.  Primary hemostasis
◦ Constriction of blood vessels
◦ Platelet plug
 Secondary hemostasis
◦ Extrinsic pathway
◦ Intrinsic pathway
◦ Common final pathway

4.  Vasoconstriction
 Platelet aggregation – primary hemostasis –
weak plug
 Coagulation and fibrin formation – secondary
hemostasis
 Fibrin clot
 Clot retraction
 Invasion by fibroblasts
 scar formation

10.  First isolated in 1922
 Heparin requires a cofactor, antithrombin III
to inhibit coagulation
 Heparin + ATIII inhibit
◦ IX, X, XIa, XIIa
◦ Indirectly suppresses thrombin induced activation
V, VIII by binding thrombin
◦ t½ 1-2 h (altered renal,
liver disease); onset immediate IV;
SQ results in 1 to 2 hr delay.
◦ Not absorbed through GI tract.

11.  Rx DVT, unstable angina: aPTT 1.5-2.5 x
control
 Angioplasty, stinting: ACT 350 sec
 CPB (cardiac surgery): ACT 480 sec
 Substantial variability in patient response
◦ Heparin resistance due to ATIII deficiency
◦ Patients at risk: cardiac surgery, use of nitroglycerin
infusion, nephrotic syndrome, cirrhosis, prolonged
heparin infusion, DIC
◦ 4 fold variation in heparin sensitivity; 3 fold variation
in rate in which it is metabolized.

12.  Monitored with test of intrinsic pathway: aPPT
 aPTT 1.5-2.5 control correlated with heparin
levels of 0.2-0.7 U ml.
 Interventional cardiology seek ACT value 200-
400seconds or heparin concentration 1-3 U ml.
 Cardiac surgical procedures ACT > 400-500
seconds consistent with level of 3-8 U ml.

13.  Follow IV administration, peak effect 1 min;
Following SQ onset 1 to 2 hours.
 Distribution limited by large molecular size to
vascular space and endothelial system
 Eliminated by kidneys or by metabolism in
reticuloendothelial system and liver.
 t½ dose dependent
◦ Low doses, 100-150 u/kg, 1 h
◦ CPB dose 350-400 u/kg 2 h; may persist 4-6 h
without neutralization
◦ Average time 1-2 hr but increased with liver/renal
disease or dose> 100u Kg.
◦ ACT used to monitor effect and reversal during CPB.

14.  Boluses decrease systemic vascular resistance
◦ Usually small, 10-20%
◦ May be greater and require vasopressors
 Rarely anaphylaxis
 During CPB ACT values for heparin
anticoagulation can be misleading due to:
1 Hypothermia
2 Hemodilution
 Heparin induced thrombocytopenia (HIT)

15.  Develops in 5-28% patients
 Marked by a fall in platelet count after
exposure to heparin
 Results from heparin’s proaggregatory effect
on platelets
 Two subtypes

16.  Type I
◦ Rapid onset: 2-5 d
◦ Characterized by mild
decrease in platelet count
without thrombosis or
immune response
 Type II
◦ Considerably more severe
◦ Occurs after more than 5 d
administration (avg 9 d)
◦ Immune mediated
◦ Antibody binding between
heparin-platelet complex
◦ Causes platelet activation,
complement activation,
white clot
◦ High morbidity
 Incidence thrombosis 20%
 Mortality after thrombosis
40%

18.  Hirudin, thrombin inhibitor derived from leech;
Bivalirudin is synthetic peptide based on hirudin
 Not associated with immune thrombocytopenia
 Binds thrombin and does not depend on ATIII
for anticoagulant activity
 Adm IV infusion; rapid onset, peak 4 h; t½ 4.5 h;
activity persists 24 h; monitoring requires
measurement and anti-Xa activity
 Monitor with ACT; DC 4-6 hr before surgery
 Indicated for patients at risk of HIT, unstable
angina having PTCA.

19.  Commercially prepared from fish sperm
 Initially combined with insulin to prolong its
effect (NPH)
 Mechanism
◦ Produces strong ionic bond with heparin devoid of
anticoagulant effects
◦ 1 mg protamine neutralizes 100 U of heparin
◦ Neutralize 5000 U administer 50 mg protamine
◦ Neutralization of heparin occurs in 5 mi

20.  Protamine cleared by RES in 10-20 minutes.
 Clearance quicker than heparin.
 Heparin rebound is bleeding 30 min to 9 hrs
after protamine administration.
 May be related to extravascular release of
heparin from protein binding sites.
 RX: Clinical monitoring and small doses( 25
mg hr X 6 hr postop) protamine as indicated.

21.  Always administer slowly
◦ Rate administration more important route
◦ Limit syringe boluses less 1 mg/kg or 20
mg/minute

22.  Systemic hypotension 10 min after
administration indicates protamine
 Normal, low pulmonary pressure indicate
rapid administration or anaphylactoid
reaction
 Rx
◦ Rapid fluid administration
◦ Anaphylaxis: IVs, epinephrine, bronchodilators,
steroids

23.  Hypotension with rapid administration
 Noncardiogenic pulmonary edema
 Anaphylactoid reactions
◦ True allergy is uncommon
◦ Patient at risk
 Prior reaction to protamine –
 Allergy to fish –
 Exposure to NPH insulin –
 Allergy to any drug –
 Men who have had vasectomy?
1 Develop antibodies to sperm antigens including protamine.
2 Vasectomized men not at > risk from protamine.
3 22-33% have antiprotamine antibodies.

24.  Increase PVR, RV failure, decreased CO,
systemic hypotension
 Heparin-protamine complexes form
thromboxane by pulmonary macrophages
leading to vasoconstriction

25.  Marked by high pulmonary pressures
◦ Inotropes pulmonary dilating properties
◦ Isuprel, milrinone
 Hemodynamic collapse: Return CPB

26.  Always administer slowly
 Peripheral sites offer no advantage over
central for diluted, slowly administered
drug
 Only patients with prior history adverse
response to protamine warrant special
consideration
 Prior problem
◦ 1 mg/100 ml over 10 min
◦ Full dose if no response develops
◦ Skin test, little predictive value, frequently false
positive

27.  Excessive dose (600-800mg) has antiplatelet
activity with increased bleeding.
 Administer 1-1.2 mg protamine for 100 U
heparin or 0.5 mg for every 100U in last 4
hours.
 Cardiac Surgery
1 0.5-1 mg for every 100 U entire procedure.
2 1 mg protamine for every 100 U initially and
during CPB.
 Monitor clinically and with Hepcon system.

28.  Interfere production Vit K factors: II, VII, IX, X
 Factors II, X most important antithrombotic activity
 Onset 8-12 h; peak 36-72 h; normal hemostasis 1-3 d
 Lab tests
◦ PT and INR (International Normalized Ratio) most sensitive
◦ PT + INR: reflect primarily factor VII, X
◦ INR > 1.2: factor VII less 55%
 Factor activity level of 40% needed for normal hemostasis
 Recovery factor VII rapid; II, X slower
 Emergent situations: vit K, FFP, 4 factor PPC
 Variability in drug response

29.  PCC trade name: Beriplex, Octaplex;Kcentra,
Cofact.
 Contains FII,VII,IX,X plus protein C and S; also
contains heparin.
 FDA approved April 30, 2013.
 Indicated to reverse coumadin in patients with:
1 INR>8;
2 prolonged prothrombin time,
3 raised d-dimer.
4 emergency operation in patient on coumadin.
5 deficiency of one of II,VII,IX,X factors.

30.  Contraindicated with DIC:
1 Adding factors provides fuel for the fire (myth)
2 If factors are low, Kcentra may restore normal
coagulation.
 Kcentra made of pooled plasma; requires lower
volume than FFP to reverse coumadin.
 May be associated with thromboembolic events.

31.  Fractions of heparin, MW 2000-6000
 Better bioavailability, longer duration: dosing qd
or BID with transatlantic differences in dosing
 Given subcu
 Examples: Enoxaparin (Lovenox),
Dalteparin(Fragmin),
 Binds ATIII to inhibit X; smaller effect on thrombin
 Effect prolonged in patients with renal failure
 t½ 4.5 h; activity persists 24 h; monitoring requires
measurement anti-Xa activity
 Only partially antagonized by protamine; reverses
only IIa activity

32.  Pharmacological properties differ from UFH:
1Lack of monitoring of anticoagulant effect.
2 Prolonged half-life
3 Irreversibility with protamine.
 After SQ administration elimination T1/2 is
3-6 hrs.
 Anti-Xa levels peak at 3-5 hrs but significant
anti-Xa activity still present 12 hours after
injection.

33.  Danapanoid or Orgaran
 Fondaparinax or Arixtra
 Rivanoxaban or Xarelto
 Apixban or Eliquis

34.  Is approved now in US, Canada,and Europe
 First available oral direct factor Xa inhibitor.
 Maximum inhibition occurs 4 hr after
administration; onset within 30 min
 Effect lasts 8-12 Hr; Factor Xa activity does not
return to normal for 24 hr.
 Dependent on renal elimination; avoid with
CrCl<30ml/min.

35.  Predictable pharmacokinetics
 Low potential for interaction with diet or
alcohol
 No routine monitoring required
 Contraindicated in severe liver disease;
hepatic metabolism.
 Contraindicated in severe hepatic disease
(metabolism) and severe renal disease
(elimination).

36.  Reversibility after cessation 24 hr depending
on plasma concentration and elimination half
life.
 No antidote available
Brighton T
Australian Prescriber
Vol 33 (2): 38-41; 2010

37.  Used for prevention thromboembolism.
 Direct factor Xa inhibitor FDA approved
December 2012.
 Highly protein bound, reaches peak plasma
concentration 2-3 hr, limited drug
interactions.
 Given at 2.5 mg BID orally.
 Half-life in healthy subjects 8-15 hr.

38.  Acts by antithrombin III inhibition of Xa.
 Administered SQ or IV q day.
 Rapidly and completely absorbed; peak
steady state 3 hr; 94% bound to ATIII.
 Eliminated unchanged in urine in 72 hr with
normal renal function.
 DC before surgery 2 days, longer with renal
disease

39.  This drug reversed anticoagulant activity of
apixaban and rivaroxaban in healthy older patients
within minutes of bolus and infusion.
1 Apixaban: 400 mg bolus; infusion 4, mg/min 2
hrs
2 Rivaroxaban: 800 mg bolus; 8 mg/min for 2 hrs.
 Andexanet is a specific, rapidly acting antidote
being developed for urgent reversal factor Xa
inhibitors.
Siegal D M et al
N Eng J Med 2015; 373:2413-24

40.  Bivalirudin or Angiomax
 Desirudin or Revasc
 Argatroban or Acova
 Dibigatian or Pradaxa
 Lepirudin or Refludan (No longer on market)

41.  IV, synthetic direct thrombin inhibitor.
 Indicated for prophylaxis or Rx thrombus in
patients at risk for HIT undergoing PCI.
 Half life 40 to 50 minutes; return to baseline
4 hours.
 Argatroban eliminated via liver; most other
replacements for heparin in patients at risk
for HIT eliminated by kidney.
 Monitored by aPTT or ACT.
 Stop 4-6 hours before surgery.

42.  Analog of hirudin approved for use in
patients with HIT.
 Irreversibly inhibits thrombin.
 HIT patients receiving this drug develop
antibodies requiring close monitoring a PTT
to avoid bleeding complications.
 Drug prolonged in patients with renal
dysfunction.
 Stop 24 hours before surgery

43.  Analog of hirudin administered SC.
 Direct thrombin inhibitor
 Approved for prevention DVT after total hip
or knee replacement surgery.
 Being studied in patients with acute coronary
syndrome or PTCA.
 Anaphylaxis reported but risk low.
 Primarily eliminated by kidney.
 Monitor by aPTT
 Hold 24 hours before surgery.

44.  Direct oral competitive reversible thrombin
inhibitor; inhibitor factor Xa
 Onset anticoagulation: 30 min
 Duration 24-36 hr
 Reversibility after cessation: 24-36 hr depending
on plasma concentration, elimination half-life.
 No routine monitoring required but PTT and
thrombin times can be used.
 Stop before surgery 48 hours normal renal
function; 72-96 hours abnormal renal function.

45.  Predictable pharmacokinetics.
 Low potential for interaction with diet or
alcohol.
 Proton pump inhibitors inhibit absorption.
 No hepatic metabolism so safe with liver
disease.
 Severe renal disease: > drug exposure,
elimination half-life.

46.  Metabolized by esterase-catalyzed
hydrolysis.
 Renal, GI clearance.
 Dose:
1 Cr Cl. 30 ml/min 150 mg PO BID
2 Cr Cl < 15mL/min 75 mg PO BID
 Antidote now available.

47.  Idarucizumab or Praxbind FDA approved in 2015
 Humanized antibody fragment binds to pradaxa
molecule reversing effect without interfering with
coagulation cascade
 Approved for :
1 Emergency surgery/urgent procedures
2 Life threatening or uncontrolled bleeding.
 Following administration of 5 gm, complete
reversal within minutes.
 In trials 1 thrombotic complication in 72 hours in a
patient who did not have anticoagulants reinitiated.
New England Journal Medicine
RE-VERSE Ad Trial

48. Coumadin Pradaxa
Dosage Varies with INR 150 mg BID CrCl>30;
75 mg BID CrCl 15-30
Administration Tablet Capsule
Onset 12-24 hr Within few hours
Half-life 36 hours 12-17 hours
Excretion Hepatic Renal
Monitoring Yes; INR No
Dietary Considerations No leafy green
vegetables or food
high in Vitamin K
No
Antidote Vitamin K Paxabind

49. Coumadin Pradaxa
Drug Interactions Several Avoid St John’s Wart,
quinidine, rifampin
Verapamil, amiodarone,
clarithromycin
Side Effects Bleeding, SOB, edema,
allergic reactions
Bleeding, GI disturbances,
> risk MI, < risk
intracranial bleed
Cost .50 cents day, $15
month + INR cost
$7 day, $210 month
Procedural Points DC 5-6 days before Skip 2-8 doses depending
renal function
Age considerations > 75 increased risk
cerebral bleed
Caution in those <age 15
or over 75

50.  If possible, DC Pradaxa 1-2 days (Cr Cl >50) or 3-
5 days (Cr Cl < 50) before invasive procedure.
 Consider longer time for patients having:
1 Major surgery
2 Spinal anesthesia
3 Epidural anesthesia

51.  Assess ecarin clotting time (ECT)
 ECT better than PT, aPTT, thrombin time.
 If ECT not available, aPTT approximates
Pradaxa activity.
Brighton T
Australian Prescriber
Vol 33 (2) 38-41, 2010

53. Dabigatran Rivaroxban Apixaban
Mechanism Direct thrombin
inhibitor
Factor Xa inhibitor Factor Xa inhibitor
Time to peak
effect(h)
1-3 2-4 1-3
Half like (h) 14-17 5-9 8-15
Dialyzable Yes No No
Metabolism/excret
ion
80% renally
excreted
30% hepatic;35%
renal excretion
15% hepatic;
25%renal
excretion
Coagulation tests
affected
aPTT PT PT
Ecarin clotting
time
Antifactor X levels Antifactor X levels
Thrombin time

54. Warfarin Dabigatran Rivaroxaban Apixban
Oral activated
charcoal
No Yes likely likely
Dialysis No Yes No No
Vitamin K Yes No No No
Fresh Frozen
Plasma
Yes Minimal Minimal Minimal
Recombinant
FVII
Yes Possible Possible Possible
3-Factor
Prothrombin
Complex
Concentrate(P
CC)
Likely Possible Possible Possible
4-Factor PCC yes Possible Possible possible

55. Drug Dose Clinical Status Indication Monitoring Hold
Before
Surgery
Bivalirudin IV Available in US HIT; PTCA; ACT 4-6 hr
Argatroban IV Available US and
Europe
HITPCT in
HIT
patients
aPTT or ACT 4-6 hr
Lepurdin IV Available in US
and Europe
HIT,
prevention
VTE
aPTT 24 hr
Desurdin SQ US and Europe Hip
Surgery
aPTT 24 hr
Dabigatran Oral US and Europe Hip knee
surgery;
VTE,A fib
Thrombin
times, aPTT
48 hr
normal
renal
function

56.  Used for full systemic anticoagulation.
 Activated protein C exerts antithrombotic
effect factor Va/VIIIa.
 Also used in severe sepsis associated with
organ dysfunction.
 DC 2 hr prior to invasive surgery or
procedure with risk of bleeding.
 May reinstate 12 hours after invasive
procedure if hemostasis achieved.

57.  Prototype: Aspirin + NSAIDs
 Mechanism of action
◦ Inhibit thromboxane by blocking cyclooxygenase
◦ Thromboxane A2 stimulator of platelet
aggregation
◦ ASA irreversibly inhibits the enzyme
 Toxicity
◦ GI bleeding
◦ CNS effect
◦ Enhance effects other anticoagulants

59.  Glycoprotein IIB/IIIA receptor inhibitor agents
 Aspirin preparations
 Platelet-ADP-receptor antagonist agents
 Platelet adhesion inhibitor agents

63. Drug Site of
Action
Route t½ Metabolism Antidote Stop
Before
Procedure
Prolonged
PT/PTT
Aspirin COX 1-2 Oral 20
min
Hepatic 0 7 d No/No
Dipyrida-
mole
Adenosine Oral 40
min
Hepatic 0 24 h No/No
Clopido-
grel
ADP Oral 7 h Hepatic 0 5 d No/No
Ticlopidine ADP Oral 4 d Hepatic 0 10 d No/No
Abciximab GP IIb/
IIIa
IV 30
min
Renal 0 72 h No/No
Eptifiba-
tide
GP IIb/IIIa IV 2.5 h Renal 0 24 h No/No
Tirofiban GP IIb/
IIIa
IV 2 h Renal Hemo-
dialysis
24 h No/No

64. Drug Site of
Action
Route t½ Metabolis
m
Antidote Stop
Before
Procedure
Prolonged
PT/PTT
Piroxicam COX 1-2 Oral 50 h Hepatic 0 10 d No/No
Indometh-
acin
COX 1-2 Oral/
supp
5 h Hepatic 0 48 h No/No
Ketorolac COX 1-2 Oral/
IV
5-7 h Hepatic 0 48 h No/No
Ibuprofen COX 1-2 Oral 2 h Hepatic 0 24 h No/No
Naproxen COX 1-2 Oral 13 h Hepatic 0 48 h No/No
Diclofenac COX 1-2 Oral 2 h Hepatic 0 24 h No/No
Rofecoxib
Celecoxib
COX 2 Oral 10-17
h
Hepatic 0 0 No/No

65.  First Generation
◦ Streptokinase
◦ Urokinase
◦ Streptase, Kabinase
◦ Abbokinas
 Second Generation
◦ Alteplase
◦ Anistreplase
◦ Prourokinase
◦ Activase
◦ Eminase
 Third Generation
◦ Reteplase
◦ Tenecteplase
◦ Lanoteplase
◦ Staphylokinase
◦ Antibody-targeted PAS
◦ Vampire bat-PA
◦ Alfimeprase
◦ Retavase
◦ TNKase

66.  Drugs
◦ Alteplase
◦ Reteplase
◦ Anistreplase
◦ Urokinase
◦ Streptokinase
 Mechanism
◦ Catalyze activation plasminogen to plasmin
◦ Plasmin is fibrinolytic enzyme
 Clinical Uses
◦ Emergency Rx thrombosis
◦ Give less 3 h
 Toxicity: bleeding

69.  Absolute
◦ Any history of hemorrhagic cerebrovascular event
◦ Any other cerebrovascular events within 1yr
◦ Active internal bleeding
◦ Known intracranial neoplasm
◦ Suspected aortic dissection

70.  Relative
◦ Blood pressure over 180/110 mmHg
◦ Anticoagulants & INR over 2
◦ Prolonged cardiopulmonary resuscitation
◦ Prior gastrointestinal hemorrhage
◦ Pregnancy
◦ Menstruation
◦ Recent trauma (within 2-4 weeks)
◦ Major surgery within 3 weeks

71.  Which surgical procedures can be performed
without stopping warfarin
 Optimal times to stop and restart warfarin
 Use of heparin as a bridge to surgery
Jaffer AK et al: Cleveland Clinic J Med 70;2003

72.  Usually, surgery is safe if the INR is < 1.5
 If INR is 2-3, almost always falls to < 1.5
within 115 h or 4.8 d after last dose
 Neurosurgical procedures, some noncardiac
surgeries, nearly normal (INR < 1.2 desired)
 Check INR immediately before surgery

73.  Fresh frozen plasma
 Vitamin K
◦ If surgery must be done within 24-96 h
◦ High doses (5-10 mg) can cause PO resistance to
warfarin
◦ Rx 1-2.5 mg, if pt to be started on PO
anticoagulation
◦ Median time for reversal with 1 mg is 27 h (R
0.7-147 h)
 Recombinant activated factor VII (rFVII2)
◦ $3,500 for dose
◦ Cannot monitor or predict hemostatic efficacy

74.  The reason the patient is taking warfarin
 The patient’s risk factors for
thromboembolism
 How long the patient remains off
anticoagulation therapy
 The degree of anticoagulation reversal
 The type of surgical procedure (this factor
mainly determines the risk of venous
thrombosis)

76. American Society of Regional Anesthesia(ASRA)
Consensus Conference on Neuraxial
Anesthesia and Anticoagulation