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Intelligent Use of

Anticoagulants

Murray L. Shames, M.D.


Assistant Professor of Surgery and
Radiology
Division of Vascular and Endovascular
Surgery

Outline

Available anticoagulants
Surgical prophylaxis
DVT and pulmonary embolus
Atrial fibrillation
Perioperative management of patients on
chronic anticoagulation
Arterial thromboembolism
Cerebral
Visceral
Extremity

Anticoagulation in pregnancy

The Coagulation Cascade


Intrinsic system
XII
XIIa
XI
Xia

Extrinsic system
Injury

IX
IXa
+
VIIa
+
Ca++

Tissue
thromboplastin
+
VII

Xa
+
Va + Ca++

Prothrombin

Thrombin

Fibrinogen

Fibrin

Available anticoagulants

Unfractionated heparin
Low Molecular Weight Heparins
Oral Anti-coagulants
Alternative agents

Unfractionated HeparinMechanism of Action

Binds anti-thrombin III 1:1


Inactivates thrombin and F Xa
Secondary effect on F V
Effects not first order kinetics
Effective after subcutaneous
and intravenous
administration
Short half life (90 min)
Reversed with protamine
(1mg per 100 U circulating
heparin)

Unfractionated HeparinLimitations
Significant protein binding
Response is unpredictable (close
monitoring required)
<25% of patients in therapeutic range
12 hours after starting Rx
Inaccessibility of clot-bound thrombin

Unfractionated HeparinDosing
Loading 80-100 U/ kg IV
Then IV infusion at 18 U/kg/hr
Normogram available for most
hospitals
Therapeutic range 1.5-2.5 X control PTT

Unfractionated HeparinComplications

Major bleeding complications 0-7%


HIT 1-5%
Osteoporosis
Alopecia
Hypoadrenalism
Anaphylaxis

Heparin Induced
Thrombocytopenia
Incidence 1-5%
Can occur with all methods of
administration
No known risk factors
Increased incidence with Bovine
preparations
Dx- plt count < 100-150 000/uL

Heparin Induced
Thrombocytopenia I
HIT I

Heparin induced platelet aggregation


Platelet sequestration and consumption
Mild
Thrombocytopenia in first few days of therapy
Plt count usually > 100 000/uL
Asymptomatic
Resolves spontaneously without d/c heparin

Heparin Induced
Thrombocytopenia II
HIT II (HITT)

Immunologically mediated
Ab to Heparin-PF 4 complex
More severe but less common
5-7 days after initiating Tx
PLT << 100 000/uL
Bleeding complications unusual
Diffuse thrombotic events
Separate and distinct from initial event requiring
heparin Rx

Heparin Induced
Thrombocytopenia II

Thrombotic events arterial and venous


Associated skin necrosis
Global amnesia
Prosthetic valve thrombosis
29% mortality and 21% amputation rate

Heparin Induced
Thrombocytopenia
Treatment
Withdrawal of ALL heparin and heparin
products
Plasmapheresis - anecdotal success
Further treatment should await confirmation
of Dx
Start anti-platelet therapy
? LMWH
Thrombin inhibitors
Ancrod
Conversion to Warfarin

Available Anticoagulants

Unfractionated heparin
Low Molecular Weight Heparins
Oral Anti-coagulants
Alternative agents

Characteristics of UFH and


LMWH Chains
5,400

10,000

5,000

15,000

20,000

Molecular weight (daltons)


Anti-Xa
Resistant to PF4
Little non-specific binding
Inhibition of thrombin generation

Hirsh J, Levine MN. Blood. 1992; 79: 1-17.

Anti-IIa and anti-Xa


Sensitivity to PF4
Non-specific binding
Less inhibition thrombin generation

Low Molecular Weight Heparins


Effect through AT III
Inhibits Factor Xa
More predictable
anticoagulant response
Longer half-life
Better bioavailability at
low doses
Renal clearance
Lower incidence of HIT
No need to monitor PTT
in most cases

FDA-Approved Indications (May 2001)


for Available LMWHs

Advantages of LMWH Over


UFH

Less platelet activation

Less vascular permeability

Smaller size

Increased release of TFPI


from vascular endothelium
Less plasma protein binding

Less interaction with PF4


Less osteoclast activation

Less binding to VWF


Stimulates megakaryopoiesis

Less thrombin, growth factor


production
May limit tumor movement into
intravascular space
More potent anti-angiogenesis
activity
More potent anticoagulant and
anti-cancer activity
Predictable PK, safety, once daily
dosing
Lower incidence of HIT
Less osteoporosis with long term
use
Less bleeding
May attenuate chemotherapy induced thrombocytopenia

Low Molecular Weight HeparinsDosing


1mg/kg q12H
Can monitor anti-factor Xa levels

Available Anticoagulants

Unfractionated heparin
Low Molecular Weight Heparins
Oral Anti-coagulants
Alternative agents

Oral AnticoagulationMechanism of Action


Inhibition of Vitamin K-dependant
coagulation factors II, VII, IX, X
Inhibition of Vitamin K- dependant
carboxylation of Protein C and S

Oral AnticoagulationLimitations
May create initial hypercoaguable state
3-5 days for anticoagulant effect
3-5 days to reverse effects
Reversed rapidly by FFP
Can reduce time of reversal with
supplemental Vit K (10mg IV or 3-5mg PO)

Oral AnticoagulationComplications
Hemorrhage
Skin necrosis
Protein C deficiency
Malignancy

Teratogenic

Oral Anticoagulation- Dosing


Loading 5mg PO QD
Adjust daily dose to reach goal INR

Available Anticoagulants

Unfractionated heparin
Low Molecular Weight Heparins
Oral Anti-coagulants
Alternative agents

Alternative Anticoagulants
Danaproid
Thrombin Inhibitors
Hirudin
Lepirudin
Argatroban

Ancrod

Alternative AnticoagulantsDanaproid
Heparinoid
Mixture heparin-like glycosaminoglycans and
chondroitins
Anti-factor Xa and anti-factor IIa activity
Can be used in patients with HIT
Approved for DVT prophylaxis
Longer duration than UF heparin
Measure by anti-factor Xa levels
Weight based dosing

Alternative AnticoagulantsThrombin Inhibitors


Hirudin
Protein isolated from salivary gland of
leech
Irreversible binding to thrombin
High incidence of bleeding complications
Monitor by PTT and ACT
Substitute for heparin in patients with HIT
Efective DVT prophylaxis

Alternative AnticoagulantsThrombin Inhibitors


Lepirudin
Recombinant Hirudidn derivative
Reduced mortality and morbidity in HIT
patients
Renally excreted
Dosing - 0.4mg/kg IV loading and
0.15mg/kg maintenance
Monitor PTT
Therapeutic range: 1.5 2.5 X normal

Alternative AnticoagulantsThrombin Inhibitors


Argatroban
Competitive thrombin inhibitor
Univalent thrombin inhibitor (less
specificity and affinity)
Short plasma life- no adj. for RF
2ug/kg/min IV
Monitor by PTT or ACT (2-3.5 X baseline)

Alternative AnticoagulantsAncrod
Venom of Malaysian Pit Viper
Defibrinating agent
Converts fibrinogen to soluble aggregate
removed by plasmin and RES
Increases FDP augments anticagulant
effect
Indirect micro-fibrinolytic by increasing TPA
release
Monitor fibrin levels

Venous Thromboembolism
Virchows Triad
Stasis
Intimal injury
Activation of coagulation
(hypercoaguable state)

Venous ThrombosisEpidemiology
Venous thromboembolism is the 3rd most
common vascular disease in the United
States
Mortality and morbidity associated with VTE
is enormous
Average cost per admission in the US:
PE = $12,595
DVT = $9,337
Additional long-term costs of morbidity > 75% of
initial therapy costs

Venous ThrombosisRationale for Prophylaxis


Clinically silent disease
High prevalence in hospitalized patients
Dire consequences of missed DVT
First manifestation may be fatal PE
Most deaths within 30 min of acute event
Long term morbidity from post-phlebitic
syndrome

Wide variations in practice of physicians


Only 1/3 of at risk patients receive adequate
prophylaxis
58% of fatal PE patients not prophylaxed in spite
of risk factors

Venous ThrombosisRisk Factors

Obesity
Varicose Veins
Cardiac dysfunction
Indwelling vascular
catheter
IBD
Nephrotic syndrome
Pregnancy or estrogen
use

Advanced age
Prolonged immobility
Stroke or Paralysis
Previous VTE
Cancer and its
treatment
Major Surgery
esp. abdomen,
pelvis, and lower
extremities
Trauma
esp. fractures of
pelvis, hip, or leg

Surgical ProphylaxisLow Risk Patient


Risk Factors

Event rate

Recommended Regimens

Age under 40 years


Calf DVT
No specific measures
Minor surgery
Proximal DVT
Aggressive
No other
risk factors mobilization
Clinical PE
Fatal PE

2.0%
0.4%
0.2%
0.002%

Surgical ProphylaxisModerate Risk Patient


Risk Factors

Event Rates

Calf DVT
10-20%
Major surgery in
Recommended
Regimens
patients
with additional
Proximal DVT 2-4%
risk LMWH
factors
Clinical PE
1-2%
Non-major surgery in
Fatal PE
0.1-0.4%
Low
dose
UFH
patients 40-60 with no
Elastic
additional
risk stockings
factors
Intermittent
Pneumatic Compression
Major
surgery in
patients < 40 with no
additional risk factors

Surgical ProphylaxisHigh Risk Patient


Risk Factors

Event Rate

Non-major surgery
Calf DVT
20-40%
Recommended
in patients
> 60 or
Regimen
Proximal DVT 4-8%
additional risk
Clinical PE
2-4%
LMWH
factors
Fatal PE
0.4-1.0%
Major
surgery
inUFH q8h
Low
dose
patient < 40 or
IPC risk
additional
factors

Surgical ProphylaxisHighest Risk Patient


Risk Factors

Event Rate

Recommended
Major
surgery in
Regimen
Calf DVT
40-80%
patients > 40 plus
Proximal DVT 10-20%
priorLMWH
VTE, cancer,
Clinical PE
4-10%
hypercoaguable
Oral Anticoagulants
Fatal PE
0.2-5.0%
state
Hip IPC/ES
or knee + LMWH/LDUFH
arthroplasty
Major
Adjustable
trauma
dose UFH
Spinal cord injury

Deep Venous ThrombosisTreatment


Start LMWH (SC enoxaparin 1mg/kg q12h
or 1.5mg/kg q24) and warfarin
Stop LMWH after 4-5 days when INR >
2.0 for 2 consecutive days
Continue warfarin for at least 90 days at
INR 2.0-3.0

LMWH vs. UFH


In Acute Treatment of VTE
Venous Thromboembolism
Pulmonary Embolism
Major Bleeding
Minor Bleeding
Total Mortality
Thrombocytopenia
0.0

0.25

0.5

0.75

In Favor of LMWH

1.5

1.25

In Favor of UFH

Pooled Relative Risk


Dolovich L, et al. Arch Intern Med. 2000:160:181-187.

0.75

LMWH: Fewer Deaths


Meta-Analysis: N=3,566

Mortality

LMWH

UFH

5.1%

6.7%

0.02

Overall 30% mortality reduction from:


Recurrent Thromboembolism, Bleeding,
and Cancer
Gould, et al. Ann Intern Med. 1999; 130: 800-9.

Outpatient Treatment of DVT


Enoxaparin q12h vs. Heparin
Study Design
Documented
acute, proximal
DVT without PE

Enoxaparin
sodium 1mg/kg
q12h SC

Clinical
endpoints

Adjusted-dose
heparin
infusion

Clinical
endpoints

Warfarin therapy
initiated on 2nd day

Warfarin 90 days
post randomization

Outpatient Treatment of DVT


Enoxaparin q12h vs. Heparin
Results: Recurrences of Thromboembolism
Embolic Event
Total VTE*
DVT only
Proximal DVT
PE
*

Enoxaparin sodium
n=247 (%)
13 (5.3)
11 (4.5)
10 (4.0)
2 (0.8)

Heparin
n=254 (%)
17 (6.7)
14 (5.5)
12 (4.7)
3 (1.2)

VTE = venous thromboembolic event (deep vein thrombosis [DVT] and/or


pulmonary embolism [PE]).
95% CI = -5.6 to 2.7.
Two died during the study.

Outpatient Treatment of DVT


Enoxaparin q12h vs. Heparin
Results: Episodes of Major Bleeding
Treatment Group & Event
Enoxaparin sodium (n=5)
Soft-tissue hematoma of hip
Abdominal-wall hematoma
Abdominal-wall hematoma
Subdural hematoma
Hematemesis

Study Day

INR*

aPTT
(sec)

6
7
7
5

2.7
2.7
3.2
3.4

27
55
40
40

2.4

40

2
3
1

1.3
3.0
2.7

64
88
64

(n=3)

Heparin
Hematuria
Gastrointestinal bleeding
Hematemesis

* International Normalized Ratio.


P = 0.50.
Patient had cancer and associated thrombocytopenia due to chemotherapy and radiation.

Atrial Fibrillation
Most common arrythmia in adults
Responsible for 15% CVA
Better survival with combined rate
control and anticoagulation
IV heparin/ LMWH + coumadin
Administer anticoagulation before and
3 - 4 weeks after cardioversion

Atrial Fibrillation
Age

Risk Factors
For Stroke*

Therapy

< 65

None

ASA or none

>65-75

None

ASA or Warfarin

Any

1 or more

Warfarin

*Mitral stenosis, HTN, previous TIA or stroke, CHF, LV


dysfunction, or age > 75

Perioperative Management Of
Patients on Chronic
Anticoagulation
Patients at low risk
VTE adequatelt treated for > 3 months, no
predisposing factors
Nonvalvular A. Fib without embolic events
Most bioprosthetic and mechanical heart
valves without thromboembolism

Perioperative Management Of
Patients on Chronic
Anticoagulation
Recommendations
Hold warfarin 4 days before surgery
Recheck PT day of surgery
Resume warfarin on post-op day 2

Perioperative Management Of
Patients on Chronic
Anticoagulation
Patients at intermediate risk
Venous or arterial embolism
In 2nd to 3rd month of Tx, no predisposing
factors
Recurrent VTE tx for 12 months

Valvular heart disease, A. Fib,


prosthetic heart valve with distant h/o
embolism

Perioperative Management Of
Patients on Chronic
Anticoagulation
Recommendations

Hold warfarin 4 days before surgery


Prophylactic SC UFH or LMWH pre-op
Recheck PT day of surgery
Continue prophylaxis in peri-operative period
Restart warfarin at pre-operative dose on
post-op day 2
Stop heparin when INR > 2

Perioperative Management Of
Patients on Chronic
Anticoagulation
Patients at highest risk
Venous thromboembolism with specific
circumstances (consider IVC filter)
Onset within last month
Idiopathic, last 6 months
Recurrent VTE, within last 12 months

Documented hypercoaguable state


Recent embolism from A. Fib, prosthetic or
diseased heart valve
Acute arterial embolism within 1 month

Perioperative Management Of
Patients on Chronic
Anticoagulation
Recommendations
Hold warfarin 4 days prior to surgery
Begin IV heparin or SC LMWH 2 days prior to
surgery
Recheck PT day of surgery
Hold heparin 6-12 hrs before surgery
Resume heparin 12 hours after surgery if
adequate hemostasis
Resume warfarin on post-op day 2
D/C heparin when INR > 2

Arterial ThromboembolismGoals of Therapy


Prevent recurrent thrombosis or embolism
Adequate anticoagulation reduces inhospital recurrence from 31% to 9%
Decrease mortality from 25% to 4%
Does result in increased wound
complications (without major bleeding
episodes)
UFH first choice in therapy
Increased flexibility in monitoring and control

Arterial ThromboembolismExtremity

Patient with
suspected ALI

History
PE
Doppler

Diagnosis confirmed

HEPARIN

Arterial ThromboembolismExtremity
Protection against clot propagation

Prevent embolus

IV HEPARIN
5000 u bolus
Titrate to PTT 60-80 sec

Arterial Thromboembolism Cerebral


No benefit to anticoagulation in completed
stroke
May benefit stroke-in-progress if < 25 hrs
and submaximal
Need to eliminate other causes of
neurologic deterioration

Arterial Thromboembolism Cerebral


Cardioembolic
stroke
Recommendations

Risk of recurrence 10-20% within 2-4 weeks


IVheparin
loading
dose
Evaluatewithout
for cardiac
source
(13-34%)

No clear
consensus
Start
Warfarin
after 24 hrs

Cerebral
embolism
study
group
INR 2.0-3.0

Anticoagulation in normotensive patients with


Long-term
therapy in
patients
Atrial
small moderate
strokes
afterwith
24 hrs
Fibrillation
Larger strokes after 5-7 days

Arterial ThromboembolismVisceral
Acute mesenteric ischemia
Embolic
Thrombotic
Non-occlusive
Venous thrombosis

Arterial ThromboembolismVisceral
Diagnosis requires high index of suspicion
Angiography diagnostic
Treatment
Initiate IV heparin at time of diagnosis (bolus
and titrate to PTT 60-80 sec)
Thrombolysis if no evidence of peritonitis
Surgical thrombectomy/revascularization with
bowel resection

Arterial ThromboembolismVisceral
Non-occlusive mesenteric ischemia
Multi-system organ failure, low-flow states,
and visceral vasoconstriction
Rarely exists without severe cardiac
dysfunction
Abdominal pain 75%

Arterial ThromboembolismVisceral
Arteriography demonstrate mesenteric arterial
spasm
Reversible with intra-arterial papaverine infusion
or other vasodilating agents
Adjunctive use of IV heparin recommended

Arterial ThromboembolismVisceral
Venous thrombosis
Hypercoaguable state
Intraabdominal infection or inflammation
Asymptomatic state to catastrophic illness
Generalized abdominal pain out of proportion to physical
exam

Diagnosis by CT, angiography


Treatment

Rigorous resuscitation
IV heparin anticoagulation (PTT 60-80)
Surgical exploration for peritonitis
Long-term therapy with warfarin (life-time if hypercoaguable
state identified)

Anticoagulation in Pregnancy
Sixfold risk of venous thrombembolism
PE most common cause of maternal
mortality in US
Gravid uterus compressing Vena Cava
Pregnancy related hypercoagulability
(increase II, VII, VIII, X)
Decreased fibrinolytic activity and AT III

Anticoagulation in Pregnancy
Coumadin during first trimester associated
with specific malformations in > 25% of
births
Fetal Warfarin Syndrome (nasal
hypoplasia, stippled epiphyses)
Increase CNS anomalies if used during
other time during pregnancy

Anticoagulation in Pregnancy
Drugs with molecular weight < 1000
daltons pass through placental
membranes
Fetus has already low levels of Vit-K
dependant factors- further depleted by
warfarin effect

Anticoagulation in PregnancyRecommendations
Initiate anticoagulation with intravenous heparin
Continue Tx with subcutaneous heparin or
LMWH
Continue Tx through delivery and post-partum
period
After delivery coumadin for 6 months
Prophylaxis (LMWH) recommended during
subsequent pregnancy
Acute iliofemoral DVT consider thrombectomy
or vena Caval filter placement