Intelligent Use of Anticoagulants Murray L. Shames, M.D. Assistant Professor of Surgery and...

Intelligent Use of Intelligent Use of AnticoagulantsAnticoagulants

Murray L. Shames, M.D.Murray L. Shames, M.D.Assistant Professor of Surgery and Assistant Professor of Surgery and

RadiologyRadiologyDivision of Vascular and Endovascular Division of Vascular and Endovascular

SurgerySurgery

OutlineOutline

• 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

X

Xa+

Va + Ca++

Intrinsic system

XIIXIIaXI IXXia

IXa +

VIIa +

Ca++

Extrinsic system

Injury

Tissue thromboplastin

+

VII

ProthrombinProthrombin ThrombinThrombin

Fibrinogen Fibrin

Available anticoagulantsAvailable anticoagulants

• Unfractionated heparin

• Low Molecular Weight Heparins

• Oral Anti-coagulants

• Alternative agents

Unfractionated Heparin-Unfractionated Heparin-Mechanism of ActionMechanism 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 Heparin-Unfractionated Heparin-LimitationsLimitations

• 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 Heparin-Unfractionated Heparin-DosingDosing

• 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 Heparin- Unfractionated Heparin- ComplicationsComplications

• Major bleeding complications 0-7%

• HIT 1-5%

• Osteoporosis

• Alopecia

• Hypoadrenalism

• Anaphylaxis

Heparin – Induced Heparin – Induced ThrombocytopeniaThrombocytopenia

• 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 Heparin – Induced Thrombocytopenia IThrombocytopenia I

• HIT IHIT 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 Heparin – Induced Thrombocytopenia IIThrombocytopenia II

• HIT II (HITT)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 Heparin – Induced Thrombocytopenia IIThrombocytopenia II

• Thrombotic events arterial and venous

• Associated skin necrosis

• Global amnesia

• Prosthetic valve thrombosis

• 29% mortality and 21% amputation rate

Heparin – Induced Heparin – Induced Thrombocytopenia –Thrombocytopenia –

TreatmentTreatment• Withdrawal of ALLALL 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 AnticoagulantsAvailable Anticoagulants





Characteristics of UFH and Characteristics of UFH and LMWH ChainsLMWH Chains

Molecular weight (daltons)10,000 15,000 20,0005,000

5,400

Anti-Xa

Anti-IIa and anti-Xa Resistant to PF4

Sensitivity to PF4 Little non-specific binding

Non-specific binding Inhibition of thrombin generation

Less inhibition thrombin generation

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

Low Molecular Weight HeparinsLow 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 FDA-Approved Indications (May 2001) 2001)

for Available LMWHsfor Available LMWHs

Advantages of LMWH Over Advantages of LMWH Over UFHUFH

• 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 Heparins- Low Molecular Weight Heparins- DosingDosing

• 1mg/kg q12H

• Can monitor anti-factor Xa levels

Oral Anticoagulation- Oral Anticoagulation- Mechanism of ActionMechanism 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 Anticoagulation-Oral Anticoagulation-LimitationsLimitations

• 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 Anticoagulation-Oral Anticoagulation-ComplicationsComplications

• Hemorrhage

• Skin necrosis– Protein C deficiency– Malignancy

• Teratogenic

Oral Anticoagulation- Oral Anticoagulation- DosingDosing

• Loading 5mg PO QD

• Adjust daily dose to reach goal INR

Alternative Alternative AnticoagulantsAnticoagulants

• Danaproid

• Thrombin Inhibitors– Hirudin– Lepirudin– Argatroban

• Ancrod

Alternative Alternative Anticoagulants-Anticoagulants-DanaproidDanaproid

• 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 Alternative Anticoagulants-Anticoagulants-Thrombin InhibitorsThrombin 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


• 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


• 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 Alternative Anticoagulants-Anticoagulants-AncrodAncrod

• 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 ThromboembolismVenous Thromboembolism

Virchow’s TriadVirchow’s Triad

• Stasis

• Intimal injury

• Activation of coagulation (hypercoaguable state)

Venous Thrombosis-Venous Thrombosis-EpidemiologyEpidemiology

• 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 Thrombosis-Venous Thrombosis-Rationale for ProphylaxisRationale 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 Thrombosis- Venous Thrombosis- Risk FactorsRisk 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 Prophylaxis-Surgical Prophylaxis-Low Risk PatientLow Risk Patient

Risk Factors •Age under 40 years•Minor surgery•No other risk factors

Event rate

•Calf DVT 2.0%•Proximal DVT 0.4%•Clinical PE 0.2%•Fatal PE 0.002%

Recommended RegimensRecommended Regimens•No specific measuresNo specific measures•Aggressive mobilizationAggressive mobilization

Surgical Prophylaxis-Surgical Prophylaxis-Moderate Risk PatientModerate Risk Patient

Risk Factors• Major surgery in

patients with additional risk factors

• Non-major surgery in patients 40-60 with no additional risk factors

• Major surgery in patients < 40 with no additional risk factors

Event Rates• Calf DVT 10-20%• Proximal DVT 2-4%• Clinical PE 1-2%• Fatal PE 0.1-0.4%

Recommended RegimensRecommended Regimens•LMWHLMWH•Low dose UFHLow dose UFH•Elastic stockingsElastic stockings•Intermittent Pneumatic CompressionIntermittent Pneumatic Compression

Surgical Prophylaxis-Surgical Prophylaxis-High Risk PatientHigh Risk Patient

Risk Factors• Non-major surgery

in patients > 60 or additional risk factors

• Major surgery in patient < 40 or additional risk factors

Event Rate• Calf DVT 20-40%• Proximal DVT 4-8%• Clinical PE 2-4%• Fatal PE 0.4-

1.0%

Recommended RegimenRecommended Regimen

•LMWHLMWH

•Low dose UFH q8hLow dose UFH q8h

•IPCIPC

Surgical Prophylaxis-Surgical Prophylaxis-Highest Risk PatientHighest Risk Patient

Risk Factors• Major surgery in

patients > 40 plus prior VTE, cancer, hypercoaguable state

• Hip or knee arthroplasty

• Major trauma• Spinal cord injury

Event Rate• Calf DVT 40-80%• Proximal DVT 10-20%• Clinical PE 4-10%• Fatal PE 0.2-

5.0%

Recommended Regimen

•LMWH

•Oral Anticoagulants

•IPC/ES + LMWH/LDUFH

•Adjustable dose UFH

Deep Venous Thrombosis-Deep Venous Thrombosis-TreatmentTreatment

• 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 LMWH vs. UFH In Acute Treatment of VTEIn Acute Treatment of VTE

In Favor of LMWH In Favor of UFH

0.0 1 20.25 0.5 0.75 1.5 0.751.25

Venous Thromboembolism

Pulmonary Embolism

Major Bleeding

Thrombocytopenia

Total Mortality

Minor Bleeding

Pooled Relative Risk

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

LMWH: Fewer DeathsLMWH: Fewer Deaths

Meta-Analysis: N=3,566

LMWH UFH P

Mortality 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.

Study DesignEnoxaparin

sodium 1mg/kg q12h SC

Adjusted-dose heparin

infusion

Documented acute, proximal DVT without PE

Warfarin therapy initiated on 2nd day

Warfarin 90 days post randomization

Clinical endpoints

Clinical endpoints

Outpatient Treatment of DVTOutpatient Treatment of DVTEnoxaparin q12h vs. HeparinEnoxaparin q12h vs. Heparin

Embolic Event

Total VTE*

DVT onlyProximal DVTPE

13 (5.3)†

11 (4.5)10 (4.0) 2 (0.8)

17 (6.7) 14 (5.5) 12 (4.7) 3‡ (1.2)

Enoxaparin sodiumn=247 (%)

Heparinn=254 (%)

Outpatient Treatment of DVTOutpatient Treatment of DVTEnoxaparin q12h vs. HeparinEnoxaparin q12h vs. HeparinResults: Recurrences of Thromboembolism

* 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.

Treatment Group & Event

Enoxaparin sodium (n=5)†

Soft-tissue hematoma of hip 6 2.7 27 Abdominal-wall hematoma 7 2.7 55 Abdominal-wall hematoma 7 3.2 40 Subdural hematoma 5 3.4 40 Hematemesis‡

6 2.4 40

Heparin (n=3)†

Hematuria 2 1.3 64 Gastrointestinal bleeding 3 3.0 88 Hematemesis 1 2.7 64

Study Day INR*

* International Normalized Ratio.† P = 0.50.‡ Patient had cancer and associated thrombocytopenia due to chemotherapy and radiation.

Outpatient Treatment of DVTOutpatient Treatment of DVTEnoxaparin q12h vs. HeparinEnoxaparin q12h vs. Heparin

Results: Episodes of Major Bleeding

aPTT (sec)

Atrial FibrillationAtrial 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 FibrillationAtrial Fibrillation

AgeAge

< 65< 65

>65-75>65-75

AnyAny

Risk FactorsRisk FactorsFor Stroke*For Stroke*

NoneNone

NoneNone

1 or more1 or more

*Mitral stenosis, HTN, previous TIA or stroke, CHF, LV dysfunction, or age > 75

TherapyTherapy

ASA or noneASA or none

ASA or WarfarinASA or Warfarin

WarfarinWarfarin

Perioperative Management Of Perioperative Management Of Patients on Chronic Patients on Chronic

AnticoagulationAnticoagulation

Patients at low riskPatients 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


AnticoagulationAnticoagulationRecommendationsRecommendations

• Hold warfarin 4 days before surgeryHold warfarin 4 days before surgery

• Recheck PT day of surgeryRecheck PT day of surgery

• Resume warfarin on post-op day 2Resume warfarin on post-op day 2


AnticoagulationAnticoagulationPatients at intermediate riskPatients 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



RecommendationsRecommendations

• Hold warfarin 4 days Hold warfarin 4 days before surgery surgery• Prophylactic SC UFH or LMWH pre-opProphylactic SC UFH or LMWH pre-op• Recheck PT day of surgeryRecheck PT day of surgery• Continue prophylaxis in peri-operative periodContinue prophylaxis in peri-operative period• Restart warfarin at pre-operative dose on Restart warfarin at pre-operative dose on

post-op day 2post-op day 2• Stop heparin when INR > 2Stop heparin when INR > 2



Patients at highest riskPatients 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


AnticoagulationAnticoagulationRecommendationsRecommendations

• Hold warfarin 4 days prior to surgeryHold warfarin 4 days prior to surgery• Begin IV heparin or SC LMWH 2 days prior to Begin IV heparin or SC LMWH 2 days prior to

surgerysurgery• Recheck PT day of surgeryRecheck PT day of surgery• Hold heparin 6-12 hrs before surgeryHold heparin 6-12 hrs before surgery• Resume heparin 12 hours after surgery if Resume heparin 12 hours after surgery if

adequate hemostasisadequate hemostasis• Resume warfarin on post-op day 2Resume warfarin on post-op day 2• D/C heparin when INR > 2D/C heparin when INR > 2

Arterial Thromboembolism- Arterial Thromboembolism- Goals of TherapyGoals of Therapy

• Prevent recurrent thrombosis or embolism• Adequate anticoagulation reduces in-hospital

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 Thromboembolism-Arterial Thromboembolism-ExtremityExtremity

Patient with Patient with suspected ALIsuspected ALI

HistoryHistoryPEPEDopplerDoppler

HEPARINHEPARIN

Diagnosis confirmedDiagnosis confirmed

Arterial Thromboembolism-Arterial Thromboembolism-ExtremityExtremity

IV HEPARINIV HEPARIN5000 u bolus5000 u bolusTitrate to PTT 60-80 secTitrate to PTT 60-80 sec

Protection against clot propagationProtection against clot propagation Prevent embolusPrevent embolus

Arterial Thromboembolism -Arterial Thromboembolism -CerebralCerebral

• 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 -Arterial Thromboembolism -CerebralCerebral

• Cardioembolic stroke– Risk of recurrence 10-20% within 2-4 weeks– Evaluate for cardiac source (13-34%)

• No clear consensus

• Cerebral embolism study group– Anticoagulation in normotensive patients with

small – moderate strokes after 24 hrs– Larger strokes after 5-7 days

Recommendations

•IV heparin without loading dose

•Start Warfarin after 24 hrs

•INR 2.0-3.0

•Long-term therapy in patients with Atrial Fibrillation

Arterial Thromboembolism-Arterial Thromboembolism-VisceralVisceral

• Acute mesenteric ischemia– Embolic– Thrombotic– Non-occlusive– Venous thrombosis


• 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


Non-occlusive mesenteric ischemia• Multi-system organ failure, low-flow states,

and visceral vasoconstriction• Rarely exists without severe cardiac

dysfunction• Abdominal pain – 75%


• Arteriography demonstrate mesenteric arterial spasm

• Reversible with intra-arterial papaverine infusion or other vasodilating agents

• Adjunctive use of IV heparin recommended


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 PregnancyAnticoagulation 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


• 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


• 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 Pregnancy- Anticoagulation in Pregnancy- RecommendationsRecommendations

• 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

Intelligent Use of Anticoagulants Murray L. Shames, M.D. Assistant Professor of Surgery and...

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Transcript of Intelligent Use of Anticoagulants Murray L. Shames, M.D. Assistant Professor of Surgery and...